Jonathan S. Berek, MD, MMS

All Publications

Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomised controlled trial LANCET ONCOLOGY Oza, A. M., Matulonis, U. A., Malander, S., Hudgens, S., Sehouli, J., del Campo, J. M., Berton-Rigaud, D., Banerjee, S., Scambia, G., Berek, J. S., Lund, B., Tinker, A. V., Hilpert, F., Palacio Vazquez, I., D'Hondt, V., Benigno, B., Provencher, D., Buscema, J., Agarwal, S., Mirza, M. R. 2018; 19 (8): 1117–25
Abstract

Quality of life (QOL) has become an important complementary endpoint in cancer clinical studies alongside more traditional assessments (eg, tumour response, progression-free survival, overall survival). Niraparib maintenance treatment has been shown to significantly improve progression-free survival in patients with recurrent ovarian cancer. We aimed to assess whether the benefits of extending progression-free survival are offset by treatment-associated toxic effects that affect QOL.The ENGOT-OV16/NOVA trial was a multicentre, double-blind, phase 3, randomised controlled trial done in 107 study sites in the USA, Canada, Europe, and Israel. Patients with recurrent ovarian cancer who were in response to their last platinum-based chemotherapy were randomly assigned (2:1) to receive either niraparib (300 mg once daily) as a maintenance treatment or placebo. Randomisation was stratified based on time to progression after the penultimate platinum-based regimen, previous use of bevacizumab, and best response (complete or partial) to the last platinum-based regimen with permuted-block randomisation (six in each block) using an interactive web response system. The trial enrolled two independent cohorts on the basis of germline BRCA (gBRCA) mutation status (determined by BRACAnalysis Testing, Myriad Genetics, Salt Lake City, UT, USA). The primary endpoint of the trial was progression-free survival, and has already been reported. In this study, we assessed patient-reported outcomes (PROs) in the intention-to-treat population using the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L). We collected PROs from trial entry every 8 weeks for the first 14 cycles and every 12 weeks thereafter. If a patient discontinued, we collected PROs at discontinuation and during a postprogression visit 8 weeks (plus or minus 2 weeks) later. We assessed the effect of haematological toxic effects on QOL with disutility analyses of the most common grade 3-4 adverse events (thrombocytopenia, anaemia, and neutropenia) using a mixed model with histology, region, previous treatment, age, planned treatment, and baseline score as covariates. This study is registered with ClinicalTrials.gov, number NCT01847274.Between Aug 28, 2013, and June 1, 2015, 553 patients were enrolled and randomly assigned to receive niraparib (n=138 in the gBRCAmut cohort, n=234 in the non-gBRCAmut cohort) or placebo (n=65 in the gBRCAmut cohort, n=116 in the non-gBRCAmut cohort). The mean FOSI score at baseline was similar between the two groups (range between 25·0-25·6 in the two groups). Overall QOL scores remained stable during the treatment and preprogression period in the niraparib group; no significant differences were observed between the niraparib and placebo group, and preprogression EQ-5D-5L scores were similar between the two groups in both cohorts (0·838 [0·0097] in the niraparib group vs 0·834 [0·0173] in the placebo group in the gBRCAmut cohort; and 0·833 [0·0077] in the niraparib group vs 0·815 [0·0122] in the placebo group in the non-gBRCAmut cohort). The most common adverse events reported at screening (baseline) were lack of energy (425 [79%]; 97 [18%] reporting severe lack of energy), pain (236 [44%]), and nausea (118 [22%]). All symptoms, except nausea, either remained stable or improved over time in the niraparib group. The most common grade 3 or 4 toxicities observed in the niraparib group were haematological in nature: thrombocytopenia (124 [34%] of 367 patients), anaemia (93 [25%]), and neutropenia (72 [20%]); disutility analyses showed no significant QOL impairment associated with these toxic effects.These PRO data suggest that women who receive niraparib as maintenance treatment for recurrent ovarian cancer after responding to platinum treatment are able to maintain QOL during their treatment when compared with placebo.TESARO.

View details for DOI 10.1016/S1470-2045(18)30333-4

View details for Web of Science ID 000440573800060

View details for PubMedID 30026000
Occult Gynecologic Cancer in Women Undergoing Hysterectomy or Myomectomy for Benign Indications. Obstetrics and gynecology Chalas, E., Clarke-Pearson, D., Berek, J. S. 2018; 132 (2): 519
View details for DOI 10.1097/AOG.0000000000002769

View details for PubMedID 30045197
30 years of Current Opinion in Obstetrics and Gynecology: looking back and looking forward CURRENT OPINION IN OBSTETRICS & GYNECOLOGY Berek, J. S., Fairbairn, S. 2018; 30 (2): 99
View details for DOI 10.1097/GCO.0000000000000445

View details for Web of Science ID 000427985300001

View details for PubMedID 29406462
Commonly Occurring Cell Subsets in High-Grade Serous Ovarian Tumors Identified by Single-Cell Mass Cytometry CELL REPORTS Gonzalez, V. D., Samusik, N., Chen, T. J., Savig, E. S., Aghaeepour, N., Quigley, D. A., Huang, Y., Giangarra, V., Borowsky, A. D., Hubbard, N. E., Chen, S., Han, G., Ashworth, A., Kipps, T. J., Berek, J. S., Nolan, G. P., Fantl, W. J. 2018; 22 (7): 1875–88
Abstract

We have performed an in-depth single-cell phenotypic characterization of high-grade serous ovarian cancer (HGSOC) by multiparametric mass cytometry (CyTOF). Using a CyTOF antibody panel to interrogate features of HGSOC biology, combined with unsupervised computational analysis, we identified noteworthy cell types co-occurring across the tumors. In addition to a dominant cell subset, each tumor harbored rarer cell phenotypes. One such group co-expressed E-cadherin and vimentin (EV), suggesting their potential role in epithelial mesenchymal transition, which was substantiated by pairwise correlation analyses. Furthermore, tumors from patients with poorer outcome had an increased frequency of another rare cell type that co-expressed vimentin, HE4, and cMyc. These poorer-outcome tumors also populated more cell phenotypes, as quantified by Simpson's diversity index. Thus, despite the recognized genomic complexity of the disease, the specific cell phenotypes uncovered here offer a focus for therapeutic intervention and disease monitoring.

View details for DOI 10.1016/j.celrep.2018.01.053

View details for Web of Science ID 000424981600021

View details for PubMedID 29444438
Measuring what matters MOST: validation of the Measure of Ovarian Symptoms and Treatment, a patient-reported outcome measure of symptom burden and impact of chemotherapy in recurrent ovarian cancer QUALITY OF LIFE RESEARCH King, M. T., Stockler, M. R., O'Connell, R. L., Buizen, L., Joly, F., Lanceley, A., Hilpert, F., Okamoto, A., Aotani, E., Bryce, J., Donnellan, P., Oza, A., Avall-Lundqvist, E., Berek, J. S., Sehouli, J., Feeney, A., Berton-Rigaud, D., Costa, D. J., Friedlander, M. L., GCIG Symptom Benefit Grp 2018; 27 (1): 59–74
Abstract

Gynecologic Cancer Intergroup Symptom Benefit Study (GCIG-SBS) Stage 2 aimed to review, revise, and validate a patient-reported outcome measure (PROM), the Measure of Ovarian Symptoms and Treatment concerns (MOST), developed in GCIG-SBS Stage 1 (MOSTv1, 35 items), and document recurrent ovarian cancer (ROC) symptom burden and benefit.GCIG-SBS Stage 2 recruited patients with platinum-resistant/refractory ROC (PRR-ROC) or potentially platinum-sensitive ROC with ≥ 3 lines of prior chemotherapy (PPS-ROC ≥ 3). Patients completed MOSTv1, QLQ-C30, QLQ-OV28, and FACT-O/FOSI at baseline and before cycle 3 of chemotherapy (pre-C3), and global assessments of change (MOST-Change) pre-C3. Clinicians rated patients' cancer-related symptoms, performance status, and adverse events. Convergent and divergent validity (Spearman's correlations), discriminative validity (effect sizes between groups classified by clinician-rated characteristics), and responsiveness (paired t tests in patients expected to experience clinically meaningful change) were assessed.Of 948 recruits, 903 completed PROMs at baseline and 685 pre-C3. Baseline symptom burden was substantial for PRR-ROC and PPS-ROC ≥ 3. MOSTv2 has 24 items and five multi-item scales: abdominal symptoms (MOST-Abdo), disease or treatment-related symptoms (MOST-DorT), chemotherapy-related symptoms (MOST-Chemo), psychological symptoms (MOST-Psych), and MOST-Well-being. Correlations confirmed concurrent and divergent validity. Discriminative validity was confirmed by effect sizes that conformed with a priori hypotheses. MOST-Abdo was responsive to improvements in abdominal symptoms and MOST-Chemo detected the adverse effects of chemotherapy.The MOSTv2 validly quantifies patient-reported symptom burden, adverse effects, and symptom benefit in ROC, and as such is fit-for-purpose for clinical trials of palliative chemotherapy in ROC. Further research is required to assess test-retest reliability.

View details for DOI 10.1007/s11136-017-1729-8

View details for Web of Science ID 000422793600007

View details for PubMedID 29248998
Validation of the modified Glasgow Prognostic Score (mGPS) in recurrent ovarian cancer (ROC) - Analysis of patients enrolled in the GCIG Symptom Benefit Study (SBS) GYNECOLOGIC ONCOLOGY Roncolato, F. T., Berton-Rigaud, D., O'Connell, R., Lanceley, A., Sehouli, J., Buizen, L., Okamoto, A., Aotani, E., Lorusso, D., Donnellan, P., Oza, A., Avall-Lundqvist, E., Berek, J., Hilpert, F., Ledermann, J. A., Kaminsky, M., Stockler, M. R., King, M. T., Friedlander, M. 2018; 148 (1): 36–41
Abstract

Modified Glasgow Prognostic Score (mGPS) is predictive of survival in many advanced cancers, but has not been evaluated in recurrent ovarian cancer (ROC). The aim was to determine validity of mGPS in ROC, investigate its associations with health related quality of life (HRQL) and ECOG performance status (PS).mGPS is based on serum C reactive protein (CRP) and albumin, with scores ranging from 0 (least) to 2 (most). HRQL was measured with EORTC QLQ C-30 and OV-28. χ2 tests for trend were used to examine the relationship between HRQL, PS and mGPS. Cox proportional hazards regression was used to assess associations between mGPS, HRQL, clinicopathological factors, and overall survival (OS).Inflammatory markers were available in 516 of 948 patients in GCIG SBS. 200(39%) had potentially platinum sensitive ROC with ≥3 lines of chemotherapy, 316(61%) had platinum resistant ROC. 282(55%), 123(24%), 111(22%) had mGPS of 0, 1, 2, respectively. Median OS (months) was 18.1, 9.6, and 6.6 for mGPS 0, 1, and 2 respectively. mGPS was an independent predictor of OS after adjusting for PS and platinum sensitivity (p<0.001). mGPS remained a predictor of OS after adjusting for physical function, role function, global health status, abdominal/GI symptoms, and multiple clinicopathologic factors (p=0.02). Worse PS and higher mGPS were associated with poorer HRQL (p<0.001). Higher mGPS was associated with worse HRQL, independent of PS.The mGPS is an independent predictor of OS in ROC after adjusting for HRQL and clinicopathological factors. Higher mGPS is associated with worse HRQL independent of PS. mGPS is simple, inexpensive and may be suitable for clinical practice, clinical trial patient selection and stratification.

View details for DOI 10.1016/j.ygyno.2017.10.019

View details for Web of Science ID 000423139400007

View details for PubMedID 29107348
5th Ovarian Cancer Consensus Conference: Individualized Therapy and Patient Factors. Annals of oncology McGee, J., Bookman, M., Harter, P., Marth, C., McNeish, I., Moore, K. N., Poveda, A., Hilpert, F., Hasegawa, K., Bacon, M., Gatsonis, C., Brand, A., Kridelka, F., Berek, J., OTTEVANGER, N., Levy, T., Silverberg, S., Kim, B., Hirte, H., Okamoto, A., Stuart, G., Ochiai, K. 2017
Abstract

This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives.

View details for DOI 10.1093/annonc/mdx010

View details for PubMedID 28119296
Immunotherapy in ovarian cancer CURRENT PROBLEMS IN CANCER Krishnan, V., Berek, J. S., Dorigo, O. 2017; 41 (1): 48-63
Abstract

Immunotherapy aims to develop combination approaches that simultaneously augment immunity while preventing local immune suppression. Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for patients with ovarian cancer are inadequate. Advances in immunotherapy offer a promising frontier for treating ovarian tumors. Multiple immunotherapeutic modalities are currently developed and tested in clinical trials. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery.

View details for DOI 10.1016/j.currproblcancer.2016.11.003

View details for Web of Science ID 000398869800004
Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer NEW ENGLAND JOURNAL OF MEDICINE Mirza, M. R., Monk, B. J., Herrstedt, J., Oza, A. M., Mahner, S., Redondo, A., Fabbro, M., Ledermann, J. A., Lorusso, D., Vergote, I., Ben-Baruch, N. E., Marth, C., Madry, R., Christensen, R. D., Berek, J. S., Dorum, A., Tinker, A. V., du Bois, A., Gonzalez-Martin, A., Follana, P., Benigno, B., Rosenberg, P., Gilbert, L., Rimel, B. J., Buscema, J., Balser, J. P., Agarwal, S., Matulonis, U. A. 2016; 375 (22): 2154-2164
Abstract

Niraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer.In this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival.Of 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications.Among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274 .).

View details for DOI 10.1056/NEJMoa1611310

View details for Web of Science ID 000389030400007

View details for PubMedID 27717299
Immunotherapy in ovarian cancer. Current problems in cancer Krishnan, V., Berek, J. S., Dorigo, O. 2016
Abstract

Immunotherapy aims to develop combination approaches that simultaneously augment immunity while preventing local immune suppression. Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for patients with ovarian cancer are inadequate. Advances in immunotherapy offer a promising frontier for treating ovarian tumors. Multiple immunotherapeutic modalities are currently developed and tested in clinical trials. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery.

View details for DOI 10.1016/j.currproblcancer.2016.11.003

View details for PubMedID 28169004
Pharmacological activation of FOXO3 suppresses triple-negative breast cancer in vitro and in vivo ONCOTARGET Park, S., Chung, Y. M., Ma, J., Yang, Q., Berek, J. S., Hu, M. C. 2016; 7 (27): 42110-42125
View details for DOI 10.18632/oncotarget.9881

View details for Web of Science ID 000380942600090
Impact of the 2014 Food and Drug Administration Warnings Against Power Morcellation JOURNAL OF MINIMALLY INVASIVE GYNECOLOGY Lum, D. A., Sokol, E. R., Berek, J. S., Schulkin, J., Chen, L., McElwain, C., Wright, J. D. 2016; 23 (4): 548-556
Abstract

To determine whether members of the AAGL Advancing Minimally Invasive Gynecologic Surgery Worldwide (AAGL) and members of the American College of Obstetricians and Gynecologists Collaborative Ambulatory Research Network (ACOG CARN) have changed their clinical practice based on the 2014 Food and Drug Administration (FDA) warnings against power morcellation.A survey study.Participants were invited to complete this online survey (Canadian Task Force classification II-2).AAGL and ACOG CARN members.An online anonymous survey with 24 questions regarding demographics and changes to clinical practice during minimally invasive myomectomies and hysterectomies based on the 2014 FDA warnings against power morcellation.A total of 615 AAGL members and 54 ACOG CARN members responded (response rates of 8.2% and 60%, respectively). Before the FDA warnings, 85.8% and 86.9%, respectively, were using power morcellation during myomectomies and hysterectomies. After the FDA warnings, 71.1% and 75.8% of respondents reported stopping the use of power morcellation during myomectomies and hysterectomies. The most common reasons cited for discontinuing the use of power morcellation or using it less often were hospital mandate (45.6%), the concern for legal consequences (16.1%), and the April 2014 FDA warning (13.9%). Nearly half of the respondents (45.6%) reported an increase in their rate of laparotomy. Most (80.3%) believed that the 2014 FDA warnings have not led to an improvement in patient outcomes and have led to harming patients (55.1%).AAGL and ACOG CARN respondents reported decreased use of power morcellation during minimally invasive gynecologic surgery after the 2014 FDA warnings, the most common reason cited being hospital mandate. Rates of laparotomy have increased. Most members surveyed believe that the FDA warnings have not improved patient outcomes.

View details for DOI 10.1016/j.jmig.2016.01.019

View details for Web of Science ID 000375821000018

View details for PubMedID 26827905
In Reply. Obstetrics and gynecology Parker, W. H., Kaunitz, A. M., Pritts, E. A., Olive, D. L., Chalas, E., Clarke-Pearson, D. L., Berek, J. S. 2016; 127 (5): 966-967
View details for DOI 10.1097/AOG.0000000000001416

View details for PubMedID 27101114
US Food and Drug Administration's Guidance Regarding Morcellation of Leiomyomas OBSTETRICS AND GYNECOLOGY Parker, W. H., Kaunitz, A. M., Pritts, E. A., Olive, D. L., Chalas, E., Clarke-Pearson, D. L., Berek, J. S. 2016; 127 (1): 18-22
View details for DOI 10.1097/AOG.0000000000001157

View details for Web of Science ID 000366914600005
Progression-free and overall survival in ovarian cancer patients treated with CVac, a mucin 1 dendritic cell therapy in a randomized phase 2 trial. Journal for immunotherapy of cancer Gray, H. J., Benigno, B., Berek, J., Chang, J., Mason, J., Mileshkin, L., Mitchell, P., Moradi, M., Recio, F. O., Michener, C. M., Secord, A. A., Tchabo, N. E., Chan, J. K., Young, J., Kohrt, H., Gargosky, S. E., Goh, J. C. 2016; 4: 34-?
Abstract

CAN-003 was a randomized, open-label, Phase 2 trial evaluating the safety, efficacy and immune outcomes of CVac, a mucin 1 targeted-dendritic cell (DC) treatment as a maintenance therapy to patients with epithelial ovarian cancer (EOC).Patients (n = 56) in first (CR1) or second clinical remission (CR2) were randomized (1:1) to standard of care (SOC) observation or CVac maintenance treatment. Ten doses were administered over 56 weeks. Both groups were followed for progression-free survival (PFS) and overall survival (OS).Fifty-six patients were randomized: 27 to SOC and 29 to CVac. Therapy was safe with only seven patients with Grade 3-4 treatment-emergent adverse events. A variable but measurable mucin 1 T cell-specific response was induced in all CVac-treated and some standard of care (SOC) patients. Progression free survival (PFS) was not significantly longer in the treated group compared to SOC group (13 vs. 9 months, p = 0.36, hazard ratio [HR] = 0.73). Analysis by remission status showed in the CR1 subgroup a median PFS of 18 months (SOC) vs. 13 months (CVac); p = 0.69 (HR = 1.18; CI 0.52-2.71). However CR2 patients showed a longer median PFS in the CVac-treated group (median PFS not yet reached, >13 vs. 5 months; p = 0.04, HR = 0.32 CI). OS for CR2 patients at 42 months of follow-up showed a difference of 26 months for SOC vs. > 42 months for CVac-treated (as median OS had not been reached; HR = 0.17 (CI 0.02-1.4) with a p = 0.07).CVac, a mucin 1-dendritic cell maintenance treatment was safe and well tolerated in ovarian cancer patients. A variable but observed CVac-derived, mucin 1-specific T cell response was measured. Notably, CR2 patients showed an improved PFS and lengthened OS. Further studies in CR2 ovarian cancer patients are warranted (NCT01068509).NCT01068509. Study Initiation Date (first patient screened): 20 July 2010. Study Completion Date (last patient observation): 20 August 2013, the last patient observation for progression-free survival; 29 April 2015, the last patient was documented regarding overall survival.

View details for DOI 10.1186/s40425-016-0137-x

View details for PubMedID 27330807
U.S. Food and Drug Administration's Guidance Regarding Morcellation of Leiomyomas: Well-Intentioned, But Is It Harmful for Women? Obstetrics and gynecology Parker, W. H., Kaunitz, A. M., Pritts, E. A., Olive, D. L., Chalas, E., Clarke-Pearson, D. L., Berek, J. S. 2016; 127 (1): 18-22
Abstract

The U.S. Food and Drug Administration (FDA) is warning against the use of laparoscopic power morcellators in the majority of women undergoing myomectomy or hysterectomy for the treatment of leiomyomas because of the concern for inadvertent spread of tumor cells if an undiagnosed cancer were present. The authors, representing a 45-member review group, reviewed the current literature to formulate prevalence rates of leiomyosarcoma in women with presumed leiomyomas and to asses reliable data regarding patient survival after morcellation. The authors disagree with the FDA's methodology in reaching their conclusion and provide clinical recommendations for care of women with leiomyomas who are planning surgery.

View details for DOI 10.1097/AOG.0000000000001157

View details for PubMedID 26646134
Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer NATURE REVIEWS CANCER Bowtell, D. D., Boehm, S., Ahmed, A. A., Aspuria, P., Bast, R. C., Beral, V., Berek, J. S., Birrer, M. J., Blagden, S., Bookman, M. A., Brenton, J. D., Chiappinelli, K. B., Martins, F. C., Coukos, G., Drapkin, R., Edmondson, R., Fotopoulou, C., Gabra, H., Galon, J., Gourley, C., Heong, V., Huntsman, D. G., Iwanicki, M., Karlan, B. Y., Kaye, A., Lengyel, E., Levine, D. A., Lu, K. H., McNeish, I. A., Menon, U., Narod, S. A., Nelson, B. H., Nephew, K. P., Pharoah, P., Powell, D. J., Ramos, P., Romero, I. L., Scott, C. L., Sood, A. K., Stronach, E. A., Balkwill, F. R. 2015; 15 (11): 668-679
View details for DOI 10.1038/nrc4019

View details for Web of Science ID 000363691100007

View details for PubMedID 26493647
Impact of the 2014 FDA Warnings Against Laparoscopic Power Morcellation. Journal of minimally invasive gynecology Lum, D., Berek, J. S., Sheikhi, F., Sokol, E. R. 2015; 22 (6S): S77-?
View details for DOI 10.1016/j.jmig.2015.08.207

View details for PubMedID 27679337
Cancer of the ovary, fallopian tube, and peritoneum INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS Berek, J. S., Crum, C., Friedlander, M. 2015; 131: S111-S122
View details for DOI 10.1016/j.ijgo.2015.06.007

View details for Web of Science ID 000362856700007

View details for PubMedID 26433667
Immunotherapeutic approaches to ovarian cancer treatment. Journal for immunotherapy of cancer Chester, C., Dorigo, O., Berek, J. S., Kohrt, H. 2015; 3: 7-?
Abstract

Despite advances in combinatorial chemotherapy regimens and the advent of intraperitoneal chemotherapy administration, current therapeutic options for ovarian cancer patients are inadequate. Immunotherapy offers a novel and promising therapeutic strategy for treating ovarian tumors. Following the demonstration of the immunogenicity of ovarian tumors, multiple immunotherapeutic modalities have been developed. Antibody-based therapies, immune checkpoint blockade, cancer vaccines, and chimeric antigen receptor-modified T cells have demonstrated preclinical success and entered clinical testing. In this review, we discuss these promising immunotherapeutic approaches and emphasize the importance of combinatorial treatment strategies and biomarker discovery.

View details for DOI 10.1186/s40425-015-0051-7

View details for PubMedID 25806106
The prevalence of occult leiomyosarcoma at surgery for presumed uterine fibroids: a meta-analysis. Gynecological surgery Pritts, E. A., Vanness, D. J., Berek, J. S., Parker, W., Feinberg, R., Feinberg, J., Olive, D. L. 2015; 12 (3): 165-177
Abstract

There is a concern regarding the risk of occult leiomyosarcomas found at surgery for presumed benign fibroids. We sought to produce a comprehensive review of published data addressing this issue and provide high-quality prevalence estimates for clinical practice and future research. A comprehensive literature search using the PubMed/MEDLINE database and the Cochrane Library was performed. Inclusion criteria were human studies, peer-reviewed, with original data, involving cases for surgery in which fibroid-related indications were the primary reason for surgery, and histopathology was provided. Candidate studies (4864) were found; 3844 were excluded after review of the abstract. The remaining 1020 manuscripts were reviewed in their entirety, and 133 were included in the Bayesian binomial random effect meta-analysis. The estimated rate of leiomyosarcoma was 0.51 per 1000 procedures (95 % credible interval (CrI) 0.16-0.98) or approximately 1 in 2000. Restricting the meta-analysis to the 64 prospective studies resulted in a substantially lower estimate of 0.12 leiomyosarcomas per 1000 procedures (95 % CrI <0.01-0.75) or approximately 1 leiomyosarcoma per 8300 surgeries. Results suggest that the prevalence of occult leiomyosarcomas at surgery for presumed uterine fibroids is much less frequent than previously estimated. This rate should be incorporated into both clinical practice and future research.

View details for PubMedID 26283890
Lynch Syndrome Screening Should Be Considered for All Patients With Newly Diagnosed Endometrial Cancer AMERICAN JOURNAL OF SURGICAL PATHOLOGY Mills, A. M., Liou, S., Ford, J. M., Berek, J. S., Pai, R. K., Longacre, T. A. 2014; 38 (11): 1501-1509
Abstract

Lynch syndrome (LS) is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Mutation carriers are at substantially increased risk of developing cancers of the colorectum and endometrium, among others. Given recent recommendations for universal, cost-effective screening of all patients with newly diagnosed colorectal cancer using MMR protein immunohistochemistry, we evaluated MMR protein expression in a series of endometrial cancers in the general population. A total of 605 consecutive cases of primary endometrial cancer at a single institution (1997 to 2013) were evaluated regardless of age, family history, or histologic features. Evaluation methods consisted of immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMS2, followed by DNA methylation analysis for cases with MLH1/PMS2 deficiency. Germline mutation testing was performed on a subset of cases. Forty MMR-deficient, nonmethylated endometrial cancers were identified: 3 MLH1/PMS2 and 37 MSH6/MSH2 protein deficiencies. Only 25% occurred in women below 50 years of age (range, 39 to 88 y), 1 of which was in a risk-reducing hysterectomy specimen. Only 15% of patients had a prior history of carcinoma, including only 2 patients with prior colorectal carcinoma. Most (80%) of the endometrial cancers were purely endometrioid; there were 2 mixed endometrioid/mucinous, 1 mucinous, 1 serous, 2 clear cell, and 2 carcinosarcoma cases. When grading was applicable, 40% of the endometrial malignancies were FIGO grade 1, 34% grade 2, and 26% grade 3. Thirteen percent arose in the lower uterine segment, and 23% had tumor-infiltrating lymphocytes. Of the tumors with known germline testing, 41% with a LS-associated germline mutation were not associated with any of the traditional indicators that have been recommended for LS screening (ie, age 50 y or younger, personal/family cancer pedigree that meets Bethesda guideline criteria, presence of MMR-associated tumor morphology, or location in the lower uterine segment). These data suggest that a significant number of LS-associated endometrial carcinomas are missed using clinical, histologic, and locational screening parameters and provide support for universal screening of all newly diagnosed endometrial cancers.

View details for Web of Science ID 000343880200006

View details for PubMedID 25229768
Catumaxomab for the Treatment of Malignant Ascites in Patients With Chemotherapy-Refractory Ovarian Cancer A Phase II Study INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Berek, J. S., Edwards, R. P., Parker, L. P., DeMars, L. R., Herzog, T. J., Lentz, S. S., Morris, R. T., Akerley, W. L., Holloway, R. W., Method, M. W., Plaxe, S. C., Walker, J. L., Friccius-Quecke, H., Krasner, C. N. 2014; 24 (9): 1583-1589
Abstract

The aim of this study was to investigate the efficacy and safety of intraperitoneal catumaxomab in heavily pretreated patients with chemotherapy-refractory ovarian cancer and recurrent symptomatic malignant ascites.The study is a single-arm open-label multicenter US phase II study. Patients received 4 three-hour intraperitoneal catumaxomab infusions (10, 20, 50, and 150 μg within 10 days). The primary end point was the percentage of patients with at least a 4-fold increase in the puncture-free interval (PuFI) relative to the pretreatment interval. The main secondary end points were puncture-free survival, overall survival, ascites symptoms, and safety. Time to first therapeutic puncture (TTPu) was analyzed post hoc.Forty patients were screened, and 32 patients (80%) were treated. Seven patients (23%) achieved the primary end point. The median PuFI was prolonged 2-fold from 12 to 27.5 days. The median TTPu was prolonged 4-fold from 12 to 52 days. The median puncture-free survival and overall survival were 29.5 and 111 days, respectively. Nineteen patients (59%) required puncture after catumaxomab treatment. Ascites symptoms improved in most of the 13 predefined categories. At study end, most symptoms were still improved compared with screening. The most frequent treatment-related adverse events were related to cytokine release (vomiting, nausea, pyrexia, fatigue, and chills) or intraperitoneal administration (abdominal pain). Transient increases in liver parameters and transient decreases in blood lymphocytes were regularly observed but were generally without clinical relevance.Catumaxomab prolonged PuFI and TTPu had a beneficial effect on quality of life, as shown by the improvement in ascites symptoms, and had an acceptable safety profile, which is consistent with its mode of action.

View details for DOI 10.1097/IGC.0000000000000286

View details for Web of Science ID 000344611800011

View details for PubMedID 25254563
Auranofin displays anticancer activity against ovarian cancer cells through FOXO3 activation independent of p53. International journal of oncology Park, S., Lee, J. H., Berek, J. S., Hu, M. C. 2014; 45 (4): 1691-1698
Abstract

Auranofin is a gold-containing compound classified by the World Health Organization as a clinically established rheumatoid arthritis therapeutic agent. Through drug screening for novel anticancer therapeutics, we unexpectedly identified auranofin as a potent anticancer agent against a p53-null ovarian carcinoma SKOV3 cell line. However, the molecular mechanism underlying auranofin-mediated anticancer activity in ovarian cancer cells is basically unknown. Here, we show that auranofin inhibits proliferation and survival of SKOV3 cells in a dose‑ and time‑dependent manner. Auranofin treatment activates the pro-apoptotic caspase-3, increases protein levels of apoptosis-inducing proteins Bax and Bim and reduces the expression of the anti-apoptotic mediator Bcl-2 in SKOV3 cells. Moreover, auranofin downregulates IκB kinase (IKK)-β and promotes nuclear localization and the activation of FOXO3 tumor suppressor, leading to cellular apoptosis in SKOV3 cells. In contrast, silencing FOXO3 diminishes the pro-apoptotic signaling of auranofin in SKOV3 cells. These results suggest that auranofin may induce caspase-3-mediated apoptosis in a FOXO3-dependent manner. The observed upregulation of pro-apoptotic genes and apoptosis in cancer cells without p53 in response to auranofin suggests a novel p53-independent mechanism underlying auranofin-induced apoptosis in ovarian cancer cells.

View details for DOI 10.3892/ijo.2014.2579

View details for PubMedID 25096914
Reprogramming ovarian and breast cancer cells into non-cancerous cells by low-dose metformin or SN-38 through FOXO3 activation. Scientific reports Hu, T., Chung, Y. M., Guan, M., Ma, M., Ma, J., Berek, J. S., Hu, M. C. 2014; 4: 5810-?
Abstract

Cancer is a leading cause of death worldwide. Because the cytotoxic effects of conventional chemotherapies often harm normal tissue cells along with cancer cells, conventional chemotherapies cause many unwanted or intolerable side effects. Thus, there is an unmet medical need to establish a paradigm of chemotherapy-induced differentiation of cancer cells with tolerable side effects. Here we show that low-dose metformin or SN-38 inhibits cell growth or survival in ovarian and breast cancer cells and suppresses their tumor growth in vivo. Low-dose metformin or SN-38 increases FOXO3 nuclear localization as well as the amount of DNA damage markers and downregulates the expression of a cancer-stemness marker CD44 and other stemness markers, including Nanog, Oct-4, and c-Myc, in these cancer cells. This treatment also inhibits spheroid body-formation in 3-dimensional culture. In contrast, silencing FOXO3 diminishes all these cellular events when ovarian/breast cancer cells are treated with the mentioned drugs. These results suggest that low-dose metformin or SN-38 may reprogram these cancer cells into non-cancerous cells in a FOXO3-dependent manner, and may allow patients to overcome these cancers with minimal side effects.

View details for DOI 10.1038/srep05810

View details for PubMedID 25056111

View details for PubMedCentralID PMC4108946
A statement on abortion by 100A professors of obstetrics: 40 years later CONTRACEPTION Archer, D. F., Autry, A. (., Barbieri, R. L., Berek, J. S., Berga, S. L., Bernstein, I. M., Brodman, M., Brown, H., Buekens, P., Bulun, S. E., Burkman, R. T., Campbell, W. A., Carson, L. F., Caughey, A. B., Chaudhuri, G., Chelmow, D., Chervenak, F., Clarke-Pearson, D. L., Creinin, M., D'alton, M., Dandolu, V., Darney, P. D., Derman, R., Driscoll, D. A., Eschenbach, D. A., Ferguson, J. E., Fox, H. E., Friedman, A. J., Gilliam, M., Griffin, T., Grimes, D. A., Grow, D. R., Giudice, L., Haney, A., Hansen, W. F., Harman, C., Heffner, L. J., Hendessi, P., Hogge, W. A., Horowitz, I. R., Jensen, J., Johnson, T. R., Johnson, D., Johnson, J., Jonas, H. S., Jones, H. W., Keefe, D., Kilpatrick, S. J., Landon, M. B., Larsen, J. W., Laube, D. W., Learman, L. A., Leslie, K. K., Linn, E., Liu, J. H., Lowery, C., Macones, G. A., Mallet, V., Maulik, D., Merkatz, I. R., Mishell, D. R., Montgomery, O., Rice, V. M., Moore, T., Muderspach, L., Nelson, A. L., Niebyl, J. R., Norwitz, E. R., Parisi, V., Jones, K. P., Phipps, M. G., Porto, M., Pridjian, G., Quirk, J. G., Rader, J. S., Rayburn, W. F., Reindollar, R., Ricciotti, H. A., Rice, L., Richard-Davis, G., Rivera-Vinas, J. I., Santoro, N., Satin, A. J., Sauvage, L. M., Schlaff, W. D., Sciarra, J., Silverman, R. K., Smith, C. V., Speroff, L., Stenchever, M., Strauss, J. F., Stubblefield, P., Taylor, H. S., Van Dorsten, J. P., Washington, E., Weiss, G., Westhoff, C., Williams, R. S., Woods, J., Yankowitz, J. 2013; 88 (4): 568-576
Abstract

In this Journal in 1972, 100 leaders in obstetrics and gynecology published a compelling statement that recognized the legalization of abortion in several states and anticipated the 1973 Supreme Court decision in Roe v Wade. They projected the numbers of legal abortions that likely would be required by women in the United States and described the role of the teaching hospital in meeting that responsibility. They wrote to express their concern for women's health in a new legal and medical era of reproductive control and to define the responsibilities of academic obstetrician-gynecologists. Forty years later, 100 professors examine the statement of their predecessors in light of medical advances and legal changes and suggest a further course of action for obstetrician gynecologists.

View details for DOI 10.1016/j.contraception.2013.07.003

View details for Web of Science ID 000324974900016
Chemoimmunotherapy Using Pegylated Liposomal Doxorubicin and Interleukin-18 in Recurrent Ovarian Cancer: A Phase I Dose-Escalation Study CANCER IMMUNOLOGY RESEARCH Simpkins, F., Flores, A., Chu, C., Berek, J. S., Lucci, J., Murray, S., Bauman, J., Struemper, H., Germaschewski, F., Jonak, Z., Gardner, O., Toso, J., Coukos, G. 2013; 1 (3): 168-178
Abstract

Recombinant interleukin (IL)-18 (SB-485232) is an immunostimulatory cytokine, with shown antitumor activity in combination with pegylated liposomal doxorubicin (PLD) in preclinical models. This phase I study evaluated the safety, tolerability, and biologic activity of SB-485232 administered in combination with PLD in subjects with recurrent ovarian cancer. The protocol comprised four cycles of PLD (40 mg/m(2)) on day 1 every 28 days, in combination with SB-485232 at increasing doses (1, 3, 10, 30, and 100 μg/kg) on days 2 and 9 of each cycle, to be administered over five subject cohorts, followed by discretionary PLD monotherapy. Sixteen subjects were enrolled. One subject withdrew due to PLD hypersensitivity. Most subjects (82%) were platinum-resistant or refractory, and had received a median of three or more prior chemotherapy regimens. SB-485232 up to 100 μg/kg with PLD had an acceptable safety profile. Common drug-related adverse events were grade 1 or 2 (no grade 4 or 5 adverse events). Concomitant PLD administration did not attenuate the biologic activity of IL-18, with maximal SB-485232 biologic activity already observed at 3 μg/kg. Ten of 16 enrolled subjects (63%) completed treatment, whereas five (31%) subjects progressed on treatment. A 6% partial objective response rate and a 38% stable disease rate were observed. We provide pilot data suggesting that SB-485232 at the 3 μg/kg dose level in combination with PLD is safe and biologically active. This combination warrants further study in a phase II trial.

View details for DOI 10.1158/2326-6066.CIR-13-0098

View details for Web of Science ID 000340029700006

View details for PubMedID 24777679
In reply. Obstetrics and gynecology Parker, W. H., Feskanich, D., Broder, M. S., Chang, E., Shoupe, D., Farquhar, C. M., Berek, J. S., Manson, J. E. 2013; 122 (2): 396-?
View details for DOI 10.1097/AOG.0b013e31829d438c

View details for PubMedID 23969818
Abagovomab As Maintenance Therapy in Patients With Epithelial Ovarian Cancer: A Phase III Trial of the AGO OVAR, COGI, GINECO, and GEICO-The MIMOSA Study 47th Annual Meeting of American-Society-of-Clinical-Oncology (ASCO) Sabbatini, P., Harter, P., Scambia, G., Sehouli, J., Meier, W., Wimberger, P., Baumann, K. H., Kurzeder, C., Schmalfeldt, B., Cibula, D., Bidzinski, M., Casado, A., Martoni, A., Colombo, N., Holloway, R. W., Selvaggi, L., Li, A., Del Campo, J., Cwiertka, K., Pinter, T., Vermorken, J. B., Pujade-Lauraine, E., Scartoni, S., Bertolotti, M., Simonelli, C., Capriati, A., Maggi, C. A., Berek, J. S., Pfisterer, J. AMER SOC CLINICAL ONCOLOGY. 2013: 1554–61
Abstract

To determine whether abagovomab maintenance therapy prolongs recurrence-free (RFS) and overall survival (OS) in patients with ovarian cancer in first clinical remission.Patients with International Federation of Gynecology and Obstetrics stage III to IV ovarian cancer in complete clinical remission after primary surgery and platinum- and taxane-based chemotherapy were randomly assigned at a ratio of 2:1 in a phase III, double-blind, placebo-controlled, multicenter study. Abagovomab 2 mg or placebo was administered as 1-mL suspension once every 2 weeks for 6 weeks (induction phase) and then once every 4 weeks (maintenance phase) until recurrence or up to 21 months after random assignment of the last patient. The primary end point was RFS; secondary end points were OS and immunologic response.Characteristics of the 888 patients included: mean age, 56.3 years; Eastern Cooperative Oncology Group performance status, ≤ 1 in > 99% of patients; serous papillary subtype, 81.5%; stage III, 85.9%; and cancer antigen 125 ≤ 35 U/mL after third cycle, 80.9%. Mean exposure to study treatment (± standard deviation) was 449.7 ± 333.08 days. Hazard ratio (HR) of RFS for the treatment group using tumor size categorization (≤ 1 cm, > 1 cm) was 1.099 (95% CI, 0.919 to 1.315; P = .301). HR of OS using tumor size categorization (≤ 1 cm, > 1 cm) was 1.150 (95% CI, 0.872 to 1.518; P = .322). The most frequently reported type of adverse event was an injection site reaction in 445 patients (50.2%), followed by injection site erythema and fatigue in 227 (25.6%) and 212 patients (23.9%), respectively. By the final visit, median anti-anti-idiotypic antibody level was 493,000.0 ng/mL, indicating a robust response.Abagovomab administered as repeated monthly injections is safe and induces a measurable immune response. Administration as maintenance therapy for patients with ovarian cancer in first remission does not prolong RFS or OS.

View details for DOI 10.1200/JCO.2012.46.4057

View details for Web of Science ID 000317831500018

View details for PubMedID 23478059
Long-Term Mortality Associated With Oophorectomy Compared With Ovarian Conservation in the Nurses' Health Study OBSTETRICS AND GYNECOLOGY Parker, W. H., Feskanich, D., Broder, M. S., Chang, E., Shoupe, D., Farquhar, C. M., Berek, J. S., Manson, J. E. 2013; 121 (4): 709-716
Abstract

To report long-term mortality after oophorectomy or ovarian conservation at the time of hysterectomy in subgroups of women based on age at the time of surgery, use of estrogen therapy, presence of risk factors for coronary heart disease, and length of follow-up.This was a prospective cohort study of 30,117 Nurses' Health Study participants undergoing hysterectomy for benign disease. Multivariable adjusted hazard ratios for death from coronary heart disease, stroke, breast cancer, epithelial ovarian cancer, lung cancer, colorectal cancer, total cancer, and all causes were determined comparing bilateral oophorectomy (n=16,914) with ovarian conservation (n=13,203).Over 28 years of follow-up, 16.8% of women with hysterectomy and bilateral oophorectomy died from all causes compared with 13.3% of women who had ovarian conservation (hazard ratio 1.13, 95% confidence interval 1.06-1.21). Oophorectomy was associated with a lower risk of death from ovarian cancer (four women with oophorectomy compared with 44 women with ovarian conservation) and, before age 47.5 years, a lower risk of death from breast cancer. However, at no age was oophorectomy associated with a lower risk of other cause-specific or all-cause mortality. For women younger than 50 years at the time of hysterectomy, bilateral oophorectomy was associated with significantly increased mortality in women who had never used estrogen therapy but not in past and current users: assuming a 35-year lifespan after oophorectomy: number needed to harm for all-cause death=8, coronary heart disease death=33, and lung cancer death=50.Bilateral oophorectomy is associated with increased mortality in women aged younger than 50 years who never used estrogen therapy and at no age is oophorectomy associated with increased survival.I.

View details for DOI 10.1097/AOG.0b013e3182864350

View details for Web of Science ID 000316610000004

View details for PubMedID 23635669
Cancer of the ovary, fallopian tube, and peritoneum INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS Berek, J. S., Crum, C., Friedlander, M. 2012; 119: S118-S129
View details for Web of Science ID 000309374500006

View details for PubMedID 22999503
FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage NATURE COMMUNICATIONS Chung, Y. M., Park, S., Tsai, W., Wang, S., Ikeda, M., Berek, J. S., Chen, D. J., Hu, M. C. 2012; 3
Abstract

DNA damage as a result of environmental stress is recognized by sensor proteins that trigger repair mechanisms, or, if repair is unsuccessful, initiate apoptosis. Defects in DNA damage-induced apoptosis promote genomic instability and tumourigenesis. The protein ataxia-telangiectasia mutated (ATM) is activated by DNA double-strand breaks and regulates apoptosis via p53. Here we show that FOXO3 interacts with the ATM-Chk2-p53 complex, augments phosphorylation of the complex and induces the formation of nuclear foci in cells on DNA damage. FOXO3 is essential for DNA damage-induced apoptosis and conversely FOXO3 requires ATM, Chk2 and phosphorylated p53 isoforms to trigger apoptosis as a result of DNA damage. Under these conditions FOXO3 may also have a role in regulating chromatin retention of phosphorylated p53. These results suggest an essential link between FOXO3 and the ATM-Chk2-p53-mediated apoptotic programme following DNA damage.

View details for DOI 10.1038/ncomms2008

View details for Web of Science ID 000308801100016

View details for PubMedID 22893124

View details for PubMedCentralID PMC3589124
Current Management of Vulvar Cancer HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Fuh, K. C., Berek, J. S. 2012; 26 (1): 45-?
Abstract

1. Vulvar cancer is surgically staged. 2. Imaging such as CT of the abdomen and pelvis should be performed for women with tumors 2 cm or larger or to detect lymph node or other metastases. 3. Staging should include evaluation of factors related to prognosis: tumor size, depth of invasion, lymph node involvement, and presence of distant metastases. 4. Inguinofemoral lymph node metastasis is the most important predictor of overall prognosis. 5. Inguinofemoral lymphadenectomy or sentinel lymph node evaluation can be omitted for lesions 2 cm or smaller and depth of invasion less than 1 mm. 6. Sentinel node biopsy seems to be a reliable means to pathologically assess inguinofemoral lymph node metastasis. 7. All tumors larger than 2 cm require pathologic inguinofemoral lymph node evaluation. 8. Radical local excision or modified radical vulvectomy is appropriate for most stage I and II lesions located on the lateral or posterior aspects of the vulva. 9. A tumor-free surgical margin of at least 1 cm decreases the risk of local recurrence. 10. Chemoradiation therapy is the preferred approach for most patients with very advanced vulvar cancer.

View details for DOI 10.1016/j.hoc.2011.10.006

View details for Web of Science ID 000300467600005

View details for PubMedID 22244661
A Risk Model for Secondary Cytoreductive Surgery in Recurrent Ovarian Cancer: An Evidence-Based Proposal for Patient Selection ANNALS OF SURGICAL ONCOLOGY Tian, W., Chi, D. S., Sehouli, J., Trope, C. G., Jiang, R., Ayhan, A., Cormio, G., Xing, Y., Breitbach, G., Braicu, E. I., Rabbitt, C. A., Oksefjell, H., Fotopoulou, C., Meerpohl, H., du Bois, A., Berek, J. S., Zang, R., Harter, P. 2012; 19 (2): 597-604
Abstract

To develop a risk model for predicting complete secondary cytoreductive surgery (SCR) in patients with recurrent ovarian cancer.Individual data of 1075 patients with recurrent ovarian cancer undergoing SCR from 7 worldwide centers were pooled and analyzed. The risk model was developed based on the factors impacting on SCR surgical outcome. Additional data on 117 patients who were not included in the development of the model were used for external validation and to assess the discrimination of the model.Of the 1075 patients, 434 (40.4%) underwent complete resection. Complete secondary cytoreduction was associated with six variables: FIGO stage (odds ratio [OR] = 1.32, 95% confidence interval [95% CI]: 0.97-1.80), residual disease after primary cytoreduction (OR = 1.69, 95% CI: 1.26-2.27), progression-free interval (OR = 2.27, 95% CI: 1.71-3.01), Eastern Cooperative Oncology Group (ECOG) performance status (OR = 2.23, 95% CI: 1.45-3.44), CA125 (OR = 1.85, 95% CI: 1.41-2.44), and ascites at recurrence (OR = 2.79, 95% CI: 1.88-4.13). These variables were entered into the risk model and assigned scores ranging from 0 to 11.9. Patients with total scores of 0-4.7 were categorized as the low-risk group, in which the proportion of complete cytoreduction was 53.4% compared with 20.1% in the high-risk group (OR = 4.55, 95% CI: 3.43-6.04). In external validation, the sensitivity and specificity was 83.3% and 57.6%, respectively. Area under the curve of the receiver-operating characteristics for predicting complete SCR was 0.68 (95% CI: 0.60-0.79).This model and scoring system may well predict the outcome of SCR and could potentially be useful in future clinical trials to determine which patients with recurrent ovarian cancer should have SCR as part of their management.

View details for DOI 10.1245/s10434-011-1873-2

View details for Web of Science ID 000299483200036

View details for PubMedID 21732142
Rethinking ovarian cancer: recommendations for improving outcomes NATURE REVIEWS CANCER Vaughan, S., Coward, J. I., Bast, R. C., Berchuck, A., Berek, J. S., Brenton, J. D., Coukos, G., Crum, C. C., Drapkin, R., Etemadmoghadam, D., Friedlander, M., Gabra, H., Kaye, S. B., Lord, C. J., Lengyel, E., Levine, D. A., McNeish, I. A., Menon, U., Mills, G. B., Nephew, K. P., Oza, A. M., Sood, A. K., Stronach, E. A., Walczak, H., Bowtell, D. D., Balkwill, F. R. 2011; 11 (10): 719-725
Abstract

There have been major advances in our understanding of the cellular and molecular biology of the human malignancies that are collectively referred to as ovarian cancer. At a recent Helene Harris Memorial Trust meeting, an international group of researchers considered actions that should be taken to improve the outcome for women with ovarian cancer. Nine major recommendations are outlined in this Opinion article.

View details for DOI 10.1038/nrc3144

View details for Web of Science ID 000295155600011

View details for PubMedID 21941283

View details for PubMedCentralID PMC3380637
Predictors of survival in patients with recurrent ovarian cancer undergoing secondary cytoreductive surgery based on the pooled analysis of an international collaborative cohort BRITISH JOURNAL OF CANCER Zang, R. Y., Harter, P., Chi, D. S., Sehouli, J., Jiang, R., Trope, C. G., Ayhan, A., Cormio, G., Xing, Y., Wollschlaeger, K. M., Braicu, E. I., Rabbitt, C. A., Oksefjell, H., Tian, W. J., Fotopoulou, C., Pfisterer, J., du Bois, A., Berek, J. S. 2011; 105 (7): 890-896
Abstract

This study aims to identify prognostic factors and to develop a risk model predicting survival in patients undergoing secondary cytoreductive surgery (SCR) for recurrent epithelial ovarian cancer.Individual data of 1100 patients with recurrent ovarian cancer of a progression-free interval at least 6 months who underwent SCR were pooled analysed. A simplified scoring system for each independent prognostic factor was developed according to its coefficient. Internal validation was performed to assess the discrimination of the model.Complete SCR was strongly associated with the improvement of survival, with a median survival of 57.7 months, when compared with 27.0 months in those with residual disease of 0.1-1 cm and 15.6 months in those with residual disease of >1 cm, respectively (P<0.0001). Progression-free interval (≤23.1 months vs >23.1 months, hazard ratio (HR): 1.72; score: 2), ascites at recurrence (present vs absent, HR: 1.27; score: 1), extent of recurrence (multiple vs localised disease, HR: 1.38; score: 1) as well as residual disease after SCR (R1 vs R0, HR: 1.90, score: 2; R2 vs R0, HR: 3.0, score: 4) entered into the risk model.This prognostic model may provide evidence to predict survival benefit from secondary cytoreduction in patients with recurrent ovarian cancer.

View details for DOI 10.1038/bjc.2011.328

View details for Web of Science ID 000295357900004

View details for PubMedID 21878937
Personalizing CA125 Levels for Ovarian Cancer Screening CANCER PREVENTION RESEARCH Dorigo, O., Berek, J. S. 2011; 4 (9): 1356-1359
Abstract

Screening trials for the early detection of ovarian cancer in the general population and in patients at a high risk for this disease have so far failed to show a reduction of ovarian cancer-specific mortality. Current screening modalities include pelvic examinations, transvaginal ultrasounds, and cancer antigen 125 (CA125) serum marker levels, which are associated with a high false-positive rate. The last decade has witnessed significant modifications in the interpretation of serum CA125 that extend beyond a static CA125 cutoff point. The Risk of Ovarian Cancer Algorithm (ROCA) incorporates changes of CA125 levels over time and an individual's age-specific risk. Ongoing screening trials have incorporated ROCA, but it is still unclear whether the algorithm will increase the sensitivity and specificity of early ovarian cancer diagnosis. A very recent study analyzed baseline CA125 serum marker levels from high-risk patients included in ovarian cancer screening trials conducted by the Cancer Genetics Network and the Gynecologic Oncology Group. The findings show that the distribution of CA125 serum marker levels in this population is significantly affected by various demographic and clinical factors, in particular menopausal status and oral contraceptive use in premenopausal patients. The data suggest that CA125 cutoff points might have to be stratified for subgroups of patients to reduce false-positive results. These intriguing observations will need to be validated in future screening trials for ovarian cancer.

View details for DOI 10.1158/1940-6207.CAPR-11-0378

View details for Web of Science ID 000294490100005

View details for PubMedID 21893498
First-Line Therapy in Ovarian Cancer Trials INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Thigpen, T., duBois, A., McAlpine, J., DiSaia, P., Fujiwara, K., Hoskins, W., Kristensen, G., Mannel, R., Markman, M., Pfisterer, J., Quinn, M., Reed, N., Swart, A. M., Berek, J., Colombo, N., Freyer, G., Gallardo, D., Plante, M., Poveda, A., Rubinstein, L., Bacon, M., Kitchener, H., Stuart, G. C. 2011; 21 (4): 756-762
Abstract

At the 4th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup (GCIG) held in Vancouver, Canada, in June 2010, representatives of 23 cooperative research groups studying gynecologic cancers gathered to establish international consensus on issues critical to the conduct of large randomized trials. The process focused on 13 predetermined questions. Group A, 1 of the 3 discussion groups, addressed the first 5 questions, examining first-line therapies in newly diagnosed ovarian cancer patients. A1: What are the appropriate end points for different trials (maintenance, upfront chemotherapy trials including molecular drugs)? A2: Are there any subgroups defined by tumor biology who need specific treatment options/trials? A3: Is the 2004 GCIG-recommended standard comparator arm still valid? A4: What is the role of modifying dose, schedule, and delivery of chemotherapy? A5: What role does surgery play today?

View details for DOI 10.1097/IGC.0b013e31821ce75d

View details for Web of Science ID 000290250600028

View details for PubMedID 21543937
Abagovomab for ovarian cancer EXPERT OPINION ON BIOLOGICAL THERAPY Pfisterer, J., Harter, P., Simonelli, C., Peters, M., Berek, J., Sabbatini, P., du Bois, A. 2011; 11 (3): 395-403
Abstract

Ovarian cancer (OC) is the fifth most common cancer in women. Unfortunately, more than 70% of cases are detected at an advanced stage with a risk of recurrence, after front line therapy, of over 75%. The need for new therapeutic strategies is extremely high.The development status and the possible role of specific immunotherapy of abagovomab are discussed in the context of the possible therapeutic options for maintenance therapy in advanced OC. An overview of abagovomab, generation and mechanism of action, Phase I/II results and the status of the Phase II/III ongoing trial is given.Abagovomab stimulates the humoral immune response and the cell-mediated immune response in the studies conducted to date. In the proof of concept (POC) study abagovomab prolonged overall survival in those OC recurrent patients who showed an immune response. Abagovomab has an excellent safety and tolerability profile. These characteristics make abagovomab an optimal candidate for a maintenance treatment for OC patients after frontline therapy. The final results of the Phase II/III pivotal study evaluating abagovomab in this setting will be available in the first half of 2011.

View details for DOI 10.1517/14712598.2011.553598

View details for Web of Science ID 000287098500012

View details for PubMedID 21241213
Abagovomab: an anti-idiotypic CA-125 targeted immunotherapeutic agent for ovarian cancer IMMUNOTHERAPY Grisham, R. N., Berek, J., Pfisterer, J., Sabbatini, P. 2011; 3 (2): 153-162
Abstract

Ovarian cancer remains the leading cause of death due to gynecologic malignancies. Most patients present with advanced disease at the time of diagnosis. Although many have a good initial response to surgical debulking and platinum-based chemotherapy, relapse is common, with the eventual development of chemotherapy resistance. Innovative treatments are needed in the remission setting to prolong the disease-free interval or prevent recurrence. Abagovomab is a murine monoclonal anti-idiotypic antibody (molecular weight: 165-175 kDa) that functionally imitates the tumor-associated antigen, CA-125. It has been shown to be well tolerated and to induce a sustained immune response in initial Phase I and II clinical trials. An ongoing, double-blind, placebo-controlled, multicenter, Phase III trial (MIMOSA) completed its double-blind period in December 2010 and will compare abagovomab maintenance therapy to placebo, which will definitively determine the efficacy of this immunotherapeutic approach in patients with ovarian cancer.

View details for DOI 10.2217/IMT.10.100

View details for Web of Science ID 000288627900009

View details for PubMedID 21322756
Strategies and Goals: The Future of the International Gynecologic Cancer Society IGCS Presidential Address INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Berek, J. S. 2010; 20 (9): 1434-1439
View details for DOI 10.1097/IGC.0b013e318202df07

View details for Web of Science ID 000284822900002

View details for PubMedID 21119361
Prophylactic and Risk-Reducing Bilateral Salpingo-oophorectomy Recommendations Based on Risk of Ovarian Cancer OBSTETRICS AND GYNECOLOGY Berek, J. S., Chalas, E., Edelson, M., Moore, D. H., Burke, W. M., Cliby, W. A., Berchuck, A. 2010; 116 (3): 733-743
Abstract

Women who do not have a documented germline mutation or who do not have a strong family history suspicious for a germline mutation are considered to be at average risk of ovarian cancer. Women who have confirmed deleterious BRCA1 and BRCA2 germline mutations are high risk of ovarian cancer. In addition, women who have a strong family history of either ovarian or breast cancer may carry a deleterious mutation and must be presumed to be at higher-than-average risk, even if they have not been tested, because there could be other mutations that are either untested or yet undiscovered that confirm higher-than-average risk of these diseases. We reviewed studies pertaining to prophylactic bilateral salpingo-oophorectomy in women at average risk of ovarian cancer who are undergoing hysterectomy for benign disease. We also reviewed the role of prophylactic bilateral salpingo-oophorectomy in preventing ovarian cancer based on the level of risk of the patient. For women at average risk of ovarian cancer who are undergoing a hysterectomy for benign conditions, the decision to perform prophylactic bilateral salpingo-oophorectomy should be individualized after appropriate informed consent, including a careful analysis of personal risk factors. Several studies suggest an overall negative health effect when prophylactic bilateral salpingo-oophorectomy is performed before the age of menopause. Ovarian conservation before menopause may be especially important in patients with a personal or strong family history of cardiovascular or neurological disease. Conversely, women at high risk of ovarian cancer should undergo risk-reducing bilateral salpingo-oophorectomy.

View details for DOI 10.1097/AOG.0b013e3181ec5fc1

View details for Web of Science ID 000281176400026

View details for PubMedID 20733460
Toll-like receptor-3 as a target to enhance bioactivity of cancer immunotherapy 76th Annual Meeting of the Pacific-Coast-Obstetrical-and-Gynecological-Society Nicodemus, C. F., Wang, L., Lucas, J., Varghese, B., Berek, J. S. MOSBY-ELSEVIER. 2010
Abstract

The purpose of this study was to explore the potential of toll-like receptor-3 stimulation, with polyI:C(12)U (poly[l].poly[C(12),U]; rintatolimod [Ampligen; Hemispherx Biopharma, Philadelphia, PA]) to enhance bioactivity of cancer immunotherapies.Several models of immune activation were assessed with polyI:C(12)U at concentrations that were achieved clinically. Dendritic cell maturation and antigen-specific immune responses were evaluated in vitro and in a murine model. The potential for polyI:C(12)U to enhance antibody-dependent cellular cytotoxicity against tumor was also evaluated.Dendritic cells are matured and T-cell stimulation is enhanced in the presence of polyI:C(12)U. In addition, polyI:C(12)U induced the release of proinflammatory chemokines and cytokines. Prostate-specific antigen-specific T-cell and antibody responses were enhanced significantly in a BALB/c prostate-specific antigen transgenic mouse model. Finally, rituximab-mediated antibody-dependent cellular cytotoxicity against tumor targets was improved significantly by the addition of polyI:C(12)U.PolyI:C(12)U shows promise as a potential agent for selective enhancement of effect with currently available and future cancer immunotherapies.

View details for DOI 10.1016/j.ajog.2009.12.001

View details for Web of Science ID 000278534200038

View details for PubMedID 20080226
The emergence of immunomodulation: Combinatorial immunochemotherapy opportunities for the next decade GYNECOLOGIC ONCOLOGY Kandalaft, L. E., Singh, N., Liao, J. B., Facciabene, A., Berek, J. S., Powell, D. J., Coukos, G. 2010; 116 (2): 222-233
Abstract

In the past decade we have witnessed important advances in the treatment of gynecological cancers and have recognized their potential immunogenicity. This has opened the door to explore immune therapy not only in HPV-induced cancers but also in ovarian and endometrial cancers. Here we will review the off-target immune effects of select chemotherapy drugs commonly used to treat gynecologic cancers and novel tools that can stimulate both the adaptive and innate immune mechanisms such as novel pleiotropic cytokines, Toll-like receptors, and powerful antibodies that can target inhibitory checkpoints, thereby activating effector cellular immune mechanisms and neutralizing suppressor cells. We will also review how existing drugs can be used for combinatorial tumor therapy.

View details for DOI 10.1016/j.ygyno.2009.11.001

View details for Web of Science ID 000274504200013

View details for PubMedID 19959212
Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: A Gynecologic Oncology Group study GYNECOLOGIC ONCOLOGY Fleming, G. F., Sill, M. W., Darcy, K. M., McMeekin, D. S., Thigpen, J. T., Adler, L. M., Berek, J. S., Chapman, J. A., Disilvestro, P. A., Horowitz, I. R., Fiorica, J. V. 2010; 116 (1): 15-20
Abstract

This study evaluated efficacy of single-agent trastuzumab against advanced or recurrent HER2-positive endometrial carcinoma (EC), and explored predictors for HER2 amplification.Eligible patients had measurable stage III, IV, or recurrent EC. There was no limit on prior therapy although total prior doxorubicin dose was limited to 320 mg/m(2). Tumors were required to have HER2 overexpression (2+ or 3+ immunohistochemical staining) or HER2 amplification (FISH HER2/CEP 17 ratio >2.0). Trastuzumab was administered intravenously at a dose of 4 mg/kg in week 1, then 2 mg/kg weekly until disease progression. The primary endpoint was tumor response.Of the 286 tumors centrally screened by LabCorp, 33 (11.5%) were HER2-amplified. Three of 8 clear (38%) cell carcinomas and 7 of 25 serous carcinomas (28%) screened exhibited HER2 amplification compared with 7% (2/29) of endometrioid adenocarcinomas. HER2 overexpression was correlated with HER2 amplification (r=0.459; p<0.0001). Thirty-four women were enrolled; 1 was excluded (refused treatment); and 18 had tumors with known HER2 amplification. No major tumor responses were observed. Twelve women experienced stable disease, 18 had increasing disease, and 3 were indeterminate for tumor response. Neither HER2 overexpression nor HER2 amplification appeared to be associated with progression-free survival or overall survival.Trastuzumab as a single agent did not demonstrate activity against endometrial carcinomas with HER2 overexpression or HER2 amplification, although full planned accrual of women with HER2 amplified tumors was not achieved due to slow recruitment. Serous and clear cell endometrial carcinomas appear to be more likely to demonstrate HER2 amplification.

View details for DOI 10.1016/j.ygyno.2009.09.025

View details for Web of Science ID 000273108700004

View details for PubMedID 19840887
Lymph Node-Positive Stage IIIC Ovarian Cancer A Separate Entity? International Symposium on Advanced Ovarian Cancer - Optimal Therapy Berek, J. S. LIPPINCOTT WILLIAMS & WILKINS. 2009: S18–S20
Abstract

Ovarian cancer spreads via the retroperitoneal lymphatics, and these lymph nodes frequently contain metastasis. A subset of patients whose disease was classified as stage IIIC has retroperitoneal lymph node metastases in the pelvic and/or para-aortic lymph nodes without intraperitoneal carcinomatosis and was upstaged from stage I to IIIB diseases based on these findings. Patients undergoing cytoreductive surgery for advanced-stage ovarian cancer undergo concomitant retroperitoneal lymphadenectomy in an effort to improve their survival.Stratification of patients with stage IIIC ovarian cancer by lymph node status and presence and extent of metastatic disease in the peritoneal cavity has been performed. Studies have determined the impact on disease-free and overall survivals of the resection of retroperitoneal lymph nodes as part of primary and secondary cytoreductive operations.The overall survival of patients with stage IIIC ovarian cancer based on retroperitoneal lymph node metastasis without peritoneal carcinomatosis is 58% to 84% compared with 18% to 36% for those with macroscopic peritoneal carcinomatosis. Although the performance of a pelvic and para-aortic lymphadenectomy in patients with stage IIIC to IV diseases has been reported to prolong survival, an international randomized study did not confirm this finding. Patients who undergo secondary resection of isolated recurrent lymph node metastasis have a better survival than those with more extensive recurrent disease.These data support the stratification of patients with stage IIIC ovarian cancer based on the finding of metastasis to the retroperitoneal lymph nodes without peritoneal carcinomatosis versus those who have peritoneal carcinomatosis. The International Federation of Gynecology and Obstetrics Committee should consider modifying the ovarian cancer staging system by further stratifying stage III disease. Although systematic lymphadenectomy during primary cytoreductive surgery does not appear to improve overall survival, resection of isolated lymph node metastasis and recurrences in lymph nodes may be associated with a survival benefit.

View details for DOI 10.1111/IGC.0b013e3181bf8111

View details for Web of Science ID 000273151800005

View details for PubMedID 19955908
Ovarian Conservation at the Time of Hysterectomy and Long-Term Health Outcomes in the Nurses' Health Study OBSTETRICS AND GYNECOLOGY Parker, W. H., Broder, M. S., Chang, E., Feskanich, D., Farquhar, C., Liu, Z., Shoupe, D., Berek, J. S., Hankinson, S., Manson, J. E. 2009; 113 (5): 1027-1037
Abstract

To report long-term health outcomes and mortality after oophorectomy or ovarian conservation.We conducted a prospective, observational study of 29,380 women participants of the Nurses' Health Study who had a hysterectomy for benign disease; 16,345 (55.6%) had hysterectomy with bilateral oophorectomy, and 13,035 (44.4%) had hysterectomy with ovarian conservation. We evaluated incident events or death due to coronary heart disease (CHD), stroke, breast cancer, ovarian cancer, lung cancer, colorectal cancer, total cancers, hip fracture, pulmonary embolus, and death from all causes.Over 24 years of follow-up, for women with hysterectomy and bilateral oophorectomy compared with ovarian conservation, the multivariable hazard ratios (HRs) were 1.12 (95% confidence interval [CI] 1.03-1.21) for total mortality, 1.17 (95% CI 1.02-1.35) for fatal plus nonfatal CHD, and 1.14 (95% CI 0.98-1.33) for stroke. Although the risks of breast (HR 0.75, 95% CI 0.68-0.84), ovarian (HR 0.04, 95% CI 0.01-0.09, number needed to treat=220), and total cancers (HR 0.90, 95% CI 0.84-0.96) decreased after oophorectomy, lung cancer incidence (HR=1.26, 95% CI 1.02-1.56, number needed to harm=190), and total cancer mortality (HR=1.17, 95% CI 1.04-1.32) increased. For those never having used estrogen therapy, bilateral oophorectomy before age 50 years was associated with an increased risk of all-cause mortality, CHD, and stroke. With an approximate 35-year life span after surgery, one additional death would be expected for every nine oophorectomies performed.Compared with ovarian conservation, bilateral oophorectomy at the time of hysterectomy for benign disease is associated with a decreased risk of breast and ovarian cancer but an increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung cancer. In no analysis or age group was oophorectomy associated with increased survival.

View details for Web of Science ID 000265451700009

View details for PubMedID 19384117
Survival After Second-Line Intraperitoneal Therapy for the Treatment of Epithelial Ovarian Cancer The Gynecologic Oncology Group Experience INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Markman, M., Brady, M., Hutson, A., Berek, J. S. 2009; 19 (2): 223-229
Abstract

To assess the association between patient-disease characteristics and overall survival (OS) after second-line intraperitoneal (IP) treatment of ovarian cancer.Data were aggregated from 7 Gynecologic Oncology Group (GOG) phase 2 studies conducted between 1988 and 1995 to evaluate IP therapy for partially responsive or recurrent disease but no tumor masses greater than 0.5 cm. Factors evaluated include age, performance status, extent of residual disease, tumor grade, and histologic diagnosis.A total of 432 eligible women were treated on 1 of the 7 second-line phase 2 IP trials. The median OS was 2.4 years (range of individual study medians, 1.9-2.9 years). Relative to women with grade 1 cancers, those with grade 2 or 3 cancers experienced 1.82 (95% confidence interval [CI], 1.21-2.74) and 2.02 (95% CI, 1.35-3.03) times greater instantaneous death rates, respectively, and those with clear cell adenocarcinoma experienced death rates 6.00 (95% CI, 3.27-10.9) times greater. The extent of residual disease, surgically assessed before starting study treatment, was also associated with OS. Relative to those who had no evidence of gross disease, those with gross disease that was completely resected, or with unresectable disease (not larger than 0.5 cm), experienced death rates 1.74 (95% CI, 1.25-2.42) and 2.26 (95% CI, 1.67-3.05) times greater, respectively.There are patient and disease characteristics strongly associated with survival after second-line IP treatments. These factors are relevant to clinicians considering IP therapy outside the investigative setting and for the development of future studies in this area.

View details for DOI 10.1111/IGC.0b013e31819bdc7e

View details for Web of Science ID 000266976400008

View details for PubMedID 19395997
Oregovomab Maintenance Monoimmunotherapy Does Not Improve Outcomes in Advanced Ovarian Cancer JOURNAL OF CLINICAL ONCOLOGY Berek, J., Taylor, P., McGuire, W., Smith, L. M., Schultes, B., Nicodemus, C. F. 2009; 27 (3): 418-425
Abstract

This phase III study tested the hypothesis that the CA-125-specific murine monoclonal antibody, oregovomab, administered as a monoimmunotherapy after front-line therapy in a selected ovarian cancer population would prolong time to relapse (TTR) and, ultimately, survival.Patients with stage III to IV ovarian cancer with preoperatively elevated CA-125 and objectively defined characteristics were randomly assigned 4 to 12 weeks after front-line carboplatin and paclitaxel chemotherapy to maintenance monoimmunotherapy in a fully blinded protocol. Two mg of oregovomab or placebo was infused over 20 minutes at weeks 0, 4, and 8 and then 12 weeks until recurrence or up to year 5. Patients were evaluated with serial imaging and clinical evaluation for evidence of recurrence at quarterly visits. TTR was the primary end point.Three hundred seventy-three patients were accrued at more than 60 centers; 251 patients were assigned to oregovomab and 120 patients were assigned to placebo. The treatment arms were well balanced. There were no differences in the clinical outcomes between treatment groups. Median TTR measured from randomization after completion of chemotherapy for the integrated study was 10.3 months (95% CI, 9.7 to 13.0 months) for oregovomab and 12.9 months (95% CI, 10.1 to 17.4 months) for placebo (P = .29, log-rank test). The treatment was well tolerated. Grade 3 to 4 toxicity was reported in 24.6% of patients in the placebo group and 20.1% of patients in the oregovomab group, respectively.Although oregovomab has demonstrated bioactivity, the strategy of monoimmunotherapy is not effective as maintenance therapy after front-line treatment of a favorable subset of patients with advanced ovarian cancer. Future studies of this or other tumor-antigen specific immunization strategies should seek ways to further augment induced immunity.

View details for DOI 10.1200/JCO.2008.17.8400

View details for Web of Science ID 000262499100017

View details for PubMedID 19075271
HER-2/neu targeting for recurrent vulvar Paget's disease A case report and literature review GYNECOLOGIC ONCOLOGY Karam, A., Berek, J. S., Stenson, A., Rao, J., Dorigo, O. 2008; 111 (3): 568-571
Abstract

The treatment of Paget's disease of the vulva particularly for recurrences can be challenging. Overexpression of the HER-2/neu protein has been found in about 30% of vulvar Paget's cases therefore presenting a potential therapeutic target.We report the case of a 52-year-old patient with persistent Paget's disease of the vulva despite eight surgical excisions over a 15-year period. Immunohistochemistry demonstrated overexpression of the HER-2/neu protein in the vulva resection specimen. Treatment with Trastuzumab resulted in a significant regression of her disease and resolution of symptoms.Based on our case report, therapeutic targeting of HER-2/neu for patients with Paget's disease of the vulva using for example Trastuzumab is a potentially effective, alternative approach, and warrants further investigation.

View details for DOI 10.1016/j.ygyno.2007.12.014

View details for Web of Science ID 000261758000037

View details for PubMedID 18252264
Opportunities and challenges in ovarian cancer research, a perspective from the 11th Ovarian cancer action/HHMT Forum, Lake Como, March 2007 GYNECOLOGIC ONCOLOGY Ashworth, A., Balkwill, F., Bast, R. C., Berek, J. S., Kaye, A., Boyd, J. A., Mills, G., Weinstein, J. N., Woolley, K., Workman, P. 2008; 108 (3): 652-657
Abstract

Advances in surgery and chemotherapy have improved the 5-year survival for patients with epithelial ovarian cancer, but have not impacted on the ultimate rate of cure in a disease that is diagnosed in late stage and that recurs in the majority of patients. "Omic" technologies promise to define genetically driven aberrant signaling pathways in malignant cells, provided that bioinformatic expertise can be focused on a cancer that is neither common nor rare. Molecular therapeutics must be linked to molecular diagnostics to permit individualized therapy. Not only epithelial cancer cells but also stroma, vasculature and the immune response must be targeted. Closer collaboration between academic institutions, biotech and pharma will be required to facilitate this process and to interest the private sector in an orphan disease. New preclinical models may permit more efficient development of drugs and siRNA that can target dormant drug resistant stem cells. Strategies must be developed to deal with the heterogeneity of different grades and histotypes. Identification of women at increased risk will facilitate prevention and early detection in subsets of patients. BRCA1/2 might be sequenced in all ovarian cancer patients to identify new kindreds. Epidemiologic algorithms are being developed and validated. Awareness must be raised that oral contraceptives can reduce risk of developing ovarian cancer by 50%. Early detection is likely to require panels of complementary biomarkers, analyzed by sophisticated statistical techniques, to improve sensitivity while maintaining extremely high specificity. As ovarian cancer becomes a chronic disease, greater emphasis will be placed on the challenges facing survivors.

View details for DOI 10.1016/j.ygyno.2007.11.014

View details for Web of Science ID 000253697500031

View details for PubMedID 18096210
Prognostic factors and risk of extrauterine metastases in 3867 women with grade 1 endometrioid corpus cancer AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Chan, J. K., Kapp, D. S., Cheung, M. K., Shin, J. Y., Stieglitz, D., Husain, A., Teng, N. N., Berek, J. S., Osann, K., Guo, H. 2008; 198 (2)
Abstract

The purpose of this study was to evaluate the role of surgical staging in patients with grade 1 endometrioid uterine cancer.Data were extracted from Surveillance, Epidemiology, and End Results Program from 1988 to 2001. Kaplan-Meier and Cox proportional hazards analyses were used to determine predictors for disease-specific survival.Twelve thousand seven hundred and twelve women were reported with endometrioid carcinoma, including 3867 with grade 1 disease, of which 25.5% had stage IC or more advanced disease, 15.4% with disease extending beyond the uterine corpus, 7.3% with extrauterine metastases, and 3.3% with lymph node metastases. On multivariate analysis, younger age and earlier stage remained as significant prognostic factors for improved survival.Since grade 1 endometrioid uterine cancers have a 15.4% risk of extrauterine spread, a complete surgical staging procedure is recommended when clinically feasible. Younger age and earlier stage are significant prognostic factors for improved survival.

View details for DOI 10.1016/j.ajog.2007.08.028

View details for Web of Science ID 000253587300026

View details for PubMedID 18226629
Her2neu over-expression and PI3kinase/Akt pathway activation in Paget's disease of the vulva. 55th Annual Meeting of the Society-for-Gynecologic-Investigation Stenson, A., Behjatnia, B., Shamonki, J., Rao, J., Karam, A., Berek, J., Dorigo, O. SAGE PUBLICATIONS INC. 2008: 307A–307A
View details for Web of Science ID 000253581600881
CA125 velocity at relapse is a highly significant predictor of survival post relapse: Results of a 5-year follow-up survey to a randomized placebo-controlled study of maintenance oregovomab immunotherapy in advanced ovarian cancer JOURNAL OF IMMUNOTHERAPY Berek, J. S., Taylor, P. T., Nicodemus, C. F. 2008; 31 (2): 207-214
Abstract

This report presents final survival survey results from a previously reported study using oregovomab immunotherapy in patients with advanced ovarian epithelial cancer. Follow-up surveys to 5 years from randomization were collected for the cohort of stage III/IV ovarian cancer patients achieving initial remission who received subsequent maintenance immunotherapy with oregovomab or placebo. The relationship of time-to-relapse, survival postrelapse, and overall survival was analyzed. One hundred forty-five patients in the intent-to-treat population and the hypothesis generating subset of 67 patients (debulked to < or =2 cm, CA125 < or =65 U/mL before cycle 3, normal CA125 and no evidence of disease postchemotherapy) previously reported were evaluated for long-term outcomes. Patterns of relapse and survival were consistent in both groups for the intent-to-treat population. Median survival time was 57.5 months for oregovomab and 48.6 months for placebo with an adjusted hazard ratio of 0.72 (95% confidence interval, 0.41-1.25). Median survival has not been reached in the hypothesis generating subset of patients receiving oregovomab. Cox multivariate regression analysis identified velocity of CA125 rise at relapse to be a highly statistically significant predictor of postrelapse outcome (P = 0.006). Although time-to-relapse may be a useful surrogate of survival in ovarian cancer immunotherapy studies, 5 years of follow-up has proved insufficient to permit a definitive survival analysis and it has been extended in ongoing phase III studies of oregovomab. Velocity of CA125 rise at relapse is a highly significant predictor of survival after relapse.

View details for Web of Science ID 000253433300010

View details for PubMedID 18481390
Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Ueda, S. M., Kapp, D. S., Cheung, M. K., Shin, J. Y., Osann, K., Husain, A., Teng, N. N., Berek, J. S., Chan, J. K. 2008; 198 (2)
Abstract

The purpose of this study was to determine factors responsible for the increasing number of deaths from corpus cancer over three time periods.Data were collected from the Surveillance, Epidemiology and End Results database from 1988-2001. Kaplan-Meier and Cox proportional hazards regression analyses were performed.Of 48,510 women with corpus cancer, there was an increase in the proportion of patients dying from advanced cancers (52.1% to 56.0% to 68.8%; P < .001), grade 3 disease (47.5% to 53.3% to 60.6%; P < .001), serous tumors (14.3% to 18.4% to 16.6%; P < .001), and sarcomas (19.1% to 20.4% to 27.2%; P < .001) over time. On multivariate analysis, older age, African American race, lack of primary staging procedures, advanced-stage, high-grade, and non-endometrioid histology were independent prognostic factors for worse survival.Our data suggest that the increase in mortality in women with corpus cancer over the last 14 years may be related to an increased rate of advanced-stage cancers and high-risk histologies.

View details for DOI 10.1016/j.ajog.2007.08.075

View details for Web of Science ID 000253587300027

View details for PubMedID 18226630
Elective oophorectomy in the gynecological patient: when is it desirable? CURRENT OPINION IN OBSTETRICS & GYNECOLOGY Parker, W. H., Shoupe, D., Broder, M. S., Liu, Z., Farquhar, C., Berek, J. S. 2007; 19 (4): 350-354
Abstract

Oophorectomy is electively performed in approximately 300,000 US women per year who are having hysterectomy for benign disease.New studies have suggested that elective oophorectomy may not be advisable for the majority of women, as it may lead to a higher risk of death from cardiovascular disease and hip fracture, and may result in a higher incidence of dementia and Parkinson's disease. Women with known BRCA 1/2 germ-line mutations clearly benefit from oophorectomy after childbearing.Prophylactic oophorectomy should be undertaken with caution in the majority of women with an average risk of ovarian cancer who are having a hysterectomy for benign disease.

View details for Web of Science ID 000248562000010

View details for PubMedID 17625417
Vulvar melanoma - A multivariable analysis of 644 patients OBSTETRICS AND GYNECOLOGY Sugiyama, V. E., Chan, J. K., Shin, J. Y., Berek, J. S., Osann, K., Kapp, D. S. 2007; 110 (2): 296-301
Abstract

To determine the prognostic factors associated with the survival of vulvar melanoma patients.Data were obtained from the Surveillance Epidemiology and End Results database from 1973 to 2003. Kaplan-Meier survival curves and Cox regression models were used for analysis.Of the 644 vulvar melanoma patients, the median age was 68 years. Of these 572 women were white, 28 were Hispanic, 18 were African-American, and 14 were Asian. A total of 302 had localized disease, 168 had regional disease, and 28 had distant disease. Of the participants who underwent surgical resection, 171 (26.6%) had conservative surgery, 164 (25.5%) had radical excision, and 241 (37.5%) had unspecified surgical resections. One hundred seventy-nine (27.8%) had lymph node resections, and 33 patients had concurrent radiation therapy. Nodal metastases were identified in 58 (9%) of the participants. The 5-year disease-specific survival rates for those with localized, regional, and distant disease were 75.5%, 38.7%, and 22.1%, respectively (P<.001). Women aged 68 years or younger had a better survival rate than older patients (72.0% compared with 47.7%; P<.001). Those with 0, 1, and 2 or more positive lymph nodes had survival rates of 68.3%, 29%, and 19.5%, respectively (P<.001). In a multivariable analysis, younger age, localized disease, and negative lymph nodes were independent prognostic factors for improved survival.Age, stage, and lymph node involvement were significant factors for survival in vulvar melanoma.III.

View details for Web of Science ID 000248290500011

View details for PubMedID 17666603
Impact of the human papilloma vaccine on cervical cancer JOURNAL OF CLINICAL ONCOLOGY Chan, J. K., Berek, J. S. 2007; 25 (20): 2975-2982
Abstract

During the last decade, research progress on cervical cancer has elucidated the role of human papilloma virus (HPV) in the pathogenesis of cervical cancer. Clinical trials on the viral-like particle HPV vaccines have good safety profiles and promising efficacy in preventing genital warts, cervical neoplasia, and cervical cancer. The implementation of the HPV vaccine is a tremendous milestone in our effort toward preventing cervical cancers. However, screening programs will continue to serve as a critical component in prevention due to the limitations of the current vaccines. The greatest impact in cervical cancer incidence worldwide requires improved health care access to underserved areas. Advances are needed to develop single-dose, heat-stable, needle-free, and affordable formulations of the HPV vaccine to overcome the socioeconomic barriers associated with this disease.

View details for DOI 10.1200/JCO.2007.10.8662

View details for Web of Science ID 000247928400014

View details for PubMedID 17617529
The potential therapeutic role of lymph node resection in epithelial ovarian cancer: a study of 13,918 patients BRITISH JOURNAL OF CANCER Chan, J. K., Urban, R., Hu, J. M., Shin, J. Y., Husain, A., Teng, N. N., Berek, J. S., Osann, K., Kapp, D. S. 2007; 96 (12): 1817-1822
Abstract

The aim of the study is to determine the role of lymphadenectomy in advanced epithelial ovarian cancer. The data were obtained from the Surveillance, Epidemiology and End Results (SEER) program reported between 1988 and 2001. Kaplan-Meier estimates and Cox proportional hazards regression models were used for analysis. Of 13 918 women with stage III-IV epithelial ovarian cancer (median age: 64 years), 87.9% were Caucasian, 5.6% African Americans, and 4.4% Asians. A total of 4260 (30.6%) underwent lymph node dissections with a median number of six nodes reported. For all patients, a more extensive lymph node dissection (0, 1, 2-5, 6-10, 11-20, and >20 nodes) was associated with an improved 5-year disease-specific survival of 26.1, 35.2, 42.6, 48.4, 47.5, and 47.8%, respectively (P<0.001). Of the stage IIIC patients with nodal metastases, the extent of nodal resection (1, 2-5, 6-10, 11-20, and >20 nodes) was associated with improved survivals of 36.9, 45.0, 47.8, 48.7, and 51.1%, respectively (P=0.023). On multivariate analysis, the extent of lymph node dissection and number of positive nodes were significant independent prognosticators after adjusting for age, year at diagnosis, stage, and grade of disease. The extent of lymphadenectomy is associated with an improved disease-specific survival of women with advanced epithelial ovarian cancer.

View details for DOI 10.1038/sj.bjc.6603803

View details for Web of Science ID 000247218100007

View details for PubMedID 17519907
Lymphadenectomy in endometrioid uterine cancer staging - How many lymph nodes are enough? A study of 11,443 patients CANCER Chan, J. K., Urban, R., Cheung, M. K., Shin, J. Y., Husain, A., Teng, N. N., Berek, J. S., Walker, J. L., Kapp, D. S., Osann, K. 2007; 109 (12): 2454-2460
Abstract

The purpose of the current study was investigate the association between the number of lymph nodes examined and the probability of detecting at least a single lymph node involved by metastatic disease in patients with endometrioid corpus cancer.Demographic, clinicopathologic, and surgical information were obtained from the National Cancer Institute between 1990 and 2001. A logistic regression model was used to investigate the relation between the number of lymph nodes identified and the probability of detecting at least a single positive lymph node.Of 11,443 patients, the median age was 64 years (range, 22-74 years). In all, 78.7% had stage I disease, 10.3% had stage II disease, and 11.0% had stage III disease; 31.5% had grade 1 histology, 40.6% had grade 2 histology, and 24.3% had grade 3 histology. The median number of lymph nodes reported was 9 (range, 1-90 lymph nodes). The median number of lymph nodes and the percent of patients with positive lymph nodes have increased from 1988 to 2001. An increasing number of lymph nodes removed was associated with a higher likelihood of identifying those with lymph node metastases. Based on the logistic regression model, the largest increase in probability of detecting at least a single positive lymph node was observed when 21 to 25 lymph nodes were resected (odds ratio [OR] of 1.45; 95% confidence interval [95% CI], 1.08-1.94 [P < .01]). Removing greater than 25 lymph nodes did not improve the statistical probability (OR of 1.23; 95% CI, 0.94-1.61 [P = .13]).The current study data suggest that the removal of 21 to 25 lymph nodes significantly increases the probability of detecting at least 1 positive lymph node in endometrioid uterine cancer. The definition of an adequate lymphadenectomy deserves further investigation.

View details for DOI 10.1002/cncr.22727

View details for Web of Science ID 000247113500009

View details for PubMedID 17503431
Influence of the gynecologic oncologist on the survival of ovarian cancer patients OBSTETRICS AND GYNECOLOGY Chan, J. K., Kapp, D. S., Shin, J. Y., Husain, A., Teng, N. N., Berek, J. S., Osann, K., Leiserowitz, G. S., Cress, R. D., O'Malley, C. 2007; 109 (6): 1342-1350
Abstract

To estimate the influence of gynecologic oncologists on the treatment and outcome of patients with ovarian cancer.Data were obtained from California Cancer Registry from 1994 to 1996. Kaplan-Meier and Cox proportional hazard methods were used for analyses.Of 1,491 patients, the median age was 65 years (range: 13-100). Only 34.1% received care by gynecologic oncologists (group A) while 65.9% were treated by others (group B). Women in group A were more affluent (P<.001), were more educated (P=.036), were classified as white-collar employees (P=.128), and lived in urban regions (P<.001) compared with group B. Patients who saw gynecologic oncologists were more likely to have surgery as their initial treatment (91.9% versus 69.1%; P<.001), present with advanced (stage III-IV) cancers (78.2% versus 70.5%; P<.001), have more grade 3 tumors (61.7% versus 39.9%; P=.048), and receive chemotherapy (90.0% versus 70.1%; P<.001). Women in group B had a fourfold higher risk of having unstaged cancers (8.0% versus 2.1%; P<.001). The 5-year disease-specific survival of group A patients was 38.6% compared with 30.3% in group B (P<.001). On multivariable analysis, early stage, lower grade, and treatment by gynecologic oncologists were independent prognostic factors for improved survival. After adjusting for surgery and chemotherapy, there was no improvement in survival associated with care by gynecologic oncologists (hazard ratio=0.90, 95% confidence interval 0.78-1.03; P=.133).In this study of 1,491 women, those who were treated by gynecologic oncologists were more likely to undergo primary staging surgery and receive chemotherapy. Stage, grade of disease, and treatment by gynecologic oncologists were important prognosticators.

View details for Web of Science ID 000247010200013

View details for PubMedID 17540806
Ovarian conservation at the time of hysterectomy for benign disease CLINICAL OBSTETRICS AND GYNECOLOGY Parker, W. H., Broder, M. S., Liu, Z., Shoupe, D., Farquhar, C., Berek, J. S. 2007; 50 (2): 354-361
Abstract

Approximately 78% of women between the ages of 45 and 64 years have prophylactic oophorectomy when hysterectomy is performed for benign disease to prevent the development of ovarian cancer. However, after menopause, the ovary continues to produce androstenedione and testosterone in significant amounts and these androgens are converted in fat, muscle, and skin into estrone. Evidence suggests that oophorectomy increases the subsequent risk of coronary heart disease (CHD) and osteoporosis and whereas 14,000 women die of ovarian cancer every year nearly 490,000 women die of heart disease and 48,000 women die within 1 year after hip fracture. PubMed and the Cochrane database were used to identify studies that examined the incidence of disease and mortality from 5 conditions that seem to be related to ovarian hormones: CHD, ovarian cancer, breast cancer, stroke and hip fracture, and also data for death from all other causes. The data were applied to a Markov decision analytic computer model to calculate risk estimates for mortality from these conditions until the age of 80. The model shows for a hypothetical cohort of 10,000 women undergoing hysterectomy and who chose oophorectomy (vs. ovarian conservation) between the ages of 50 and 54 [without estrogen therapy(ET)], that by the time they reach age 80, 47 fewer women will have died from ovarian cancer, but 838 more women will have died from CHD and 158 more will have died from hip fracture. Therefore, the decision to perform prophylactic oophorectomy should be approached with great caution for the majority of women who are at low risk of developing ovarian cancer.

View details for Web of Science ID 000246780100004

View details for PubMedID 17513923
Elective oophorectomy for benign gynecological disorders MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Shoupe, D., Parker, W. H., Broder, M. S., Liu, Z., Farquhar, C., Berek, J. S. 2007; 14 (3): 580-585
Abstract

To review the risks and benefits of elective oophorectomy and to make a clinical recommendation for an appropriate age when benefits of this procedure outweigh the risks.The risks and benefits of oophorectomy as detailed in published articles are reviewed with regard to quality-of-life issues and mortality outcomes in oophorectomized versus non-oophorectomized women from five diseases linked to ovarian hormones (coronary heart disease, ovarian cancer, breast cancer, stroke, and hip fracture).Numerous reports link oophorectomy to higher rates of cardiovascular disease, osteoporosis, hip fractures, dementia, short-term memory impairment, decline in sexual function, decreased positive psychological well-being, adverse skin and body composition changes, and adverse ocular changes, as well as more severe hot flushes and urogenital atrophy. The potential benefits associated with oophorectomy include prevention of ovarian cancer, a decline in breast cancer risk, and a reduced risk of pelvic pain and subsequent ovarian surgery. In our study of long-term mortality after oophorectomy using Markov modeling, preservation of ovaries until women are at least aged 65 years was associated with higher survival rates. For women between ages 50 and 54 with hysterectomy and ovarian preservation, the probability of surviving to age 80 was 62% versus 54% if oophorectomy was performed. This 8% difference in survival is primarily due to fewer women dying from cardiovascular heart disease and/or hip fracture. This survival advantage far outweighs the 0.47% increased mortality rate from ovarian cancer prevented by oophorectomy. If surgery occurred between ages 55 and 59, the survival advantage was 4%. After age 64 there were no significant differences in survival rates. Prior literature supports our conclusion of a benefit over risk for ovarian conservation.Elective oophorectomy is associated with short-and long-term health consequences that merit serious consideration. For women with an average risk of ovarian cancer, ovarian conservation until at least age 65 seems to benefit long-term survival.

View details for DOI 10.1097/gme.0b013e31803c56a4

View details for Web of Science ID 000246374700006

View details for PubMedID 17476148
Association of lymphadenectomy and survival in stage I ovarian cancer patients - In reply OBSTETRICS AND GYNECOLOGY Chan, J. K., Munro, E., Cheung, M., Husain, A., Teng, N. N., Berek, J. S., Osann, K. 2007; 109 (4): 1000-1001
View details for Web of Science ID 000248384500032
Prognostic factors for uterine cancer in reproductive-aged women OBSTETRICS AND GYNECOLOGY Lee, N. K., Cheung, M. K., Shin, J. Y., Husain, A., Teng, N. N., Berek, J. S., Kapp, D. S., Sann, K., Chan, J. K. 2007; 109 (3): 655-662
Abstract

To determine the prognostic factors that influence the survival of younger women diagnosed with uterine cancer.Demographic and clinico-pathologic data were collected from the National Cancer Institute database between 1988 and 2001. Data were analyzed with Kaplan-Meier methods and Cox proportional hazards regression.Of the 51,471 women diagnosed with uterine cancer in the study period, 2,076 (4.0%) patients were aged 40 years or younger, and 49,395 (96.0%) were older than 40. The mean age in the younger group was 35.6 years, compared with 65.2 years of the older group. The overall distribution by stage was stage I 75.4%, II 8.1%, III 6.7%, and IV 9.8%. Younger patients were more likely to be nonwhite (42.4% versus 18.3%, P<.001) and have stage I disease (79.2% versus 75.3%, P<.001), grade 1 lesions (47.6% versus 35.6%, P<.001), and sarcomas (15.9% versus 8.2%, P<.001) compared with their older counterparts. The overall 5-year disease-specific survival for younger patients was significantly better than that of older women (93.2% versus 86.4%, P<.001). On multivariable analysis, younger age, earlier stage, lower grade, nonblack race, endometrioid histology, and surgical treatment remained as significant independent prognostic factors for improved survival.This large population-based study demonstrates that patients 40 years and younger have an overall survival advantage compared with women older than 40 years, independent of other clinico-pathologic prognosticators.III.

View details for Web of Science ID 000246771200011

View details for PubMedID 17329517
A multivariate analysis of vulvar melanomas: A study of 359 patients Sugiyama, V. E., Shin, J. Y., Osann, K., Kapp, D. S., Husain, A., Teng, N. N., Berek, J. S., Chan, J. K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: S5–S6
View details for Web of Science ID 000244834100010
Racial disparities in the surgical treatment of epithelial ovarian cancer in the United States Chan, J. K., Zhang, M., Hu, J., Shin, J. Y., Husain, A., Teng, N. N., Berek, J. S., Kapp, D. S., Osann, K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: S31–S31
View details for Web of Science ID 000244834100065
Factors responsible for the increase in death rate of women diagnosed with uterine corpus cancer Ueda, S. M., Cheung, M. K., Osann, K., Husain, A., Teng, N. N., Berek, J. S., Kapp, D. S., Chan, J. K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: S8–S8
View details for Web of Science ID 000244834100015
Access to gynecologic oncologists and its impact on survival of women with epithelial ovarian cancer Chan, J. K., Shin, J. Y., Husain, A., Teng, N. N., Berek, J. S., Kapp, D. S., Osann, K., Leiserowitz, G., O'Malley, C. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2007: S23–S23
View details for Web of Science ID 000244834100047
CA125: Megadaltons of novel opportunities GYNECOLOGIC ONCOLOGY Dorigo, O., Berek, J. S. 2007; 104 (3): 505-507
View details for DOI 10.1016/j.ygyno.2007.01.035

View details for Web of Science ID 000244796500001

View details for PubMedID 17306691
Prognostic factors responsible for survival in sex cord stromal tumors of the ovary- An analysis of 376 women GYNECOLOGIC ONCOLOGY Zhang, M., Cheung, M. K., Shin, J. Y., Kapp, D. S., Husain, A., Teng, N. N., Berek, J. S., Osann, K., Chan, J. K. 2007; 104 (2): 396-400
Abstract

To evaluate prognostic factors that impact on the survival of women with ovarian sex cord stromal tumors (SCST).Data including age at diagnosis, stage, histology, grade, treatment, and survival were extracted from the 1988-2001 Surveillance, Epidemiology, and End Results Program. Kaplan-Meier and Cox proportional hazards analyses were used to determine the predictors for survival.376 women (median age: 51) with ovarian sex cord stromal cell tumors were identified, including 339 with granulosa cell and 37 with Sertoli-Leydig cell tumors. 265 (71%) patients had stage I, 39 (10%) stage II, 40 (11%) stage III, and 32 (8%) had stage IV disease. Women with stage I-II disease had a 5-year disease-specific survival of 95% compared to 59% in those with stage III-IV cancers (p<0.001). Patients50 years (93% vs. 84%, p<0.001). This age-associated survival advantage was observed for early (97% vs. 92%, p=0.003), but not for advanced-staged (68% vs. 53%, p=0.09) patients. 110 patients with stage I-II disease underwent conservative surgery without hysterectomy. The survival for this group was similar to patients who underwent a standard surgery including a hysterectomy (94.8% and 94.9%, p=0.38). On multivariate analysis, age
View details for DOI 10.1016/j.ygyno.2006.08.032

View details for Web of Science ID 000244101200021

View details for PubMedID 17030354
Association of lymphadenectomy and survival in stage I ovarian cancer patients OBSTETRICS AND GYNECOLOGY Chan, J. K., Munro, E. G., Cheung, M. K., Husain, A., Teng, N. N., Berek, J. S., Osann, K. 2007; 109 (1): 12-19
Abstract

To estimate the survival impact of lymphadenectomy in women diagnosed with clinical stage I ovarian cancer.Demographic and clinicopathologic information were obtained from the Surveillance, Epidemiology and End Results Program between 1988 and 2001. Data were analyzed using Kaplan-Meier methods and Cox proportional hazards regression.A total of 6,686 women had clinical stage I ovarian cancer (median age 54 years, range 1-99). Of this total, 75.9% of patients were Caucasian, 8.3% were Hispanic, 5.8% were African American, and 7.3% were Asian. Epithelial tumors were present in 85.8% of the women, and 2,862 (42.8%) patients underwent lymphadenectomy. Patients aged 50 years or more were less likely to undergo lymphadenectomy compared with their younger cohorts (39.8% compared with 60.2%, P<.001). Only 32.7% of African-American women had lymphadenectomy compared with 42.7% of Caucasian women, 47.2% of Hispanics, and 48.8% of Asians (P<.001). Lymphadenectomy was associated with improved 5-year disease-specific survival of all patients from 87.0% to 92.6% (P<.001). More specifically, lymphadenectomy improved the survival in those with non-clear cell epithelial ovarian cancer (85.9% to 93.3%, P<.001) but not in those with clear cell carcinoma, germ cell tumors, sex cord stromal tumors, and sarcomas. Moreover, the extent of lymphadenectomy (0 nodes, less than 10 nodes, and 10 or more nodes) increased the survival rates from 87.0% to 91.9% to 93.8%, respectively (P<.001). On multivariable analysis, the extent of lymphadenectomy was a significant prognostic factor for improved survival, independently of other factors such as age, stage, histology, and grade of disease.Our data suggest that women with stage I non-clear cell ovarian cancers who underwent lymphadenectomy had a significant improvement in survival.II.

View details for Web of Science ID 000246771500003

View details for PubMedID 17197582
The benefit of adjuvant radiation therapy in single-node-positive squamous cell vulvar carcinoma GYNECOLOGIC ONCOLOGY Parthasarathy, A., Cheung, M. K., Osann, K., Husain, A., Teng, N. N., Berek, J. S., Kapp, D. S., Chan, J. K. 2006; 103 (3): 1095-1099
Abstract

To determine if adjuvant radiotherapy improves the survival of women with invasive squamous cell carcinoma of the vulva involving one inguinal node.Demographic, pathologic, and treatment information was obtained on patients with vulvar cancers from the Surveillance, Epidemiology, and End Results database between 1988 and 2001. Kaplan-Meier estimates and Cox-proportional hazards model were used for analyses.Of the 490 patients with stage III, node-positive vulvar cancers, 208 had a single positive inguinal node. The median age of this group was 71 years (range: 29-100). 82.2% of patients were White, 7.2% were Hispanic, 7.7% were Black, 1.4% were Asian, and 1.4% were Others. 91.8% of patients underwent a radical vulvectomy with a unilateral or bilateral inguinal lymphadenectomy. The median number of lymph nodes resected was 13 (range: 1-34). 102 women underwent adjuvant radiotherapy, while 106 did not receive any radiation treatment. Women who received adjuvant radiotherapy had a 5-year disease-specific survival of 77.0% compared to 61.2% in those without radiotherapy (p=0.02). After stratifying the study group based on the extent of lymphadenectomy, we found that radiation treatment improved the survival of those with
View details for DOI 10.1016/j.ygyno.2006.06.030

View details for Web of Science ID 000242809500053

View details for PubMedID 16889821
Ovarian cancer in younger vs older women: a population-based analysis BRITISH JOURNAL OF CANCER Chan, J. K., Urban, R., Cheung, M. K., Osann, K., Husain, A., Teng, N. N., Kapp, D. S., Berek, J. S., Leiserowitz, G. S. 2006; 95 (10): 1314-1320
Abstract

To compare the clinico-pathologic prognostic factors and survival of younger vs older women diagnosed with epithelial ovarian cancer. Demographic, clinico-pathologic, treatment, and surgery information were obtained from patients with ovarian cancer from the Surveillance, Epidemiology, and End Results Program from 1988 to 2001 and analysed using Kaplan-Meier estimates. Of 28 165 patients, 400 were <30 years (very young), 11 601 were 30-60 (young), and 16 164 were >60 (older) years of age. Of the very young, young, and older patients, 261 (65.3%), 4664 (40.2%), and 3643 (22.5%) had stage I-II disease, respectively (P<0.001). Across all stages, very young women had a significant survival advantage over the young and older groups with 5-year disease-specific survival estimates at 78.8% vs 58.8 and 35.3%, respectively (P<0.001). This survival difference between the age groups persists even after adjusting for race, stage, grade, and surgical treatment. Reproductive age (16-40 years) women with stage I-II epithelial ovarian cancer who received uterine-sparing procedures had similar survivals compared to those who underwent standard surgery (93.3% vs 91.5%, P=0.26). Younger women with epithelial ovarian cancer have a survival advantage compared to older patients.

View details for DOI 10.1038/sj.bjc.6603457

View details for Web of Science ID 000242046700002

View details for PubMedID 17088903
Response to commentaries on retention of the ovaries and long-term survival after hysterectomy CLIMACTERIC Parker, W. H., Broder, M. S., Liu, Z., Shoupe, D., Farquhar, C., Berek, J. S. 2006; 9 (5): 396-398
View details for DOI 10.1080/13697130600967646

View details for Web of Science ID 000241677900010

View details for PubMedID 17000587
Patterns and progress in ovarian cancer over 14 years OBSTETRICS AND GYNECOLOGY Chan, J. K., Cheung, M. K., Husain, A., Teng, N. N., West, D., Whittemore, A. S., Berek, J. S., Osann, K. 2006; 108 (3): 521-528
Abstract

To estimate the change in survival rates of women with ovarian cancer during the past 14 years.Women diagnosed with epithelial, germ cell, sarcomas, and sex-cord stromal ovarian tumors were identified from the Surveillance Epidemiology and End Results Database. Demographic and clinicopathologic factors, and survival information were extracted and tested using chi 2 and Kaplan-Meier and Cox regression analyses.A total of 30,246 women were diagnosed with ovarian cancer, including 26,753 non-clear cell epithelial, 1,411 clear cell, 818 sarcoma, 778 germ cell, and 486 sex-cord stromal tumors. The 5-year disease-specific survival rate across 1988-1992 and 1993-1997 improved from 45.4% to 48.6% (P < .001). The corresponding estimates show increases for non-clear cell epithelial carcinoma from 42.5% to 45.8% (P < .001), and for sarcomas from 33.5% to 38.8% (P = .07). However, improvements were not observed in those with clear cell, 64.3% to 63.9% (P = .82), and sex-cord stromal, 89.7% to 85.7% (P = .18), tumors of the ovary. In multivariable analyses, younger age, early stage, favorable histologic cell types, low-grade tumors, standard surgery, and recent time interval from 1993-1997 were independent prognostic factors for improved survival.In this large population-based study, there has been some improvement in the overall survival of women with ovarian cancers during a 14-year period. However, new treatment strategies are warranted for those with epithelial cancer and sarcomas of the ovary, given their overall poor prognosis. These results from our updated analyses might help to counsel women diagnosed with ovarian cancers.

View details for Web of Science ID 000246769000008

View details for PubMedID 16946210
Intraperitoneal chemotherapy for ovarian cancer CURRENT OPINION IN ONCOLOGY Hamilton, C. A., Berek, J. S. 2006; 18 (5): 507-515
Abstract

Intraperitoneal chemotherapy for ovarian cancer is based on sound pharmacological principles and is technically feasible. There is mounting evidence, bolstered by a recent randomized trial, that in certain patients, this route of delivery may be superior to traditional intravenous chemotherapy. This review explores the background and pharmacokinetic principles of intraperitoneal chemotherapy, the recent evidence supporting an intraperitoneal approach, and some of the logistical and technical challenges involved.Intraperitoneal chemotherapy has been evaluated in several settings. Most phase I and II data came from second-line treatment of ovarian cancer, and there have been a few series, including one recent phase III trial, exploring intraperitoneal consolidation. The greatest impact among recent studies will be from a large, intergroup phase III trial evaluating intraperitoneal therapy in the front-line setting. This study will probably change the dialogue of standard treatment for optimally cytoreduced, advanced epithelial ovarian cancer.Based on recent findings, intraperitoneal chemotherapy should be considered for the front-line treatment of women with minimal residual advanced ovarian cancer. Efforts should continue to facilitate the integration of intraperitoneal treatment into mainstream practice, and future trials should be designed to address lingering controversy surrounding this route of treatment.

View details for Web of Science ID 000240160400016

View details for PubMedID 16894301
The number of lymph nodes with metastatic disease portends for a poorer prognosis in women with stage IIIC-IV endometrioid uterine cancer. 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Chan, J. K., Cheung, M. K., Osann, K., Husain, A., Teng, N. N., Berek, J. S., Kapp, D. S. AMER SOC CLINICAL ONCOLOGY. 2006: 265S–265S
View details for Web of Science ID 000239009401494
The. role of extensive lymphadenectomy in stage I ovarian cancer. 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Munro, E. G., Lee, N. K., Cheung, M. K., Osann, K., Husain, A., Teng, N. N., Kapp, D. S., Berek, J. S., Chan, J. K. AMER SOC CLINICAL ONCOLOGY. 2006: 272S–272S
View details for Web of Science ID 000239009401523
The impact of lymphadenectomy in women with endometrioid uterine cancer: A study of 39,396 women. 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Lee, N. K., Wu, H., Cheung, M. K., Osann, K., Husain, A., Teng, N. N., Berek, J. S., Kapp, D. S., Chan, J. K. AMER SOC CLINICAL ONCOLOGY. 2006: 256S–256S
View details for Web of Science ID 000239009401456
The role of surgical staging in grade 1 endometrioid corpus cancer. 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Chan, J. K., Guo, H., Cheung, M. K., Osann, K., Husain, A., Teng, N. N., Berek, J. S., Kapp, D. S. AMER SOC CLINICAL ONCOLOGY. 2006: 258S–258S
View details for Web of Science ID 000239009401464
Surgery for ovarian cancer: how to improve survival LANCET Bristow, R. E., Berek, J. S. 2006; 367 (9522): 1558-1560
View details for Web of Science ID 000237598000008

View details for PubMedID 16698396
10th Biennial Helene Harris Memorial Trust Meeting CANCER RESEARCH Balkwill, F. R., Ashworth, A., Bast, R. C., Berek, J. S., Boyd, J., Disis, M. L., Gabra, H., Gore, M. E., HAMILTON, T. C., Jacobs, I. J., Kaye, S. B., Kohn, E. C., Mills, G. B., Urban, N. D. 2006; 66 (6): 2904-2906
Abstract

Improving the prognosis of ovarian cancer patients is a major challenge to scientists and clinicians. At a recent multidisciplinary meeting in Washington DC, advances in identification of precursor lesions, progress in disease biomarkers and animal models, the promise of nanotechnology, and strategies for manipulation of the innate and adaptive immune response offered prospects for real progress in this difficult-to-treat disease.

View details for DOI 10.1158/0008-5472.CAN-05-2093

View details for Web of Science ID 000236093500005

View details for PubMedID 16540635
Progress in ovarian cancer research: Proceedings of the 5th biennial ovarian cancer research symposium INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Disis, M. L., Rivkin, S. E., Baron, A., Markman, M., Connolly, D., Ueland, F., Kohn, E., Trimble, E., Berek, J. S. 2006; 16 (2): 463-469
Abstract

Ovarian cancer remains the most lethal gynecological malignancy. The 5th Biennial Symposium overviewed the progress of ovarian cancer research over the last few years. Molecularly based technologies have allowed the identification of multiple biomarkers to aid in ovarian cancer diagnosis and treatment. Furthermore, data analysis systems evaluating the behavior of these markers have been designed. Therapeutic use of ovarian cancer protein markers has been fueled by the development of animal models that more closely simulate the pathogenesis of ovarian cancer, and multiple new therapies are being developed that may have impact against the disease. Finally, the design of clinical trials both for ovarian cancer treatment and prevention are key in advancing the science of ovarian cancer into the clinic. The need for strategies that would optimize patient participation in clinical trials is paramount.

View details for Web of Science ID 000236943200001

View details for PubMedID 16681712
An analysis of surgical versus chemotherapeutic intervention for the management of intestinal obstruction in advanced ovarian cancer INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Bryan, D. N., Radbod, R., Berek, J. S. 2006; 16 (1): 125-134
Abstract

The objective of this study was to compare the treatment outcomes of surgical versus chemotherapeutic interventions for the management of intestinal obstruction secondary to metastatic epithelial ovarian cancer. A retrospective analysis of 39 patients with epithelial ovarian cancer who had 98 events of intestinal obstruction was performed. A medical records review of patients treated for advanced ovarian cancer from 1973 to 2003 was conducted. Time from treatment to obstruction, complications, and predictors of outcome were analyzed. Mean time from diagnosis of cancer to first obstruction was 38 months (range, 7-234 months). Of 39 patients with obstruction, 5% were stage I, 2% stage II, 85% stage III, and 8% stage IV. Prior to first obstruction, the median number of prior surgeries was 2 and chemotherapy regimens 3. Sites of the 98 events of obstruction were small intestine, 79 (81%); large intestine, 8 (8%); and combined small and large intestines, 11 (11%). The mean time to re-obstruction was 6.4 months (0-24) for chemotherapy, 5.1 months (0-40) for surgery, and 1.9 months (0-15) for supportive care. The mean hospital stays were 7 days (2-10) for chemotherapy, 18 days (3-50) for surgery, and 7 days (0-20) for supportive care. There were 4 major complications in the chemotherapy patients, 11 in the surgical patients, and 2 in the supportive only patients. The only significant factor predictive of > or =6 month obstruction-free period was prior response to platinum-based chemotherapy. Of the 13 patients with a response to chemotherapeutic or surgical treatment, 46% had an initial response to platinum-based chemotherapy, while 27% of 22 patients who re-obstructed in <6 months were platinum sensitive. In this retrospective analysis of selected patients, surgery and chemotherapy were found to have similar outcomes. The surgical approach had higher morbidity. The best predictor of either treatment's effectiveness is tumor sensitivity to platinum-based chemotherapeutic agents (P= 0.168).

View details for Web of Science ID 000234800100021

View details for PubMedID 16445622
Pelvic exenteration for recurrent gynecologic malignancy: Survival and morbidity analysis of the 45-year experience at UCLA GYNECOLOGIC ONCOLOGY Berek, J. S., Howe, C., Lagasse, L. D., Hacker, N. F. 2005; 99 (1): 153-159
Abstract

To retrospectively assess the outcome of patients undergoing pelvic exenteration for recurrent or persistence gynecologic malignancy and the clinical features associated with outcome and survival.A review was conducted of patients who underwent pelvic exenteration over a 45-year period (1956-2001) at the UCLA Medical Center. Numerous clinical variables were analyzed, including time to relapse, type of exenteration and reconstructive operation, early (<60 days) and late (>60 days) morbidity, and survival. Variables were analyzed by chi-square and life-table analysis.Seventy-five patients (ages 26-74 years) had persistent cervical and vaginal (67) and uterine (8) cancer. Forty-six patients underwent total exenteration, 23 anterior, and 6 posterior. Sixty-nine (92%) patients underwent urinary diversion or neocystoplasty, 54 (72%) patients had a simultaneous neovagina created, and 43 of 52 (83%) patients who had a low colon resection had a primary reanastomosis. Twenty-nine patients died from recurrent malignancy, 28 were alive without disease, 11 were alive with disease, and 7 died from other causes at last follow-up. Survival for patients with cervical and vaginal cancer was 73% at 1 year, 57% at 3 years, and 54% at 5 years. Survival for patients with uterine cancer was 86% at 1 year, 62% at 3 and 5 years. The most frequent early morbidity was urinary tract infection, wound infection, and intestinal fistula; the most frequent late morbidity was urinary tract infection and intestinal obstruction.Pelvic exenteration in patients with recurrent cervical and vaginal malignancy is associated with a durable > 50% 5-year survival. Simultaneously performed pelvic reconstructive operations with a continent urinary diversion, the creation of a neovagina, and the reanastomosis of the colon with the formation of a J-pouch is now our standard; and these operations tend to improve the outcome of patients. Based on our initial experience, recurrent uterine corpus cancer in young women (< 55 years) should be included as an indication for the surgery.

View details for DOI 10.1016/j.ygyno.2005.05.034

View details for Web of Science ID 000232449300023

View details for PubMedID 16054678
Design, conduct and evaluation of a communication course for oncology fellows JOURNAL OF CANCER EDUCATION Lenzi, R., Baile, W. F., Berek, J., Back, A., Buckman, R., Cohen, L., Parker, P. A. 2005; 20 (3): 143-149
Abstract

Training in the communication components of cancer care is necessary for the practice of oncology. We conducted a communication course for oncology fellows.Teaching methods included lectures, role playing and simulated patient interviews. We used self-reports, knowledge questionnaires and course/faculty evaluations.A total of 17 fellows participated. Skills in dealing with bad news, denial and end-of-life issues improved. We obtained information on communication tasks commonly performed during patient interactions, various aspects of the course and faculty performance.Fellows' knowledge and self-efficacy improved postcourse. Information on challenges faced by trainees and their feedback may help focus the design of future courses.

View details for Web of Science ID 000231684800004

View details for PubMedID 16122361
Lower urinary tract reconstruction with ileum in. the treatment of gynecologic malignancies GYNECOLOGIC ONCOLOGY Elkas, J. C., Berek, J. S., Leuchter, R., Lagasse, L. D., Karlan, B. Y. 2005; 97 (2): 685-692
Abstract

Advanced or recurrent gynecologic malignancies can invade or obstruct the lower urinary tract. If extirpation is necessary for cytoreduction or repair of radiation sequelae, treatment has typically involved creation of either an ileal conduit or a cutaneous continent urinary diversion. As an alternative, a more limited resection with urinary tract reconstruction using ileum for interposition or augmentation may allow for the preservation of urethral voiding.We describe the use of ileal segments for lower urinary tract reconstruction in the treatment of ten patients with advanced or recurrent gynecologic malignancies. The clinical history, surgical technique, and patient outcomes are reviewed.These cases demonstrate that limited bladder or ureteral resection with reconstruction using ileal segments may offer select patients preservation of urethral voiding.

View details for DOI 10.1016/j.ygyno.2005.01.009

View details for Web of Science ID 000229231000062

View details for PubMedID 15863183
Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical-pathologic analysis of a Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trial GYNECOLOGIC ONCOLOGY Monk, B. J., Wang, J. M., Im, S., Stock, R. J., Peters, W. A., Liu, P. Y., Barrett, R. J., Berek, J. S., Souhami, L., Grigsby, P. W., Gordon, W., ALBERTS, D. S. 2005; 96 (3): 721-728
Abstract

To retrospectively analyze data from a previously reported randomized trial of either pelvic radiation (RT) or RT + chemotherapy (CT) in patients undergoing radical hysterectomy and pelvic lymphadenectomy with positive pelvic lymph nodes, parametrial involvement, or surgical margins; to explore associations between RT + CT; and to investigate histopathologic and clinical factors which might be predictive of recurrence.Histopathologic sections from biopsies and hysterectomies and clinical data were reviewed from patients with stage IA2, IB, or IIA cervical cancer treated with RT or RT + CT (cisplatin 70 mg/m2 plus fluorouracil 1000 mg/m2 every 3 weeks for four cycles). A univariate analysis was performed because the relatively small sample size limited the interpretation of a multivariate analysis.Of the 268 enrolled women, 243 (RT = 116; RT + CT = 127) were evaluable. The beneficial effect of adjuvant CT was not strongly associated with patient age, histological type, or tumor grade. The prognostic significance of histological type, tumor size, number of positive nodes, and parametrial extension in the RT group was less apparent when CT was added. The absolute improvement in 5-year survival for adjuvant CT in patients with tumors < or =2 cm was only 5% (77% versus 82%), while for those with tumors >2 cm it was 19% (58% versus 77%). Similarly, the absolute 5-year survival benefit was less evident among patients with one nodal metastasis (79% versus 83%) than when at least two nodes were positive (55% versus 75%).In this exploratory, hypothesis-generating analysis, adding CT to RT after radical hysterectomy, appears to provide a smaller absolute benefit when only one node is positive or when the tumor size is < 2 cm. Further study of the role of CT after radical hysterectomy in patients with a low risk of recurrence may be warranted.

View details for DOI 10.1016/j.ygyno.2004.11.007

View details for Web of Science ID 000227615600022

View details for PubMedID 15721417
Monoclonal antibody therapy of ovarian cancer EXPERT REVIEW OF ANTICANCER THERAPY Nicodemus, C. F., Berek, J. S. 2005; 5 (1): 87-96
Abstract

Despite advances in understanding and treatment, ovarian cancer remains a major cause of cancer mortality worldwide. Debulking surgery and paclitaxel/carboplatin chemotherapy induce good initial responses in most patients, although most cases of advanced disease are not controlled. Monoclonal antibodies hold promise as a potential incremental advance for the treatment of the disease. Antibodies can be used to stimulate the immune response, target tumor-specific receptors to induce antibody-dependent cellular cytotoxicity or interfere with biologic pathways. They can also be used to deliver therapeutic radioisotopes to malignant cells. Oregovomab is in Phase III clinical trials as a consolidation treatment post front-line therapy to trigger tumor-specific cellular immunity. Bevacizumab, which blocks vascular endothelial growth factor, will be entering Phase III as an adjuvant to front-line chemotherapy with a direct effect on angiogenesis. Additional immunostimulating, immune counter-regulatory and receptor-targeting approaches are also reviewed. The family of epidermal growth factor receptors including epidermal growth factor receptor 1 (HER-1) and 2 (HER-2) are both expressed in ovarian cancer and are the subject of ongoing research and development. The recent disappointing results with 90-yttrium-labeled anti-HMFG by single intraperitoneal administration have left the radiopharmaceutical field without a Phase III candidate. Identification of novel targets may advance this therapeutic area in the future. The rapid advances in the fields of immunoregulation and tumor biology should permit an accelerated introduction of antibodies for the treatment of ovarian cancer. These antibodies could complement novel small molecules that are also in development.

View details for DOI 10.1586/14737140.5.1.87

View details for Web of Science ID 000233979300010

View details for PubMedID 15757441
Evaluation of vinorelbine in persistent or recurrent nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group Study GYNECOLOGIC ONCOLOGY Muggia, F. M., Blessing, J. A., Waggoner, S., Berek, J. S., Monk, B. J., Sorosky, J., Pearl, M. L. 2005; 96 (1): 108-111
Abstract

The Gynecologic Oncology Group (GOG) has studied a number of drugs to determine their activity in patients with previously treated squamous and nonsquamous cancer arising in the uterine cervix. A Phase II study with intravenous vinorelbine was initiated for this purpose in patients with Stage IVB, recurrent, or persistent nonsquamous carcinomas who had received one prior chemotherapy or were not eligible for other studies.Eligible patients had to have measurable disease, GOG performance status of 0-2 and adequate bone marrow, liver, and renal function. The treatment consisted of vinorelbine 30 mg/m(2) on days 1 and 8, repeated every 21 days. Tumor measurements and toxicities were recorded every treatment cycle.Thirty patients were enrolled with 28 patients deemed eligible and evaluable. Only two confirmed partial responses (7.1%) were noted. Neutropenia was the most common toxicity with 9 of 28 (32%) experiencing either grade 3 or 4 changes. Anemia was severe in seven. Neuropathy was more than mild in three patients. Severe events, such as fatigue, hypertension, or pulmonary changes attributed to drug administration, occurred only in one or two instances.With the dose schedule and assessment criteria employed, vinorelbine had only minimal activity in nonsquamous cancer of the cervix.

View details for DOI 10.1016/j.ygyno.2004.09.028

View details for Web of Science ID 000226040800017

View details for PubMedID 15589588
Randomized, placebo-controlled study of oregovomab for consolidation of clinical remission in patients with advanced ovarian cancer 39th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) Berek, J. S., Taylor, P. T., Gordon, A., Cunningham, M. J., Finkler, N., Orr, J., Rivkin, S., Schultes, B. C., Whiteside, T. L., Nicodemus, C. F. AMER SOC CLINICAL ONCOLOGY. 2004: 3507–16
Abstract

To assess oregovomab as consolidation treatment of advanced ovarian cancer and refine the immunotherapeutic strategy for subsequent study.Patients with stage III/IV ovarian cancer who had a complete clinical response to primary treatment were randomly assigned to oregovomab or placebo administered at weeks 0, 4, and 8, and every 12 weeks up to 2 years or until recurrence. The primary end-point was time to relapse (TTR).One hundred forty-five patients were treated with oregovomab (n = 73) or placebo (n = 72). For the population overall, median TTR was not different between treatments at 13.3 months for oregovomab and 10.3 months for placebo (P =.71). Immune responses were induced in most actively treated patients. This was associated with prolonged TTR. Quality of life was not adversely impacted by treatment. Adverse events were reported with similar frequency in oregovomab and placebo groups, indicating a benign safety profile. A long-term survival follow-up is ongoing. Cox analysis of relapse data identified significant factors: performance status, CA-125 before third cycle, and baseline CA-125. Further evaluation identified a subpopulation with favorable prognostic indicators designated as the successful front-line therapy (SFLT) population. For the SFLT population, TTR was 24.0 months in the oregovomab group compared with 10.8 months for placebo (unadjusted hazard ratio of 0.543 [95% CI, 0.287 to 1.025]), a hypothesis-generating observation.Consolidation therapy with oregovomab did not significantly improve TTR overall. A set of confirmatory phase III studies has been initiated to determine whether the SFLT population derives benefit from oregovomab treatment.

View details for DOI 10.1200/JCO.2004.09.016

View details for Web of Science ID 000223711300012

View details for PubMedID 15337799
Using fresh tissue dissection to teach human anatomy in the clinical years ACADEMIC MEDICINE Robinson, A. G., Metten, S., Guiton, G., Berek, J. 2004; 79 (7): 711-716
Abstract

Gross anatomy is taught in medical school with textbooks, cadaver dissection, plastic models, and multimedia illustration, but all lack the reality of color and texture that is possible with fresh tissue dissection. The authors studied the use of fresh tissue dissection of the thorax and abdomen of the rat to teach human anatomy.In a half-day exercise, 52 fourth-year medical students paired off and completed an exercise to dissect in less than three hours the thorax and abdomen of a euthanized rat. Observation of organs was augmented by active manipulation such as passing a tube down the esophagus, cannulating the trachea and inflating the lungs, injecting dye in the kidney to trace the ureter and bladder, and pulling the testis through the inguinal canal. Comparison of the rat and human was emphasized to enhance the education. The exercise ended with practice suturing fresh tissue.Students rated the exercise to teach anatomy as 4.9 positive on a 5.0 (high) scale. The significant positive structures (p <.05) for texture were heart, liver, lungs and trachea; for color they were lungs and spleen; for location and size they were adrenal gland and urinary bladder; and for function they were adrenal gland and esophagus.Fresh tissue dissection of the thorax and abdomen of the rat is a valuable tool for human anatomy education. The dissonances in human and rat anatomy enhance abstraction and transfer of knowledge. Active manipulation of organs promotes retention of knowledge, and suturing provides a "clinical" context. Fresh tissue dissection is an efficient innovative method to provide a global review of anatomy of the thorax and abdomen during the busy clinical years of medical education.

View details for Web of Science ID 000222832000016

View details for PubMedID 15234927
Immunotherapy of ovarian cancer with antibodies: a focus on oregovomab EXPERT OPINION ON BIOLOGICAL THERAPY Berek, J. S. 2004; 4 (7): 1159-1165
Abstract

Recent advances in the molecular and cellular biology of malignancy and tumour immunology have stimulated significant progress in the application of immunotherapies as adjuvant treatments in cancer. Oregovomab (OvaRex, AltaRex) is a murine monoclonal antibody with high affinity to the ovarian cancer associated antigen CA125. Infusion of low-dose antibody results in formation of circulating immune complexes which can trigger a cellular immune response targeting CA125 and the ovarian cancer. Oregovomab has activity following initial chemotherapy and in recurrent disease settings and is in Phase III trials to establish its efficacy to prolong time to relapse in patients with advanced ovarian cancer and favourable outcomes to their front-line treatment. Additional studies of antigen processing and combination chemo-immunotherapy are ongoing. The treatment shows promise as a potential new addition to the standard care of ovarian cancer.

View details for Web of Science ID 000222794600014

View details for PubMedID 15268682
Detection of residual subclinical ovarian carcinoma after completion of adjuvant chemotherapy CLINICAL CANCER RESEARCH Nouriani, M., Bahador, A., Berek, J. S., Cheng, J. P., Chi, D. S., Cliby, W. A., Del Priore, G., Dodson, M. K., Duggan, B. D., Gershenson, D. M., Lentz, S. E., Penson, R. T., Robinson, W. R., Rodriguez, M., Roman, L. D., Yu, M. C., Zempolich, K., Dubeau, L. 2004; 10 (8): 2681-2686
Abstract

We sought to test the hypothesis that the presence of telomerase activity in peritoneal washings of patients treated for ovarian carcinoma is a sensitive and specific indicator of the presence of residual disease. We hypothesized that this test, if added to second-look procedure protocols, could help determine whether residual disease is present or not in patients who have completed their adjuvant chemotherapy for ovarian carcinoma.Peritoneal washings were obtained from 100 consecutive patients undergoing a second-look procedure after treatment for ovarian carcinoma (cases) and from 100 patients undergoing surgery for benign gynecological conditions (controls). The washings were assayed for telomerase activity using the telomerase repeat amplification protocol. The results were compared to the histological and cytological findings.Among our 100 cases, 82 (82%) had either positive second-look procedures or expressed telomerase in their peritoneal washings. Fifty-three (53%) had positive second-look procedures, whereas 66 (66%) tested positive for telomerase. Twenty-nine of the 47 patients (62%) with negative second-look procedures tested positive for telomerase. Of the 53 patients with positive second-look procedures, 37 (70%) tested positive for telomerase. None of the 100 controls (0%) expressed telomerase in their peritoneal washings.Telomerase activity in peritoneal washings of patients treated for ovarian carcinoma and undergoing a second-look procedure may provide a means of increasing the sensitivity of such procedures for the detection of residual disease while maintaining a high level of specificity.

View details for Web of Science ID 000220933800015

View details for PubMedID 15102671
Lymphovascular and perineural invasion in the parametria: A prognostic factor for early-stage cervical cancer OBSTETRICS AND GYNECOLOGY Memarzadeh, S., Natarajan, S., Dandade, D. P., Ostrzega, N., Saber, P. A., Busuttil, A., Lentz, S. E., Berek, J. S. 2003; 102 (3): 612-619
Abstract

To estimate the impact of parametrial lymphovascular and perineural involvement on nodal metastasis and failure pattern of women with early-stage, surgically treated cervical cancer.Clinical records and pathologic slides of 93 patients with early-stage cervical cancer (2 IA2, 52 IB1, 31 IB2, and 8 IIA) treated with radical hysterectomy and pelvic lymphadenectomy with or without paraaortic lymphadenectomy were reviewed. The study group comprised 80 patients with squamous cell carcinoma and 13 patients with adenocarcinoma of the cervix. Median follow-up time was 33 months. The association among the various histopathologic predictors of outcome was determined with chi2 analysis. The influence of the predictors on outcome was examined with log rank survival methods and the Cox regression model.The presence of parametrial lymphovascular space invasion is a predictor of disease in the pelvic (P<.001) and paraaortic (P<.05) lymphatics independently. Large tumor size (greater than 4 cm), parametrial perineural invasion, cervical lymphovascular space invasion, and tumor depth (greater than two thirds) were found to be simultaneous predictors of recurrence on multivariate analysis (P<.05). Using these four binary predictor variables, we have computed a model-based relative risk. Based on this model, the presence of perineural invasion in the parametria more than doubles the risk of recurrence in the cohort of patients with large (greater than 4 cm) tumors (P<.05). In a subset analysis of patients with negative nodal disease, parametrial perineural invasion and tumor size were independent predictors of poor outcome (P<.05).Presence of parametrial lymphovascular space invasion correlates significantly with the risk of nodal metastasis in women with early-stage cervical cancer. Parametrial perineural invasion is an independent poor prognostic factor. Histopathologic findings within the parametria are a valuable independent predictor of recurrence and thus may influence the selection of patients for adjuvant treatment.

View details for DOI 10.1016/S0029-7844(03)00569-6

View details for Web of Science ID 000185007400034

View details for PubMedID 12962952
Current research and treatment for epithelial ovarian cancer - A Position Paper from the Helene Harris Memorial Trust EUROPEAN JOURNAL OF CANCER Balkwill, F., Bast, R. C., Berek, J., Chenevix-Trench, G., Gore, M., Hamilton, T., Jacobs, I., Mills, G., Souhami, R., Urban, N., Ursulic, S., Smyth, J. 2003; 39 (13): 1818-1827
Abstract

In March 2003, an international mulltidisciplinary group of scientists and clinicians with a specific interest in ovarian cancer met for 4 days to discuss research into and treatment of this challenging disease. Under the headings of molecular genetics, molecular biology, the biology of ovarian cancer, old therapies, new targets and the early detection of the disease, this Position Paper summarises the presentations and discussion from the 9th Biennial Helene Harris Memorial Trust Forum on Ovarian Cancer. In particular, we highlight the potential of international collaborations in translating laboratory science into useful clinical interventions.

View details for DOI 10.1016/S0959-8049(03)00511-2

View details for Web of Science ID 000185327400002

View details for PubMedID 12932658
Cervical cancer: An opportunity to prevent and cure CANCER JOURNAL Berek, J. S. 2003; 9 (5): 325-326
View details for Web of Science ID 000187158200002

View details for PubMedID 14690306
Amifostine pretreatment for protection against topotecan-induced hematologic toxicity: results of a multicenter phase III trial in patients with advanced gynecologic malignancies GYNECOLOGIC ONCOLOGY Gold, M. A., Walker, J. L., Berek, J. S., Hallum, A. V., Garcia, D. J., ALBERTS, D. S. 2003; 90 (2): 325-330
Abstract

To determine if amifostine could reduce the hematologic toxicity associated with topotecan.Thirty patients with recurrent/refractory gynecologic malignancies were randomized to receive topotecan (TOPO) (1.5 mg/m(2)/day days 1-5) with or without amifostine (AMI/TOPO) (500 mg/m(2)/day days 1-5) every 3 weeks for six cycles. The primary study endpoints were the incidence of grade 3 and 4 neutropenia.Fifteen patients were randomized to each arm for a total of 49 TOPO and 53 AMI/TOPO cycles. Patient characteristics and pretreatment ANC were similar between groups. Topotecan 1.5 mg/m(2)/day days 1-5 was initially administered to seven patients. Five developed neutropenic fevers, one an uncomplicated grade 4 neutropenia, and the other an uncomplicated grade 3 neutropenia. There were two treatment-related deaths due to sepsis (one in each treatment arm). The starting dose was thereafter reduced to 1.25 mg/m(2)/day days 1-5 every 21 days. No treatment related deaths occurred after this dose reduction. The incidence of combined grade 3/4 neutropenia was reduced from 67% (33/49 cycles) to 38% (20/53 cycles) with the addition of amifostine (P = 0.003; OR 0.29; 95% CI 0.12-0.71).Topotecan at 1.5 mg/m(2)/day days 1-5 in heavily pretreated patients resulted in excessive toxicity not manageable with amifostine. At the reduced topotecan dose (1.25 mg/m(2) x 5 days), pretreatment with amifostine reduced the hematologic toxicity associated with topotecan chemotherapy in women with recurrent/refractory gynecologic malignancies.

View details for DOI 10.1016/S0090-8258(03)00319-6

View details for Web of Science ID 000184608600014

View details for PubMedID 12893194
Phase II evaluation of oxaliplatin in previously treated squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study GYNECOLOGIC ONCOLOGY Fracasso, P. M., Blessing, J. A., Wolf, J., Rocereto, T. F., Berek, J. S., Waggoner, S. 2003; 90 (1): 177-180
Abstract

A phase II study was conducted to determine the efficacy of oxaliplatin therapy in patients with previously treated squamous cell carcinoma of the cervix.Eligible patients were to have measurable disease and not more than one prior chemotherapy regimen that could include carboplatin or cisplatin but not oxaliplatin. Oxaliplatin 130 mg/m(2) was administered intravenously over 2 h. This treatment was repeated every 21 days until progression of disease or adverse effects prohibited further therapy.Twenty-eight patients were entered onto this study, of whom 24 were evaluable for toxicity and 22 were evaluable for response; 23/24 evaluable patients had had prior platinum. There were two (8.3%) responses. One patient achieved a complete response which lasted 2.2 months, and a second patient attained a partial response which lasted 3.2 months. Nine (37.5%) patients had stable disease with a median duration of 7.6+ (3.1-21.2) months. The most frequently reported drug-related toxicities consisted of anemia, nausea and vomiting, and neurotoxicity. Three (12.5%) patients had a grade 3 allergic response that was infusion-related and was largely resolved by increasing infusion time.Oxaliplatin has limited activity in patients with persistent or recurrent squamous cell carcinoma of the cervix at the dose and schedule tested.

View details for DOI 10.1016/S0090-8258(03)00253-1

View details for Web of Science ID 000183833600028

View details for PubMedID 12821360
Progress in the management of gynecologic cancer: consensus summary statement. Journal of clinical oncology Cannistra, S. A., Bast, R. C., Berek, J. S., Bookman, M. A., Crum, C. P., DePriest, P. D., Garber, J. E., Koh, W., Markman, M., McGuire, W. P., Rose, P. G., Rowinsky, E. K., Rustin, G. J., Skates, S. J., Vasey, P. A., King, L. 2003; 21 (10): 129s-132s
View details for PubMedID 12743127
Biologic and immunologic therapies for ovarian cancer. Journal of clinical oncology Berek, J. S., Schultes, B. C., Nicodemus, C. F. 2003; 21 (10): 168s-174s
Abstract

Biologic therapy of ovarian cancer has been conducted using nonspecific biologic response modifiers, cytokines, monoclonal antibodies (MAbs), vaccines, and gene therapy. Antibodies directed toward her2/neu have also been studied. Phase I and II gene therapy trials using adenoviral vectors containing a wild-type or modified p53 have shown that the treatment is well tolerated. Phase II and III trials are ongoing with MAbs directed against CA-125 (MAb B43.13) and an antibody directed against HMFG1 (anti-HMFG1-yttrium-90-labeled antibody). The trials have shown that these agents are well tolerated and that immunologic responses occur, although the ultimate clinical value of these agents remains to be determined. Prolonged survival after MAb B43.13 treatment has been correlated with changes in several immune parameters, including human antimurine antibody, Ab2, anti-CA-125 antibody development, and induced T-cell immunity. Clinical trials using a MAb directed toward the encoded products of her2/neu have shown minimal activity against ovarian cancer in a phase I and II trial conducted by the Gynecologic Oncology Group. Cytokine therapies have been administered systemically and intraperitoneally. Intracavitary interferon alfa, interferon gamma, and interleukin-2 alone or in combination with cytotoxic therapy in phase I and II trials demonstrated intraperitoneal lymphoid cell stimulation and produced antitumor responses. A randomized trial of chemotherapy with or without interferon gamma in primary treatment produced a response and a progression-free survival advantage in the arm that incorporated the interferon gamma, without a statistically significant benefit in overall survival. A phase III study of interferon gamma in combination with first-line chemotherapy is currently ongoing.

View details for PubMedID 12743131
Surgical resection of solitary brain metastasis from cervical cancer INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Tajran, D., Berek, J. S. 2003; 13 (3): 368-370
Abstract

This is the first report of a patient with cervical cancer who underwent surgical resection of a solitary brain metastasis eight years following diagnosis. This case is unique because of the indolent nature of the tumor and because the patient had resection of metastatic lung nodules three years earlier. In this particular case, the patient's survival was not prolonged, so craniotomy and resection cannot be recommended in this disease, even when there has been a prolonged disease progression-free interval. Palliative management should include steroids and radiation therapy.

View details for Web of Science ID 000183479500018

View details for PubMedID 12801271
The use of continuous infusion topotecan in persistent and recurrent ovarian cancer INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Elkas, J. C., Holschneider, C. H., Katz, B., Li, A. J., Louie, R., McGonigle, K. F., Berek, J. S. 2003; 13 (2): 138-141
Abstract

We retrospectively review our experience with continuous infusion topotecan for the treatment of persistent or recurrent ovarian cancer in this paper. Nine patients were identified who were treated at the University of California Los Angeles Medical Center between January 1997 and December 1999 using a 14-21 day continuous infusion schedule (0.3-0.7 mg/m2/d). Dose adjustments were performed for grade 3-4 toxicities and treatment was discontinued for persistent severe toxicity or progressive disease. Response to treatment was analyzed and stratified by platinum refractory, resistant, and sensitive disease. A total of 41 treatment cycles were given to nine patients with a median of five per patient (range 1-11). Median follow-up was 8 months. There were two partial responses (22%) and four patients had stable disease (44%), which included two patients with platinum-refractory tumors. No grade 3 or 4 hematologic toxicities were observed. However, two patients suffered grade 3 gastrointestinal toxicity during the first cycle leading to discontinuation of topotecan administration. There was no cumulative toxicity. Topotecan administered by continuous infusion demonstrated response rates comparable to other dosing schedules with minimal hematologic toxicity. Treatment of patients with persistent or recurrent ovarian cancer with continuous infusion topotecan warrants further investigation.

View details for Web of Science ID 000181803400006

View details for PubMedID 12657113
CA125 levels are a weak predictor of optimal cytoreductive surgery in patients with advanced epithelial ovarian cancer INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Memarzadeh, S., Lee, S. B., Berek, J. S., Farias-Eisner, R. 2003; 13 (2): 120-124
Abstract

The utility of preoperative CA125 to predict optimal primary tumor cytoreduction in patients with advanced (stages IIIC and IV) epithelial ovarian cancer is controversial. In this paper, we retrospectively review patients with stage IIIC and IV epithelial ovarian cancer who underwent primary cytoreductive surgery from 1989 to 2001. Ninety-nine patients were identified and included in the analysis. All patients had preoperative CA125 levels measured. Operative and pathology reports were reviewed. Optimal cytoreduction was defined as largest volume of residual disease < 1 cm in maximal dimension. Mean values were compared with t-test on a log scale when needed. The optimal cut-point for discriminating between those with vs. without optimal cytoreduction was determined using the receiver operator curve (ROC) method. Optimal cytoreduction was achieved in 73% of patients. Among patients with optimal cytoreductive status the mean CA125 level was 569, while among patients with suboptimal cytoreduction the mean CA125 level was 1520 (P < 0.007). A CA125 level of 912 was identified as the optimal cut-point to distinguish the two groups. Using this CA125 level, the sensitivity of this test in predicting optimal cytoreduction was 58% and the specificity was 54%. The positive predictive value of CA125 for optimal cytoreduction was 78% and the negative predictive value was 31%. We conclude that CA125 level is a weak positive and negative predictor of optimal cytoreductive surgery in patients with advanced epithelial ovarian cancer. The CA125 level should not be used as a primary predictor of the outcome of cytoreductive surgery and should be viewed in the context of all other preoperative features.

View details for Web of Science ID 000181803400003

View details for PubMedID 12657110
Simplification of the new Bethesda 2001 classification System AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Berek, J. S. 2003; 188 (3): S2-S5
Abstract

In 1989, a National Cancer Institute workshop resulted in the development of the Bethesda System for cytologic reporting of Papanicolaou smears. In the Bethesda III System (2001), potentially premalignant squamous lesions fall into 3 categories: Atypical squamous cells (ASC), low-grade squamous intraepithelial lesions (LGSIL), and high-grade intraepithelial lesions (HGSIL). The ASC category is subdivided into 2 categories: Those of unknown significance (ASC-US) and those in which high-grade lesions must be excluded (ASC-H). Further revision included the elimination of the category "benign cellular changes," which is now referred to as "negative for intraepithelial lesion or malignancy." The revision also refined the criteria for abnormal glandular epithelium, including atypical glandular cells (AGC). The principal modification in the updated system is the revision of the ASC category, which was done to facilitate triage of women for more intense screening when a true suspicion of a high-grade lesion was present.

View details for DOI 10.1067/mob.2003.220

View details for Web of Science ID 000181812700002

View details for PubMedID 12634623
Specific keynote: Immunological therapy for ovarian cancer 8th International Forum on Ovarian Cancer Berek, J. S., Dorigo, O., Schultes, B., Nicodemus, C. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2003: S105–S109
View details for DOI 10.1006/gyno.2002.6695

View details for Web of Science ID 000180777000024

View details for PubMedID 12586097
FIGO stage III and IV uterine papillary serous carcinoma: Impact of residual disease on survival INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Memarzadeh, S., Holschneider, C. H., Bristow, R. E., JONES, N. L., Fu, Y. S., Karlan, B. Y., Berek, J. S., Farias-Eisner, R. 2002; 12 (5): 454-458
Abstract

The objective of this study was to assess the impact of surgical cytoreduction on the survival of patients with uterine papillary serous carcinoma (UPSC). Patients added to the institutional tumor registries between January 1980 and September 2001 with the diagnosis of UPSC were reviewed. The records of 43 patients who underwent surgical cytoreduction for FIGO stage III and IV disease were reviewed. The median survival of UPSC patients with microscopic residual disease was significantly improved compared to those with macroscopic residual disease following primary surgical cytoreduction. We conclude that primary surgical cytoreduction resulting in microscopic residual disease is associated with an improvement in recurrence-free survival and overall survival in women with UPSC.

View details for Web of Science ID 000178476100009

View details for PubMedID 12366662
Advances in the management of epithelial ovarian cancer JOURNAL OF REPRODUCTIVE MEDICINE Memarzadeh, S., Berek, J. S. 2001; 46 (7): 621-629
Abstract

More than 23,400 new cases of ovarian cancer and 13,900 deaths are expected in the United States this year. Epithelial ovarian cancer is the most common histologic type of ovarian malignancy. Although there have been advances in the chemotherapeutic treatment of ovarian cancer, the five year survival of women with advanced-stage disease is 25-30%. Because the disease is typically asymptomatic until the disease has metastasized and because effective screening strategies are not unavailable, 70-75% of women present with advanced-stage disease. Of ovarian cancer cases, 90-95% are sporadic and 5-10% associated with germ-line mutations, including BRCA1 and BRCA2. Known risk factors for ovarian cancer include nulliparity and a strong family history of ovarian cancer. The use of oral contraceptives is known to decrease the risk of ovarian cancer: five years of use will decrease the risk by 50%. The staging of ovarian cancer (according to the International Federation of Obstetrics and Gynecology) requires surgical exploration. Determining the extent of disease is essential to appropriate management. Survival in patients with metastatic disease is improved in those who undergo optimal primary cytoreductive surgery. Adjuvant chemotherapy is recommended in patients with high-risk, early-stage disease and all patients with advanced-stage disease. Standard chemotherapy is a combination of paclitaxel and carboplatin. Selected patients with recurrent disease can undergo secondary cytoreductive surgery. Second-line chemotherapy for patients who initially respond to paclitaxel and carboplatin and who have a prolonged disease progression-free intervals (longer than 12 months) can be re-treated with either drug or both. Those whose responses to initial therapy were less successful can be treated with other chemotherapeutic agents--e.g., liposomal doxorubicin, topotecan, etoposide, gemcitabine or taxotere.

View details for Web of Science ID 000170205600001

View details for PubMedID 11499181
A radical debulking of leiomyomatosis peritonealis disseminata from a colonic obstruction: A case report and review of the literature JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Ghosh, K., Dorigo, O., Bristow, R., Berek, J. 2000; 191 (2): 212-215
View details for Web of Science ID 000088583900019

View details for PubMedID 10945368
[Epithelial ovarian cancer (advanced stage): consensus conference (1998)]. Gynecologie, obstetrique & fertilite Berek, J. S., Bertelsen, K., du Bois, A., Brady, M. F., Carmichael, J., Eisenhauer, E. A., Gore, M., Grenman, S., HAMILTON, T. C., Hansen, S. W., Harper, P. G., Horvath, G., Kaye, S. B., Lück, H. J., Lund, B., McGuire, W. P., Neijt, J. P., OZOLS, R. F., Parmar, M. K., Piccart-Gebhart, M. J., van Rijswijk, R., Rosenberg, P., Rustin, G. J., Sessa, C., Thigpen, J. T., Tropé, C., Tuxen, M. K., Vergote, I., Vermorken, J. B., Willemse, P. H. 2000; 28 (7-8): 576-583
View details for PubMedID 10996969
Ovarian cancer: Epidemiology, biology, and prognostic factors SEMINARS IN SURGICAL ONCOLOGY Holschneider, C. H., Berek, J. S. 2000; 19 (1): 3-10
Abstract

Ovarian cancer varies widely in frequency among different geographic regions and ethnic groups, with a high incidence in Northern Europe and the United States, and a low incidence in Japan. The majority of cases are sporadic, and only 5% to 10% of ovarian cancers are familial. The etiology of ovarian cancer is poorly understood. Models of ovarian carcinogenesis include the theory of incessant ovulation, in which a person's age at ovulation, i.e., lifetime number of ovulatory cycles, is an index of her ovarian cancer risk. Excessive gonadotropin and androgen stimulation of the ovary have been postulated as contributing factors. Exposure of the ovaries to pelvic contaminants and carcinogens may play a role in the pathogenesis of ovarian cancer. Epidemiologic and molecular-genetic studies identify numerous risk and protective factors. The most significant risk factor is a family history of the disease. Recent advances in molecular genetics have found mutations in the BRCA1 and BRCA2 tumor suppressor genes responsible for the majority of hereditary ovarian cancer. Additional risk factors include nulliparity and refractory infertility. Protective factors include multiparity, oral contraceptives, and tubal ligation or hysterectomy. With five years of oral contraceptive use, women can cut their risk of ovarian cancer approximately in half; this also holds true for individuals with a family history. Stage at diagnosis, maximum residual disease following cytoreductive surgery, and performance status are the three major prognostic factors. Using a multimodality approach to treatment, including aggressive cytoreductive surgery and combination chemotherapy, five-year survival rates are as follows: Stage I (93%), Stage II (70%), Stage III (37%), and Stage IV (25%).

View details for Web of Science ID 000087957700002

View details for PubMedID 10883018
Interferon plus chemotherapy for primary treatment of ovarian cancer LANCET Berek, J. S. 2000; 356 (9223): 6-7
View details for Web of Science ID 000087933400004

View details for PubMedID 10892754
Preoperative prediction of optimal resectability in advanced ovarian cancer using CA-125 GYNECOLOGIC ONCOLOGY Berek, J. S. 2000; 77 (2): 225-226
View details for Web of Science ID 000087028300001

View details for PubMedID 10785468
Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix JOURNAL OF CLINICAL ONCOLOGY Peters, W. A., Liu, P. Y., Barrett, R. J., Stock, R. J., Monk, B. J., Berek, J. S., Souhami, L., Grigsby, P., Gordon, W., ALBERTS, D. S. 2000; 18 (8): 1606-1613
Abstract

To determine whether the addition of cisplatin-based chemotherapy (CT) to pelvic radiation therapy (RT) will improve the survival of early-stage, high-risk patients with cervical carcinoma.Patients with clinical stage IA(2), IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium were eligible for this study. Patients were randomized to receive RT or RT + CT. Patients in each group received 49.3 GY RT in 29 fractions to a standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m(2) and a 96-hour infusion of fluorouracil 1,000 mg/m(2)/d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT.Between 1991 and 1996, 268 patients were entered onto the study. Two hundred forty-three patients were assessable (127 RT + CT patients and 116 RT patients). Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT + CT arm are 2.01 (P =.003) and 1.96 (P =. 007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT + CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT + CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT + CT group.The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.

View details for Web of Science ID 000086655500002

View details for PubMedID 10764420
Fraud. What is the evidence? Care management journals : Journal of case management ; The journal of long term home health care Berek, J., Gutierrez, N., Stone, J., Testa, L. 2000; 2 (1): 44-53
Abstract

The home health industry complains that Medicare fraud and abuse initiatives and legislation, namely, Operation Restore Trust (ORT), the Health Insurance Portability and Accountability Act (HIPAA) of 1996, and the Balanced Budget Act (BBA) of 1997 developed when home health care was vulnerable to reimbursement reductions from Medicaid and commercial insurers, particularly Health Maintenance Organizations. Additionally, it contends that the Health Care Financing Administration (HCFA) founded these initiatives on controversial government studies showing high rates of home health fraud and abuse and inappropriate assumptions that rising costs were indicative of fraudulent activities (Sarraille & William, 1998). We summarize reasons why the home health industry became a focus for enhanced Medicare fraud and abuse reduction efforts by HCFA and provide evidence supporting enforcement actions by HCFA's partners.

View details for PubMedID 11000723
IL-2 plasmid therapy of murine ovarian carcinoma inhibits the growth of tumor ascites and alters its cytokine profile JOURNAL OF IMMUNOLOGY Horton, H. M., Dorigo, O., Hernandez, P., Anderson, D., Berek, J. S., Parker, S. E. 1999; 163 (12): 6378-6385
Abstract

We have evaluated whether i.p. murine ovarian tumors could be treated with an IL-2 plasmid DNA complexed with the cationic lipid, (+/-)-N-(2-hydroxyethyl)-N,N-dimethyl-2, 3-bis(tetradecyloxy)-1-propanaminium bromide/dioleoylphosphatidylethanolamine (DMRIE/DOPE). Reporter gene studies were initially conducted in which mice bearing i.p. murine ovarian teratocarcinoma (MOT) were injected i.p. with reporter gene plasmid DNA (pDNA):DMRIE/DOPE. Histochemical analyses revealed that transfection occurred primarily in the tumor cells of the ascites, with only a minority of other ascitic cells or surrounding tissues transfected. IL-2 levels in the MOT ascites were determined after i. p. injection of either IL-2 pDNA:DMRIE/DOPE or recombinant IL-2 protein. IL-2 was detected in tumor ascites for up to 10 days after a single i.p. injection of IL-2 pDNA:DMRIE/DOPE, but was undetectable 24 h after a single i.p. injection of IL-2 protein. In an antitumor efficacy study, MOT tumor-bearing mice injected i.p. with IL-2 pDNA:DMRIE/DOPE on days 5, 8, and 11 after tumor cell implant had a significant inhibition of tumor ascites (p = 0.001) as well as a significant increase in survival (p = 0.008). A cytokine profile of the MOT tumor ascites revealed that mice treated with IL-2 pDNA:DMRIE/DOPE had an IL-2-specific increase in the levels of IFN-gamma and GM-CSF. Taken together, these findings indicate that i. p. treatment of ovarian tumors with IL-2 pDNA:DMRIE/DOPE can lead to an increase in local IL-2 levels, a change in the cytokine profile of the tumor ascites, and a significant antitumor effect.

View details for Web of Science ID 000084134200005

View details for PubMedID 10586027
Endometrial cancer: Recent developments in evaluation and treatment ONCOLOGY-NEW YORK Chen, L. M., McGonigle, K. F., Berek, J. S. 1999; 13 (12): 1665-?
Abstract

Endometrial carcinoma is the most common gynecologic malignancy in the United States. Most cases are diagnosed at an early stage. However, the outcome for women diagnosed with advanced-stage disease remains poor. The etiology of most endometrial carcinomas stems from the effects of excess estrogen, whether this comes from exogenous or endogenous sources. Differences in epidemiology and presentation suggest the existence of two forms of endometrial cancer: those related to and those unrelated to hormonal stimulation. Most women with endometrial cancer present with abnormal uterine bleeding; endometrial sampling is essential to exclude endometrial carcinoma in such patients. Endometrial cancer is surgically staged, and staging usually includes a hysterectomy and bilateral salpingooophorectomy. Lymphadenectomy also should be performed in selective cases to better assess disease spread and to evaluate the need for adjuvant therapy. Adjuvant treatment may include the use of radiation, progestins, or cytotoxic chemotherapeutic agents. Several clinical trials are underway to compare these treatment modalities, as well as to determine the optimal combination of active chemotherapeutic agents, such as doxorubicin, platinum agents, and paclitaxel (Taxol).

View details for Web of Science ID 000090128400012

View details for PubMedID 10631700
Recurrent mature cystic teratoma presenting as a perihepatic mass OBSTETRICS AND GYNECOLOGY Chen, L. M., Nelson, S. D., Berek, J. S. 1999; 94 (5): 856-856
View details for Web of Science ID 000083361700034

View details for PubMedID 10546767
Intraperitoneal interferon-alpha in residual ovarian carcinoma: A Phase II Gynecologic Oncology Group study GYNECOLOGIC ONCOLOGY Berek, J. S., Markman, M., Stonebraker, B., Lentz, S. S., Adelson, M. D., DeGeest, K., Moore, D. 1999; 75 (1): 10-14
Abstract

The purpose of this study was to confirm the activity of interferon-alpha intraperitoneally in minimal residual epithelial ovarian cancer in a Phase II multi-institutional trial and to investigate the activity of the agent based on prior response to first-line platinum compounds.Ninety-two patients with minimal residual (<0.5 cm) epithelial ovarian cancer at reassessment laparotomy were entered into a multicenter trial of intraperitoneal interferon-alpha given for 12 cycles unless disease progression or unacceptable toxicity occurred first. Patients were considered favorable if they were platinum sensitive and/or relapsed 6 months or longer after completing treatment and unfavorable if they were platinum insensitive and/or relapsed shorter than 6 months after completing treatment and/or had stable or progressive disease during initial therapy. A third-look laparotomy was performed within 12 weeks of completion of treatment in those patients who were in clinical remission.Eighty patients were clinically evaluable for toxicity only (48 favorable, 32 unfavorable) and 46 of them were evaluable for response, of whom 25 were favorable (platinum sensitive) and 21 unfavorable (platinum resistant). In the favorable group, there was a 28% surgically documented response rate (7/25 patients): 16% (4/25) had complete responses (negative reassessment operation), 12% (3/25) had partial responses, 32% (8/25) were nonresponders, and 40% (10 patients) developed progressive disease before planned reassessment operation. In the unfavorable group, there were no responding patients: 6 were nonresponders at reassessment operation and 15 developed progressive disease before planned reassessment operation. Of the 80 patients evaluable for toxicity, the most common adverse effects that were more than grade 2 were gastrointestinal (12; 15%), fever (8; 10%), neutropenia (7;9%), and leukopenia (6; 8%). Grade 4 toxicity was seen in 5 patients; each had fever and gastrointestinal toxicity, and 1 each had neutropenia and thrombocytopenia.Interferon-alpha is an active and generally well-tolerated agent in favorable patients with minimal residual epithelial ovarian cancer at second-look surgery. These results are comparable to those achieved with cytotoxic chemotherapy. If Phase III trials are considered in the patients with minimal residual ovarian cancer, they should be limited to the platinum-sensitive patient population.

View details for Web of Science ID 000083051700003

View details for PubMedID 10502418
Intraperitoneal alpha-interferon alternating with cisplatin in residual ovarian carcinoma: A phase II Gynecologic Oncology Group study GYNECOLOGIC ONCOLOGY Berek, J. S., Markman, M., Blessing, J. A., Kucera, P. R., Nelson, B. E., Anderson, B., Hanjani, P. 1999; 74 (1): 48-52
Abstract

The aim of this study was to study the combination of intraperitoneal alpha-interferon and cisplatin administered second-line in an alternating sequence in small volume residual epithelial ovarian cancer after second-look surgery and the activity of this combination based on prior response to first-line platinum compounds.Sixty-two patients with minimal residual (<0.5 cm) epithelial ovarian cancer at reassessment laparotomy were entered into a multicenter trial of intraperitoneal alpha-interferon alternating with cisplatin given for eight cycles unless disease progression or unacceptable toxicity occurred. The patients were considered favorable if they were platinum-sensitive and/or relapsed 6 months or longer after completing treatment. Another reassessment laparotomy was performed within 12 weeks of completion of treatment in patients who were in clinical remission.Fifty-four patients were clinically evaluable and 18 were surgically reassessed, 5 of whom had a negative reassessment operation (20% complete response and 8% partial response). Of the 54 patients evaluable for toxicity, the most common adverse effects of more than grade 2 were gastrointestinal in 13 (47%), neutropenia in 9 (17%), and leukopenia in 6 (12%). Grade 4 toxicity was seen in 10 instances: 4 gastrointestinal, 2 neutropenia, 2 thrombocytopenia, 1 wound infection, and 1 allergic reaction.alpha-Interferon and cisplatin are active agents in favorable patients with minimal residual epithelial ovarian cancer at second-look. The combination of the two drugs administered in an alternating sequence appears to be associated with more side effects than when either drug is administered alone. The combination produced response rates similar to those seen when either drug is given alone.

View details for Web of Science ID 000081483200008

View details for PubMedID 10385550
Advanced epithelial ovarian cancer: 1998 consensus statements Workshop on Advanced Ovarian Cancer - What Do We Know and What Do We Need Berek, J. S., Bertelsen, K., du Bois, A., Brady, M. F., Carmichael, J., Eisenhauer, E. A., Gore, M., Grenman, S., HAMILTON, T. C., Hansen, S. W., Harper, P. G., Horvath, G., Kaye, S. B., Luck, H. J., Lund, B., McGuire, W. P., Neijt, J. P., OZOLS, R. F., Parmar, M. K., Piccart-Gebhart, M. J., van Rijswijk, R., Rosenberg, P., Rustin, G. J., Sessa, C., Thigpen, J. T., Trope, C., Tuxen, M. K., Vergote, I., Vermorken, J. B., Willemse, P. H. OXFORD UNIV PRESS. 1999: 87–92
Abstract

During an international workshop held in September 1998, a group of specialists in the field of ovarian cancer reached consensus on a number of issues with implications for standard practice and for research of advanced epithelial ovarian cancer.Five groups of experts considered several issues which included: biologic factors, prognostic factors, surgery, initial chemotherapy, second-line treatment, the use of CA 125, investigational drugs, intra-peritoneal treatment and high-dose chemotherapy. The group attempted to arrive at answers to questions such as: Are there prognostic factors, which help to identify patients who will not do well with current therapy? What is the current best therapy for advanced ovarian carcinoma? What directions should research take in advanced ovarian cancer? These issues were discussed in a plenary meeting.One of the major conclusions drawn by the consensus committee was that in previously untreated advanced ovarian cancer, cisplatin plus paclitaxel has been shown to be superior to previous standard therapy with cisplatin plus cyclophosphamide (level I evidence). However, for many patients, carboplatin plus paclitaxel is a reasonable alternative because of toxicity and convenience considerations. Most participants felt that the benefits in terms of toxicity for the paclitaxel-carboplatin are such that its widespread adoption at this stage is justified. Until mature survival data are available a minority of investigators would recommend continued use of cisplatin plus paclitaxel, specifically for those patients with advanced disease with the best prognostic characteristics. For future clinical research in this area, new end points for randomised clinical trials, together with a new Trials Network, are proposed.

View details for Web of Science ID 000080354700016

View details for PubMedID 10219460
Basic research: how much do we know, and what are we likely to learn about ovarian cancer in the near future? Workshop on Advanced Ovarian Cancer - What Do We Know and What Do We Need HAMILTON, T. C., Berek, J. S., Kaye, S. B. OXFORD UNIV PRESS. 1999: 69–73
Abstract

The scientific community, which studies ovarian cancer in the laboratory, is making progress in understanding many aspects of the disease. At present there is evidence that the cancer prone ovary has a preneoplastic phenotype. These genetic changes may constitute a surrogate intermediate end-point biomarker of cancer risk, which might be altered by preventive measures. Studies that aim at understanding the genetic basis of the disease are reviewed. Many of these studies use clinical ovarian cancer samples. To augment study of clinical specimens, an experimental system has been developed where malignancy is induced in the rat ovarian surface epithelium (ROSE). This system markedly facilitates examination of how genes fit into the ovarian cancer puzzle. The problem of drug resistance in ovarian cancer has received considerable attention. Although the functional changes responsible for resistance have been identified there has been little progress in identifying the actual genes capable of conferring the substantial resistance seen in cell lines.

View details for Web of Science ID 000080354700013

View details for PubMedID 10219457
Surgery during chemotherapy and at relapse of ovarian cancer Workshop on Advanced Ovarian Cancer - What Do We Know and What Do We Need Berek, J. S., Trope, C., Vergote, I. OXFORD UNIV PRESS. 1999: 3–7
Abstract

During chemotherapy and after relapse several types of operations are used in ovarian cancer: secondary cytoreductive surgery, interval cytoreductive surgery, second-look surgery, and palliative secondary surgery. The role of these operations has been difficult to define because there is considerable variation in the patterns of behaviour of tumours among those with persistent or recurrent disease. The definitions, indications and impact of these procedures are reviewed.

View details for Web of Science ID 000080354700002

View details for PubMedID 10219446
A phase II study of intraperitoneal cisplatin and thiotepa in residual ovarian carcinoma. A gynecologic oncology group study GYNECOLOGIC ONCOLOGY Feun, L. G., Blessing, J. A., Major, F. J., Disaia, P. J., Alvarez, R. D., Berek, J. S. 1998; 71 (3): 410-415
Abstract

Patients with advanced epithelial ovarian cancer treated with salvage therapy using new combinations of systemic chemotherapy, radiation therapy, and systemic immunotherapy have had limited success. Since the most common site of relapse or failure to conventional systemic chemotherapy has been the peritoneal cavity, intraperitoneal (IP) chemotherapy was selected to treat small-volume residual disease.Sixty-five patients were entered on a protocol using intraperitoneal cisplatin and thiotepa following a response to intravenous cisplatin-based chemotherapy. Patients had surgically documented residual disease (0.5 cm or less maximum tumor diameter) at completion of preprotocol surgery and had no clinical, radiologic, or histologic evidence of extraperitoneal disease. Cisplatin (100 mg/m2) and thiotepa 30 mg/m2 was delivered intraperitoneally every 4 weeks for a maximum of six cycles. The dose of thiotepa was reduced to 12 mg/m2 due to unexpected severe myelosuppression.Of the 52 evaluable patients, grade 4 neutropenia, thrombocytopenia, neurotoxicity, and nephrotoxicity were observed in 31, 19, 13, and 6% of patients, respectively. For all evaluable patients, the complete response rate was 19% and the partial response rate was 2% for a total response rate of 21%. Of 16 patients who had a reassessment laparotomy, 10 patients achieved a surgically documented complete response and 1 patient had a partial response. Four patients are still in response for 67+, 70+, 70+, and 73+ months after third-look surgery. Three patients who did not undergo third-look surgery after chemotherapy are alive and clinically free of disease at 49+, 69+, and 85+ months.Thiotepa, when used with cisplatin for IP salvage therapy in patients with advanced or recurrent ovarian cancer, may produce significant myelosuppression and doses must be adjusted accordingly. In cisplatin-sensitive patients with small-volume residual ovarian cancer, IP cisplatin and thiotepa appears to have activity. Determining the utility of this approach will require a randomized trial.

View details for Web of Science ID 000078029000015

View details for PubMedID 9887240
Combination of transforming growth factor beta antisense and interleukin-2 gene therapy in the murine ovarian teratoma model GYNECOLOGIC ONCOLOGY Dorigo, O., Shawler, D. L., Royston, I., SOBOL, R. E., Berek, J. S., Fakhrai, H. 1998; 71 (2): 204-210
Abstract

The immunosuppressive protein transforming growth factor beta (TGF-beta) inhibits the activation of various immune effector cells including cytotoxic T lymphocytes and may therefore inhibit the efficacy of immunostimulatory interleukin-2 (IL-2) gene therapy. In this study, we investigated the effect of TGF-beta downregulation on IL-2 gene therapy in the intraperitoneal model of murine ovarian teratoma (MOT). MOT cells, like many human ovarian carcinomas, were found to produce TGF-beta. Production of TGF-beta by MOT cells was suppressed using a TGF-beta antisense plasmid vector (pCEP4/TGF-beta antisense). Subcutaneous immunization of C3H mice with a mixture of IL-2 gene-transduced fibroblasts and TGF-beta antisense-modified MOT cells induced significantly better protection against a subsequent intraperitoneal tumor challenge compared with immunization with unmodified MOT cells alone [11/16 (69%) vs 4/21 (19%) tumor-free animals, P < 0.01]. Immunization with either a mixture of IL-2 gene modified fibroblasts and unmodified MOT cells [2/12 (17%) tumor-free animals] or TGF-beta antisense-modified MOT cells alone (0/13 tumor free animals) failed to induce significant protection compared with immunization with unmodified MOT cells. These data show that combined TGF-beta antisense and IL-2 gene therapy is required to generate effective antitumor responses in the MOT model. Our findings suggest that tumor cell expression of immunosuppressive factors may inhibit cytokine immunogene therapy and may have potential implications for the development of future clinical immunogene therapy protocols.

View details for Web of Science ID 000077351700010

View details for PubMedID 9826461
Psammocarcinoma with an aggressive course OBSTETRICS AND GYNECOLOGY Poggi, S. H., Bristow, R. E., Nieberg, R. K., Berek, J. S. 1998; 92 (4): 659-661
Abstract

Psammocarcinoma is an unusual variant of serous cystadenocarcinoma characterized by heavy deposits of psammoma bodies. This disease has been suggested to be similar to carcinomas of low malignant potential in its indolent clinical course. We present this case report of an aggressive course of this disease to alert others that psammocarcinoma may not always follow a benign course.A 66-year-old woman underwent staging laparotomy for bilateral ovarian cystadenofibromata with rare foci of borderline serous tumors and several small bowel peritoneal surface nodules showing infiltrating psammocarcinoma. She was not recommended for adjuvant therapy because of the previously reported indolent course of this disease. Eighteen months later she represented with small bowel obstruction and underwent an exploratory laparotomy that demonstrated diffuse recurrence of the psammocarcinoma.Psammocarcinoma may have a more aggressive course than has been suggested. Patients with this disease should have optimal tumor debulking. There may be a role for adjuvant therapy in its treatment.

View details for Web of Science ID 000076159900009

View details for PubMedID 9764653
Reducing loss-to-follow-up among women with abnormal Pap smears - Results from a randomized trial testing an intensive follow-up protocol and economic incentives MEDICAL CARE Marcus, A. C., Kaplan, C. P., Crane, L. A., Berek, J. S., Bernstein, G., Gunning, J. E., McClatchey, M. W. 1998; 36 (3): 397-410
Abstract

This study evaluates the efficacy of two interventions designed to reduce loss-to-follow-up among women with abnormal Pap smears.The two interventions were evaluated in two large public hospitals using a randomized 2 x 2 factorial design. One intervention involved an intensive follow-up protocol that relied on multiple attempts (mail and telephone) to contact the patient. The second intervention provided patients with economic vouchers to offset out-of-pocket expenses associated with the follow-up visits. Loss-to-follow-up was addressed by medical chart reviews and telephone interviews.The study population (n = 1453) was primarily Hispanic, married or otherwise living with a significant other, relatively young in age, and with no source of payment for health care. Overall, 30% of the total sample was loss-to-follow-up (i.e., no return visits). Among patients assigned to the control condition, loss-to-follow-up was 36.1% compared with 27.8% for the intensive follow-up condition, 28.8% for the voucher condition, and 29.0% for the intensive follow-up plus voucher condition. Both intervention conditions significantly improved follow-up rates. The odds ratio for intensive follow-up was 1.56 compared with 1.50 for the voucher intervention. The combined intervention condition (intensive follow-up x voucher program) did not have a significant effect after taking into account the main effects of the two interventions. Correlates of loss-to-follow-up included age (younger women had lower return rates), race/ethnicity (African American women had lower return rates), live-in relationship (women who were not married or living as married had lower return rates), and severity of the abnormal Pap smear (less severe abnormalities were associated with lower return rates).Both interventions were associated with moderate reductions in loss-to-follow-up in this underserved population. The implications of these findings are discussed relative to implementing cervical cancer control programs within state and local health departments.

View details for Web of Science ID 000072467300015

View details for PubMedID 9520963
Diagnostic and therapeutic advances in gynecologic oncology: screening for gynecologic cancer. Cancer treatment and research Kim, Y. B., Ghosh, K., Ainbinder, S., Berek, J. S. 1998; 95: 253-276
Abstract

Endometrial carcinoma is associated with a good prognosis because patients tend to present with early disease. Mass screening is therefore unlikely to be of benefit. High-risk populations may benefit from screening, but no prospective studies have demonstrated a benefit in any population. The most promising modality for screening appears to be TVS, and a normal TVS may also preclude the need for further evaluation of symptomatic patients. The appropriate use of TVS in patients on tamoxifen is currently unknown. Hysteroscopy and endometrial biopsy may have a role in the evaluation of symptomatic patients but do not appear promising as screening modalities.

View details for PubMedID 9619288
Chemotherapy for ovarian cancer XV FIGO World Congress of Gynaecology and Obstetrics Berek, J. S., Markman, M., McGuire, W. P., Thigpen, J. T., OZOLS, R. F. PARTHENON PUBLISHING GROUP LTD. 1998: 211–218
View details for Web of Science ID 000075567700030
Progress in ovarian cancer CURRENT OPINION IN OBSTETRICS & GYNECOLOGY Chen, L., Berek, J. S. 1998; 10 (1): 51-56
Abstract

The management of advanced ovarian cancer relies on appropriate surgical cytoreduction in conjunction with appropriate adjuvant chemotherapy. In the past year several studies have continued to support aggressive cytoreduction at the initial operation, including for stage IV disease, as well as in a second-look setting. Ongoing research has identified several agents active in ovarian cancer, yet the optimal first-line regimen has yet to be developed.

View details for Web of Science ID 000071663600010

View details for PubMedID 9484630
Conclusions and recommendations from the Helene Harris Memorial Trust Sixth Biennial International Forum on Ovarian Cancer, May 10-14, 1997, Los Angeles, California, USA INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Sharp, F., Blackett, A. D., Berek, J. S., Bast, R. C. 1997; 7 (5): 416-424
View details for Web of Science ID A1997YG58600013
Gene therapy for ovarian cancer: Development of novel treatment strategies INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Dorigo, O., Berek, J. S. 1997; 7 (1): 1-13
Abstract

In the last decade, advances in molecular biology have lead to the development of techniques that permit the manipulation of mammalian cell DNA for diagnostic and therapeutic purposes. Gene therapy has subsequently evolved as a treatment option in patients with malignancies. In this article, we have summarized current strategies in gene therapy for ovarian cancer.

View details for Web of Science ID A1997VZ43800001

View details for PubMedID 12795798
Dysgerminoma: The role of conservative surgery GYNECOLOGIC ONCOLOGY Casey, A. C., Bhodauria, S., Shapter, A., NIEBERG, R., Barek, J. S., FARIASEISNER, R. 1996; 63 (3): 352-357
Abstract

Twenty-five cases of pure ovarian dysgerminoma treated at UCLA Medical Center between 1958 and 1992 were reviewed retrospectively. Patterns of recurrence and overall survival were analyzed with regard to primary surgery (conservative versus nonconservative), use of adjuvant therapy, and stage of disease. Fourteen patients (56%) underwent conservative surgical therapy defined as preservation of the contralateral ovary, 10 patients (40%) had nonconservative primary surgery, and one patient (4%) had chemotherapy as primary treatment. Three patients (12%) received adjuvant chemotherapy and nine patients (36%) received postoperative radiation therapy. Fifteen patients (60%) had stage I disease, four (16%) stage II, and three each (12%) had stage III and IV disease. Nine patients (36%) experienced recurrence of disease. Seven of these nine patients (78%) had stage I disease and all seven had undergone conservative primary surgery with preservation of the contralateral ovary. Six of the seven had received no adjuvant therapy. Only one of these seven patients experienced recurrence in the preserved ovary. She was found to have a dysgenetic ovary and an XY karyotype. Three patients with recurrent disease had received radiation therapy after primary surgery. Twenty patients (80%) were alive without disease at follow-up, two patients (8%) were alive with disease, and three (12%) had died of disease. There was no statistically significant difference in recurrence rates between those patients treated with conservative surgery and those treated with nonconservative surgery, although the total number of patients with recurrences was greater in the former group. Our data suggest that a conservative surgical approach is the preferred treatment in patients with pure dysgerminoma of the ovary who desire future fertility. Lack of adjuvant chemotherapy or radiation therapy, rather than type of initial surgery, may be associated with a higher risk of recurrence.

View details for Web of Science ID A1996VY31800012

View details for PubMedID 8946871
Complete debulking of epithelial ovarian cancer. cancer journal from Scientific American Berek, J. S. 1996; 2 (3): 132-133
View details for PubMedID 9166511
Mixed mesodermal sarcoma of the ovary in a young patient EUROPEAN JOURNAL OF OBSTETRICS GYNECOLOGY AND REPRODUCTIVE BIOLOGY Fowler, J. M., Nathan, L., Nieberg, R. K., Berek, J. S. 1996; 65 (2): 249-253
Abstract

Mixed mesodermal tumors (MMT) of the ovary are rare and have a poor prognosis. This ovarian malignancy usually occurs in postmenopausal women. We report an unusual ovarian MMT in a young woman given treatment similar to one used for ovarian germ cell malignancies. We believe this is the youngest patient reported with an homologous MMT of the ovary.

View details for Web of Science ID A1996UD59400018

View details for PubMedID 8730635
Evidence for a unifocal origin in familial ovarian cancer 14th Annual Meeting of the American-Gynecological-and-Obstetrical-Society Gallion, H. H., Guarino, D., DePriest, P. D., VANNAGELL, J. R., Vaccarello, L., Berek, J. S., Pieretti, M. MOSBY-ELSEVIER. 1996: 1102–6
Abstract

The purpose of this investigation was to determine the pattern of loss of heterozygosity in multiple tumor sites from familial ovarian cancer cases. If ovarian cancer arises focally in one ovary and then metastasizes to other sites, a similar pattern should be seen in all tumor sites. However, if ovarian cancer arises multifocally throughout the peritoneal cavity, a different pattern of loss would be expected among the different sites.The presence or absence of loss of specific alleles for 9 loci on chromosomes 1, 6, 11, 13, 16, and 17 was determined in multiple tumor sites from 12 familial ovarian cancer cases.The frequency of loss of heterozygosity was as follows: chromosome 17 (100%), chromosome 13 (82%), chromosome 6 (80%), chromosome 16 (73%), chromosome 1 (57%), and chromosome 11 (22%). In every case an identical pattern was present for at least one locus. In four cases loss of the same allele was present in tumor from the ovary and all metastatic sites for all informative loci. In the remaining eight cases loss of the same allele for one to five (mean three) loci was detected.The pattern of loss of heterozygosity in the 12 familial ovarian cancers included in this investigation favors a unifocal origin of disease. A dual primary origin could not be absolutely excluded in 3 cases. High frequencies on chromosomes 17q and 13 suggest that loss of whole or part of these chromosomes is important in ovarian carcinogenesis.

View details for Web of Science ID A1996UH18400004

View details for PubMedID 8623836
Vascular endothelial growth factor expression is not regulated by estradiol or medroxyprogesterone acetate in endometrial carcinoma GYNECOLOGIC ONCOLOGY Kim, Y. B., Berek, J. S., MARTINEZMAZA, O., Satyaswaroop, P. G. 1996; 61 (1): 97-100
Abstract

To determine whether the expression of vascular endothelial growth factor (VEGF) is altered by treatment in an in vivo tumor with 17 beta-estradiol (E2) or medroxyprogesterone acetate (MPA).A well-differentiated endometrial carcinoma tumor was isolated from a patient and explanted into the dorsal skin of ovariectomized nude mice, from which it was serially passaged in vivo. The explanted tumor retained all the properties of the original tumor, including estrogen and progesterone receptor expression and growth promotion and inhibition by E2 and MPA, respectively. The mice were treated with continuous E2 administration followed by treatment with either a single intramuscular administration of 2 mg MPA or weekly administrations of 2 mg MPA. Untreated tumor-bearing mice served as controls. The tumors were harvested at 0 to 21 days from first MPA administration. RNA from the tumors was isolated and VEGF expression was determined by Northern analysis.VEGF was expressed in the absence of treatment with E2 or MPA, and expression was unaltered by continuous treatment with E2. Additional treatment with a single does of MPA did not alter expression at Days 1, 2, 3, 7, 14, and 21, and additional treatment with E2 or E2 + MPA. Regulation of VEGF expression is not a mechanism by which these hormones exert their growth effects on endometrial tumors.

View details for Web of Science ID A1996UC96100019

View details for PubMedID 8626126
Complications of pelvic radiation therapy for gynecologic malignancies in elderly women INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER McGonigle, K. F., Lavey, R. S., Juillard, G., Berek, J. S. 1996; 6 (2): 149-155
View details for Web of Science ID A1996UC12900013
OVARIAN-CANCER SCREENING - THE USE OF SERIAL COMPLEMENTARY TUMOR-MARKERS TO IMPROVE SENSITIVITY AND SPECIFICITY FOR EARLY DETECTION 5th National Conference of the American-Cancer-Society on Gynecologic Cancers Berek, J. S., Bast, R. C. WILEY-LISS. 1995: 2092–96
Abstract

The use of serum tumor markers for the early detection of ovarian cancer has been limited because of their low sensitivity and low positive predictive value. CA 125 levels are elevated in only about one half of women with Stage I ovarian cancer, thus researchers have focused on using the serial measurement of complementary markers to improve the sensitivity, specificity, and positive predictive value of this approach for screening.Multiple serum markers have been analyzed in women with early stage epithelial ovarian cancer. CA 125, CA 15-3, C19-9, CA 54-61, CA 72-4, CEA, HMFG2, IL-6, IL-10, LSA, M-CSF, NB70K, OVX1, PLAP, TAG72, TNF, TPA, and UGTF have been studied alone and in combination in this setting. Complementarity and logistic regression analyses have been performed to assess those markers with the highest likelihood of improving sensitivity and specificity for early detection. Serial analysis of a second-generation CA 125 measuring the intercept (initial level) and slope (change of levels over time) can be used to discriminate malignant cases from benign and normal cases.Analyses have shown that the serial measurement of the new, more sensitive CA 125 has a high sensitivity (83%), specificity (99.7%), and positive predictive value (16%) for the early detection of ovarian cancer. OVX1 used in combination with CA 125 provides the best complementarity. Serial measurements of the two markers have sensitivities in the range of that for transvaginal ultrasonography.The serial measurement of complementary serum markers can improve the use of marker screening for epithelial ovarian cancer. With the use of several different methods of analysis, it has been shown that this approach improves the sensitivity, specificity, and positive predictive value of serum markers CA 125 and OVX1. A procedure that measures complementary serum markers over time can be used as a primary screening technique followed by transvaginal ultrasonography. This could provide a cost-effective means of early detection and could significantly decrease the probability of surgical intervention for false-positive test results.

View details for Web of Science ID A1995TE56300029

View details for PubMedID 8635006
CONCLUSIONS AND RECOMMENDATIONS FROM THE HELENE-HARRIS-MEMORIAL-TRUST 5TH BIENNIAL INTERNATIONAL FORUM ON OVARIAN-CANCER, MAY 4-7, 1995, GLASGOW, UK INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Sharp, F., Blackett, A. D., Leake, R. E., Berek, J. S. 1995; 5 (6): 449-458
View details for Web of Science ID A1995TE83200009
RADIATION-THERAPY FOR ADENOCARCINOMA OF THE UTERINE CERVIX - DOES THE HISTOLOGY MATTER INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Berek, J. S. 1995; 32 (5): 1543-1544
View details for Web of Science ID A1995RM87800035

View details for PubMedID 7635801
OVARIAN-CANCER SPREAD - IS LAPAROSCOPY TO BLAME LANCET Berek, J. S. 1995; 346 (8969): 200-200
View details for Web of Science ID A1995RK41900006

View details for PubMedID 7616797
ASSESSMENT OF DOSE-INTENSIVE THERAPY IN SUBOPTIMALLY DEBULKED OVARIAN-CANCER - A GYNECOLOGIC-ONCOLOGY-GROUP STUDY JOURNAL OF CLINICAL ONCOLOGY McGuire, W. P., Hoskins, W. J., Brady, M. F., Homesley, H. D., Creasman, W. T., Berman, M. L., Ball, H., Berek, J. S., Woodward, J. 1995; 13 (7): 1589-1599
Abstract

We report a prospective randomized trial in women with advanced ovarian cancer to evaluate the importance of chemotherapy dose-intensity on survival, progression-free survival (PFS), and response.A total of 485 patients with epithelial ovarian cancer and residual masses more than 1 cm following surgery (stage III presentation) or any stage IV presentation were randomly assigned to receive either standard therapy (cyclophosphamide 500 mg/m2 and cisplatin 50 mg/m2 intravenously every 3 weeks for eight courses) or intense therapy (cyclophosphamide 1,000 mg/m2 and cisplatin 100 mg/m2 intravenously every 3 weeks for four courses). Dose modification was rigidly controlled to maintain intensity. Clinical and pathologic responses were assessed, when appropriate, as well as PFS interval and survival.A total of 458 patients met all eligibility criteria and were assessed for survival and PFS. The dose-intensive group received the same total dose of cyclophosphamide and cisplatin, but 1.97 times greater dose-intensity than the standard group. Clinical and pathologic response rates; response duration, and survival were similar in both groups of patients. Hematologic, gastrointestinal, febrile episodes, septic events, and renal toxicities were significantly more common and severe in the dose-intensive group.A doubling of the dose-intensity in the treatment of bulky ovarian epithelial cancers led to no discernible improvement in patient outcome and was associated with more severe toxicity. This study provides no evidence to support the hypothesis that modest increases in dose-intensity without increasing total dose are associated with significant improvement in overall survival or PFS.

View details for Web of Science ID A1995RG15700010

View details for PubMedID 7602348
INTERVAL DEBULKING OF OVARIAN-CANCER - AN INTERIM MEASURE NEW ENGLAND JOURNAL OF MEDICINE Berek, J. S. 1995; 332 (10): 675-677
View details for Web of Science ID A1995QK06600010

View details for PubMedID 7845434
INTRAPERITONEAL ADMINISTRATION OF CISPLATIN AND 5-FLUOROURACIL IN RESIDUAL OVARIAN-CANCER - A PHASE-II GYNECOLOGIC-ONCOLOGY-GROUP TRIAL GYNECOLOGIC ONCOLOGY Braly, P. S., Berek, J. S., Blessing, J. A., Homesley, H. D., Averette, H. 1995; 56 (2): 164-168
Abstract

Forty-eight patients with persistent or recurrent epithelial ovarian cancer who had persistent or recurrent disease following intravenous (i.v.) cisplatin-based chemotherapy were treated with intraperitoneal (ip) cisplatin and 5-fluorouracil (5-FU) as salvage therapy. All patients had surgically documented minimal residual disease (1.0 cm or less maximum tumor diameter) at the completion of surgery and were without clinical, radiographic, or histologic evidence of extraperitoneal disease. Of the 45 patients evaluable for response, 13 had a documented partial response (PR) or complete response (CR) to previously administered i.v. cisplatin (cisplatin-sensitive) while the remaining 32 patients were noted to have stable or progressive disease on the previous i.v. cisplatin regimen (cisplatin-refractory). The median number of treatment cycles was six. At the completion of eight cycles of chemotherapy, 22 patients had no clinical or radiographic evidence of persistent disease and were thus eligible for a third-look laparotomy. Seven patients refused surgical evaluation. Three of the 15 patients who underwent a third-look laparotomy had a pathologic complete response (PCR) while 3 other patients had surgically documented partial response. All the surgically documented responses were in cisplatin-sensitive patients for a surgically documented response rate in this patient population of 66.7% (3 of 9 PCR and 3 of 9 PR). The remaining nine patients, who were all previously cisplatin-refractory, had stable or progressive disease documented at third-look laparotomy. Thirty-four patients experienced leukopenia with a median WBC nadir of 2800/microliters while 12 patients experienced thrombocytopenia with the median platelet nadir of 122,000/microliters. There was one treatment-related death secondary to sepsis. Four patients experienced catheter-related complications, ip cisplatin and 5-FU as salvage therapy is feasible in a multi-institutional cooperative group trial and, in cisplatin-sensitive patients, is an effective treatment option.

View details for Web of Science ID A1995QN34000003

View details for PubMedID 7896179
Conclusions and recommendations from the Helene Harris Memorial Trust Fifth Biennial International Forum on Ovarian Cancer, May 4-7, 1995, Glasgow, UK. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society Sharp, F., Blackett, A. D., Leake, R. E., Berek, J. S. 1995; 5 (6): 449–58
Abstract

The Fifth Biennial International Forum on Ovarian Cancer was held by the Helene Harris Memorial Trust in Glasgow, UK. The main points of the presentations given by the invited speakers, together with the fruits of extensive discussions are presented here as a series of conclusions and recommendations which should be given consideration by all those having an interest in researching or treating ovarian cancer. The individual points are grouped into topics considering whether there is an identifiable ovarian pro-cancer, whether ovarian cancer is preventable, advances in familial ovarian cancer, its molecular genetics, ways of optimizing treatment, obstacles to successful treatment and approaches to gene therapy.

View details for PubMedID 11578520
A MULTICENTER STUDY OF LAPAROSCOPIC MANAGEMENT OF SELECTED CYSTIC ADNEXAL MASSES IN POSTMENOPAUSAL WOMEN JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Parker, W. H., Levine, R. L., Howard, F. M., SANSONE, B., Berek, J. S. 1994; 179 (6): 733-737
Abstract

The objective of this study was to determine the ability to predict benign adnexal masses in postmenopausal women and to evaluate the effectiveness of laparoscopic management in selected patients.Postmenopausal women found to have an adnexal mass were prospectively evaluated with clinical examination, sonography, and serum CA-125 levels. Women with cystic masses greater than 3 cm but less than 10 cm, with distinct borders, without solid parts or septations greater than 2 mm, without ascites or matted bowel, and with serum CA-125 levels less than 35 IU per mL were operated upon by laparoscopy.Sixty-one women gave consent for the study. Cyst size ranged from 3 to 10 cm. All masses were accurately predicted to be benign. Fifty-eight (95 percent) women were successfully managed by operative laparoscopy and three required laparotomy. For the patients managed by laparoscopy, the mean operative time was 63 minutes, the mean postoperative hospitalization period was 12 hours, and the mean return to normal activity was 5.6 days.The combination of clinical examination, sonographic appearance and serum CA-125 levels can accurately predict benign masses in postmenopausal women. Operative laparoscopy is acceptable for these patients and provides for a short period of hospitalization and a rapid recovery.

View details for Web of Science ID A1994PV57200015

View details for PubMedID 7952486
PROGNOSTIC IMPORTANCE OF INTRAOPERATIVE RUPTURE OF MALIGNANT OVARIAN EPITHELIAL NEOPLASMS OBSTETRICS AND GYNECOLOGY Parker, W. H., Berek, J. S. 1994; 84 (5): 897-897
View details for Web of Science ID A1994PN55100036

View details for PubMedID 7936536
CYTOTOXICITY OF NEW AZA-ALKYL LYSOPHOSPHOLIPIDS AGAINST DRUG-SENSITIVE AND RESISTANT HUMAN OVARIAN TUMOR-CELL LINES - ROLE OF FREE-RADICALS AND POTENTIATION OF CYTOTOXICITY BY TNF-ALPHA AND CDDP ONCOLOGY REPORTS Hourizadeh, A., Broquet, C., MENCIAHUERTA, J. M., BRAQUET, P., Berek, J., Bonavida, B. 1994; 1 (6): 1253-1259
Abstract

Three aza-alkyl lysophospholipids (AALP) with related chemical structures (BN52205, BN52218, BN52227) were examined for their anti-tumor cytotoxic activity when used alone or in combination with TNF-alpha or CDDP. The three compounds were cytotoxic, though to a different degree, against a battery of human ovarian tumor cell lines. The compounds were cytotoxic to both drug sensitive and drug resistant lines and were also cytotoxic to an MDR(+) tumor cell line. BN52205 was the most potent cytotoxic AALP and differed from the least cytotoxic compound BN52227 by a substitution of a methoxy group for an ethoxy group at position 1. The AALP-mediated cytotoxicity was found to be mediated in large part by free radicals as: i) treatment of the tumor cells with an inhibitor of glutathione biosynthesis, buthionine sulfoximine (BSO), augmented cytotoxicity and often resulted in synergy and ii) the addition of the anti-oxidant glutathione inhibited cytotoxicity. Since free radicals have also been involved in both TNF-alpha and CDDP-mediated cytotoxicity, we examined the potentiating effect of combination treatment of AALP with these cytotoxic agents. Depending on the cell line, there was either an additive or a synergistic activity by the combination treatment. Furthermore, combination of BN52205 and TNF-alpha resulted in a synergistic activity against the MDR(+) ovarian line, AD10, and the cis-platinum resistant line, C30. These results demonstrate that AALP are cytotoxic to tumor cell lines and can overcome drug resistance. Further, low concentrations of AALP and TNF-alpha/drug/BSO result in additive or synergistic cytotoxic activity. These findings suggest that combination treatment can be effective in the therapy of drug resistant ovarian tumors and can achieve reduced overall toxicity.

View details for Web of Science ID A1994PX14500040

View details for PubMedID 21607526
THE INFLUENCE OF TUMOR GRADE, DISTRIBUTION, AND EXTENT OF CARCINOMATOSIS IN MINIMAL RESIDUAL STAGE-III EPITHELIAL OVARIAN-CANCER AFTER OPTIMAL PRIMARY CYTOREDUCTIVE SURGERY GYNECOLOGIC ONCOLOGY FARIASEISNER, R., Teng, F., Oliveira, M., Leuchter, R., Karlan, B., Lagasse, L. D., Berek, J. S. 1994; 55 (1): 108-110
Abstract

The purpose of this study was to determine the influence of tumor grade, distribution, and extent of carcinomatosis in minimal residual epithelial ovarian cancer after primary optimal cytoreductive surgery. Between 1978 and 1990, 112 patients with stage III epithelial ovarian cancer underwent primary cytoreductive surgery and had minimal residual disease, i.e., < 5 mm maximum diameter of residual tumor nodules. Seventy-eight patients (70%) had operative reports that contained sufficient detail to be included in this study. We retrospectively reviewed histopathological reports to determine tumor grade, operative and clinical notes to determine one predominant distribution pattern of residual metastases (pelvic/omental, diaphragmatic, or intestinal/mesenteric), and the approximate extent of residual disease (no gross disease, scattered nodules, or extensive carcinomatosis). Standard actuarial survival analysis was performed, and the log-rank chi 2 was used. At the mean follow-up time of 24.4 months, survival was 65% for grade 2 or 3 disease versus 93% for grade 1 (log-rank P < 0.01). Survival was 66% for residual disease in the intestines/mesentery versus 70 and 81% for residual disease in the diaphragm and pelvis/omentum, respectively (log-rank P < 0.03). Survival was 48% for residual extensive carcinomatosis versus 76 and 93% for minimal residual nodules and no gross residual, respectively (log-rank P < 0.001). In conclusion, in women who have minimal residual ovarian cancer after primary cytoreductive surgery, tumor grade and the distribution and extent of carcinomatosis can independently affect survival. The shortest survival correlated with high-grade tumor and extensive carcinomatosis predominantly involving the intestines and mesentery.

View details for Web of Science ID A1994PP04600022

View details for PubMedID 7959250
Papillary serous cystadenocarcinoma arising in benign glandular inclusion cysts in pelvic and inguinal lymph nodes. Obstetrics and gynecology Casey, A. C., Berek, J. S. 1994; 84 (4): 724-726
Abstract

Benign glandular inclusion cysts occurring within lymph nodes have been well described in the literature. However, the malignant potential of these glands is unknown. One previous case report described an adenoacanthoma arising within one of these glands.A 65-year-old woman was previously diagnosed with papillary serous cystadenocarcinoma in the inguinal and pelvic lymph nodes. She had no tumor involving the ovaries or peritoneal surfaces at the time of initial diagnosis. She presented to us 9 years later with a recurrence of this tumor in the obturator fossa and along the vaginal sidewall. Treatment consisted of surgery, radiation, and chemotherapy.Although rare, müllerian tumors can occur in the lymph nodes without simultaneous ovarian or peritoneal involvement, and most likely arise de novo within lymph node inclusion cysts.

View details for PubMedID 9205465
Advances in the biology of gynecologic cancer. Current opinion in oncology Gotlieb, W. H., Berek, J. S. 1994; 6 (5): 513-518
Abstract

This review discusses recent insights into the roles of the p53 tumor-suppressor gene and growth factors in the development of ovarian cancer and describes the genes implicated in familial ovarian cancer syndromes related to the MSH2 (Lynch II) and BRCA1 (breast and ovarian cancer) genes. Evidence of the monoclonality of ovarian cancer, which contrasts with data supporting the polyclonal origin of primary peritoneal carcinoma, is presented. Finally, the roles of the human papillomavirus and the HIV virus in the etiology of cervical cancer are analyzed in view of the growing importance of this HIV-associated cancer and the poor outcome in these patients.

View details for PubMedID 7827156
SALVAGE THERAPY FOR RECURRENT AND REFRACTORY OVARIAN-CANCER WITH HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS BONE-MARROW SUPPORT - A GYNECOLOGIC-ONCOLOGY-GROUP PILOT-STUDY GYNECOLOGIC ONCOLOGY Broun, E. R., Belinson, J. L., Berek, J. S., McIntosh, D., Hurd, D., Ball, H., Williams, S. 1994; 54 (2): 142-146
Abstract

Nine patients with recurrent or refractory epithelial ovarian carcinoma following previous chemotherapy were treated with high-dose carboplatin (300 mg/m2) and ifosfamide according to a dose escalation schedule (1.50, 1.75, 2.00 g/m2), each given intravenously daily for 5 days with autologous bone marrow support. Eight of the nine patients were evaluable for response. Five achieved complete response (CR), all of whom relapsed at 4, 5, 6, 8, and 23 months following treatment. Two partial responses persisted for 6 months, and one patient with stable disease progressed after 2 months and has since died of disease. The median duration of remission was 6 months. The treatment was well tolerated across the doses of ifosfamide with the exception of one treatment-related death which was due to acute renal failure and central nervous system toxicity from ifosfamide. It appears that the use of high-dose chemotherapy with autologous bone marrow support in the treatment of ovarian cancer produced a high rate of response of short duration in this small group of heavily pretreated women.

View details for Web of Science ID A1994PC29000006

View details for PubMedID 8063237
Management of Selected Adnexal Masses in Postmenopausal Women by Operative Laparoscopy-A Multicentered Study journal of the American Association of Gynecologic Laparoscopists Parker, Levine, Howard, SANSONE, Berek 1994; 1 (4): S27-?
Abstract

With careful preoperative assessment we have selected postmenopausal women who were believed to have benign adnexal masses and who were candidates for removal of these masses via operative laparoscopy. Criteria for inclusion were: postmenopausal status; cystic adnexal mass less than 10 cm. with distinct borders and without irregular solid parts or thick septa; CA 125<35 U/ml; and no contraindications for surgery. Sixty-one women were entered into the study. All of the masses were benign, including 27 serous cysts, 15 serous cystadenomas, 1 mucinous cystadenoma, 5 serous cystadenofibromas, 6 paratubal cysts, 3 retroperitoneal cysts, and 4 chronic hydrosalpinges. Fifty-eight patients had successful pelviscopic removal of their adnexal mass. Three patients (5%) required laparotomy. For patients managed by operative laparoscopy, mean operating time was 63 minutes, mean postoperative stay was 12 hours, and mean time to return to normal activity was 5.6 days. We conclude that the combination of CA 125 values and pelvic ultrasound can successfully predict benign masses in postmenopausal women, and removal of these masses by operative laparoscopy is acceptable in carefully selected women.

View details for PubMedID 9073734
SURGICAL-MANAGEMENT OF OVARIAN-CANCER SEMINARS IN SURGICAL ONCOLOGY FARIASEISNER, R., Kim, Y. B., Berek, J. S. 1994; 10 (4): 268-275
Abstract

Although several surgical approaches to the diagnosis and management of epithelial ovarian cancer are now standard, surprisingly few prospective data exist to support many of these procedures. However, retrospective data have accumulated over the past decade, much of it very recent, which allow clinicians to make informed decisions regarding most of the commonly performed procedures. This review is an attempt to critically evaluate the best available data regarding the following procedures: primary surgical staging, primary cytoreductive surgery, second look laparotomy and secondary cytoreductive surgery, and palliative surgery for relief of bowel obstruction. We conclude that there is evidence to support the continued use of primary surgical staging and primary cytoreductive surgery. However, data in support of second look laparotomy and secondary cytoreductive surgery are lacking, and we recommend that these procedures not be performed on a routine basis. Finally, we conclude that palliative surgery is hazardous at best and results in questionable benefits for most patients.

View details for Web of Science ID A1994NX26600006

View details for PubMedID 7522338
THE EFFECT OF DIAMETER OF LARGEST RESIDUAL DISEASE ON SURVIVAL AFTER PRIMARY CYTOREDUCTIVE SURGERY IN PATIENTS WITH SUBOPTIMAL RESIDUAL EPITHELIAL OVARIAN-CARCINOMA 12th Annual Meeting of the American-Gynecological-and-Obstetrical-Society Hoskins, W. J., McGuire, W. P., Brady, M. F., Homesley, H. D., Creasman, W. T., Berman, M., Ball, H., Berek, J. S. MOSBY-YEAR BOOK INC. 1994: 974–80
Abstract

The Gynecologic Oncology Group has divided patients with advanced epithelial ovarian cancer into those with optimal residual cancer, in which the maximum diameter of residual is < or = 1 cm, and suboptimal residual cancer, in which the residual disease is > 1 cm. Within the optimal group of patients there is a survival difference between patients with microscopic residual disease and those with any macroscopic disease < or = 1 cm. No analysis of the effect of various residual disease diameters in patients with residual disease > or = 1 cm has been performed. This study evaluates the effect of residual disease diameter in patients with suboptimal disease entered on a randomized trial of intense versus standard chemotherapy.Gynecologic Oncology Group protocol 97 compared cisplatin 50 mg/m2 and cyclophosphamide 500 mg/m2 for eight courses with the same drugs at 100 mg/m2 and 1000 mg/m2 for four courses, respectively. There was no difference in progression-free interval or survival between the two arms. Of the 458 stage III (with residual disease > 1 cm) and stage IV patients entered in this study, 294 stage III patients comprise the current analysis. Surgical reporting forms, operation reports, and pathology reports were reviewed to determine initial greatest tumor diameter and residual tumor diameter. Patients were grouped by residual diameter. Multivariate analysis considered residual diameter of disease, age, histologic characteristics, performance status, and ascites. An adjusted relative hazard of dying of ovarian cancer was calculated for each residual disease group.Patients ranged in age from 20 to 80 years, with a median of 60 years. All patients were Gynecologic Oncology Group performance status 0 to 2. Fifty-two percent had grade 3 tumors, and 39% and 9%, respectively, had grade 2 or 1 tumors. All patients had stage III disease. Ninety percent had serous, endometrioid, or mixed epithelial cell type tumors. Multivariate analysis revealed a relative risk of dying as follows: residual disease < 2 cm, relative risk 1.00; 2 to 2.9 cm, relative risk 1.90; 3 to 3.9 cm, relative risk 1.91; 4 to 5.9 cm, relative risk 1.74; 6 to 7.9 cm, relative risk 1.85; 8 to 9.9 cm, relative risk 2.16; > or = 10 cm, relative risk 1.82. The difference in survival between those with < 2 cm residual disease and those with > or = 2 cm residual disease was significant (p < 0.01). There is no significant difference in the risk of dying between groups with residual disease > or = 2 cm.Among patients with suboptimal (> 1 cm residual disease) epithelial ovarian cancer, those who have small diameter residual disease (< 2 cm) tend to survive longer than those who have larger residual disease. Among those with larger residual disease, size does not affect prognosis appreciably.

View details for Web of Science ID A1994NG74200003

View details for PubMedID 8166218
CYTOKINE-INDUCED MODULATION OF TUMOR-SUPPRESSOR GENE-EXPRESSION IN OVARIAN-CANCER CELLS - UP-REGULATION OF P53 GENE-EXPRESSION AND INDUCTION OF APOPTOSIS BY TUMOR-NECROSIS-FACTOR-ALPHA 12th Annual Meeting of the American-Gynecological-and-Obstetrical-Society Gotlieb, W. H., Watson, J. M., Rezai, A., Johnson, M., MARTINEZMAZA, O., Berek, J. S. MOSBY-YEAR BOOK INC. 1994: 1121–30
Abstract

Our purpose was to determine the effect of tumor necrosis factor-alpha on anti-oncogene expression and to investigate the relationship between the up-regulation of the p53 tumor suppressor gene and tumor necrosis factor-alpha-mediated apoptosis in epithelial ovarian cancer cell lines.By means of Northern blot techniques p53 messenger ribonucleic acid expression was assayed in ovarian cancer cells. Tumor cells explanted from patients into Balb/c nude mice were exposed to supernatants from activated monocytes, activated T cells, or the recombinant cytokines interleukin-6 and tumor necrosis factor-alpha. Time- and dose-dependence of p53 up-regulation was measured. Induction of programmed cell death (apoptosis) by tumor necrosis factor-alpha was quantitated by means of a deoxyribonucleic acid fragmentation assay.Detectable levels of messenger ribonucleic acid for p53 were seen in ovarian cancer cells. Tumor necrosis factor-alpha induced a significant up-regulation of p53 messenger ribonucleic acid levels in ovarian cancer cells grown in nude mice and in vitro, whereas interleukin-6 did not. The maximum level of induction was 8 hours, and the up-regulation of p53 was dose dependent. In addition, tumor necrosis factor-alpha induced a dose-dependent increase in deoxyribonucleic acid fragmentation.Tumor necrosis factor-alpha induced up-regulation of p53 tumor suppressor gene expression in epithelial ovarian cancer cell lines, together with the induction of cell death by apoptosis.

View details for Web of Science ID A1994NG74200019

View details for PubMedID 8166195
MOLECULAR AND BIOLOGIC FACTORS IN THE PATHOGENESIS OF OVARIAN-CANCER JOURNAL OF REPRODUCTIVE MEDICINE Berek, J. S., MARTINEZMAZA, T. 1994; 39 (4): 241-248
Abstract

The development and progression of epithelial ovarian cancer can be correlated with various biologic and molecular factors. Tumor growth has been associated with aberrant and dysfunctional expression and mutation of various genes. These genetic defects include oncogene overexpression, amplification or mutation, aberrant tumor suppressor gene expression or mutation, and the inappropriate expression of cytokines and growth factors and/or the cellular receptors for these molecules. Dysregulation of host immune responses may also play a permissive role in the pathogenesis of the disease. Since ovarian cancer has been associated with the frequency of ovulation, the repeated proliferation of epithelial cells may increase the chance of a genetic accident that could contribute to the activation of an oncogene or inactivation of a suppressor gene. These events, combined with the inherent ability of ovarian epithelial cells to respond to and produce various cytokines and growth factors, could promote oncogenesis.

View details for Web of Science ID A1994NG93200003

View details for PubMedID 8040839
CONSERVATIVE AND INDIVIDUALIZED SURGERY FOR EARLY SQUAMOUS CARCINOMA OF THE VULVA - THE TREATMENT OF CHOICE FOR STAGE-I AND II (T1-2N0-1M0) DISEASE GYNECOLOGIC ONCOLOGY FARIASEISNER, R., Cirisano, F. D., GROUSE, D., Leuchter, R. S., Karlan, B. Y., Lagasse, L. D., Berek, J. S. 1994; 53 (1): 55-58
Abstract

We studied the outcome of patients undergoing radical local excision (modified radical vulvectomy) with inguinal-femoral lymphadenectomy through separate groin incisions for stage I and II invasive squamous carcinoma of the vulva. The purpose was to determine whether less radical and more individualized surgery is consistent with local control and cure. We have reported previously our experience using radical local excision and modified radical vulvectomy in stage I disease (Obstet. Gynecol. 63, 155 (1984)) and with separate groin incisions (Obstet. Gynecol. 58, 574 (1981)). This current report expands our experience with stage I and adds stage II patients treated over the past decade. Seventy-four patients were studied retrospectively over the 5-year period ending in January 1990. Reviews of both patient charts and histopathology reports were correlated with recurrence and survival. Factors analyzed included FIGO stage and grade, histology, lesion size and depth of invasion, surgical procedure, radiotherapy, lymph node status, interval to and site of recurrence, and survival. Thirty-nine patients had stage I disease and 35 had stage II. The primary operation was a radical local excision (modified radical vulvectomy) in 56 patients and radical vulvectomy in 18 patients; 13 underwent ipsilateral inguinal-femoral lymphadenectomy and 58 bilateral lymphadenectomy, each through separate groin incisions. The survival of those treated conservatively (97 and 90% for stages I and II, respectively) is the same as those undergoing a radical vulvectomy (100 and 75% for stages I and II, respectively) with only the presence of inguinal-femoral lymph node metastases impacting negatively on survival. In the entire group, the survival for negative and positive nodes was 98 and 45%, respectively. In conclusion, conservative, modified, and individualized vulvectomy in both stage I and II disease is associated with the same outcome and survival as radical vulvectomy, and lymph node status is the most important prognostic factor.

View details for Web of Science ID A1994NL95200011

View details for PubMedID 8175023
LAPAROSCOPIC MANAGEMENT OF THE ADNEXAL MASS OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA Parker, W. H., Berek, J. S. 1994; 21 (1): 79-92
Abstract

Careful preoperative evaluation of women found to have an adnexal mass may select patients for whom operative laparoscopy is appropriate. The role of ultrasonography and serum tumor markers in patient selection is discussed. Operative techniques for the laparoscopic management of the adnexal mass are also presented.

View details for Web of Science ID A1994NA78600006

View details for PubMedID 8015768
UTERINE SARCOMA IN PATIENTS OPERATED ON FOR PRESUMED LEIOMYOMA AND RAPIDLY GROWING LEIOMYOMA OBSTETRICS AND GYNECOLOGY Parker, W. H., Fu, Y. S., Berek, J. S. 1994; 83 (3): 414-418
Abstract

To determine the incidence of uterine sarcoma in patients operated on for symptomatic uterine leiomyomas or "rapidly growing" leiomyomas.We reviewed the medical records of 1332 women admitted to either of two community hospitals between 1988-1992 for hysterectomy or myomectomy for uterine leiomyomas. The incidence of leiomyosarcoma, endometrial stromal sarcoma, and mixed mesodermal tumor was calculated. Patient ages, admitting symptoms, and operative and pathologic findings were analyzed. The study included 371 women (28%) operated on for rapidly growing leiomyomas. All patients operated on during the same interval and found to have a uterine sarcoma were reviewed.One of the 1332 patients operated on for presumed leiomyoma was found to have a leiomyosarcoma. This women was the only patient found to have a sarcoma among 371 women operated on for rapid growth of the uterus. None of 198 patients who met a published definition of rapid growth had a uterine sarcoma. Two women (0.15%) had endometrial stromal sarcoma, but none had a mixed mesodermal tumor. During the same interval, nine additional patients were found to have uterine sarcomas, and for these women, the preoperative diagnosis was sarcoma in four, endometrial cancer in three, ovarian cancer in one, and prolapsed uterus in one.The total incidence of uterine sarcoma (leiomyosarcoma, endometrial stromal sarcoma, and mixed mesodermal tumor) among patients operated on for uterine leiomyoma is extremely low (0.23%). The incidence of sarcoma among patients having surgery for "rapidly growing" leiomyoma (0.27%) or among those who met published criteria for rapid growth (0%) does not substantiate the concept of increased risk of sarcoma in these women.

View details for Web of Science ID A1994MX85700017

View details for PubMedID 8127535
Peritoneal adenocarcinoma (serous) of Müllerian type: a subgroup of women presenting with peritoneal carcinomatosis. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society Fowler, J. M., Nieberg, R. K., Schooler, T. A., Berek, J. S. 1994; 4 (1): 43–51
Abstract

Peritoneal adenocarcinoma (serous or other subtype) of Müllerian type (PAMT) is frequently misclassified as another primary tumor. Peritoneal carcinomatosis in women without evidence of a primary site may occur secondary to a number of processes. Confusion regarding the nomenclature has made it difficult to determine the incidence and natural history of this unique malignancy. Other terms used for this tumor include mesothelioma, peritoneal papillary serous carcinoma, extra-ovarian serous carcinoma, and normal-sized ovarian carcinoma syndrome. Thirty-four patients (33 serous and one endometrioid) were identified with PAMT during 1976 through 1988. One hundred and thirty-seven patients underwent primary cytoreductive surgery for a preoperative diagnosis consistent with ovarian cancer. Twenty-nine (21.2%) were classified as PAMT (5 of the 34 had their initial surgery at other institutions). The mean age was 61.4 years. The primary symptoms and signs were abdominal pain (68%) and ascites (52%). Twenty-five (73%) had a preoperative diagnosis of ovarian cancer while the postoperative diagnosis was unknown (44%), PAMT (29%), and ovarian cancer (27%). Univariate and multivariate survival analysis were performed. Survival was independent of age, residual disease, grade, ascites, type of chemotherapy, and second-look results. In patients with residual disease < 1.5 cm, extended survival was found in (hose with ascites < 1000 ml, residual disease in pelvis only, and small residual volume but statistical significance was not obtained. Twenty-eight patients received >/=4 courses of chemotherapy after primary surgery. Twelve of 21 patients (57%) who received cisplatin (CDDP) survived between 23 and 92 months, while no patient receiving other chemotherapeutic regimens survived more than 25 months. The 2 and 3 year survival rate for CDDP was 47% and 33% vs. 14% and 0% for other regimens. Optimal cytoreductive surgery was not an independent prognostic factor as found in ovarian cancer, probably secondary to unresectable peritoneal carcinomatosis. PAMT is sensitive to chemotherapy but only the use of CDDP was associated with long term survival. Based on these results, women with peritoneal carcinomatosis consistent with PAMT should receive a CDDP-based regimen after primary surgery.

View details for PubMedID 11578384
PERITONEAL ADENOCARCINOMA (SEROUS) OF MULLERIAN TYPE - A SUBGROUP OF WOMEN PRESENTING WITH PERITONEAL CARCINOMATOSIS INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER Fowler, J. M., Nieberg, R. K., SCHOOLER, T. A., Berek, J. S. 1994; 4 (1): 43-51
View details for Web of Science ID A1994MN20700007
Fine-needle aspiration cytology in the management of gynecologic oncology patients. Cancer treatment and research Layfield, L. J., Berek, J. S. 1994; 70: 1-13
Abstract

Fine-needle aspiration cytology has received little attention by physicians involved in the care of gynecologic oncology patients. Concerns over diagnostic accuracy and complications such as rupture of cystic ovarian tumors with resultant tumor dissemination have limited the technique's utilization. Recent studies have shown the method to have a diagnostic accuracy (percent of neoplasms correctly categorized as benign or malignant) of approximately 95% for ovarian tumors [2-8]. The method is generally free of major complication when patients are properly selected, but severe pelvic infections have followed transvaginal or transrectal puncture of cystic ovarian neoplasms, resulting in a complication rate of about 1.6% [28]. Presently, FNA of ovarian tumors has a role in the workup of cystic lesions in young women where epithelial malignancies are unlikely and preservation of ovarian function is highly desirable. In peri- or postmenopausal women with adnexal masses, operative intervention is appropriate in most cases. Sevin and colleagues defined four clinical situations where FNA is useful [16]. These are 1) workup of primary neoplasms, 2) biopsy of superficial masses in patients with known prior disease, 3) follow-up of irradiated patients, and 4) follow-up of patients undergoing chemotherapy. From the available data, FNA has an accuracy of approximately 90% [10,18] and a low complication rate. The technique is an excellent method for the detection of recurrent or metastatic disease in patients being followed for gynecologic malignancies. When FNA is used for the investigation of newly discovered adnexal masses, patient selection is critical. FNA is helpful in carefully selected young women with cystic ovarian masses. However, its utility is limited in peri- or postmenopausal women with solid and solid-cystic adnexal masses, because these should be investigated by operative intervention.

View details for PubMedID 8060746
CONSTITUTIVE PRODUCTION OF MACROPHAGE-COLONY-STIMULATING FACTOR AND INTERLEUKIN-6 BY HUMAN OVARIAN SURFACE EPITHELIAL-CELLS EXPERIMENTAL CELL RESEARCH LIDOR, Y. J., Xu, F. J., MARTINEZMAZA, O., Olt, G. J., Marks, J. R., Berchuck, A., Ramakrishnan, S., Berek, J. S., Bast, R. C. 1993; 207 (2): 332-339
Abstract

Normal and neoplastic epithelial cells produce growth factors that can affect cells from different lineages. Epithelial ovarian cancers produce M-CSF and IL-6. In the present study, production of these cytokines has been measured in the apparently normal epithelial cells from which epithelial ovarian neoplasms are thought to arise. Epithelial cells from the surface of premenopausal human ovaries were established in short-term cultures. The cells bound anti-cytokeratin antibodies and exhibited characteristic epithelial morphology by light and transmission electron microscopy. M-CSF and IL-6 were detected in supernatants from cultures of these cells, using assays specific for each factor. Cytokine levels were comparable to those in supernatants from ovarian and breast cancer cell lines. M-CSF expression could also be demonstrated by immunohistochemical analysis with specific rabbit heteroantiserum. Thus, M-CSF and IL-6 are produced constitutively by normal as well as by neoplastic ovarian epithelium.

View details for Web of Science ID A1993LP89100016

View details for PubMedID 8344385
PROGNOSTIC FACTORS FOR GROIN NODE METASTASIS IN SQUAMOUS-CELL CARCINOMA OF THE VULVA (A GYNECOLOGIC-ONCOLOGY-GROUP-STUDY) GYNECOLOGIC ONCOLOGY Homesley, H. D., Bundy, B. N., Sedlis, A., YORDAN, E., Berek, J. S., Jahshan, A., MORTEL, R. 1993; 49 (3): 279-283
Abstract

From 1977 to 1984 the Gynecologic Oncology Group (GOG) conducted a prospective clinical and surgical staging protocol of squamous cell carcinoma of the vulva (n = 637). The patients with superficial (5 mm or less invasion) lesions were the subject of a previous report (n = 272). The subject of this report is on factors that predict groin node metastasis based on all 588 evaluable patients. Comparisons between the two reports are made. Almost half of this group (49.3%) had minimal tumor thickness (< or = mm). Almost one-third of patients had small vulvar lesions (< or = cm). Groin node metastasis was 18.9% for the < or = 2-cm diameter tumors and 41.6% for the > 2-cm diameter lesions. The inaccuracy of clinical palpation of the groin nodes (23.9% false negative) largely accounts for underestimation of extent of disease. Body weight was not related to the sensitivity of detecting positive groin nodes (P = 0.26). Using the logistic model, independent predictors of positive groin nodes were identified (in order of importance): less tumor differentiation by GOG criteria (P < 0.0001), suspicious or fixed/-ulcerated nodes (P < 0.0001), presence of capillary-lymphatic involvement (P < 0.0001), older age (P = 0.0002), and greater tumor thickness (invasion) (P = 0.03). Lesion size and location were not independent predictors of positive groin nodes.

View details for Web of Science ID A1993LJ51200003

View details for PubMedID 8314530
IMPACT OF CONTRACEPTION ON GYNECOLOGIC CANCERS SYMP ON CONTRACEPTIVE CHOICES FOR WOMEN WITH MEDICAL PROBLEMS Herbst, A. L., Berek, J. S. MOSBY-YEAR BOOK INC. 1993: 1980–85
Abstract

In considering the appropriate contraceptive method for a particular woman, the potential effect of that method on her risk of developing cancer of the breast, cervix, endometrium, or ovary is crucial. Among the most closely studied of the risk factors for gynecologic neoplasm has been the potential role of contraceptives, especially oral contraceptives, intrauterine devices, and injectable progestins. Physicians need to consider the potential impact of these agents on the disease process, therapy for the disease, future fertility, and the health of the fetus. Although much of the epidemiologic data is inconsistent and difficult to interpret, most studies find no association between oral contraceptive use and increased risk of breast cancer, except possibly in younger women (< 45 years of age) with prolonged use. Oral contraceptive use may also protect against benign breast disease. Data concerning oral contraceptive use and cervical neoplasm are confounded by several interacting variables, the most important of which is that oral contraceptive users tend to have more Papanicolaou smears than nonusers. Some studies have indicated an increased risk of two- to fourfold after 10 years of use. Oral contraceptive use provides clear protection against endometrial and ovarian cancer, an effect that persists for years after discontinuation. Less data have been collected regarding the relationship between intrauterine devices and injectable hormonal preparations and various types of cancer. No evidence suggests that the intrauterine device predisposes to the development of preneoplastic conditions of the cervix, nor to endometrial or ovarian cancer. A reliable form of contraception is indicated in women with cancer of any kind that may require chemotherapy or radiation, because these treatments can have adverse effects on the fetus, especially if given during the first trimester.

View details for Web of Science ID A1993LK18800002

View details for PubMedID 8512041
GROWTH-INHIBITION OF OVARIAN-CANCER CELLS INDUCED BY ANTISENSE IL-6 OLIGONUCLEOTIDES GYNECOLOGIC ONCOLOGY Watson, J. M., Berek, J. S., MARTINEZMAZA, O. 1993; 49 (1): 8-15
Abstract

In previous work, we saw that interleukin-6 (IL-6), a multifunctional cytokine, is produced by epithelial ovarian cancer cells and that ovarian cancer cells express the IL-6 receptor. Here, we examined the possibility that IL-6 acts as an autocrine growth factor for ovarian cancer cells. Inhibition of IL-6 gene expression by exposure to IL-6 antisense oligonucleotides resulted in greatly decreased cellular proliferation. Exposure of ovarian cancer cell lines (CAOV-3, OVCAR-3, and OC-436), to 1-5 microM of a 15-base single-stranded antisense IL-6 oligodeoxynucleotide, specific for a sequence in the second coding exon of the IL-6 gene, resulted in decreased IL-6 production and a > 80-85% inhibition of cellular proliferation. However, the addition of exogenous IL-6 failed to restore the proliferation of the antisense-treated cells. Antibodies to IL-6 did not consistently inhibit cell growth nor did rIL-6 enhance precursor frequency in a limiting dilution analysis. These results suggest that IL-6 does not directly induce the proliferation of ovarian cancer cells although endogenous IL-6 production is needed for optimal cell growth. As the majority of epithelial ovarian cancers produce IL-6, the direct specific inhibition of IL-6 gene expression is of potential therapeutic value.

View details for Web of Science ID A1993LB92300003

View details for PubMedID 8482564
PRIMARY LEIOMYOSARCOMA OF THE OVARY IN A PERIMENARCHAL FEMALE GYNECOLOGIC ONCOLOGY Monk, B. J., NIEBERG, R., Berek, J. S. 1993; 48 (3): 389-393
Abstract

A case of primary leiomyosarcoma of the ovary in a perimenarchal female is presented. Previous to this report, ovarian leiomyosarcoma was thought to arise predominantly in postmenopausal women and, indeed, this is the first reported case in a pubertal adolescent. The sarcoma was associated with bilateral cellular ovarian leiomyomas, suggesting malignant degeneration of such tumors. After complete resection, the patient is alive without evidence of recurrent disease 20 months after diagnosis. A review of the literature suggests that chemoradiation is of unproven benefit and aggressive surgical management is recommended.

View details for Web of Science ID A1993KU91200018

View details for PubMedID 8462904
SOLITARY RECURRENT METASTASIS OF EPITHELIAL OVARIAN-CANCER IN THE SPLEEN GYNECOLOGIC ONCOLOGY FARIASEISNER, R., Braly, P., Berek, J. S. 1993; 48 (3): 338-341
Abstract

In epithelial ovarian cancer, solitary metastasis to and recurrences in the parenchyma of the spleen are rare in the absence of apparent disease in other sites. We report four patients who developed isolated, solitary splenic parenchymal recurrences of their epithelial ovarian adenocarcinomas and underwent a splenectomy to remove the recurrent disease. They had undergone optimal cytoreductive surgery for stage III grades 2-3 serous cystadenocarcinoma of the ovary, followed by six to nine cycles of cisplatin and cyclophosphamide chemotherapy and a negative second-look laparotomy. Evidence of relapse developed 2, 4, 6, and 10 years after initial treatment. In two patients, a rising CA-125 heralded the recurrence that was subsequently documented by computed tomography (CT) of the abdomen and pelvis with a single defect noted only in the splenic parenchyma. Two others had only a defect on CT scan. Based on these findings, the otherwise healthy women underwent an exploratory laparotomy, each had a single focus of recurrent poorly differentiated disease that was found in the splenic parenchyma and a splenectomy was performed. Multiple biopsies and cytologies revealed no other evidence of microscopic disease. There was no major postoperative morbidity. Subsequently, one woman was treated with intraperitoneal cisplatin, two with intravenous carboplatin, and one declined further therapy. Three women are alive and free of disease at 6 months to 3 years. The fourth woman is alive with recurrent disease near the site of the resected spleen found 10 months postsplenectomy. Thus, splenic recurrence of epithelial ovarian cancer can occur in the absence of other demonstrable metastasis, and it can be preceded by elevation of CA-125 and an abnormal CT scan. Based on this limited experience with selected patients, splenectomy may have a role in the management of this unusual recurrence.

View details for Web of Science ID A1993KU91200010

View details for PubMedID 8462900
SENSITIVITY OF DRUG-RESISTANT HUMAN OVARIAN TUMOR-CELL LINES TO COMBINED EFFECTS OF TUMOR-NECROSIS-FACTOR (TNF-ALPHA) AND DOXORUBICIN - FAILURE OF THE COMBINATION TO MODULATE THE MDR PHENOTYPE GYNECOLOGIC ONCOLOGY Safrit, J. T., Berek, J. S., Bonavida, B. 1993; 48 (2): 214-220
Abstract

We have examined four human ovarian tumor lines (A2780, AD10, OVC-8, and SKOV-3) selected for their sensitivity and/or resistance to the recombinant human tumor necrosis factor alpha (TNF-alpha) and the chemotherapeutic drug doxorubicin (DOXO). The tumor lines were either sensitive to both agents, resistant to one or the other, or resistant to both. Of the four lines examined only the DOXO-resistant line AD10 exhibited the multidrug-resistance (MDR) phenotype. Enhanced cytotoxicity was seen with the combination of TNF-alpha and DOXO in each line regardless of their sensitivity or resistance patterns and, thus, demonstrates that drug resistance due to the expression of the MDR phenotype or its absence can be overcome by TNF-alpha and DOXO. We then examined whether TNF-alpha or TNF-alpha and DOXO modulated the MDR phenotype in AD10 as a possible mechanism of overcoming drug resistance. TNF-alpha had no effect on either DOXO intake or efflux as measured by flow cytometry. Further, TNF-alpha treatment showed no effect on the level of MDR-1 mRNA. These results suggest that the enhanced cytotoxicity seen with the combination of TNF-alpha and DOXO is not the result of any modulation of drug influx or efflux levels by TNF-alpha. Overall, these findings suggest that combination treatment with TNF-alpha and DOXO can overcome resistance inflicted by different mechanisms.

View details for Web of Science ID A1993KP00500013

View details for PubMedID 8428693
Current management of invasive squamous carcinoma of the vulva. Clinics in geriatric medicine Farias-Eisner, R., Berek, J. S. 1993; 9 (1): 131-143
Abstract

Because invasive vulvar cancer is generally discovered in elderly women, a careful pretreatment evaluation of the patient and the extent of her disease must be conducted. Thereafter, the treatment plan should be consistent with the principle of effective disease control with the minimum disruption and morbidity. It is essential to try to avoid overly aggressive surgeries that can commit the patient to prolonged hospitalization. The rarity of these lesions makes it essential to obtain appropriate consultation for the gynecologic oncologist who is most familiar with the condition.

View details for PubMedID 8443731
MOLECULAR AND BIOLOGICAL FACTORS IN THE PATHOGENESIS OF OVARIAN-CANCER International Workshop on Advanced Ovarian Cancer: where Do We Stand and Where Do We Go Berek, J. S., MARTINEZMAZA, O., Hamilton, T., Trope, C., Kaern, J., Baak, J., Rustin, G. J. OXFORD UNIV PRESS. 1993: 3–16
Abstract

The classic prognostic parameters are insufficient for predicting the prognosis of the individual patient. Knowledge of molecular and biological factors which are responsible for the development and progression of ovarian cancer may improve the prediction of prognosis.Recent data both on factors associated with the development and control of ovarian cancer cells and on DNA ploidy have been reviewed.Observations suggest that steroid and peptide hormones have a role in disease etiology and progression, and that peptide growth factors and cytokines, oncogenes and tumor suppressor genes, by their impact on mitosis and cell number may influence the rate of mutations, which could confer malignant transformation. DNA ploidy is an objective independent prognostic factor. DNA aneuploidy indicates high risk, diploidy low risk. Only tumours shown to be DNA diploid by flow-cytometry and image cytometry are considered diploid. S-phase fraction is currently not reliable.Understanding the mechanisms involved in ovarian cancer development and growth will allow opportunities for the rational design of effective anti-tumour treatment modalities. More objective and reproducible prognostic variables will improve the predictiveness of prognosis.

View details for Web of Science ID A1993MP74700002

View details for PubMedID 8312207
TUMOR-MARKERS International Workshop on Advanced Ovarian Cancer: where Do We Stand and Where Do We Go Rustin, G. J., VANDERBURG, M. E., Berek, J. S. OXFORD UNIV PRESS. 1993: 71–77
View details for Web of Science ID A1993MP74700011
ADVANCED EPITHELIAL OVARIAN-CANCER - 1993 CONSENSUS STATEMENTS ANNALS OF ONCOLOGY Allen, D. G., Baak, J., Belpomme, D., Berek, J. S., Bertelsen, K., Huinink, W. W., VANDERBURG, M. E., Calvert, A. H., Conte, P. E., Dauplat, J., Eisenhauer, E. A., Favalli, G., Hacker, N. F., HAMILTON, T. C., Hansen, H. H., Hansen, M., VANHOUWELINGEN, H. C., Kaye, S. B., Levin, L., Lund, B., Neijt, J. P., OZOLS, R. F., Piccart, M. J., Rustin, G. J., Sessa, C., Soutter, W. P., Thigpen, J. T., Trope, C., Vermorken, J. B., DeVries, E. G. 1993; 4: 83-88
Abstract

Over the last few days of a 5-day international workshop held in June 1993, a group of specialists in the field of advanced epithelial ovarian cancer tried to reach consensus on a number of issues with implications for standard practice and for research.Five groups of experts considered several issues which included: biologic factors, prognostic factors, surgery, management recommendations, dose intensity, supportive care, drug resistance, second-line treatment, investigational drugs, and tumour markers. Discussing the management recommendations, the group attempted to arrive at answers to four questions: Is there in fact a cure rate for advanced ovarian carcinoma? Are there prognostic factors which help to identify patients who will not do well with current therapy? What is the current best therapy for advanced ovarian carcinoma? What directions should research take in advanced ovarian cancer? In a plenary meeting these issues were discussed.Consensus statements were achieved on all topics mentioned above. This article reports on the statements written by the chairmen and approved by the consensus group.

View details for Web of Science ID A1993MP74700013

View details for PubMedID 8312205
Advanced ovarian cancer. Tumour markers. Annals of oncology Rustin, G. J., Van der Burg, M. E., Berek, J. S. 1993; 4: 71-77
Abstract

There is a need to discover new tumour markers for ovarian carcinoma as well to delineate how the best currently available marker, CA 125 should be used.This review examines the potential of growth factors and cytokines such as M-CSF, IL-6 and IL-10 as tumour markers as well as the over expression of oncogenes such as HER-2/neu in ovarian cancer. The major part of this review critically examines the uses of serum CA 125.Precise definitions for progression of ovarian carcinoma during treatment and on follow up were produced from studying a group of 71 and tested in a separate group of 164 women with ovarian carcinoma. They were found to predict progression with a false positive rate of only 8%. Definitions for response according to CA 125 are proposed.CA 125 remains the best tumour marker for ovarian carcinoma. It is not sensitive enough for screening and lack of specificity reduces its diagnostic accuracy. It's main role is in monitoring response to therapy and detecting tumour recurrence early and more reliably than by other methods.

View details for PubMedID 8312203
PRESENCE OF INTERLEUKIN 10 (IL-10) IN THE ASCITES OF PATIENTS WITH OVARIAN AND OTHER INTRAABDOMINAL CANCERS CYTOKINE Gotlieb, W. H., Abrams, J. S., Watson, J. M., VELU, T. J., Berek, J. S., MARTINEZMAZA, O. 1992; 4 (5): 385-390
Abstract

Typically, ovarian cancer remains restricted to the peritoneal cavity. Because of this unique localization, the study of ovarian cancer is particularly suitable for immune analysis and for the development of immunotherapy. Here we report that peritoneal fluid from patients with ovarian or other intra-abdominal cancers contained significantly elevated levels of interleukin 10 (IL-10) (542 +/- 77 pg/ml, N = 35), compared with peritoneal fluid from patients with benign gynecological conditions (34.2 +/- 7.5 pg/ml, N = 63) (P < 0.001). Peritoneal fluid IL-10 levels did not correlate with histology, tumor stage, grade, or prognosis. IL-10 levels were also elevated in the serum of patients with intra-abdominal cancer (1353 +/- 906, N = 8). Established ovarian cancer cell lines (N = 5) did not produce any detectable IL-10. Investigation of the cell surface phenotype of the cells in the peritoneal cavity indicated the presence of significant amounts of activated immune cells. The presence of cytokines such as IL-10 in the peritoneal cavity of ovarian cancer bearing patients could be important in the growth and development of cancer, more specifically, in relation to host immune responsiveness.

View details for Web of Science ID A1992JR61600008

View details for PubMedID 1421000
BIOLOGIC AND IMMUNOLOGICAL THERAPY OF OVARIAN-CANCER HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Bookman, M. A., Berek, J. S. 1992; 6 (4): 941-965
Abstract

Conventional cytotoxic chemotherapy fails to cure the majority of patients with advanced-stage ovarian cancer, in spite of encouraging initial antitumor responses. With the emergence of drug resistance in refractory tumors, new biologic and immunologic treatment strategies are needed. Small-volume residual peritoneal disease remains an attractive target for therapeutic trials; however, even in this optimal circumstance, few regimens have yet achieved a high frequency of pathologically confirmed complete remissions. Considerable progress has been made in understanding the impact of growth factors and their receptors on tumor growth regulation and modulation of response to chemotherapy. Better characterization of the antigens recognized by monoclonal antibodies, as well as sequencing of the antibodies themselves, has permitted the rational design of therapeutic reagents that take full advantage of molecular biology techniques for production and conjugation. Important limitations of preclinical models for prediction of host toxicity are recognized, and the reasons for treatment failure in situ, as well as strategies to prevent serious dose-limiting toxicities, are being explored. Further developments in cytokine biology, adoptive cellular therapy, monoclonal antibody conjugation, and molecular biology will continue to provide a growing array of reagents for critical evaluation.

View details for Web of Science ID A1992JG43800015

View details for PubMedID 1500395
INTRAPERITONEAL IMMUNOTHERAPY FOR OVARIAN-CANCER WITH ALPHA-INTERFERON EUROPEAN JOURNAL OF CANCER Berek, J. S. 1992; 28A (4-5): 719-721
View details for Web of Science ID A1992HV13000002

View details for PubMedID 1524888
CHARACTERISTICS OF PATIENTS WITH SMALL-VOLUME RESIDUAL OVARIAN-CANCER UNRESPONSIVE TO CISPLATIN-BASED IP CHEMOTHERAPY - LESSONS LEARNED FROM A GYNECOLOGIC ONCOLOGY GROUP PHASE-II TRIAL OF IP CISPLATIN AND RECOMBINANT ALPHA-INTERFERON GYNECOLOGIC ONCOLOGY Markman, M., Berek, J. S., Blessing, J. A., McGuire, W. P., Bell, J., Homesley, H. D. 1992; 45 (1): 3-8
Abstract

The Gynecologic Oncology Group conducted a phase II trial of intraperitoneal (ip) cisplatin plus recombinant human alpha-interferon in patients with small-volume persistent/recurrent ovarian cancer. This study was based on the known single agent activity of the drugs administered by the ip route and experimental evidence of cytotoxic synergy between the agents. In 18 evaluable patients, only 1 partial response was observed (5.5% response rate). In an effort to explain these disappointing findings, patients were retrospectively divided into two groups; those with favorable disease (documented response to systemic platinum and absence of surgical findings of diffuse carcinomatosis at laparotomy prior to initiation of ip therapy) or unfavorable disease (no evidence of response to systemic platinum and/or laparotomy findings of diffuse carcinomatosis before ip treatment). The favorable patient population would be predicted to have a far greater chance of responding to local therapy, but only 3 of the evaluable patients fell into this category. In the 15 unfavorable patients, only 1 partial response was observed (7% response rate). We conclude that patients who have failed to demonstrate a response to systemic cisplatin or carboplatin or who have diffuse carcinomatosis at second-look laparotomy are poor candidates for second-line ip cisplatin-based therapy, even if they are considered to have small-volume residual disease (each individual tumor nodules less than 0.5-1 cm). Such patients should be considered for alternative therapeutic strategies.

View details for Web of Science ID A1992HN57000002

View details for PubMedID 1601332
IMPROVING ADHERENCE TO SCREENING FOLLOW-UP AMONG WOMEN WITH ABNORMAL PAP SMEARS - RESULTS FROM A LARGE CLINIC-BASED TRIAL OF 3 INTERVENTION STRATEGIES MEDICAL CARE Marcus, A. C., Crane, L. A., Kaplan, C. P., READING, A. E., Savage, E., Gunning, J., Bernstein, G., Berek, J. S. 1992; 30 (3): 216-230
Abstract

In a large randomized trial involving over 2,000 women with abnormal cervical cytology (pap smear), three clinic-based interventions were tested as strategies to increase return rates for screening follow-up: 1) a personalized follow-up letter and pamphlet; 2) a slide-tape program on pap smears; and 3) transportation incentives (bus passes/parking permits). The three interventions were evaluated using a 2 x 2 x 2 factorial design. Results of this study confirm a high rate of loss to screening follow-up (i.e., no return visits) among women with abnormal pap smears (29% overall), with substantial variability among the 12 participating clinics (13% to 42/%). For the sample as a whole, both transportation incentives and the combined intervention condition of personalized follow-up and slide-tape program had a significant positive impact on screening follow-up. However, transportation incentives emerged as the dominant intervention condition among patient subgroups that can be characterized as more disadvantaged socioeconomically and at higher risk of developing cervical cancer, including patients receiving care from the county health department (odds ratio (OR) = 1.51; P less than .05); patients without health insurance (OR = 1.77; P less than .01); and patients with more severe pap smear results (OR = 1.71; P less than .05). In contrast, among patient subgroups that can be characterized as relatively more advantaged and at lower risk of developing cervical cancer, only the combined intervention condition of personalized follow-up and slide-tape program was associated with a higher patient return rate. Subgroups reflecting this pattern included patients seen in noncounty clinics (OR = 4.54; P less than .05) and patients with less severe pap smear results (OR = 5.16; P less than .01). The implications of these findings are discussed in terms of designing clinic-based interventions to improve screening follow-up.

View details for Web of Science ID A1992HG30400004

View details for PubMedID 1538610
STIMULATION OF OVARIAN TUMOR-CELL PROLIFERATION WITH MONOCYTE PRODUCTS INCLUDING INTERLEUKIN-1, INTERLEUKIN-6, AND TUMOR-NECROSIS-FACTOR-ALPHA AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Wu, S., Rodabaugh, K., MARTINEZMAZA, O., Watson, J. M., Silberstein, D. S., BOYER, C. M., Peters, W. P., Weinberg, J. B., Berek, J. S., Bast, R. C. 1992; 166 (3): 997-1007
Abstract

We investigated whether monocyte-derived factors could stimulate the growth of ovarian cancer cells.Human peripheral blood monocytes or human monocyte-like cell lines THP-1 and U-937 were cultured with or without macrophage colony-stimulating factor, lipopolysaccharide, or phorbol myristate acetate. Culture supernatants or recombinant cytokines were assayed for growth stimulation of ovarian cancer cell lines by tritium-thymidine incorporation and direct cell counts followed by statistical analysis with Student t test.Conditioned medium from peripheral blood monocytes or from THP-1 or U-937 cells stimulated ovarian cancer cell growth. Interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6 also stimulated ovarian cancer cell growth, whereas macrophage, granulocyte, and granulocyte-macrophage colony-stimulating factor did not. Concentrations of tumor necrosis factor, interleukin-1, and interleukin-6 in conditioned medium could not account for all the growth stimulation, and activity remained after neutralization of tumor necrosis factor, interleukin-1, and interleukin-6 with antibodies.Interleukin-1, interleukin-6, tumor necrosis factor, and additional monocyte factor(s) could provide paracrine growth stimulation when monocytes are attracted to ovarian cancers that produce macrophage colony-stimulating factor.

View details for Web of Science ID A1992HJ88500047

View details for PubMedID 1550178
EARLY-STAGE SQUAMOUS-CELL AND ADENOCARCINOMA OF THE CERVIX CURRENT OPINION IN OBSTETRICS & GYNECOLOGY McGonigle, K. F., Berek, J. S. 1992; 4 (1): 109-119
Abstract

Articles on early-stage squamous cell and adenocarcinoma of the cervix published between August 1990 and July 1991 are reviewed. A new monoclonal antibody used to distinguish endocervical from endometrial differentiation is described, as well as a histochemical means of distinguishing in situ from invasive adenocarcinoma. In vitro and in vivo studies of cell lines immortalized with human papillomavirus DNA are described with a discussion of the mechanism of the development of malignancy. An animal model to test and develop an anti-human papillomavirus vaccine is presented. The epidemiology of adenocarcinoma is also reviewed, and the development of invasive carcinoma after conservative therapy or conization for dysplasia is discussed. Computed tomography scanning has been found to be no more accurate than examination for staging of early cervical cancer. Several studies in the review period have evaluated risk factors for recurrent disease in patients treated for early-stage cervical cancer, including a prospective surgical pathologic study by the Gynecologic Oncology Group. The optimal treatment of early stage I adenocarcinoma of the cervix is discussed, comparing the efficacy of primary surgical therapy with the efficacy of radiation therapy. The risk of ovarian metastases in patients with early-stage cervical cancer is very low for both squamous cell and adenocarcinoma. The surgical technique and efficacy of laparoscopic pelvic lymphadenectomy for patients with early-stage cervical cancer are discussed. Lateral transposition of the ovaries at the time of radical hysterectomy for cervical cancer has significant potential benefits but also risks. Finally, surveillance methods that detect recurrent cervical cancer after treatment for early-stage disease are discussed.

View details for Web of Science ID A1992HG24000016

View details for PubMedID 1311965
2ND-LOOK VERSUS 2ND NATURE GYNECOLOGIC ONCOLOGY Berek, J. S. 1992; 44 (1): 1-2
View details for Web of Science ID A1992HA83800001

View details for PubMedID 1730414
Interleukin 6 and cancer treatment. In vivo Martínez-Maza, O., Berek, J. S. 1991; 5 (6): 583-588
Abstract

Interleukin 6 (IL-6) is a pleiotropic cytokine, with a wide range of biological effects. The diverse biological actions of IL-6 could play important roles in the enhancement or suppression of tumor growth and development. IL-6 has been seen to act as an autocrine and/or paracrine growth factor for various human tumors, including multiple myeloma, renal cancer, and AIDS-associated Kaposi's sarcoma. However, IL-6 also can exert potent anti-tumor effects: administration of IL-6 has been seen to result in decreased tumor appearance in experimental animal systems. Therefore, potentially useful anti-tumor therapeutic strategies could include the inhibition of the activity of IL-6, or alternatively, the enhancement of anti-tumor responses by the administration of exogenous IL-6.

View details for PubMedID 1810443
CONCURRENT CISPLATIN AND 5-FLUOROURACIL CHEMOTHERAPY AND RADIATION-THERAPY FOR ADVANCED-STAGE SQUAMOUS CARCINOMA OF THE VULVA 22ND ANNUAL MEETING OF THE SOC OF GYNECOLOGIC ONCOLOGISTS Berek, J. S., HEAPS, J. M., Fu, Y. S., Juillard, G. J., Hacker, N. F. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1991: 197–201
Abstract

A phase II trial of concurrent cisplatin and 5-fluorouracil (5-FU) chemotherapy and radiation therapy (CT + RT) was conducted for the primary treatment of 12 patients with retrospective surgical FIGO stages III-IV squamous carcinoma of the vulva. Eight patients were stage III and four were stage IV. Chemotherapy was used as a radiation sensitizer and it was administered in two 5-day cycles 28 days apart. Cisplatin, 50 mg/m2/day iv on Days 1 and 2 or 100 mg/m2 on Day 1 or 2, plus continuous-infusion 5-FU, 1000 mg/m2/day for 4-5 days commencing on Days 1 and 28 of external-beam radiation therapy, are given. The pelvic radiation to a dose of 4400-5400 cGy is administered AP and PA to treat the primary tumor, the groin nodes, and the iliac vessels to the level below the common iliac nodes. Complete tumor responses were seen in 8 of 12 (67%) patients. Responses were observed in 6 of 8 (75%) stage III patients and 2 of 4 (50%) stage IV patients. Partial response were observed in 3 patients, and 1 patient had persistent disease. At the completion of concurrent chemoradiation therapy, radical vulvectomy or excision was used in 3 patients and posterior exenteration in 1. With a median follow-up of 37 months (range, 7-60 months), 10 patients are alive and free of disease, and 2 patients died at 12 and 15 months. There were no treatment-related deaths and no grade 4 toxicity. The morbidity included moist desquamation of the vulva in all patients, with grade 2 toxicity in 10 and grade 3 in 2. One patient had a deep venous thrombosis that responded to anticoagulation therapy. These data support the use of concurrent cisplatin and 5-FU chemotherapy and radiation therapy as an alternative to primary radical surgery to treat advanced-stage squamous carcinoma of the vulva.

View details for Web of Science ID A1991GQ07000003

View details for PubMedID 1955180
ADNEXAL TORSION - AN UNUSUAL CAUSE OF ABDOMINAL-PAIN IN POSTMENOPAUSAL WOMEN AMERICAN SURGEON Shih, S., Vetto, J. T., Berek, J. S., HEAPS, J. M., Hiatt, J. R. 1991; 57 (5): 327-329
Abstract

Adnexal torsion is a rare cause of abdominal pain in older women. Because the presenting symptoms and signs are vague, the diagnosis is not often considered. Lower abdominal pain with nausea and vomiting are usual in patients with torsion. Ultrasonography or computed tomography are useful diagnostic tests. Two case reports of older patients with adnexal torsion are presented to emphasize the diagnostic features of this entity, including lower abdominal pain, nausea and vomiting, and abdominal mass. Although the condition is uncommon, adnexal torsion should be considered in the differential diagnosis of acute abdominal pain.

View details for Web of Science ID A1991FP10400014

View details for PubMedID 2039132
CORRELATION OF ENDOCERVICAL CURETTAGE WITH SUBSEQUENT CONE BIOPSY IN THE INVESTIGATION OF ABNORMAL CERVICAL CYTOLOGY INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER TAKAMI, C. Y., Nieberg, R. K., Berek, J. S. 1991; 1 (3): 97-103
View details for Web of Science ID A1991GN80700001
SERUM INTERLEUKIN-6 LEVELS CORRELATE WITH DISEASE STATUS IN PATIENTS WITH EPITHELIAL OVARIAN-CANCER 9TH ANNUAL MEETING OF THE AMERICAN GYNECOLOGICAL AND OBSTETRICAL SOC Berek, J. S., Chung, C., Kaldi, K., Watson, J. M., Knox, R. M., MARTINEZMAZA, O. MOSBY-ELSEVIER. 1991: 1038–43
Abstract

Interleukin-6 is a pleiotropic cytokine with a wide range of effects, including induction of B-cell and cytotoxic T-cell differentiation, and induction of acute phase reactant production by hepatocytes. Interleukin-6 also can act as an autocrine growth factor in malignancy. Various cell types produce interleukin-6, including T and B cells, monocytes, fibroblasts, and some solid tumor cells. In previous work we detected the production of substantial amounts of interleukin-6 by human ovarian cancer cells, including the ovarian cancer cell lines CAOV-3, OVCAR-3, and SKOV-3, and several primary ovarian tumor cultures. In this study we retrospectively examined 90 separate serum specimens for interleukin-6 in 36 patients with epithelial ovarian cancer. The mean serum interleukin-6 concentration of those ovarian cancer patients with macroscopic disease (n = 57) was 0.26 +/- 0.04 U/ml (mean +/- SEM). Healthy adult donors have interleukin-6 serum levels of 0.12 +/- 0.03 U/ml. Sixteen of 21 ovarian cancer patients with macroscopic disease (76%) had elevated (greater than 0.20 U/ml) levels of serum interleukin-6, with levels approaching 1 U/ml in some patients (p less than 0.01). Of those nine patients with bulky tumor (residual greater than 2 cm), eight (89%) had an elevated interleukin-6 level (mean, 0.31 +/- 0.05), while eight of 12 (66%) with minimal residual disease (less than 2 cm) had elevated levels. Only two of 15 (13%) patients who were in clinical remission and who had microscopic disease had elevated values. Of the 36 patients, 22 were CA 125 negative (less than 35 U/ml), and of these, four had elevated interleukin-6 levels. Of the 14 patients with an elevated CA 125 level, 12 (86%) had elevated interleukin-6 levels. In those 16 patients in whom serial levels of interleukin-6 were measured, rising levels were found over a 3 to 4 month interval in nine (56%); this correlated with tumor progression. Furthermore, the subsequent survival of patients was shown to correlate with the level of interleukin-6, such that patients whose levels were elevated greater than 0.20 U/ml interleukin-6 survived a mean of 12.5 months, compared with 27.2 months for patients with normal levels (p less than 0.001). These data support the concept that interleukin-6 may be a useful tumor marker in some patients with epithelial ovarian cancer, as it correlates with the tumor burden, clinical disease status, and survival.

View details for Web of Science ID A1991FG94500014

View details for PubMedID 2014824
ASSESSMENT OF CURRENT INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS STAGING OF VULVAR CARCINOMA RELATIVE TO PROGNOSTIC FACTORS FOR SURVIVAL (A GYNECOLOGIC ONCOLOGY GROUP-STUDY) 9TH ANNUAL MEETING OF THE AMERICAN GYNECOLOGICAL AND OBSTETRICAL SOC Homesley, H. D., Bundy, B. N., Sedlis, A., YORDAN, E., Berek, J. S., Jahshan, A., MORTEL, R. MOSBY-ELSEVIER. 1991: 997–1004
Abstract

Analysis of 588 patients with vulvar carcinoma delineated four risk groups by the proportional hazards model. Groin node status (laterality and number positive) and lesion diameter were the only two important independent prognostic factors. The 5-year relative survival rates were 98%, 87%, 75%, and 29% for the risk group categories of minimal (negative groin nodes and lesion diameter less than or equal to 2 cm), low (one positive groin node and lesion diameter less than or equal to 2 cm or negative groin nodes and fewer than two lesions less than or equal to 8 cm diameter), intermediate (negative groin nodes and lesion diameter greater than 8 cm diameter, one positive groin node and lesion diameter greater than 2 cm, or two unilaterally positive groin nodes and lesion diameter less than or equal to 8 cm), and high (three or more positive groin nodes or two bilaterally positive groin nodes), respectively. Applying the International Federation of Gynecology and Obstetrics staging (1988) to these data discriminated risk of death (caused by recurrent vulvar cancer); the 5-year rates were 98%, 85%, 74%, and 31% for stages I, II, III, and IV, respectively. However, within International Federation of Gynecology and Obstetrics stage III there were 47 low-, 95 intermediate-, and 28 high-risk patients with relative survivals of 95%, 74%, and 34%, respectively. Overall, this assessment validates current International Federation of Gynecology and Obstetrics vulvar carcinoma staging, but further refinements are warranted in stage III.

View details for Web of Science ID A1991FG94500009

View details for PubMedID 2014852
A PHASE I-II TRIAL OF INTRAPERITONEAL CISPLATIN AND ALPHA-INTERFERON IN PATIENTS WITH PERSISTENT EPITHELIAL OVARIAN-CANCER GYNECOLOGIC ONCOLOGY Berek, J. S., WELANDER, C., Schink, J. C., Grossberg, H., Montz, F. J., ZIGELBOIM, J. 1991; 40 (3): 237-243
Abstract

A toxicity, dose, and schedule study of intraperitoneal (ip) cisplatin and alpha-interferon was conducted as a salvage therapy for patients with persistent, advanced epithelial ovarian cancer after primary systemic therapy with cisplatin-combination chemotherapy. Twenty-four patients were entered into this prospective, nonrandomized phase I-II trial conducted at two institutions following a uniform protocol. Cisplatin doses were escalated from 45 to 90 mg/m2, and alpha-interferon doses were escalated from 10 to 50 x 10(6) IU. At protocol entry, 4 (16%) patients had microscopic residual disease at second-look laparotomy, 5 (21%) had minimal residual disease less than 5 mm, 7 (30%) had residual disease 5-20 mm, and 8 (33%) had bulky residual disease greater than 20 mm. Toxicity was acceptable overall. Hematopoietic toxicity included a grade 3 total white cell count in 12% of courses when the cisplatin dose was equal to or greater than 60 mg/m2. Renal toxicity was modest with grade 2 toxicity in 20% of courses with a cisplatin dose greater than 60 mg/m2. Gastrointestinal toxicity, especially nausea and vomiting was seen in most courses; however, it was grade 3 and dose-limiting in greater than 30% of courses with cisplatin 75-90 mg/m2. General malaise, fever, flu-like symptoms, chills, and myalgias were seen in most courses, but it was dose-limiting (grade 3) toxicity in 6-11% of cycles when the dose of interferon was 25-50 x 10(6) IU. There was no grade 4 toxicity. Thus, the maximum tolerated dose (MTD) of the combination is 60 mg/m2 cisplatin and 25 x 10(6) IU interferon. Eighteen patients were evaluable for response, 15 of whom had responded to prior cisplatin therapy and 3 had not. Of the 10 patients evaluable for clinical response, one patient (10%) achieved a complete response (CCR), and one (10%) had a partial response (PCR). The progression free interval (PFI) and survival were 11 months and 19 months, respectively, for the CCR patient, 6 and 11 months, respectively, for the PCR patient, and the mean survival for nonresponders was 8 months. The other 8 patients underwent a reassessment laparotomy: 2 (25%) achieved a complete pathologic response (CPR), and 3 (38%) had a partial pathologic response (PPR). Both pathologic responses were in patients with minimal residual disease less than 5 mm.(ABSTRACT TRUNCATED AT 400 WORDS)

View details for Web of Science ID A1991FF76200008

View details for PubMedID 2013446
FINE-NEEDLE ASPIRATION CYTOLOGY ACCURACY WITH PALPABLE GYNECOLOGIC NEOPLASMS GYNECOLOGIC ONCOLOGY Layfield, L. J., HEAPS, J. M., Berek, J. S. 1991; 40 (1): 70-73
Abstract

From 1984 to 1988, 62 fine-needle aspirations (FNA) were performed on palpable lesions in 59 gynecologic oncology patients at the UCLA Medical Center. Sites of aspiration included abdomen, cervix, vagina, superficial lymph nodes, and pelvic masses. Confirmatory open biopsy (41) or adequate clinical follow-up (17) was obtained in 55 patients (58 aspirates). FNA correctly established the diagnosis of malignancy in 19 of 26 (73%) biopsied patients. The predictive value for a positive test was 100%, and the predictive value for a negative test was 82%. Initial surgical biopsy had been incorrectly benign in 4 of these patients who were shown subsequently to have malignant tumors by FNA and clinical findings. In 7 patients, FNA failed to diagnose the malignancy found by open biopsy. Two of the false-negative FNAs were insufficient and five were in masses where palpation was inadequate. In 17 patients who were followed clinically without open biopsy, FNA correctly predicted the subsequent clinical course in 15 (88%). There were no false-positive FNA diagnoses obtained when cytologic results were correlated with both clinical outcome and surgical biopsy. Aspiration cytology has a specificity of 100% and a sensitivity of 65%. A negative FNA obtained from a clinically suspicious lesion should be followed by a repeat aspiration or surgical biopsy.

View details for Web of Science ID A1991EW18400015

View details for PubMedID 1989918
SURGICAL STAGING OF CERVICAL-CANCER CLINICAL OBSTETRICS AND GYNECOLOGY HEAPS, J. M., Berek, J. S. 1990; 33 (4): 852-863
Abstract

Noninvasive radiologic methods to detect paraaortic lymph node metastases are reliable when combined with FNA of enlarged lymph nodes. However, the sensitivity is low, and undetected microscopic metastases leads to treatment failure. These patients with paraaortic lymph node metastasis are not treated with extended-field radiation, and they all die within 3 years. The CT scanning is probably the best diagnostic method to evaluate cervical cancer, because it can assess the primary tumor, the urinary tract, gastrointestinal tract, liver parenchyma, and retroperitoneum. It also permits the guidance of FNA and the arrangement of radiation ports. Surgical staging provides the direct assessment of the peritoneal cavity and the retroperitoneal spaces. Metastatic tumor, including enlarged lymph nodes, can be resected, but this is of dubious benefit. The operative morbidity is acceptable, with fewer intestinal complications when the extraperitoneal approach is used, and long-term morbidity is minimal when appropriate paraaortic radiation doses are employed (less than 5,000 cGy). Surgical staging has provided data on the frequency of paraaortic lymph node metastasis by stage of cervical cancer, and thus, treatment strategies can be better developed. Extended-field radiation results in 5-year survival rates of 20-25% in patients with microscopic paraaortic lymph node metastasis, patients who would not survive without the treatment. However, surgical staging has produced only a modest boost in survival rates, because of the high rate of pelvic and systemic failure. When extended-field radiation is used prophylactically or in patients with probable lymph node metastasis seen on radiographic studies, survival rates are similar to patients irradiated after surgical staging finds paraaortic lymph node disease. As our ability to predict, and detect nonsurgically, positive paraaortic node disease improves, extended radiation (or other adjuvant therapy) could be used more frequently without operation in patients who are at high risk for metastatic disease. In a study by Haie et al, prophylactic paraaortic radiation was given to patients at high risk for paraaortic metastasis. In patients with a high probability of local disease control, paraaortic radiation significantly reduced the incidence of paraaortic and distant metastases. Patients with known paraaortic lymph node metastases frequently have occult systemic metastases. In these same patients, pelvic failure is also common. Thus, until effective systemic therapies emerge, a marked improvement in survival is unlikely in patients who have paraaortic lymph node metastasis.(ABSTRACT TRUNCATED AT 400 WORDS)

View details for Web of Science ID A1990EM70900018

View details for PubMedID 2289352
RESISTANCE OF HUMAN OVARIAN-CANCER CELLS TO TUMOR-NECROSIS-FACTOR AND LYMPHOKINE-ACTIVATED KILLER-CELLS - CORRELATION WITH EXPRESSION OF HER2 NEU ONCOGENES CANCER RESEARCH Lichtenstein, A., Berenson, J., Gera, J. F., Waldburger, K., MARTINEZMAZA, O., Berek, J. S. 1990; 50 (22): 7364-7370
Abstract

Since overexpression of HER2/neu oncogenes in breast cancer cells is associated with resistance to the cytotoxic effect of tumor necrosis factor (TNF), we investigated whether this correlation also existed for ovarian cancer targets. Nine continuously cultured human ovarian cancer lines were studied and compared to 3 breast cancer lines. Three of the ovarian and 1 breast cancer line demonstrated amplified HER2/neu genes by Southern analysis, increased HER2/neu RNA by Northern analysis, and marked immunoperoxidase staining for HER2/neu protein. The other 8 lines contained unamplified genes and undetectable RNA and protein. All 4 overexpressed lines were relatively resistant to the cytotoxic effects of TNF. Interestingly, they were also resistant to lymphokine-activated killer cells. In contrast, 7 of 8 nonexpressed lines showed sensitivity to TNF and all 8 were sensitive to lymphokine-activated killer cells. There was no difference in sensitivity to lysis by hydrogen peroxide or peptide defensins between over- and nonexpressed lines. These data indicate that expression of HER2/neu oncogenes may impart a proliferative advantage in tumor cells due to induction of resistance to several different cytotoxic mechanisms.

View details for Web of Science ID A1990EH00600044

View details for PubMedID 1977519
MANAGEMENT OF SELECTED CYSTIC ADNEXAL MASSES IN POSTMENOPAUSAL WOMEN BY OPERATIVE LAPAROSCOPY - A PILOT-STUDY AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Parker, W. H., Berek, J. S. 1990; 163 (5): 1574-1577
Abstract

Twenty-five postmenopausal patients were predicted to have benign masses by screening criteria that included ultrasonographic findings of a cystic adnexal mass less than 10 cm with distinct borders and no evidence of irregular solid parts, thick septa, ascites, or matted bowel, and a normal serum CA 125 value (less than 35 U/ml). All 25 masses were accurately predicted to be benign. The size of the cysts on ultrasonography ranged from 3 to 9 cm with a mean of 5 cm. Twenty-two patients (88%) were successfully managed by operative laparoscopy and adnexectomy. Mean operative time was 70 minutes and mean postoperative hospital stay was 12 hours. Mean time of return to normal activity was 5 days. Three patients required laparotomy. We conclude that removal of these cystic adnexal masses by operative laparoscopy is an acceptable alternative in carefully selected postmenopausal women.

View details for Web of Science ID A1990EJ61400032

View details for PubMedID 2146879
CONSTITUTIVE PRODUCTION OF INTERLEUKIN-6 BY OVARIAN-CANCER CELL-LINES AND BY PRIMARY OVARIAN TUMOR CULTURES CANCER RESEARCH Watson, J. M., Sensintaffar, J. L., Berek, J. S., MARTINEZMAZA, O. 1990; 50 (21): 6959-6965
Abstract

We examined the production and utilization of interleukin 6 (IL-6), a multifunctional cytokine with diverse biological effects, by both ovarian cancer cell lines and primary ovarian tumor cultures. We have found that epithelial ovarian cancer cell lines (CAOV-3, OVCAR-3, and SKOV-3) constitutively produce varying amounts of IL-6. This molecule is biologically active as determined by the proliferation of an IL-6-dependent hybridoma cell line, MH60.BSF-2, and is detectable by an IL-6 enzyme-linked immunosorbent assay. By cytoplasmic immunoperoxidase staining, greater than 98% of the cells produce at least some IL-6, with variation in the staining intensity between individual cells. The ovarian cancer cell-produced protein has a molecular weight of approximately 24,000, and exhibits some molecular weight heterogeneity, with Mr 27,000 and 28,000 minor forms of IL-6. The levels of IL-6 produced by ovarian cancer cells can be modulated by other inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interferon-gamma. Our results suggest that IL-6 is not an autocrine growth factor for these established ovarian tumor cell lines, because the addition of either exogenous IL-6 or antibodies to IL-6 did not affect the cellular proliferation of the cell lines. We also found significant levels (greater than 3 ng/ml) of IL-6 in ascitic fluids of ovarian cancer patients and in the supernants of primary cultures from freshly excised ovarian tumors. The production of IL-6 by epithelial ovarian cancer cells may prove to be a useful diagnostic tool and aid in investigation of the host immune response to ovarian cancer.

View details for Web of Science ID A1990EF20500035

View details for PubMedID 2208162
INTRAPERITONEAL ADOPTIVE IMMUNOTHERAPY FOR PERITONEAL CANCER JOURNAL OF CLINICAL ONCOLOGY Berek, J. S. 1990; 8 (10): 1610-1612
View details for Web of Science ID A1990EB34400002

View details for PubMedID 2213098
OVARIAN METASTASES ARE RARE IN STAGE-I ADENOCARCINOMA OF THE CERVIX OBSTETRICS AND GYNECOLOGY Brown, J. V., Fu, Y. S., Berek, J. S. 1990; 76 (4): 623-623
Abstract

Over a 32-year period at the University of California, Los Angeles Medical Center, all cases of adenocarcinoma and adenosquamous carcinoma of the uterine cervix were reviewed to determine the incidence of ovarian metastases in stage I disease. One of 25 patients (4.0%) who underwent an exploratory laparotomy and radical hysterectomy had a microscopic ovarian metastasis. A literature review identified nine additional patients who had ovarian metastases and stage I adenocarcinoma of the cervix. Including our series, the overall reported rate of ovarian metastases is 1.8%. All ten patients had at least one of the following additional characteristics: They were postmenopausal, they had adnexal pathology, or they had positive pelvic lymph nodes. Thus, ovarian preservation is warranted in premenopausal patients who do not have ovarian pathology or evidence of other metastatic disease at surgery. Bilateral oophorectomy may be performed if frozen-section examination of enlarged or suspicious nodes documents metastases. If the ovaries are left in the pelvis at the completion of the surgical procedure and microscopic spread to other pelvic tissues is documented, pelvic irradiation can be administered.

View details for Web of Science ID A1990EA16900010

View details for PubMedID 2216191
SYNERGY IS DOCUMENTED INVITRO WITH LOW-DOSE RECOMBINANT TUMOR-NECROSIS-FACTOR, CISPLATIN, AND DOXORUBICIN IN OVARIAN-CANCER CELLS 1990 ANNUAL MEETING OF THE SOC OF GYNECOLOGIC ONCOLOGISTS Bonavida, B., Tsuchitani, T., ZIGHELBOIM, J., Berek, J. S. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1990: 333–39
Abstract

Ovarian carcinomas have been shown to be sensitive or insensitive to the in vitro exposure of several cytotoxic drugs and cytokines. Because of the potential for cytokines to enhance the efficacy of chemotherapeutic agents and to improve their therapeutic index, the optimal dose and schedule of the combination of these agents have been studied. We examined the cytotoxic effect of a combined modality using a variety of concentrations of recombinant tumor necrosis factor (rTNF) (a cytotoxic cytokine) with Adriamycin (ADR) and cisplatin (CDDP) on human ovarian carcinoma cell lines. Cytotoxicity was determined in a 24-hr 51Cr-release assay and confirmed in a 5-day viability culture assay. Five cell lines were used: PA-1, 222, OVCAR-3, SKOV-3, and OVCAR-8. Doses of rTNF that were minimally cytotoxic resulted in significant cytotoxicity and synergy when used with optimal or suboptimal concentrations of ADR or CDDP. This synergy was observed in four cell lines. Interestingly, the rTNF- and drug resistant SKOV-3 cell line was sensitive to the synergistic effect of Adriamycin and rTNF. The synergistic effect that was obtained was specific to rTNF, while the combined use of ADR and CDDP or recombinant interleukin-2 and cytotoxic drugs had no synergistic effect on tumor cell lysis. Further, the addition of anti-TNF antibody abrogated the synergistic effect seen with rTNF and the cytotoxic drugs. These studies demonstrate clearly that significant synergistic antitumor cytotoxic activity against human ovarian carcinoma cell lines can be achieved with combinations of low doses of rTNF and ADR or CDDP, suggesting their possible adaptation in vivo for cancer therapy. Further, the studies suggest that rTNF and the cytotoxic drugs tested may share a common lytic pathway. Since rTNF used alone has been relatively inactive in clinical trials, its potential activity may be apparent only when combined with conventional cytotoxic chemotherapeutic agents and when administered in relatively low concentration.

View details for Web of Science ID A1990EE33000007

View details for PubMedID 2227544
SURGICAL-PATHOLOGICAL VARIABLES PREDICTIVE OF LOCAL RECURRENCE IN SQUAMOUS-CELL CARCINOMA OF THE VULVA 1990 ANNUAL MEETING OF THE SOC OF GYNECOLOGIC ONCOLOGISTS HEAPS, J. M., Fu, Y. S., Montz, F. J., Hacker, N. F., Berek, J. S. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1990: 309–14
Abstract

One hundred and thirty-five patients with squamous carcinoma of the vulva were treated at UCLA and City of Hope Medical Centers between 1957 and 1985. Sixty-two cases were stage I, 48 stage II, 18 stage III, and 7 stage IV. Twenty-one patients developed a local vulvar recurrence after primary radical resection. Ninety-one patients had a surgical tumor-free margin greater than or equal to 8 mm on tissue section and none had a local vulvar recurrence. Forty-four patients had a margin less than 8 mm; 21 had a local recurrence and 23 did not (P less than 0.0001). Of the 23 patients with a margin less than 8 mm who did not recur locally, 14 remained free of disease, and 9 had either advanced disease, declining health, or short follow-up. Depth of invasion is associated with local recurrence, with a 9.1-mm reference value correctly predicting outcome in 81.5% of cases. Increasing tumor thickness is associated with local recurrence, with a 10-mm reference value predictive of 90% non-recurrence and 33% recurrences. A pushing border pattern is less likely to recur than an infiltrative growth pattern. Lymph-vascular space invasion has a combined predictive accuracy of 81.5%. Increasing keratin and greater than 10 mitoses per 10 high-power fields correlate with local recurrence. Neither clinical tumor size nor coexisting benign vulvar pathology correlates with local recurrence. Fourteen of twenty-one patients with vulvar recurrence died of metastatic disease, four died of intercurrent disease, and three were alive at 32, 68, and 157 months, with 16 recurring in less than 1 year. Surgical margin is the most powerful predictor of local vulvar recurrence. Combining factors in a stepwise logistical regression does not significantly improve this predictive value. Accounting for specimen preparation and fixation, a 1-cm tumor-free surgical margin on the vulva results in a high rate of local control, whereas a margin less than 8 mm is associated with a 50% chance of recurrence.

View details for Web of Science ID A1990EE33000003

View details for PubMedID 2227541
PATHOPHYSIOLOGY AND MANAGEMENT OF ENDOMETRIAL HYPERPLASIA AND CARCINOMA WESTERN JOURNAL OF MEDICINE Fu, Y. S., Gambone, J. C., Do, Berek, J. S. 1990; 153 (1): 50-61
Abstract

Endometrial cancer is currently the commonest pelvic malignancy affecting American women, most of whom share the same pathophysiologic basis, that is, unopposed estrogenic stimulation. The initial result of hyperestrogenism is the development of endometrial hyperplasia, which is reversible in most cases by appropriate hormonal therapy. Persistent stimulation eventually leads to atypical hyperplasia with nuclear atypia and invasive carcinoma. Because there is no cost-effective screening method for the detection of endometrial hyperplasia and carcinoma, it is essential to survey the high-risk population with appropriate diagnostic techniques. After diagnosis, therapy should be individualized based on pathologic findings (cell type and histologic grade) and extent of disease (International Federation of Gynaecologists and Obstetricians stage, depth of myometrial invasion, and pelvic and para-aortic lymph node status). Recent studies suggest that sex hormone receptors and nuclear DNA ploidy patterns provide useful prognostic information independent of histologic grade.

View details for Web of Science ID A1990DQ62200007

View details for PubMedID 2202159
MALIGNANT NEOPLASMS ARISING IN ENDOMETRIOSIS OBSTETRICS AND GYNECOLOGY HEAPS, J. M., Nieberg, R. K., Berek, J. S. 1990; 75 (6): 1023-1028
Abstract

Ten cases of malignant tumors arising in foci of gonadal and extragonadal endometriosis are reported and added to 195 previously reported cases from the English literature. The ovary was the primary site in 165 (78.7%) of the cases, whereas extragonadal sites represented 44 (21.3%). Endometrioid adenocarcinomas accounted for 69% of the lesions, clear-cell carcinomas 13.5%, sarcomas 11.6%, and rare cell types 6%. Extragonadal lesions were mostly endometrioid tumors (66%) and sarcomas (25%). Tumors arising in endometriosis were predominantly low grade and confined to the site of origin. Radiation therapy was often able to control completely tumors limited to the pelvis, but was not beneficial in metastatic disease. Only one patient had a response to chemotherapy. Fourteen patients received postoperative progestin therapy, with a 77% 5-year survival. Follow-up has been reported in 86 patients. The tumor was either confined to the ovary (57), confined to the extragonadal site of origin (11), or spread throughout the peritoneal cavity (18). With each of these situations, the 5-year survival was 65, 100, and 10%, respectively. Fourteen patients had malignant transformation in endometriosis associated with presumed estrogenic stimulation; most lesions (69%) were well differentiated and the 5-year survival was 82%. After surgical resection, we recommend that progestin therapy be included in the treatment of cancer arising in endometriosis. The actual frequency of malignancy arising in endometriosis may be higher than reported.

View details for Web of Science ID A1990DE77800027

View details for PubMedID 2188180
CYTOREDUCTIVE SURGERY FOR ADVANCED OVARIAN-CANCER - CARDIOVASCULAR EVALUATION WITH PULMONARY-ARTERY CATHETERS GYNECOLOGIC ONCOLOGY EISNER, R. F., Montz, F. J., Berek, J. S. 1990; 37 (3): 311-314
Abstract

Twenty-three patients underwent pulmonary artery (Swan-Ganz) catheterization for hemodynamic monitoring immediately after cytoreductive surgery for advanced ovarian cancer. Seventeen patients were studied continuously for at least 24 hr to determine the postoperative hemodynamic changes; 6 patients were intermittently monitored. The mean age was 63 years, mean operating time was 4.4 hr, mean ascites volume was 2300 ml, and estimated mean blood loss was 1300 ml. The mean nadir arterial pressure was 90 mm Hg at 6 hr, rising to a maximum of 105 mm Hg at 18 hr. The mean right atrial pressure was 2.6 mm Hg at 6 hr and 7.5 mm Hg at 24 hr; and mean pulmonary capillary wedge pressure nadir was 7.3 mm Hg at 6 hr and 10.7 mm Hg at 24 hr. The systemic vascular resistance zenith was 1400 dyne/sec/cm-5 at 6 hr and 860 dyne/sec/cm-5 at 24 hr. The monitoring technique permitted the early identification of myocardial infarction in two patients, both of whom had increased systemic vascular resistance and pulmonary capillary wedge pressure, and required dopamine to maintain arterial pressure. One patient had a pulmonary embolus, reflected by an increased right atrial pressure, decreased cardiac output, and normal pulmonary capillary wedge pressure. In all three instances, pulmonary artery catheterization facilitated prompt, early diagnosis of cardiovascular compromise and permitted early therapeutic intervention. These data document that rapid and extreme changes in the cardiovascular system occur in patients undergoing cytoreductive surgery. These changes include a rapid increase in systemic vascular resistance, a decrease in pulmonary capillary wedge pressure, a reflex tachycardia, and a decrease in cardiac output; all of these changes result from an acute shift of intravascular volume to the extracellular space and a relative hypovolemia requiring active resuscitation. Pulmonary artery catheterization plays an important role in monitoring these hemodynamic changes and a predictable uniform recovery with fluid resuscitation.

View details for Web of Science ID A1990DH50800002

View details for PubMedID 2351312
PHASE-II STUDY OF N-METHYLFORMAMIDE (N-MF) (NSC 3051) IN PATIENTS WITH ADVANCED EPITHELIAL OVARIAN-CANCER - A GYNECOLOGIC ONCOLOGY GROUP-STUDY INVESTIGATIONAL NEW DRUGS McGuire, W. P., Blessing, J. A., Berek, J. S., Munoz, A. 1990; 8 (2): 191-194
Abstract

Forty-four patients with advanced, measurable, epithelial carcinoma of the ovary were treated with 97 courses of N-methylformamide (N-MF) at doses ranging from 600-800 mg/m2, intravenously, daily for 5 days every 28 days. Forty-one patients had prior surgery and had received one prior chemotherapy regimen. Only seven patients had received any prior radiation therapy. All patients were Gynecologic Oncology Group (GOG) performance status 0, 1, or 2. Three partial responses were seen. Hematologic adverse effects were extremely rare as predicted by early clinical trials. One major toxicity was a syndrome consisting of some combination of myalgias, arthralgias, pleuritic pain, abdominal pain, peripheral neuropathy, anorexia, lethargy, and declining performance status (pain-lethargy syndrome) that was reversible with discontinuation of the drug. This adverse effect was as common a reason as hepatic toxicity for discontinuation of N-MF. As reported in previous studies with this drug, hepatic toxicity was also common, usually reversible, and also a cause for discontinuation of the drug. The low level of clinical activity and the unpleasant adverse effects in this population of patients with previously treated ovarian cancer makes it unlikely that this drug will play any significant role in treatment of epithelial ovarian cancer.

View details for Web of Science ID A1990DK20800011

View details for PubMedID 2384305
ADJUVANT THERAPY FOR EARLY-STAGE OVARIAN-CANCER NEW ENGLAND JOURNAL OF MEDICINE Berek, J. S. 1990; 322 (15): 1076-1078
View details for Web of Science ID A1990CX86900010

View details for PubMedID 2181311
RISK-FACTORS FOR THE DEVELOPMENT OF LYMPH-NODE METASTASIS IN VULVAR SQUAMOUS-CELL CARCINOMA GYNECOLOGIC ONCOLOGY Binder, S. W., Huang, I., Fu, Y. S., Hacker, N. F., Berek, J. S. 1990; 37 (1): 9-16
Abstract

One hundred and ten women who underwent vulvectomy and inguinal-femoral lymphadenectomy for stages I-IV vulvar squamous cell carcinoma were studied. The most important factors that affected the inguinal lymph node status in the order of importance were vascular invasion, clinical stage, tumor thickness, depth of stromal invasion, and amount of keratin. Fourteen (88%) of 16 tumors with vascular invasion in the primary tumor metastasized. In the absence of vascular invasion, 18 (19%) of 94 tumors metastasized. Overall, 82% of tumors were correctly classified into lymph node negative and positive groups on the basis of vascular invasion. Tumor thickness and depth of stromal invasion had a similar accuracy in predicting lymph node status. The risk of lymph node metastasis increased from 0% when tumor thickness or depth of stromal invasion was less than 2 mm, to over 20% when depth of stromal invasion was greater than 2 mm, and to over 40% when tumor thickness exceeded 4 mm. A combination of vascular invasion, tumor thickness (or depth of stromal invasion), and the amount of keratin correctly classified 97% (76/78) of the lymph node negative group and 63% (20/32) of the positive group with an overall accuracy of 87%. The probability of having lymph node metastasis was computed for individual patients on the basis of one or more pathologic parameters using a logistic regression model. This feasibility is an important step toward individualized therapy for vulvar carcinoma.

View details for Web of Science ID A1990DA10500003

View details for PubMedID 1691127
AUGMENTATION OF CYTOTOXICITY OF LYMPHOKINE ACTIVATED KILLER-CELLS ON OVARIAN TUMOR-CELLS BY VARIOUS BIOLOGICAL RESPONSE MODIFIERS ANTICANCER RESEARCH Nio, Y., ZIGHELBOIM, J., Berek, J. S., Bonavida, B. 1990; 10 (2A): 441-446
Abstract

The effect of combining lymphokine activated killer (LAK) cells with either recombinant interleukin-2 (rlL-2), recombinant interferon-alpha (rIFN-alpha), recombinant tumor necrosis factor (rTNF) or streptococcal preparation OK-432 were assessed, using Raji, 2 kinds of cultured ovarian lines (PA-1 and SKOV-3), and 7 fresh ovarian tumor lines. LAK cells were generated by culturing peripheral blood lymphocytes (PBL) with rIL-2 for 3-5 days. The simultaneous combination of LAK cells with rIFN alpha or OK-432 augmented the cytotoxicity of LAK cells. The susceptibility of tumor cells to LAK cells also increased after the pretreatment of tumor cells with OK-432. These results suggest that the simultaneous injection of LAK cells with rIFN-alpha or OK-432 and the intralesional injection of OK-432 prior to the adoptive transfer of LAK cells may be a beneficial combination treatment for LAK treatment.

View details for Web of Science ID A1990DG72300028

View details for PubMedID 2346317
PELVIC HEMANGIOPERICYTOMAS - A REPORT OF 5 CASES AND LITERATURE-REVIEW GYNECOLOGIC ONCOLOGY Munoz, A. K., Berek, J. S., Fu, Y. S., HEINTZ, P. A. 1990; 36 (3): 380-382
Abstract

Five cases of pelvic hemangiopericytomas are reported. One of these tumors arose from the uterus, and four patients had extrauterine, pelvic hemangiopericytomas. The patient with a primary uterine hemangiopericytomas had only simple excision, and, after 6 years, is alive and free of disease. All four patients with extrauterine, pelvic hemangiopericytomas had incomplete resection of their tumors because of hemorrhage. However, pelvic radiation therapy was then employed in these patients and produced a complete regression in one patient and partial regression in two patients with minimal shrinkage in another patient. The latter patients were reexplored after pelvic radiation and underwent complete resection of their disease. Two patients developed pelvic recurrences at 2 and 9 years, respectively, and these were effectively resected. All four patients are all alive and free of disease 5 to 18 years later. If this lesion is unexpectedly discovered at laparotomy, our experience suggests that the resection should be discontinued and that they should be treated with pelvic radiation and delayed resection of persistent and recurrent pelvic tumors.

View details for Web of Science ID A1990CX71600018

View details for PubMedID 2318448
CYCLOHEXIMIDE-INDUCED MODULATION OF TNF-MEDIATED CYTOTOXICITY IN SENSITIVE AND RESISTANT OVARIAN TUMOR-CELLS CANCER CHEMOTHERAPY AND PHARMACOLOGY Nio, Y., ZIGHELBOIM, J., Berek, J., Bonavida, B. 1990; 26 (1): 1-8
Abstract

The mechanism of sensitivity and resistance of various ovarian carcinoma lines to recombinant tumor necrosis factor (rTNF)-mediated cytotoxicity has been investigated using a 24-h 51Cr-release assay. The cell line PA-1 is sensitive to TNF in a dose-dependent manner, whereas the cell line SKOV-3 is resistant to TNF even at high concentrations. The simultaneous addition of TNF and cycloheximide (CHX) in the assay converted the resistant SKOV-3 line into a sensitive line, but no detectable change was observed with PA-1. rTNF inhibited DNA, RNA, and protein synthesis of the sensitive PA-1 line, whereas it had no effect on SKOV-3. This finding was not due to differences in the expression of TNF receptors, as both cell lines expressed equivalent numbers of receptors. The addition of CHX to TNF resulted in suppression of DNA, RNA, and protein synthesis in both the sensitive and the resistant cell lines. Pretreatment of the cell line with TNF for 3 h and subsequent washing resulted in significant cytotoxicity of the sensitive PA-1 line and some cytotoxicity against SKOV-3. However, if the cells were pretreated with CHX for 3 h followed by rTNF for 24 h, a significant decrease in cytotoxicity was observed in both cell lines. Under these conditions, there was no significant inhibition of DNA, RNA, or protein synthesis. Pretreatment of cells for 24 h with TNF and 24 h with CHX resulted in augmentation of the cytotoxicity of PA-1 and SKOV-3, whereas pretreatment for 24 h with CHX followed by 24 h with TNF resulted in no cytotoxicity. Cells pretreated with CHX for 24 h showed poor binding of [125]I-TNF and poor internalization, whereas cells pretreated for 24 h with TNF showed marked enhancement of internalization. The sensitivity of freshly derived ovarian carcinoma lines to TNF and CHX demonstrated that TNF-resistant cells became more sensitive if treated with CHX. These results demonstrate the potential use of metabolic inhibitors in increasing the sensitivity of fresh ovarian tumor cells to TNF.

View details for Web of Science ID A1990CX06000001

View details for PubMedID 2322985
RESECTION OF DIAPHRAGMATIC PERITONEUM AND MUSCLE - ROLE IN CYTOREDUCTIVE SURGERY FOR OVARIAN-CANCER GYNECOLOGIC ONCOLOGY Montz, F. J., Schlaerth, J. B., Berek, J. S. 1989; 35 (3): 338-340
Abstract

Fourteen patients undergoing primary cytoreductive surgery for stage III ovarian malignancies had diaphragmatic peritoneum, muscle, or both resected in an attempt to remove all metastatic disease greater than 0.5 cm in diameter. Resection was completed in 13 of 14 patients (93%), all obtaining optimal cytoreduction. Size of resected specimens varied from 12 x 7 to 17 x 11 cm. The mediastinum was entered in two patients. Four patients had resection of diaphragmatic muscle. All defects were closed primarily and a thoracostomy tube was placed. One patient who did not have muscle resection had a 30% pneumothorax that spontaneously resolved. No subdiaphragmatic hematomas or abscesses occurred. Time (mean 65 min, range 40-150 min) and blood loss (mean 175 ml, range 100-1500 ml) for the surgery depended upon extent of disease. One procedure was terminated due to bleeding from a lacerated liver capsule. We conclude that diaphragmatic peritoneum/muscle resection can be completed successfully with acceptable morbidity.

View details for Web of Science ID A1989CD97300012

View details for PubMedID 2599468
Screening, diagnosis, and monitoring of gynecologic malignancies. Current opinion in oncology Montz, F. J., Berek, J. S. 1989; 1 (1): 75-81
View details for PubMedID 2489952
SYNERGISTIC EFFECT OF COMBINED INTRAPERITONEAL CISPLATIN AND CYTOSINE-ARABINOSIDE IN A MURINE OVARIAN-CANCER MODEL OBSTETRICS AND GYNECOLOGY Berek, J. S., Schink, J. C., Knox, R. M. 1989; 74 (4): 663-666
Abstract

The chemotherapeutic combination of cisplatin and cytosine arabinoside has synergy in vitro. We used a murine ovarian teratocarcinoma in C3HeB/FeJ mice to evaluate these drugs for synergy in vivo. Several dose-response schedules and various sequences were tested to determine the optimal delivery schedule. Survival of control mice injected with 10(4) murine ovarian teratocarcinoma was 28 days. Tumor-bearing mice treated with intraperitoneal cisplatin alone had significantly prolonged survival, whereas intraperitoneal cytosine arabinoside alone did not prolong survival. Repeated doses of cytosine arabinoside every 24 hours for 4 days resulted in minimal prolongation of survival. Simultaneous one-time administration of cisplatin and cytosine arabinoside resulted in synergy as measured by survival, with 50% of mice surviving at 80 days. Combined simultaneous administration of cisplatin and cytosine arabinoside daily for 3 days resulted in 100% survival at 120 days. Both cisplatin and cytosine arabinoside have an outstanding pharmacokinetic advantage when given intraperitoneally. A clinical trial of these drugs with a 3-day schedule is warranted.

View details for Web of Science ID A1989AR52500024

View details for PubMedID 2797645
HUMAN NEUTROPHIL-MEDIATED LYSIS OF OVARIAN-CANCER CELLS BLOOD Lichtenstein, A., Seelig, M., Berek, J., ZIGHELBOIM, J. 1989; 74 (2): 805-809
Abstract

Because of recent questions concerning the sensitivity of human tumor cells to neutrophil-induced oxidative injury, we studied six freshly obtained human ovarian cancer (OC) specimens. Stimulation of neutrophils (PMNs) by phorbol myristate acetate (PMA) did not result in OC cytolysis during the first nine hours of incubation. However, three of six specimens were significantly lysed by stimulated PMNs when assay length was increased to 18 hours. Cytotoxicity was mediated by PMN production of reactive oxidative intermediates (ROIs). Presentation of ROIs to OC targets as preformed or enzymatically generated molecules in cell-free systems duplicated the enhanced lysis at 18 hours (as compared with six hours). Since addition of catalase at three or six hours did not inhibit enhanced lysis at 18 hours (achieved by PMNs or in cell-free systems), it appears that an initial ROI-mediated lethal event occurs early, but longer incubations are required for the event to become manifested as cell death. These data suggest that shorter assays may underestimate the potential of PMNs as effector cells against human tumor cells.

View details for Web of Science ID A1989AH17500039

View details for PubMedID 2546632
CYTO-TOXIC AND CYTOSTATIC EFFECTS OF THE STREPTOCOCCAL PREPARATION OK-432 AND ITS SUBCELLULAR-FRACTIONS ON HUMAN OVARIAN TUMOR-CELLS CANCER Nio, Y., ZIGHELBOIM, J., Berek, J., Bonavida, B. 1989; 64 (2): 434-441
Abstract

Previous studies have indicated that OK-432 is a potent biologic response modifier (BRM) and that it augments immune responses to tumor cells. We studied the direct effect of OK-432 on tumor cells. Established and freshly derived human ovarian carcinoma lines were examined for their susceptibility to OK-432 or its subcellular fractions in direct cytotoxicity, cytostatic activity, and inhibition of metabolic activity. OK-432 was cytotoxic to 13 of 15 freshly derived ovarian carcinoma lines in a 24-hour chromium-51 (51Cr) release assay. The optimal effect was noticed at OK-432 concentrations between 0.1 and 1.0 Klinishe Einhert (KE) per milliliter. The cytostatic effect on two established lines and one fresh line correlated with the cytotoxic activity. In all three lines, however, the metabolic activities (DNA, RNA, and protein synthesis) were inhibited by OK-432, suggesting that cell lysis by OK-432 may not be directly correlated with the inhibition of metabolic activities. Several subcellular fractions were derived from OK-432 and only the cytoplasmic and protoplast membrane fractions showed cytotoxic activity against the OK-432-sensitive tumor cell lines, although the cytotoxicity obtained was greatly less than the whole microorganism OK-432. The direct binding of 14C-OK-432 to tumor cells was examined. Binding took place rapidly after 1 hour of incubation and reached a maximum activity at 37 degrees C. Binding in all three lines ranged between 1.7 and 2.7 pg/cell. These results demonstrate the direct cytotoxic effect of OK-432 and some subcellular fractions on human ovarian carcinoma lines. These results also show that the BRM OK-432 may exert its effect by both potentiating the antitumor response and directly inhibiting tumor cell growth.

View details for Web of Science ID A1989AD24100015

View details for PubMedID 2736490
UTILIZATION OF A MURINE MODEL TO OPTIMIZE VOLUME AND DWELL TIME OF INTRAPERITONEAL CISPLATIN GYNECOLOGIC ONCOLOGY Pretorius, R. G., Eisenkop, S., Berek, J. S., Hacker, N. F., Ashikaga, T., Knox, R. M., Lagasse, L. D. 1989; 34 (1): 66-69
Abstract

The pharmacokinetics of intraperitoneal (ip) cisplatin were investigated in a murine model. Groups of six animals were studied at initial cisplatin concentrations (Ci) of 50, 100, 200, and 400 micrograms/ml, and at injection volumes (V) of 0.5, 1, 2, and 4 ml. For each Ci and V, four dwell times (Dt) between 1.5 and 120 min were studied. At 180 min mice were killed and five tissues (heart, kidney, liver, bowel, and peritoneum) were obtained for platinum measurement. Platinum recovered from the peritoneal cavity at the end of the dwell time and platinum tissue levels were determined by a radioactive tracer assay using Pt 195m-labeled cisplatin. A total of 384 mice were studied. The permeability times the effective surface area product (pS) was found to be independent of Ci, V, and Dt. Platinum tissue levels were proportional to absorbed dose. As the ratio of platinum tissue level to absorbed dose is constant, it is not possible to change Ci, V, nor Dt to minimize toxicity from a given absorbed dose. This study suggests that the therapeutic index of an individual intraperitoneal cisplatin treatment will not be changed by modifying Ci, V, nor Dt.

View details for Web of Science ID A1989AC05800016

View details for PubMedID 2737529
SYNCHRONOUS PRIMARY NEOPLASMS OF THE FEMALE REPRODUCTIVE-TRACT GYNECOLOGIC ONCOLOGY EISNER, R. F., Nieberg, R. K., Berek, J. S. 1989; 33 (3): 335-339
Abstract

A histopathologic review of synchronous primary neoplasms of the female reproductive tract is presented. During a 30-year period, 3863 patients with female genital malignancies were accessioned to the UCLA Tumor Registry: 958 had ovarian cancer, 776 endometrial cancer, 1556 cervical cancer, and 573 other gynecologic malignancies. Twenty-six (0.7%) patients with invasive synchronous primary cancers were identified. The most frequent synchronous genital lesions were ovarian and endometrial cancers in 11 patients (0.3%). No association was documented between genital and extragenital cancers. Patients with synchronous ovarian and endometrial cancers each were low stage and low grade, and the prognosis was excellent. Their detection in a relatively early stage suggests diagnosis may be facilitated by early symptoms from the endometrial carcinoma, and that these lesions are biologically of relatively low grade. These data support the conclusion that there is an association between low-stage epithelial carcinoma of the ovary and endometrial carcinoma.

View details for Web of Science ID A1989U719000014

View details for PubMedID 2722060
LYMPHOCYTE-ACTIVATION BY RECOMBINANT INTERLEUKIN-2 IN OVARIAN-CANCER PATIENTS OBSTETRICS AND GYNECOLOGY Boyer, P. J., Berek, J. S., ZIGHELBOIM, J. 1989; 73 (5): 793-797
Abstract

Peripheral blood lymphocytes from 42 patients and peritoneal cavity lymphocytes from eight patients with advanced ovarian carcinoma were tested for lymphokine-activated killer lymphocyte cytotoxicity against several ovarian carcinoma lines before and after exposure to recombinant interleukin-2 in vitro for 3-5 days. Only four of 42 (9.5%) of peripheral blood lymphocytes and zero of eight (0%) of peritoneal cavity lymphocytes had spontaneous cytotoxicity (greater than 20%) against the ovarian carcinoma lines. After in vitro exposure to recombinant interleukin-2, 41 of 42 (98%) of patients' blood lymphocytes showed a two- to fivefold increase in cytotoxicity against K562 (a lymphoblastoid human target), and 40 of 42 (95%) demonstrated lymphokine-activated killer cytotoxicity (greater than 20%) to the ovarian carcinoma lines. Lymphokine-activated killer activity against fresh allogeneic cell lines was variable, although most patients' peripheral blood lymphocytes (70%) had significant cytotoxicity. By contrast, incubation of patients' peritoneal cavity lymphocytes with recombinant interleukin-2 in vitro did not result in the generation of lymphokine-activated killer cell activity against K562 or ovarian cell lines. Peritoneal lymphocytes did produce lymphokine-activated killer cells in the presence of OK432 in half of the patients tested. The presence of autologous serum during recombinant interleukin-2 activation with blood lymphocytes had an augmentative effect on the resulting lymphokine-activated killer cytotoxicity in two of 20 patients, a suppressive effect in four of 20, and no effect in the other 14 of 20 patients tested.(ABSTRACT TRUNCATED AT 250 WORDS)

View details for Web of Science ID A1989U240800023

View details for PubMedID 2784847
VULVOVAGINAL MELANOMA - REPORT OF 7 CASES AND LITERATURE-REVIEW GYNECOLOGIC ONCOLOGY Brand, E., Fu, Y. S., Lagasse, L. D., Berek, J. S. 1989; 33 (1): 54-60
Abstract

Five cases of primary vaginal melanoma were treated at UCLA Medical Center between 1976 and 1986. Two additional cases of melanoma arising at the junction of the vulva and vagina are presented. One of seven (13%) patients is alive, with a median time to recurrence of 7 months, and median survival of 31 months. Four of five vaginal melanomas were located in the distal vagina, and all were advanced at diagnosis (greater than 3 mm depth). Mean size was 3 cm. Initial therapy was local excision in four patients and radical surgery in three. All patients had suboptimal surgical margins: two vaginal primaries had positive margins after local excision, both recurred vaginally within 5 months. Two patients had margins less than 1 mm, one died of distant metastases, the other is alive with disease 30 months after radical distal vaginectomy and hemivulvectomy with post-op pelvic radiotherapy. Three patients had melanoma in situ at the surgical margins, and each had pelvic recurrences between 6 and 26 months. Five of seven cases developed local recurrence as the initial site of treatment failure. All five vaginal cases ultimately developed distant disease, but only two patients had distant disease without local-regional recurrence. Chemotherapy and immunotherapy enabled disease stabilization in three patients. The vulvovaginal junction at the introitus is a high risk site for vaginal and vulvar melanoma. Intraoperative management requires assessment of lateral and deep spread of invasive and in situ melanoma.

View details for Web of Science ID A1989T995600011

View details for PubMedID 2649420
RANDOMIZED TRIAL OF CYCLOPHOSPHAMIDE PLUS CISPLATIN WITH OR WITHOUT DOXORUBICIN IN OVARIAN-CARCINOMA - A GYNECOLOGIC ONCOLOGY GROUP-STUDY JOURNAL OF CLINICAL ONCOLOGY Omura, G. A., Bundy, B. N., Berek, J. S., Curry, S., Delgado, G., MORTEL, R. 1989; 7 (4): 457-465
Abstract

A randomized clinical trial was conducted in women with stage III ovarian carcinoma (less than or equal to 1 cm residual lesions), using cyclophosphamide plus cisplatin (CP) with or without doxorubicin. There were 349 evaluable patients, of whom 176 received CP while 173 patients received CP plus doxorubicin (CAP). Hematologic toxicity was almost identical. There was no significant difference in progression-free interval (PFI) (median, 22.7 months and 24.6 months), frequency of negative second-look laparotomy (30.2% and 32.8%), or survival (median, 31.2 months and 38.9 months) between CP and CAP, respectively. Thus, doxorubicin in the dose schedule employed does not improve combination chemotherapy of optimal stage III ovarian carcinoma. Several other findings, independent of treatment arm, were of interest. There was a significant difference in PFI and survival by residual disease category (yes v no) and by grade of differentiation (1 v 2 + 3). In multivariate analysis, age, residual disease at entry, cell type (clear cell carcinoma), and time from surgery to initiation of chemotherapy were significant predictors of survival. There was no difference in outcome comparing those who refused second-look with those who had a second-look.

View details for Web of Science ID A1989T977100009

View details for PubMedID 2926470
PERITONEAL CYTOLOGY OF OVARIAN-CANCER PATIENTS RECEIVING INTRAPERITONEAL THERAPY - QUANTITATION OF MALIGNANT-CELLS AND RESPONSE OBSTETRICS AND GYNECOLOGY Sagae, S., Berek, J. S., Fu, Y. S., Chang, N., Dauplat, J., Hacker, N. F. 1988; 72 (5): 782-788
Abstract

An analysis was performed of malignant and host cells found in peritoneal fluids obtained during intraperitoneal chemotherapy and immunotherapy in patients with ovarian cancer. The concentration of malignant cells and the surgically documented response to the intraperitoneal treatment were correlated. Twenty-three patients were treated with intraperitoneal cisplatin or alpha-2 interferon (rIFN-alpha 2) after persistent carcinoma was documented at second-look laparotomy. Six patients (26%) had a complete response to therapy, and all of these patients had a malignant cell concentration of less than 10(2)cells/cm2/dL. No responses were seen in patients whose initial malignant cell concentration was greater than 10(3)cells/cm2/dL. Among patients treated with intraperitoneal alpha-interferon, five of 11 whose initial concentration of malignant cells was less than 10(2) cells/cm2/dL responded to therapy, whereas none of the patients whose malignant cell concentration was 10(2) cells/cm2/dL or greater responded. In patients treated with intraperitoneal cisplatin, the initial concentration of malignant cells associated with any surgically documented response was less than 10(3)cells/cm2/dL. A host mesothelial reaction was prominent after intraperitoneal alpha-interferon, but not observed in women treated with intraperitoneal cis-platin. The fluctuating pattern of peritoneal white blood cells documented during therapy did not correlate with response. THe evaluation of peritoneal cytology specimens during intraperitoneal chemotherapy should include a quantitative assessment of malignant cells and reactive mesothelial cells in order to reflect more accurately the histologically documented findings. Initial quantitative cytology appears to correlate with the likelihood of a surgically documented response to intraperitoneal therapy.

View details for Web of Science ID A1988Q648700020

View details for PubMedID 3173930
INTRAPERITONEAL ADMINISTRATION OF HUMAN RECOMBINANT INTERFERON-ALPHA IN PATIENTS WITH OVARIAN-CANCER - EFFECTS ON LYMPHOCYTE PHENOTYPE AND CYTO-TOXICITY CANCER RESEARCH Lichtenstein, A., Spina, C., Berek, J. S., Jung, T., ZIGHELBOIM, J. 1988; 48 (20): 5853-5859
Abstract

Eleven patients with persistent Stage III ovarian cancer, documented at second look laparotomy, received i.p. human recombinant interferon-alpha (5-50 x 10(6) units/week). Prior to immunotherapy, patients' peritoneal cell lymphocytes (PCLs) contained decreased proportions of Leu-7+ and Fc-receptor+ cells and almost nondetectable natural killer (NK) and antibody-dependent cell cytotoxic (ADCC) activity. In contrast, patients' peripheral blood lymphocytes (PBLs) contained normal proportions of lymphocyte subsets and cytotoxic activity compared to control donor PBLs. During therapy, there was a concurrent increase in PCL Leu-7+ cells and NK lysis. Both peaked predictably at 24 h after each treatment, regardless of the dose injected, and usually returned to baseline by Day 7 of each weekly cycle. PCL NK enhancement was striking, usually increasing from 2-6% (effector:target ratio, 25:1) to over 30% lysis. Enhancement of PCL ADCC was less impressive. PCLs of several patients developed lytic activity towards NK-resistant Raji targets. During therapy, patients' PBLs demonstrated: (a) modestly enhanced NK lysis at Day 4 of each cycle, and; (b) no development of Raji lysis. These data clearly demonstrate the efficacy of i.p. interferon in activation of peritoneal NK activity. However, increased NK lysis did not correlate with individual tumor responses in this cohort of patients.

View details for Web of Science ID A1988Q354700042

View details for PubMedID 3167841
SENSITIVITY OF FRESH AND CULTURED OVARIAN TUMOR-CELLS TO TUMOR NECROSIS FACTOR, INTERFERON-ALPHA-2, AND OK-432 CANCER IMMUNOLOGY IMMUNOTHERAPY Nio, Y., ZIGHELBOIM, J., Berek, J. S., Bonavida, B. 1988; 27 (3): 246-254
Abstract

The in vitro sensitivity to rTNF, rIFN-alpha 2, and OK-432 of 11 freshly derived human ovarian tumors and 2 established tumor cell lines was examined in a cytotoxic assay using the 51 Cr release test. Nine fresh lines were sensitive to rTNF, 8 to OK-432, and only 2 were sensitive to rIFN-alpha 2. Cytotoxicity by rIFN-alpha 2 was of lesser magnitude than the cytotoxicity mediated by rTNF or OK-432. The time of exposure and the concentration of BRM required for maximal cytotoxicity varied from line to line. Two fresh tumor cell lines and 1 established cell line (PA-1) were sensitive to all 3 BRMs, while 2 other FOCs and 1 cell line (SKOV-3) were resistant to all BRMs. The remaining FOC showed an intermediate degree of sensitivity. These results demonstrate the existence of heterogeneity of ovarian carcinoma tumor cell lines to lysis by BRMs. Among the FOCs, the 2 endometrioid carcinomas tested were highly sensitive to rTNF, whereas the serous carcinomas were more sensitive to OK-432. Low grade tumors were more sensitive to BRM than high grade tumors, and tumor extension did not correlate with sensitivity to the BRM. When tumor targets were exposed to more than 1 BRM added either simultaneously or sequentially, the net cytotoxic effect achieved was usually inferior to the sum cytotoxicity obtained by each BRM alone. Furthermore, rTNF and OK-432 were cytostatic to most ovarian tumor cell lines examined. The results of this study demonstrate that certain BRMs exert a direct effect on fresh ovarian tumor cells independently of host factors. These findings suggest that in vitro screening of a patient's tumor cells for sensitivity to a particular BRM prior to therapy could be beneficial for the proper identification of patients most likely to benefit from the treatment.

View details for Web of Science ID A1988Q373100009

View details for PubMedID 3180149
PREOPERATIVE EVALUATION OF SERUM CA-125 LEVELS IN PREMENOPAUSAL AND POSTMENOPAUSAL PATIENTS WITH PELVIC MASSES - DISCRIMINATION OF BENIGN FROM MALIGNANT DISEASE AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Malkasian, G. D., Knapp, R. C., Lavin, P. T., Zurawski, V. R., Podratz, K. C., Stanhope, C. R., MORTEL, R., Berek, J. S., Bast, R. C., RITTS, R. E. 1988; 159 (2): 341-346
Abstract

CA 125 levels were measured in 158 patients with palpable pelvic masses who were about to undergo diagnostic laparotomy. When the 68 patients found to have cancer were compared with the 90 patients with benign disease, those with malignancies were significantly older, were more frequently postmenopausal, and had significantly higher values of serum CA 125. Patients with benign pelvic masses had CA 125 levels greater than 65 U/ml in 8% of cases, whereas those with malignancies had CA 125 levels greater than 65 U/ml in 75% of cases. If only those patients who had frankly malignant, primary, nonmucinous epithelial ovarian carcinomas were considered, CA 125 levels greater than 65 U/ml predicted malignancy with a sensitivity of 91% for all patients. Greater sensitivity and specificity were observed in the postmenopausal subgroup than in the premenopausal subgroup. In the postmenopausal group with a 63% prevalence of ovarian cancer the predictive positive value was 98% and the predictive value negative was 72%. In a premenopausal population with a 15% prevalence of ovarian cancer the predictive value for a positive test was 49%, while the predictive value for a negative test was 93%.

View details for Web of Science ID A1988P880500015

View details for PubMedID 2457318
IMMUNOLOGICAL CONTROL OF OVARIAN-CANCER NATURAL IMMUNITY AND CELL GROWTH REGULATION ZIGHELBOIM, J., Nio, Y., Berek, J. S., Bonavida, B. 1988; 7 (4): 216-225
View details for Web of Science ID A1988R295200002

View details for PubMedID 3070371
Uterine corpus and cervical cancer. Current problems in cancer Berek, J. S., Hacker, N. F., Hatch, K. D., Young, R. C. 1988; 12 (2): 61-131
Abstract

Cancers of the cervix and uterus occur in approximately 50,000 women each year in the United States. As a group, these cancers represent our sixth most common cancer overall, are second only to breast cancer, and are roughly equal to the lung cancer incidence in women. Although they comprise 11% of all cancers in females, they represent only 4% of cancer deaths in women. This results from the effective application of surgery and radiation therapy in the management of these two malignancies as well as effective techniques for early diagnosis. The overall death rate from these two malignancies has decreased more than 70% in the last 40 years. Successful outcome rests on both early diagnosis and the careful application of established treatment approaches. This monograph summarizes the management approaches to both uterine corpus and cervical cancer and discusses the role of adjuvant therapy for these major malignancies. Detailed presentations of the management of special problems, including the uterine sarcomas, are also presented. Although standard management approaches are detailed, discussion of experimental approaches, including adjuvant hormonal treatment, single agent and combination chemotherapy, and the use of radiation sensitizers is included.

View details for PubMedID 3286130
UTERINE CORPUS AND CERVICAL-CANCER CURRENT PROBLEMS IN CANCER Berek, J. S., Hatch, K. D., Hacker, N. F., Young, R. C. 1988; 12 (2): 65-129
View details for Web of Science ID A1988N187000001
CONTROVERSIES IN THE MANAGEMENT OF CERVICAL ADENOCARCINOMA OBSTETRICS AND GYNECOLOGY Brand, E., Berek, J. S., Hacker, N. F. 1988; 71 (2): 261-269
Abstract

Adenocarcinoma of the uterine cervix appears to be more prevalent now than a decade ago, and currently constitutes 10-20% of invasive cervical cancers. Because precursor lesions arise within the endocervical canal, identification and diagnosis of invasive disease is often more difficult than for squamous carcinoma. There is disagreement regarding the optimal treatment of adenocarcinoma. Adenocarcinoma may have a poorer prognosis than squamous carcinoma because it may be more difficult to detect and because it tends to metastasize earlier in its course. The controversies in the diagnosis and management of adenocarcinoma and adenosquamous carcinoma of the uterine cervix are reviewed.

View details for Web of Science ID A1988L881700027

View details for PubMedID 3275916
Minimal cervical cancer: definition and histology. Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer Fu, Y. S., Berek, J. S. 1988; 106: 47-56
View details for PubMedID 3285416
INTRAPERITONEAL CISPLATINUM AS SALVAGE THERAPY FOR REFRACTORY EPITHELIAL OVARIAN-CANCER OBSTETRICS AND GYNECOLOGY Hacker, N. F., Berek, J. S., Pretorius, R. G., Zuckerman, J., Eisenkop, S., Lagasse, L. D. 1987; 70 (5): 759-764
Abstract

Eighteen patients with residual epithelial ovarian cancer at second-look laparotomy were treated with a combined total of 210 cycles of intraperitoneal cis-platinum. Sixteen patients had previously received cis-platinum containing combination chemotherapy systemically. Seven patients had microscopic residual disease at the start of intraperitoneal therapy, eight had macroscopic disease of 5 mm in diameter or less, and three had disease of 6-10 mm in diameter. The drug was administered weekly in 2 L of Ringer's lactate solution via an indwelling Tenckhoff catheter, and the dose ranged from 30-270 mg per cycle (median 120 mg). The dwell time was 20 minutes. After 12 cycles, response was assessed by open laparoscopy (six patients), laparotomy (eight patients), or peritoneal cytology (three patients). One patient developed distant metastases. Local and systemic toxicity was mild. Delays of therapy were necessary for eight of the 210 cycles because of hematologic toxicity. Of the 15 patients available for pathologic evaluation, four (26.6%) had a complete response and two (13.3%) had a partial response. Results of this pilot study suggest a possible role for intraperitoneal cis-platinum in the management of carefully selected patients with epithelial ovarian cancer.

View details for Web of Science ID A1987K565800020

View details for PubMedID 3658287
RHABDOMYOSARCOMA OF THE UTERINE CERVIX - SARCOMA BOTRYOIDES CANCER Brand, E., Berek, J. S., Nieberg, R. K., Hacker, N. F. 1987; 60 (7): 1552-1560
Abstract

Twenty-one cases of sarcoma botryoides of the uterine cervix, including four previously unreported cases, are reviewed. The age of the patients ranged from 5 months to 48 years, with a peak incidence in the group aged 14 to 18 years. Eighty percent of the patients are alive, with a mean follow-up period of 68 months. Seventy-five percent of the patients had Group I disease, of whom 88% are alive. Eleven of 14 patients (79%) receiving vincristine and dactinomycin based chemotherapy are alive. There were five patients with recurrent disease (24%) of whom two (40%) are alive. The prognosis for cervical sarcoma botryoides is similar to that of other female genital tract embryonal rhabdomyosarcomas. Primary therapy should consist of vincristine and dactinomycin based chemotherapy. Surgery should be guided by the response to initial chemotherapy and should attempt to conserve the function of the bladder, rectum, vagina, and ovaries.

View details for Web of Science ID A1987K249600023

View details for PubMedID 3621128
DISTANT METASTASES IN EPITHELIAL OVARIAN-CARCINOMA CANCER Dauplat, J., Hacker, N. F., Nieberg, R. K., Berek, J. S., Rose, T. P., Sagae, S. 1987; 60 (7): 1561-1566
Abstract

A review of 255 patients with epithelial ovarian carcinoma revealed that metastases consistent with Stage IV disease developed in 97 patients (38.0%) at some time during the natural history of their disease. Malignant pleural effusions developed in 63 patients (24.7%), and their median survival (from the time of diagnosis of the effusion) was 6 months. Parenchymal liver metastases developed in 24 patients (9.4%; median survival, 5 months); parenchymal lung metastases in 18 patients (7.1%; median survival, 8 months); distant lymph node metastases in 18 patients (7.1%; median survival, 9 months); subcutaneous nodules in nine patients (3.5%; median survival, 12 months); a malignant pericardial effusion in six patients (2.4%; median survival, 2.3 months); central nervous system metastases in five patients (2%; median survival, 1.3 months); and bone metastases in four patients (1.6%; median survival, 4 months). Patients with Stage IV disease at the time of diagnosis had a median survival of 9.1 months, while patients with a delayed occurrence of distant metastases had a median survival of only 4 months from the time of diagnosis of the distant metastases. Significant risk factors for distant metastases were malignant ascites, peritoneal carcinomatosis, large metastatic disease within the abdomen, and retroperitoneal lymph node involvement at the time of the initial surgery. The significance of positive retroperitoneal nodes and bulky upper abdominal disease has important therapeutic implications.

View details for Web of Science ID A1987K249600024

View details for PubMedID 3621129
PROGNOSTIC-SIGNIFICANCE OF DNA PLOIDY AND MORPHOMETRIC ANALYSES OF ADENOCARCINOMA OF THE UTERINE CERVIX ANALYTICAL AND QUANTITATIVE CYTOLOGY AND HISTOLOGY Fu, Y. S., Hall, T. L., Berek, J. S., Hacker, N. F., Reagan, J. W. 1987; 9 (1): 17-24
Abstract

In an effort to improve the prognostic accuracy of the histologic criteria used for cervical adenocarcinomas, the nuclear DNA ploidy levels, means and standard deviations of nuclear areas and amounts of lumen and neoplastic tissue were quantitated. Useful thresholds in discriminating recurrent disease, as identified by logistic regression analysis, included a DNA ploidy level of 3.0 N, a percent of lumen of 34.6% and nuclear area mean and standard deviation of 53.1 sq micron and 20.1 sq micron, respectively. These parameters should provide useful guidelines in the visual assessment of histologic features that have prognostic significance.

View details for Web of Science ID A1987G675400004

View details for PubMedID 3580081
CA 125 FOR THE MONITORING OF OVARIAN-CARCINOMA DURING PRIMARY THERAPY OBSTETRICS AND GYNECOLOGY Lavin, P. T., Knapp, R. C., MALKASIAN, G., Whitney, C. W., BEREK, J. C., Bast, R. C. 1987; 69 (2): 223-227
Abstract

Thirty-one patients with ovarian cancer were monitored with the CA 125 antigenic determinant in the interval between cytoreductive surgery and the completion of subsequent chemotherapy. Distinct CA 125 assay trends have emerged from prospective serial monitoring. Among patients who were clinically and surgically free of disease after the completion of cytoreductive chemotherapy, the CA 125 assay always fell to levels under 35 U/mL within the first three months of cytoreductive chemotherapy, and stayed at low levels. Patients with partial cytoreduction operations had decreases in serum CA 125 levels only if there was a response to further therapy. The rate of fall of the CA 125 levels correlated with clinical outcome. All 13 patients with serum CA 125 above 35 U/mL after three months of treatment invariably had persistent tumors after subsequent chemotherapy, whereas in patients showing reduction of the CA 125 to levels below 35 U/mL, there were no surgically detectable tumors. Measurement of CA 125 during treatment might permit an early change to alternative and optimal forms of therapeutic management. The CA 125 level three months after treatment appears to be a critical predictor of response to therapy.

View details for Web of Science ID A1987F892100016

View details for PubMedID 2433652
Diagnostic problems of in situ and invasive adenocarcinomas of the uterine cervix. Applied pathology Fu, Y. S., Berek, J. S., Hilborne, L. H. 1987; 5 (1): 47-56
Abstract

In this study of 58 cervical in situ and invasive adenocarcinomas, the diagnostic accuracy of cervical biopsies was found to be closely related to the extent and the degree of differentiation of the neoplasm. Biopsies of in situ and early, well-differentiated adenocarcinomas were often limited in amount, precluding an accurate assessment of stromal invasion. In such cases, a comprehensive sample, e.g., by conization, was required to establish the diagnosis. Invasive adenocarcinoma could be distinguished from the in situ change by the loss of branching pattern of normal endocervical glands, a marked variation in the size and shape of the glands, and a complex papillary or solid growth pattern. The presence of a desmoplastic reaction further supported the invasive nature of the neoplasm.

View details for PubMedID 3620207
INTRAPERITONEAL RECOMBINANT ALPHA-INTERFERON FOR SALVAGE IMMUNOTHERAPY IN STAGE-III EPITHELIAL OVARIAN-CANCER - A GYNECOLOGIC ONCOLOGY GROUP-STUDY SEMINARS IN ONCOLOGY Berek, J. S., Hacker, N. F., Lichtenstein, A., Jung, T., Spina, C., Knox, R. M., Brady, J., Greene, T., Ettinger, L. M., Lagasse, L. D., Bonnem, E. M., Spiegel, R. J., ZIGHELBOIM, J. 1986; 13 (3): 61-71
View details for Web of Science ID A1986E248600010
HUMAN PAPILLOMAVIRUS DEOXYRIBONUCLEIC-ACID IN ADENOCARCINOMA AND ADENOSQUAMOUS CARCINOMA OF THE UTERINE CERVIX OBSTETRICS AND GYNECOLOGY Smotkin, D., Berek, J. S., Fu, Y. S., Hacker, N. F., Major, F. J., WETTSTEIN, F. O. 1986; 68 (2): 241-244
Abstract

This report describes the detection of human papillomavirus type 16 or 18 deoxyribonucleic acid (DNA) in nine of 15 invasive tumors of the cervix, including three squamous carcinomas, four adenosquamous carcinomas, one glassy cell carcinoma, and one adenocarcinoma. The viral DNA was identified by Southern blotting and DNA hybridization. Human papillomaviruses may play an etiologic role in the development of at least some adenocarcinomas and adenosquamous carcinomas as well as most squamous tumors of the cervix.

View details for Web of Science ID A1986D432000020

View details for PubMedID 3016624
THE CA 125 ASSAY AS A PREDICTOR OF CLINICAL RECURRENCE IN EPITHELIAL OVARIAN-CANCER AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Niloff, J. M., Knapp, R. C., Lavin, P. T., Malkasian, G. D., Berek, J. S., MORTEL, R., Whitney, C., Zurawski, V. R., Bast, R. C. 1986; 155 (1): 56-60
Abstract

Serum CA 125 levels were obtained from 55 women with epithelial ovarian cancer before a second-look surgical procedure and serially thereafter. All patients were clinically and radiographically free of tumor at the time of the second-look operation and were followed to clinical recurrence. Median follow-up was 12 months. CA 125 levels obtained at the second-look operation had a sensitivity and specificity for predicting clinical recurrence of 94% and 88%, respectively. Patients with an elevated CA 125 level (greater than or equal to 35 U/ml) had a 60% chance of clinical recurrence within 4 months, while patients with levels less than 35 U/ml had a 5% chance of clinical recurrence over the same time period. Serial CA 125 levels obtained after second-look operations were strong predictors of clinical outcome, and distinctly different monitoring profiles were observed among those patients remaining clinically free of tumor and those suffering clinical recurrence. The CA 125 assay became elevated (greater than or equal to 35 U/ml) before clinical recurrence in 94% of 35 cases with a median lead time of 3 months. The CA 125 assay identifies patients destined to suffer a clinical recurrence and provides a warning measurable in months. This may have important implications for therapy.

View details for Web of Science ID A1986D282900014

View details for PubMedID 3460341
CYTOREDUCTIVE SURGERY IN OVARIAN-CARCINOMA - FEASIBILITY AND MORBIDITY OBSTETRICS AND GYNECOLOGY Heintz, A. P., Hacker, N. F., Berek, J. S., Rose, T. P., Munoz, A. K., Lagasse, L. D. 1986; 67 (6): 783-788
Abstract

Between 1974 and 1984, 70 patients underwent primary cytoreductive surgery for ovarian carcinoma at the University of California at Los Angeles. During the period of January 1974 to December 1978, optimal cytoreduction was achieved in 56.4% of the patients. With increased experience, this figure improved to 87.1% in the period of January 1979 to December 1983. The most common morbidity associated with the procedure was fever and prolonged ileus. Bowel resection was required in 20% of the patients and was not associated with increased morbidity. More liberal use of the end-to-end anastomosis stapling device facilitated low colon reanastomosis without colostomy, which contributed to the improved patient acceptance.

View details for Web of Science ID A1986C500300007

View details for PubMedID 3010203
CA-125 SERUM LEVELS CORRELATED WITH 2ND-LOOK OPERATIONS AMONG OVARIAN-CANCER PATIENTS OBSTETRICS AND GYNECOLOGY Berek, J. S., Knapp, R. C., Malkasian, G. D., Lavin, P. T., Whitney, C., Niloff, J. M., Bast, R. C. 1986; 67 (5): 685-689
Abstract

CA 125, which is an antigenic determinant expressed by many epithelial ovarian cancers, is measured in serum using a solid phase immunoradiometric assay. Sera from 55 patients who were in clinical remission and underwent a second-look operation to assess disease status after chemotherapy were studied prospectively. All patients had the CA 125 assay performed within one week before their second-look operation. Twenty-four patients (44%) had no histologic or cytologic evidence of disease, seven patients (13%) had microscopic disease, 13 patients (24%) had disease measuring 1 mm to 1.5 cm, and ten patients (18%) had disease greater than or equal to 1.5 cm in maximum tumor dimension. None of the 24 patients with a negative second-look operation had a positive CA 125 antigen level (greater than or equal to 35 U/mL), compared with six of 20 patients (30%) with less than 1.5 cm disease, and six of ten (60%) with greater than or equal to 1.5 cm disease (P less than .0001). All 12 patients with an elevated CA 125 antigen level (greater than or equal to 35 U/mL) had disease discovered at their second-look operation. Thus, in this setting the predictive value of a positive CA 125 titer (greater than or equal to 35 U/mL) was 100%. The predictive value of a negative CA 125 antigen level (less than 35 U/mL) was 56%, ie, the test did not exclude the presence of disease in 44% of patients with a positive second look. The maximum tumor size associated with at least one prior negative antigen level was 1.9 cm.(ABSTRACT TRUNCATED AT 250 WORDS)

View details for Web of Science ID A1986C064800016

View details for PubMedID 3457330
NUCLEAR DEOXYRIBONUCLEIC-ACID HETEROGENEITY OF OVARIAN BORDERLINE MALIGNANT SEROUS TUMORS OBSTETRICS AND GYNECOLOGY Fu, Y. S., Ro, J., Reagan, J. W., Hall, T. L., Berek, J. 1986; 67 (4): 478-482
Abstract

Sixteen borderline malignant serous ovarian tumors and seven well-differentiated invasive serous ovarian carcinomas were examined with the technique of Feulgen microspectrophotometry for the determination of nuclear deoxyribonucleic acid (DNA) ploidy patterns (diploid versus aneuploid) and ploidy levels of the stem cell lines. Of the nine stage I-II borderline malignant tumors, only one (11%) was aneuploid. In contrast, four of seven (57%) stage III borderline malignant neoplasms and all stage III carcinomas were aneuploid. The stem cell modal values in all borderline serous tumors were less than triploid (3N) while in five of seven carcinomas stem cell modal values were greater than triploidy. This contrast in ploidy patterns and ploidy levels may explain the differences in biologic behavior between borderline malignant serous tumors and invasive serous carcinomas of the ovary.

View details for Web of Science ID A1986A661200005

View details for PubMedID 3960418
PHASE-II TRIAL OF CISPLATIN IN ADVANCED OR RECURRENT CANCER OF THE VAGINA - A GYNECOLOGIC ONCOLOGY GROUP-STUDY GYNECOLOGIC ONCOLOGY Thigpen, J. T., Blessing, J. A., Homesley, H. D., Berek, J. S., Creasman, W. T. 1986; 23 (1): 101-104
Abstract

Twenty-six patients with advanced or recurrent cancer of the vagina no longer amenable to control with surgery and/or radiotherapy were entered into a phase II study of cisplatin 50 mg/m2 intravenously every 3 weeks. Two were deemed ineligible because of a primary site of origin other than vagina. Two were deemed inevaluable, one because of the lack of measurable disease and the other because she never received drug. The remaining 22 included a variety of histologies (16 squamous cell carcinomas, 2 adenosquamous carcinomas, 1 clear cell carcinoma, 1 leiomyosarcoma, and 2 carcinomas not otherwise specified). One complete responder was observed among the 16 patients with squamous cell carcinoma. Adverse effects were tolerable and were essentially those reported in other series. These results suggest that cisplatin has insignificant activity in advanced or recurrent squamous cell carcinoma of the vagina at least at the dose and schedule tested. No comment can be made regarding the activity of cisplatin in other histologies.

View details for Web of Science ID A1986AYY3300014

View details for PubMedID 3943746
ANTITUMOR AND IMMUNOLOGICAL EFFECTS OF A PYRIDINE-EXTRACTED FRACTION OF PROPIONIBACTERIUM-ACNES CANCER IMMUNOLOGY IMMUNOTHERAPY Lichtenstein, A., Berek, J. 1986; 22 (1): 24-30
Abstract

The antitumor and immunological effects of a pyridine extractable fraction of Propionibacterium acnes were tested in a murine ovarian teratocarcinoma (MOT) model. Previous studies have demonstrated that tumor rejection in this model depends upon sequential activation of tumoricidal neutrophils (PMNs) followed by cytostatic macrophages. The pyridine extract significantly prolonged the survival of mice challenged with 10(3) or 10(4) MOT cells but had little impact on a 10(5) tumor inoculum. In vivo cytoreduction occurred within the first 24 h following IP treatment which correlated temporally with the influx of tumoricidal PMNs into the peritoneal cavity. Immunotherapy failure in mice challenged with 10(5) MOT cells occurred between 48 and 72 h after treatment when macrophage chemotaxis into the peritoneal cavity was initiated. Although injection of unfractionated bacteria activated MOT-cytostatic macrophages, the pyridine extract was deficient in this regard. Intraperitoneal injection of the pyridine extract resulted in an early (day +1) depression and late (day +5) enhancement of peritoneal NK cytotoxicity. These data suggest that the retention of neutrophil-activating moieties in the pyridine extract are sufficient for antitumor effects against low tumor inocula while the depletion of macrophage-activating determinants results in diminished effects against larger tumor cell challenges.

View details for Web of Science ID A1986C300500004

View details for PubMedID 3708631
Intraperitoneal recombinant alpha 2-interferon for 'salvage' immunotherapy in persistent epithelial ovarian cancer. Cancer treatment reviews Berek, J. S., Hacker, N. F., Lichtenstein, A., Jung, T., Spina, C., Knox, R. M., Brady, J., Greene, T., Ettinger, L. M., Lagasse, L. D. 1985; 12: 23-32
Abstract

Fourteen patients with epithelial ovarian cancer were treated with intraperitoneal (i.p.) administration of alpha-recombinant interferon (rIFN-alpha 2) after documentation of persistent disease at second-look laparotomy and combination chemotherapy. After therapy, 11 patients had a surgical re-evaluation which confirmed 4 complete responses (36%), 1 partial response (9%), and disease progression in 6 (55%). Five of 7 patients (71%) with minimal residual disease (MRD, i.e. less than 5 mm) had a surgically-documented response, whereas there was none in the 4 patients whose tumors were greater than or equal to 5 mm. Fever greater than or equal to 38 degrees C was seen in 58%, greater than or equal to 39.0 degrees C in 18%; nausea and vomiting in 37%, and abdominal pain in 22%. There was no consistent alteration in peripheral WBC's during treatment, while i.p. monocytes and lymphocytes showed a significant boost on day 1 after each dose of rIFN-alpha 2. Natural killer (NK) lymphocyte cytotoxicity was elevated in the i.p. cavity fluid obtained from most patients on day 1 after treatment, while blood NK values showed considerable variability. Pharmacokinetic studies showed i.p. levels of rIFN-alpha 2 were 30-1000 times blood levels. I.p. rIFN-alpha 2 may act by increasing concentrations of drug and augmenting regional host cells in patients with MRD ovarian cancer.

View details for PubMedID 3833327
INTRAPERITONEAL RECOMBINANT INTERFERON-ALPHA-2 FOR SALVAGE IMMUNOTHERAPY IN PERSISTENT EPITHELIAL OVARIAN-CANCER CANCER TREATMENT REVIEWS Berek, J. S., Hacker, N. F., Lichtenstein, A., Jung, T., Spina, C., Knox, R. M., Brady, J., Greene, T., Ettinger, L. M., Lagasse, L. D., Bonnem, E. M., Spiegel, R. J., ZIGHELBOIM, J. 1985; 12: 23-32
View details for Web of Science ID A1985C233500005
INTRAPERITONEAL RECOMBINANT ALPHA-INTERFERON FOR SALVAGE IMMUNOTHERAPY IN STAGE-III EPITHELIAL OVARIAN-CANCER - A GYNECOLOGIC ONCOLOGY GROUP-STUDY CANCER RESEARCH Berek, J. S., Hacker, N. F., Lichtenstein, A., Jung, T., Spina, C., Knox, R. M., Brady, J., Greene, T., Ettinger, L. M., Lagasse, L. D., Bonnem, E. M., Spiegel, R. J., ZIGHELBOIM, J. 1985; 45 (9): 4447-4453
Abstract

Fourteen patients with persistent epithelial ovarian cancer documented at second look laparotomy after combination chemotherapy were treated with 146 cycles of alpha-recombinant interferon (rIFN-alpha 2) administered i.p. The initial dose was 5 X 10(6) units which was escalated weekly to 50 X 10(6) units over 4 weeks and then continued weekly for a total of 16 weeks. Eleven patients underwent surgical reevaluation after therapy which confirmed four pathological complete responses (36%), one partial response (9%), and disease progression in six patients (55%). Five of seven patients (71%) with residual tumor less than 5 mm had a surgically documented response, whereas there was no response in the four patients whose tumors were greater than or equal to 5 mm. Three patients were evaluable for clinical response only: one patient who refused surgery had a complete clinical response with total resolution of ascites; one had stable disease; and one had disease progression. Fever greater than or equal to 38 degrees C was seen in 58%, fever greater than or equal to 39.0 degrees C was seen in 18%, vomiting in 37%, abdominal pain was reported in 22%, and one patient had infectious peritonitis. Peripheral white blood cell counts and i.p. washings were obtained pretreatment and on days 1, 3, and 7 after treatment. While there was no consistent alteration in peripheral white blood cell counts, the numbers of i.p. monocytes and lymphocytes showed a significant boost on day 1 after each dose of rIFN-alpha 2. Natural killer lymphocyte cytotoxicity was elevated in the i.p. cavity fluid obtained from most patients on day 1 after treatment, while blood natural killer lymphocyte cytotoxicity values showed considerable variability. Pharmacokinetic studies show that i.p. levels of rIFN-alpha 2 were 30-1000 times blood levels. rIFN-alpha 2 i.p. may act by increasing concentrations of drug and augmenting regional host cells in patients with minimal residual ovarian cancer.

View details for Web of Science ID A1985APR5700073

View details for PubMedID 4028027
INTRAPERITONEAL IMMUNOTHERAPY OF EPITHELIAL OVARIAN-CARCINOMA WITH CORYNEBACTERIUM-PARVUM AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Berek, J. S., Knapp, R. C., Hacker, N. F., Lichtenstein, A., Jung, T., Spina, C., Obrist, R., Griffiths, C. T., Berkowitz, R. S., PARKER, L., ZIGHELBOIM, J., Bast, R. C. 1985; 152 (8): 1003-1010
Abstract

Corynebacterium parvum was administered intraperitoneally to 21 patients with epithelial ovarian cancer. Nineteen patients had surgically measurable disease and two received adjuvant therapy. Surgically confirmed responses were documented in six of 19 patients (31.6%), with two complete responses (10.5%) and four partial responses (21.1%). Three patients (15.8%) had stable disease, and 10 patients (52.6%) had disease progression. The mean survival of the patients who had a complete response was 35.5 months; the four patients who had a partial response the mean survival was 26.6 months, and of the nonresponders the mean survival was 12.6 months (p less than 0.02). The mean survival of the entire group was 18.2 months. Initial response and patient survival correlated with the amount of disease pretreatment. Thus six responding patients had less than or equal to 5 mm maximum diameter tumors, that is, minimal residual disease. Toxicity in the 86 courses of therapy included abdominal pain in 78% of cases, fever in 56%, nausea in 40%, and vomiting in 22%. Stimulation of cytotoxic lymphocytes resulted from the administration of C. parvum, which induced a significant increase of both intraperitoneal natural killer lymphocyte cytotoxicity and antibody-dependent cell-mediated cytotoxicity in six of nine patients tested; these two types of cytotoxicity correlated with response to therapy and may be partially responsible for the surgically documented tumor regression. While the clinical usefulness of intraperitoneal C. parvum is limited because of its toxicity, intraperitoneal immunotherapy may prove useful in patients with minimal residual ovarian cancer when more refined agents become available.

View details for Web of Science ID A1985AQE9200008

View details for PubMedID 2992276
WHOLE ABDOMINAL RADIATION AS SALVAGE THERAPY FOR EPITHELIAL OVARIAN-CANCER OBSTETRICS AND GYNECOLOGY Hacker, N. F., Berek, J. S., Burnison, C. M., Heintz, A. P., Juillard, G. J., Lagasse, L. D. 1985; 65 (1): 60-66
Abstract

Thirty patients found to have residual epithelial ovarian cancer at second-look laparotomy were treated with whole abdominal radiation as salvage therapy. Dosage fractions were 120 rad per day until 3000 rad were delivered, then the pelvis was boosted to 5000 rad at 180 rad per day. Fourteen patients (47%) completed therapy without interruption and seven (23%) completed therapy with interruptions due to myelosuppression ranging from one to four weeks. Therapy was not completed in nine patients (30%). Four of 16 patients (25%) with microscopic residual disease before radiation remain alive and free of disease at 22 to 41 months. Two of six (33%) patients with minimal (less than or equal to 5 mm) residual disease remain alive and free of disease 19 to 40 months after radiation treatment. Patients with residual nodules greater than 5 mm uniformly did poorly. Patients who progressed on primary chemotherapy had a median survival of seven months, compared with more than 38 months for chemotherapy responders. Chronic bowel morbidity was a significant problem, with 30% of patients surviving at least four months from completion of radiation requiring laparotomy for small bowel obstruction. These preliminary results suggest that whole abdominal radiation may be useful in the management of patients who have responded to primary chemotherapy, but the benefit is confined to those patients who have minimal or microscopic disease at second-look laparotomy.

View details for Web of Science ID A1985TY97600011

View details for PubMedID 3966024
ADENOCARCINOMA OF THE UTERINE CERVIX - HISTOLOGIC VARIABLES ASSOCIATED WITH LYMPH-NODE METASTASIS AND SURVIVAL OBSTETRICS AND GYNECOLOGY Berek, J. S., Hacker, N. F., Fu, Y. S., SOKALE, J. R., LEUCHTER, R. C., Lagasse, L. D. 1985; 65 (1): 46-52
Abstract

One hundred and two patients were treated for primary adenocarcinoma of the uterine cervix over a ten-year period from 1973 to 1982. Of these, 51 patients underwent initial surgical management that included a pelvic and para-aortic lymphadenectomy with a radical hysterectomy or a surgical staging operation. Clinical lesion size, grade, and depth of stromal invasion were correlated with lymph node metastasis and survival. The incidence of positive lymph nodes was 14.6% for stage I and 40.0% for stage II. Positive lymph nodes were documented in none of 15 patients with lesions smaller than 2 cm, 16.7% (five of 30) with 2 to 4 cm, and 82.3% (five of six) with larger than 4 cm; 5.3% of grade 1 tumors, 11.1% of grade 2, and 50.0% of grade 3. There were no lymph node metastases (zero of six) in patients with a tumor that had a depth invasion of less than 2 mm, whereas positive nodes were found in 11.1% (two of 18) patients with 2 to 5 mm of invasion, 28.6% (two of seven) with 5 to 10 mm, and 57.1% (four of seven) with greater than 10 mm of invasion. Five-year survival was 82.9% for stage I and 42.9% for stage II patients; 91.7% with negative lymph nodes, and 10% with positive nodes (P less than .0001). The size of the primary tumor (P less than .0001), tumor grade (P less than .05), and depth of invasion (P less than .05) correlated with patient survival.(ABSTRACT TRUNCATED AT 250 WORDS)

View details for Web of Science ID A1985TY97600009

View details for PubMedID 3966022
NATURAL-KILLER INHIBITORY SUBSTANCE PRODUCED BY THE PERITONEAL-CELLS OF PATIENTS WITH OVARIAN-CANCER JOURNAL OF THE NATIONAL CANCER INSTITUTE Lichtenstein, A. K., Berek, J., ZIGHELBOIM, J. 1985; 74 (2): 349-355
Abstract

Peritoneal cells obtained from 8 patients with minimal residual ovarian cancer produced a substance during in vitro culture that markedly inhibited the expression of natural killer (NK) cell-mediated lysis. Its molecular weight was less than 2,000, the same size as the NK-inhibiting substance (NK-IS), a similar NK-suppressive molecule produced by the peritoneal cells of rats. Human NK-IS suppressed the expression of antibody-dependent cell cytotoxicity as well as NK lysis, but it had no effect on erythrocyte-rosette formation and was not cytotoxic to peripheral blood lymphocytes or cell fractions enriched for large granular lymphocytes. NK-IS inhibited lysis mediated by interferon-activated lymphocytes and completely prevented NK activation when used in a preincubation. During intraperitoneal immunotherapy with Corynebacterium parvum, an agent that can activate peritoneal cytotoxic effectors, the production of NK-IS by peritoneal cells decreased considerably. Human peritoneal cells produce an NK-IS similar to the peritoneal cells of rats, and this material may create an environment within the peritoneal cavity that is permissive to the growth of NK-sensitive tumor cells.

View details for Web of Science ID A1985ADV6000011

View details for PubMedID 3856049
SYNERGISTIC EFFECTS OF COMBINATION SEQUENTIAL IMMUNOTHERAPIES IN A MURINE OVARIAN-CANCER MODEL CANCER RESEARCH Berek, J. S., Lichtenstein, A. K., Knox, R. M., Jung, T. S., Rose, T. P., Cantrell, J. L., ZIGHELBOIM, J. 1985; 45 (9): 4215-4218
Abstract

The antitumor effects of Corynebacterium parvum in a murine ovarian teratocarcinoma model depend upon a sequential activation of neutrophils and macrophages within the peritoneal cavity. We studied the sequential administration of biological response modifiers that independently activate each phase of the response. Tumor-challenged mice treated by i.p. injection of a pyridine-extracted fraction of cell-free Propionibacterium acnes (PA-PE, 1400 micrograms) demonstrated prolonged survival in less than 20% of the cases. An i.p. injection of a detoxified Salmonella endotoxin (DSE) preparation (150 micrograms) had no effect on tumor outgrowth. However, i.p. treatment with PA-PE (1400 micrograms), followed by 150 micrograms of DSE 1 day later, resulted in long-term survival (greater than 100 days) in 40 to 60% of mice. This antitumor effect was only evident when PA-PE was administered first (before DSE) and optimal when DSE was administered 24 h after PA-PE. The synergistic antitumor effect could be duplicated when tumor-challenged mice were first treated i.p. with peritoneal polymorphonuclear leukocytes, elicited by injection of PA-PE, and then treated with DSE 18 h later. These data indicate that appropriately timed injection of biological response modifiers with complementary effects can result in a synergistic prevention of tumor growth.

View details for Web of Science ID A1985APR5700038

View details for PubMedID 4028011
LYMPHOCYTE CYTO-TOXICITY IN THE PERITONEAL-CAVITY AND BLOOD OF PATIENTS WITH OVARIAN-CANCER OBSTETRICS AND GYNECOLOGY Berek, J. S., Bast, R. C., Lichtenstein, A., Hacker, N. F., Spina, C. A., Lagasse, L. D., Knapp, R. C., ZIGHELBOIM, J. 1984; 64 (5): 708-714
Abstract

After an intensive course of combination chemotherapy, 16 patients with minimal residual ovarian cancer that was documented at second-look laparotomy, had an indwelling Tenckhoff catheter placed and underwent multiple peritoneal saline lavages. Lymphocyte-enriched populations from the peritoneal cavity and peripheral blood were obtained by density gradient centrifugation and examined for cell-surface phenotype and a variety of immune functions, including natural killer cytotoxicity and antibody-dependent cell-mediated cytotoxicity. Phenotypic characterization revealed that peritoneal lymphocytes consisted primarily of T cells and cells bearing receptors for the crystallizable fragment of immunoglobulin G (IgG) (crystallizable fragment-receptor), and contained a very low number of B cells. Peritoneal natural killer lymphocyte cytotoxicity and antibody-dependent cell-mediated cytotoxicity were very low in all but two patients. Incubation of peritoneal lymphocytes with Corynebacterium parvum and interferon in vitro did not result in augmented cytotoxicity against susceptible targets. Supernatants from cultured peritoneal cells of all patients markedly inhibited natural cytotoxic activity of normal donor blood lymphocytes. These results suggest that lymphocytes collected from the peritoneal cavity of patients with minimal residual ovarian cancer are deficient in natural and antibody-dependent cytotoxic effector function. This deficiency may influence the host's ability to control the spread and proliferation of tumor cells in the peritoneal cavity.

View details for Web of Science ID A1984TQ35800023

View details for PubMedID 6493663
SUCCESSFUL IMMUNOTHERAPY WITH INTRAPERITONEAL CORNYEBACTERIUM-PARVUM IN A MURINE OVARIAN-CANCER MODEL IS ASSOCIATED WITH THE RECRUITMENT OF TUMOR-LYTIC NEUTROPHILS INTO THE PERITONEAL-CAVITY JOURNAL OF IMMUNOLOGY Lichtenstein, A. K., Kahle, J., Berek, J., ZIGHELBOIM, J. 1984; 133 (1): 519-526
Abstract

The rejection of a murine ovarian teratocarcinoma (MOT) after i.p. injection of Corynebacterium parvum was investigated. Treatment with C. parvum (1400 micrograms) 24 hr after i.p. inoculation of a lethal number of tumor cells (10(5] induced an antitumor effect that cured 75 to 95% of the mice. Morphologic analysis and an in vivo cytotoxicity assay that measured the rate of disappearance of radioactivity from the peritoneal cavity after injection of 125IUdR-labeled tumor cells indicated that the antitumor effect was initiated during the first 24 hr after C. parvum injection. During this period of time, host effector cells retrieved from the peritoneal cavity prevented tumor growth in a Winn assay and lysed radiolabeled MOT targets in a 4-hr Cr-release assay. After separation of peritoneal inflammatory cells on a Percoll gradient, neutrophil-enriched fractions demonstrated significant in vitro tumor lysis, but neutrophil-depleted populations were ineffective. Microscopic analysis of lysis at the single cell level confirmed that neutrophils were binding to and lysing MOT targets. Further characterization of these tumor cytolytic neutrophils revealed that they are nylon wool-adherent, not generated in indomethacin-pretreated mice (but effectively generated in whole body-irradiated mice), and achieve lysis within 30 min after binding to MOT targets. These results indicate that neutrophils must be considered potential antitumor effectors that can be recruited by treatment with biologic response modifiers.

View details for Web of Science ID A1984SW96300086

View details for PubMedID 6373934
INDIVIDUALIZATION OF TREATMENT FOR STAGE-I SQUAMOUS-CELL VULVAR CARCINOMA OBSTETRICS AND GYNECOLOGY Hacker, N. F., Berek, J. S., Lagasse, L. D., Nieberg, R. K., Leuchter, R. S. 1984; 63 (2): 155-162
Abstract

Of 177 cases of invasive squamous cell vulvar cancer seen at the University of California at Los Angeles and the City of Hope National Medical Center from 1957 to 1980, 84 (47.5%) had stage I disease. Seventy-seven patients with stage I disease (91.7%) had stromal invasion of 5 mm or less. Correlation between lymph node status and depth of invasion was as follows: 1 mm or less, none of 34 (0%); 1.1 to 2 mm, two of 19 (10.5%); 2.1 to 3 mm, two of 17 (11.8%); 3 to 5 mm, one of seven (14.3%); more than 5 mm, three of seven (42.9%). Fifty-six patients had radical vulvectomy for the primary lesion, and 28 had more conservative excision, but the incidence of local invasive recurrence (4%) was the same in each group. None of 58 patients treated with inguinal-femoral lymphadenectomy developed a groin recurrence, but three of 26 patients (11.5%) who had omission or modification of inguinal-femoral lymphadenectomy died with groin recurrence within 12 months. These data suggest that although some modification of the standard radical vulvectomy is appropriate for the primary lesion in patients with stage I disease, patients with greater than 1 mm of stromal invasion require at least an ipsilateral inguinal-femoral lymphadenectomy.

View details for Web of Science ID A1984SA75600005

View details for PubMedID 6694808
PREOPERATIVE RADIATION-THERAPY FOR LOCALLY ADVANCED VULVAR CANCER CANCER Hacker, N. F., Berek, J. S., Juillard, G. J., Lagasse, L. D. 1984; 54 (10): 2056-2061
Abstract

Eight patients with locally advanced vulvar cancer that would have necessitated pelvic exenteration to encompass the primary tumor were given preoperative radiation therapy in an attempt to shrink the primary tumor and allow more conservative surgery. From 4400 to 5400 rad of external radiation were delivered to the primary tumor, and one patient received an additional 2400 rad from intracavitary therapy. Satisfactory shrinkage of tumor occurred in seven of the eight patients (87.5%), thus allowing conservative surgical excision. In four patients (50%), there was no viable tumor in the surgical specimen. Moist desquamation of the vulva occurred in all patients and was of sufficient severity to require temporary cessation of radiation in four patients (50%). Five received groin radiation, and one (20%) subsequently developed bilateral hip fractures. No other major morbidity occurred. Five of the eight patients (62.5%) are alive without evidence of disease at intervals ranging from 15 months to 10 years. Preoperative radiation in this group obviated the need for pelvic exenteration, resulting in significantly less morbidity without compromising survival.

View details for Web of Science ID A1984TQ49900002

View details for PubMedID 6488136
2ND-LOOK LAPAROTOMY IN STAGE-III EPITHELIAL OVARIAN-CANCER - CLINICAL-VARIABLES ASSOCIATED WITH DISEASE STATUS OBSTETRICS AND GYNECOLOGY Berek, J. S., Hacker, N. F., Lagasse, L. D., Poth, T., Resnick, B., Nieberg, R. K. 1984; 64 (2): 207-212
Abstract

Variables associated with a negative second-look laparotomy in patients with stage III epithelial ovarian carcinoma are analyzed. Fifty-six patients were clinically free of disease after systemic chemotherapy and were subjected to second-look laparotomy to assess tumor status. Eighteen of these patients (32.1%) had no evidence of malignancy. Eight (14.3%) additional patients with no gross evidence of disease at laparotomy had microscopic persistence; five of these had disease documented in the pelvic or para-aortic lymph nodes. Significant variables associated with a histologically and cytologically negative second-look operation were low tumor grade (P less than .01), the use of cis-platinum containing combination chemotherapy (P less than .01), patient age less than or equal to 50 years (P less than .02), small residual tumor (less than 0.5 cm) before chemotherapy (P less than .05), and metastatic tumor less than or equal to 10 cm before initial cytoreduction (P less than .05). Patients treated with six to nine cycles of combination chemotherapy had the same probability of a negative second-look laparotomy as those treated with ten to 12 cycles. Multivariate discriminate analysis indicated that patients with low tumor grade, those receiving cis-platinum containing combination chemotherapy, and those with minimal residual tumors (less than 0.5 cm) after primary cytoreductive surgery correctly classify second-look status in 78.6% of patients. Until a nonsurgical method of monitoring subclinical disease is available, a through second-look laparotomy, including a pelvic and para-aortic lymphadenectomy, should be performed.

View details for Web of Science ID A1984TC63100011

View details for PubMedID 6539884
RECTOSIGMOID COLECTOMY AND REANASTOMOSIS TO FACILITATE RESECTION OF PRIMARY AND RECURRENT GYNECOLOGIC CANCER OBSTETRICS AND GYNECOLOGY Berek, J. S., Hacker, N. F., Lagasse, L. D. 1984; 64 (5): 715-720
Abstract

From 1976 through 1982, 72 rectosigmoid colectomies were performed on patients treated at the gynecologic oncology service at UCLA. Thirty-five of these were performed to resect primary or recurrent ovarian cancer, and 37 were performed as part of an exenteration for recurrent cervical or vaginal carcinoma. In 24 of the patients with ovarian cancer and 11 of the patients undergoing exenteration, the rectosigmoid colon was primarily reanastomosed, using either a primary suture technique or the end-to-end anastomosis stapler. Intraoperative management included adequate mobilization of the colonic mesentery to eliminate tension on the anastomosis, and liberal use of pelvic drains. Eighteen of 24 (75%) patients with ovarian cancer who received a primary reanastomosis did not have a protecting colostomy, whereas all 11 patients who underwent exenteration had a protecting colostomy. There were no anastomotic leaks in any of these patients, although morbidity occurred in seven of 35 patients (20%). There were no operative mortalities. The end-to-end anastomosis stapler has facilitated lower resections with primary reanastomosis. Colostomy is not mandatory in patients who have not had prior pelvic radiation therapy, and in whom no pelvic infection exists. Rectosigmoid colectomy permitted optimal or curative tumor resection in the majority of these patients, and thus should be performed whenever necessary to accomplish this goal.

View details for Web of Science ID A1984TQ35800024

View details for PubMedID 6387559
VAGINAL RECONSTRUCTION PERFORMED SIMULTANEOUSLY WITH PELVIC EXENTERATION OBSTETRICS AND GYNECOLOGY Berek, J. S., Hacker, N. F., Lagasse, L. D. 1984; 63 (3): 318-323
Abstract

Twenty-eight patients underwent vaginal reconstruction simultaneously with pelvic exenteration performed for recurrent pelvic malignancy. A satisfactory neovagina was created in 24 (86%) patients. Successful bilateral grafting was accomplished in 18 of 21 (86%) patients using gracilis myocutaneous grafts. Seven patients had a split-thickness skin graft, most of which was combined with an omental pedicle graft; six of these patients had a satisfactory neovagina. None of the patients developed herniation of the bowel through the reconstructed pelvic floor, or fistulas in the absence of recurrent malignancy. The gracilis myocutaneous graft is most feasible in patients in whom total pelvic exenteration is performed, whereas a split-thickness graft is preferable in those patients who undergo anterior exenteration or who have rectosigmoid reconstruction using low colon reanastomosis.

View details for Web of Science ID A1984SG41000009

View details for PubMedID 6700853
IMMUNOTHERAPY WITH BIOCHEMICALLY DISSOCIATED FRACTIONS OF PROPIONIBACTERIUM ACNES IN A MURINE OVARIAN-CANCER MODEL CANCER RESEARCH Berek, J. S., Cantrell, J. L., Lichtenstein, A. K., Hacker, N. F., Knox, R. M., Nieberg, R. K., Poth, T., Elashoff, R. M., Lagasse, L. D., ZIGHELBOIM, J. 1984; 44 (5): 1871-1875
Abstract

The antitumor effect of two strains of Propionibacterium acnes (PAI and PAII) and chemically derived fractions from the whole bacterial cell were studied using a murine ovarian teratocarcinoma (MOT) model. When injected i.p. in high doses (700 to 1400 micrograms/mouse), both strains produce survival of a significant proportion of tumor-bearing mice (30 to 90%). On a weight to weight basis, however, PAI was significantly more effective than PAII. PAI and PAII were extracted using pyridine, which yielded four fractions, i.e., pyridine-extracted strains PAI and PAII (PA-PEI and PA-PEII, respectively) which are composed of the cell wall material extracted by pyridine, and the residues of PA-PEI and PA-PEII (PA-RI and PA-RII, respectively) which are composed of the residue material following the chemical extraction. The chemical composition of PA-PEI was different from that of PA-PEII (the latter had proportionately three times as many carbohydrates and one-third of the protein content of the former) and so were their antitumor properties in the MOT model. PA-PEI had markedly reduced antitumor effect when compared to the untreated cell on a per weight basis. Furthermore, curability was only seen when using a high dose (1400 micrograms/mouse). By contrast, the cell wall components extracted by pyridine from PAII (PA-PEII) had powerful antitumor effects, i.e., greater than 50% of mice given 1400-micrograms injections survived. The material contained in PA-PEII was further fractionated on the basis of its organic solubility in chloroform:methanol solvent. The water-soluble and solvent-insoluble fractions retained most of the antitumor effects of PA-PEII, while the water-insoluble and solvent-soluble fractions were only moderately effective, suggesting that the active moiety(ies) was associated with the nonlipid components of this fraction. Both residue fractions (PA-RI and PA-RII) were as effective on a per weight basis in controlling the growth of 10(5) tumor inoculum as were whole untreated cells. However, periodate oxidation of PA-RI resulted in complete loss of its antitumor effects. When surviving mice that had no evidence of tumor persistence following a tumor challenge (10(5) MOT cells) and i.p. treatment with PA were subsequently rechallenged with 10(4) tumor cells, survival was significantly prolonged, as compared to tumor-challenged (10(4) MOT) naive mice. In addition, 10 to 20% of these rechallenged mice had complete eradication of the tumor inoculum (no evidence of disease for greater than 120 days).(ABSTRACT TRUNCATED AT 400 WORDS)

View details for Web of Science ID A1984SP29800027

View details for PubMedID 6713388
ROLE OF INFLAMMATORY NEUTROPHILS IN ANTITUMOR EFFECTS INDUCED BY INTRAPERITONEAL ADMINISTRATION OF CORYNEBACTERIUM-PARVUM IN MICE CANCER RESEARCH Lichtenstein, A. K., Berek, J., Kahle, J., ZIGHELBOIM, J. 1984; 44 (11): 5118-5123
Abstract

We studied the role of inflammatory neutrophils in the antitumor effects that follow i.p. injection of Corynebacterium parvum (1400 micrograms) into C3HeB/FeJ mice challenged with the murine ovarian teratocarcinoma. Peritoneal neutrophils, obtained from mice 6 hr after injection of C. parvum, exerted significant antitumor effects when injected admixed with murine ovarian terato-carcinoma cells into the peritoneal cavities of normal mice. Treatment of recipient mice with whole-body irradiation or repeated injections of silica prevented the antitumor effects, indicating that neutrophils were activating a second effector mechanism in recipient mice. Peritoneal cells obtained at 24 or 72 hr or at 7 or 11 days following C. parvum injection were considerably less effective in activation of this effector mechanism. Heat-killed C. parvum (6 hr)-induced neutrophils activated antitumor responses, but thioglycolate-induced cells were without effect. Antitumor responses in mice receiving peritoneal neutrophils were not due to simple transfer of C. parvum organisms in the inocula. These results indicate that inflammatory neutrophils, elicited into the peritoneal cavity by injection of C. parvum, play an important role in the activation of subsequent antitumor effects.

View details for Web of Science ID A1984TP41300036

View details for PubMedID 6488171
ACTIVATION OF PERITONEAL LYMPHOCYTE CYTO-TOXICITY IN PATIENTS WITH OVARIAN-CANCER BY INTRAPERITONEAL TREATMENT WITH CORYNEBACTERIUM-PARVUM JOURNAL OF BIOLOGICAL RESPONSE MODIFIERS Lichtenstein, A., Berek, J., Bast, R., Spina, C., Hacker, N., Knapp, R. C., ZIGHELBOIM, J. 1984; 3 (4): 371-378
Abstract

Following an intensive course of combination chemotherapy, patients with minimal residual ovarian cancer were treated with increasing concentrations of intraperitoneal Corynebacterium parvum to assess whether or not natural killer (NK) cells could be activated. Immunotherapy was administered every 2 weeks, initially with a dose of 250 micrograms/m2, which was progressively escalated as tolerated. Each treatment induced a peritoneal cellular exudate which consisted primarily of neutrophils 48h after injection and of lymphocytes and macrophages at 7 and 14 days after injection. Peritoneal NK cytotoxicity increased during treatment in six of nine patients tested. NK precursor cells susceptible to in vitro activation with either C. parvum or interferon became detectable during treatment in all five patients tested. In four of these five, precursors were detected prior to the development of enhanced spontaneous NK activity. In four patients serially studied, peripheral blood NK activity increased during therapy. These results indicate that regional intraperitoneal therapy with C. parvum can enhance nonspecific antitumor cytotoxic mechanisms within the peritoneal cavity.

View details for Web of Science ID A1984TD21500003

View details for PubMedID 6541243
ESTROGEN AND PROGESTERONE RECEPTORS IN OVARIAN NEOPLASMS GYNECOLOGIC ONCOLOGY Ford, L. C., Berek, J. S., Lagasse, L. D., Hacker, N. F., Heins, Y., Esmailian, F., Leuchter, R. S., DELANGE, R. J. 1983; 15 (3): 299-304
Abstract

The cytoplasmic receptors for 17 beta-estradiol (ER) and progesterone (PR) were measured in 39 malignant and 15 benign ovarian neoplasms. All eight endometroid carcinomas had positive ER sites, one-half contained PR. The number of ER binding sites decreased as tumor grade increased. Conversely, none of the 11 mucinous tumors contained either ER or PR receptors. One-half of the well-differentiated serous tumors had ER (57 +/- 23 fmole/mg protein) while none of the poorly differentiated tumors had measurable binding. In serous carcinomas, PR was only detected in well-differentiated lesions (447 +/- 240 fmole/mg protein). Only one of 15 benign neoplasms contained ER and PR receptors. Correlation of tumor grade and type may help to plan hormonal therapies in advanced ovarian malignancies.

View details for Web of Science ID A1983QV14400001

View details for PubMedID 6862289
ESTROGEN AND PROGESTERONE-RECEPTOR SITES IN MALIGNANCIES OF THE UTERINE CERVIX, VAGINA, AND VULVA GYNECOLOGIC ONCOLOGY Ford, L. C., Berek, J. S., Lagasse, L. D., Hacker, N. F., HEINS, Y. L., DELANGE, R. J. 1983; 15 (1): 27-31
Abstract

Cytoplasmic receptors for 17 beta-estradiol (ER) and progesterone (PR) were measured in uterine cervical, vaginal, and vulvar carcinomas by the dextran-coated charcoal (DCC) technique. Tissues from 30 patients with cervical carcinoma were examined. Thirteen percent (2 of 16) of well-differentiated squamous carcinomas had positive ER, and 19% (3 of 19) had positive PR. None of the three patients with moderately well-differentiated disease have positive ER or PR, while two of five patients with poorly differentiated lesions contained measurable ER and PR. In contrast, all four of the well-differentiated adenocarcinomas of the cervix had detectable ER, and three of four for PR. Neither of the two patients with poorly differentiated adenocarcinoma had either ER or PR. None of the five vulvar and seven vaginal epidermoid carcinomas studied had ER or PR activity. Hormonal therapies may be useful in the treatment of adenocarcinoma of the cervix.

View details for Web of Science ID A1983QC30200004

View details for PubMedID 6822366
MANAGEMENT OF REGIONAL LYMPH-NODES AND THEIR PROGNOSTIC INFLUENCE IN VULVAR CANCER OBSTETRICS AND GYNECOLOGY Hacker, N. F., Berek, J. S., Lagasse, L. D., Leuchter, R. S., MOORE, J. G. 1983; 61 (4): 408-412
Abstract

One hundred thirteen patients with invasive carcinoma of the vulva underwent radical vulvectomy and bilateral inguinal-femoral lymphadenectomy between 1957 and 1978. Eighteen had unilateral pelvic lymphadenectomy. Thirty-one patients (27.4%) had positive lymph nodes. The corrected actuarial five-year survival for patients with negative nodes was 96%, whereas it was 94% for patients with one positive node, 80% for those with two positive nodes, and 12% for those with three or more positive nodes. All patients with positive pelvic nodes or pelvic recurrence had three or more positive unilateral groin nodes, and all had palpably suspicious groin nodes preoperatively. Groin and systemic recurrences occurred in 2.9 and 3.8%, respectively, of patients with fewer than three positive unilateral inguinal-femoral nodes, as compared to 33 and 66%, respectively, of patients with three or more positive nodes. These data do not support routine pelvic lymphadenectomy in patients who have no clinically suspicious groin nodes and fewer than three positive nodes on histologic examination.

View details for Web of Science ID A1983QH82700002

View details for PubMedID 6828268
INTRAPERITONEAL IMMUNOTHERAPY OF HUMAN OVARIAN-CARCINOMA WITH CORYNEBACTERIUM-PARVUM CANCER RESEARCH Bast, R. C., Berek, J. S., Obrist, R., Griffiths, C. T., Berkowitz, R. S., Hacker, N. F., PARKER, L., Lagasse, L. D., Knapp, R. C. 1983; 43 (3): 1395-1401
Abstract

Corynebacterium parvum has been administered i.p. to 14 patients with advanced ovarian cancer. Two patients had responded completely to cytoreductive surgery and combination chemotherapy prior to immunotherapy, and one patient with residual disease had received only a single course of C. parvum due to i.p. catheter malfunction. Among the 11 patients with residual disease evaluable for response, from three to eight i.p. treatments with C. parvum produced surgically confirmed tumor regression in five patients (45%) with three partial responses and two complete responses of 5 and 12 months duration. All responders had (a) multiple tumor nodules less than 0.5 cm at the initiation of immunotherapy, and (b) severe abdominal pain and fever after C. parvum injection. Overall, 58 courses of immunotherapy were associated with abdominal pain (91%), fever (67%), nausea (52%), vomiting (31%), and hypotension that responded promptly to i.v. infusion of fluids (10%). Use of i.p. cathethers was associated with two episodes each of infection and intraabdominal bleeding. Administration of C. parvum i.p. has augmented the ability of human peritoneal cells to lyse human ovarian carcinoma cell lines in the presence of specific rabbit heteroantiserum. C. parvum administered i.p. has inhibited the growth of human ovarian carcinoma and may prove useful for modulating the activity of human effectors for antibody-dependent cell-mediated cytotoxicity.

View details for Web of Science ID A1983QC83800074

View details for PubMedID 6825108
SUPERFICIALLY INVASIVE VULVAR CANCER WITH NODAL METASTASES GYNECOLOGIC ONCOLOGY Hacker, N. F., Nieberg, R. K., Berek, J. S., Leuchter, R. S., LUCAS, W. E., Tamimi, H. K., Nolan, J. F., MOORE, J. G., Lagasse, L. D. 1983; 15 (1): 65-77
Abstract

Seven patients with superficially invasive vulvar cancer and lymph node metastases are reported. Histology of the primary tumor does not seem to correlate reliably with its metastatic potential in any individual case, though "spray," pseudoglandular, and small cell carcinomas may be particularly aggressive lesions. While wide local excision seems to be adequate treatment for the primary lesion, it is recommended that for lesions with greater than 1 mm of stromal invasion, bilateral inguinal-femoral lymphadenectomy should be performed for midline lesions, and at least ipsilateral inguinal-femoral lymphadenectomy should be performed for lateralized lesions.

View details for Web of Science ID A1983QC30200009

View details for PubMedID 6822368
PRIMARY CYTOREDUCTIVE SURGERY FOR EPITHELIAL OVARIAN-CANCER OBSTETRICS AND GYNECOLOGY Hacker, N. F., Berek, J. S., Lagasse, L. D., Nieberg, R. K., Elashoff, R. M. 1983; 61 (4): 413-420
Abstract

Forty-seven patients with stage III or IV invasive epithelial carcinoma of the ovary underwent primary cytoreductive surgery at UCLA during the five-year period 1974 to 1979. Optimal cytoreduction (defined as largest residual tumor mass 1.5 cm or less in diameter) was achieved in 31 patients (66%), including ten of 14 (71%) who underwent laparotomy and biopsy before referral. Median survival for the suboptimal group was six months, compared with 18 months for patients whose largest residual disease was 0.5 to 1.5 cm, and 40 months if residual nodules were less than 0.5 cm (P less than .001). All patients in the suboptimal group died of disease from 22 months to seven years and four months postoperatively. Given the limited ability of chemotherapy to cure ovarian cancer, and the acceptable morbidity of extended operation, the availability of ideal initial surgical effort for patients with advanced stage disease may be the most important variable in current ovarian cancer care. Optimal cytoreduction is most effective in prolonging survival in patients first seen without clinical ascites or large metastatic disease.

View details for Web of Science ID A1983QH82700003

View details for PubMedID 6828269
SURVIVAL OF PATIENTS FOLLOWING SECONDARY CYTOREDUCTIVE SURGERY IN OVARIAN-CANCER OBSTETRICS AND GYNECOLOGY Berek, J. S., Hacker, N. F., Lagasse, L. D., Nieberg, R. K., Elashoff, R. M. 1983; 61 (2): 189-193
View details for Web of Science ID A1983PZ73500010

View details for PubMedID 6823360
DELAYED VAGINAL RECONSTRUCTION IN THE FIBROTIC PELVIS FOLLOWING RADIATION OR PREVIOUS RECONSTRUCTION OBSTETRICS AND GYNECOLOGY Berek, J. S., Hacker, N. F., Lagasse, L. D., Smith, M. L. 1983; 61 (6): 743-748
Abstract

Vaginal reconstruction was performed in 14 patients who had developed vaginal stenosis secondary to extensive pelvic fibrosis after pelvic radiation therapy (12 patients) or prior vaginal reconstruction (2 patients). Sixteen procedures were performed using a split-thickness skin graft. All patients had satisfactory vaginal restoration, and 12 patients reported good vaginal function. No fistula developed as a result of the operative procedure, but one patient later developed a rectovaginal fistula resulting from tumor recurrence. Successful vaginal reconstruction can be achieved even years after initial therapy in patients who develop an obliterated vagina from previous radiation or surgery.

View details for Web of Science ID A1983QS71000015

View details for PubMedID 6843934
MICROINVASIVE CARCINOMA OF THE VULVA OBSTETRICS AND GYNECOLOGY Hacker, N. F., Berek, J. S., Lagasse, L. D., Nieberg, R. K. 1983; 62 (1): 134-135
View details for Web of Science ID A1983QX82400029

View details for PubMedID 6856216
LAPAROSCOPY IN THE MANAGEMENT OF PATIENTS WITH OVARIAN-CARCINOMA CLINICS IN OBSTETRICS AND GYNAECOLOGY Berek, J. S., Hacker, N. F. 1983; 10 (2): 213-222
Abstract

Since operative evaluations of patients undergoing therapy for ovarian cancer are necessary, the laparoscope will continue to play a role in the management of these patients. However, the sensitivity of the laparoscope for detecting disease either prior to or at the completion of chemotherapy is significantly less than that of laparotomy, and therefore its utility must be more narrowly defined. The morbidity of laparoscopy is low when performed correctly and utilizing techniques to avoid bowel perforation. Most patients require only a brief hospitalization, and those who cannot medically tolerate an extensive laparotomy might be able to undergo a laparoscopy. The major limitations of laparoscopy are the inability to adequately inspect the peritoneal cavity and pelvis in at least one-quarter of patients because of extensive adhesions, to assess retroperitoneal lymph nodes in all patients, and to resect tumour masses necessary to cytoreduce the tumour prior to therapy. The successful performance of interval laparoscopy, however, is predictive of survival and can select a group of patients whose likelihood of recurrence is relatively low (30 per cent) after more than three years. The observation that the majority of patients who have a negative laparoscopy following six months of chemotherapy remain free of disease for several years, suggests that sensitive tumours are most likely to respond during the initial courses of chemotherapy, and that consideration should be given to briefer and more intensive courses of therapy prior to operative evaluation of the patients.

View details for Web of Science ID A1983RB66700005

View details for PubMedID 6225603
PHARMACOKINETICS OF IP CISPLATIN IN REFRACTORY OVARIAN-CARCINOMA CANCER TREATMENT REPORTS Pretorius, R. G., Hacker, N. F., Berek, J. S., Ford, L. C., Hoeschele, J. D., Butler, T. A., Lagasse, L. D. 1983; 67 (12): 1085-1092
Abstract

Four patients with small residual ovarian carcinoma following treatment with cisplatin, doxorubicin, and cyclophosphamide have subsequently received 57 courses of ip cisplatin. Cisplatin (120-270 mg in 2 L of Ringer's lactate) was administered via Tenckhoff catheter, with a dwell time of 15-20 mins. Courses were given weekly for 12 weeks, with response documented by laparoscopy or laparotomy prior to and following the trial. With a dwell time of 20 mins, 75% +/- 5% (mean +/- SD) of platinum was recovered. With 120 mg of cisplatin and a dwell time of 20 mins, total plasma platinum peaked at 1.23 +/- 0.42 microgram/ml and by 8 hrs decreased to 0.67 +/- 0.12 microgram/ml. Filterable (non-protein-bound) platinum peaked at 0.73 +/- 0.21 microgram/ml and by 8 hrs fell to 0.03 microgram/ml. Excretion rate paralleled the filterable plasma curve, peaking at 40 mins; 30% +/- 7% of absorbed drug was recovered in urine within 24 hrs. Renal clearance of filterable platinum was 106 +/- 20 ml/min. Creatinine clearance was 76 +/- 7 ml/min. Three responses, one complete and two partial, were noted. Zero to two episodes of vomiting occurred in each course. One patient had a creatinine clearance decrease to 40 ml/min, one had two episodes of thrombocytopenia, and one had mild abdominal pain with a cisplatin dose of greater than or equal to 210 mg. No neurotoxicity, catheter infection, or peritonitis was encountered.

View details for Web of Science ID A1983SA60900006

View details for PubMedID 6228294
MANAGEMENT OF POST-EXENTERATION PERINEAL HERNIAS BY MYOCUTANEOUS AXIAL FLAPS GYNECOLOGIC ONCOLOGY Leuchter, R. S., Lagasse, L. D., Hacker, N. F., Berek, J. S. 1982; 14 (1): 15-22
View details for Web of Science ID A1982PA71900003

View details for PubMedID 7095586
RECENT PROGRESS IN THE TREATMENT OF EPITHELIAL OVARIAN MALIGNANCY WESTERN JOURNAL OF MEDICINE Berek, J. S., Hacker, N. F., Lagasse, L. D. 1982; 137 (4): 273-277
Abstract

Improved surgical and chemotherapeutic management has ensured that more than half the patients with advanced ovarian cancer will be clinically free of disease shortly after treatment begins. Aggressive cytoreductive surgical treatment and combination cytotoxic chemotherapy have appreciably prolonged survival and have induced cures in some women with metastatic disease. An increasing number of women are being seen with small residual disease at second-look laparotomy, and intraperitoneal administration of chemotherapeutic and immunotherapeutic agents is being investigated for these patients. Specific immunotherapies, including monoclonal antibodies raised against patients' own tumor cells, are also being investigated. During the next five years we may see significant improvement in the cure rate for this disease.

View details for Web of Science ID A1982PM45400001

View details for PubMedID 7179943
PRIMARY-CARCINOMA OF THE BARTHOLIN GLAND - A REPORT OF 14 CASES AND REVIEW OF THE LITERATURE OBSTETRICS AND GYNECOLOGY Leuchter, R. S., Hacker, N. F., Voet, R. L., Berek, J. S., Townsend, D. E., Lagasse, L. D. 1982; 60 (3): 361-368
Abstract

Fourteen cases of primary carcinoma of the Bartholin gland were treated between 1955 and 1980. Follow-up information was available on all patients. Ten patients have survived free of disease for 5 or more years. Three patients with positive inguinal lymph nodes have survived 5 years. Histological patterns and lymph node involvement are analyzed. The authors' data and a review of the literature support the concept that radical vulvectomy with bilateral inguinal-femoral lymphadenectomy is required for all histologic types of Bartholin gland carcinoma. Routine pelvic lymph node dissection is not necessary when the inguinal-femoral nodes are negative for metastases.

View details for Web of Science ID A1982PC78300020

View details for PubMedID 7121917
LOWER URINARY-TRACT RESECTION AS PART OF CYTOREDUCTIVE SURGERY FOR OVARIAN-CANCER GYNECOLOGIC ONCOLOGY Berek, J. S., Hacker, N. F., Lagasse, L. D., Leuchter, R. S. 1982; 13 (1): 87-92
View details for Web of Science ID A1982NC77800012

View details for PubMedID 7060996
LEVATOR ANI TRANSPOSITION FOR ANAL INCOMPETENCE SECONDARY TO SPHINCTER DAMAGE OBSTETRICS AND GYNECOLOGY Berek, J. S., Lagasse, L. D., Hacker, N. F., Leuchter, R. S. 1982; 59 (1): 108-112
Abstract

An operative procedure is described in which the levator ani muscles are used to correct anal incompetence secondary to sphincter damage. The relevant pelvic anatomy and operative procedure are described in detail. Four patients in whom sphincter damage occurred during surgery for posterior vulvar carcinoma underwent the procedure; in 3, good sphincter function was attained. Morbidity was minimal. The transposition of the levator ani muscle to replace partially obliterated anal sphincter muscles is a suitable procedure for patients who have insufficient sphincter tissue for simpler repairs.

View details for Web of Science ID A1982MX10200020

View details for PubMedID 7078841
CARCINOMA OF THE CERVIX ASSOCIATED WITH PREGNANCY OBSTETRICS AND GYNECOLOGY Hacker, N. F., Berek, J. S., Lagasse, L. D., Charles, E. H., SAVAGE, E. W., MOORE, J. G. 1982; 59 (6): 735-747
View details for Web of Science ID A1982NR43400013

View details for PubMedID 7078912
RADICAL VULVECTOMY AND BILATERAL INGUINAL LYMPHADENECTOMY THROUGH SEPARATE GROIN INCISIONS OBSTETRICS AND GYNECOLOGY Hacker, N. F., Leuchter, R. S., Berek, J. S., CASTALDO, T. W., Lagasse, L. D. 1981; 58 (5): 574-579
Abstract

One hundred patients underwent radical vulvectomy and bilateral inguinal lymphadenectomy using separate groin incisions. Forty-nine had stage I disease, 37 stage II, and 14 stage III. Corrected actuarial 5-year survival for each stage was 97.4, 86, and 49.2%, respectively. Inguinal lymph nodes were positive in 25% of cases: 10.2% of stage I, 27% of stage II, and 71.4% of stage III cases. Major complications occurred in 21 patients, including major groin breakdown in 14. Thirty patients experienced no acute postoperative morbidity. The mean postoperative hospital stay was 19 days, and mean operative blood loss was 620 ml. No patients developed isolated metastases in either the groin or the inguinal skin bridge, but 2 stage III patients developed simultaneous metastases in the skin bridge and elsewhere. For appropriately selected patients, separate groin incisions for inguinal lymphadenectomy appear to result in lower morbidity than traditional methods, without compromising survival.

View details for Web of Science ID A1981MN87500007

View details for PubMedID 7301232
ADENOCARCINOMA OF THE UTERINE CERVIX CANCER Berek, J. S., CASTALDO, T. W., Hacker, N. F., PETRILLI, E. S., Lagasse, L. D., MOORE, J. G. 1981; 48 (12): 2734-2741
Abstract

One hundred patients with primary adenocarcinoma of the uterine cervix were evaluated. Of the 48 Stage I patients, 13 were treated with radical surgery, 16 with radiation alone, and 19 with combination therapy. Life table analysis of Stage I patients showed no significant difference in survival for those treated with radical surgery or combination therapy. Both groups had a greater five-year survival (P less than 0.05) than those treated with radiation. Recurrences in Stage I were more frequent with primary radiation alone, both locally and at distant sites (P less than 0.01). Greater tumor size was related to poorer survival, and failures in patients with larger lesions were more common in those treated with radiation therapy. Survival for the 32 Stage II patients was greater for those treated with combination therapy. Higher tumor grade was associated with poorer survival for each stage, regardless of treatment. More complications were associated with radiation therapy than with radical surgery. Radiation therapy alone is not sufficient for patients with Stage I and II disease, and radical surgery may be appropriate treatment for Stage I disease.

View details for Web of Science ID A1981MU07800029

View details for PubMedID 7306929
LAPAROSCOPY FOR 2ND-LOOK EVALUATION IN OVARIAN-CANCER OBSTETRICS AND GYNECOLOGY Berek, J. S., Griffiths, C. T., Leventhal, J. M. 1981; 58 (2): 192-198
Abstract

Although second-look laparotomy to ascertain primary therapeutic effect on ovarian cancer has been generally accepted, laparoscopy for this purpose has been controversial. Between 1974 and 1978, 119 consecutive laparoscopic examinations were performed on 57 patients with ovarian cancer to monitor the effect of chemotherapy or to determine disease status. Most procedures included intraperitoneal biopsy and cytologic evaluation of peritoneal washings. Seventy-three percent of the procedures were successful. Fourteen percent of the patients had major complications requiring laparotomy, most of which involved bowel perforation. Complications were significantly reduced when routine laparoscopy was preceded by needle laparoscopy. A negative laparoscopy including biopsy and cytologic evaluation was associated with a significant increase in survival when compared with the entire patient group. Repetitive laparoscopy permitted early detection of recurrence and identified patients whose risk of recurrence after 24 months was low. With each successive negative laparoscopy, the mean duration of remission was longer and the probability of recurrence lower.

View details for Web of Science ID A1981LY12800011

View details for PubMedID 6454868
PERINATAL-MORTALITY IN TERM AND POST-TERM BIRTHS OBSTETRICS AND GYNECOLOGY Stubblefield, P. G., Berek, J. S. 1980; 56 (6): 676-682
Abstract

The hospital records were reviewed of 64 infants born at or after 37 weeks of amenorrhea who suffered perinatal mortality during a 3-year period at Boston Hospital for Women. The most frequent cause of death of a term or post-term infant was extrinsic perinatal hypoxia, and the second most common was lethal malformation. Half the deaths of term infants occurred ante partum. Further reduction in perinatal mortality for this group may require extension of antepartum fetal monitoring techniques to all pregnancies. Intrapartum loss was rare, occurring at a rate of 0.43 per 1000 for infants delivered at term, and not at all among post-term infants. Massive aspiration of amniotic sac content was found frequently in antepartum and intrapartum death, and death from meconium aspiration occurred in neonates despite intrapartum monitoring and early suctioning of the pharynx and trachea. Asphyxiated term and post-term infants consistently pass meconium. Prevention of all deaths from meconium aspiration, thus, will require the prevention of asphyxia. A goal for obstetric care is that no fetus alive in utero at 37 weeks of amenorrhea should subsequently die in the perinatal period, provided no lethal malformation is present.

View details for Web of Science ID A1980KS58400002

View details for PubMedID 7443108
MASSIVE EXUDATIVE ASCITES PRODUCED FROM A TUBAL PSEUDOCYST IN CHRONIC PELVIC INFLAMMATORY DISEASE OBSTETRICS AND GYNECOLOGY Berek, J. S., Darney, P. D. 1979; 54 (4): 490-492
Abstract

A case of massive exudative hemorrhagic ascites occurring as a serious complication of chronic pelvic inflammatory disease (PID) is presented. The clinical manifestations, simulating diffuse carcinomatosis in a young female patient, are described.

View details for Web of Science ID A1979HM89100021

View details for PubMedID 492635
ANATOMIC AND CLINICAL CORRELATES OF UTERINE PERFORATION AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Berek, J. S., Stubblefield, P. G. 1979; 135 (2): 181-184
Abstract

We reviewed cases of uterine perforations which occurred at or were referred to the Boston Hospital for Women, Lying-In Division, over the 2 year period from mid-1975 to mid-1977. There were 25 uterine perforations; twenty patients were pregnant and five were not. In the pregnant patients, 16 perforations involved the cervix or the lower uterine segment, whereas only four were located in the uterine fundus; in the nonpregnant patients, all five were fundal perforations. In the pregnant patients, 12 required laparotomy, eight had serious lacerations of the uterine artery, and three had hysterectomy while none of the nonpregnant patients had lacerations or required subsequent procedures. Thus, there is a significant anatomic difference between those perforations which occurred in the pregnant patients and in the nonpregnant patients, the manner in which they presented clinically, and the need for intervention via laparotomy, subsequent morbidity, and outcome as reflected in future reproductive capability. Perforation at or near the cervix may be more common than previously assumed. Furthermore, two distinct clinical entities of cervical perforation exist in pregnant patients as based on the anatomic location of the defect. The anatomy of cervical perforations, their recognition, and their management are discussed.

View details for Web of Science ID A1979HM49800003

View details for PubMedID 474668
EVALUATION OF A BALLOON DILATOR BEFORE 2ND-TRIMESTER ABORTION BY VACUUM CURETTAGE AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Stubblefield, P. G., Frederiksen, M. C., Berek, J. S., GATTER, M. A., Kayman, D. J., BORTEN, M. 1979; 135 (2): 199-201
Abstract

We evaluated the cervical dilator device (CDD), an expanding balloon, as a substitute for laminaria tents before abortion at 13 to 16 1/2 weeks by extraction and vacuum curettage. The CDD was found to be an effective dilator, although it did not appear to have any advantage over laminaria tents when placed overnight and was associated with significant pain upon insertion and an apparent increased risk of endometritis. The present CDD or a subsequent modification may offer advantages over laminaria tents for short-term placement.

View details for Web of Science ID A1979HM49800007

View details for PubMedID 474671

Laurie Kraus Lacob Professor

Obstetrics & Gynecology - Gynecologic Oncology

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