Journal Articles

Ex vivo Evans blue assessment of the blood brain barrier in three breast cancer brain metastasis models. Breast cancer research and treatment Do, J., Foster, D., Renier, C., Vogel, H., Rosenblum, S., Doyle, T. C., Tse, V., Wapnir, I. 2014; 144 (1): 93-101
Abstract

The limited entry of anticancer drugs into the central nervous system represents a special therapeutic challenge for patients with brain metastases and is primarily due to the blood brain barrier (BBB). Albumin-bound Evans blue (EB) dye is too large to cross the BBB but can grossly stain tissue blue when the BBB is disrupted. The course of tumor development and the integrity of the BBB were studied in three preclinical breast cancer brain metastasis (BCBM) models. A luciferase-transduced braintropic clone of MDA-231 cell line was used. Nude mice were subjected to stereotactic intracerebral inoculation, mammary fat pad-derived tumor fragment implantation, or carotid artery injections. EB was injected 30�min prior to euthanasia at various timepoints for each of the BCBM model animals. Serial bioluminescent imaging demonstrated exponential tumor growth in all models. Carotid BCBM appeared as diffuse multifocal cell clusters. EB aided the localization of metastases ex vivo. Tumor implants stained blue at 7�days whereas gross staining was not evident until day 14 in the stereotactic model and day 28 for the carotid model. EB assessment of the integrity of the BBB provides useful information relevant to drug testing in preclinical BCBM models.

View details for DOI 10.1007/s10549-014-2854-5

View details for PubMedID 24510011
Intraoperative imaging of nipple perfusion patterns and ischemic complications in nipple-sparing mastectomies. Annals of surgical oncology Wapnir, I., Dua, M., Kieryn, A., Paro, J., Morrison, D., Kahn, D., Meyer, S., Gurtner, G. 2014; 21 (1): 100-106
Abstract

Nipple-sparing mastectomies (NSM) have gained acceptance in the field of breast oncology. Ischemic complications involving the nipple-areolar complex (NAC) occur in 3-37 % of cases. Skin perfusion can be monitored intraoperatively using indocyanine green (IC-GREEN?, ICG) and a specialized infrared camera-computer system (SPY Elite?). The blood flow pattern to the breast skin and the NAC were evaluated and a classification scheme was developed.Preincision baseline and postmastectomy skin perfusion studies were performed intraoperatively using 3 mL of ICG. The pattern of arterial blood inflow was classified according to whether perfusion appeared to originate predominantly from the underlying breast tissue (V1), the surrounding skin (V2), or a combination of V1 and V2 (V3). Ischemia, resection, or delayed complications of NAC were recorded.Thirty-nine breasts were interrogated. Seven (18 %) demonstrated a V1 pattern, 18 (46 %) a V2 pattern, and 14 (36 %) a V3 pattern. Seven (18 %) NACs were removed; six intraoperatively and the seventh in a delayed fashion. Notably, five of the seven resected NACs had a V1 pattern. Overall, 71 % of all V1 cases demonstrated profound ischemic changes by intraoperative clinical judgment and SPY imaging. The rates of resection of the NAC differed significantly between perfusion patterns (Fisher's exact test, p = 0.0003).Three perfusion patterns for the NAC are defined. The V1 pattern had the highest rate of NAC ischemia in NSM. Imaging NAC and skin perfusion during NSMs is a useful adjunctive tool with potential to direct placement of mastectomy incisions and minimize ischemic complications.

View details for DOI 10.1245/s10434-013-3214-0

View details for PubMedID 24046104
Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial Lancet Oncology Aebi, S. 2014
View details for DOI 10.1016/S0140-6736 (08)61345-8
Outcomes of Partial Mastectomy in Male Breast Cancer Patients: Analysis of SEER, 1983-2009 ANNALS OF SURGICAL ONCOLOGY Cloyd, J. M., Hernandez-Boussard, T., Wapnir, I. L. 2013; 20 (5): 1545-1550
Abstract

Although mastectomy is considered the gold standard for male breast cancer (MBC), the utilization of lumpectomy and its impact on outcomes in MBC patients has not been previously studied.The Surveillance, Epidemiology and End Results (SEER) database was used to identify all MBC patients who underwent either mastectomy or less than mastectomy (i.e., lumpectomy) between 1983 and 2009.A total of 4707 (86.8 %) men underwent mastectomy and 718 (13.2 %) underwent lumpectomy. A greater proportion of patients underwent lumpectomy later in the study period (1983 to 1986, 10.6 %, vs. 2007 to 2009, 15.1 %). A greater percentage of lumpectomy patients were 80 years or older (21.3 % vs. 16.3 %), had stage IV disease (7.3 % vs. 3.1 %), and received no lymph node sampling (34.3 % vs. 6.9 %). Only 35.4 % of patients underwent adjuvant radiotherapy after lumpectomy. Ten-year breast cancer-specific survival and overall survival were 82.8 % and 46.9 %, respectively, in lumpectomy patients vs. 77.3 % and 46.4 %, respectively, in mastectomy patients. On Cox proportional hazards regression, lumpectomy was not independently associated with worse breast cancer-specific survival (odds ratio 1.09, 95 % confidence interval 0.87-1.37) or overall survival (odds ratio 1.12, 95 % confidence interval 0.98-1.27) after controlling for age, race, stage, and grade, as well as whether radiotherapy was received.Lumpectomy is performed in a small but growing proportion of MBC patients. These patients are not only older and more likely to have advanced disease at the time of diagnosis, but they also are less likely to receive standard of care therapy, such as lymph node sampling and adjuvant radiotherapy. Despite these observations, breast cancer-specific survival is unaffected by the type of surgery.

View details for DOI 10.1245/s10434-013-2918-5

View details for Web of Science ID 000317308200021

View details for PubMedID 23460016
Poor compliance with breast cancer treatment guidelines in men undergoing breast-conserving surgery. Breast cancer research and treatment Cloyd, J. M., Hernandez-Boussard, T., Wapnir, I. L. 2013; 139 (1): 177-182
Abstract

Lumpectomy is performed in a small but growing proportion of men with breast cancer. It is unknown whether men undergoing breast-conserving surgery (BCS) receive care compliant with breast cancer treatment guidelines. Patients with breast cancer in the surveillance, epidemiology, and end results (SEER) database who underwent lumpectomy between 1983 and 2009 were identified. Gender differences in the receipt of lymph node staging and adjuvant radiation therapy were assessed. Multivariate logistic regression was utilized to evaluate the independent association of gender on these outcomes. The influence of gender on breast cancer-specific survival (BCSS) was analyzed. 382,030 of 824,408 (46.3�%) women compared to 712 of 6,039 (11.8�%) men with breast cancer underwent lumpectomy. Men were older, more likely to be black, less likely to have stage I disease and more likely to have stage IV disease. Only 59.2�% of men had lymph nodes sampled at the time of surgery compared to 81.6�% of women (p�<�0.0001). In addition, only 35.4�% of men received adjuvant breast radiation therapy compared to 69.8�% of women (p�<�0.0001). After controlling for age, race, stage, grade, and year of diagnosis, female gender was significantly associated with receiving adjuvant radiation therapy (OR 2.9, 95�% CI 2.4-3.4) and lymph node staging (OR 1.6, 95�% CI 1.3-1.90). Five- and ten-year BCSS were 88.0 and 83.5�% for men compared to 93.2 and 88.2�% for women (p�<�0.001). Men with breast cancer are less likely to receive lymph node staging or adjuvant radiation therapy following BCS compared to women.

View details for DOI 10.1007/s10549-013-2517-y

View details for PubMedID 23572298
The diagnostic value of nipple discharge cytology: Breast imaging complements predictive value of nipple discharge cytology JOURNAL OF SURGICAL ONCOLOGY Kalu, O. N., Chow, C., Wheeler, A., Kong, C., Wapnir, I. 2012; 106 (4): 381-385
Abstract

Papilloma is the most common finding associated with pathologic nipple discharge. In the absence of breast imaging abnormalities, the incidence of occult malignancy is <3%.To determine the predictive value of nipple discharge cytology in conjunction with breast imaging.Retrospective review of 160 charts; inclusion criteria of clinically pathologic nipple discharge, subsequent excisional biopsy, and absence of palpable abnormalities. Nipple discharge cytology categorized as negative, atypical, suspicious, and papillary. Breast imaging was analyzed. Preoperative tests were correlated to final surgical pathology.89 patients identified. Sixty-five had positive cytology, with a false positive rate of 32.3%. They were associated with papillomas in 52%, benign non-papillary in 33% and malignant lesions in 9% of cases. Nipple discharge cytology was positive in 69.6% of papillomas and 92% of atypical/malignant lesions; 30% had abnormal breast imaging and positive cytology. Nipple discharge cytology had a sensitivity of 74.5%, specificity of 30%, and positive predictive value of 68%. The positive predictive value increased to 85% with associated abnormal breast imaging.Nipple discharge cytology is useful in evaluating pathologic discharge. However, negative cytology with negative imaging is not enough to avoid surgery in cases of suspicious clinical presentation.

View details for DOI 10.1002/jso.23091

View details for Web of Science ID 000307550900005

View details for PubMedID 22396104
MRI Enhancement Correlates With High Grade Desmoid Tumor of Breast BREAST JOURNAL Kim, M. J., Wapnir, I. L., Ikeda, D. M., Chisholm, K. M., Do, Y., Daniel, B. L. 2012; 18 (4): 374-376
View details for DOI 10.1111/j.1524-4741.2012.01255.x

View details for Web of Science ID 000305968600016

View details for PubMedID 22716922
Integration and safety of fertility preservation in a breast cancer program GYNECOLOGIC ONCOLOGY Westphal, L. M., Wapnir, I. L. 2012; 124 (3): 474-476
Abstract

Young women diagnosed with breast cancer typically face systemic treatments that may delay childbearing or permanently impair their fertility. These concerns add to the stress experienced by young cancer survivors. Timely counseling and providing fertility preservation through cryopreservation of eggs or embryos have become an important quality of life issue. We analyzed the impact of fertility preservation procedures on the initiation of treatment for breast cancer and discuss critical aspects of the process.

View details for DOI 10.1016/j.ygyno.2011.11.028

View details for Web of Science ID 000300751900018

View details for PubMedID 22173210
Long-Term Outcomes of Invasive Ipsilateral Breast Tumor Recurrences After Lumpectomy in NSABP B-17 and B-24 Randomized Clinical Trials for DCIS JOURNAL OF THE NATIONAL CANCER INSTITUTE Wapnir, I. L., Dignam, J. J., Fisher, B., Mamounas, E. P., Anderson, S. J., Julian, T. B., Land, S. R., Margolese, R. G., Swain, S. M., Costantino, J. P., Wolmark, N. 2011; 103 (6): 478-488
Abstract

Ipsilateral breast tumor recurrence (IBTR) is the most common failure event after lumpectomy for ductal carcinoma in situ (DCIS). We evaluated invasive IBTR (I-IBTR) and its influence on survival among participants in two National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trials for DCIS.In the NSABP B-17 trial (accrual period: October 1, 1985, to December 31, 1990), patients with localized DCIS were randomly assigned to the lumpectomy only (LO, n = 403) group or to the lumpectomy followed by radiotherapy (LRT, n = 410) group. In the NSABP B-24 double-blinded, placebo-controlled trial (accrual period: May 9, 1991, to April 13, 1994), all accrued patients were randomly assigned to LRT+ placebo, (n=900) or LRT + tamoxifen (LRT + TAM, n = 899). Endpoints included I-IBTR, DCIS-IBTR, contralateral breast cancers (CBC), overall and breast cancer-specific survival, and survival after I-IBTR. Median follow-up was 207 months for the B-17 trial (N = 813 patients) and 163 months for the B-24 trial (N = 1799 patients).Of 490 IBTR events, 263 (53.7%) were invasive. Radiation reduced I-IBTR by 52% in the LRT group compared with LO (B-17, hazard ratio [HR] of risk of I-IBTR = 0.48, 95% confidence interval [CI] = 0.33 to 0.69, P < .001). LRT + TAM reduced I-IBTR by 32% compared with LRT + placebo (B-24, HR of risk of I-IBTR = 0.68, 95% CI = 0.49 to 0.95, P = .025). The 15-year cumulative incidence of I-IBTR was 19.4% for LO, 8.9% for LRT (B-17), 10.0% for LRT + placebo (B-24), and 8.5% for LRT + TAM. The 15-year cumulative incidence of all contralateral breast cancers was 10.3% for LO, 10.2% for LRT (B-17), 10.8% for LRT + placebo (B-24), and 7.3% for LRT + TAM. I-IBTR was associated with increased mortality risk (HR of death = 1.75, 95% CI = 1.45 to 2.96, P < .001), whereas recurrence of DCIS was not. Twenty-two of 39 deaths after I-IBTR were attributed to breast cancer. Among all patients (with or without I-IBTR), the 15-year cumulative incidence of breast cancer death was 3.1% for LO, 4.7% for LRT (B-17), 2.7% for LRT + placebo (B-24), and 2.3% for LRT + TAM.Although I-IBTR increased the risk for breast cancer-related death, radiation therapy and tamoxifen reduced I-IBTR, and long-term prognosis remained excellent after breast-conserving surgery for DCIS.

View details for DOI 10.1093/jnci/djr027

View details for Web of Science ID 000288554900008

View details for PubMedID 21398619
KT5823 Differentially Modulates Sodium Iodide Symporter Expression, Activity, and Glycosylation between Thyroid and Breast Cancer Cells ENDOCRINOLOGY Beyer, S., Lakshmanan, A., Liu, Y., Zhang, X., Wapnir, I., Smolenski, A., Jhiang, S. 2011; 152 (3): 782-792
Abstract

Na(+)/I(-) symporter (NIS)-mediated iodide uptake into thyroid follicular cells serves as the basis of radioiodine therapy for thyroid cancer. NIS protein is also expressed in the majority of breast tumors, raising potential for radionuclide therapy of breast cancer. KT5823, a staurosporine-related protein kinase inhibitor, has been shown to increase thyroid-stimulating hormone-induced NIS expression, and thus iodide uptake, in thyroid cells. In this study, we found that KT5823 does not increase but decreases iodide uptake within 0.5 h of treatment in trans-retinoic acid and hydrocortisone-treated MCF-7 breast cancer cells. Moreover, KT5823 accumulates hypoglycosylated NIS, and this effect is much more evident in breast cancer cells than thyroid cells. The hypoglycosylated NIS is core glycosylated, has not been processed through the Golgi apparatus, but is capable of trafficking to the cell surface. KT5823 impedes complex NIS glycosylation at a regulatory point similar to brefeldin A along the N-linked glycosylation pathway, rather than targeting a specific N-glycosylated site of NIS. KT5823-mediated effects on NIS activity and glycosylation are also observed in other breast cancer cells as well as human embryonic kidney cells expressing exogenous NIS. Taken together, KT5823 will serve as a valuable pharmacological reagent to uncover mechanisms underlying differential NIS regulation between thyroid and breast cancer cells at multiple levels.

View details for DOI 10.1210/en.2010-0782

View details for Web of Science ID 000287520900006

View details for PubMedID 21209020
Eusorbents and Eusorption: A Review of Physiological Events to Therapeutic Concepts JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION Wapnir, R. A., Wapnir, I., Lifshitz, F. 2011; 30 (1): 1-10
Abstract

Eusorbents are considered the exogenous substances that facilitate and enhance intestinal absorption. Eusorption is the process by which eusorbents affect the mechanisms of intestinal absorption. These 2 concepts should be distinguished from the well-known probiotics and prebiotics that may also play a role in benefiting the host. This review covers the eusorption paradigm in the optimization of oral rehydration and the treatment of diarrhea. The various factors that influence the validity of eusorbents to facilitate the eusorption were considered (i.e., viscosity, hydrating agents, and minerals such as zinc). The role of surface tension in solute absorption was addressed. The possible effects that eusorbents could play in the gene activation of the intestinal mucosa were also considered. This review should contribute to the understanding of absorptive enhancements of specific substances and their properties that facilitate the desired effects in health and disease.

View details for Web of Science ID 000292663900001

View details for PubMedID 21697533
In Situ Vaccination With a TLR9 Agonist Induces Systemic Lymphoma Regression: A Phase I/II Study JOURNAL OF CLINICAL ONCOLOGY Brody, J. D., Ai, W. Z., Czerwinski, D. K., Torchia, J. A., Levy, M., Advani, R. H., Kim, Y. H., Hoppe, R. T., Knox, S. J., Shin, L. K., Wapnir, I., Tibshirani, R. J., Levy, R. 2010; 28 (28): 4324-4332
Abstract

Combining tumor antigens with an immunostimulant can induce the immune system to specifically eliminate cancer cells. Generally, this combination is accomplished in an ex vivo, customized manner. In a preclinical lymphoma model, intratumoral injection of a Toll-like receptor 9 (TLR9) agonist induced systemic antitumor immunity and cured large, disseminated tumors.We treated 15 patients with low-grade B-cell lymphoma using low-dose radiotherapy to a single tumor site and-at that same site-injected the C-G enriched, synthetic oligodeoxynucleotide (also referred to as CpG) TLR9 agonist PF-3512676. Clinical responses were assessed at distant, untreated tumor sites. Immune responses were evaluated by measuring T-cell activation after in vitro restimulation with autologous tumor cells.This in situ vaccination maneuver was well-tolerated with only grade 1 to 2 local or systemic reactions and no treatment-limiting adverse events. One patient had a complete clinical response, three others had partial responses, and two patients had stable but continually regressing disease for periods significantly longer than that achieved with prior therapies. Vaccination induced tumor-reactive memory CD8 T cells. Some patients' tumors were able to induce a suppressive, regulatory phenotype in autologous T cells in vitro; these patients tended to have a shorter time to disease progression. One clinically responding patient received a second course of vaccination after relapse resulting in a second, more rapid clinical response.In situ tumor vaccination with a TLR9 agonist induces systemic antilymphoma clinical responses. This maneuver is clinically feasible and does not require the production of a customized vaccine product.

View details for DOI 10.1200/JCO.2010.28.9793

View details for Web of Science ID 000282272700032

View details for PubMedID 20697067
Breast cancer brain metastases express the sodium iodide symporter JOURNAL OF NEURO-ONCOLOGY Renier, C., Vogel, H., Offor, O., Yao, C., Wapnir, I. 2010; 96 (3): 331-336
Abstract

Breast cancer brain metastases are on the rise and their treatment is hampered by the limited entry and efficacy of anticancer drugs in this sanctuary. The sodium iodide symporter, NIS, actively transports iodide across the plasma membrane and is exploited clinically to deliver radioactive iodide into cells. As in thyroid cancers, NIS is expressed in many breast cancers including primary and metastatic tumors. In this study NIS expression was analyzed for the first time in 28 cases of breast cancer brain metastases using a polyclonal anti-NIS antibody directed against the terminal C-peptide of human NIS gene and immunohistochemical methods. Twenty-five tumors (84%) in this retrospective series were estrogen/progesterone receptor-negative and 15 (53.6%) were HER2+. Overall 21 (75%) cases and 80% of HER2 positive metastases were NIS positive. While the predominant pattern of NIS immunoreactivity is intracellular, plasma membrane immunopositivity was detected at least focally in 23.8% of NIS-positive samples. Altogether, these findings indicate that NIS expression is prevalent in breast cancer brain metastases and could have a therapeutic role via the delivery of radioactive iodide and selective ablation of tumor cells.

View details for DOI 10.1007/s11060-009-9971-8

View details for Web of Science ID 000273788700004

View details for PubMedID 19618116
Timing of Breast Cancer Treatments with Oocyte Retrieval and Embryo Cryopreservation JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Baynosa, J., Westphal, L. M., Madrigrano, A., Wapnir, I. 2009; 209 (5): 603-607
Abstract

Protecting future childbearing motivates young women with breast cancer to seek oocyte or embryo cryopreservation. Concerns about delays in cancer treatment may influence patients and practitioners considering these procedures. In this study, we compared timing of chemotherapy in women who underwent ovarian stimulation/oocyte retrieval (OR) and embryo cryopreservation with those who did not.Eighty-two women younger than 40 years of age, who received adjuvant chemotherapy for breast cancer, were retrospectively identified. Nineteen underwent OR and 63 did not (CON). The timing of OR, surgery, and chemotherapy were compared with the time intervals between diagnosis and treatments in the CON group.The mean ages of women were 33.7 years (OR group) and 35.2 years (CON group); 84.2% of OR and 25.4% of CON were nulliparous. The median time from initial diagnosis to reproductive endocrinology consultation was 30.1 days (range 4 to 133 days) and from referral to OR was 32 days (range 13 to 66 days). The median times from initial diagnosis to chemotherapy in OR versus CON groups were 71 days (range 45 to 161 days) and 67 days (range 27 to 144 days), respectively, p < 0.27. The median time interval from definitive operation to chemotherapy was similar in the two groups: 30 days (OR; range 14 to 100 days) and 29 days (CON; range 12 to 120 days), p < 0.79.Fertility preservation is an important component of quality of life for young women with breast cancer. The time investment required for OR and cryopreservation is manageable and does not significantly prolong the time interval from diagnosis to start of adjuvant chemotherapy.

View details for DOI 10.1016/j.jamcollsurg.2009.08.006

View details for Web of Science ID 000271876400008

View details for PubMedID 19854400
Prognosis After Ipsilateral Breast Tumor Recurrence and Locoregional Recurrences in Patients Treated by Breast-Conserving Therapy in Five National Surgical Adjuvant Breast and Bowel Project Protocols of Node-Negative Breast Cancer JOURNAL OF CLINICAL ONCOLOGY Anderson, S. J., Wapnir, I., Dignam, J. J., Fisher, B., Mamounas, E. P., Jeong, J., Geyer, C. E., Wickerham, D. L., Costantino, J. P., Wolmark, N. 2009; 27 (15): 2466-2473
Abstract

Locoregional failure (LRF) after breast-conserving therapy (BCT) is associated with increased risk of distant disease and death. The magnitude of this risk has not been adequately characterized in patients with lymph node-negative disease.Our study population included 3,799 women randomly assigned to five National Surgical Adjuvant Breast and Bowel Project protocols of node-negative disease (ie, B-13, B-14, B-19, B-20, and B-23) who underwent lumpectomy and whole breast irradiation with or without adjuvant systemic therapy. Cumulative incidences of ipsilateral breast tumor recurrence (IBTR) and other locoregional recurrence (oLRR) were calculated, along with distant-disease-free interval (DDFI) and overall survival (OS) after these events. Cox models were employed to model mortality by using clinical and pathologic factors jointly with these events.Four hundred nineteen patients (11.0%) experienced LRF: 342 (9.0%) experienced IBTR, and 77 (2.0%) experienced oLRR. The 12-year cumulative incidences of IBTR and oLRR in patients treated with adjuvant systemic therapy were 6.6% and 1.8%, respectively. Overall, 37.1% of IBTRs and 72.7% of oLRRs occurred within 5 years of diagnosis. Older age, black race, higher body mass index (BMI), larger tumors, and occurrence of IBTR or oLRR were significantly associated with increased mortality. The 5-year OS after IBTR and oLRR were 76.6% and 34.9%, respectively. Adjusted hazard ratios for mortality associated with IBTR and oLRR were significantly higher in estrogen receptor (ER)-negative patients than in ER-positive patients (P = .002 and P < .0001, respectively). Patients with early LRF had worse OS and DDFI than those with later-occurring LRF.Although LRF is uncommon in patients with node-negative breast cancer who are treated with lumpectomy, radiation, and adjuvant systemic therapy, those who do develop LRF have substantially worse OS and DDFI.

View details for DOI 10.1200/JCO.2008.19.8424

View details for Web of Science ID 000266195400011

View details for PubMedID 19349544
Association of reactive oxygen species levels and radioresistance in cancer stem cells NATURE Diehn, M., Cho, R. W., Lobo, N. A., Kalisky, T., Dorie, M. J., Kulp, A. N., Qian, D., Lam, J. S., Ailles, L. E., Wong, M., Joshua, B., Kaplan, M. J., Wapnir, I., Dirbas, F. M., Somlo, G., Garberoglio, C., Paz, B., Shen, J., Lau, S. K., Quake, S. R., Brown, J. M., Weissman, I. L., Clarke, M. F. 2009; 458 (7239): 780-U123
Abstract

The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.

View details for DOI 10.1038/nature07733

View details for Web of Science ID 000265193600045

View details for PubMedID 19194462
Endogenous NIS Expression in Triple-Negative Breast Cancers ANNALS OF SURGICAL ONCOLOGY Renier, C., Yao, C., Goris, M., Ghosh, M., Katznelson, L., Nowles, K., Gambhir, S. S., Wapnir, I. 2009; 16 (4): 962-968
Abstract

The sodium iodide symporter (NIS) mediates iodide transport into cells and has been identified in approximately 70% of breast cancers. Functional NIS expression raises the possibility of using (131)I for therapeutic targeting of tumor cells. Treatment of triple-negative breast cancers [estrogen/progesterone receptor-negative and HER2-negative (ER-/PR-/HER2-)] is primarily limited to chemotherapy. Our aim was to characterize NIS expression in this subset of tumors.Archival tissue sections from 23 women with triple-negative breast cancer were analyzed for NIS expression using immunohistochemical methods and an anti-human NIS antibody. Tumors were evaluated for the presence of plasma membrane immunoreactivity. One patient with a NIS-expressing positive tumor underwent (123)I scintigraphic imaging with dosimetric analysis.Fifteen cases (65.2%) demonstrated NIS-positivity with 11 tumors (47.8%) exhibiting strong expression. Plasma membrane immunoreactivity was observed in four breast cancers and was equivocal in another four tumors. Tumor-specific radioiodide uptake was demonstrated by (123)I scintigraphy in a patient with a large primary breast cancer unresponsive to neoadjuvant therapy. The tumor concentrated 2.05, 1.53, and 1.96 times more isotope than normal breast tissue at 1, 5, and 21 h. The relative increased uptake is consistent with positive NIS expression in the tumor on definitive surgery; however, the cumulative concentration in the tumor was not sufficient to achieve a therapeutic effect, had the isotope been (131)I.NIS is strongly expressed in a significant proportion of triple-negative breast cancer cells, suggesting a potential role for NIS-directed (131)I-radioablative strategies in this patient population.

View details for DOI 10.1245/s10434-008-0280-9

View details for Web of Science ID 000263976000026

View details for PubMedID 19184238
Progress on BIG 1-02/IBCSG 27-02/NSABP B-37, a Prospective Randomized Trial Evaluating Chemotherapy after Local Therapy for Isolated Locoregional Recurrences of Breast Cancer ANNALS OF SURGICAL ONCOLOGY Wapnir, I. L., Aebi, S., Gelber, S., Anderson, S. J., Lang, I., Robidoux, A., Mamounas, E. P., Wolmark, N. 2008; 15 (11): 3227-3231
Abstract

The utility of chemotherapy for women who experience a locoregional recurrence after primary treatment of early breast cancer remains an open question. An international collaborative trial is being conducted by the Breast International Group (BIG), the International Breast Cancer Study Group (IBCSG), and the National Surgical Adjuvant Breast and Bowel Project (NSABP) to determine the effectiveness of cytotoxic therapy for these patients, either alone or in addition to selective use of hormonal therapy and trastuzumab.The trial population includes women who have had a previous diagnosis of invasive breast cancer treated by mastectomy or breast-conserving surgery, but subsequently develop an isolated local and/or regional ipsilateral invasive recurrence. Excision of all macroscopic tumor without evidence of systemic disease is required for study entry. Patients are randomized to receive chemotherapy or no chemotherapy; type of chemotherapy is not protocol-specified. Radiation, hormonal therapy, and trastuzumab are given as appropriate. The primary endpoint is disease-free survival (DFS). Quality-of-life measurements are collected at baseline, and then at 9 and 12 months. The accrual goal is 977 patients.This report describes the characteristics of the first 99 patients. Sites of recurrence at study entry were: breast (56%), mastectomy scar/chest wall (35%), and regional lymph nodes (9%). Two-thirds of patients have estrogen-receptor-positive recurrences.This is the only trial actively investigating the question of "adjuvant" chemotherapy in locally recurrent breast cancer. The case mix of accrual to date indicates a broad representation of this patient population.

View details for DOI 10.1245/s10434-008-0129-2

View details for Web of Science ID 000260509400033

View details for PubMedID 18784962
A randomized clinical trial of adjuvant chemotherapy for radically resected locoregional relapse of breast cancer: IBCSG 27-02, BIG 1-02, and NSABP B-37 CLINICAL BREAST CANCER Wapnir, I. L., Aebi, S., Geyer, C. E., Zahrieh, D., Gelber, R. D., Anderson, S. J., Robidoux, A., Bernhard, J., Maibach, R., Castiglione-Gertsch, M., Coates, A. S., Piccart, M. J., Clemons, M. J., Costantino, J. P., Wolmark, N. 2008; 8 (3): 287-292
Abstract

In this phase III, multinational, randomized trial, the International Breast Cancer Study Group, Breast International Group, and the National Surgical Adjuvant Breast and Bowel Project will attempt to define the effectiveness of cytotoxic therapy for patients with locoregional recurrence of breast cancer. We will evaluate whether chemotherapy prolongs disease-free survival and, secondarily, whether its use improves overall survival and systemic disease-free survival. Quality of life measurements will be monitored during the first 12 months of the study. Women who have had a previous diagnosis of invasive breast cancer treated by mastectomy or breast-conserving surgery and who have undergone complete surgical excision of all macroscopic disease but who subsequently develop isolated local and/or regional ipsilateral invasive recurrence are eligible. Patients are randomized to observation/no adjuvant chemotherapy or to adjuvant chemotherapy; all suitable patients receive radiation, hormonal, and trastuzumab therapy. Radiation therapy is recommended for patients who have not received previous adjuvant radiation therapy but is required for those with microscopically positive margins. The radiation field must encompass the tumor bed plus a surrounding margin to a dose of >or= 40 Gy. Radiation therapy will be administered before, during, or after chemotherapy. All women with estrogen receptor-positive and/or progesterone receptor-positive recurrence must receive hormonal therapy, with the agent and duration to be determined by the patient's investigator. Adjuvant trastuzumab therapy is permitted for those with HER2- positive tumors, provided that intent to treat is declared before randomization. Although multidrug regimens are preferred, the agents, doses, and use of supportive therapy are at the discretion of the investigator.

View details for DOI 10.3816/CBC.2008.n.035

View details for Web of Science ID 000256914800013

View details for PubMedID 18650162
New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients BMC CANCER Kohrt, H. E., Olshen, R. A., Bermas, H. R., Goodson, W. H., Wood, D. J., Henry, S., Rouse, R. V., Bailey, L., Philben, V. J., Dirbas, F. M., Dunn, J. J., Johnson, D. L., Wapnir, I. L., Carlson, R. W., Stockdale, F. E., Hansen, N. M., Jeffrey, S. S. 2008; 8
Abstract

Current practice is to perform a completion axillary lymph node dissection (ALND) for breast cancer patients with tumor-involved sentinel lymph nodes (SLNs), although fewer than half will have non-sentinel node (NSLN) metastasis. Our goal was to develop new models to quantify the risk of NSLN metastasis in SLN-positive patients and to compare predictive capabilities to another widely used model.We constructed three models to predict NSLN status: recursive partitioning with receiver operating characteristic curves (RP-ROC), boosted Classification and Regression Trees (CART), and multivariate logistic regression (MLR) informed by CART. Data were compiled from a multicenter Northern California and Oregon database of 784 patients who prospectively underwent SLN biopsy and completion ALND. We compared the predictive abilities of our best model and the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram) in our dataset and an independent dataset from Northwestern University.285 patients had positive SLNs, of which 213 had known angiolymphatic invasion status and 171 had complete pathologic data including hormone receptor status. 264 (93%) patients had limited SLN disease (micrometastasis, 70%, or isolated tumor cells, 23%). 101 (35%) of all SLN-positive patients had tumor-involved NSLNs. Three variables (tumor size, angiolymphatic invasion, and SLN metastasis size) predicted risk in all our models. RP-ROC and boosted CART stratified patients into four risk levels. MLR informed by CART was most accurate. Using two composite predictors calculated from three variables, MLR informed by CART was more accurate than the Nomogram computed using eight predictors. In our dataset, area under ROC curve (AUC) was 0.83/0.85 for MLR (n = 213/n = 171) and 0.77 for Nomogram (n = 171). When applied to an independent dataset (n = 77), AUC was 0.74 for our model and 0.62 for Nomogram. The composite predictors in our model were the product of angiolymphatic invasion and size of SLN metastasis, and the product of tumor size and square of SLN metastasis size.We present a new model developed from a community-based SLN database that uses only three rather than eight variables to achieve higher accuracy than the Nomogram for predicting NSLN status in two different datasets.

View details for DOI 10.1186/1471-2407-8-66

View details for Web of Science ID 000255935500001

View details for PubMedID 18315887
Metastases to the breast: Alveolar soft part sarcoma in adolescents CLINICAL BREAST CANCER Madrigrano, A., Beach, B., Wheeler, A., Wapnir, I. 2008; 8 (1): 92-93
Abstract

Metastases to the breast comprise 0.5%-2% of breast neoplasms. This is a case report of an 18-year-old woman with an alveolar soft part sarcoma metastatic to the breast.

View details for Web of Science ID 000253503000010

View details for PubMedID 18501064
Leiomyosarcoma of the breast in a patient with a 10-year-history of cyclophosphamide exposure: a case report. Cases journal De la Pena, J., Wapnir, I. 2008; 1 (1): 301-?
Abstract

A 50 year old woman with a 10-year history of systemic lupus erythematosus (SLE) and intermittent low-dose cyclophosphamide therapy developed a palpable mass at the periphery of her left breast. Ultrasound guided core biopsy revealed a spindle cell neoplasm characterized on final pathology as a low grade leiomyosarcoma.

View details for DOI 10.1186/1757-1626-1-301

View details for PubMedID 18992149
Progress on BIG 1-02/IBCSG 27-2/NSABP B-37, A prospective randomized trial of evaluating chemotherapy after local therapy for isolated locoregional recurrences of breast cancer Annals of Surgical Oncology Wapnir IL, Aebi S, Gelber SAebi S, Gelber S, Robidoux A, Lang, I, Mamounas E, Wolmark N 2008; 15 (11): 3227-31
Egg retrieval with cryopreservation does not delay breast cancer treatment AMERICAN JOURNAL OF SURGERY Madrigrano, A., Westphal, L., Wapnir, I. 2007; 194 (4): 477-481
Abstract

Infertility is a concern to young women diagnosed with breast cancer. Advances in fertility technology have made it possible to bank fertilized embryos.Twenty-three women, ages 27 to 40 years, underwent stimulation/oocyte retrieval before the start of adjuvant therapies. Time intervals between retrieval and therapeutic procedures were analyzed.The average stimulation to egg retrieval was 11.5 days (range 9-20 d). The average time interval from first evaluation to oocyte retrieval was 33.3 days (range 10-65 d). Overall, the mean time from definitive surgery to initiation of chemotherapy was 46.8 days (n = 20). For 6 patients referred by surgeons, the mean time from fertility consult to retrieval was 48.8 days (range 16-118 d), and from definitive surgery to initiation of chemotherapy was 45 days (range 15-93 d).Egg retrieval cryopreservation can be integrated with breast cancer work-up and surgical procedures. Early referrals to a fertility specialist by surgeons will help patients' safeguard future childbearing.

View details for DOI 10.1016/j.amjsurg.2007.06.008

View details for Web of Science ID 000249933000011

View details for PubMedID 17826059
Expression of the Na+/I- symporter (NIS) is markedly decreased or absent in gastric cancer and intestinal metaplastic mucosa of Barrett esophagus BMC CANCER Altorjay, A., Dohan, O., Szilagyi, A., Paroder, M., Wapnir, I. L., Carrasco, N. 2007; 7
Abstract

The sodium/iodide symporter (NIS) is a plasma membrane glycoprotein that mediates iodide (I-) transport in the thyroid, lactating breast, salivary glands, and stomach. Whereas NIS expression and regulation have been extensively investigated in healthy and neoplastic thyroid and breast tissues, little is known about NIS expression and function along the healthy and diseased gastrointestinal tract.Thus, we investigated NIS expression by immunohistochemical analysis in 155 gastrointestinal tissue samples and by immunoblot analysis in 17 gastric tumors from 83 patients.Regarding the healthy Gl tract, we observed NIS expression exclusively in the basolateral region of the gastric mucin-producing epithelial cells. In gastritis, positive NIS staining was observed in these cells both in the presence and absence of Helicobacter pylori. Significantly, NIS expression was absent in gastric cancer, independently of its histological type. Only focal faint NIS expression was detected in the direct vicinity of gastric tumors, i.e., in the histologically intact mucosa, the expression becoming gradually stronger and linear farther away from the tumor. Barrett mucosa with junctional and fundic-type columnar metaplasia displayed positive NIS staining, whereas Barrett mucosa with intestinal metaplasia was negative. NIS staining was also absent in intestinalized gastric polyps.That NIS expression is markedly decreased or absent in case of intestinalization or malignant transformation of the gastric mucosa suggests that NIS may prove to be a significant tumor marker in the diagnosis and prognosis of gastric malignancies and also precancerous lesions such as Barrett mucosa, thus extending the medical significance of NIS beyond thyroid disease.

View details for DOI 10.1186/1471-2407-7-5

View details for Web of Science ID 000244252900001

View details for PubMedID 17214887
Expression of the Na+/I- symporter (NIS) is markedly decreased or absent in gastric cancer BMC Cancer Altorjay A, Dohan O, Szilagyi A, Paroder M, Wapnir IL, Carrasco N 2007; 7: 5
Resolution of hypoalbuminemia after excision of malignant phyllodes tumor CLINICAL BREAST CANCER Samiian, L., Daniel, B., Wapnir, I. 2006; 7 (5): 411-412
Abstract

A 42-year-old woman presented with a rapidly growing tumor of the breast accompanied by anemia (7.4 g/dL), hypoalbuminemia (1.6 g/dL), and increased alkaline phosphatase (256 U/L). Magnetic resonance imaging of the breast demonstrated a heterogeneous mass composed of verrucous solid components with hemorrhagic areas. There was no evidence of cachexia, and the metastatic workup was negative. Final pathology revealed a 22-cm malignant phyllodes tumor. Hypoalbuminemia and alkaline phosphatase quickly resolved after surgical excision without any further treatment.

View details for Web of Science ID 000243327200008

View details for PubMedID 17239267
Prognosis after ipsilateral breast tumor recurrence and locoregional recurrences in five national surgical adjuvant breast and bowel project node-positive adjuvant breast cancer trials JOURNAL OF CLINICAL ONCOLOGY Wapnir, I. L., Anderson, S. J., Mamounas, E. P., Geyer, C. E., Jeong, J. H., Tan-Chiu, E., Fisher, B., Wolmark, N. 2006; 24 (13): 2028-2037
Abstract

Locoregional failure after breast-conserving surgery is associated with increased risk of distant disease and death. The magnitude of this risk in patients receiving chemotherapy has not been adequately characterized.Our study population included 2,669 women randomly assigned onto five National Surgical Adjuvant Breast and Bowel Project node-positive protocols (B-15, B-16, B-18, B-22, and B-25), who were treated with lumpectomy, whole-breast irradiation, and adjuvant systemic therapy. Cumulative incidences of ipsilateral breast tumor recurrence (IBTR) and other locoregional recurrence (oLRR) were calculated. Kaplan-Meier curves were used to estimate distant-disease-free survival (DDFS) and overall survival (OS) after IBTR or oLRR. Cox models were used to model survival using clinical and pathologic factors jointly with IBTR or oLRR as time-varying predictors.Four hundred twenty-four patients (15.9%) experienced locoregional failure; 259 (9.7%) experienced IBTR, and 165 (6.2%) experienced oLRR. The 10-year cumulative incidence of IBTR and oLRR was 8.7% and 6.0%, respectively. Most locoregional failures occurred within 5 years (62.2% for IBTR and 80.6% for oLRR). Age, tumor size, and estrogen receptor status were significantly associated with IBTR. Nodal status and estrogen and progesterone receptor status were significantly associated with oLRR. The 5-year DDFS rates after IBTR and oLRR were 51.4% and 18.8%, respectively. The 5-year OS rates after IBTR and oLRR were 59.9% and 24.1%, respectively. Hazard ratios for mortality associated with IBTR and oLRR were 2.58 (95% CI, 2.11 to 3.15) and 5.85 (95% CI, 4.80 to 7.13), respectively.Node-positive breast cancer patients who developed IBTR or oLRR had significantly poorer prognoses than patients who did not experience these events.

View details for DOI 10.1200/JCO.2005.04.3273

View details for Web of Science ID 000237371500012

View details for PubMedID 16648502
Bioluminescent-inescent monitoring of NIS-mediated I-131 ablative effects in MCF-7 Xenografts MOLECULAR IMAGING Ghosh, M., Gambhir, S. S., De, A., Nowels, K., Goris, M., Wapnir, I. 2006; 5 (2): 76-84
Abstract

Optical imaging has made it possible to monitor response to anticancer therapies in tumor xenografts. The concept of treating breast cancers with (131)I is predicated on the expression of the Na(+)/I- symporter (NIS) in many tumors and uptake of I- in some. The pattern of (131)I radioablative effects were investigated in an MCF-7 xenograft model dually transfected with firefly luciferase and NIS genes. On Day 16 after tumor cell implantation, 3 mCi of (131)I was injected. Bioluminescent imaging using d-luciferin and a cooled charge-coupled device camera was carried out on Days 1, 2, 3, 7, 10, 16, 22, 29, and 35. Tumor bioluminescence decreased in (131)I-treated tumors after Day 3 and reached a nadir on Day 22. Conversely, bioluminescence steadily increased in controls and was 3.85-fold higher than in treated tumors on Day 22. Bioluminescence in (131)I-treated tumors increased after Day 22, corresponding to tumor regrowth. By Day 35, treated tumors were smaller and accumulated 33% less (99m)TcO(4)(-) than untreated tumors. NIS immunoreactivity was present in <50% of (131)I-treated cells compared to 85-90% of controls. In summary, a pattern of tumor regression occurring over the first three weeks after (131)I administration was observed in NIS-expressing breast cancer xenografts.

View details for DOI 10.2310/7290.2006.00008

View details for Web of Science ID 000239285900004

View details for PubMedID 16954021
Magnetic resonance imaging of suspicious breast masses seen on one mammographic view. breast journal Offodile, R. S., Daniel, B. L., Jeffrey, S. S., Wapnir, I., Dirbas, F. M., Ikeda, D. M. 2004; 10 (5): 416-422
Abstract

The purpose of this study was to assess the utility of contrast-enhanced breast magnetic resonance imaging (MRI) in identifying lesions unidentified on the craniocaudal projection. The authors reviewed five patients with suspicious mammographic lesions not imaged on the craniocaudal mammogram who were referred for contrast-enhanced MRI and underwent subsequent preoperative needle localization in four of the five cases. Five patients, ages 56 to 69 years, had suspicious lesions identified on mediolateral oblique (MLO) or mediolateral (ML) projections only. Ultrasound did not identify the lesion in any of these cases. MRI identified suspicious breast lesions measuring 5 to 12 mm in size. These were located high on the chest wall or in the upper inner quadrant. Suspicious lesions seen only on the MLO or ML projections may reside high on the chest wall or in the upper inner quadrant. Lesions in these locations may be typically excluded on the craniocaudal projection during mammography. Breast MRI has the advantage of imaging the entire breast and is particularly useful for these lesions. In this series, MRI prevented delay in breast cancer diagnosis.

View details for PubMedID 15327495
The Na+/I- symporter mediates iodide uptake in breast cancer metastases and can be selectively down-regulated in the thyroid CLINICAL CANCER RESEARCH Wapnir, I. L., Goris, M., Yudd, A., Dohan, O., Adelman, D., Nowels, K., Carrasco, N. 2004; 10 (13): 4294-4302
Abstract

The Na(+)/I(-) symporter (NIS) is a key plasma membrane protein that mediates active iodide (I(-)) transport in the thyroid, lactating breast, and other tissues. Functional NIS expression in thyroid cancer accounts for the longstanding success of radioactive iodide ((131)I) ablation of metastases after thyroidectomy. Breast cancer is the only other cancer demonstrating endogenous functional NIS expression. Until now, NIS activity in breast cancer metastases (BCM) was unproven.Twenty-seven women were scanned with (99m)TcO(4)(-) or (123)I(-) to assess NIS activity in their metastases. An (131)I dosimetry study was offered to patients with I(-)-accumulating tumors. Selective down-regulation of thyroid NIS was tested in 13 patients with T(3) and in one case with T(3) + methimazole (MMI; blocks I(-) organification). NIS expression was evaluated in index and/or metastatic tumor samples by immunohistochemistry.I(-) uptake was noted in 25% of NIS-expressing tumors (two of eight). The remaining cases did not show NIS expression or activity. Thyroid I(-) uptakes were decreased to
View details for Web of Science ID 000222457300002

View details for PubMedID 15240514
Elephantiasic prefibial myxedema THYROID Cohen, J. B., Balzer, B., Wapnir, I., McDougall, I. R. 2004; 14 (3): 237-238
View details for Web of Science ID 000220580300011

View details for PubMedID 15072707
Immunohistochemical profile of the sodium/iodide symporter in thyroid, breast, and other carcinomas using high density tissue microarrays and conventional sections JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Wapnir, I. L., van de Rijn, M., Nowels, K., Amenta, P. S., Walton, K., Montgomery, K., Greco, R. S., Dohan, O., Carrasco, N. 2003; 88 (4): 1880-1888
Abstract

Extrathyroidal cancers could potentially be targeted with (131)I, if the Na(+)/I(-) symporter (NIS) were functional. Using immunohistochemical methods we probed 1278 human samples with anti-NIS antibody, including 253 thyroid and 169 breast conventional whole tissue sections (CWTS). Four high density tissue microarrays containing a wide variety of breast lesions, normal tissues, and carcinoma cores were tested. The results of the normal microarray were corroborated in 50 CWTS. Nineteen of 34 normal tissues, including bladder, colon, endometrium, kidney, prostate, and pancreas, expressed NIS. Nineteen of 25 carcinomas demonstrated NIS immunopositivity; 55.7% of 479 carcinoma microarray cores expressed NIS, including prostate (74%), ovary (73%), lung (65%), colon (62.6%), and endometrium (56%). NIS protein was present in 75% benign thyroid lesions, 73% thyroid cancers, 30% normal-appearing, peritumoral breasts, 88% ductal carcinomas in situ, and 76% invasive breast carcinoma CWTS. Comparatively, breast microarray cores had lower immunoreactivity. Plasma membrane immunopositivity was confirmed in thyrocytes, salivary ductal, gastric mucosa, and lactating mammary cells. In other tissues, immunoreactivity was predominantly intracellular, particularly in malignant lesions. Thus, NIS is present in many normal epithelial tissues and is predominantly expressed intracellularly in many carcinomas. Elucidating the regulatory mechanisms that render NIS functional in extrathyroidal carcinomas may make (131)I therapy feasible.

View details for DOI 10.1210/jc.2002-021544

View details for Web of Science ID 000182211000072

View details for PubMedID 12679487
The inverse relationship between microvessel counts and tumor volume in breast cancer. breast journal Wapnir, I. L., Barnard, N., Wartenberg, D., Greco, R. S. 2001; 7 (3): 184-188
Abstract

Angiogenesis has emerged as an indicator of metastatic potential in invasive breast cancer. Exponential tumor growth and the appearance of metastasis are observed as new microvessels form. We postulated that the relevance of angiogenesis would be enhanced if analyzed as a function of tumor volume rather than greatest diameter alone and that microvessel counts would proportionately increase as does volume. Since tumors are three-dimensional solids, volume was calculated using the formula for an ellipsoid, V = pi/6 (a x b x c). Sixty-four tumors < or = 2.5 cm were studied and analyzed in 5 mm incremental ranges. Mean microvessel counts did not vary significantly among these tumor size groups. However, analysis of microvessel counts as a function of tumor volume decreased from 947.1/cm3 (0-0.5 cm) to 18.1/cm3 (2.1-2.5 cm), a greater than 50-fold difference. High microvessel density in small cancers supports the notion of metastasis as an early event, making these small tumors perhaps ideal targets for antiangiogenic agents.

View details for PubMedID 11469933
The mammary gland iodide transporter is expressed during lactation and in breast cancer NATURE MEDICINE Tazebay, U. H., Wapnir, I. L., Levy, O., Dohan, O., Zuckier, L. S., Zhao, Q. H., Deng, H. F., Amenta, P. S., Fineberg, S., Pestell, R. G., Carrasco, N. 2000; 6 (8): 871-878
Abstract

The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By exploiting this activity, radioiodide has been used for decades with considerable success in the detection and treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide should be studied as a possible option in the diagnosis and treatment of breast cancer.

View details for Web of Science ID 000165473800029

View details for PubMedID 10932223
The verbal abuse of resident physicians Disease Management and Clinical Outcomes Wapnir IL, Cody RP, Greco RS 1999; 1 (6): 203-206
Collagen gene expression in the neomatrix of carcinoma of the breast INVASION & METASTASIS Wapnir, I. L., Southard, H., Chen, G. H., Friedman, J., BOYD, C. D., Amenta, P. S. 1996; 16 (6): 308-316
Abstract

Excessive deposition of extracellular matrix or neomatrix is a characteristic of desmoplastic invasive breast carcinomas. Type I and III collagens are abundant neomatrix components. Archival breast tissue sections were studied using 35S-labeled cDNA probes for alpha 1(I) and alpha 1(III) procollagen and in situ hybridization. Among the 33 invasive breast cancers, hybridization was seen forming a gradient-like pattern in fibroblasts closest to tumor cells. In the 10 ductal carcinomas in situ studied, a ring-like pattern of hybridization was seen in proximity to the basement membrane zone. Adjacent normal and benign tissues did not demonstrate the patterns of hybridization described in malignant tissues. Gene expression for neomatrix interstitial collagens occurs before there is evidence of invasion in carcinoma of the breast.

View details for Web of Science ID A1997YE40000005

View details for PubMedID 9371230
Three dimensional staging of breast cancer BREAST CANCER RESEARCH AND TREATMENT Wapnir, I. L., WARTENBERG, D. E., Greco, R. S. 1996; 41 (1): 15-19
Abstract

Breast cancers are three dimensional solids but very few are spherical. We hypothesized that calculations based on the greatest diameter would not accurately reflect tumor volume and that three dimensional measurements would affect tumor staging.165 invasive carcinomas measuring 2.5 cm or less and having three measured diameters (a > or = b > or = c) noted were evaluated. Tumor volume was calculated using four geometric models: the spherical 4/3 pi (a/2)3, prolate spheroid 4/3 pi (a/2) (c/2)2, oblate spheroid 4/3 pi (a/2)2 (b/2), and ellipsoid 4/3 pi (a/2 x b/2 x c/2). The ellipsoid correctly determined the volume for any tumor shape. All cases were stratified according to the TNM staging system. Differences in mean volume calculated as a sphere and ellipsoid for each tumor subclass were analyzed using Student's T test. The reclassification of tumors by the ellipsoid formula was determined.Seventy-six (46.1%) had tumors with three different diameters while only six (3.6%) were true spheres having three identical diameters. Mean tumor volume analysis of T1a, T1b, T1c, and T2 tumors demonstrated a statistically significant overestimation of volume when utilizing the sphere formula instead of the ellipsoid formula (p < 0.05). The differences in volume were more dramatic as the diameters increased. A total of 41 tumors were moved into smaller T subclasses including 10 node positive patients.Tumor volume analysis demonstrates that use of only the greatest diameter poorly reflects the true volume of a lesion and consistently overestimates volume. The ellipsoid formula accurately calculates volume for these three dimensional tumors and when utilized has significant relevance to staging small invasive breast cancers.

View details for Web of Science ID A1996VR62000002

View details for PubMedID 8932872
Pathologic differences in nonpalpable breast cancers detected by xeromammography and film screen mammography Breast Disease Wapnir IL, Fang M, Zicherman B, Greco RS 1996; 9 (4): 203-210
Superior quality of life following lumpectomy-axillary dissection in patients with stage I and stage II beast cancer Surgical Forum Wapnir IL, Cody RP, Greco RS 1996; XLVII: 635-636
Local recurrence after breast conservation Current Surgery Wapnir IL 1996; 53 (161): 8-13
Stage II ductal carcinoma arising in a fibroadenoma Breast Disease Wapnir, I., Barnard N 1995; 8: 57-61
COLLAGEN-INDUCED MMP-2 ACTIVATION IN HUMAN BREAST-CANCER BREAST CANCER RESEARCH AND TREATMENT Thompson, E. W., Yu, M., Bueno, J., Jin, L., Maiti, S. N., PALAOMARCO, F. L., Pulyaeva, H., Tamborlane, J. W., TIRGARI, R., Wapnir, I., Azzam, H. 1994; 31 (2-3): 357-370
Abstract

Matrix metalloproteinase-2 (MMP-2), a zymogen requiring proteolytic activation for catalytic activity, has been implicated broadly in the invasion and metastasis of many cancer model systems, including human breast cancer (HBC). MMP-2 has been immunolocalized to carcinomatous human breast, where the degree of activation of MMP-2 correlates well with tumor grade and patient prognosis. Using Matrigel assays, we have stratified HBC cell lines for invasiveness in vitro, and compared this to their potential for metastatic spread in nude mice. HBC cell lines expressing the mesenchymal marker protein vimentin were found to be highly invasive in vitro, and tended to form metastases in nude mice. We have further discovered that culture on collagen-I gels (Vitrogen; Vg) induces MMP-2-activator in highly invasive but not poorly invasive HBC cell lines. As seen for other MMP-2-activator inducing regimens, this induction requires protein synthesis and an intact MMP-2 hemopexin-like domain, appears to be mediated by a cell surface activity, and can be inhibited by metalloproteinase inhibitors. The induction is highly specific to collagen I, and is not seen with thin coatings of collagen I, collagen IV, laminin, or fibronectin, or with 3-dimensional gels of laminin, Matrigel, or gelatin. This review focuses on collagen I and MMP-2, their localization and source in HBC, and their relationship(s) to MMP-2 activation and HBC metastasis. The relevance of collagen I in activation of MMP-2 in vivo is discussed in terms of stromal cell: tumor cell interaction for collagen I deposition, MMP-2 production, and MMP-2-activation. Such cooperativity may exist in vivo for MMP-2 participation in HBC dissemination. A more complete understanding of the regulation of MMP-2-activator by type I collagen may provide new avenues for improved diagnosis and prognosis of human breast cancer.

View details for Web of Science ID A1994PK88900022

View details for PubMedID 7881112
Mammographic changes following biopsy and lumpectomy-breast irradiation. New Jersey medicine : the journal of the Medical Society of New Jersey Wapnir, I. L., Alden-Corbett, S., Zicherman, B., Greco, R. S. 1993; 90 (1): 55-59
Abstract

Mammographic architectural distortion occurred at the operative site in 86 percent of lumpectomy patients and in 34 percent of biopsy patients during the first year (P < 0.001). These changes can mimic carcinoma and may be slow to resolve.

View details for PubMedID 8380491
A REAPPRAISAL OF PROPHYLACTIC MASTECTOMY SURGERY GYNECOLOGY & OBSTETRICS Wapnir, I. L., Rabinowitz, B., Greco, R. S. 1990; 171 (2): 171-184
Abstract

The concept of prophylactic mastectomy was nurtured in the shadow of the radical mastectomy. It evolved as preferable to the mutilation caused by the procedure. It developed during a time when the difference between benignancy and malignancy was not as clear and when patients with benign disease were thought to be at significant risk. The idea of surgical prophylaxis accompanied by a superior cosmetic result, in comparison to the radical mastectomy is a noble one. In retrospect, however, it is clear that the indications were ill defined, based often on unfounded risk and predicated on patient and physician anxiety. The scope of risk in carcinoma of the breast has been narrowed, with new information identifying only specific subsets of women with proliferative types of benign disease as more susceptible to the subsequent development of carcinoma. Extensive reviews of material taken at biopsy that had been validated longitudinally have provided data to substantiate this contention. The concept of familial high risk must take into account the number of affected family members, at age diagnosis, menopausal status and bilaterality. The majority of indicants that motivated and propitiated the performance of the bulk of prophylactic mastectomies have lost their relevance. Prophylactic mastectomy for carcinoma, therefore, can perhaps be reserved for women with biopsy-proved, high-risk lesions or an exceptional familial risk, or both, or hereditary risk. Such women must choose for themselves and accept the uncertainty of hypothetic risk reduction, life-long continued surveillance and an altered body image. Guiding patients in the decision should involve a multidisciplinary team composed of a surgical oncologist, geneticist, pathologist, psychotherapist and plastic surgeon. As a concept, the reduction of risk is appealing, but remains yet to prove itself superior to rigorous clinical surveillance with high-quality mammography. The experience reflected in the literature of a seemingly low rate of subsequent carcinoma cannot be judged, because it seems that operations were applied indiscriminantly to patients selected by unknown means and from an unknown population pool. Success based on protecting those not at increased risk only invalidates the operation further. Most surgical and medical oncologists recognize that carcinoma of the breast is either localized or disseminated at the time of the initial diagnosis.(ABSTRACT TRUNCATED AT 400 WORDS)

View details for Web of Science ID A1990DR88900018

View details for PubMedID 2200150
COMPARTMENT SYNDROME IN COMBINED ARTERIAL AND VENOUS INJURIES OF THE LOWER-EXTREMITY AMERICAN JOURNAL OF SURGERY Shah, P. M., Wapnir, I., Babu, S., Stahl, W. M., CLAUSS, R. H. 1989; 158 (2): 136-141
Abstract

In 9 of 45 patients treated for dual vascular injuries of the lower extremity, concomitant fasciotomies were performed at the time of initial surgery for associated soft tissue injury, fracture, or prolonged ischemia. Eight other patients developed compartment syndrome requiring delayed fasciotomy. In seven of them, vein was either ligated or the repaired vein became occluded. In the eighth patient, peripheral venous hypertension was caused by massive swelling of the thigh. In the laboratory, compartment pressure was monitored by wick catheter in 24 hind limbs of 12 dogs subjected to experimental conditions simulating vascular injuries and their management. There was a significant increase in compartment pressure in a group that simulated arterial and venous injuries managed by arterial repair and venous outflow obstruction. Based on our study, we suggest that obstruction to venous drainage and venous hypertension are major factors in the development of compartment syndrome in dual vascular injuries of the lower extremity.

View details for Web of Science ID A1989AK11300011

View details for PubMedID 2757141
Residual tumor and breast biopsy margins Breast Disease Wapnir, I., Bancila E, Devereux DF, Grecor RS 1989; 2: 81-86
ASYMMETRICAL BREASTS IN AN ADOLESCENT PLASTIC AND RECONSTRUCTIVE SURGERY Wapnir, I., Rabinowitz, B., Snyderman, R. 1988; 81 (5): 813-813
View details for Web of Science ID A1988N215900039

View details for PubMedID 3363001
NONOPERATIVE MANAGEMENT VERSUS EARLY OPERATION FOR BLUNT SPLENIC TRAUMA IN ADULTS SURGERY GYNECOLOGY & OBSTETRICS NALLATHAMBI, M. N., Ivatury, R. R., Wapnir, I., Rohman, M., Stahl, W. M. 1988; 166 (3): 252-258
Abstract

Forty-eight adult patients with isolated splenic trauma from blunt injury were analyzed during a six year period (1980 to 1986). Early laparotomy was performed upon 38 patients and splenic preservation was accomplished in 18. The remaining ten patients who were hemodynamically stable were managed nonoperatively with close monitoring. Splenic injuries were confirmed by one of the imaging methods, such as computed tomography, radionuclide scan or ultrasound. One patient with known hepatic cirrhosis underwent embolization of the splenic artery and recovered. Nonoperative treatment failed in seven of the remaining nine patients, mandating an exploratory laparotomy between the third and tenth day of admission. In six of the seven patients, splenic preservation was unsuccessful, necessitating a splenectomy. The length of hospital stay was longer for this latter group (a mean of 15.8 days) than for patients who had splenorrhaphy (a mean of 7.5 days), or splenectomy (a mean of 8.7 days, p less than 0.001). Patients managed nonoperatively required more units of blood compared with those undergoing splenorrhaphy (4.1 units versus 1.7 units, p less than 0.01). A review of the literature reveals that splenic preservation is possible in less than 25 per cent of the patients who fail to respond to nonoperative management. We conclude that splenic injuries after blunt trauma in adults are treated best by early laparotomy in order to achieve maximal splenic preservation.

View details for Web of Science ID A1988M333100010

View details for PubMedID 3344454
PORTAL-VEIN INJURIES - NONINVASIVE FOLLOW-UP OF VENORRHAPHY ANNALS OF SURGERY Ivatury, R. R., NALLATHAMBI, M., LANKIN, D. H., Wapnir, I., Rohman, M., Stahl, W. M. 1987; 206 (6): 733-737
Abstract

The authors report their experience with 14 patients with portal vein injuries (1976-1986) treated at a level I trauma center. Seven patients (50%) survived and included six of 10 patients (60%) who had venorrhaphy and one in whom the portal vein was ligated. Associated injuries were present in all the patients (mean Abdominal Trauma Index: 39.5) and accounted for the high mortality rate. Follow-up data after repair or ligation of the portal vein seldom are reported in the literature. The authors studied all three patients who survived portal venorrhaphy since 1982 by real-time ultrasonography. Patency of the repair could be established in two patients. In the third patient postvenorrhaphy thrombosis was diagnosed by ultrasonographic examination. Sequential ultrasonographic examinations demonstrated resolution of the thrombus on anticoagulant therapy. Ultrasonography provides a noninvasive and easily reproducible method of studying the portal vein after repair.

View details for Web of Science ID A1987L074700008

View details for PubMedID 3318729
PYOGENIC SPLENIC ABSCESS IN INTRAVENOUS DRUG-ADDICTION AMERICAN SURGEON NALLATHAMBI, M. N., Ivatury, R. R., LANKIN, D. H., Wapnir, I. L., Stahl, W. M. 1987; 53 (6): 342-346
Abstract

Among the surgical complications of intravenous drug addiction, pyogenic splenic abscess is considered to be a rare entity. A review of the literature reveals only 24 cases of splenic abscess secondary to this particular etiology. The authors report five patients with intravenous drug addiction who underwent splenectomy for pyogenic splenic abscess within 1 year. Fever and abdominal pain were the only constant physical signs. Three patients had associated infective endocarditis, and the other two patients sustained blunt trauma to the left side of the trunk weeks earlier. Computed tomography (CT) and ultrasound were diagnostic in all five patients preoperatively, and they were complementary when combined. Four of the five patients had Staphylococcus aureus septicemia at the time of splenectomy. Three patients recovered from their operations, and the other two, both with endocarditis, died postoperatively from causes unrelated to splenic abscess and splenectomy. A high index of suspicion is warranted in this susceptible group of patients with vague abdominal signs and persistent sepsis to rule out splenic suppuration. The noninvasive imaging methods, CT scan and ultrasound, facilitate early diagnosis in these patients.

View details for Web of Science ID A1987H551200010

View details for PubMedID 3579050
[Gastroesophageal reflux in children. Experience in 100 cases treated by Nissen's fundoplication]. Bolet�n m�dico del Hospital Infantil de M�xico P�rez-Fern�ndez, L., Pe�a-Rodr�guez, A., Wapnir, I. 1985; 42 (4): 256-265
View details for PubMedID 4005025
LATENT MAMMARY TUBERCULOSIS - A CASE-REPORT SURGERY Wapnir, I. L., PALLAN, T. M., Gaudino, J., Stahl, W. M. 1985; 98 (5): 976-978
Abstract

Tuberculosis of the breast was diagnosed in this 63-year-old woman 14 years after she was treated for tuberculous pericarditis. Case history and a review of the literature are presented.

View details for Web of Science ID A1985ATV0100019

View details for PubMedID 4060074
Muerte inesperada y sindrome de muerte subita en la infancia PAtologia (Mexico) Ridaura-Sanz C, Wapnir-Michalewicz IL, Lopez-Corella E, Mendoza-Lopez E 1980; 18: 341-350
MAGNESIUM-METABOLISM IN EXPERIMENTAL DIABETES-MELLITUS DIABETES Fort, P., Lifshitz, F., Wapnir, I. L., Wapnir, R. A. 1977; 26 (9): 882-886
View details for Web of Science ID A1977DU41100010

View details for PubMedID 142678

Conference Proceedings

New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients Kohrt, H., Olshen, R., Bermas, H., GOODSON, W., Henry, S., Rouse, R., Bailey, L., Philben, V., Dirbas, F., Dunn, J., Johnson, D., Wapnir, I., Carlson, R., STOCKDALE, F., Hansen, N., JEFFREY, S. SPRINGER. 2008: 588-588
View details for Web of Science ID 000255851900029
Subtle differences in quality of life after breast cancer surgery Wapnir, I. L., Cody, R. P., Greco, R. S. SPRINGER. 1999: 359-366
Abstract

Lumpectomy with axillary dissection (LAD) has taken its place alongside mastectomy (M) as the treatment of choice for stage I and II breast cancer. Its appeal is based on lessening disfigurement and thus improving quality of life.We used the SF-36 Health Survey modified with ten questions relevant to breast cancer surgery to evaluate whether quality of life with LAD was better than with mastectomy in women with stage I and II disease. The additional questions addressed satisfaction with intimate relationships and sexuality, and explored impact on the way women dress, use bathing suits, hug people, are comfortable with nudity, and rate their sexual drive and sexual responsiveness.LAD was not associated with statistically significant better quality-of-life scores on any SF-36 questions, except vitality (P = .02). No differences were noted in the areas of intimacy and sexual satisfaction. LAD patients reported significant differences in matters of dress, use of bathing suits, hugging, comfort with nudity, and sexual drive compared to patients undergoing mastectomy.The SF-36 health survey detected few differences in quality of life measures between patients with LAD and those with mastectomy. However, LAD impacts favorably on the way women dress, on comfort with nudity, and on sexual drive.

View details for Web of Science ID 000080715300009

View details for PubMedID 10379856

Irene Wapnir

Professor of Surgery (General Surgery) at the Stanford University Medical Center

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