Frederick M. Dirbas

All Publications

• Breast Surgical Techniques and Interdisciplinary Management Frederick M. Dirbas, Carol Scott-Conner 2011; Springer
• Accelerated Partial Breast Irradiation: Where Do We Stand? JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Dirbas, F. M. 2009; 7 (2): 215-225

  Abstract

  Accelerated partial breast irradiation (APBI) is a new form of postlumpectomy radiotherapy delivered over 1 to 5 days. Early trials showed high local recurrence rates. More recent single and multiinstitutional studies, as well as a single phase III trial, have shown local control more comparable to whole breast radiotherapy. Patient selection and surgical technique are important variables preparatory to irradiation, which is delivered using 1 of 4 accelerated radiotherapy methods. Phase I/II studies have produced most of the information currently available regarding APBI. Additional phase III studies are underway to determine whether any or all of these accelerated radiotherapy approaches may safely substitute for whole breast radiotherapy in women seeking breast conservation.

  View details for Web of Science ID 000270264400008

  View details for PubMedID 19200419

• Streamlining clinical breast examination JOURNAL OF THE NATIONAL CANCER INSTITUTE Goodson, W. H., Grissom, N. A., Moore, D. H., Dirbas, F. M. 2005; 97 (19): 1476-1477

  View details for DOI 10.1093/jnci/dji309

  View details for Web of Science ID 000232953400016

  View details for PubMedID 16204698

• The evolution of accelerated, partial breast irradiation as a potential treatment option for women with newly diagnosed breast cancer considering breast conservation CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS Dirbas, F. M., Jeffrey, S. S., Goffinet, D. R. 2004; 19 (6): 673-705

  Abstract

  Breast conservation therapy (BCT) is a safe, effective alternative to mastectomy for many women with newly diagnosed breast cancer. This approach involves local excision of the malignancy with tumor-free margins, followed by 5-7 weeks of external beam whole breast (WB) radiotherapy (XRT) to minimize the risk of an in-breast tumor recurrence (IBTR). Though clearly beneficial, the extended course of almost daily postoperative radiotherapy interrupts normal activities and lengthens care. Additional options are now available that shorten the radiotherapy treatment time to 1-5 days (accelerated) and focus an increased dose of radiation on just the breast tissue around the excision cavity (partial breast). Recent trials with accelerated, partial breast irradiation (APBI) have shown promise as a potential replacement to the longer, whole breast treatments for select women with early-stage breast cancer. Current APBI approaches include interstitial brachytherapy, intracavitary (balloon) brachytherapy, and accelerated external beam (3-D conformal) radiotherapy, all of which normally complete treatment over 5 days, while intraoperative radiotherapy (IORT) condenses the entire treatment into a single dose delivered immediately after tumor excision. Each approach has benefits and limitations. This study covers over 2 decades of clinical trials exploring APBI, discusses treatment variables that appear necessary for successful implementation of this new form of radiotherapy, compares and contrasts the various APBI approaches, and summarizes current and planned randomized trials that will shape if and how APBI is introduced into routine clinical care. Some of the more important outcome variables from these trials will be local toxicity, local and regional recurrence, and overall survival. If APBI options are ultimately demonstrated to be as safe and effective as current whole breast radiotherapy approaches, breast conservation may become an even more appealing choice, and the overall impact of treatment may be further reduced for certain women with newly diagnosed breast cancer.

  View details for Web of Science ID 000226744200003

  View details for PubMedID 15665616

• IL6 Signaling in Peripheral Blood T Cells Predicts Clinical Outcome in Breast Cancer. Cancer research Wang, L., Miyahira, A. K., Simons, D. L., Lu, X., Chang, A. Y., Wang, C., Suni, M. A., Maino, V. C., Dirbas, F. M., Yim, J., Waisman, J., Lee, P. P. 2017; 77 (5): 1119-1126

  Abstract

  IL6 is a pleiotropic cytokine with both pro- and anti-inflammatory properties, which acts directly on cancer cells to promote their survival and proliferation. Elevated serum IL6 levels negatively correlate with survival of cancer patients, which is generally attributed to the direct effects of IL6 on cancer cells. How IL6 modulates the host immune response in cancer patients is unclear. Here, we show the IL6 signaling response in peripheral blood T cells is impaired in breast cancer patients and is associated with blunted Th17 differentiation. The mechanism identified involved downregulation of gp130 and IL6Rα in breast cancer patients and was independent of plasma IL6 levels. Importantly, defective IL6 signaling in peripheral blood T cells at diagnosis correlated with worse relapse-free survival. These results indicate that intact IL6 signaling in T cells is important for controlling cancer progression. Furthermore, they highlight a potential for IL6 signaling response in peripheral blood T cells at diagnosis as a predictive biomarker for clinical outcome of breast cancer patients. Cancer Res; 77(5); 1119-26. ©2016 AACR.

  View details for DOI 10.1158/0008-5472.CAN-16-1373

  View details for PubMedID 27879265

  View details for PubMedCentralID PMC5334262

• Five-year results of a prospective clinical trial investigating accelerated partial breast irradiation using 3D conformal radiotherapy after lumpectomy for early stage breast cancer BREAST Horst, K. C., Fasola, C., Ikeda, D., Daniel, B., Ognibene, G., Goffinet, D. R., Dirbas, F. M. 2016; 28: 178-183

  Abstract

  Accelerated partial breast irradiation (APBI) is emerging as an alternative to whole-breast irradiation. This study presents the results of a prospective trial evaluating 3-dimensional conformal radiotherapy (3D-CRT) to deliver APBI for early-stage breast cancer.Patients with unifocal stage 0-II breast cancer measuring ≤2.5 cm without lymph node involvement were eligible. After lumpectomy, 3D-CRT APBI was delivered to the lumpectomy cavity + margin (34-38.5 Gy in 10 fractions over 5 days).141 patients with 143 breast cancers (2 bilateral) were treated with 3D-CRT APBI. Median age was 60. Median tumor size was 1.1 cm. At a median follow up of 60 months (range, 5-113), the 5-year and 8-year cumulative incidence rate of a true recurrence is 0.9%. The 5-year and 8-year cumulative incidence rates of an elsewhere failure are 2.4% and 4.4%, respectively. The 5-year and 8-year overall survival is 100% and 94%, respectively. Among the 62 patients with follow up >5 years, 95% had excellent/good cosmetic results.Our experience with 3D-CRT APBI demonstrates excellent cosmesis and local control. Longer follow up will be necessary to evaluate long-term efficacy and toxicity of 3D-CRT APBI. CLINICALTRIALS.NCT00185744.

  View details for DOI 10.1016/j.breast.2016.06.001

  View details for Web of Science ID 000379683300027

  View details for PubMedID 27322859

• CT-Guided Wire Localization for Involved Axillary Lymph Nodes After Neo-adjuvant Chemotherapy in Patients With Initially Node-Positive Breast Cancer BREAST JOURNAL Long Trinh, L., Miyake, K. K., Dirbas, F. M., Kothary, N., Horst, K. C., Lipson, J. A., Carpenter, C., Thompson, A. C., Ikeda, D. M. 2016; 22 (4): 390-396

  Abstract

  Resection of biopsy-proven involved axillary lymph nodes (iALNs) is important to reduce the false-negative rates of sentinel lymph node (SLN) biopsy after neo-adjuvant chemotherapy (NAC) in patients with initially node-positive breast cancer. Preoperative wire localization for iALNs marked with clips placed during biopsy is a technique that may help the removal of iALNs after NAC. However, ultrasound (US)-guided localization is often difficult because the clips cannot always be reliably visible on US. Computed tomography (CT)-guided wire localization can be used; however, to date there have been no reports on CT-guided wire localization for iALNs. The aim of this study was to describe a series of patients who received CT-guided wire localization for iALN removal after NAC and to evaluate the feasibility of this technique. We retrospectively analyzed five women with initially node-positive breast cancer (age, 41-52 years) who were scheduled for SLN biopsy after NAC and received preoperative CT-guided wire localization for iALNs. CT visualized all the clips that were not identified on post-NAC US. The wire tip was deployed beyond or at the target, with the shortest distance between the wire and the index clip ranging from 0 to 2.5 mm. The total procedure time was 21-38 minutes with good patient tolerance and no complications. In four of five cases, CT wire localization aided in identification and resection of iALNs that were not identified with lymphatic mapping. Residual nodal disease was confirmed in two cases: both had residual disease in wire-localized lymph nodes in addition to SLNs. Although further studies with more cases are required, our results suggest that CT-guided wire localization for iALNs is a feasible technique that facilitates identification and removal of the iALNs as part of SLN biopsy after NAC in situations where US localization is unsuccessful.

  View details for DOI 10.1111/tbj.12597

  View details for Web of Science ID 000379824600004

  View details for PubMedID 27061012

• Pain Duration and Resolution following Surgery: An Inception Cohort Study PAIN MEDICINE Carroll, I. R., Hah, J. M., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Mackey, S. C. 2015; 16 (12): 2386-2396

  View details for DOI 10.1111/pme.12842

  View details for Web of Science ID 000368297000020

• Pain Duration and Resolution following Surgery: An Inception Cohort Study. Pain medicine Carroll, I. R., Hah, J. M., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Mackey, S. C. 2015; 16 (12): 2386-2396

  Abstract

  Preoperative determinants of pain duration following surgery are poorly understood. We identified preoperative predictors of prolonged pain after surgery in a mixed surgical cohort.We conducted a prospective longitudinal study of patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured pain and opioid use after surgery until patients reported the cessation of both opioid consumption and pain. The primary endpoint was time to opioid cessation, and those results have been previously reported. Here, we report preoperative determinants of time to pain resolution following surgery in Cox proportional hazards regression.Between January 2007 and April 2009, we enrolled 107 of 134 consecutively approached patients undergoing the aforementioned surgical procedures. In the final multivariate model, preoperative self-perceived risk of addiction predicted more prolonged pain. Unexpectedly, anxiety sensitivity predicted more rapid pain resolution after surgery. Each one-point increase (on a four point scale) of self-perceived risk of addiction was associated with a 38% (95% CI 3-61) reduction in the rate of pain resolution (P = 0.04). Furthermore, higher anxiety sensitivity was associated with an 89% (95% CI 23-190) increased rate of pain resolution (P = 0.004).Greater preoperative self-perceived risk of addiction, and lower anxiety sensitivity predicted a slower rate of pain resolution following surgery. Each of these factors was a better predictor of pain duration than preoperative depressive symptoms, post-traumatic stress disorder symptoms, past substance use, fear of pain, gender, age, preoperative pain, or preoperative opioid use.

  View details for DOI 10.1111/pme.12842

  View details for PubMedID 26179223

• A cell-intrinsic role for TLR2-MYD88 in intestinal and breast epithelia and oncogenesis. Nature cell biology Scheeren, F. A., Kuo, A. H., van Weele, L. J., Cai, S., Glykofridis, I., Sikandar, S. S., Zabala, M., Qian, D., Lam, J. S., Johnston, D., Volkmer, J. P., Sahoo, D., van de Rijn, M., Dirbas, F. M., Somlo, G., Kalisky, T., Rothenberg, M. E., Quake, S. R., Clarke, M. F. 2014; 16 (12): 1238-1248

  Abstract

  It has been postulated that there is a link between inflammation and cancer. Here we describe a role for cell-intrinsic toll-like receptor-2 (TLR2; which is involved in inflammatory response) signalling in normal intestinal and mammary epithelial cells and oncogenesis. The downstream effectors of TLR2 are expressed by normal intestinal and mammary epithelia, including the stem/progenitor cells. Deletion of MYD88 or TLR2 in the intestinal epithelium markedly reduces DSS-induced colitis regeneration and spontaneous tumour development in mice. Limiting dilution transplantations of breast epithelial cells devoid of TLR2 or MYD88 revealed a significant decrease in mammary repopulating unit frequency compared with the control. Inhibition of TLR2, its co-receptor CD14, or its downstream targets MYD88 and IRAK1 inhibits growth of human breast cancers in vitro and in vivo. These results suggest that inhibitors of the TLR2 pathway merit investigation as possible therapeutic and chemoprevention agents.

  View details for DOI 10.1038/ncb3058

  View details for PubMedID 25362351

• A cell-intrinsic role for TLR2 MYD88 in intestinal and breast epithelia and oncogenesis NATURE CELL BIOLOGY Scheeren, F. A., Kuo, A. H., van Weele, L. J., Cai, S., Glykofridis, I., Sikandar, S. S., Zabala, M., Qian, D., Lam, J. S., Johnston, D., Volkmer, J. P., Sahoo, D., van de Rijn, M., Dirbas, F. M., Somlo, G., Kalisky, T., Rothenberg, M. E., Quake, S. R., Clarke, M. F. 2014; 16 (12): 1238-U245

  View details for DOI 10.1038/ncb3058

  View details for Web of Science ID 000345777300014

  View details for PubMedID 25362351

• miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway ELIFE Isobe, T., Hisamori, S., Hogan, D. J., Zabala, M., Hendrickson, D. G., Dalerba, P., Cai, S., Scheeren, F., Kuo, A. H., Sikandar, S. S., Lam, J. S., Qian, D., Dirbas, F. M., Somlo, G., Lao, K., Brown, P. O., Clarke, M. F., Shimono, Y. 2014; 3

  View details for DOI 10.7554/eLife.01977

  View details for Web of Science ID 000345638500001

• Breast magnetic resonance imaging alters patient selection for accelerated partial breast irradiation. American journal of clinical oncology Horst, K. C., Ikeda, D. M., Fero, K. E., Daniel, B. L., Goffinet, D. R., Dirbas, F. M. 2014; 37 (3): 248-254

  Abstract

  OBJECTIVES:: To determine whether pretreatment contrast-enhanced breast magnetic resonance imaging (MRI) alters patient selection for accelerated partial breast irradiation (APBI). MATERIALS AND METHODS:: Women aged 40 years or older with unifocal invasive or intraductal carcinoma ≤2.5 cm on physical examination, mammography, and ultrasound (US) were evaluated with breast MRI before enrollment on an APBI trial using single-fraction intraoperative radiotherapy (IORT) or fractionated 3-dimensional conformal radiotherapy. Abnormal MRI findings were evaluated with US-guided or MRI-guided biopsy. RESULTS:: Between December 2002 and March 2005, 51 women (median age=61 y; range, 40 to 83 y) who met inclusion criteria underwent breast MRI before APBI. MRI demonstrated limited disease in 41 patients (80.4%): 34 received APBI using IORT (22) or 3DCRT (12), whereas 7 elected standard whole-breast radiotherapy. Ten of the 51 patients (19.6%) had indeterminate or suspicious enhancement patterns on MRI. Five of these 10 (9.8% of MRI cohort) underwent US-guided or MRI-guided biopsy revealing normal breast tissue without atypia: 3 were treated with APBI using IORT (5.9% of MRI cohort) and 2 underwent standard breast conservation therapy (3.9% of MRI cohort). The remaining 5 patients (9.8% of MRI cohort) had MRI findings revealing previously unsuspected pectoral fascia involvement (1), multifocal disease (3), or multicentric disease (1): 2 were treated with standard breast conservation therapy, whereas 3 underwent mastectomy without adjuvant radiotherapy. CONCLUSIONS:: Pretreatment breast MRI altered patient selection for APBI by identifying additional disease in 9.8% of the candidates, all of whom fit into the "cautionary" or "unsuitable" categories as defined by the American Society for Radiation Oncology APBI consensus guidelines. The clinical significance of these findings will be clarified with the results of ongoing randomized trials of APBI that do not incorporate breast MRI as part of the selection criteria.

  View details for DOI 10.1097/COC.0b013e318277d7c8

  View details for PubMedID 23275271

• Breast Magnetic Resonance Imaging Alters Patient Selection for Accelerated Partial Breast Irradiation AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS Horst, K. C., Ikeda, D. M., Fero, K. E., Daniel, B. L., Goffinet, D. R., Dirbas, F. M. 2014; 37 (3): 248-254

  View details for DOI 10.1097/COC.0b013e318277d7c8

  View details for Web of Science ID 000336958200006

• Self-loathing aspects of depression reduce postoperative opioid cessation rate. Pain medicine Hah, J. M., Mackey, S., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Schmidt, P. C., Carroll, I. R. 2014; 15 (6): 954-964

  Abstract

  We previously reported that increased preoperative Beck Depression Inventory II (BDI-II) scores were associated with a 47% (95% CI 24%-64%) reduction in the rate of opioid cessation following surgery. We aimed to identify the underlying factors of the BDI-II (affective/cognitive vs somatic) associated with a decreased rate of opioid cessation after surgery.We conducted a secondary analysis of the data from a previously reported prospective, longitudinal, observational study of opioid use after five distinct surgical procedures (total hip replacement, total knee replacement, thoracotomy, mastectomy, and lumpectomy) in 107 patients. The primary endpoint was time to opioid cessation. After exploratory factor analysis of the BDI-II, mean summary scores were calculated for each identified factor. These scores were evaluated as predictors of time to opioid cessation using Cox proportional hazards regression.The exploratory factor analysis produced three factors (self-loathing symptoms, motivational symptoms, emotional symptoms). All three factors were significant predictors in univariate analysis. Of the three identified factors of the BDI-II, only preoperative self-loathing symptoms (past failure, guilty feelings, self-dislike, self-criticalness, suicidal thoughts, worthlessness) independently predicted a significant decrease in opioid cessation rate after surgery in the multivariate analysis (HR 0.86, 95% CI 0.75-0.99, P value 0.037).Our results identify a set of negative cognitions predicting prolonged time to postoperative opioid cessation. Somatic symptoms captured by the BDI-II were not primarily responsible for the association between preoperative BDI-II scores and postoperative prolonged opioid use.

  View details for DOI 10.1111/pme.12439

  View details for PubMedID 24964916

• Self-Loathing Aspects of Depression Reduce Postoperative Opioid Cessation Rate PAIN MEDICINE Hah, J. M., Mackey, S., Barelka, P. L., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F. M., Schmidt, P. C., Carroll, I. R. 2014; 15 (6): 954-964

  View details for DOI 10.1111/pme.12439

  View details for Web of Science ID 000338025900009

• Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition BREAST CANCER RESEARCH Zhang, H., Cohen, A. L., Krishnakumar, S., Wapnir, I. L., Veeriah, S., Deng, G., Coram, M. A., Piskun, C. M., Longacre, T. A., Herrler, M., Frimannsson, D. O., Telli, M. L., Dirbas, F. M., Matin, A. C., Dairkee, S. H., Larijani, B., Glinsky, G. V., Bild, A. H., Jeffrey, S. S. 2014; 16 (2)

  View details for DOI 10.1186/bcr3640

  View details for Web of Science ID 000338990900021

• miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. eLife Isobe, T., Hisamori, S., Hogan, D. J., Zabala, M., Hendrickson, D. G., Dalerba, P., Cai, S., Scheeren, F., Kuo, A. H., Sikandar, S. S., Lam, J. S., Qian, D., Dirbas, F. M., Somlo, G., Lao, K., Brown, P. O., Clarke, M. F., Shimono, Y. 2014; 3

  Abstract

  MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. We previously reported that miR-142 and miR-150 are upregulated in human breast cancer stem cells (BCSCs) as compared to the non-tumorigenic breast cancer cells. In this study, we report that miR-142 efficiently recruits the APC mRNA to an RNA-induced silencing complex, activates the canonical WNT signaling pathway in an APC-suppression dependent manner, and activates the expression of miR-150. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression.

  View details for DOI 10.7554/eLife.01977

  View details for PubMedID 25406066

• Defining an optimal role for breast magnetic resonance imaging when evaluating patients otherwise eligible for accelerated partial breast irradiation. Radiotherapy and oncology Horst, K. C., Fero, K. E., Ikeda, D. M., Daniel, B. L., Dirbas, F. M. 2013; 108 (2): 220-225

  Abstract

  BACKGROUND AND PURPOSE: Pre-treatment breast magnetic resonance imaging (MRI) findings in a cohort of women prospectively evaluated for accelerated partial breast irradiation (APBI) are reviewed and characterized to determine the optimal use of MRI in these patients. MATERIALS AND METHODS: Candidates initially deemed eligible for a prospective APBI trial based on physical examination, mammography, and ultrasound (US) were further evaluated with breast MRI before treatment. All abnormal MRI findings were biopsied. RESULTS: Between 2002 and 2011, 180 women who met inclusion criteria for APBI underwent breast MRI prior to treatment (median age=59; range 38-86). 126 tumors (70%) were invasive carcinomas with or without associated DCIS, while 54 (30%) were pure DCIS. Breast MRI confirmed unifocal disease in 109 patients with 111 cancers (60.5% of MRI cohort). Multifocal disease was identified in 19 patients (10.5% of MRI cohort), while multicentric disease was present in 3 patients (1.6% of MRI cohort). Five patients (4%) had an MRI-detected contralateral cancer. False positive MRI findings were seen in 45 patients (25% of MRI cohort). Pre-menopausal patients and patients with tumors >2cm were more likely to have MRI-detected multifocal/multicentric disease. While there was no statistically significant correlation between multifocal/multicentric disease and breast density, tumor histology, grade, ER status, or Her2/Neu expression, numbers in each category were small, suggesting a lack of statistical power to detect differences that may be clinically meaningful. One hundred and fifty-two of the 180 patients (84.4%) successfully completed lumpectomy and APBI, while 6.7% of the cohort underwent mastectomy. CONCLUSIONS: Breast MRI identified additional disease in 12% of APBI candidates. Premenopausal women and patients with tumors >2cm were more likely to have MRI-detected multifocal/multicentric disease.

  View details for DOI 10.1016/j.radonc.2013.01.019

  View details for PubMedID 23597699

• Altered local and systemic immune profiles underlie lymph node metastasis in breast cancer patients INTERNATIONAL JOURNAL OF CANCER Zuckerman, N. S., Yu, H., Simons, D. L., Bhattacharya, N., Carcamo-Cavazos, V., Yan, N., Dirbas, F. M., Johnson, D. L., Schwartz, E. J., Lee, P. P. 2013; 132 (11): 2537-2547

  Abstract

  Cancer-mediated immune dysfunction contributes to tumor progression and correlates with patient outcome. Metastasis to tumor draining lymph nodes (TDLNs) is an important step in breast cancer progression and is used to predict patient outcome and survival. Although lymph nodes are important immune organs, the role of immune cells in TDLNs has not been thoroughly investigated. We hypothesized that the host immune response in node negative (NN) patients is more intact and thereby can resist tumor invasion compared to node positive (NP) patients. As such, lymph node metastasis requires breakdown of the host immune response in addition to escape of cancer cells from the tumor. To investigate the immunological differences between NN and NP breast cancer patients, we purified and profiled immune cells from the three major compartments where cancer and immune cells interact: tumor, TDLNs and peripheral blood. Significant down-regulation of genes associated with immune-related pathways and up-regulation of genes associated with tumor-promoting pathways was consistently observed in NP patients' TDLNs compared to NN patients. Importantly, these signatures were seen even in NP patients' tumor-free TDLNs, suggesting that such immune changes are not driven solely by local tumor invasion. Furthermore, similar patterns were also observed in NP patients' tumor and blood immune cells, suggesting that immunological differences between NN and NP patients are systemic. Together, these findings suggest that alterations in overall immune function may underlie risk for LN metastasis in breast cancer patients.

  View details for DOI 10.1002/ijc.27933

  View details for Web of Science ID 000316824000009

  View details for PubMedID 23136075

• PRC2/EED-EZH2 Complex Is Up-Regulated in Breast Cancer Lymph Node Metastasis Compared to Primary Tumor and Correlates with Tumor Proliferation In Situ PLOS ONE Yu, H., Simons, D. L., Segall, I., Carcamo-Cavazos, V., Schwartz, E. J., Yan, N., Zuckerman, N. S., Dirbas, F. M., Johnson, D. L., Holmes, S. P., Lee, P. P. 2012; 7 (12)

  Abstract

  Lymph node metastasis is a key event in the progression of breast cancer. Therefore it is important to understand the underlying mechanisms which facilitate regional lymph node metastatic progression.We performed gene expression profiling of purified tumor cells from human breast tumor and lymph node metastasis. By microarray network analysis, we found an increased expression of polycomb repression complex 2 (PRC2) core subunits EED and EZH2 in lymph node metastatic tumor cells over primary tumor cells which were validated through real-time PCR. Additionally, immunohistochemical (IHC) staining and quantitative image analysis of whole tissue sections showed a significant increase of EZH2 expressing tumor cells in lymph nodes over paired primary breast tumors, which strongly correlated with tumor cell proliferation in situ. We further explored the mechanisms of PRC2 gene up-regulation in metastatic tumor cells and found up-regulation of E2F genes, MYC targets and down-regulation of tumor suppressor gene E-cadherin targets in lymph node metastasis through GSEA analyses. Using IHC, the expression of potential EZH2 target, E-cadherin was examined in paired primary/lymph node samples and was found to be significantly decreased in lymph node metastases over paired primary tumors.This study identified an over expression of the epigenetic silencing complex PRC2/EED-EZH2 in breast cancer lymph node metastasis as compared to primary tumor and its positive association with tumor cell proliferation in situ. Concurrently, PRC2 target protein E-cadherin was significant decreased in lymph node metastases, suggesting PRC2 promotes epithelial mesenchymal transition (EMT) in lymph node metastatic process through repression of E-cadherin. These results indicate that epigenetic regulation mediated by PRC2 proteins may provide additional advantage for the outgrowth of metastatic tumor cells in lymph nodes. This opens up epigenetic drug development possibilities for the treatment and prevention of lymph node metastasis in breast cancer.

  View details for DOI 10.1371/journal.pone.0051239

  View details for Web of Science ID 000312201900057

  View details for PubMedID 23251464

  View details for PubMedCentralID PMC3519681

• A Pilot Cohort Study of the Determinants of Longitudinal Opioid Use After Surgery ANESTHESIA AND ANALGESIA Carroll, I., Barelka, P., Wang, C. K., Wang, B. M., Gillespie, M. J., McCue, R., Younger, J. W., Trafton, J., Humphreys, K., Goodman, S. B., Dirbas, F., Whyte, R. I., Donington, J. S., Cannon, W. B., Mackey, S. C. 2012; 115 (3): 694-702

  Abstract

  Determinants of the duration of opioid use after surgery have not been reported. We hypothesized that both preoperative psychological distress and substance abuse would predict more prolonged opioid use after surgery.Between January 2007 and April 2009, a prospective, longitudinal inception cohort study enrolled 109 of 134 consecutively approached patients undergoing mastectomy, lumpectomy, thoracotomy, total knee replacement, or total hip replacement. We measured preoperative psychological distress and substance use, and then measured the daily use of opioids until patients reported the cessation of both opioid consumption and pain. The primary end point was time to opioid cessation. All analyses were controlled for the type of surgery done.Overall, 6% of patients continued on new opioids 150 days after surgery. Preoperative prescribed opioid use, depressive symptoms, and increased self-perceived risk of addiction were each independently associated with more prolonged opioid use. Preoperative prescribed opioid use was associated with a 73% (95% confidence interval [CI] 0.51%-87%) reduction in the rate of opioid cessation after surgery (P = 0.0009). Additionally, each 1-point increase (on a 4-point scale) of self-perceived risk of addiction was associated with a 53% (95% CI 23%-71%) reduction in the rate of opioid cessation (P = 0.003). Independent of preoperative opioid use and self-perceived risk of addiction, each 10-point increase on a preoperative Beck Depression Inventory II was associated with a 42% (95% CI 18%-58%) reduction in the rate of opioid cessation (P = 0.002). The variance in the duration of postoperative opioid use was better predicted by preoperative prescribed opioid use, self-perceived risk of addiction, and depressive symptoms than postoperative pain duration or severity.Preoperative factors, including legitimate prescribed opioid use, self-perceived risk of addiction, and depressive symptoms each independently predicted more prolonged opioid use after surgery. Each of these factors was a better predictor of prolonged opioid use than postoperative pain duration or severity.

  View details for DOI 10.1213/ANE.0b013e31825c049f

  View details for Web of Science ID 000307942900028

  View details for PubMedID 22729963

• Toward MR-guided high intensity focused ultrasound for presurgical localization: Focused ultrasound lesions in cadaveric breast tissue JOURNAL OF MAGNETIC RESONANCE IMAGING Bitton, R. R., Kaye, E., Dirbas, F. M., Daniel, B. L., Pauly, K. B. 2012; 35 (5): 1089-1097

  Abstract

  To investigate magnetic resonance image-guided high intensity focused ultrasound (MR-HIFU) as a surgical guide for nonpalpable breast tumors by assessing the palpability of MR-HIFU-created lesions in ex vivo cadaveric breast tissue.MR-HIFU ablations spaced 5 mm apart were made in 18 locations using the ExAblate2000 system. Ablations formed a square perimeter in mixed adipose and fibroglandular tissue. Ablation was monitored using T1-weighted fast spin echo images. MR-acoustic radiation force impulse (MR-ARFI) was used to remotely palpate each ablation location, measuring tissue displacement before and after thermal sonications. Displacement profiles centered at each ablation spot were plotted for comparison. The cadaveric breast was manually palpated to assess stiffness of ablated lesions and dissected for gross examination. This study was repeated on three cadaveric breasts.MR-ARFI showed a collective postablation reduction in peak displacement of 54.8% ([4.41 ± 1.48] μm pre, [1.99 ± 0.82] μm post), and shear wave velocity increase of 65.5% ([10.69 ± 1.60] mm pre, [16.33 ± 3.10] mm post), suggesting tissue became stiffer after the ablation. Manual palpation and dissection of the breast showed increased palpability, a darkening of ablation perimeter, and individual ablations were visible in mixed adipose/fibroglandular tissue.The results of this preliminary study show MR-HIFU has the ability to create palpable lesions in ex vivo cadaveric breast tissue, and may potentially be used to preoperatively localize nonpalpable breast tumors.

  View details for DOI 10.1002/jmri.23529

  View details for Web of Science ID 000302721800011

  View details for PubMedID 22170814

  View details for PubMedCentralID PMC3307904

• Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Liu, H., Patel, M. R., Prescher, J. A., Patsialou, A., Qian, D., Lin, J., Wen, S., Chang, Y., Bachmann, M. H., Shimono, Y., Dalerba, P., Adorno, M., Lobo, N., Bueno, J., Dirbas, F. M., Goswami, S., Somlo, G., Condeelis, J., Contag, C. H., Gambhir, S. S., Clarke, M. F. 2010; 107 (42): 18115-18120

  Abstract

  To examine the role of breast cancer stem cells (BCSCs) in metastasis, we generated human-in-mouse breast cancer orthotopic models using patient tumor specimens, labeled with optical reporter fusion genes. These models recapitulate human cancer features not captured with previous models, including spontaneous metastasis in particular, and provide a useful platform for studies of breast tumor initiation and progression. With noninvasive imaging approaches, as few as 10 cells of stably labeled BCSCs could be tracked in vivo, enabling studies of early tumor growth and spontaneous metastasis. These advances in BCSC imaging revealed that CD44(+) cells from both primary tumors and lung metastases are highly enriched for tumor-initiating cells. Our metastatic cancer models, combined with noninvasive imaging techniques, constitute an integrated approach that could be applied to dissect the molecular mechanisms underlying the dissemination of metastatic CSCs (MCSCs) and to explore therapeutic strategies targeting MCSCs in general or to evaluate individual patient tumor cells and predict response to therapy.

  View details for DOI 10.1073/pnas.1006732107

  View details for Web of Science ID 000283184800050

  View details for PubMedID 20921380

  View details for PubMedCentralID PMC2964232

• Freehand MRI-Guided Preoperative Needle Localization of Breast Lesions After MRI-Guided Vacuum-Assisted Core Needle Biopsy Without Marker Placement JOURNAL OF MAGNETIC RESONANCE IMAGING van de Ven, S. M., Lin, M. C., Daniel, B. L., Sareen, P., Lipson, J. A., Pal, S., Dirbas, F. M., Ikeda, D. M. 2010; 32 (1): 101-109

  Abstract

  To evaluate the feasibility of magnetic resonance imaging (MRI)-guided preoperative needle localization (PNL) of breast lesions previously sampled by MRI-guided vacuum-assisted core needle biopsy (VACNB) without marker placement.We reviewed 15 women with 16 breast lesions undergoing MRI-guided VACNB without marker placement who subsequently underwent MRI-guided PNL, both on an open 0.5T magnet using freehand techniques. Mammograms and specimen radiographs were rated for lesion visibility; MRI images were rated for lesion visibility and hematoma formation. Imaging findings were correlated with pathology.The average prebiopsy lesion size was 16 mm (range 4-50 mm) with 13/16 lesions located in mammographically dense breasts. Eight hematomas formed during VACNB (average size 13 mm, range 8-19 mm). PNL was performed for VACNB pathologies of cancer (5), high-risk lesions (5), or benign but discordant findings (6) at 2-78 days following VACNB. PNL targeted the lesion (2), hematoma (4), or surrounding breast architecture (10). Wire placement was successful in all 16 lesions. Final pathology showed six cancers, five high-risk lesions, and five benign findings.MRI-guided PNL is successful in removing lesions that have previously undergone VACNB without marker placement by targeting the residual lesion, hematoma, or surrounding breast architecture, even in mammographically dense breasts.

  View details for DOI 10.1002/jmri.22148

  View details for Web of Science ID 000279439600013

  View details for PubMedID 20575077

• 3.0-T MR-Guided Focused Ultrasound for Preoperative Localization of Nonpalpable Breast Lesions: An Initial Experimental Ex Vivo Study JOURNAL OF MAGNETIC RESONANCE IMAGING Schmitz, A. C., Van den Bosch, M. A., Rieke, V., Dirbas, F. M., Pauly, K. B., Mali, W. P., Daniel, B. L. 2009; 30 (4): 884-889

  Abstract

  To compare the accuracy of magnetic resonance-guided focused ultrasound (MRgFUS) with MR-guided needle-wire placement (MRgNW) for the preoperative localization of nonpalpable breast lesions.In this experimental ex vivo study, 15 turkey breasts were used. In each breast phantom an artificial nonpalpable "tumor" was created by injecting an aqueous gel containing gadolinium. MRgFUS (n = 7) was performed with the ExAblate 2000 system (InSightec). With MRgFUS the ablated tissue changes in color and increases in stiffness. A rim of palpable and visible ablations was created around the tumor to localize the tumor and facilitate excision. MRgNW (n = 8) was performed by MR-guided placement of an MR-compatible needle-wire centrally in the tumor. After surgical excision of the tumor, MR images were used to evaluate tumor-free margins (negative/positive), minimum tumor-free margin (mm), and excised tissue volume (cm(3)).With MRgFUS localization no positive margins were found after excision (0%). With MRgNW two excision specimens (25%) had positive margins (P = 0.48). Mean minimum tumor-free margin (+/-SD) with MRgFUS was significantly larger (5.5 +/- 2.4 mm) than with MRgNW (0.9 +/- 1.4 mm) (P < 0.001). Mean volume +/- SD of excised tissue did not differ between MRgFUS and MRgNW localization, ie, 44.0 +/- 9.4 cm(3) and 39.5 +/- 10.7 cm(3) (P = 0.3).The results of this experimental ex vivo study indicate that MRgFUS can potentially be used to localize nonpalpable breast lesions in vivo.

  View details for DOI 10.1002/jmri.21896

  View details for Web of Science ID 000270522900026

  View details for PubMedID 19787736

• Downregulation of miRNA-200c Links Breast Cancer Stem Cells with Normal Stem Cells CELL Shimono, Y., Zabala, M., Cho, R. W., Lobo, N., Dalerba, P., Qian, D., Diehn, M., Liu, H., Panula, S. P., Chiao, E., Dirbas, F. M., Somlo, G., Pera, R. A., Lao, K., Clarke, M. F. 2009; 138 (3): 592-603

  Abstract

  Human breast tumors contain a breast cancer stem cell (BCSC) population with properties reminiscent of normal stem cells. We found 37 microRNAs that were differentially expressed between human BCSCs and nontumorigenic cancer cells. Three clusters, miR-200c-141, miR-200b-200a-429, and miR-183-96-182 were downregulated in human BCSCs, normal human and murine mammary stem/progenitor cells, and embryonal carcinoma cells. Expression of BMI1, a known regulator of stem cell self-renewal, was modulated by miR-200c. miR-200c inhibited the clonal expansion of breast cancer cells and suppressed the growth of embryonal carcinoma cells in vitro. Most importantly, miR-200c strongly suppressed the ability of normal mammary stem cells to form mammary ducts and tumor formation driven by human BCSCs in vivo. The coordinated downregulation of three microRNA clusters and the similar functional regulation of clonal expansion by miR-200c provide a molecular link that connects BCSCs with normal stem cells.

  View details for DOI 10.1016/j.cell.2009.07.011

  View details for Web of Science ID 000268771900022

  View details for PubMedID 19665978

• Impaired interferon signaling is a common immune defect in human cancer PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Critchley-Thorne, R. J., Simons, D. L., Yan, N., Miyahira, A. K., Dirbas, F. M., Johnson, D. L., Swetter, S. M., Carlson, R. W., Fisher, G. A., Koong, A., Holmes, S., Lee, P. P. 2009; 106 (22): 9010-9015

  Abstract

  Immune dysfunction develops in patients with many cancer types and may contribute to tumor progression and failure of immunotherapy. Mechanisms underlying cancer-associated immune dysfunction are not fully understood. Efficient IFN signaling is critical to lymphocyte function; animals rendered deficient in IFN signaling develop cancer at higher rates. We hypothesized that altered IFN signaling may be a key mechanism of immune dysfunction common to cancer. To address this, we assessed the functional responses to IFN in peripheral blood lymphocytes from patients with 3 major cancers: breast cancer, melanoma, and gastrointestinal cancer. Type-I IFN (IFN-alpha)-induced signaling was reduced in T cells and B cells from all 3 cancer-patient groups compared to healthy controls. Type-II IFN (IFN-gamma)-induced signaling was reduced in B cells from all 3 cancer patient groups, but not in T cells or natural killer cells. Impaired-IFN signaling was equally evident in stage II, III, and IV breast cancer patients, and downstream functional defects in T cell activation were identified. Taken together, these findings indicate that defects in lymphocyte IFN signaling arise in patients with breast cancer, melanoma, and gastrointestinal cancer, and these defects may represent a common cancer-associated mechanism of immune dysfunction.

  View details for DOI 10.1073/pnas.0901329106

  View details for Web of Science ID 000266580500043

  View details for PubMedID 19451644

• 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

  View details for PubMedCentralID PMC2778612

• New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients 30th Annual San Antonio Breast Cancer Symposium 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: 588–88

  View details for Web of Science ID 000255851900029

• 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

  View details for PubMedCentralID PMC2311316

• Axillary surgery in breast cancer patients CLINICAL & TRANSLATIONAL ONCOLOGY Millet, A., FUSTER, C. A., Lluch, A., Dirbas, F. 2007; 9 (8): 513-520

  Abstract

  Surgeons have routinely removed ipsilateral axillary lymph nodes from women with breast cancer for over 100 years. The procedure provides important staging information, enhances regional control of the malignancy and may improve survival. As screening of breast cancer has increased, the mean size of newly diagnosed primary invasive breast cancers has steadily decreased and so has the number of women with lymph node metastases. Recognising that the therapeutic benefit of removing normal nodes may be low, alternatives to the routine level I/II axillary lymph node dissection have been sought. A decade ago sentinel lymph node biopsy (SLNB) was introduced. Because of its high accuracy and relatively low morbidity, this technique is now widely used to identify women with histologically involved nodes prior to the formal axillary node dissection. Specifically, SLNB has allowed surgeons to avoid a formal axillary lymph node biopsy in women with histologically uninvolved sentinel nodes, while identifying women with involved sentinel nodes who derive the most benefit from a completion axillary node dissection. Despite the increasing use of SLNB for initial management of the axilla in women with breast cancer, important questions remain regarding patient selection criteria and optimal surgical methods for performing the biopsy. This article discusses the evolution of axillary node surgery for women with breast cancer.

  View details for DOI 10.1007/s12094-007-0095-3

  View details for Web of Science ID 000256944200007

  View details for PubMedID 17720654

• Phyllodes tumors of the breast: natural history, diagnosis, and treatment. Journal of the National Comprehensive Cancer Network Telli, M. L., Horst, K. C., Guardino, A. E., Dirbas, F. M., Carlson, R. W. 2007; 5 (3): 324-330

  Abstract

  Phyllodes tumors of the breast are unusual fibroepithelial tumors that exhibit a wide range of clinical behavior. These tumors are categorized as benign, borderline, or malignant based on a combination of histologic features. The prognosis of phyllodes tumors is favorable, with local recurrence occurring in approximately 15% of patients overall and distant recurrence in approximately 5% to 10% overall. Wide excision with a greater than 1 cm margin is definitive primary therapy. Adjuvant systemic therapy is of no proven value. Patients with locally recurrent disease should undergo wide excision of the recurrence with or without subsequent radiotherapy.

  View details for PubMedID 17439760

• Impact of increasing margin around the lumpectomy cavity to define the planning target volume for 3d conformal external beam accelerated partial breast irradiation 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Cox, B. W., Horst, K. C., Thornton, S., Dirbas, F. M. ELSEVIER SCIENCE INC. 2007: 254–62

  Abstract

  The purpose of this study was to evaluate the dose to normal tissues as a function of increasing margins around the lumpectomy cavity in accelerated partial breast irradiation (APBI) using 3D-conformal radiotherapy (3DCRT). Eight patients with Stage 0-I breast cancer underwent treatment planning for 3DCRT APBI. The clinical target volume (CTV) was defined as a 15-mm expansion around the cavity limited by the chest wall and skin. Three planning target volumes (PTV1, PTV2, PTV3) were generated for each patient using a 0, 5-, and 10-mm expansion around the CTV, for a total margin of 15, 20, and 25 mm. Three treatment plans were generated for every patient using the 3 PTVs, and dose-volume analysis was performed for each plan. For each 5-mm increase in margin, the mean PTV:total breast volume ratio increased 10% and the relative increase in the mean ipsilateral breast dose was 15%. The mean volume of ipsilateral breast tissue receiving 75%, 50%, and 25% of the prescribed dose increased 6% to 7% for every 5 mm increase in PTV margin. Compared to lesions located in the upper outer quadrant, plans for medially located tumors revealed higher mean ipsilateral breast doses and 20% to 22% more ipsilateral breast tissue encompassed by the 25% IDL. The use of 3DCRT for APBI delivers higher doses to normal breast tissue as the PTV increases around the lumpectomy cavity. Efforts should be made to minimize the overall PTV when this technique is used. Ongoing studies will be necessary to determine the clinical relevance of these findings.

  View details for DOI 10.1016/j.meddos.2007.02.003

  View details for Web of Science ID 000251075200004

  View details for PubMedID 17980825

• Outcomes of women with metachronous breast and ovarian carcinomas GYNECOLOGIC ONCOLOGY Liou, W., Hamilton, C. A., Cheung, M. K., Osann, K., Longacre, T. A., Teng, N. N., Husain, A., Dirbas, F. M., Chan, J. K. 2006; 103 (1): 190-194

  Abstract

  Women with a history of breast cancer have a significantly increased risk of developing a second primary ovarian cancer and vice versa. We proposed to determine the characteristics and outcomes of women diagnosed with metachronous breast and ovarian cancer.Patients were identified from the Surveillance, Epidemiology, and End Results program database between 1988 and 2001. Kaplan-Meier and Cox proportional hazards regression tests were used to determine survival outcomes.Of 704 women, 526 developed breast cancer then ovarian cancer (B-O) and 178 developed ovarian cancer then breast cancer (O-B). The mean age at diagnosis of the first cancer in the B-O versus O-B group was 60.3 versus 58.9 years, respectively (P = 0.23). Twenty-five percent of women in the B-O group had stage I-II ovarian cancer versus 63% in the O-B group (P < 0.001). The percentage of those with stage I-II breast cancer was 94% and 91% in the B-O versus O-B group, respectively (P = 0.13). Women in the B-O group had more high grade of ovarian cancer compared to those in the O-B group (P < 0.001). The mean time interval between diagnoses of breast then ovarian versus ovarian then breast cancer was 58 versus 56 months, respectively (P = 0.42).In the largest series to date, we found that women diagnosed with ovarian cancer first had significantly more early stage and lower grade ovarian cancers with better survival compared to those with breast cancer followed by ovarian cancer. Since half of the women had their second cancer beyond 5 years, continued surveillance of these high risk patients is recommended.

  View details for DOI 10.1016/j.ygyno.2006.02.022

  View details for Web of Science ID 000240887100036

  View details for PubMedID 16569424

• Predicting non-sentinel lymph node involvement in breast cancer patients. 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Kohrt, H. E., Olshen, R. A., Goodson, W. H., Rouse, R. V., Bailey, L., Philben, V., Dirbas, F. M., Stockdale, F. E., Carlson, R. W., Jeffrey, S. S. AMER SOC CLINICAL ONCOLOGY. 2006: 10S–10S

  View details for Web of Science ID 000239009400039

• Pathologic correlates of false positive breast magnetic resonance imaging findings: which lesions warrant biopsy? 6th Annual Meeting of the American-Society-of-Breast-Surgeons Langer, S. A., Horst, K. C., Ikeda, D. M., Daniel, B. L., Kong, C. S., Dirbas, F. M. EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC. 2005: 633–40

  Abstract

  Contrast-enhanced breast magnetic resonance imaging (MRI) is highly sensitive for breast cancer. However, adoption of breast MRI is hampered by frequent false positive (FP) findings. Though ultimately proven benign, these suspicious findings require biopsy due to abnormal morphology and/or kinetic enhancement curves that simulate malignancy on MRI. We hypothesized that analysis of a series of FP MRI findings could reveal a pattern of association between certain "suspicious" lesions and benign disease that might help avoid unnecessary biopsy of such lesions in the future.A retrospective chart review identified women undergoing breast MRI between June 1995 and March 2002 with FP findings identified by MRI alone. Lesions were retrospectively characterized according to an MRI Breast Imaging-Reporting and Data System lexicon and matched to pathology.Twenty-two women were identified with 29 FP lesions. Morphology revealed 1 focus (3.5%), 5 masses less than 5 mm (17%), 11 masses greater than 5 mm (38%), 1 (3.5%) linear enhancement, and 11 (38%) non-mass-like enhancement. Kinetic curves were suspicious in 15 (52%). Histology demonstrated 20 (69%) variants of normal tissue and 9 (31%) benign masses. MRI lesions less than 5 mm (n = 6, 20.5%) were small, well-delineated nodules of benign breast tissue.Suspicious MRI lesions less than 5 mm often represent benign breast tissue and could potentially undergo surveillance instead of biopsy.

  View details for DOI 10.1016/j.amjsurg.2005.06.030

  View details for Web of Science ID 000232189600028

  View details for PubMedID 16164938

• Rates of reexcision for breast cancer after magnetic resonance imaging-guided bracket wire localization JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Wallace, A. M., Daniel, B. L., Jeffrey, S. S., Birdwell, R. L., Nowels, K. W., Dirbas, F. M., Schraedley-Desmond, P., Ikeda, D. M. 2005; 200 (4): 527-537

  Abstract

  We performed this study to determine rates of close or transected cancer margins after magnetic resonance imaging-guided bracket wire localization for nonpalpable breast lesions.Of 243 women undergoing MRI-guided wire localizations, 26 had MRI bracket wire localization to excise either a known cancer (n = 19) or a suspicious MRI-detected lesion (n = 7). We reviewed patient age, preoperative diagnosis, operative intent, mammographic breast density, MRI lesion size, MRI enhancement curve and morphology, MRI Breast Imaging Reporting and Data System (BI-RADS) assessment code, number of bracket wires, and pathology size. We analyzed these findings for their relationship to obtaining clear margins at first operative excision.Twenty-one of 26 (81%) patients had cancer. Of 21 patients with cancer, 12 (57%) had negative margins at first excision and 9 (43%) had close/transected margins. MRI size > or = 4 cm was associated with a higher reexcision rate (7 of 9, 78%) than those < 4 cm (2 of 12, 17%) (p = 0.009). MRI BI-RADS score, enhancement curve, morphology, and preoperative core biopsy demonstrating ductal carcinoma in situ (DCIS) were not predictive of reexcision. The average number of wires used for bracketing increased with lesion size, but was not associated with improved outcomes. On pathology, cancer size was smaller in patients with negative margins (12 patients, 1.2 cm) than in those with close/transected margins (9 patients, 4.6 cm) (p < 0.001). Reexcision was based on close/transected margins involving DCIS alone (6, 67%), infiltrating ductal carcinoma and DCIS (2, 22%), or infiltrating ductal carcinoma alone (1, 11%). Reexcision pathology demonstrated DCIS (3, 33%), no residual cancer (5, 55%), and 1 patient was lost to followup (1, 11%). Interestingly, cancer patients who required reexcision were younger (p = 0.022), but breast density was not associated with reexcision.To our knowledge, this is the first report of MRI-guided bracket wire localization. Patients with MRI-detected lesions less than 4 cm had clear margins at first excision; larger MRI-detected lesions were more likely to have close/transected margins. Reexcision was often because of DCIS and was the only pathology found at reexcision, perhaps because MRI is more sensitive for detecting invasive carcinoma than DCIS.

  View details for DOI 10.1016/j.jamcollsurg.2004.12.013

  View details for Web of Science ID 000228085200005

  View details for PubMedID 15804466

• Survival analysis of women with double primary breast and ovarian carcinomas 53rd Annual Clinical Meeting of the American-College-of-Obstetricians-and-Gynecologists Liou, W. S., Cheung, M. K., Hamilton, C., Osann, K., Dirbas, F., Chan, J. K. LIPPINCOTT WILLIAMS & WILKINS. 2005: 86S–86S

  View details for Web of Science ID 000228065900199

• Breast magnetic resonance imaging alters patient selection for accelerated, partial breast irradiation 47th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Horst, K. C., Ikeda, D. M., Birdwell, R. L., Daniel, B. L., Goffinet, D. R., Pal, S., Nowels, K. W., Dirbas, F. M. ELSEVIER SCIENCE INC. 2005: S4–S5

  View details for Web of Science ID 000232083300011

• 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

• Breast magnetic resonance image screening and ductal lavage in women at high genetic risk for breast carcinoma CANCER Hartman, A. R., Daniel, B. L., Kurian, A. W., Mills, M. A., Nowels, K. W., Dirbas, F. M., Kingham, K. E., Chun, N. M., Herfkens, R. J., Ford, J. M., Plevritis, S. K. 2004; 100 (3): 479-489

  Abstract

  Intensive screening is an alternative to prophylactic mastectomy in women at high risk for developing breast carcinoma. The current article reports preliminary results from a screening protocol using high-quality magnetic resonance imaging (MRI), ductal lavage (DL), clinical breast examination, and mammography to identify early malignancy and high-risk lesions in women at increased genetic risk of breast carcinoma.Women with inherited BRCA1 or BRCA2 mutations or women with a >10% risk of developing breast carcinoma at 10 years, as estimated by the Claus model, were eligible. Patients were accrued from September 2001 to May 2003. Enrolled patients underwent biannual clinical breast examinations and annual mammography, breast MRI, and DL.Forty-one women underwent an initial screen. Fifteen of 41 enrolled women (36.6%) either had undergone previous bilateral oophorectomy and/or were on tamoxifen at the time of the initial screen. One patient who was a BRCA1 carrier had high-grade ductal carcinoma in situ (DCIS) that was screen detected by MRI but that was missed on mammography. High-risk lesions that were screen detected by MRI in three women included radial scars and atypical lobular hyperplasia. DL detected seven women with cellular atypia, including one woman who had a normal MRI and mammogram.Breast MRI identified high-grade DCIS and high-risk lesions that were missed by mammography. DL detected cytologic atypia in a high-risk cohort. A larger screening trial is needed to determine which subgroups of high-risk women will benefit and whether the identification of malignant and high-risk lesions at an early stage will impact breast carcinoma incidence and mortality.

  View details for DOI 10.1002/cncr.11926

  View details for Web of Science ID 000188611400006

  View details for PubMedID 14745863

• A simplified clinical breast examination will work. 27th Annual San Antonio Breast Cancer Symposium Goodson, W. H., Dirbas, F. M., Grissom, N. A., Moore, D. H. SPRINGER. 2004: S189–S189

  View details for Web of Science ID 000225589600536

• A pilot breast cancer screening trial for women at high inherited risk using clinical breast exam, mammography, breast magnetic resonance imaging, and ductal lavage: updated results after median follow-up of fourteen months. 27th Annual San Antonio Breast Cancer Symposium Kurian, A. W., Daniel, B. L., Mills, M. A., Nowels, K. W., Ford, J. M., Plevritis, S. K., Kingham, K. E., Chun, N. M., Herfkens, R. J., Dirbas, F. M., Garber, J. M., Hartman, A. R. SPRINGER. 2004: S187–S188

  View details for Web of Science ID 000225589600532

• Results from a pilot breast cancer screening trial using a combination of clincal breast exam, mammography, breast MRI, and ductal lavage in a high-risk population 26th Annual San Antonio Breast Cancer Symposium Hartman, A. R., Kurian, A., Mills, M. A., Daniel, B. L., Ford, J. M., Kingham, K. E., Chun, N. M., Nowels, K. W., Herfkens, R. J., Dirbas, F. M., Plevritis, S. K. SPRINGER. 2003: S22–S23

  View details for Web of Science ID 000186783100066

• Comprehensive screening using breast MRI and ductal lavage in high-risk women. 25th San Antonio Breast Cancer Symposium Hartman, A. R., Daniel, B. L., Ford, J. M., Chun, N. M., Kingham, K. E., Mills, M. A., Grekowicz, A. M., Jacobs, C. D., Herfkens, R. J., Nowels, K. W., Dirbas, F. M., Plevritis, S. K. SPRINGER. 2002: S152–S152

  View details for Web of Science ID 000179770100485

• Clinical management of breast pain: A review OBSTETRICAL & GYNECOLOGICAL SURVEY Millet, A. V., Dirbas, F. M. 2002; 57 (7): 451-461

  Abstract

  Breast pain (mastalgia) is a common cause of anxiety among women and frequently leads to a primary care clinic for consultation. Fortunately, mild premenstrual breast discomfort lasting for 1 to 4 days can be considered "normal." However, moderate-to-severe breast pain lasting over 5 days can interfere with usual activities, lead to unnecessary medical tests, and potentially invite the use of ineffective, occasionally harmful medications. Despite the severity of some patients' symptoms, mastalgia is still considered a trivial complaint by many physicians; often it is felt to be psychological in nature. Careful evaluation to rule out breast cancer and reassure the patient is enough to make the pain resolve in most cases. In a few patients, however, mastalgia is severe enough to deserve further evaluation and treatment. Overall, 92% of patients with cyclical mastalgia (CM) and 64% with noncyclical mastalgia (NCM) can obtain relief of their pain with the judicious use of several available therapies.

  View details for Web of Science ID 000176771600002

  View details for PubMedID 12172222

• Freehand iMRI-guided large-gauge core needle biopsy: A new minimally invasive technique for diagnosis of enhancing breast lesions 7th Annual Meeting of the International-Society-for-Magnetic-Resonance-in-Medicine (ISMRM) Daniel, B. L., Birdwell, R. L., Butts, K., Nowels, K. W., Ikeda, D. M., Heiss, S. G., Cooper, C. R., Jeffrey, S. S., Dirbas, F. M., Herfkens, R. J. JOHN WILEY & SONS INC. 2001: 896–902

  Abstract

  The lack of reliable methods for minimally invasive biopsy of suspicious enhancing breast lesions has hindered the utilization of contrast-enhanced magnetic resonance imaging (MRI) for the detection and diagnosis of breast cancer. In this study, a freehand method was developed for large-gauge core needle biopsy (LCNB) guided by intraprocedural MRI (iMRI). Twenty-seven lesions in nineteen patients were biopsied using iMRI-guided LCNB without significant complications. Diagnostic tissue was obtained in all cases. Nineteen of the 27 lesions were subsequently surgically excised. Histopathologic analysis confirmed that iMRI-guided LCNB correctly distinguished benign lesions from malignancy in 18 of the 19 lesions. The histology revealed by core biopsy was partially discrepant with surgical biopsy in 2 of the other 19 lesions. Freehand iMRI-guided LCNB of enhancing breast lesions is promising. Larger studies are needed to determine the smallest lesion that can be sampled reliably and to precisely measure the accuracy of iMRI-guided LCNB as a minimally invasive tool to diagnose suspicious lesions found by breast MRI. J. Magn. Reson. Imaging 2001;13:896-902.

  View details for Web of Science ID 000171296500013

  View details for PubMedID 11382950

• Locally advanced breast cancer: is surgery necessary? breast journal Favret, A. M., Carlson, R. W., Goffinet, D. R., Jeffrey, S. S., Dirbas, F. M., Stockdale, F. E. 2001; 7 (2): 131-137

  Abstract

  A retrospective analysis of the treatment of locally advanced breast cancer (LABC) was undertaken at Stanford Medical Center to assess the outcome of patients who did not undergo surgical removal of their tumors. Between 1981 and 1998, 64 patients with locally advanced breast cancer were treated with induction chemotherapy, radiation with or without breast surgery, and additional chemotherapy. Sixty-two (97%) patients received cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) induction chemotherapy. Induction chemotherapy was followed by local radiotherapy in 59 (92%) patients. Based on the clinical response to chemotherapy and patient preference, 44 (69%) patients received no local breast surgery. Radiotherapy was followed by an additional, non-doxorubicin-containing chemotherapy in all patients. The mean age of patients was 49 years. Of the 65 locally advanced breast cancers in 64 patients, 26 (41%) were stage IIIA, 35 (55%) were stage IIIB, and 4 (6%) were stage IV (supraclavicular lymph nodes only). Response to induction chemotherapy was seen in 59 patients (92%), with 29 (45%) achieving a complete clinical response and 30 (47%) a partial clinical response. With a mean follow-up of 51 months (range 7-187 months), 43 patients (67.2%) have no evidence of recurrent disease. Eight (12.5%) have recurred locally, and 21 (32.8%) have recurred with distant metastasis. Actuarial 5-year survival is 75%, disease-free survival is 58%, and local control rate is 87.5%. These data indicate that the routine inclusion of breast surgery in a combined modality treatment program for LABC does not appear necessary for the majority of patients who experience a response to induction chemotherapy.

  View details for PubMedID 11328324

• Radiofrequency ablation of breast cancer - First report of an emerging technology ARCHIVES OF SURGERY Jeffrey, S. S., Birdwell, R. L., Ikeda, D. M., Daniel, B. L., Nowels, K. W., Dirbas, F. M., Griffey, S. M. 1999; 134 (10): 1064-1068

  Abstract

  Radiofrequency (RF) energy applied to breast cancers will result in cancer cell death.Prospective nonrandomized interventional trial.A university hospital tertiary care center.Five women with locally advanced invasive breast cancer, aged 38 to 66 years, who were undergoing surgical resection of their tumor. One patient underwent preoperative chemotherapy and radiation therapy, 3 patients received preoperative chemotherapy, and 1 had no preoperative therapy. All patients completed the study.While patients were under general anesthesia and just before surgical resection, a 15-gauge insulated multiple-needle electrode was inserted into the tumor under sonographic guidance. Radiofrequency energy was applied at a low power by a preset protocol for a period of up to 30 minutes. Only a portion of the tumor was treated to evaluate the zone of RF ablation and the margin between ablated and nonablated tissue. Immediately after RF ablation, the tumor was surgically resected (4 mastectomies, 1 lumpectomy). Pathologic analysis included hematoxylin-eosin staining and enzyme histochemical analysis of cell viability with nicotinamide adenine dinucleotide-diaphorase (NADH-diaphorase) staining of snap-frozen tissue to assess immediate cell death.Cancer cell death as visualized on hematoxylin-eosin-stained paraffin section and NADH-diaphorase cell viability stains.There was evidence of cell death in all patients. Hematoxylin-eosin staining showed complete cell death in 2 patients. In 3 patients there was a heterogeneous pattern of necrotic and normal-appearing cells within the ablated tissue. The ablated zone extended around the RF electrode for a diameter of 0.8 to 1.8 cm. NADH-diaphorase cell viability stains of the ablated tissue showed complete cell death in 4 patients. The fifth patient had a single focus of viable cells (<1 mm) partially lining a cyst. There were no perioperative complications related to RF ablation.Intraoperative RF ablation results in invasive breast cancer cell death. Based on this initial report of the use of RF ablation in breast cancer, this technique merits further investigation as a percutaneous minimally invasive modality for the local treatment of breast cancer.

  View details for Web of Science ID 000083020900010

  View details for PubMedID 10522847

• Parathyroid localization with high-resolution ultrasound and technetium Tc 99m sestamibi 70th Annual Session of the Pacific-Coast-Surgical-Association Purcell, G. P., Dirbas, F. M., Jeffrey, R. B., Lane, M. J., Desser, T., McDougall, R., Weigel, R. J. AMER MEDICAL ASSOC. 1999: 824–28

  Abstract

  High-resolution ultrasound and technetium Tc 99m sestamibi scanning can be used for preoperative localization of abnormal parathyroid glands in patients with hyperparathyroidism.Ultrasound and sestamibi scanning were performed in patients undergoing neck exploration for hyperparathyroidism. If the 2 scans agreed in identifying a single adenoma, and surgery confirmed the location of a single adenoma and an ipsilateral normal gland, a unilateral exploration was performed.University tertiary care center.Sixty-one consecutive patients undergoing surgery for hyperparathyroidism from September 1, 1994, through September 30, 1997.High-resolution ultrasound was performed in 59 patients and sestamibi scanning in 58 patients; all patients underwent neck exploration by a single surgeon.The results of preoperative ultrasound and sestamibi scanning were compared with operative and histological findings.All patients were cured of hypercalcemia. Specificity of ultrasound and sestamibi scanning was 98% and 99%, respectively; however, their sensitivity was only 57% and 54%, respectively. Both imaging modalities had lower sensitivities in the setting of multigland disease. If both imaging studies were considered as a single test, sensitivity for imaging in patients with primary hyperparathyroidism reached 78%. Our localization protocol allowed a unilateral approach in 43% of patients (23 of 53).These results confirm the value of preoperative localization in patients with hyperparathyroidism. A unilateral approach can be used with a high degree of success in cases when ultrasound and sestamibi scanning agree in the identification of a single adenoma confirmed by surgical exploration with the identification of a normal ipsilateral gland.

  View details for Web of Science ID 000081876300006

  View details for PubMedID 10443804

• Perforated jejunal diverticula Southeastern-Surgical-Congress 63rd Annual Scientific Meeting and Postgraduate Course Program Koger, K. E., Shatney, C. H., Dirbas, F. M., McClenathan, J. H. SOUTHEASTERN SURGICAL CONGRESS. 1996: 26–29

  Abstract

  Jejunal diverticular (JD) perforation is an uncommon cause of acute abdominal pain in the elderly. From 1971 to 1994 we treated 13 such patients, 9 men and 4 women, with a mean age of 68 years. All patients experienced sudden onset of abdominal pain, nausea and vomiting, and leukocytosis (range of white blood cell counts, 14,000-21,000). On physical examination, three patients had localized peritonitis, were thought to have appendicitis, and underwent immediate laparotomy and segmental jejunal resection for perforated JD. The remaining 10 patients had abdominal tenderness without peritoneal signs. They were hospitalized and managed expectantly. All experienced worsening signs and symptoms and underwent exploratory laparotomy and resection of the involved jejunal segment 13 hours to 8 days after admission. Although 6 of 13 patients had had JD documented previously, in only 2 patients was perforated JD diagnosed preoperatively. In 8 of 13 patients peritoneal contamination was minimal and was contained within the leaves of the mesentery. Soilage was severe with abscess formation in 5 patients. The longer the delay in operative intervention, the greater the peritoneal soilage. The 3 patients undergoing immediate surgery had minimal contamination. Of the 10 patients initially observed, the mean interval before operation was 74 hours in the 5 patients with severe soilage versus 21 hours in those with minimal contamination. The postoperative course was uneventful in 11 patients. Two patients died. Surgical consultation was delayed (8 days, 12 days) in both patients, who had severe peritoneal contamination and died of sepsis. In conclusion, JD perforation is an uncommon and frequently overlooked cause of acute abdominal pain in elderly patients. Timely operative intervention and resection of the involved jejunum are the keys to a successful outcome. Because the presentation and physical findings of perforated JD can be highly variable, a history of preexisting JD should arouse suspicion for JD perforation as the etiology of acute abdominal pain in the elderly.

  View details for Web of Science ID A1996TM58900005

  View details for PubMedID 8540641

• HUMANIZED ANTIBODY-DIRECTED TO THE IL-2 RECEPTOR BETA-CHAIN PROLONGS PRIMATE CARDIAC ALLOGRAFT SURVIVAL JOURNAL OF IMMUNOLOGY TINUBU, S. A., Hakimi, J., KONDAS, J. A., Bailon, P., Familletti, P. C., Spence, C., Crittenden, M. D., Parenteau, G. L., Dirbas, F. M., Tsudo, M., BACHER, J. D., KASTENSPORTES, C., MARTINUCCI, J. L., Goldman, C. K., Clark, R. E., Waldmann, T. A. 1994; 153 (9): 4330-4338

  Abstract

  IL-2Rs are expressed by T cells activated in response to foreign histocompatibility Ags but not by normal cells. This difference in IL-2R expression is exploited by blockade of IL-2Rs to achieve immunosuppression. High affinity IL-2Rs involve three subunits, IL-2R alpha, IL-2R beta, and IL-2R gamma. Murine Mik beta 1, a mAb that blocks IL-2 binding to IL-2R beta, was developed as an immunosuppressive agent. There was modest prolongation of cynomolgus cardiac allograft survival in animals treated with murine Mik beta 1 (mean survival 11.8 +/- 1.6 days compared with 8.2 +/- 0.4 days in untreated animals; p = 0.06). However, murine Mik beta 1 is ineffective in recruiting primate effector cells and is neutralized by monkey Abs directed toward the infused Ab. To circumvent these limitations, a humanized form of Mik beta 1, which is a largely human IgG1k Ab, except that murine hypervariable regions are retained, was developed. In vivo plasma survival of humanized Mik beta 1 was threefold longer than simultaneously administered murine Mik beta 1 (terminal t1/2, 104 +/- 10 h vs 37 +/- 2 h). Furthermore, humanized Mik beta 1 manifests Ab-dependent cellular cytotoxicity, an activity that is absent with the parental murine Mik beta 1. Graft survival was significantly prolonged by humanized Mik beta 1 treatment with survivals of 22, 22, 24, 27, 44, and > 300 days (p vs control < 0.01; p vs murine Mik beta 1 < 0.01). Survival was not prolonged further (p > 0.3) by the addition of humanized anti-Tac, which blocks interaction of IL-2 with IL-2R alpha subunits. There was no toxicity attributable to the use of Mik beta 1 Abs. Thus, humanized Mik beta 1 prolonged cardiac allograft survival in primates without toxicity and may be effective as an adjunct to standard immunosuppressive therapy.

  View details for Web of Science ID A1994PN07100049

  View details for PubMedID 7930631

• PROLONGATION OF GRAFT-SURVIVAL IN PRIMATE ALLOGRAFT TRANSPLANTATION BY YTTRIUM-90-LABELED ANTI-TAC IN CONJUNCTION WITH GRANULOCYTE COLONY-STIMULATING FACTOR TRANSPLANTATION Parenteau, G. L., Dirbas, F. M., Garmestani, K., Brechbiel, M. W., BUKOWSKI, M. A., Goldman, C. K., Clark, R., Gansow, O. A., Waldmann, T. A. 1992; 54 (6): 963-968

  Abstract

  High-affinity IL-2 receptors are expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting T cells. To exploit this difference in IL-2R expression, anti-Tac, a murine monoclonal antibody specific for the IL-2R alpha subunit, was used to inhibit organ allograft rejection. To enhance its effector function, anti-Tac was armed by chelation with yttrium-90, a pure beta-emitting radionuclide. Animals received no immunosuppression (n = 5, group I, controls), unmodified anti-Tac (n = 5, 1 mg/kg q.o.d., group II), or 90Y-anti-Tac (n = 5, 1.6 mCi/kg divided into four doses, group III). The animals in group IV (n = 4) were treated identically to those in group III with the exception that 5 micrograms/kg/dose of granulocyte colony-stimulating factor was administered intramuscularly on the days when the yttrium-90 was given and on postoperative days 12 through 35 in order to reduce hematopoietic toxicity. Mean graft survival +/- S.E.M. for the control group was 8.2 +/- 0.5 days as compared with 13.8 +/- 2.1 days (P < 0.05) for those monkeys treated with unmodified anti-Tac. Graft survival was further prolonged in animals of group III that received 90Y-anti-Tac, with a mean graft survival of 45.0 +/- 11.8 days; however, three of the five monkeys retained viable grafts within this group but died secondary to bone marrow suppression. In comparison, the monkeys in group IV that were treated with G-CSF in conjunction with 90Y-anti-Tac had a mean graft survival of 49.2 +/- 2.9 days. In contrast to group III there were no deaths in the group (IV) receiving G-CSF. Furthermore, animals in group IV had a reduced magnitude and shortened duration of irradiation-induced neutropenia when compared with that observed in group III animals that did not receive G-CSF. Thus, treatment with 90Y-anti-Tac in conjunction with G-CSF may have potential applications in organ transplantation and the treatment of IL-2 receptor-expressing neoplastic diseases.

  View details for Web of Science ID A1992KD06200004

  View details for PubMedID 1281566

• ANTI-TAC-H, A HUMANIZED ANTIBODY TO THE INTERLEUKIN-2 RECEPTOR, PROLONGS PRIMATE CARDIAC ALLOGRAFT SURVIVAL PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Brown, P. S., Parenteau, G. L., Dirbas, F. M., Garsia, R. J., Goldman, C. K., BUKOWSKI, M. A., Junghans, R. P., Queen, C., Hakimi, J., BENJAMIN, W. R., Clark, R. E., Waldmann, T. A. 1991; 88 (7): 2663-2667

  Abstract

  High-affinity interleukin 2 receptors (IL-2Rs) are expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting T cells. To exploit this difference in IL-2R expression, anti-Tac-M, a murine monoclonal antibody specific for the IL-2R alpha chain, was used to inhibit organ allograft rejection. However, the use of murine anti-Tac as an immunosuppressive agent was limited by neutralization by human anti-murine antibodies and by weak recruitment of effector functions. To circumvent these difficulties, a humanized antibody to the IL-2R, anti-Tac-H, was prepared. This molecule is human with the exception of the hypervariable segments, which are retained from the mouse. In vivo survival of anti-Tac-H is 2.5-fold longer than simultaneously administered anti-Tac-M (terminal t1/2, 103 hr vs. 38 hr). In addition, anti-Tac-H is less immunogenic than anti-Tac-M when administered to cynomolgus monkeys undergoing heterotopic cardiac allografting. Specifically, all monkeys treated with anti-Tac-M developed measurable anti-anti-Tac-M levels by day 15 (mean onset, 11 days). In contrast, none of the animals receiving anti-Tac-H produced measurable antibodies to this monoclonal antibody before day 33. Finally, there was a prolongation of graft survival in the cynomolgus heterotopic cardiac allograft model in animals receiving anti-Tac. In animals that received anti-Tac-M, the allograft survival was prolonged compared to that of the control group (mean survival, 14 +/- 1.98 days compared to 9.2 +/- 0.48 days; P less than 0.025). Graft survival was further prolonged by anti-Tac-H with a mean survival of 20.0 +/- 0.55 days (compared to controls, P less than 0.001; compared to anti-Tac-M, P less than 0.02). There was no toxicity attributable to the administration of either form of anti-Tac. Thus, anti-Tac-H significantly prolonged allograft survival in primates, without toxic side effects, and may be of value as an adjunct to standard immunosuppressive therapy in humans.

  View details for Web of Science ID A1991FE86400011

  View details for PubMedID 2011577

• DISSEMINATED CUTANEOUS HERPES-ZOSTER FOLLOWING CARDIAC-SURGERY JOURNAL OF CARDIOVASCULAR SURGERY Dirbas, F. M., Swain, J. A. 1990; 31 (4): 531-532

  Abstract

  Our case report describes disseminated cutaneous Herpes Zoster in the early post-operative period following cardiac surgery with cardiopulmonary bypass. This has not been reported previously in the absence of immunosuppressive therapy. Despite associated neurologic and respiratory impairment, our patient was treated successfully with intravenous Acyclovir and subsequently discharged.

  View details for Web of Science ID A1990DY91000023

  View details for PubMedID 2211810

• CONTROLLED REPERFUSION FOLLOWING REGIONAL ISCHEMIA ANNALS OF THORACIC SURGERY Lazar, H. L., Wei, J., Dirbas, F. M., Haasler, G. B., Spotnitz, H. M. 1987; 44 (4): 350-355

  Abstract

  The ability to reverse acute coronary occlusion with fibrinolytic agents and percutaneous transluminal angioplasty has increased interest in the revascularization of ischemic myocardium. This study defines changes in global ventricular function, mass, and compliance during acute coronary occlusion and following reperfusion with blood in the beating and arrested heart. In 17 dogs on cardiopulmonary bypass, the proximal left anterior descending coronary artery was occluded for 45 minutes. In 12 dogs, flow was reestablished by releasing the coronary snare in the beating heart. In the other 5 dogs, the snare was released during a continuous 10-minute infusion of blood potassium cardioplegia in the arrested heart. Coronary occlusion resulted in significant decreases in stroke work index and left ventricular (LV) mass, but compliance was unchanged. Reperfusion in the beating heart increased LV mass compared with the values measured before ischemia (104 +/- 5 versus 95 +/- 5 gm; p less than 0.05) and decreased LV compliance (39 +/- 4 versus 53 +/- 4 ml at LV end-diastolic pressure of 8 mm Hg; p less than 0.05). In contrast, with blood cardioplegia-based reperfusion in the arrested heart, LV mass and LV compliance remained unchanged from control values. We conclude that revascularization of acutely ischemic myocardium in the beating heart further impairs LV function by increasing LV mass and decreasing compliance. This damage can be avoided by reperfusion with blood cardioplegia in the arrested heart.

  View details for Web of Science ID A1987K491900004

  View details for PubMedID 3662681

• CONTROLLED REPERFUSION OF REGIONAL ISCHEMIA SURGICAL FORUM Lazar, H. L., Wei, J., Dirbas, F. M., Spotnitz, H. M. 1983; 34: 257-258

  View details for Web of Science ID A1983RX76000104

• EXPERIMENTS ON THE ABIOTIC AMPLIFICATION OF OPTICAL-ACTIVITY ORIGINS OF LIFE AND EVOLUTION OF BIOSPHERES Bonner, W. A., Blair, N. E., Dirbas, F. M. 1981; 11 (1-2): 119-134

  Abstract

  Our earlier experiments are briefly reviewed, involving the abiotic generation of optical activity by exposure of DL-amino acids to various "chiral" physical forces. The enantiomeric enrichments so obtained were low, however, and additional experiments were undertaken with the objective of abiotically enhancing such small enantiomeric excesses. D not equal to L Mixtures of leucine N-carboxy anhydride gave enantiomerically enriched polymers on partial polymerization, while valine NCA mixtures behaved oppositely. Leucine polymers were also found to hydrolyze stereoselectively, providing for additional enantiomeric enhancement. A repetitive sequence of partial polymerization-hydrolysis steps is suggested as a possible mechanism for the abiotic genesis of optically enriched polypeptides on the primitive Earth.

  View details for Web of Science ID A1981LJ65100011

  View details for PubMedID 7231975

• STEREOSELECTIVE HYDROLYSIS OF LEUCINE OLIGOMERS TETRAHEDRON Blair, N. E., Dirbas, F. M., Bonner, W. A. 1981; 37 (1): 27-29

  View details for Web of Science ID A1981LD05600004