Suzanne Klimberg

Society of Surgical Oncology–American Society for Radiation Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Stages I and II Invasive Breast Cancer

PURPOSE Controversy exists regarding the optimal margin width in breast-conserving surgery for invasive breast cancer. METHODS A multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 33 studies including 28,162 patients as the primary evidence base for consensus. RESULTS Positive margins (ink on invasive carcinoma or ductal carcinoma in situ) are associated with a two-fold increase in the risk of IBTR compared with negative margins. This increased risk is not mitigated by favorable biology, endocrine therapy, or a radiation boost. More widely clear margins do not significantly decrease the rate of IBTR compared with no ink on tumor. There is no evidence that more widely clear margins reduce IBTR for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component. CONCLUSION The use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. J Clin Oncol 32. 2014 American Society of Clinical Oncology®, American Society for Radiation Oncology®, and Society of Surgical Oncology®. All rights reserved. No part of this document may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by the American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology.

Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer.

PurposeControversy exists regarding the optimal margin width in breast-conserving surgery for invasive breast cancer.MethodsA multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 33 studies including 28,162 patients as the primary evidence base for consensus.ResultsPositive margins (ink on invasive carcinoma or ductal carcinoma in situ) are associated with a two-fold increase in the risk of IBTR compared with negative margins. This increased risk is not mitigated by favorable biology, endocrine therapy, or a radiation boost. More widely clear margins than no ink on tumor do not significantly decrease the rate of IBTR compared with no ink on tumor. There is no evidence that more widely clear margins reduce IBTR for young patients or for those with unfavorable biology, lobular cancers, or cancers with an extensive intraductal component.ConclusionThe use of no ink on tumor as the standard for an adequate margin in invasive cancer in the era of multidisciplinary therapy is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs.

Comprehensive geriatric assessment of risk factors associated with adverse outcomes and resource utilization in cancer patients undergoing abdominal surgery

The purpose of this prospective study was to identify risk factors for adverse outcomes or increased resource utilization after abdominal cancer surgery in geriatric patients.

In vitro induction of tumor-specific HLA class I-restricted CD8+ cytotoxic T lymphocytes from patients with locally advanced breast cancer by tumor antigen-pulsed autologous dendritic cells.

BACKGROUND Early dissemination of treatment-resistant tumor cells remains the major cause of metastatic recurrence and death in breast cancer patients. Dendritic cells (DCs) are the most powerful antigen-presenting cells, and recently DC-based vaccination has shown great promise for the treatment of human malignancies by immunological intervention. MATERIALS AND METHODS CD8+ T lymphocytes derived from peripheral blood mononuclear cells stimulated in vitro with autologous breast tumor antigen-pulsed DCs were tested for their ability to induce a HLA class I restricted cytotoxic T lymphocyte (CTL) response against autologous tumor cells. To correlate cytotoxic activity by CTL with T cell phenotype, two-color flow cytometric analysis of surface markers and intracellular cytokine expression was performed. RESULTS DC pulsed with breast tumor extracts consistently elicited a tumor-specific HLA class I restricted CTL response in vitro in three consecutive patients harboring locally advanced breast cancer. CTL expressed strong cytolytic activity against autologous tumor cells but did not lyse autologous Epstein Barr virus-transformed lymphoblastoid cell lines and showed variable cytotoxicity against the natural killer-sensitive cell line K-562. In all patients, two color flow cytometric analysis of surface markers and intracellular cytokine expression demonstrated that tumor-specific CTL exhibited an heterogeneous CD8+/CD56+ expression and a striking Th1 cytokine bias (IFNgamma(high)/IL-4 (low)). CONCLUSIONS Tumor lysate-pulsed DCs can consistently stimulate specific CD8+ CTLs able to kill autologous tumor cells in patients with locally advanced breast cancer in vitro. Tumor antigen-pulsed DC-based vaccinations may be appropriate for the treatment of residual and/or chemotherapy-resistant breast cancer refractory to standard salvage treatment modalities.

Comparison between Freeze-dried and Ready-to-use AlloDerm in Alloplastic Breast Reconstruction

Background: AlloDerm, a brand of acellular dermal matrix, is commonly used as an internal hammock to support the tissue expander or permanent implant in breast reconstruction. The aim of our study is to evaluate the complication rates associated with the freeze-dried (FD) AlloDerm and the ready-to-use (RTU) AlloDerm. Methods: This institutional review board–approved retrospective study involved 103 patients who underwent immediate postmastectomy breast reconstructions from June 2011 to August 2012. The first 51 patients underwent 96 immediate breast reconstructions with FD AlloDerm. The subsequent 52 patients underwent 100 immediate breast reconstructions with RTU AlloDerm. Patient demographics, postoperative complication rates in study cohort, and complication rates stratified by body mass index (BMI) were analyzed. Results: Multiple patient demographics in the 2 cohorts are closely matched (P > 0.05). RTU AlloDerm was associated with higher rates of seroma and cellulitis compared with FD AlloDerm (22.0% vs 18.8%, P = 0.599 and 21.0% vs 12.5%, P = 0.129, respectively). Significantly higher rates of seroma and cellulitis were found in patients with BMI ≥ 30 compared with BMI < 30 (34.5% vs 9.2%, P < 0.001 and 29.9% vs 6.4%, P < 0.001, respectively). A generalized linear mixed model shows that obesity and RTU AlloDerm are statistically significant predictors of cellulitis (adjusted odds ratio = 10.413, P < 0.001 and adjusted odds ratio = 3.712, P = 0.011, respectively). Conclusions: Our study demonstrates a clinically higher postoperative complication rate in immediate breast reconstruction with RTU AlloDerm compared with FD AlloDerm and highlights the unfavorable risk factor correlation with significant obesity.

Are “Breast-Focused” Surgeons More Competent?

Breast cancer affects 1 in 8 women today.1 The treatment of breast diseases comprises 14–25% of general surgeons’ practice volume.2,3 Yet, approximately half of all general surgeons perform only two or fewer breast cases per month. Unquestionably, long-term survival after surgery for breast cancer depends upon stage.4 More recently, survival has been linked to performance measures. For instance, survival is greater at hospitals performing greater than 125–150 breast cancer surgeries per year.5–8 Additionally, survival is greater if surgeons perform greater than 15 breast cancer operations per year.8 Finally, completion of a surgical oncology fellowship resulted in a 36% reduction in the risk of death at 5 years when controlled for hospital volume, surgeon volume, age, stage, and race.8–10 Can one infer from these studies that “breast-focused” surgeons are more competent? The criticisms of these studies have been that they often emanate from authors who may be prejudiced toward the results. In fact, there is an observation that, if a surgeon works in a hospital with a cancer center designation, the results from the treatment of breast cancer are not based on any specific surgical or breast disease training other than the general surgical residence.8 The implication would be that the multimodality approach to the treatment of the disease is the reason for any increased survival rather than the judgmental or technical expertise of the surgeon.

Restoration of tumor-specific HLA class I restricted cytotoxicity in tumor infiltrating lymphocytes of advanced breast cancer patients by in vitro stimulation with tumor antigen-pulsed autologous dendritic cells.

Breast tumor infiltrating lymphocytes (TIL) are enriched in tumor-specific cytotoxic T lymphocytes (CTL), and may represent a superior source of CTL compare to peripheral blood lymphocytes (PBL), for adoptive T cell immunotherapy of breast cancer. However, the immunocompetence of TIL and the possibility to consistently restore their tumor-specific lytic activity in vitro remains an open issue. In this study we evaluated the potential of tumor antigen-pulsed fully mature dendritic cell (DC) stimulation in restoring tumor-specific cytotoxicity in anergic TIL populations from advanced breast cancer patients. In addition we have compared tumor-specific T cell responses induced by tumor antigen-loaded DC stimulation of TIL to responses induced from PBL. Although TIL were consistently non-cytotoxic after isolation or culture in the presence of interleukin-2 (IL-2), in matched experiments from three consecutive patients, tumor-lysate-pulsed DC-stimulated CD8+ T cell derived from TIL were found to be significantly more cytotoxic than PBL (p < 0.05). In addition, cytotoxicity against autologous tumor cells was more significantly inhibited by an anti-HLA class I (W6/32) MAb in TIL compared to PBL (p < 0.05). CTL populations derived from TIL and PBL did not lyse autologous EBV-transformed lymphoblastoid cell lines, and showed negligible cytotoxicity against the NK-sensitive cell line K562. Furthermore, in both CD8+ T cell populations the majority of the tumor-specific CTL exhibited a Th1 cytokine bias (IFN-γhigh/IL-4low). Taken together, these data show that tumor lysate-pulsed mature DC can consistently restore tumor-specific lytic activity in non-cytotoxic breast cancer TIL. These results may have important implications for the treatment of chemotherapy resistant breast cancer with active or adoptive immunotherapy.

Assessment of Proliferating Cell Nuclear Antigen Activity Using Digital Image Analysis in Breast Carcinoma Following Magnetic Resonance‐Guided Interstitial Laser Photocoagulation

Abstract:  This study examines proliferative activity in tumor cells of patients with histologically documented invasive breast carcinoma treated with magnetic resonance‐guided interstitial laser photocoagulation (MR‐GILP). Immunohistochemical marker for proliferating cell nuclear antigen (PCNA), a nuclear protein abundant in actively proliferating cells, is used. The study demonstrates the effectiveness of MR‐GILP in ablating tumor cells of infiltrating breast cancer. The diagnosis of infiltrating breast carcinoma was confirmed by core needle biopsies. Using a specially designed magnetic resonance imaging (MRI) device, rotating delivery of excitation off‐resonance (RODEO), tumors were measured ranging from 1.8 to 4.0 cm in greatest dimension. Seven formalin‐fixed, paraffin‐embedded archival tissues from seven patients with infiltrating carcinoma, status post‐MR‐GILP, were analyzed. Using PCNA immunoperoxidase (Biomeda Corp.), the proliferative capability of the remaining tumor cells around the focus of laser photocoagulation was determined. The lesions were digitally acquired using a Nikon Eclipse E800 microscope with an automated stage. Images were analyzed using Cool SNAP image editing software (version 1.0). Appropriate thresholds were set for positive staining and limited concentric radial measurements of equal area between all samples were compared at radial millimeter intervals from the center of laser ablation. The integrated area occupied by PCNA‐positive cells per radial millimeter from the charcoal site (the center of the laser) increased as the distance from this site increased (a mean average at each radial measurement revealed: at the 1 mm radius the positive integrated area was 0.0024 mm2; at 2 mm, 0.0145 mm2; at 3 mm, 0.0351 mm2; at 4 mm, 0.0696 mm2; at 5 mm, 0.1025 mm2; and at 6 mm, 0.1263 mm2). MR‐GILP is an effective mean of ablating breast carcinoma. This treatment option may represent an alternative to lumpectomy for a single lesion ≤1 cm, or make patients with two separate lesions eligible for lumpectomy.

Racial disparity in colorectal cancer: the role of equal treatment.

BACKGROUND: Racial disparity exists in colorectal cancer outcomes. The reasons for this are multifactorial. OBJECTIVE: The aim of this study was to evaluate the role of equal treatment of blacks and whites in the elimination of racial disparity in colorectal cancer outcomes. DESIGN: A retrospective cohort study of 878 patients with colorectal cancer diagnosed between 1998 and 2008 was done at a University tertiary referral center. Demographic variables including age, sex, and race were abstracted. Tumor-specific variables including American Joint Committee on Cancer stage, anatomic tumor location, vital status, and survival were obtained. Treatment-specific variables including surgery, chemotherapy, radiotherapy, and follow-up were also obtained. Racial differences in these variables were studied and their effect on overall survival was determined by using univariate and multivariate analyses. The findings were then compared with previous data from our institution. SETTING: University tertiary referral center. MAIN OUTCOME MEASURES: The primary outcomes measured were overall survival and cancer-specific mortality. RESULTS: A total of 878 patients met the inclusion criteria, 186 (21.2%) of whom were black. Blacks were significantly younger at diagnosis in comparison with whites, with a median (quartiles) age of 55 years (28–87) compared with 59 years (23–94) (p = 0.0012). Equal proportions of blacks (78.5%) and whites (79.2%) underwent surgery (p = 0.84), similar proportions of blacks (55.4%) and whites (60.8%) received chemotherapy (p = 0.18), and similar proportions of blacks (17.2%) and whites (20.5%) received radiation therapy (p = 0.31). There was no difference in overall survival or cancer-specific mortality between the 2 racial groups. Univariate analysis showed American Joint Committee on Cancer stage and surgery as the only statistically significant factors for overall survival. On multivariate analysis, stage, surgery, and chemotherapy were the only statistically significant factors. Race was not an independent determinant of survival. CONCLUSIONS: There were no differences in overall survival and cancer-related mortality between blacks and whites, and this may have resulted from identical treatment. The previously noted disparities in treatment and overall survival at our institution have disappeared.

Conductive interstitial thermal therapy (CITT) device evaluation in VX2 rabbit model.

We have developed a conductive interstitial thermal therapy (CITT) device to precisely and reliably deliver controlled thermal doses to the surgical margins at the cavity site following tumor resection, intraoperatively. The temperature field created by CITT ablation of a perfused tissue was modeled with a finite element package Femlab™. The modeling suggested that a maximum probe temperature of 120°C and an ablation time of 20 minutes were required to ablate highly perfused tissue such as the VX2 carcinoma. Deployable pins enable faster and more reliable thermal ablation. The model predictions were tested by thermal ablation of VX2 carcinoma tumors implanted in adult New Zealand rabbits. The size of the ablated region was confirmed with a viability stain, triphenyltetrazolium chloride (TTC). Histopathological examination revealed 3 regions in the ablated area: a carbonized region (1–3 mm); a region that contained thermally fixed cells; and an area of coagulated necrosis cells. Cells in the thermally fixed region stained for PCNA (proliferating cell nuclear antigen) and were bounded by the carbonized layer at the cavity wall, and by necrotic cells that exhibit nuclear fragmentation and cell dissociation, 5 to 10 mm away from the CITT probe. Adjacent tissue outside the target region was spared with a clear demarcation between ablated and normal viable tissue. It is suggested that the CITT device can be used, clinically, to inhibit local recurrence by creating negative surgical margins following the resection of a primary tumor in non-metastatic early staged tumors.