Irene Wapnir, MD

Abstract

PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Antibodies targeting PD-1/PD-L1 have entered the therapeutic landscape in TNBC, but only a minority of patients benefit. A way to reliably enhance immunogenicity, T cell infiltration, and predict responsiveness is critically needed.EXPERIMENTAL DESIGN: Utilizing mouse models of TNBC, we evaluate immune activation and tumor targeting of intratumoral IL-12 plasmid followed by electroporation (tavokinogene telseplasmid; Tavo). We further present a single arm, prospective clinical trial of Tavo monotherapy in patients with treatment refractory, advanced TNBC (OMS-I140). Finally, we expand these findings using publicly available breast cancer and melanoma data sets.RESULTS: Single cell RNA sequencing of murine tumors identified a CXCR3 gene signature (CXCR3-GS) following Tavo treatment associated with enhanced antigen presentation, T cell infiltration and expansion, and PD-1/PD-L1 expression. Assessment of pre- and post-treatment tissue from patients confirms enrichment of this CXCR3-GS in tumors from patients that exhibited an enhancement of CD8+ T cell infiltration following treatment. One patient, previously unresponsive to anti-PD-L1 therapy, but who exhibited an increased CXCR3-GS after Tavo treatment, went on to receive additional anti-PD-1 therapy as their immediate next treatment after OMS-I140, and demonstrated a significant clinical response.CONCLUSIONS: These data show a safe, effective intratumoral therapy that can enhance antigen presentation and recruit CD8 T cells, which are required for the anti-tumor efficacy. We identify a Tavo treatment-related gene signature associated with improved outcomes and conversion of non-responsive tumors, potentially even beyond TNBC.

View details for DOI 10.1158/1078-0432.CCR-20-3944

View details for PubMedID 33593880

Abstract

Nipple-sparing mastectomy (NSM) and autologous breast reconstruction are associated with higher patient satisfaction, quality of life, and aesthetic outcome. For patients with naturally ptotic breasts, this ideal reconstructive treatment of NSM and autologous breast reconstruction poses a challenge. We describe our experience in treating patients with ptotic natural breasts using a 2-staged approach: oncoplastic breast reduction in the first stage followed by nipple-sparing mastectomy and immediate autologous reconstruction in a second stage.We reviewed cases of patients with grade III ptosis who underwent a staged reconstruction approach with reduction mammaplasty followed by NSM and immediate reconstruction with an abdominally based free flap (2014-2019). We compared this group of patients to a second group who underwent staging with a technique of nipple-areola complex (NAC) devascularization. A survey was administered to assess for patient satisfaction and aesthetic outcome 1 year after the second stage procedure.Eight patients were identified in our reduction group, and 9 patients were identified in our devascularization group. No cases of total NAC necrosis were noted in either group (0%). Two cases of partial NAC necrosis were noted in the devascularization group (11%), whereas none were observed in the reduction group. All patients were satisfied with final outcome (100%, P = 1.0). Aesthetic scores across all factors were higher in the reduction group. Scores for overall outcome (4.6 vs 3.7, P = 0.04), natural appearance (4.8 vs 3.8, P = 0.01), breast contour (4.8 vs 3.2, P = 0.002), and position of breasts (5.0 vs 3.9, P = 0.03) were significantly higher in the reduction group.Breast ptosis no longer represents a contraindication for patients desiring nipple-sparing mastectomy and immediate autologous reconstruction. This series supports the use of a 2-staged approach with reduction mammaplasty in patients with naturally ptotic breasts. A staged reduction approach may offer fewer NAC complications while also allowing for superior aesthetic outcomes.

View details for DOI 10.1097/SAP.0000000000002725

View details for PubMedID 33470622

View details for DOI 10.1136/jitc-2020-SITC2020.0789

View details for Web of Science ID 000616665301301

View details for Web of Science ID 000582792300413

View details for DOI 10.1158/1538-7445.SABCS19-OT3-09-04

View details for Web of Science ID 000527012500151

View details for DOI 10.1245/s10434-019-07419-3

View details for Web of Science ID 000474357200022

View details for Web of Science ID 000473833600035

View details for Web of Science ID 000467382700224

View details for Web of Science ID 000467382700043

View details for Web of Science ID 000467382700020

View details for DOI 10.1001/jama.2018.21596

View details for Web of Science ID 000461683500026

View details for DOI 10.1056/NEJMoa1814017

View details for Web of Science ID 000458612900005

View details for DOI 10.1158/1538-7445.SABCS18-P2-09-11

View details for Web of Science ID 000478677001049

View details for DOI 10.4300/JGME-D-19-00002.1

View details for PubMedID 30805095

View details for PubMedCentralID PMC6375331

Abstract

Idiopathic granulomatous mastitis (IGM) is a disfiguring inflammatory breast disease without effective treatment. We report the largest IGM cohort treated with methotrexate monotherapy.Chart review was performed on patients evaluated by the Rheumatology Clinic, with histopathologically-established IGM, treated with methotrexate, and at least one follow up appointment.Nineteen female patients with an mean age of 33.5 years were identified. Most failed treatment with antibiotics, prednisone, and surgical intervention. By 15 months of treatment with methotrexate, 94% had disease improvement and 75% achieved disease remission.Methotrexate monotherapy is an effective treatment for IGM.

View details for DOI 10.3899/jrheum.181205

View details for PubMedID 31203215

View details for Web of Science ID 000456311000004

View details for DOI 10.1001/jama.2018.13080

View details for Web of Science ID 000448069100009

View details for Web of Science ID 000433587300141

Abstract

Purpose Isolated locoregional recurrence (ILRR) predicts a high risk of developing breast cancer distant metastases and death. The Chemotherapy as Adjuvant for LOcally Recurrent breast cancer (CALOR) trial investigated the effectiveness of chemotherapy (CT) after local therapy for ILRR. A report at 5 years of median follow-up showed significant benefit of CT for estrogen receptor (ER)-negative ILRR, but additional follow-up was required in ER-positive ILRR. Patients and Methods CALOR was an open-label, randomized trial for patients with completely excised ILRR after unilateral breast cancer. Eligible patients were randomly assigned to receive CT or no CT and stratified by prior CT, hormone receptor status, and location of ILRR. Patients with hormone receptor-positive ILRR received adjuvant endocrine therapy. Radiation therapy was mandated for patients with microscopically involved margins, and anti-human epidermal growth factor receptor 2 therapy was optional. End points were disease-free survival (DFS), overall survival, and breast cancer-free interval. Results From August 2003 to January 2010, 162 patients were enrolled: 58 with ER-negative and 104 with ER-positive ILRR. At 9 years of median follow-up, 27 DFS events were observed in the ER-negative group and 40 in the ER-positive group. The hazard ratios (HR) of a DFS event were 0.29 (95% CI, 0.13 to 0.67; 10-year DFS, 70% v 34%, CT v no CT, respectively) in patients with ER-negative ILRR and 1.07 (95% CI, 0.57 to 2.00; 10-year DFS, 50% v 59%, respectively) in patients with ER-positive ILRR ( Pinteraction = .013). HRs were 0.29 (95% CI, 0.13 to 0.67) and 0.94 (95% CI, 0.47 to 1.85), respectively, for breast cancer-free interval ( Pinteraction = .034) and 0.48 (95% CI, 0.19 to 1.20) and 0.70 (95% CI, 0.32 to 1.55), respectively, for overall survival ( Pinteraction = .53). Results for the three end points were consistent in multivariable analyses adjusting for location of ILRR, prior CT, and interval from primary surgery. Conclusion The final analysis of CALOR confirms that CT benefits patients with resected ER-negative ILRR and does not support the use of CT for ER-positive ILRR.

View details for PubMedID 29443653

View details for PubMedCentralID PMC5891132

Abstract

Sentinel lymph node (SLN) resection is imperative for breast cancer staging. Axillary reverse mapping (ARM) can preserve arm draining nodes and lymphatics during surgery. ARM is generally performed with isosulfan blue (ISB), restricting its use for concurrent SLN biopsy. Indocyanine green (ICG) could serve as an alternative to ISB for ARM procedures.SLN mapping and biopsy was performed via periareolar injection of 99 technetium-sulfur colloid (99m TcSc, TSC). ISB and ICG were injected in the upper arm. Blue-stained lymphatics or nodes were visualized in the axilla; ICG was identified using the SPY Elite system.Twenty-three patients underwent SLN biopsy with or without axillary node dissection and ARM procedures. Twenty of these patients had at least one hot node; 12 patients had SLNs that were only hot, 6 hot/blue/fluorescent, and 2 hot/fluorescent. Overall, crossover of ARM agents with SLNs occurred in 8 cases. Inspection of the axillary cavity after SLN biopsy revealed fluorescent lymphatics and nodes remaining in 14 and 7 patients, respectively. Blue lymphatics and blue nodes were detected in fewer cases.Nearly one-third of patients showed crossover between breast and arm draining nodes, which provides insight as to why some patients develop lymphedema symptoms after SLN biopsy. ICG and ISB identify similar numbers of SLNs. As such ICG could substitute for ISB in ARM procedures.

View details for PubMedID 29228459

Abstract

Purpose: Disparities in surgical breast cancer care have been documented for racial and ethnic minorities. On average, these minorities are less likely to utilize National Cancer Institute (NCI)-designated cancer centers and travel shorter distances to receive care. With the growing population of Hispanic patients in California, we analyzed the travel distance and surgical care of Hispanic and non-Hispanic patients at our large referral cancer center. Methods: Patients included were those who initiated treatment for a new diagnosis of ductal carcinoma in situ or invasive breast cancer at our NCI-designated cancer center during the period 2010-2014. Ethnicity was dichotomized as Hispanic and non-Hispanic. Google Maps were used to determine the distance from patient zip code to our institution, classified as 0-10, 10-30, 30-60, and >60 miles. Results: A total of 1765 non-Hispanic and 173 Hispanic patients were identified. Clinical stage by tumor size and nodal status were comparable between the two groups. Hispanic patients were younger (p<0.001) and more had Medicaid insurance (p<0.001). Hispanic patients traveled further when compared with non-Hispanics (p<0.001). In non-Hispanics and Hispanics, rates of breast conservation were 57.4% and 52.3% (p=0.30), unilateral mastectomy 34.2% and 36.2% (p=0.44), bilateral mastectomy 8.4% and 11.5% (p=0.24), and immediate postmastectomy reconstruction 42.6% and 50.6% (p=0.34), respectively. Hispanic ethnicity was not associated with different odds of receiving breast conservation (odds ratio [OR] 1.01, confidence interval [CI] 0.73-1.40), unilateral mastectomy (OR 1.05, CI 0.75-1.44), bilateral mastectomy (OR 1.37, CI 0.81-2.31), or immediate postmastectomy breast reconstruction (OR 1.27, CI 0.86-1.88), when compared with non-Hispanic ethnicity, after controlling for patient age, insurance status, and distance traveled. Conclusions: Surgical care was similar for Hispanic and non-Hispanic patients treated at our NCI-designated cancer center. However, this Hispanic population traveled further than non-Hispanic patients. Our findings suggest that accessibility to transportation and institutional practices are instrumental in delivering equitable breast cancer surgical care for Hispanic patients.

View details for PubMedID 30283856

View details for DOI 10.1245/s10434-017-6028-7

View details for Web of Science ID 000435688900096

Abstract

Isolated locoregional recurrences (ILRRs) of breast cancer confer a significant risk for the development of distant metastasis. Management practices and second ILRR events in the Chemotherapy as Adjuvant for LOcally Recurrent breast cancer (CALOR) trial were investigated.In this study, 162 patients with ILRR were randomly assigned to receive postoperative chemotherapy or no chemotherapy. Descriptive statistics characterize outcomes according to local therapy and the influence of hormone receptor status on subsequent recurrences. Competing risk regression models, Kaplan-Meier estimates, and Cox proportional hazards models were used to evaluate associations between treatment, site of second recurrence, and outcome.The median follow-up period was 4.9 years. Of the 98 patients who received breast-conserving primary surgery 89 had an ipsilateral-breast tumor recurrence. Salvage mastectomy was performed for 73 patients and repeat lumpectomy for 16 patients. Another eight patients had nodal ILRR, and one patient had chest wall ILRR. Among 64 patients whose primary surgery was mastectomy, 52 had chest wall/skin ILRR, and 12 had nodal ILRR. For 15 patients, a second ILRR developed a median of 1.6 years (range 0.08-4.8 years) after ILRR. All second ILRRs occurred for patients with progesterone receptor-negative ILRR. Death occurred for 7 (47 %) of 15 patients with a second ILRR and 19 (51 %) of 37 patients with a distant recurrence. As shown in the multivariable analysis, the significant predictors of survival after either a second ILRR or distant recurrence were chemotherapy for the primary cancer (hazard ratio [HR], 3.55; 95 % confidence interval [CI], 1.15-10.9; p = 0.03) and the interval (continuous) from the primary surgery (HR, 0.87; 95 % CI, 0.75-1.00; p = 0.05).Second ILRRs represented about one third of all recurrence events after ILRR, and all were PR-negative. These second ILRRs and distant metastases portend an unfavorable outcome.

View details for DOI 10.1245/s10434-016-5571-y

View details for PubMedID 27663567

Abstract

Controversy exists regarding the optimal negative margin width for ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and whole-breast irradiation (WBRT).A multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 20 studies including 7883 patients and other published literature as the evidence base for consensus.Negative margins halve the risk of IBTR compared with positive margins defined as ink on DCIS. A 2 mm margin minimizes the risk of IBTR compared with smaller negative margins. More widely clear margins do not significantly decrease IBTR compared with 2 mm margins. Negative margins less than 2 mm alone are not an indication for mastectomy, and factors known to impact rates of IBTR should be considered in determining the need for re-excision.The use of a 2 mm margin as the standard for an adequate margin in DCIS treated with WBRT is associated with low rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcome, and decrease health care costs. Clinical judgment should be used in determining the need for further surgery in patients with negative margins < 2 mm.

View details for DOI 10.1200/JCO.2016.68.3573

View details for PubMedID 27528719

Abstract

Controversy exists regarding the optimal negative margin width for ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and whole-breast irradiation.A multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 20 studies including 7,883 patients and other published literature as the evidence base for consensus.Negative margins halve the risk of IBTR compared with positive margins defined as ink on DCIS. A 2-mm margin minimizes the risk of IBTR compared with smaller negative margins. More widely clear margins do not significantly decrease IBTR compared with 2-mm margins. Negative margins narrower than 2 mm alone are not an indication for mastectomy, and factors known to affect rates of IBTR should be considered in determining the need for re-excision.Use of a 2-mm margin as the standard for an adequate margin in DCIS treated with whole-breast irradiation is associated with lower rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. Clinical judgment should be used in determining the need for further surgery in patients with negative margins narrower than 2 mm.

View details for DOI 10.1245/s10434-016-5449-z

View details for PubMedID 27527714

Abstract

Lymph node ratios (LNR), the proportion of positive lymph nodes over the number excised, both defined as ranges and single ratio values are prognostic of outcome. Little is known of the prognostic value of LNR after neoadjuvant chemotherapy (NAC) according to molecular subtype.From 2003 to 2014, patients who underwent definitive surgery after NAC were identified. LNR was calculated for node-positive patients who received axillary dissection or had at least 6 nodes removed. DFS was calculated using the Kaplan-Meier log rank test for yp N0-3 status, LNR categories (LNRC) 0.20 (low), 0.21-0.65 (intermediate), >0.65 (high), and single LNR values.Of 428 NAC recipients, 263 were node negative and 165 (38.6%) node positive: ypN1=97 (58.8%), ypN2=43 (26.1%), and ypN3=25 (15.2%). Among node-positive cancers, the median number of LN removed was 14 (range, 6-51) and the median LNR was 0.22 (range, 0.03-1.0). Nodal stage was inversely associated with 5-year DFS: 91.5% (ypN0), 74.5% (ypN1), 49.8% (ypN2), and 50.7% (ypN3) (p<0.001). LNRC was similarly inversely associated with DFS: 69.1% (low), 71.4% (intermediate), 49.3% (high) (p<0.001). Significant associations between LNRC and DFS were demonstrated in hormone receptor (HR)-positive and triple negative breast cancer (TNBC) subtypes, p=0.02 and p=0.003. A single-value LNR0.15 in node-positive, HR-positive (94.1 vs 67.7%; p=0.04) and TNBC (94.1 vs 47.8%; p=0.001) groups was also significant.Residual nodal disease after NAC, analyzed by LNRC or LNR=0.15 cutoff value, is prognostic and can discriminate between favorable and unfavorable outcomes for HR-positive and TNBC cancers.

View details for DOI 10.1245/s10434-016-5319-8

View details for PubMedID 27401442

Abstract

To study the impact of rising bilateral mastectomy rates among neoadjuvant chemotherapy (NAC) recipients in California.NAC for operable breast cancer (BC) can downstage disease and facilitate breast conservation. We assessed trends in NAC use and surgical procedures in California from January 1, 1998 to December 31, 2012 using statewide population-based cancer registry data.A total of 236,797 females diagnosed with stage I-III BC were studied. Information regarding NAC, adjuvant chemotherapy (aCT), breast conserving surgery (BCS), bilateral mastectomy (BLM), and unilateral mastectomy (ULM) was abstracted from the medical records. Multivariable polytomous logistic regression was used to estimate odds ratios (OR) of receiving NAC and of type of surgery after NAC.Approximately, 40.1% (94,980) of patients received chemotherapy: 87% (82,588) aCT and 13.0% (12,392) NAC. NAC use more than doubled over time and increased with stage (Stage I, 0.7%; Stage III, 29.9%). Multivariable predictors of NAC treatment were stage (III), younger age (<40 yrs), Black or Hispanic race/ethnicity versus non-Hispanic White (OR 1.10, 95% confidence interval (CI) 1.05-1.16), and care at a National Cancer Institute (NCI)-designated center (OR 1.70, CI 1.58-1.82). Most NAC recipients (68.4%) had mastectomies, and 14.3% of them underwent BLM. In contrast, 47.9% aCT patients had mastectomies with 7.3% BLM. The only independent predictor of BCS after NAC was care at a NCI-designated center (OR 1.28, CI 1.10-1.49), and of BLM, age <40 years versus 50 to 64 years (OR 2.59, CI 2.21-3.03), or residence in the highest socioeconomic neighborhood quintile versus lowest (OR 2.10, CI 1.67-2.64).NAC use remains low. Predictors of surgery type after NAC were sociodemographic rather than clinical, raising concern for disparities in care access.

View details for PubMedID 27611617

Abstract

Controversy exists regarding the optimal negative margin width for ductal carcinoma in situ (DCIS) treated with breast-conserving surgery and whole-breast irradiation.A multidisciplinary consensus panel used a meta-analysis of margin width and ipsilateral breast tumor recurrence (IBTR) from a systematic review of 20 studies including 7883 patients and other published literature as the evidence base for consensus.Negative margins halve the risk of IBTR compared with positive margins defined as ink on DCIS. A 2-mm margin minimizes the risk of IBTR compared with smaller negative margins. More widely clear margins do not significantly decrease IBTR compared with 2-mm margins. Negative margins narrower than 2 mm alone are not an indication for mastectomy, and factors known to affect rates of IBTR should be considered in determining the need for re-excision.Use of a 2-mm margin as the standard for an adequate margin in DCIS treated with whole-breast irradiation is associated with lower rates of IBTR and has the potential to decrease re-excision rates, improve cosmetic outcomes, and decrease health care costs. Clinical judgment should be used in determining the need for further surgery in patients with negative margins narrower than 2 mm.

View details for DOI 10.1016/j.prro.2016.06.011

View details for PubMedID 27538810

Abstract

Treating breast cancer brain metastases (BCBMs) is challenging. Na+/I- symporter (NIS) expression in BCBMs would permit their selective targeting with radioiodide (131I-). We show impressive enhancement of tumor response by combining131I- with gemcitabine (GEM), a cytotoxic radiosensitizer. Nude mice mammary fat-pad (MFP) tumors and BCBMs were generated with braintropic MDA-MB-231Br cells transduced with bicistronically-linked NIS and firefly luciferase cDNAs. Response was monitored in vivo via bioluminescent imaging and NIS tumor expression.131I-/GEM therapy inhibited MFP tumor growth more effectively than either agent alone. BCBMs were treated with: high or low-dose GEM (58 or 14.5 mg/Kg4); 131I- (1mCi or 20.5 mCi 7 days apart); and 131I-/GEM therapy. By post-injection day (PID) 25, 82-86% of controls and 78-83% of 131I--treated BCBM grew, whereas 17% low-dose and 36% high-dose GEM regressed. The latter tumors were smaller than the controls with comparable NIS expression (~20% of cells). High and low-dose 131I-/ GEM combinations caused 89% and 57% tumor regression, respectively. High-dose GEM/131I- delayed tumor growth: tumors increased 5-fold in size by PID45 (controls by PID18). Although fewer than 25% of cells expressed NIS, GEM/131I- caused dramatic tumor regression in NIS-transduced BCBMs. This effect was synergistic, and supports the hypothesis that GEM radiosensitizes cells to 131I-.

View details for DOI 10.18632/oncotarget.10238

View details for Web of Science ID 000385435000059

Abstract

Indications for nipple-sparing mastectomy (NSM) are expanding; however, high-risk patients have more ischemic complications. Surgical devascularization of the nipple-areolar complex (NAC) prior to NSM can reduce complications. This study reports perfusion patterns and complications in high-risk patients undergoing 2-stage NSM.Surgical devascularization of the NAC was performed 3-6weeks prior to NSM in 28 women. Risk factors included ptosis, obesity, smoking, prior breast surgery, and radiation. Using indocyanine green (ICG)-based fluorescence and an infrared camera, blood inflow was visualized intraoperatively. NAC perfusion patterns were classified as: V1, underlying breast; V2, surrounding skin; V3=V1+V2, or V4, capillary fill following devascularization. Ischemic complications were analyzed.Baseline perfusion for 54 breasts was 35% V1, 32% V2, and 33% V3. Increasing ptosis was associated with V1 pattern: 86% for grade 3, 31% for grade 2, and 18% for grade 1. Postdevascularization epidermolysis was observed in 63% of V1 baseline, 41% of V2, and 22% of V3 (P=.042) and after NSM in 26% for V1, 7% for V2, and 6% for V3 (P=.131). Ptosis was significantly associated with epidermolysis postdevascularization (P=.002) and NSM (P=.002). Smoking and BMI 30 were related to increased ischemic complications. Two or more risk factors were associated with postdevascularization ischemic changes (P=.026), but were not significant after NSM. Nipple loss was not observed, but 2 patients underwent partial areolar resection.Adaptive circulatory changes after devascularization allow tissues to tolerate the additional ischemic challenge of mastectomy. Our findings support extending 2-staged operations to high-risk women previously considered unsuitable for NSM.

View details for DOI 10.1245/s10434-016-5201-8

View details for PubMedID 27038458

View details for DOI 10.1200/JCO.2016.34.15_suppl.1052

View details for Web of Science ID 000404665401172

Abstract

This study was designed to assess efficacy, safety, and predictors of response to iniparib in combination with gemcitabine and carboplatin in early-stage triple-negative and BRCA1/2 mutation-associated breast cancer.This single-arm phase II study enrolled patients with stage I to IIIA (T 1 cm) estrogen receptor-negative ( 5%), progesterone receptor-negative ( 5%), and human epidermal growth factor receptor 2-negative or BRCA1/2 mutation-associated breast cancer. Neoadjuvant gemcitabine (1,000 mg/m(2) intravenously [IV] on days 1 and 8), carboplatin (area under curve of 2 IV on days 1 and 8), and iniparib (5.6 mg/kg IV on days 1, 4, 8, and 11) were administered every 21 days for four cycles, until the protocol was amended to six cycles. The primary end point was pathologic complete response (no invasive carcinoma in breast or axilla). All patients underwent comprehensive BRCA1/2 genotyping, and homologous recombination deficiency was assessed by loss of heterozygosity (HRD-LOH) in pretreatment core breast biopsies.Among 80 patients, median age was 48 years; 19 patients (24%) had germline BRCA1 or BRCA2 mutations; clinical stage was I (13%), IIA (36%), IIB (36%), and IIIA (15%). Overall pathologic complete response rate in the intent-to-treat population (n = 80) was 36% (90% CI, 27 to 46). Mean HRD-LOH scores were higher in responders compared with nonresponders (P = .02) and remained significant when BRCA1/2 germline mutations carriers were excluded (P = .021).Preoperative combination of gemcitabine, carboplatin, and iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. The HRD-LOH assay was able to identify patients with sporadic triple-negative breast cancer lacking a BRCA1/2 mutation, but with an elevated HRD-LOH score, who achieved a favorable pathologic response. Confirmatory controlled trials are warranted.

View details for DOI 10.1200/JCO.2014.57.0085

View details for PubMedID 25847929

View details for Web of Science ID 000360941400041

View details for DOI 10.1158/1538-7445.SABCS14-P2-01-05

View details for Web of Science ID 000356730201074

View details for Web of Science ID 000360940500367

Abstract

Sentinel lymph node (SLN) biopsy has become the standard method of determining regional lymph node involvement in cutaneous melanoma. Although traditionally performed via injection of radioisotope tracers and blue dyes, fluorescent lymphangiography with indocyanine green (ICG) is an attractive alternative.Fifty two consecutive patients with cutaneous melanoma of the trunk or extremities underwent SLNB. Preoperative lymphoscintigraphy was performed with technetium-99m sulfur colloid (TSC). Peritumoral intradermal injection of isosulfan blue (ISB) and ICG was then performed. Successful identification of a sentinel lymph node via each modality was then assessed.A total of 77 lymph nodes were identified from the 52 patients (range 1-3). The majority of melanomas were extremity-based, superficial spreading type, and had SLN localized to the axilla. There were no complications related to IcG administration. Rates of SLN detection were 96.2% for TSC, 59.6% for ISB, and 88.5% for IcG (P<0.05 for ICG vs ISB). On univariate logistic regression analysis, no factors were found to be associated with failure of ICG.Fluorescent lymphangiography using ICG is an effective method of SLN identification in patients with cutaneous melanoma of the trunk and extremities. When ICG and TSC are used in combination, ISB offers no additional advantage and may be safely omitted. J. Surg. Oncol. 2014 Wiley Periodicals, Inc.

View details for DOI 10.1002/jso.23745

View details for PubMedID 25124992

Abstract

Sentinel lymph node (SLN) biopsy has become the standard method of determining regional lymph node involvement in cutaneous melanoma. Although traditionally performed via injection of radioisotope tracers and blue dyes, fluorescent lymphangiography with indocyanine green (ICG) is an attractive alternative.Fifty two consecutive patients with cutaneous melanoma of the trunk or extremities underwent SLNB. Preoperative lymphoscintigraphy was performed with technetium-99m sulfur colloid (TSC). Peritumoral intradermal injection of isosulfan blue (ISB) and ICG was then performed. Successful identification of a sentinel lymph node via each modality was then assessed.A total of 77 lymph nodes were identified from the 52 patients (range 1-3). The majority of melanomas were extremity-based, superficial spreading type, and had SLN localized to the axilla. There were no complications related to IcG administration. Rates of SLN detection were 96.2% for TSC, 59.6% for ISB, and 88.5% for IcG (P<0.05 for ICG vs ISB). On univariate logistic regression analysis, no factors were found to be associated with failure of ICG.Fluorescent lymphangiography using ICG is an effective method of SLN identification in patients with cutaneous melanoma of the trunk and extremities. When ICG and TSC are used in combination, ISB offers no additional advantage and may be safely omitted. J. Surg. Oncol. 2014 Wiley Periodicals, Inc.

View details for DOI 10.1002/jso.23745

View details for Web of Science ID 000344552200020

View details for DOI 10.4300/JGME-D-14-00086.1

View details for PubMedID 24949168

View details for Web of Science ID 000334211800148

View details for Web of Science ID 000334211800041

Abstract

Patients with isolated locoregional recurrences (ILRR) of breast cancer have a high risk of distant metastasis and death from breast cancer. We aimed to establish whether adjuvant chemotherapy improves the outcome of such patients.The CALOR trial was a pragmatic, open-label, randomised trial that accrued patients with histologically proven and completely excised ILRR after unilateral breast cancer who had undergone a mastectomy or lumpectomy with clear surgical margins. Eligible patients were enrolled from hospitals worldwide and were centrally randomised (1:1) to chemotherapy (type selected by the investigator; multidrug for at least four courses recommended) or no chemotherapy, using permuted blocks, and stratified by previous chemotherapy, oestrogen-receptor and progesterone-receptor status, and location of ILRR. Patients with oestrogen-receptor-positive ILRR received adjuvant endocrine therapy, radiation therapy was mandated for patients with microscopically involved surgical margins, and anti-HER2 therapy was optional. The primary endpoint was disease-free survival. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00074152.From Aug 22, 2003, to Jan 31, 2010, 85 patients were randomly assigned to receive chemotherapy and 77 were assigned to no chemotherapy. At a median follow-up of 49 years (IQR 36-6 0), 24 (28%) patients had disease-free survival events in the chemotherapy group compared with 34 (44%) in the no chemotherapy group. 5-year disease-free survival was 69% (95% CI 56-79) with chemotherapy versus 57% (44-67) without chemotherapy (hazard ratio 059 [95% CI 035-099]; p=0046). Adjuvant chemotherapy was significantly more effective for women with oestrogen-receptor-negative ILRR (pinteraction=0046), but analyses of disease-free survival according to the oestrogen-receptor status of the primary tumour were not statistically significant (pinteraction=043). Of the 81 patients who received chemotherapy, 12 (15%) had serious adverse events. The most common adverse events were neutropenia, febrile neutropenia, and intestinal infection.Adjuvant chemotherapy should be recommended for patients with completely resected ILRR of breast cancer, especially if the recurrence is oestrogen-receptor negative.US Department of Health and Human Services, Swiss Group for Clinical Cancer Research (SAKK), Frontier Science and Technology Research Foundation, Australian and New Zealand Breast Cancer Trials Group, Swedish Cancer Society, Oncosuisse, Cancer Association of South Africa, Foundation for Clinical Research of Eastern Switzerland (OSKK), Grupo Espaol de Investigacin en Cncer de Mama (GEICAM), and the Dutch Breast Cancer Trialists' Group (BOOG).

View details for DOI 10.1016/S1470-2045(13)70589-8

View details for PubMedID 24439313

Abstract

Triple-negative breast cancer (TNBC) is aggressive and lacks targeted therapies. Phosphatidylinositide 3-kinase (PI3K) / mammalian target of rapamycin (mTOR) pathways are frequently activated in TNBC patient tumors at the genome, gene expression and protein levels, and mTOR inhibitors have been shown to inhibit growth in TNBC cell lines. We describe a panel of patient-derived xenografts representing multiple TNBC subtypes and use them to test preclinical drug efficacy of two mTOR inhibitors, sirolimus (rapamycin) and temsirolimus (CCI-779).We generated a panel of seven patient-derived orthotopic xenografts from six primary TNBC tumors and one metastasis. Patient tumors and corresponding xenografts were compared by histology, immunohistochemistry, array comparative genomic hybridization (aCGH) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) sequencing; TNBC subtypes were determined. Using a previously published logistic regression approach, we generated a rapamycin response signature from Connectivity Map gene expression data and used it to predict rapamycin sensitivity in 1401 human breast cancers of different intrinsic subtypes, prompting in vivo testing of mTOR inhibitors and doxorubicin in our TNBC xenografts.Patient-derived xenografts recapitulated histology, biomarker expression and global genomic features of patient tumors. Two primary tumors had PIK3CA coding mutations, and 5/6 primary tumors showed flanking intron single nucleotide polymorphisms (SNPs) with conservation of sequence variations between primary tumors and xenografts, even on subsequent xenograft passages. Gene expression profiling showed that our models represent at least four of six TNBC subtypes. The rapamycin response signature predicted sensitivity for 94% of basal-like breast cancers in a large dataset. Drug testing of mTOR inhibitors in our xenografts showed 77 to 99% growth inhibition, significantly more than doxorubicin; protein phosphorylation studies indicated constitutive activation of the mTOR pathway that decreased with treatment. However, no tumor was completely eradicated.A panel of patient-derived xenograft models covering a spectrum of TNBC subtypes was generated that histologically and genomically matched original patient tumors. Consistent with in silico predictions, mTOR inhibitor testing in our TNBC xenografts showed significant tumor growth inhibition in all, suggesting that mTOR inhibitors can be effective in TNBC, but will require use with additional therapies, warranting investigation of optimal drug combinations.

View details for DOI 10.1186/bcr3640

View details for PubMedID 24708766

View details for DOI 10.1186/bcr3640

View details for Web of Science ID 000338990900021

View details for DOI 10.1016/j.fertnstert.2013.07.1649

View details for Web of Science ID 000342554500377

View details for Web of Science ID 000335419600185

View details for Web of Science ID 000318174800123

View details for Web of Science ID 000318174700129

Abstract

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

View details for DOI 10.1002/jso.23091

View details for PubMedID 22396104

View details for Web of Science ID 000318009800478

Abstract

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

View details for DOI 10.1016/j.ygyno.2011.11.028

View details for PubMedID 22173210

View details for DOI 10.1158/0008-5472.SABCS11-P3-14-08

View details for Web of Science ID 000209699801149

Abstract

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

View details for DOI 10.1093/jnci/djr027

View details for PubMedID 21398619

Abstract

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

View details for Web of Science ID 000292663900001

View details for PubMedID 21697533

View details for DOI 10.1158/0008-5472.SABCS10-P6-03-01

View details for Web of Science ID 000209695800216

Abstract

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

View details for DOI 10.1200/JCO.2010.28.9793

View details for Web of Science ID 000282272700032

View details for PubMedID 20697067

View details for PubMedCentralID PMC2954133

Abstract

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

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

View details for PubMedID 19618116

Abstract

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

View details for DOI 10.1200/JCO.2008.19.8424

View details for Web of Science ID 000266195400011

View details for PubMedID 19349544

View details for PubMedCentralID PMC2684852

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 PubMedID 19194462

Abstract

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

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

View details for PubMedID 19184238

View details for Web of Science ID 000262583200304

Abstract

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

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

View details for Web of Science ID 000260509400033

View details for PubMedID 18784962

View details for PubMedCentralID PMC2576492

Abstract

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

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

View details for Web of Science ID 000256914800013

View details for PubMedID 18650162

View details for Web of Science ID 000255851900029

Abstract

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

View details for PubMedID 18501064

View details for Web of Science ID 000252887900024

View details for Web of Science ID 000252887900254

View details for Web of Science ID 000455043700045

Abstract

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

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

View details for Web of Science ID 000244252900001

View details for PubMedID 17214887

View details for PubMedCentralID PMC1794416

Abstract

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

View details for DOI 10.1200/JCO.2005.04.3273

View details for Web of Science ID 000237371500012

View details for PubMedID 16648502

Abstract

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

View details for DOI 10.2310/7290.2006.00008

View details for PubMedID 16954021

View details for Web of Science ID 000230326600031

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

View details for PubMedID 15072707

View details for Web of Science ID 000223169400367

Abstract

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

View details for DOI 10.1210/jc.2002-021544

View details for PubMedID 12679487

Abstract

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

View details for PubMedID 11469933

Abstract

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

View details for Web of Science ID 000165473800029

View details for PubMedID 10932223

Abstract

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

View details for Web of Science ID 000080715300009

View details for PubMedID 10379856

Abstract

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

View details for Web of Science ID A1997YE40000005

View details for PubMedID 9371230

Abstract

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

View details for Web of Science ID A1996VR62000002

View details for PubMedID 8932872

Abstract

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

View details for Web of Science ID A1994PK88900022

View details for PubMedID 7881112

Abstract

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

View details for PubMedID 8380491

Abstract

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

View details for Web of Science ID A1990DR88900018

View details for PubMedID 2200150

Abstract

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

View details for Web of Science ID A1989AK11300011

View details for PubMedID 2757141

View details for Web of Science ID A1988N215900039

View details for PubMedID 3363001

Abstract

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

View details for Web of Science ID A1988M333100010

View details for PubMedID 3344454

Abstract

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

View details for Web of Science ID A1987L074700008

View details for PubMedID 3318729

Abstract

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

View details for Web of Science ID A1987H551200010

View details for PubMedID 3579050

View details for PubMedID 4005025

Abstract

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

View details for Web of Science ID A1985ATV0100019

View details for PubMedID 4060074

View details for Web of Science ID A1977DU41100010

View details for PubMedID 142678