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Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced HER2 + breast cancer (BC). Optimal sequencing of treatment (NAC vs. surgery first) is less clear cut in stage I (T1N0) HER2 + BC, where information from surgical pathology could impact adjuvant treatment decisions. Utilizing the NCDB, we evaluated the trend of NAC use compared to upfront surgery in patients with small HER2 + BC. We identified NCDB female patients diagnosed with T1 N0 HER2 + BC from 2010 through 2015. Prevalence ratios (PR) using multivariable robust Poisson regression models were calculated to measure the association between baseline characteristics and the receipt of NAC. Analysis of trends over time was denoted by annual percent change (APC) of NAC versus surgery upfront. Of the 14,949 that received chemotherapy and anti-HER2 therapy during the study period, overall 1281 (8.6%) received NAC and 13,668 (91.4%) received adjuvant treatment. Patients receiving NAC increased annually from 4.2% in 2010 to 17.3% in 2015, with the most rapid increase occurring between years 2013 (8.5%) and 2014 (14.2%). The greatest increase was seen in patients with cT1c tumors with an APC of 37.8% over the study period (95% CI 29.0, 47.3%, p

Neoadjuvant chemotherapy (NAC) is a well-established therapeutic option for patients with locally advanced disease often allowing downstaging and facilitation of breast conserving therapy. With evolution of better targeted treatment regimens and awareness of improved outcomes for significant responders, use of NAC has expanded particularly for triple negative and HER2-positive (HER2+) breast cancer. In this study, we explore utility of neoadjuvant chemotherapy for hormone receptor-positive HER2-negative (HR+ HER2−) patients. Patients with HR+ HER2− breast cancer treated with chemotherapy before or after surgery were identified from 2010 to 2015 in the NCDB. Multivariable regression models adjusted for covariates were used to determine associations within these groups. Among 134,574 patients (clinical stage 2A, 64%; 2B, 21%; 3, 15%), 105,324 (78%) had adjuvant chemotherapy (AC) and 29,250 (22%) received NAC. Use of NAC increased over time (2010–2015; 13.2–19.4% and PR = 1.34 for 2015; p

BACKGROUND Currently, positive margins at lumpectomy contribute to health care cost, patient anxiety, and treatment delay. Multiple technology solutions are being explored with the aim of lowering re-excision rates for breast-conserving surgery (BCS). We examined wide-field optical coherence tomography (WF-OCT), an innovative adjunct intraoperative imaging tool for tissue visualization of margins. METHODS This IRB-approved pilot study included women with invasive or in situ carcinoma scheduled for primary BCS. Lumpectomy specimens and any final/revised margins were imaged by optical coherence tomography immediately prior to standard histological processing. The optical coherence tomography used provided two-dimensional, cross-sectional, real-time depth visualization of the margin widths around excised specimens. A volume of images was captured for 10 × 10 cm tissue surface at high resolution (sub-30 μm) to a depth of 2 mm. Integrated interpretation was performed incorporating final pathology linked with the optical image data for correlation. RESULTS Wide-field optical coherence tomography was performed on 185 tissue samples (50 lumpectomy specimens and 135 additional margin shaves) in 50 subjects. Initial diagnosis was invasive ductal carcinoma (IDC) in 10, ductal carcinoma in situ (DCIS) in 14, IDC/DCIS in 22, invasive lobular carcinoma (ILC) in 2, ILC/DCIS in 1, and sarcoma in 1. Optical coherence tomography was concordant with final pathology in 178/185 tissue samples for overall accuracy of 86% and 96.2% (main specimen alone and main specimen + shave margins). Of seven samples that were discordant, 57% (4/7) were considered close (DCIS

Background and Objectives: Local and distant relapse (LR, DR) in breast cancer vary according to its molecular subtypes, with triple-negative breast cancer (TNBC) being the most aggressive. The surgical resection margin width (SRMW) for breast-conserving surgery (BCS) has been intensely debated, especially for the aforementioned subtype. The aim of this study was to examine the impact of SRMW on LR following BCS in TNBC patients. Materials and Methods: We conducted a retrospective study including all patients with TNBC for whom BCS was performed between 2005 and 2014. Results: Final analysis included a total of 92 patients, with a median tumor size of 2.5 cm (range 0–5 cm) and no distant metastasis at the time of diagnosis. A total of 87 patients had received neoadjuvant and/or adjuvant chemotherapy, and all patients had received adjuvant whole-breast radiotherapy. After a median follow-up of 110.7 months (95% CI, 95.23–126.166), there were 5 local recurrences and 8 regional/distant recurrences with an overall LR rate of 5.4%. The risk of LR and DR was similar between groups of patients with several SRMW cut-off values. Conclusions: Our study supports a safe “no ink on tumor” approach for TNBC patients treated with BCS.

Genetic predisposition accounts for 5–10% of all breast cancers (BC) diagnosed. NCCN guidelines help providers identify appropriate candidates for counseling and testing. Concerns about underutilization of genetic testing have spurred interest in broader peri-diagnostic testing. We evaluated surgeon adherence to NCCN guidelines and studied patterns of testing in newly diagnosed BC patients. A total of 397 patients were identified with newly diagnosed BC treated at our institution between 2016 and 2017 with no prior genetic testing. Eligibility for genetic testing based on NCCN criteria, referral, and patient compliance were recorded. In total, 212 of 397 (53%) met NCCN testing criteria. Fifty-nine of 212 (28%) patients went untested despite meeting one or more criteria. Fourteen of 59 (24%) of these were referred but did not comply. Most common criteria for meeting eligibility for testing both in the overall cohort and among missed patients were family history-based. Age > 45 years old and non-Ashkenazi Jewish descent were predictive of missed referral (p

Improved imaging and neoadjuvant chemotherapy (NAT) have led to higher pathologic complete response rates (pCR) in patients with invasive breast cancer. This has questioned the necessity of surgery and axillary lymph node (ALN) dissection in these patients. Prospective clinical trials are implementing extensive core biopsies of the tumor bed of patients with clinical complete response as a means to identify and spare them breast surgery. In addition, it is anticipated that patients with pCR are most likely going to have no or minimal disease in ALN as well. To verify the feasibility of these trials, we performed a pathologic analysis of all our patients who have undergone NAT from 2009 to present. Using pathology data base, we identified 362 patients treated with neoadjuvant chemotherapy followed by surgery. Clinical and pathologic information including gross and microscopic descriptions as well as biomarker status was collected. pCR was 50% for patients with negative ALN pretreatment but only 28% for patients with positive ALN at diagnosis. Despite achieving pCR in the breast, up to 10% of patients with positive ALN and 1% with negative ALN had persistent disease. Eight percent of patients that were presumed to have no ALN disease either clinically and or by imaging were found to have metastatic carcinoma in ALN. The metastases were predominantly (80%)

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare peripheral T-cell lymphoma with approximately 650-700 reported cases worldwide. The incidence, however, is increasing as more practitioners become aware of the diagnosis, and recent studies show that early diagnosis and treatment is critical to improve prognosis. There have been four cases of BIA-ALCL in total reported in the transgender population in the literature. These reported cases were reviewed in detail to determine presentation and management of BIA-ALCL in transgender patients compared to the larger population of BIA-ALCL patients. This review highlights BIA-ALCL in transgender women, a population that is often excluded from breast screening and follow-up. Transgender women may not routinely go through the same post-operative follow-up protocols as patients with breast implants for breast cancer reconstruction and can thus be at risk for delayed recognition and diagnosis. BIA-ALCL is a rare complication of breast implantation, and it is important to counsel all patients undergoing implant placement, including transgender women, on its risk.

Estrogen dependence is major driver of ER + breast cancer, which is associated with PI3K mutation. PI3K inhibition (PI3Ki) can restore dependence on ER signaling for some hormone therapy-resistant ER + breast cancers, but is ineffective in others. Here we show that short-term supplementation with estrogen strongly enhanced Pik3caH1047R-induced mammary tumorigenesis in mice that resulted exclusively in ER + tumors, demonstrating the cooperation of the hormone and the oncogene in tumor development. Similar to human ER + breast cancers that are endocrine-dependent or endocrine-independent at diagnosis, tumor lines from this model retained ER expression but were sensitive or resistant to hormonal therapies. PI3Ki did not induce cell death but did cause upregulation of the pro-apoptotic gene BIM. BH3 mimetics or PI3Ki were unable to restore hormone sensitivity in several resistant mouse and human tumor lines. Importantly however, combination of PI3Ki and BH3 mimetics had a profound, BIM-dependent cytotoxic effect in PIK3CA-mutant cancer cells while sparing normal cells. We propose that addition of BH3 mimetics offers a therapeutic strategy to markedly improve the cytotoxic activity of PI3Ki in hormonal therapy-resistant and ER-independent PIK3CA-mutant breast cancer.

Screening mammography reduces breast cancer mortality; however, screening recommendations, ordering, and compliance remain suboptimal and controversies regarding the value of screening persist. We evaluated the influence of screening mammography on the extent of breast cancer treatment. Patients ≥ 40 years of age diagnosed with breast cancer from September 2008 to May 2016 at a single institution were divided into two groups: those with screening 1–24 months prior to diagnosis, and those with screening at 25+ months, including patients with no prior mammography. The association between the two groups and various clinical factors were assessed using logistic regression models. Subgroup analysis was performed based on age groups. Analysis included 1125 patients, 819 (73%) with screening at 1–24 months, and 306 (27%) with screening at 25+ months, including 65 (6%) who never had mammography. Overall, patients in the 25+ months group were more likely to receive chemotherapy [odds ratio (OR) 1.51, p = 0.0040], undergo mastectomy (OR 1.32, p = 0.0465), and require axillary dissection (AD; OR 1.66, p = 0.0045) than those in 1–24 months group. On subgroup analysis, patients aged 40–49 years with no prior mammography were more likely to have larger tumors (p = 0.0323) and positive nodes (OR 4.52, p = 0.0058), undergo mastectomy (OR 3.44, p = 0.0068), undergo AD (OR 4.64, p = 0.0002), and require chemotherapy (OR 2.52, p = 0.0287) than the 1–24 months group. Screening mammography is associated with decreased stage at diagnosis and receipt of less-extensive treatment. This was evident in all groups, including the 40–49 years age group, where controversy exists on whether screening is even necessary.

Rationale and Objectives This study aimed to assess whether different breast cancer subspecialty physicians can be trained to distinguish non-suspicious from suspicious areas of post-lumpectomy specimen margin in patients with breast cancer using optical coherence tomography (OCT) images (a near-infrared based imaging technique) with final histology as the reference standard. Materials and Methods This institutional review board-exempt, Health Insurance Portability and Accountability Act-compliant study was performed on 63 surgically excised breast specimens from 35 female patients, creating a 90-case atlas containing both non-suspicious and suspicious areas for cancer. OCT images of the specimens were performed, providing 6.5–15 µm resolution with tissue visualization 1–2 mm subsurface. From the 90-case atlas, 40 cases were chosen for training and 40 were randomly selected for reader assessment. Three breast imaging radiologists, two pathologists, two breast surgeons, and one non-clinical reader were trained and assessed for ability to distinguish non-suspicious from suspicious findings blinded to clinical data and corresponding histology slides. Duration of training and assessment, sensitivity, specificity, positive predictive value, negative predictive value, and the area under the curve for each reader were calculated as well as averages by subspecialty. Results The average training time was 3.4 hours (standard deviation, 1.2). The average assessment time was 1.9 hours (standard deviation, 0.7). The overall average reader sensitivity, specificity, and accuracy for detecting suspicious findings with histologic confirmation of cancer at the surgical margin for all eight readers were 80%, 87%, and 87%, respectively. Radiologists demonstrated the highest average among the disciplines, 85%, 93%, and 94%, followed by pathologists, 79%, 90%, and 84%, and surgeons, 76%, 84%, and 82% respectively. Conclusions With relatively short training (3.4 hours), readers from different medical specialties were able to distinguish suspicious from non-suspicious OCT imaging findings in ex vivo breast tissue as confirmed by histology. These results support the potential of OCT as a real-time intraoperative tool for post-lumpectomy specimen margin assessment.

The role of MRI in the workup of newly diagnosed breast cancer patients remains controversial. Breast MRI detects additional disease, but this has not translated into improved outcomes. In light of a dramatic rise in MRI use, we investigated patterns of MRI ordering for newly diagnosed breast cancer. All newly diagnosed breast cancer cases presenting for surgical management to a specialized breast center from 2011 to 2013 were reviewed. Patients who had an MRI ordered by their operating surgeon were compared with those who had an MRI completed previously. Of 1037 patients, 504 (49%) with newly diagnosed breast cancer underwent MRI as part of their pre-operative evaluation. Variables associated with MRI use included commercial insurance, increased breast density, genetic testing, mamographically occult disease, and lobular pathology. Of women who presented to our center with an MRI already completed, 63 per cent were ordered by a primary care provider. Of the 504 patients, 233 (44%) who had an MRI underwent an additional biopsy, and 166 (33%) had a resultant change in management. There was no significant difference in MRI-directed change in patient care depending on ordering provider. Further research is needed to develop evidence-based guidelines for preoperative MRI evaluation to optimize patient outcomes.

Controversy surrounds management of lobular neoplasia (LN), [atypical lobular hyperplasia (ALH) or lobular carcinoma in situ (LCIS)], diagnosed on core needle biopsy (CNB). Retrospective series of pure ALH and LCIS reported “upgrade” rate to DCIS or invasive cancer in 0–40%. Few reports document radiologic/pathologic correlation to exclude cases of discordance that are the likely source of most upgrades, and there is minimal data on outcomes with follow-up imaging and clinical surveillance. Cases of LN alone on CNB (2001–2014) were reviewed. CNB yielding LN with other pathologic findings for which surgery was indicated were excluded. All patients had either surgical excision or clinical follow-up with breast imaging. All cases included were subject to radiologic–pathologic correlation after biopsy. 178 cases were identified out of 62213 (0.3%). 115 (65%) patients underwent surgery, and 54 (30%) patients had surveillance for > 12 months (mean = 55 months). Of the patients who underwent surgical excision, 13/115 (11%) were malignant. Eight of these 13 found malignancy at excision when CNB results were considered discordant (5 DCIS, and 3 invasive lobular carcinoma), with the remainder, 5/115 (4%), having a true pathologic upgrade: 3 DCIS, and 2 microinvasive lobular carcinoma. Among 54 patients not having excision, 12/54 (22%) underwent subsequent CNB with only 1 carcinoma found at the initial biopsy site. Surgical excision of LN yields a low upgrade rate when careful consideration is given to radiologic/pathologic correlation to exclude cases of discordance. Observation with interval breast imaging is a reasonable alternative for most cases.

TP53 is the most commonly mutated tumor suppressor gene and its mutation drives tumorigenesis. Using ChIP-seq for p53 in the absence of acute cell stress, we found that wild-type but not mutant p53 binds and activates numerous tumor suppressor genes, including PTEN, STK11(LKB1), miR-34a, KDM6A(UTX), FOXO1, PHLDA3, and TNFRSF10B through consensus binding sites in enhancers and promoters. Depletion of p53 reduced expression of these target genes, and analysis across 18 tumor types showed that mutation of TP53 associated with reduced expression of many of these genes. Regarding PTEN, p53 activated expression of a luciferase reporter gene containing the p53-consensus site in the PTEN enhancer, and homozygous deletion of this region in cells decreased PTEN expression and increased growth and transformation. These findings show that p53 maintains expression of a team of tumor suppressor genes that may together with the stress-induced targets mediate the ability of p53 to suppress cancer development. p53 mutations selected during tumor initiation and progression, thus, inactivate multiple tumor suppressor genes in parallel, which could account for the high frequency of p53 mutations in cancer. Implications: In this study, we investigate the activities of p53 under normal low-stress conditions and discover that p53 is capable of maintaining the expression of a group of important tumor suppressor genes at baseline, many of which are haploinsufficient, which could contribute to p53-mediated tumor suppression. Mol Cancer Res; 15(8); 1051–62. ©2017 AACR.

Background Nonpalpable breast lesions require localization before excision. This is most commonly performed with a wire (WL) or a radioactive seed (SL), which is placed into the breast under radiographic guidance. Although there are advantages of each modality, there are no guidelines to address which patients should undergo WL versus SL. We investigated factors influencing the selection of SL versus WL at our institution and assessed patient satisfaction with each procedure. Methods Patients undergoing preoperative localization of nonpalpable breast lesions from May 2014 through August 2015 were included. Physicians were surveyed on surgical scheduling to evaluate factors influencing the decision to perform SL or WL. Patient satisfaction was evaluated with a survey at the first postoperative visit. Retrospective chart review was performed. Results 341 patients were included: 104 (30%) patients underwent SL and 237 (70%) underwent WL. There was no difference in patient age, benign versus malignant disease, or need for concomitant axillary surgery comparing the SL versus WL groups. Physician survey indicated that 18% of patients were candidates for WL only. Of the patients who were eligible for both, 88 (41%) ultimately underwent SL and 126 (59%) had WL. The most commonly cited reason for selection of one localization method or the other was physician preference, followed by patient preference or avoiding additional visit. There was no significant difference in self-reported preoperative anxiety level, convenience of the localization procedure, pain of the localization procedure, operative experience, postoperative pain level or medication requirement, or overall patient satisfaction comparing patients who underwent SL and WL. Conclusions SL and WL offer patients similar comfort and satisfaction. Factors influencing selection of one modality over the other include both logistic and clinical considerations.

Pregnancy is associated with a transient increase in risk for breast cancer. However, the mechanism underlying pregnancy‐associated breast cancer (PABC) is poorly understood. Here, we identify the protease pappalysin‐1 (PAPP‐A) as a pregnancy‐dependent oncogene. Transgenic expression of PAPP‐A in the mouse mammary gland during pregnancy and involution promotes the deposition of collagen. We demonstrate that collagen facilitates the proteolysis of IGFBP‐4 and IGFBP‐5 by PAPP‐A, resulting in increased proliferative signaling during gestation and a delayed involution. However, while studying the effect of lactation, we found that although PAPP‐A transgenic mice lactating for an extended period of time do not develop mammary tumors, those that lactate for a short period develop mammary tumors characterized by a tumor‐associated collagen signature (TACS‐3). Mechanistically, we found that the protective effect of lactation is associated with the expression of inhibitors of PAPP‐A, STC1, and STC2. Collectively, these results identify PAPP‐A as a pregnancy‐dependent oncogene while also showing that extended lactation is protective against PAPP‐A‐mediated carcinogenesis. Our results offer the first mechanism that explains the link between breast cancer, pregnancy, and breastfeeding.

At times we encounter clinical prob-lems for which there are no directlyapplicable evidence-based solutions,but we are compelled by circumstan-ces to act. When doing so we rely onrelated evidence, general principles ofbest medical practice, and our expe-rience. Each “Current Clinical Prac-tice” feature article in Seminars inOncology describes such a challeng-ing presentation and offers treatmentapproaches from selected specialists.We invite readers' comments andquestions, which, with your approval,will be published in subsequentissues of the Journal. It is hoped thatsharing our views and experienceswill better inform our managementdecisions when we next encountersimilar challenging patients. Pleasesend your comments on the articles,your challenging cases, and yourtreatment successes to me at dr.gjmorris@gmail.com. I look forward to alively discussion.Gloria J. Morris, MD, PhDCurrent Clinical Practice FeatureEditor

Purpose: Despite the fact that interstitial fluid (IF) represents a third of our body fluid, it is the most poorly understood body fluid in medicine. Increased IF pressure is thought to result from the increased deposition of extracellular matrix in the affected tissue preventing its reabsorption. In the cancer field, increased rigidity surrounding a cancerous mass remains the main reason that palpation and radiologic examination, such as mammography, are used for cancer detection. While the pressure produced by IF has been considered, the biochemical composition of IF has not been considered in its effect on tumors. Experimental Design: We classified 135 IF samples from bilateral mastectomy patients based on their ability to promote the invasion of breast cancer cells. Results: We observed a wide range of invasion scores. Patients with high-grade primary tumors at diagnosis had higher IF invasion scores. In mice, injections of high-score IF (IFHigh) in a normal mammary gland promotes ductal hyperplasia, increased collagen deposition, and local invasion. In a mouse model of residual disease, IFHigh increased disease progression and promoted aggressive visceral metastases. Mechanistically, we found that IFHigh induces myofibroblast differentiation and collagen production through activation of CLIC4. IFHigh also downregulates RYBP, leading to degradation of p53. Furthermore, in mammary glands of heterozygous p53-mutant knock-in mice, IFHigh promotes spontaneous tumor formation. Conclusions: Our study indicates that IF can increase the deposition of extracellular matrix and raises the provocative possibility that they play an active role in the predisposition, development, and clinical course of sporadic breast cancers. Clin Cancer Res; 23(18); 5446–59. ©2017 AACR.

Purpose To determine the utility and rate of biopsy in women with a positive history of breast cancer screened with MRI. Methods Retrospective review of 491 breast MRI screening examinations in women with a personal history of breast cancer. Results In total, 107 biopsies were performed, an average of 0.09 biopsies per person year. The positive predictive value for biopsies prompted by MRI findings was 0.24 (95% C.I. 0.10–0.38). Eight of the nine subsequent cancers were initially identified on screening MRI alone. Conclusion Surveillance MRI in breast cancer survivors may increase detection of subsequent cancers while increasing rate of biopsy.

The proportion of patients eligible for breast-conservation therapy (BCT) yet opting for mastectomy is increasing. This decision is often driven by the desire to eliminate future screening and/or biopsy of the remaining breast or breasts. This study investigated the incidence of post-mastectomy imaging and biopsy. A retrospective review of all unilateral mastectomy (UM) and bilateral mastectomy (BM) cases managed at a single institution was undertaken. Post-mastectomy imaging and biopsy rates were determined. Between 2009 and 2015, 185 UM and 200 BM cases managed for breast cancer were identified. The mean follow-up period was 30 months (range 3–75 months). For the patients with UM, imaging studies and biopsies done on the contralateral side were excluded given the standard of care for continued surveillance of the contralateral breast. Of the 185 UM patients, 19 (10%) underwent ipsilateral imaging (all ultrasounds) for physical examination findings, 11 (6%) underwent biopsy, and 2 (1%) had malignant findings. Of the 200 BM patients, 31 (15.5%) required imaging (29 ultrasounds and 2 MRIs), with 76% of the ultrasounds performed on the side with previous cancer. Subsequently, 16 (8%) of the BM patients had biopsy, with 11 (69%) of the 16 biopsies performed on the ipsilateral side. Three (1.5%) of the biopsies done on ipsilateral side demonstrated malignancy, whereas all the contralateral biopsies were benign. For 10–15.5% of patients who undergo mastectomy, either UM or BM, subsequent imaging is required, whereas 6–8% undergo biopsy. The yield of malignancy is low, approximately 1%. Thus, after mastectomy, the need for imaging and biopsy is not eliminated. This information is critical for patient understanding and expectation related to surgical decision making.

The purposes of this article are to describe two cases of breast cancer in male-to-female transsexuals and to review eight cases previously reported in the literature.Breast cancer occurs in male-to-female transsexuals who receive high doses of exogenous estrogen and develop breast tissue histologically identical to that of a biologically female breast. This exposure to estrogen results in increased risk of breast cancer. The first patient described is a male-to-female transsexual with screening-detected ductal carcinoma in situ and a family history of breast cancer. The other patient is a male-to-female transsexual with invasive ductal carcinoma that was occult on diagnostic digital mammographic and ultrasound findings but visualized on digital breast tomosynthesis and breast MR images. The analysis of the eight previously reported cases showed that breast cancer in male-to-female transsexuals occurs at a younger age and is more frequently estrogen receptor negative than breast cancer in others born biologically male. Screening for breast cancer in male-to-female transsexuals should be undertaken for those with additional risk factors (e.g., family history, BRCA2 mutation, Klinefelter syndrome) and should be available to those who desire screening, preferably in a clinical trial.

Background. Breast pathology is a challenging field, and previous work has shown discrepancies in diagnoses, even among experts. We set out to determine whether mandatory pathology review changes the diagnosis or surgical management of breast disease. Methods. Cases were referred for pathology review after patients presented for surgical opinion to the Dubin Breast Center at Mount Sinai Medical Center over the course of 2 years. Surgical pathologists with expertise in breast disease reviewed slides submitted from the primary institution and rendered a second opinion diagnosis. Comparison of these reports was performed for evaluation of major changes in diagnosis and definitive surgical management. Results. A total of 306 patients with 430 biopsy specimens were reviewed. Change in diagnosis was documented in 72 (17 %) of 430 cases and change in surgical management in 41 (10 %). A change in diagnosis was more likely to occur in patients originally diagnosed with benign rather than malignant disease (31 vs. 7 %, p \ 0.001). Twelve (7 %) of 169 specimens initially diagnosed as benign were reclassified as malignant. A malignant diagnosis was changed to benign in 4 (2 %) of 261 cases. Change in diagnosis was less common in specimens originating from commercial laboratories than community hospitals or university hospitals (8, 19, 21 %, p = 0.023). Change in management was not dependent on initial institution. Type of biopsy specimen (surgical or core) did not influence diagnostic or management changes. Conclusions. We recommend considering breast pathology review based on the individual clinical scenario, regardless of initial pathologic diagnosis or originating institution.

Patient decision-making regarding breast cancer surgery is multifactorial, and patients derive information on surgical treatment options from a variety of sources which may have an impact on choice of surgery. We investigated the role of different information sources in patient decision-making regarding breast cancer surgery. Two hundred and sixty-eight patients with breast cancer, eligible for breast-conserving therapy were surveyed in the immediate preoperative period, and clinical data were also collected. This survey evaluated the scope and features of patient-driven research regarding their ultimate choice of surgical treatment. The two most common sources of information used by patients were written material from surgeons (199/268–74%) and the Internet (184/268–69%). There was a trend for women who chose bilateral mastectomy to use the Internet more frequently than those choosing unilateral mastectomy ( P = 0.056). Number of surgeons consulted, genetic testing, and MRI were significant predictors of patient choice of mastectomy over breast-conserving therapy. Multivariate analysis showed that the number of surgeons consulted ( P < 0.001) and genetic testing ( P < 0.001) were independent predictors of choosing mastectomy, whereas MRI was not. In conclusions, understanding factors driving patient decision-making may promote more effective education for patients requiring breast cancer surgery.

Current guidelines state that "no ink on tumor" constitutes adequate surgical margins for lumpectomy specimens. However, there remains uncertainty when tumor is close (1 mm) to multiple inked margins.All local excisions for invasive breast cancer during 3 years at one center were reviewed. Tumor characteristics, margin status, patient age, reoperations, and pathology of reexcised specimen were recorded. Chi-square analysis and regression models were used to identify factors associated with residual disease upon reoperation.In 533 lumpectomies for invasive cancer, 60 (11 %) had at least one positive margin, and 106 (20 %) had one or more close margin. Multiple margins were either close or positive in 67 cases. Reoperation was performed in 125 of 533 cases (23 %) for close or positive margins. Positive margins were significantly more likely to undergo reoperation compared with close margins (p 0.001). On reoperation, 73 of 125 (58 %) demonstrated residual cancer, including 39 of 68 (57 %) with close margins, and 34 of 57 (60 %) with positive margins (p = 0.52). When multiple margins were close or positive, residual cancer was found on reexcision in 45 of 59 (76 %) cases as opposed to 34 of 79 (43 %) cases with only one involved margin (p 0.001). When controlling for other factors, positive margins were no more associated with residual disease than close margins (p = 0.32), whereas multiple close or positive margins were associated with significantly higher risk of residual disease (odds ratio 6.1; p = 0.002; 95 % confidence interval 2.6-14.45).The only significant predictor of residual tumor was multiple close or positive margins. It may be appropriate to recommend reexcision for patients with multiple close margins.

Carcinoid tumors are indolent neoplasms derived from the enterochromaffin cells which have a wide anatomic distribution. Most common primary sites include gastrointestinal tract and bronchopulmonary system. Despite their slow growing nature, carcinoid tumors possess metastatic potential, and breast is a rare but known site of metastasis. We report a case of breast metastasis from carcinoid tumor of the terminal ileum in a 53 year old woman who initially presented with a breast mass detected by screening mammography. A review of literature was performed for this rare presentation of breast as the initial site of detection of metastatic carcinoid tumor.

We are reporting a case of a 34-year-old woman with occult primary breast cancer discovered after initially presenting with neurological symptoms. She was successfully treated with neoadjuvant chemotherapy followed by definitive axillary lymph node dissection and ipsilateral whole breast radiotherapy. The case presented is unique due to the rarity of occult primary breast cancer, especially in light of her initial confounding neurological signs and symptoms, which highlights the importance of careful staging.

Chemo-inducible cancer gene therapy is a potential new treatment for solid tumors that may in part enhance the anti-tumor effects of chemotherapy while minimizing toxicity. This approach combines viral vectors expressing cytotoxic transgenes that can be transcriptionally activated by DNA-damaging agents. The development of chemo-inducible gene therapy has numerous implications for the treatment of both localized and metastatic disease in patients with solid tumors.

Purpose of review Recognition that the gastrointestinal tract is a key element of the immune system has led to a greater interest in understanding its role as a central figure in host defenses. Biologic systems that are perturbed by any destabilizing stimulus are known to respond by adaptive strategies in an attempt to maintain or return to global homeostasis. In critically ill patients, the gut has previously been described as a promoter of progression to sepsis and multi-organ failure. However, with better understanding of gastrointestinal tract mucosal immunity, we are now provided with a new arsenal to combat nosocomial infection and significantly impact return to health. Recent findings In this review we focus on five key topics in the rapidly expanding landscape of knowledge on the gastrointestinal tract in the critical care setting. These include a discussion of probiotic therapy, now the new frontier of immuno-nutrition, the concept of ischemia/reperfusion injury and changes in gut permeability, anti-oxidant and micronutrient therapy, blood glucose regulation, and enhancement of gut motility, all in the intensive care setting. Summary Ongoing research in nutritional support in both normal and pathologic gastrointestinal function and response to injury has opened the door to several new opportunities for enhancing rapid recovery in critical care.

At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each “Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at dr.gjmor ris@gmail.com. I look forward to a lively discussion. Gloria J. Morris, MD, PhD Current Clinical Practice Feature Editor

CONCLUSIONS: When compared to NSQIP, Explorys demonstrates similar trends in DVT and PE cumulative incidence curves after breast reconstruction surgery. Furthermore, Explorys confirms known risk factors for thromboembolism after breast reconstruction surgery, validating its use. While data are not prospective, Explorys complements NSQIP in its ability to provide long term outcomes and complication trends at the population level while minimizing selection bias.

Introduction: The hedgehog signaling pathway (Hh) is frequently over expressed in pancreatic adenocarcinomas. We studied the potential cytotoxic interactions between cyclopamine, a Hh pathway inhibitor and paclitaxel, cisplatin, gemcitabine and ionizing radiation (IR). Methods: In vitro clonogenic survival analysis was performed with cyclopamine alone or cyclopamine in combination with paclitaxel, gemcitabine, cisplatin and IR in Hh expressing human pancreatic tumor cells and Hh non-expressing colon cancer cells. Relative cytotoxicity was assessed in combination treatment compared with exposure to single agents. Assays of apoptosis (annexin V) were performed in the presence of cyclopamine, chemotherapeutic agents, and IR. Results: We report that cyclopamine increased the cytotoxic effects of paclitaxel and IR in Hh expressing pancreatic carcinoma cells. These effects were not observed in Hh non-expressing cells. Cyclopamine did not significantly increase killing by cisplatin or gemcitabine in Hh expressing pancreatic cancer cells. Conclusions: These data suggest strategies to combine Hh inhibitors with radiotherapy and chemotherapeutic agents, specifically paclitaxel and related compounds in the treatment of pancreatic cancer.

Ionizing radiation potentiates the oncolytic activity of attenuated herpes simplex viruses in tumors exposed to irradiation at specific time intervals by inducing higher virus yields. Cell culture studies have shown that an attenuated virus lacking the viral γ134.5 genes underproduces late proteins whose synthesis depends on sustained synthesis of viral DNA. Here we report that ionizing radiation enhances gene expression from late viral promoters in transduced cells in the absence of other viral gene products. Consistent with this result, we show that in tumors infected with the attenuated virus, ionizing radiation increases 13.6-fold above baseline the gene expression from a late viral promoter as early as 2 hours after virus infection, an interval too short to account for viral DNA synthesis. The radiation-dependent up-regulation of late viral genes is mediated by the p38 pathway, inasmuch as the enhancement is abolished by p38 inhibitors or a p38 dominant-negative construct. The p38 pathway is not essential for wild-type virus gene expression. The results suggest that ionizing radiation up-regulates late promoters active in the course of viral DNA synthesis and provide a rationale for use of radiation to up-regulate cytotoxic genes introduced into tumor cells by viral vectors for cytoreductive therapy.

The gut has often been suggested to be one of the essential factors in the pathogenesis of many nosocomial infections and possibly multi-organ failure. In the light of several recent studies, the importance of normal gut bacterial flora and the role of the gastrointestinal tract in human immune function are now better understood. It now seems clear that stimulation of gut-associated lymphoid tissue through enteral feeding is the key to the preservation of mucosal-derived immunity; however, the role of this native gastrointestinal immune function in the subsequent development of sepsis and multi-organ dysfunction syndrome remains the subject of ongoing study.

Targeting cancer cells, as well as the nonmalignant stromal cells cross-presenting the tumor antigen (Ag), can lead to the complete destruction of well-established solid tumors by adoptively transferred Ag-specific cytotoxic T lymphocytes (CTLs). If, however, cancer cells express only low levels of the Ag, then stromal cells are not destroyed, and the tumor escapes as Ag loss variants. We show that treating well-established tumors expressing low levels of Ag with local irradiation or a chemotherapeutic drug causes sufficient release of Ag to sensitize stromal cells for destruction by CTLs. This was shown directly using high affinity T cell receptor tetramers for visualizing the transient appearance of tumor-specific peptide–MHC complexes on stromal cells. Maximum loading of tumor stroma with cancer Ag occurred 2 d after treatment and coincided with the optimal time for T cell transfer. Under these conditions, tumor rejection was complete. These findings may set the stage for developing rational clinical protocols for combining irradiation or chemotherapy with CTL therapy.