Selective breast/gynecologic pathology fellowship training in the United States: Experience of program directors.

Published data on combined breast and gynecologic [breast/gyn] surgical pathology fellowship training programs are limited. Our study aimed to survey the landscape of such fellowships in the United States (US), including specific information about their characteristics and the educational activities therein. Using web searches, we identified programs offering combined breast/gyn surgical pathology fellowship training. We developed a 26-item questionnaire asking program directors to report on the characteristics of their fellowship training structure. The search revealed 25 academic based programs offering one-year combined breast/gyn fellowship training, predominantly located (40 %) in the Northeast area. The following data was obtained: 44 % of the programs were accredited by the ACGME, 82 % required >19 weeks of breast and gyn service, and 69.6 % accepted the common application, 54.5 % of programs require completion of a research project for graduation. An annual average of 3000 breast and 3000 gyn cases appears to be the usual volume of cases. Interestingly, only 36 % of the program directors are graduates of a combined breast/gyn fellowship program. In conclusion, we present the most comprehensive and up-to-date census of combined breast/gyn pathology fellowships in the US. Our study provides valuable information on the current state of combined breast/gyn pathology fellowship training. The information will be helpful to current and prospective trainees, as well as program leaders.

The calcium channel TRPC6 promotes chemotherapy-induced persistence by regulating integrin α6 mRNA splicing.

Understanding the cell biological mechanisms that enable tumor cells to persist after therapy is necessary to improve the treatment of recurrent disease. Here, we demonstrate that transient receptor potential channel 6 (TRPC6), a channel that mediates calcium entry, contributes to the properties of breast cancer stem cells, including resistance to chemotherapy, and that tumor cells that persist after therapy are dependent on TRPC6. The mechanism involves the ability of TRPC6 to regulate integrin α6 mRNA splicing. Specifically, TRPC6-mediated calcium entry represses the epithelial splicing factor ESRP1 (epithelial splicing regulatory protein 1), which enables expression of the integrin α6B splice variant. TRPC6 and α6B function in tandem to facilitate stemness and persistence by activating TAZ and, consequently, repressing Myc. Therapeutic inhibition of TRPC6 sensitizes triple-negative breast cancer (TNBC) cells and tumors to chemotherapy by targeting the splicing of α6 integrin mRNA and inducing Myc. These data reveal a Ca2+-dependent mechanism of chemotherapy-induced persistence, which is amenable to therapy, that involves integrin mRNA splicing.

O-linked α2,3 sialylation defines stem cell populations in breast cancer.

We pursued the hypothesis that specific glycans can be used to distinguish breast cancer stem cells (CSCs) and influence their function. Comparison of CSCs and non-CSCs from multiple breast cancer models revealed that CSCs are distinguished by expression of α2,3 sialylated core2 O-linked glycans. We identified a lectin, SLBR-N, which binds to O-linked α2,3 sialic acids, that was able to enrich for CSCs in vitro and in vivo. This O-glycan is expressed on CD44 and promotes its interaction with hyaluronic acid, facilitating CD44 signaling and CSC properties. In contrast, FUT3, which contributes to sialyl Lewis X (sLeX) production, is preferentially expressed in the non-CSC population, and it antagonizes CSC function. Collectively, our data indicate that SLBR-N can be more efficient at enriching for CSCs than CD44 itself because its use avoids the issues of CD44 splicing and glycan status. These data also reveal how differential glycosylation influences CSC fate.

Educational Case: HER-2 Positive Breast Cancer.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. 1.

Insulin Receptor Substrate-1 (IRS-1) and IRS-2 expression levels are associated with prognosis in non-small cell lung cancer (NSCLC).

The insulin-like growth factor-1 (IGF-1) signaling pathway has been implicated in non-small cell lung cancer (NSCLC) outcomes and resistance to targeted therapies. However, little is known regarding the molecular mechanisms by which this pathway contributes to the biology of NSCLC. The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor proteins that signal downstream of the IGF-1R and determine the functional outcomes of this signaling pathway. In this study, we assessed the expression patterns of IRS-1 and IRS-2 in NSCLC to identify associations between IRS-1 and IRS-2 expression levels and survival outcomes in the two major histological subtypes of NSCLC, adenocarcinoma (ADC) and squamous cell carcinoma (SCC). High IRS-2 expression was significantly associated with decreased overall survival in adenocarcinoma (ADC) patients, whereas low IRS-1 cytoplasmic expression showed a trend toward association with decreased overall survival in squamous cell carcinoma (SCC) patients. Tumors with low IRS-1 and high IRS-2 expression were found to be associated with poor outcomes in ADC and SCC, indicating a potential role for IRS-2 in the aggressive behavior of NSCLC. Our results suggest distinct contributions of IRS-1 and IRS-2 to the biology of ADC and SCC that impact disease progression.

Differential involvement of the microtubule cytoskeleton in insulin receptor substrate 1 (IRS-1) and IRS-2 signaling to AKT determines the response to microtubule disruption in breast carcinoma cells.

The insulin receptor substrate (IRS) proteins serve as essential signaling intermediates for the activation of PI3K by both the insulin-like growth factor 1 receptor (IGF-1R) and its close family member, the insulin receptor (IR). Although IRS-1 and IRS-2 share significant homology, they regulate distinct cellular responses downstream of these receptors and play divergent roles in breast cancer. To investigate the mechanism by which signaling through IRS-1 and IRS-2 results in differential outcomes, we assessed the involvement of the microtubule cytoskeleton in IRS-dependent signaling. Treatment with drugs that either stabilize or disrupt microtubules reveal that an intact microtubule cytoskeleton contributes to IRS-2- but not IRS-1-mediated activation of AKT by IGF-1. Proximal IGF-1R signaling events, including IRS tyrosine phosphorylation and recruitment of PI3K, are not inhibited by microtubule disruption, indicating that IRS-2 requires the microtubule cytoskeleton at the level of downstream effector activation. IRS-2 colocalization with tubulin is enhanced upon Taxol-mediated microtubule stabilization, which, together with the signaling data, suggests that the microtubule cytoskeleton may facilitate access of IRS-2 to downstream effectors such as AKT. Of clinical relevance is that our data reveal that expression of IRS-2 sensitizes breast carcinoma cells to apoptosis in response to treatment with microtubule-disrupting drugs, identifying IRS-2 as a potential biomarker for the response of breast cancer patients to Vinca alkaloid drug treatment.

Retrospective Analysis of Point-of-Care and Laboratory-Based Hemoglobin A1c Testing.

BACKGROUND: Glycemic control is essential to diabetic management, and hemoglobin A1c (Hb A1c) has long been used for this purpose. Though laboratory-based testing is standard, point-of-care (POC) systems provide rapid results in clinic, allowing more timely patient management. A negative bias with POC testing has been observed, and our aim is to further characterize these discrepancies at our institution. METHODS: A medical record search identified patients who underwent laboratory-based and/or POC Hb A1c testing (DCA Vantage™) at our medical center from July 2015 to April 2016. Patients who underwent both tests within 30 days were grouped by age, sex, and test interval (same day, <1 day, ≤15 days, or ≤30 days). Mean laboratory-based and POC values were compared using the paired t-test. Correlation statistics were determined using the Deming regression. RESULTS: In total, 40503 data points were gathered from the database, comprising 28555 laboratory-based Hb A1c tests and 11948 POC-based Hb A1c tests. A total of 28292 unique patients were identified, of which 493 underwent both tests within 30 days. While DCA and laboratory-based testing was highly correlated, there was a mean negative bias of 0.18% with POC testing. Bias was greater for women [0.17% higher (95% CI, 0.063%-0.284%), P = 0.002] and children aged 0-13 years [0.52% higher (95% CI, 0.141%-0.891%), P = 0.007]. CONCLUSIONS: There is a consistent negative bias with POC testing, most pronounced in the female and pediatric populations. Further studies will determine what variables contribute to this discrepancy and how clinical management is modified. POC testing using the DCA Vantage should be interpreted cautiously.

Overdiagnosis of HSIL on cervical biopsy: errors in p16 immunohistochemistry implementation.

In 2012, the lower anogenital squamous terminology (LAST) project introduced new nomenclature for human papillomavirus-related squamous lesions of the lower genital tract: low-grade and high-grade squamous intraepithelial lesion (LSIL and HSIL). Biomarker p16(INK4a) immunohistochemistry (IHC) was also recommended to assist classification: block-like positive staining supports the diagnosis of HSIL. We aim to assess the impact of LAST recommendations on our practice as well as to identify challenges and errors in p16 IHC implementation. We studied 262 cervical biopsies meeting 3 criteria: (1) HSIL diagnosis; (2) p16 IHC performed at time of diagnosis; and (3) patient's follow-up more than 12 months, including cervical cytology, biopsy, and excision. Among these patients, subsequent loop electrosurgical excision procedure and surveillance revealed 163 HSILs (62%), 28 LSILs (11%), and 71 "nondysplastic changes" (27%). We reviewed the latter 2 groups' original hematoxylin and eosin and p16 IHC slides. The diagnosis of HSIL was confirmed in 49 cases (49%), whereas 50 (51%) were reclassified as LSIL (n=46) or negative for dysplasia (n=4). These cases were initially overdiagnosed as HSIL because pathologists (1) overused p16 IHC on unequivocal LSIL (n=27) or (2) upgraded questionable lesions to HSIL based on nonblock p16 staining patterns (patchy or focal, n=23). To implement LAST recommendations successfully, we advocate judicious use of p16 in the designated circumstances and careful interpretation of staining patterns in the context of morphology. A standardized threshold for p16 positivity and supplementary guidance will help clarify the biomarker's utility and will facilitate LAST implementation in routine practice.

Importance of thinking locally for mental health: data from cross-sectional surveys representing South East London and England.

BACKGROUND: Reliance on national figures may be underestimating the extent of mental ill health in urban communities. This study demonstrates the necessity for local information on common mental disorder (CMD) and substance use by comparing data from the South East London Community Health (SELCoH) study with those from a national study, the 2007 English Adult Psychiatric Morbidity Study (APMS). METHODOLOGY/PRINCIPAL FINDINGS: Data were used from two cross-sectional surveys, 1698 men and women residing in south London and 7403 men and women in England. The main outcome, CMD, was indicated by a score of 12 or above on the Revised Clinical Interview Schedule. Secondary outcomes included hazardous alcohol use and illicit drug use. SELCoH sample prevalence estimates of CMD were nearly twice that of the APMS England sample estimates. There was a four-fold greater proportion of depressive episode in the SELCoH sample than the APMS sample. The prevalence of hazardous alcohol use was higher in the national sample. Illicit drug use in the past year was higher in the SELCoH sample, with cannabis and cocaine the illicit drugs reported most frequently in both samples. In comparisons of the SELCoH sample with the APMS England sample and the APMS sample from the Greater London area in combined datasets, these differences remained after adjusting for socio-demographic and socioeconomic indicators for all outcomes. CONCLUSIONS/SIGNIFICANCE: Local information for estimating the prevalence of CMD and substance use is essential for surveillance and service planning. There were similarities in the demographic and socioeconomic factors related to CMD and substance use across samples.

Membrane localization of insulin receptor substrate-2 (IRS-2) is associated with decreased overall survival in breast cancer.

Recent studies have identified a role for insulin receptor substrate-2 (IRS-2) in promoting motility and metastasis in breast cancer. However, no published studies to date have examined IRS-2 expression in human breast tumors. We examined IRS-2 expression by immunohistochemistry (IHC) in normal breast tissue, benign breast lesions, and malignant breast tumors from the institutional pathology archives and a tumor microarray from a separate institution. Three distinct IRS-2 staining patterns were noted: diffusely cytoplasmic, punctate cytoplasmic, and localized to the cell membrane. The individual and pooled datasets were analyzed for associations of IRS-2 staining pattern with core clinical parameters and clinical outcomes. Univariate analysis revealed a trend toward decreased overall survival (OS) with IRS-2 membrane staining, and this association became significant upon multivariate analysis (P = 0.01). In progesterone receptor negative (PR-) tumors, in particular, IRS-2 staining at the membrane correlated with significantly worse OS than other IRS-2 staining patterns (P < 0.001). When PR status and IRS-2 staining pattern were evaluated in combination, PR- tumors with IRS-2 at the membrane were associated with a significantly decreased OS when compared with all other combinations (P = 0.002). Evaluation of IRS-2 staining patterns could potentially be used to identify patients with PR- tumors who would most benefit from aggressive treatment.