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Introduction: Menthol smokers (particularly African-Americans) have lower cessation success rates than non-menthol smokers. With bans being considered on characterising menthol flavour in cigarettes, data are needed regarding how switching to non-menthol cigarettes impacts cessation measures., Methods: In this randomised pilot study, African-American menthol cigarette smokers interested in quitting smoking either continued smoking menthol cigarettes (n=60) or switched to non-menthol cigarettes (n=62) for a 1-month period prior to a cessation attempt. The primary endpoint was time to smoking lapse (ie, time from quitting until any smoking). Additional endpoints included time to smoking relapse (ie, number of days from quitting until the first of seven consecutive smoking days) and difference between groups in subjective measures., Results: After attempting to quit, the non-menthol cigarette group had indications of delayed time to lapse (HR 0.82; 95% CI 0.55 to 1.22; p=0.33) and time to relapse (HR 0.67; 95% CI 0.42 to 1.06; p=0.09), although these were not statistically significant. Post hoc analyses suggest that observed differences were largely due to a smaller proportion of participants in the non-menthol group relapsing within the first day of quitting (21% vs 40%; p=0.05). Values of other measures assessed postcessation were largely similar between groups., Conclusions: These data suggest that among African-American smokers, a menthol cigarette ban would not undermine short-term cessation measures and may result in some benefits. Future research is needed to assess longer term cessation rates and to identify interventions to maximise cessation success in the event of a menthol ban., Trial Registration Number: NCT02342327., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: People living with human immunodeficiency virus (PLWH) initiating antiretroviral therapy (ART) with viral loads (VLs) ≥100 000 copies/mL are less likely to achieve virologic success, but few studies have characterized real-world treatment outcomes., Methods: ART-naive PLWH with VLs ≥100 000 copies/mL initiating dolutegravir (DTG), elvitegravir (EVG), raltegravir (RAL), or darunavir (DRV) between 12 August 2013 and 31 July 2017 were identified from the OPERA database. Virologic failure was defined as ( i ) 2 consecutive VLs ≥200 copies/mL after 36 weeks of ART; ( ii ) 1 VL ≥200 copies/mL with core agent discontinuation after 36 weeks; ( iii ) 2 consecutive VLs ≥200 copies/mL after suppression (≤50 copies/mL) before 36 weeks; or ( iv ) 1 VL ≥200 copies/mL with discontinuation after suppression before 36 weeks. Cox modeling estimated the association between regimen and virologic failure., Results: There were 2038 ART-naive patients with high VL who initiated DTG (36%), EVG (46%), DRV (16%), or RAL (2%). Median follow-up was 18.1 (interquartile range, 12.4-28.9) months. EVG and DTG initiators were similar at baseline, but RAL initiators were older and more likely to be female with low CD4 cell counts while DRV initiators differed notably on factors associated with treatment failure. Virologic failure was experienced by 9.2% DTG, 13.2% EVG, 18.4% RAL, and 18.8% DRV initiators. Compared to DTG, the adjusted hazard ratio (95% confidence interval) was 1.46 (1.05-2.03) for EVG, 2.24 (1.50-3.34) for DRV, and 4.13 (1.85-9.24) for RAL., Conclusions: ART-naive PLWH with high VLs initiating on DTG were significantly less likely to experience virologic failure compared to EVG, RAL, and DRV initiators.Antiretroviral therapy-naïve people living with HIV (PLWH) initiating therapy with viral loads ≥100,000 copies/mL varied markedly at baseline. In adjusted models, PLWH initiating dolutegravir-based regimens were less likely to experience virologic failure as compared to elvitegravir, raltegravir and darunavir initiators., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: ST-segment elevation myocardial infarction (STEMI) predominantly affects older adults. Lower incidence among younger patients may challenge diagnosis., Objectives: We hypothesize that among patients ≤ 50 years old, emergent percutaneous coronary intervention (PCI) for STEMI is delayed when compared with patients aged > 50 years., Methods: This 3-year, 10-center retrospective cohort study included emergency department (ED) STEMI patients ≥ 18 years of age treated with emergent PCI. We excluded patients with an electrocardiogram (ECG) completed prior to ED arrival or a nondiagnostic initial ECG. Our primary outcome was door-to-balloon (D2B) time. We compared characteristics and outcomes among younger vs. older STEMI patients, and among age subgroups., Results: There were 576 ED STEMI PCI patients, of whom 100 were ≤ 50 years old and 476 were > 50 years old. Median age was 44 years in the younger cohort (interquartile range [IQR] 41-47) vs. 62 years (IQR 57-70) among older patients. Median D2B time for the younger cohort was 76.5 min (IQR 67.5-102.5) vs. 81.0 min (IQR 65.0-105.5) in the older cohort (p = 0.91). This outcome did not change when ages 40 or 45 years were used to demarcate younger vs. older. The younger cohort had a higher prevalence of nonwhite races (38% vs. 21%; p < 0.001) and those currently smoking (36% vs. 23%; p = 0.005). The very young (≤30 years; 6/576) and very old (>80 years; 45/576) had 5.51 and 2.2 greater odds of delays., Conclusion: We found no statistically significant difference in D2B times between patients ≤ 50 years old and those > 50 years old. Nonwhite patients and those who smoke were disproportionately represented within the younger population. The very young and very old had higher odds of D2B times > 90 min., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Uterine sarcomas with variable CD34 and S100 expression represent an emerging class of tumor in the female genital tract which commonly presents in the endocervix of premenopausal women. Initial molecular characterization identified NTRK1 and NTRK3 gene fusions as oncogenic drivers in these tumors; however, the repertoire of genetic alterations is likely more diverse given the recent discovery of PDGFB and RET gene fusions in similarly described tumors. Importantly, these fusion events lead to the aberrant activation of kinases that are potentially therapeutically targetable; therefore, recognizing this class of tumor becomes critical for initiating the molecular testing required for an accurate diagnosis and identification of clinically actionable fusions. Here, we report our institutional experience with 12 cases of uterine spindle cell sarcomas harboring kinase-related fusions. Patients ranged from 21 to 80 years old (median, 38 y) and presented either asymptomatically or with pelvic pain and/or uterine bleeding. Eleven (92%; 11/12) tumors were localized to the cervix and 1 (8%; 1/12) tumor was localized in the anterior fundus of the uterine corpus. Tumors ranged in size from 1.5 to 15.0 cm (median, 6.0 cm) and were histologically characterized by a moderately cellular, infiltrative proliferation of spindle cells with features of benign gland entrapment, stromal collagen deposition, perivascular hyalinization, occasionally myxoid stroma, a lymphocytic infiltrate, occasional nuclear pseudoinclusions, and a pseudophyllodes architecture. RNA-sequencing identified NTRK1 (8/12), NTRK3 (1/12), and PDGFB (2/12) gene fusions, which have been previously implicated in this tumor class, as well as a novel FGFR1-TACC1 (1/12) fusion. All tumors in this cohort showed coexpression of CD34 and S100 by immunohistochemistry except for those tumors with PDGFB fusions which showed solely CD34 expression. Of the 10 surgically resected tumors with follow-up, outcomes best correlated with the stage of disease. One of 4 patients with stage IA tumors (1/4) had recurrences, half of the stage IB (2/4) tumors had recurrences and all of the stage IIB tumors (2/2) had recurrences and died of disease. Future studies are still required to better understand the spectrum of genetic alterations as well as evaluate the efficacy of targeted kinase inhibitors in this class of tumor., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Suppression of the immune system is intimately linked to the development and progression of malignancy, and immune modulating treatment options have shown promise in a variety of tumor types, including some triple-negative breast cancers (TNBC). The most dramatic therapeutic success has been seen with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand, PD-L1. Difficulty remains, however, in appropriate patient selection for treatment, as many PD-L1-positive cancers fail to show durable responses to PD-1/PD-L1 inhibition. Checkpoint inhibitor targeting of the adaptive immune response relies on the presence of major histocompatibility complex (MHC) class I molecules on the tumor cell surface for tumor antigen presentation. MHC class I loss has been previously described in breast cancer and represents a putative mechanism of immunotherapeutic resistance in this tumor type. One hundred seventeen invasive primary breast carcinomas with a range of histologic subtypes were evaluated on tissue microarrays containing formalin-fixed paraffin-embedded tissue. Loss of MHC class I expression was common among breast cancers, with greater than half of cases demonstrating either subclonal or diffuse loss. Fifty-nine percent of TNBC demonstrated loss of MHC class I, including 46% of those meeting the Food and Drug Administration-approved threshold of 1% for tumor-associated immune cell PD-L1 expression. MHC class I loss was particularly common in the apocrine subtype of TNBC (78%). MHC class I's employment as a predictive biomarker should be considered, as its loss may represent a barrier to successful enhancement of the antitumor adaptive immune response by PD-1/PD-L1 inhibition., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Major histocompatibility complex (MHC) class I is a membrane-bound protein complex expressed on nucleated human cells. MHC class I presents intracellular protein fragments to cytotoxic T cells and triggers an activation cascade upon neoantigen detection by these cells. MHC class I loss by tumor cells decreases tumor neoantigen presentation to the immune system and therefore represents a possible mechanism of immunotherapeutic resistance even among cancers that otherwise appear to be good candidates for checkpoint inhibition, such as mismatch repair (MMR)-deficient and PD-L1-positive malignancies. We herein assess MHC class I expression in a range of endometrial carcinomas, including MMR-deficient and PD-L1-positive cancers. Immunohistochemical staining for combined MHC class I A-, B-, and C-heavy chains was performed on 76 cases of endometrial carcinoma and was classified as present, subclonally lost, or diffusely lost. Tumoral PD-L1 expression, PD-L1 combined positive score, and CD3-positive T lymphocytes were also quantified. Forty-two percent of tumors showed loss of MHC class I expression, either in a subclonal (26%) or diffuse (16%) pattern. This included 46% of MMR-deficient and 25% of PD-L1-positive cancers. These findings suggest that tumoral MHC class I status may be an important factor to consider when selecting endometrial cancer patients for checkpoint inhibition.

Despite higher stages at presentation, patients with high-risk (HR) HPV-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) have better survival rates compared to those with non-HPV-related (HPV-) disease. However, significant comorbidity and the number of patients who suffer failed treatment, recurrent disease, late metastasis, and death are increasing along with the incidence of HPV+ HNSCC. A cytotoxic T-cell-dependent immune response is required to clear these antigenic cancers. This provides a unique opportunity to employ immune modulators in therapy. Galectin-3 (Gal-3) is a lectin and glycoprotein involved in numerous immunosuppressive functions. Inhibitors are currently under clinical investigation for various diseases. Gal-3 expression was evaluated in HR-HPV+ and HPV- HNSCCs and regional lymph node metastases by tissue microarray. HR-HPV+ cases were more likely to be Gal-3-positive (Gal+) [50% (14/28)] than HPV- cases [18% (9/50), p = 0.004]. No difference in the number of Gal+ cases was identified between primary [30% (16/53)] and metastatic [28% (7/25)] cancers (p = 1); 53% (9/17) of primary HPV+ cancers were Gal+ and 45% (5/11) of metastatic HPV+ cancers were Gal+ (p = 1). Nineteen percent (7/36) of primary HPV- cancers were Gal+ and 14% (2/14) of metastatic HPV- cancers were Gal+ (p = 1). Gal-3 positivity was observed in a subset of HNSCC, suggesting a potential role for therapeutic inhibition in this tumor type. The significantly higher rates of expression seen in HR-HPV+ versus HPV- HNSCC suggest particular promise in the setting of HPV infection. The relatively consistent Gal-3 expression rates observed between metastatic and primary tumors argues against progressive Gal-3 expression in metastasis.

Precursor lesions of vulvar squamous cell carcinoma (VSCC) can be divided into two major biologic and prognostic groups: HPV-associated and HPV-independent VSCC. These two pathways are categorized as usual vulvar intraepithelial neoplasia (uVIN) with progression to basaloid or warty VSCC and differentiated vulvar intraepithelial neoplasia (dVIN) with progression to the more common keratinizing VSCC. While the HPV-dependent pathway to squamous cell carcinoma is well-understood, the development of squamous cell carcinoma from HPV-independent lesions is less clear. The majority of HPV-independent lesions fall into the dVIN category, and mutations in TP53 have been implicated as the driver behind their development. Other less common HPV-independent precursor lesions, termed differentiated exophytic vulvar intraepithelial lesion (DEVIL) and vulvar acanthosis with altered differentiation (VAAD), have also been characterized as precursors to keratinizing and verrucous VSCC. Inflammatory conditions of the vulva such as lichen sclerosus and lichen simplex chronicus also put patients at risk for developing VSCC. We herein evaluate the available evidence and biologic basis for these VSCC precursor lesions, among other speculated entities, and discuss their clinical, diagnostic, and prognostic features., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: PARKIN is an E3 ubiquitin ligase that regulates mitochondrial quality control through a process called mitophagy. Recent human and rodent studies suggest that loss of hepatic mitophagy may occur during the pathogenesis of obesity-associated fatty liver and contribute to changes in mitochondrial metabolism associated with this disease. Whole-body Prkn knockout mice are paradoxically protected against diet-induced hepatic steatosis; however, liver-specific effects of Prkn deficiency cannot be discerned in this model due to pleotropic effects of germline Prkn deletion on energy balance and subsequent protection against diet-induced obesity. We therefore generated the first liver-specific Prkn knockout mouse strain (LKO) to directly address the role of hepatic Prkn., Methods: Littermate control (WT) and LKO mice were fed regular chow (RC) or high-fat diet (HFD) and changes in body weight and composition were measured over time. Liver mitochondrial content was assessed using multiple, complementary techniques, and mitochondrial respiratory capacity was assessed using Oroboros O 2 K platform. Liver fat was measured biochemically and assessed histologically, while global changes in hepatic gene expression were measured by RNA-seq. Whole-body and tissue-specific insulin resistance were assessed by hyperinsulinemic-euglycemic clamp with isotopic tracers., Results: Liver-specific deletion of Prkn had no effect on body weight or adiposity during RC or HFD feeding; however, hepatic steatosis was increased by 45% in HFD-fed LKO compared with WT mice (P < 0.05). While there were no differences in mitochondrial content between genotypes on either diet, mitochondrial respiratory capacity and efficiency in the liver were significantly reduced in LKO mice. Gene enrichment analyses from liver RNA-seq results suggested significant changes in pathways related to lipid metabolism and fibrosis in HFD-fed Prkn knockout mice. Finally, whole-body insulin sensitivity was reduced by 35% in HFD-fed LKO mice (P < 0.05), which was primarily due to increased hepatic insulin resistance (60% of whole-body effect; P = 0.11)., Conclusions: These data demonstrate that PARKIN contributes to mitochondrial homeostasis in the liver and plays a protective role against the pathogenesis of hepatic steatosis and insulin resistance., (Copyright © 2020 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Ovarian high-grade serous carcinomas (HGSC) have shown lackluster responses to immunotherapies targeting the PD-1/PD-L1 axis, perhaps due to the coexistence of other mechanisms of immune evasion in this tumor type. Lymphocyte activation gene-3 (LAG-3) is another inhibitory immune checkpoint often expressed on tumor-associated lymphocytes which is targeted by drugs currently in clinical trials. Forty-eight HGSC with known germline BRCA mutation status were immunohistochemically stained for LAG-3, CD8, and FOXP3. Positive tumor-associated lymphocytes were enumerated and averaged over 10 high-power fields (HPF). PD-L1 immunostaining was also preformed and expression was evaluated on tumor cells and using the combined positive score (CPS). The average number of LAG-3-positve tumor-associated lymphocytes was 6/HPF (range: 0-25.6). Cytotoxic (CD8) T cells averaged 30/HPF (range: 0-168.9), and regulatory (FOXP3) cells averaged 6.6/HPF (range: 0-76.3). Tumoral PD-L1 expression of ≥1% was observed in 27% (13/48) of cases, with only 8% (4/48) showing >5% staining; 81% (39/48) cases had a CPS ≥1. LAG-3-positive lymphocytes and PD-L1 expression were positively correlated, even after controlling for the overall level of CD8 and FOX3P lymphocyte infiltration. Germline BRCA status was not significantly associated with LAG-3, CD8, FOXP3, or PD-L1 expression. These findings indicate that immunotherapies targeting LAG-3 may benefit some ovarian HGSC patients, particularly when used in conjunction with anti-PD-1/PD-L1 approaches. The typically limited expression of LAG-3 and PD-L1 suggests that immunotherapeutic response may be muted in most HGSC even with a combination approach.

Tumor cell expression of major histocompatibility complex (MHC) class I is required for antigen presentation and adaptive immune recognition. Absent or diminished MHC class I expression is thought to contribute to immunotherapeutic resistance in some epithelial tumors but has not been previously studied in cervical and vulvar carcinoma. Given that anti-programmed cell death 1 (PD-1) checkpoint inhibition is deployed for programmed cell death ligand 1 (PD-L1)-positive recurrent and metastatic cervical squamous carcinomas, identifying tumors with loss of MHC class I is of clinical interest to optimize the selection of immunotherapeutic candidates. Immunohistochemistry for PD-L1 and MHC class I combined A, B, and C heavy chains (MHC class I) was assessed in 58 human papillomavirus-associated cervical and vulvar lesions, including 27 squamous intraepithelial lesions (SILs) and 31 invasive squamous cell carcinoma (SCC). Although 84% of SCC and 22% of SIL were PD-L1-positive, 35.5% (11/31) of SCC and 18.5% (5/27) of SIL also showed clonal or complete loss of MHC class I. Loss of MHC class I expression was more common in PD-L1-positive (10/26, 38%) versus PD-L1-negative SCC (1/5, 20%). In summary, over one third of human papillomavirus-associated cervical and vulvar SCC show clonal or complete loss of MHC class I expression, including many PD-L1-positive cases. This suggests that the efficacy of checkpoint inhibitors targeting the PD-1/PD-L1 axis may be limited in a subset of cervical and vulvar squamous neoplasms due to an impaired ability to engage with the adaptive immune system related to loss of MHC class I expression.

Immunotherapies targeting the PD-1/PD-L1 pathway have shown some success in cervical and vulvar squamous cell carcinomas, but little is known about the potential vulnerability of these tumors to other checkpoint inhibitors. TIM-3 is a checkpoint molecule that exerts immunosuppressive function via its interaction with Gal-9. TIM-3 and Gal-9 have been identified on a variety of malignancies but have not been studied in cervical and vulvar cancers, nor has their relationship to PD-L1 been established. Sixty-three cervical and vulvar invasive (n = 34) and intraepithelial lesions (n = 29) were assessed for TIM-3, Gal-9, and PD-L1 in tumor/lesional cells and associated immune cells. Tumoral TIM-3 expression was identified in 85% of squamous cell carcinomas but only 21% of intraepithelial lesions (p < 0.0001). When immune cells were also accounted for, 97% of invasive and 41% of intraepithelial lesions had a TIM-3 combined positive score (CPS) ≥ 1 (p < 0.0001). Tumoral membranous expression of Gal-9 was seen in 82% of squamous cell carcinomas and 31% of intraepithelial lesions (p = 0.0001); nearly all cases had Gal-9-positive immune cells. Tumoral PD-L1 was seen in 71% of squamous cell carcinomas and 10% of intraepithelial lesions (p < 0.0001), while the PD-L1 CPS was ≥1 in 82 and 21%, respectively (p < 0.0001). There were no significant differences in TIM-3, GAL-9, or PD-L1 expression in cervical vs. vulvar neoplasms, nor was HPV status significantly associated with any of the three markers. Dual TIM-3/Gal-9 expression was present in the majority (86%) of PD-L1-positive cases including 100% of PD-L1-positive squamous cell carcinomas, suggesting a possible role for TIM-3 checkpoint inhibition in concert with anti-PD-1/PD-L1.

Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is recommended in endometrial carcinomas as a screening test for Lynch syndrome, and mismatch repair deficiency (MMRd) is reported in ∼30% of cases. However, few studies have evaluated the rate of MMR loss in uterine carcinosarcomas. A 5-year retrospective database search of uterine carcinosarcomas was performed at 3 academic institutions. The histologic diagnoses, type of carcinoma present, and MMR IHC interpretations were confirmed by a gynecologic pathologist. One hundred three cases of uterine carcinosarcomas with available MMR IHC results were identified. Ninety-nine cases (96%) showed intact expression and 4 cases (4%) showed loss of MLH1/PMS2. All MMRd carcinosarcomas identified in this series had an endometrioid carcinomatous component and wild-type p53 expression. In contrast, the majority of MMR intact carcinosarcomas had a serous morphology and aberrant p53 expression. Three additional cases initially diagnosed as carcinosarcoma also revealed MMRd; however, given the lack of clear mesenchymal differentiation, these cases were reclassified as dedifferentiated endometrial carcinomas and were subsequently excluded from the carcinosarcoma category. No cases of Lynch syndrome were identified among carcinosarcoma patients, as all 4 MMRd cases were due to somatic MLH1 hypermethylation. In summary, we found that the rate of MMRd is markedly lower in uterine carcinosarcoma when compared with endometrial carcinoma. In the setting of MMR loss, a diagnosis of dedifferentiated carcinoma should be considered as almost half of the MMRd tumors which were called carcinosarcomas initially were reclassified as dedifferentiated on review. However, given the interobserver variability in the classification of carcinosarcoma versus dedifferentiated carcinoma a universal screening approach that includes uterine carcinosarcoma is still recommended.

The immunocompetence of a community of free-living animals can be affected by seasonality, sex, and parasite burden. However, each of these factors is often examined independently. Recent studies have also found that dehydration can enhance aspects of immunocompetence in drought-adapted species. To explore how all of these factors interact, and their effect on the immune system in mesic-adapted species, we collected blood samples from a community of free-ranging snakes in coastal South Carolina, United States, across 2 years. We specifically examined (a) how sex and seasonality influence humoral and cellular immunocompetence and parasite burden, (b) the dynamics among hydration state, parasite burden, and immunocompetence, and (c) whether mesic-adapted species also show enhanced innate immunity with dehydration. Consistent with previous work on drought-adapted species, we found that dehydration enhances multiple aspects of humoral immunity in mesic species, and we are the first to report that dehydration also enhances aspects of cellular immunocompetence. Contrary to previous results in other squamates, sex and season did not impact immunocompetence or parasite prevalence. Our results also reveal complex interactions among parasite prevalence, immunocompetence, and hydration state demonstrating that hydration state and parasitism are two ubiquitous factors that should continue to be considered in future studies examining ecoimmunological variation., (© 2020 Wiley Periodicals, Inc.)

LAG-3 is an immunosuppressive checkpoint molecule expressed on T cells. One of its ligands, GAL-3, can promote the progression of malignancy and has been identified on tumor cells. Both LAG-3 and GAL-3 are the targets of emerging immunotherapies, but have not been well-studied in endometrial carcinomas. LAG-3, CD3, and GAL-3 immunohistochemistry was performed on 75 endometrial cancers (25 nonmethylated mismatch repair-deficient, 25 MLH1-hypermethylated mismatch repair-deficient, and 25 mismatch repair-intact). LAG-3 and CD3 lymphocytes were averaged per high-power field. Tumoral GAL-3 expression was semiquantitatively scored. Tumor-infiltrating lymphocyte expression of LAG-3 and CD3 were positively correlated (Spearman ρ=0.521, P<0.001) and greater in mismatch repair-deficient compared with mismatch repair-intact tumors (LAG-3: P<0.001; CD3: P<0.001). The majority (64%) of endometrial carcinomas demonstrated ≥1% tumoral GAL-3 expression, with higher rates in mismatch repair-deficient versus intact tumors at the ≥1% (80% vs. 32%, P<0.001) and the ≥5% thresholds (52% vs. 16%, P=0.003). At the ≥5% threshold, nonmethylated mismatch repair-deficient cancers were more likely than intact tumors carcinomas to express GAL-3 (60% vs. 4/25 16%, P=0.003). LAG-3 lymphocytes were positively correlated with GAL-3 expression in nonmethylated mismatch repair-deficient endometrial carcinomas only (Spearman ρ=0.461, P=0.020). LAG-3 tumor-associated lymphocytes and GAL-3 neoplastic cells are common in endometrial carcinomas, particularly in nonmethylated mismatch repair-deficient cancers. This supports a role for immunotherapies targeting LAG-3 and/or GAL-3 in a subset of endometrial carcinomas, potentially in concert with other checkpoint inhibitors.

Objective: Patient satisfaction is emerging as a new health-care metric. We hypothesized that an emergency department (ED) informational pamphlet would significantly improve patient understanding of ED operations and ultimately improve patient satisfaction., Methods: We performed a prospective study of patients presenting to a single tertiary care center ED from April to July 2017. All patients were given a pamphlet on alternating weeks with regular care on opposite weeks and were surveyed upon ED discharge. The primary outcome was patient satisfaction with ED care. Secondary outcomes included patient understanding of various wait times (test results, consultants), discharge process, who was on the care team and what to expect during the ED visit., Results: Four hundred ninety-four patients were included in this study and 266 (54%) were in the control group. Of 228 (46%) patients who were given the pamphlet, 116 (51%) were unaware they received it. Of the remaining 112 (49%) patients who remembered receiving the pamphlet, 43 (38%) stated they read it. Among those reading the pamphlet, only two statements were significant: knowing what to expect during the ED visit (88% vs 71%; P = 0.012) and waiting time for test results (95% vs 75%; P = 0.003) when compared to those who did not receive or read the pamphlet., Conclusion: An ED informational pamphlet, when utilized by patients, does improve patient understanding of some aspects of the ED visit but does not appear to be the best tool to convey all information. Ultimately, sustained improvement in patient satisfaction is a complex and dynamic issue necessitating a multifactorial approach and other methods should be explored., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Introduction: Dolutegravir (DTG), Elvitegravir (EVG), Raltegravir (RAL) and Darunavir (DRV) are commonly prescribed core agents for antiretroviral therapy (ART), and a need exists to compare their clinical effectiveness, as defined by virologic failure risks in real-world settings., Methods: This observational analysis of a US clinical cohort consisted of ART-naïve people living with HIV (PLWH) in the OPERA database initiating DTG-, EVG-, RAL- or DRV-based regimens between August 2013 and July 2016, with follow-up to July 2017. PLWH were observed from first core agent initiation until core agent discontinuation, clinical activity cessation, death, or study end. Key outcomes included viral suppression (HIV RNA < 50 copies/mL) and confirmed virologic failure (two consecutive viral loads > 200 copies/mL or a viral load > 200 copies/mL followed by discontinuation). Association between core agent and time to virologic failure was assessed with multivariate Cox proportional hazards models., Results: Overall, 4049 ART-naïve PLWH initiated EVG (47.4%), DTG (34.7%), DRV (14.6%), or RAL (3.2%). DTG and EVG initiators had generally similar baseline demographics and clinical characteristics, including race, risk of infection, baseline viral load, and baseline CD4 levels. RAL and DRV initiators were older and generally sicker than DTG initiators. During follow-up, more DTG initiators achieved virologic suppression (78.7%) compared with EVG (73.6%; p < 0.05), RAL (51.9%; p < 0.0001) and DRV (48.6%; p < 0.0001) initiators. Compared to DTG, both RAL and DRV were associated with higher rates of virologic failure, with adjusted hazard ratios (95% confidence interval) of 4.70 (3.03, 7.30) and 2.38 (1.72, 3.29), respectively. No difference was observed between EVG and DTG with an adjusted hazard ratio of 1.24 (0.94, 1.64)., Conclusion: In this large cohort representative of PLWH in care in the US, ART-naïve PLWH prescribed DTG had better virologic outcomes than RAL and DRV, but had virologic failure risks comparable to EVG, although RAL and DRV were preferentially prescribed to sicker individuals., Funding: ViiV Healthcare.

In this perspective piece, we describe a multifactorial phenomenon whereby academic women physicians become invisible in the mid-career stage. Barriers, both small and large, cause a cumulative inequity effect, and women may leave academic medicine. Certainly, family and lifestyle choices play a role. And as we describe, so is a situation created where women become discouraged and disillusioned. We describe the growing evidence of subtle disparities, or micro-inequities, that cause women to be less visible and marginalized. Over time, early career women transition to mid-career with an accumulation of these micro-inequities. Women have more difficulty in building their academic portfolios and curriculum vitae-core components of academic promotion. They comprise greater than 50% of the health care workforce; yet, they are underrepresented in top leadership positions. For example, only 22% of full professors, 18% of department chairs, and 17% of medical school deans are women. Macro-inequities, which are observable and measurable, are also well documented. For example, women receive less compensation than men for the same job. We examine the contributing and causative processes and offer suggestions on how to promote equity among highly qualified mid-career women as they graduate from training and move beyond the early career stage.

Problem: Gender inequity in academic medicine is a pervasive challenge. Recommendations have been implemented to reduce inequities for female faculty. However, there are no well-established guidelines for the recruitment and retention of female residents., Approach: To address challenges faced by female physicians and support the recruitment and retention of female residents, female emergency medicine residents and attending physicians at the Hospital of the University of Pennsylvania formed a professional development group (PDG), #Shemergency, in July 2017. From July 2017 to July 2018, this PDG developed events and initiatives for female residents that addressed methods to improve awareness of and develop skills relevant to well-described gender disparities in mentorship, speakership and conference representation, compensation, evaluations, wellness and service, and award recognition., Outcomes: Over its first year (July 2017-July 2018), the PDG created a professional community and enhanced mentorship through a number of events and initiatives. The PDG secured funding for 5 residents to attend a national conference and nominated 5 residents and 2 attending physicians for professional organization awards (4 nominees won)., Next Steps: After the first year, the PDG expanded the number of joint activities with both male and female colleagues and organized a citywide event for female residents and faculty representing 5 different residency programs. Future work will focus on sustainability (e.g., holding fundraising events), generalizability (e.g., expanding the gender-disparity areas addressed as well as spreading the model to other programs), developing additional events and initiatives (e.g., expanding the number of joint activities with male colleagues), and outcome assessments (e.g., distributing pre- and postevent surveys).

Background: Smokers are often advised to use nicotine lozenge after cravings or withdrawal symptoms are present, which may be too late to prevent lapses. This study assesses if lozenge use prior to smoking cue exposure attenuates cue-induced increases in symptom severity., Methods: In this randomized, cross-over study, participants completed three laboratory sessions at which they proceeded through 4 "rooms" in a virtual reality environment. The first and last "rooms" contained neutral cues and the others contained smoking cues. At one session, a 4 mg nicotine lozenge was not given until after cue exposure (to approximate current use: i.e., after craving and withdrawal symptoms occur). At the other two sessions either a nicotine or placebo lozenge was used 15 min before cue exposure procedures. Craving and withdrawal symptoms were measured throughout each laboratory session., Results: Of 58 participants randomized; 40 completed all 3 labs. Absolute levels of craving and withdrawal symptom severity during cue exposure were lower when placebo or active lozenge was used prior to cue presentation procedures vs. no treatment until after cue presentation procedures (all p-values <0.05). There were no differences among conditions in the magnitude of symptom severity increase occurring between the first neutral room and the cue rooms., Conclusions: Lozenge use prior to cue exposure may minimize cue induced symptom severity but when taken 15 min prior to cues the decrease is not different than placebo. Research is needed to determine if another time-frame relative to cue exposure would be more effective., (Copyright © 2019 Elsevier B.V. All rights reserved.)

GATA binding protein 3 (GATA3) immunohistochemistry is primarily used as a marker of breast and urothelial differentiation, particularly in metastatic settings. In the gynecologic tract it also serves a robust marker for mesonephric and trophoblastic tumors. However, expression has also been described in more common malignancies of gynecologic tract including ovarian, endometrial, and cervical carcinomas. Data on the distribution of GATA3 expression in gynecologic malignancies is somewhat limited, particularly across different histologic subtypes of ovarian, endometrial, and cervical carcinomas. To assess the rates of GATA3 expression among common gynecologic cancers of various histologic types, 100 ovarian carcinomas, 64 endometrial carcinomas/atypical hyperplasias, 16 cervical squamous cell carcinomas (SCCs), and 14 endocervical adenocarcinomas were evaluated by immunohistochemistry for GATA3 positivity. Eight percent of endometrial carcinomas expressed GATA3, including 2 serous carcinomas, 1 carcinosarcoma, and 1 case of atypical hyperplasia. Six percent of ovarian carcinomas were GATA3-positive including 2 clear cell carcinomas, 2 mucinous adenocarcinomas, and 2 high-grade serous carcinomas. Thirty-eight percent of cervical SCCs showed weak to moderate staining in up to 50% of tumor cells. All endocervical adenocarcinomas were entirely negative for GATA3. In summary, GATA3 shows focal weak to moderate expression in a subset of endometrial and ovarian carcinomas. In contrast, usual-type endocervical adenocarcinomas are typically negative for GATA3, which can be helpful in differentiating them from mesonephric proliferations or carcinomas. A larger proportion of cervical SCCs express GATA3, therefore caution should be exercised when using this stain in the setting of a lower genitourinary carcinomas.

Mesenchymal neoplasms of the uterus (corpus and cervix) encompass a heterogeneous group of tumors with differing morphologies, immunophenotypes and molecular alterations. With the advent of modern molecular techniques, such as next generation sequencing, newly defined genetic abnormalities are being reported in this group of neoplasms. Herein we report the clinicopathological and molecular features of a series of 13 spindle cell sarcomas of the uterus and vagina (10 cervix, 2 uterine corpus, 1 vagina) with morphology resembling fibrosarcoma. After targeted RNA-sequencing, dual FISH fusion and array-CGH analysis, 7 of 13 tumors exhibited NTRK rearrangements (6 TPM3-NTRK1 and 1 EML4-NTRK3) and 3 a COL1A1-PDGFB fusion; in the other 3 neoplasms, all of which were positive with S100 (2 diffuse, 1 focal), we identified no rearrangement. All the NTRK fusion-positive sarcomas were located in the cervix and exhibited diffuse staining with Trk while all the other neoplasms were negative. CD34 was diffusely positive in all 3 of the COL1A1-PDGFB fusion sarcomas. The latter molecular abnormality is identical to that commonly found in dermatofibrosarcoma protuberans and has not been reported previously in uterine mesenchymal neoplasms. We suggest that uterine sarcomas with a morphology resembling fibrosarcoma (and in which leiomyosarcoma and the known molecularly confirmed high-grade endometrial stromal sarcomas have been excluded) can be divided into 3 groups:- an NTRK fusion group, a COL1A1-PDGFB fusion group and a group containing neither of these molecular abnormalities which, on the basis of positive staining with S100, could be tentatively classified as malignant peripheral nerve sheath tumor, although additional molecular studies may identify specific genetic alterations necessitating a nomenclature change. We suggest a diagnostic algorithm when reporting such neoplasms. Identification of these newly described fusion-associated sarcomas is important given the potential for targeted treatments.

The checkpoint molecule TIM-3 is a target for emerging immunotherapies and has been identified on a variety of malignancies. Mismatch repair-deficient endometrial carcinomas have demonstrated durable responses to other checkpoint inhibitors due to high neoantigen loads and robust tumor-associated immune responses. However, little is known about TIM-3 expression in this tumor type. Tumor-associated immune and tumoral expression of TIM-3 were evaluated by immunohistochemistry on 75 endometrial carcinomas [25 MLH1 promoter hypermethylated (MLH1-hypermethylated), 25 non-hypermethylated mismatch repair-deficient, and 25 mismatch repair-intact]. All cases showed at least focal immune staining, but moderate and robust immune cell expression were more often observed in mismatch repair-deficient vs intact cases [66 vs 12%, P = 0.00002]. While the majority (77%) of endometrial cancers showed ≥1% tumoral TIM-3 expression, the MLH1-hypermethylated subset was more likely to demonstrate >5% tumoral staining when compared to both mismatch repair-intact and non-methylated mismatch repair-deficient cancers [64 vs. 28% and 32%, respectively; P = 0.02 and P = 0.05]. Within the non-methylated mismatch repair-deficient subset, high-level expression was most often associated with MSH6 loss. Across mismatch repair subgroups, tumoral TIM-3 expression was more common among intermediate and high-grade vs. low-grade tumors using both the 1% (P = 0.02) and 5% expression cut-offs (P = 0.02). In conclusion, tumoral TIM-3 expression is common in both mismatch repair-intact and deficient endometrial cancers, with particularly high levels of expression identified in the setting of MLH1-hypermethylation, MSH6 loss, and intermediate to high histologic grade. Although focal immune cell expression was seen in all tumors, robust expression was significantly more common in the context of mismatch repair deficiency. These data support a potential role for checkpoint inhibitors targeting TIM-3 in a subset of endometrial cancers, including some mismatch repair-intact tumors which are not currently considered immunotherapy candidates.

Immunotherapies targeting the PD-1/PD-L1 checkpoint axis are of growing interest for the treatment of mesenchymal neoplasms. However, PD-L1 expression and tumor-associated lymphocytes have not been well-investigated in uterine smooth muscle tumors. Forty-nine uterine smooth muscle tumors (23 leiomyosarcomas, 8 smooth muscle tumors of uncertain malignant potential [STUMP], 7 atypical leiomyomas, and 11 benign leiomyomas) were evaluated for tumoral and tumor-associated immune PD-L1 expression and tumor-associated T-cell infiltration. ALK immunohistochemistry was performed to exclude inflammatory myofibroblastic tumors. Tumor PD-L1 expression was seen in 70% of leiomyosarcomas and 14% of atypical leiomyomas; no cases of STUMP or benign leiomyoma demonstrated tumoral PD-L1. PD-L1 positivity was seen in tumor-associated immune cells in 78% of leiomyosarcomas, 25% of STUMP, no cases of atypical leiomyomas, and 9% of benign leiomyomas. Of the 23 leiomyosarcomas, 15 (65%) had a combined positive score ≥1, while of the 26 other uterine smooth muscle tumors, only 2 (8%) had a combined positive score ≥1. Tumor-associated CD8+ cells were highest among leiomyosarcomas (mean: 87/high-power fields vs. 17/high-power fields for nonleiomyosarcomas), and were significantly associated with PD-L1 expression. One PD-L1, CD8-enriched leiomyosarcoma showed an ALK overexpression suggesting possible classification as inflammatory myofibroblastic tumor, but otherwise lacked morphologic features of this entity. Leiomyosarcomas demonstrate significantly higher PD-L1 expression and cytotoxic T-cell infiltration when compared with other uterine smooth muscle tumors. These data suggest the possibility that treatment with targeted immunotherapy may be appropriate in a selected population of patients with leiomyosarcoma and, potentially, in related tumors bearing ALK rearrangements.

Ovarian mucinous tumors range from benign cystadenomas to borderline tumors to frankly malignant adenocarcinomas, and may display either intestinal-type morphology or, less frequently, endocervical-type differentiation. The latter category has been the subject of recent controversy owing to its morphologic overlap with so-called "seromucinous" ovarian tumors, a group that shares more molecular features with endometrioid tumors than it does with either serous or mucinous ovarian neoplasias. Endocervical-type differentiation in ovarian mucinous tumors may also represent an endocervical metastasis. Distinction of primary ovarian mucinous tumors from gastrointestinal metastases can be difficult, as the morphology of intestinal-type ovarian mucinous primaries sometimes differs only subtly if at all from gastrointestinal metastases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: We assessed whether provider sitting influenced patient satisfaction in an academic emergency department (ED) and if education and/or environmental manipulation could nudge providers to sit., Methods: This was a prospective, controlled pre-post trial of provider sitting and its influence on patient satisfaction within 2 urban, academic EDs. A 12-item survey was administered to a convenience sample of patients to assess for care satisfaction before, during, and after study interventions. Study interventions included (a) placement of branded folding seats and (b) an educational campaign. Only the intervention ED received folding seats. The primary outcome examined the influence of provider sitting on patient satisfaction. A secondary outcome examined the frequency of provider sitting., Results: During the entire study period, 2827 patients were surveyed; 63% were female and 65% were between the ages of 26 and 65. Sitting at any point during an ED encounter improved responses to satisfaction questions (polite [67% vs 59%], cared [64% vs 54%], listened [60% vs 52%], informed [57% vs 47%], time [56% vs 45%], P < .0001 for all measures). The odds of provider sitting increased 30% when a seat was placed in the room (odds ratio [OR] = 1.3, 95% confidence interval [CI]: 1.1-1.5). No change in provider sitting was observed in the control ED (OR = 1.0, 95% CI: 0.8-1.2)., Conclusions: Placing a seat in a patient's room nudges providers to sit during an ED encounter. Education alone did not influence provider behavior. Sitting down resulted in significantly higher patient satisfaction scores during an ED visit., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: The Emergency Medicine Milestone Project, a framework for assessing competencies, has been used as a method of providing focused resident feedback. However, the emergency medicine milestones do not include specific objective data about resident clinical efficiency and productivity, and studies have shown that milestone-based feedback does not improve resident satisfaction with the feedback process. We examined whether providing performance metric reports to resident physicians improves their satisfaction with the feedback process and their clinical performance., Methods: We conducted a three-phase stepped-wedge randomized pilot study of emergency medicine residents at a single, urban academic site. In phase 1, all residents received traditional feedback; in phase 2, residents were randomized to receive traditional feedback (control group) or traditional feedback with performance metric reports (intervention group); and in phase 3, all residents received monthly performance metric reports and traditional feedback. To assess resident satisfaction with the feedback process, surveys using 6-point Likert scales were administered at each study phase and analyzed using two-sample t-tests. Analysis of variance in repeated measures was performed to compare impact of feedback on resident clinical performance, specifically patient treatment time (PTT) and patient visits per hour., Results: Forty-one residents participated in the trial of which 21 were randomized to the intervention group and 20 in the control group. Ninety percent of residents liked receiving the report and 74% believed that it better prepared them for expectations of becoming an attending physician. Additionally, residents randomized to the intervention group reported higher satisfaction (p = 0.01) with the quality of the feedback compared to residents in the control group. However, receiving performance metric reports, regardless of study phase or postgraduate year status, did not affect clinical performance, specifically PTT (183 minutes vs. 177 minutes, p = 0.34) or patients visits per hour (0.99 vs. 1.04, p = 0.46)., Conclusions: While feedback with performance metric reports did not improve resident clinical performance, resident physicians were more satisfied with the feedback process, and a majority of residents expressed liking the reports and felt that it better prepared them to become attending physicians. Residency training programs could consider augmenting feedback with performance metric reports to aide in the transition from resident to attending physician., (© 2019 by the Society for Academic Emergency Medicine.)

Objective: Although the majority of ovarian granulosa cell tumors can be successfully managed with surgery, a subset require chemotherapy for residual and recurrent disease. The benefit of chemotherapy in this population, however, remains controversial. There is therefore interest in the development of more tolerable and effective treatment options for advanced ovarian granulosa cell tumors. We report the use of immunohistochemistry to investigate how biomarkers could inform clinical trials in granulosa cell tumors with an emphasis on emerging androgen antagonistic, immunotherapeutic, and anti-angiogenic approaches., Methods: Immunohistochemistry for androgen receptor, the immune markers programmed cell death ligand 1, indoleamine-2,3 dioxygenase, and cluster of differentiation 8, and the vascular marker cluster of differentiation 31 were evaluated on formalin-fixed paraffin-embedded whole tissue sections from 29 cases of adult-type granulosa cell tumors. Results were evaluated with clinicopathologic variables including recurrence., Results: 59% of granulosa cell tumors were androgen receptor-positive, suggesting a potential role for anti-androgen therapy in this tumor type. In contrast, the targetable immune modulatory molecules programmed cell death ligand 1 and indoleamine-2,3 dioxygenase were scarcely expressed, with no cases showing tumorous programmed cell death ligand 1 and a single case demonstrating very focal tumorous indoleamine-2,3 dioxygenase staining. A minority of cases expressed programmed cell death ligand 1 in occasional tumor-associated macrophages and indoleamine-2,3 dioxygenase in peritumoral vessels. Tumor-infiltrating cytotoxic T cells were also scarce in granulosa cell tumors, arguing against a significant role for immunotherapy in the absence of additional immunostimulation. Cluster of differentiation 31 immunostaining revealed a range of vascular densities across granulosa cell tumors, and future studies evaluating the role of vascular density as a predictor of response to angiogenesis inhibition are warranted. None of the biomarkers investigated were significantly correlated with recurrence, and the only clinicopathologic feature significantly correlated with outcome was stage at presentation., Conclusions: Biomarker data suggest that many ovarian granulosa cell tumors could be candidates for anti-androgen therapy, while the potential role for immunotherapy appears more limited. Vascular density could be useful for identifying optimal candidates for angiogenesis inhibition. Incorporation of these biomarkers into clinical trials could help optimize patient selection., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The purpose of this study was to complete a comprehensive analysis of gender differences in faculty rank among U.S. emergency physicians that reflected all academic emergency physicians., Methods: We assembled a comprehensive list of academic emergency medicine (EM) physicians with U.S. medical school faculty appointments from Doximity.com linked to detailed information on physician gender, age, years since residency completion, scientific authorship, National Institutes of Health (NIH) research funding, and participation in clinical trials. To estimate gender differences in faculty rank, multivariable logistic regression models were used that adjusted for these factors., Results: Our study included 3,600 academic physicians (28%, or 1,016, female). Female emergency physicians were younger than their male colleagues (mean [±SD] age was 43.8 [±8.7] years for females and 47.4 [±9.9] years for males [p < 0.001]), had fewer years since residency completion (12.4 years vs. 15.6 years, p < 0.001), had fewer total and first/last author publications (4.7 vs. 8.6 total publications, p < 0.001; 4.3 vs. 7.1 first or last author publications, p < 0.001), and were less likely to be principal investigators on NIH grants (1.2% vs. 2.9%, p = 0.002) or clinical trials (1.8% vs. 4.4%, p < 0.001). In unadjusted analysis, male physicians were more likely than female physicians to hold the rank of associate or full professor versus assistant professor (13.7 percentage point difference, p < 0.001), a relationship that persisted after multivariable adjustment (5.5 percentage point difference, p = 0.001)., Conclusions: Female academic EM physicians are less likely to hold the rank of associate or full professor compared to male physicians even after detailed adjustment for other factors that may influence faculty rank., (© 2019 by the Society for Academic Emergency Medicine.)

Objective: To determine the extent of dasatinib uptake and effect on Src kinase activity in tumor, normal adjacent tissue, and blood in newly diagnosed endometrial cancer patients., Methods: Dasatinib was dosed at 100 or 200 mg PO BID at 32 and 8 h preoperatively. Blood and tissue were collected pre-treatment and at surgery to assess active (pY419) and total Src protein (pharmacodynamics [PD]) and pharmacokinetics (PK). Plasma PK and PD were also analyzed at 2, 4 and 8 h following the second dose., Results: Ten patients completed the study, 5 at each dose level (DL). Average (median, standard deviation, range) 2 h plasma concentration of drug was 119 (121, 80, 226) and 236 (162, 248, 633) ng/mL, for the 100 and 200 mg DL, respectively. Average ratio of 8 h normal and tumor tissue to plasma concentration overall was 3.6 (2.3, 3.4, 9.6) and 8.3 (3.2, 11.9, 38.7), respectively. Dasatinib concentration in tumor was higher than in plasma for both DL. Four patients displayed significant reductions in pTyr419Src at ≥ 1 time points in blood, and four patients satisfied the PD activity criteria in tissue, with reductions in pTyr419Src of ≥ 60%., Conclusions: This is the first study to show PK and PD effects of dasatinib in tumor tissue, allowing evaluation of tissue PD markers as a function of tumor dasatinib concentration. Dasatinib tissue concentrations at 8 h after dosing were associated with modulation of pTyr419Src, total Src protein, and pTyr419Src/Src ratio. All patients had reduction in at least one Src parameter in either tissue or blood.

African American women with high-grade serous ovarian carcinoma have worse outcomes compared with women of European descent. Although the discrepancy is partially attributed to differences in access to care, the tumor immune microenvironment may also contribute. Expression of targetable immune regulatory molecules such as programmed cell death ligand-1 (PD-L1) and indoleamine 2,3 dioxygenase (IDO) is of particular interest as it may help guide therapy in this population. Using cases from the largest study of African American women with ovarian cancer, the African American Cancer Epidemiology Study, we characterized PD-L1 and IDO expression in 112 high-grade serous ovarian carcinomas. Immunohistochemistry for PD-L1, IDO, CD8, FOX3p, and CD68 was performed. PD-L1 and IDO were scored as the percentage of positive tumor cells and tumor-associated immune cells. CD8 and FOX3p counts were averaged across 10 high-power fields. Cox proportional hazards regression was used to evaluate the association between PD-L1 and IDO expression and survival. Tumor cells were positive for PD-L1 and IDO in 29% and 58% of cases, respectively. The majority showed <10% staining, and no cases exceeded 25% positivity. The majority of PD-L1-positive cases coexpressed IDO. PD-L1 and IDO expression was associated with higher CD8 and FOX3p counts (P<0.05). No association was observed between PD-L1 and IDO and survival. In summary, expression of PD-L1 and IDO is seen in a subset of high-grade serous ovarian carcinoma from African American women and is correlated with elevated lymphocyte infiltration. While PD-L1 and IDO co-expression suggests a role for dual immunotherapy, diffuse expression of PD-L1 and IDO is rare, invoking caution regarding the potential for immunotherapeutic response.

Objective: The purpose of this study is to determine whether the type of feedback on evidence-based guideline adherence influences adult primary care provider (PCP) lumbar spine (LS) MRI orders for low back pain (LBP)., Materials and Methods: Four types of guideline adherence feedback were tested on eight tertiary health care system outpatient PCP practices: no feedback during baseline (March 1, 2012-October 4, 2012), randomization by practice to either clinical decision support (CDS)-generated report cards comparing providers to peers only or real-time CDS alerts at order entry during intervention 1 (February 6, 2013-December 31, 2013), and both feedback types for all practices during intervention 2 (January 14, 2014-June 20, 2014, and September 4, 2014-January 21, 2015). International Classification of Disease codes identified LBP visits (excluding Medicare fee-for-service). The primary outcome of the likelihood of LS MRI order being made on the day of or 1-30 days after the outpatient LBP visit was adjusted by feedback type (none, report cards only, real-time alerts only, or both); patient age, sex, race, and insurance status; and provider sex and experience., Results: Half of PCPs (54/108) remained for all three periods, conducting 9394 of 107,938 (8.7%) outpatient LBP visits. The proportion of LBP visits increased over the course of the study (p = 0.0001). In multilevel hierarchic regression, report cards resulted in a lower likelihood of LS MRI orders made the day of and 1-30 days after the visit versus baseline: 38% (p = 0.009) and 37% (p = 0.006) for report cards alone, and 27% (p = 0.020) and 27% (p = 0.016) with alerts, respectively. Real-time alerts alone did not affect MRI orders made the day of (p = 0.585) or 1-30 days after (p = 0.650) the visit. No patient or provider variables were associated with LS MRI orders being generated on the day of or 1-30 days after the LBP visit., Conclusion: CDS-generated evidence-based report cards can substantially reduce outpatient PCP LS MRI orders on the day of and 1-30 days after the LBP visit. Real-time CDS alerts do not.

Objective: The objectives of this study were to analyze factors associated with outcomes and missing data in women with epithelial ovarian cancer using institutional, state and national databases., Methods: Data were abstracted from the University of Virginia cancer registry, Virginia Department of Health (VDH) database, and Surveillance, Epidemiology, and End Results (SEER) Program and analyzed for correlations with demographics, cancer characteristics, and outcomes. Statewide spatial associations between health risk factors such as smoking, obesity, and missing grade/stage were evaluated using bivariate LiSA in Geoda., Results: There were 524 institutional, 3544 VDH, and 44,464 SEER cases of epithelial ovarian cancer. Institutional cases were younger, most often of white race, had increased grade 1, and decreased unknown grade and stage (all p < 0.001). Significant predictors of unknown grade were non-white race, older age, no surgery, unknown stage/stage IV, and unknown histology/adenocarcinoma. Unknown grade correlated with a significant survival disadvantage. Missing stage and grade correlated with county-level obesity and smoking, as rural regions in Southwest and Southside Virginia had high rates of health risk factors and missing stage/grade compared to urban, affluent regions in Northern Virginia., Conclusions: Over a third of nationally reported cases have an unknown grade and 10-20% have an unknown stage which correlates with the worst survival. Predictors of unknown grade include insurance, age, race, smoking status, obesity, and rural setting. Missing data may represent geographical differences or disparities in cancer care available as significantly fewer cases had an unknown grade/stage at a tertiary academic medical center compared to VDH and SEER., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: The immunoregulatory enzyme indoleamine dioxygenase 2,3 (IDO) has been implicated in cervical and vulvar squamous carcinomas (SCC) and may represent a mechanism of resistance to anti-PD-1/anti-PD-L1 therapy. However, the relationship between IDO and PD-L1 has not been well-investigated., Methods and Results: Sixty-five cases of cervical and vulvar intraepithelial neoplasia and SCC were assessed for IDO and PD-L1 expression. Overall, tumoral PD-L1 expression was seen in 72% of SCC, while 50% expressed IDO; co-expression was seen in 42%. Using the combined positive score (CPS) threshold of 1 to account for both tumoral and immune staining, 83% of SCC expressed PD-L1, 61% expressed IDO and 53% showed co-expression. Cervical SCCs were significantly more likely than human papillomavirus (HPV)-related vulvar SCCs to express tumoral IDO (75% versus 13%, P < 0.001) and demonstrate an IDO CPS ≥ 1 (88% versus 25%, P < 0.001); no significant differences were seen for PD-L1. Additionally, there were no significant differences in IDO and PD-L1 expression in dVIN-associated versus HPV-associated vulvar SCC. In contrast to SCC, the majority of intraepithelial lesions were entirely negative for tumoral PD-L1 and IDO and had a CPS score of <1., Conclusions: In summary, IDO and PD-L1 co-expression is common in cervical SCCs and, to a lesser extent, vulvar SCCs. These data suggest a role for combination immunotherapy in a subset of cervical SCCs as well as select vulvar SCCs. Expression for both markers is less common in intraepithelial lesions, providing no strong support for this form of immunotherapy in the absence of invasion., (© 2018 John Wiley & Sons Ltd.)

As multigene panel testing for hereditary cancer syndromes becomes commonplace, germline mutations in genes other than BRCA1/2 are increasingly identified in breast cancer patients. While histopathologic features of BRCA-mutated breast cancers have been well-characterized, less is known about non-BRCA-related hereditary cancers. We herein investigate the clinicopathologic characteristics of breast cancers in women with non-BRCA germline mutations. Out of 612 women who underwent germline testing, 16 (2.6%) women with 18 cancers had mutations in non-BRCA genes: ATM, CHEK2, PALB2, TP53, BMPR1A, BRIP1, MUTYH, and RAD50. An additional 2 cancers were identified in a woman with a diagnosis of Bloom syndrome (BLM mutation) who was not germline tested. Average age at diagnosis was 50 (range: 27-77), and 65% had no personal cancer history. The majority (79%) of tumors were grade 1 to 2; 35% were either lobular or ductal with lobular features. Stromal responses varied from absent to desmoplastic to sclerotic; 69% of cases had an in situ component. With the exception of a brisk lymphocytic response in BLM- and TP53-mutated cancers, lymphocytic infiltration was mild or absent. In summary, the majority of non-BRCA-related hereditary breast cancers represent the patient's sentinel malignancy. Lobular features were seen in a subset, and high-grade, immunogenic carcinomas were uncommon except in the setting of BLM and TP53 mutations. Overall, these findings demonstrate a range of involved genes in non-BRCA mutation carriers with breast cancer and histopathologic heterogeneity in the associated cancers, arguing against use of histomorphology to inform panel testing algorithms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Targeted inhibition of programmed cell death-1 (PD-1) and its ligand (PD-L1) has emerged as first-line therapy for advanced non-small cell lung cancer. Although patients with high PD-L1 expression have improved outcomes with anti-PD-1/PD-L1-directed therapies, use as a predictive biomarker is complicated by robust responses in some patients with low-level expression. Furthermore, reported PD-L1 levels in lung cancers vary widely, and discrepancies exist with different antibodies. PD-L1 expression was thus compared by immunohistochemistry (IHC) versus RNA in situ hybridization (ISH) in 112 lung cancers by tissue microarray: 51 adenocarcinoma, 42 squamous cell carcinoma, 9 adenosquamous carcinoma, 5 carcinoid, 3 undifferentiated large cell carcinoma, 1 large cell neuroendocrine carcinoma, and 1 small cell carcinoma. At least 1% tumor cell staining was considered positive in each modality. A positive concordance of only 60% (67/112) was found between IHC and ISH. Fifty percent (56/112) were positive by IHC and 50% (56/112) by ISH; however, 20% (22/112) were ISH positive but IHC negative. Conversely, 21% (23/112) were IHC positive but ISH negative. There was no significant stratification of PD-L1 positivity by histologic subtype. A trend of more PD-L1-positive stage I cancers identified by ISH versus IHC was observed but was not statistically significant (50% [27/54] by IHC and 64% [35/55] by ISH, P = .18). No significant difference in survival was identified, with an average of 5.3 months in IHC versus 5.2 months in ISH-positive cases. The results demonstrate discordance between PD-L1 RNA levels and protein expression in non-small cell lung cancers, warranting comparison as predictive biomarkers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Lynch syndrome (LS) is defined by germline mutations in DNA mismatch repair (MMR) genes, and affected patients are at high risk for multiple cancers. Reflexive testing for MMR protein loss by immunohistochemistry (IHC) is currently only recommended for colorectal and endometrial cancers, although upper tract urothelial carcinoma (UTUC) is the third-most common malignancy in patients with LS. To study the suitability of universal MMR IHC screening for UTUC, we investigated MMR expression and microsatellite status in UTUC in comparison to bladder UC (BUC), and evaluated the clinicopathologic features of UTUC. We found that 9% of UTUC showed MMR IHC loss (8 MSH6 alone; 1 MSH2 and MSH6; 1 MLH1 and PMS2; n=117) compared with 1% of BUC (1 MSH6 alone; n=160) (P=0.001). Of these, 4/10 (40%) of UTUC (3% overall; 3 MSH6 alone; 1 MLH1 and PMS2) and none (0%) of BUC had high microsatellite instability on molecular testing (P=0.03). The only predictive clinicopathologic feature for MMR loss was a personal history of colorectal cancer (P=0.0003). However, UTUC presents at a similar age to colon carcinoma in LS and thus UTUC may be the sentinel event in some patients. Combining our results with those of other studies suggests that 1% to 3% of all UTUC cases may represent LS-associated carcinoma. LS accounts for 2% to 6% of both colorectal and endometrial cancers. As LS likely accounts for a similar percentage of UTUC, we suggest that reflexive MMR IHC screening followed by microsatellite instability testing be included in diagnostic guidelines for all UTUC.

The immune inhibitory enzyme indoleamine 2,3-dioxygenase (IDO) has been associated with immune evasion in numerous malignancies and may mark these cancers as susceptible to anti-IDO therapies. We herein address IDO expression in breast cancers, examine the relationship between IDO and PD-L1, and investigate IDO fidelity across breast cancer primaries and metastases. IDO and PD-L1 expression was assessed in tissue microarrays containing 242 invasive primary breast cancers, 20 nodal metastases, and 19 distant metastases. IDO and PD-L1 were scored by extent in the tumor cells and immune infiltrate. Tumor IDO staining was seen in 14% of primaries including 38% of triple-negative cancers. IDO immune cell staining was seen in 14% of primaries and 29% of triple-negative cancers. Tumoral IDO and PD-L1 co-expression was seen in 8% of primaries, including 70% of tumoral PD-L1-positive cases. Immune IDO and PD-L1 co-expression was identified in 14% of primaries, including 48% of immune PD-L1-positive cases. Tumoral and immune cell IDO was conserved in 94% of matched primary/metastasis. In summary, IDO expression is common among high-grade, triple-negative breast cancers and is frequently associated with PD-L1 co-expression, suggesting that IDO might be a mechanism of anti-PD-1/PD-L1 immunotherapy resistance and that dual therapy may be of utility. Tumoral and immune cell IDO expression shows fidelity between primary and metastatic sites in treatment-naïve cancers, arguing against IDO as an independent driver for metastatic spread. Clinical trials are needed to assess the efficacy of IDO inhibition relative to IDO expression, as well as its possible role in combination with anti-PD-1/PD-L1 immunotherapy.

The immune regulatory enzyme indoleamine-2,3-dioxygenase (IDO-1) suppresses T cell responses and may reduce efficacy of therapies targeting immune checkpoints such as programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1). Early phase clinical trials combining IDO-1 and PD-1/PD-L1 inhibitors have shown some promise in non-small cell lung cancers (NSCLCs). However, the coexpression of IDO-1 and PD-L1 has not been thoroughly investigated, and the potential for IDO-1 immunohistochemical expression as a therapeutic biomarker is unknown. One hundred two cases of NSCLC (51 adenocarcinomas, 9 adenosquamous carcinomas, and 42 squamous cell carcinomas) were evaluated for IDO-1 and PD-L1 expression by immunohistochemistry. IDO-1 expression was identified in 43% of NSCLC (42% of adenocarcinomas, 44% of adenosquamous carcinomas, and 43% of squamous cell carcinomas). Coexpression with PD-L1 (≥1%) was common (27% overall; 27% of adenocarcinomas, 33% of adenosquamous carcinomas, and 26% of squamous cell carcinomas). A smaller population of tumors showed isolated PD-L1 (25% overall; 16% of adenocarcinomas, 44% of adenosquamous carcinomas, and 33% of squamous cell carcinomas) or IDO-1 expression (15% overall; 14% of adenocarcinomas, 11% of adenosquamous carcinomas, and 17% of squamous cell carcinomas). In summary, IDO-1 is commonly expressed by NSCLC, and its frequent coexpression with PD-L1 may account for the increased efficacy seen with dual blockade of PD-1/PD-L1 and IDO in clinical studies. IDO-1 immunohistochemistry may be a useful biomarker for selection of patients who could benefit from dual-agent therapy and should be evaluated in prospective clinical trials using PD-1/PD-L1 and IDO inhibitors.

Background: In situ hybridization for human papillomavirus (HPV) messenger RNA (HPV RNA ISH) recently was introduced as an ancillary tool in the diagnosis of cervical squamous intraepithelial lesions, and can aid in the distinction between low-grade squamous intraepithelial lesions (LSILs) versus reactive/negative biopsies. Prior work has shown that up to one-half of cases originally diagnosed as LSIL are reclassified as negative/reactive by expert consensus review of morphology, and negative HPV RNA ISH results most often correlate with an expert diagnosis of negative/reactive. Given that LSIL overdiagnoses on biopsy may result in the erroneous clinical impression that a cervical lesion has been sampled appropriately, the authors proposed that HPV RNA ISH can inform cytology-histology correlation for challenging LSIL biopsies., Methods: A total of 92 cervical biopsies originally diagnosed as LSIL were reviewed by 3 gynecologic pathologists and reclassified based on consensus opinion of morphology. ISH was performed for high-risk and low-risk HPV E6/E7 mRNA. Prior/concurrent cytology results were collected., Results: Based on expert consensus morphologic review, 49% of biopsies (45 of 92 biopsies) originally diagnosed as LSIL were reclassified as negative, 6.5% (6 of 92 biopsies) were reclassified as high-grade squamous intraepithelial lesion, and 44.5% (41 of 92 biopsies) were maintained as LSIL. The majority of LSIL biopsies reclassified as negative (80%; 36 of 45 biopsies) were HPV RNA negative, whereas 93% of LSIL biopsies (39 of 41 biopsies) and 100% of high-grade squamous intraepithelial lesion biopsies were HPV RNA positive., Conclusions: LSIL often is overdiagnosed by morphology on biopsy, potentially leading to the false impression that a lesion identified on cytology has been sampled. Performing RNA ISH on biopsies decreases histologic LSIL overdiagnosis, and potentially can prompt further sampling when there is cytology-histology discordance. Cancer (Cancer Cytopathol) 2018. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

The number of women entering medical school and careers in science is increasing; however, women remain the minority of those in senior faculty and leadership positions. Barriers contributing to the shortage of women in academics and academic leadership are numerous, including a shortage of role models and mentors. Thus, achieving equity in a timelier manner will require more than encouraging women to pursue these fields of study or waiting long enough for those in the pipelines to be promoted. Social media provides new ways to connect and augments traditional forms of communication. These alternative avenues may allow women in academic medicine to obtain the support they are otherwise lacking. In this perspective, we reflect on the role of Twitter as a supplemental method for navigating the networks of academic medicine. The discussion includes the use of Twitter to obtain (1) access to role models, (2) peer-to-peer interactions, and continuous education, and (3) connections with those entering the pipeline-students, trainees, and mentees. This perspective also offers suggestions for developing a Twitter network. By participating in the "Twittersphere," women in academic medicine may enhance personal and academic relationships that will assist in closing the gender divide., (©Jaime D Lewis, Kathleen E Fane, Angela M Ingraham, Ayesha Khan, Anne M Mills, Susan C Pitt, Danielle Ramo, Roseann I Wu, Susan M Pollart. Originally published in JMIR Medical Education (http://mededu.jmir.org), 23.07.2018.)

Introduction: Given the potential malignancy risks associated with computed tomography (CT), some physicians are increasingly advocating for risk disclosure to patients/families. Our goal was to evaluate the practices and attitudes of pediatric emergency medicine (PEM) fellowship program leaders' regarding CT radiation-risk disclosure., Methods: We conducted a cross-sectional survey study of the United States and Canadian PEM fellowship directors and associate/assistant directors. We developed a web-based survey using a modified Dillman technique. Primary outcome was the proportion who "almost always" or "most of the time" discussed potential malignancy risks from CT prior to ordering this test., Results: Of 128 physicians who received the survey, 108 (86%) responded. Of those respondents, 73%, 95% confidence interval (CI) [64-81] reported "almost always" or "most of the time" discussing potential malignancy risks when ordering a CT for infants; proportions for toddlers, school-age children, and teenagers were 72% (95% CI [63-80]), 66% (95% CI [56-75]), and 58% (95% CI [48-67]), respectively (test for trend, p=0.008). Eighty percent reported being "extremely" or "very" comfortable discussing radiation risks. Factors of "high" or "very high" importance in disclosing risks included parent request for a CT not deemed clinically indicated for 94% of respondents, and parent-initiated queries about radiation risks for 79%. If risk disclosure became mandatory, 82% favored verbal discussion over written informed consent., Conclusion: PEM fellowship program leaders report frequently disclosing potential malignancy risks from CT, with the frequency varying inversely with patient age. Motivating factors for discussions included parental request for a CT deemed clinically unnecessary and parental inquiry about risks., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.