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Biomarkers play a crucial role in the diagnosis, treatment planning, and prognosis of premalignant and malignant lesions and are increasingly used in neoplasia of the lower female genital tract (LFGT) including the cervix, vagina, and vulva. This review will discuss key biomarkers routinely used in LFGT pathology, including programmed cell death ligand 1 (PD-L1), mismatch repair (MMR), and tumor mutational burden (TMB) testing, which are FDA-approved companion diagnostics for anti-PD-1 checkpoint inhibitors. Recent developments in HER2 testing as a marker for anti-HER2 therapies, and prognostic biomarkers such as p53 in HPV-independent vulvar intraepithelial lesions and carcinomas, are also reviewed., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Timely detection of endometrial carcinoma in Lynch syndrome patients ensures prompt treatment and appropriate cancer screening for the patient and impacted family members. While cervical cytology is utilized primarily in cervical cancer screening, endometrial glandular abnormalities can be identified as part of routine cervical cancer screening or during work-up for abnormal uterine bleeding., Materials and Methods: We retrospectively evaluated cervical cytology samples from Lynch syndrome patients with endometrial carcinoma to determine how often atypical/malignant glandular cells were identified on prior/concurrent cytology., Results: We identified 14 Lynch syndrome patients with cervical cytology available within a year of endometrial carcinoma diagnosis. The average patient age was 55 years (36-73). Cervical cytology preceded diagnostic biopsy in 57% and was concurrent in 43%. A glandular abnormality was identified on original diagnosis in 43% and ranged from atypical glandular cells (AGC), not otherwise specified to adenocarcinoma consistent with endometrial primary. In 4 cases, abnormal cervical cytology triggered the subsequent biopsy. Evaluation of 8 cases with accessible cytology slides revealed 2 previously unrecognized glandular abnormalities, leading to an abnormal rate of 63% among cases reviewed retrospectively and a final glandular abnormality detection rate of 57% based on either original or review diagnosis., Conclusions: In summary, abnormal glandular cells were commonly identified in endometrial cancer patients with Lynch syndrome and led to endometrial cancer work-up and diagnosis in a subset. These results suggest that cervical cytology may have utility in endometrial cancer screening in this population and indicate that awareness of the patient's familial cancer risk is important for maximizing sensitivity of this test. They also caution against primary human papillomavirus screening in the Lynch syndrome population, as this may result in missed opportunities for early endometrial carcinoma detection among these high-risk individuals., (Copyright © 2024 American Society of Cytopathology. Published by Elsevier Inc. All rights reserved.)

Since the establishment of 4 molecular subgroups of endometrial carcinoma (EC), there has been significant interest in understanding molecular classification in the context of histologic features and diagnoses. ECs with undifferentiated, spindle, and/or sarcomatous components represent a diagnostically challenging subset of tumors with overlapping clinical and histologic features. We examined the clinicopathologic, morphologic, immunohistochemical, and molecular features of these tumors identified in our institutions' pathology databases using immunohistochemistry and targeted sequencing. Disease-specific survival (DSS) and progression-free survival (PFS) were analyzed using Kaplan-Meier curves and log-rank tests. One hundred sixty-two ECs were included: carcinosarcomas (UCS; n=96), dedifferentiated/undifferentiated EC (DDEC/UDEC; n=49), and grade 3 endometrioid EC with spindled growth (GR3spEEC) (n=17). All molecular subgroups were represented in all histologic subtypes and included 12 (7%) POLE -mutated ( POLE mut), 43 (27%) mismatch repair-deficient (MMRd), 77 (48%) p53-abnormal (p53abn), and 30 (19%) no specific molecular profile (NSMP) tumors. However, the molecular classification (irrespective of histologic diagnosis) was a significant predictor for both DSS ( P =0.008) and P≤0.0001). POLE mut EC showed an excellent prognosis with no recurrences or deaths from the disease. MMRd tumors also showed better outcomes relative to NSMP and p53abn tumors. In conclusion, molecular classification provides better prognostic information than histologic diagnosis for high-grade EC with undifferentiated and sarcomatous components. Our study strongly supports routine molecular classification of these tumors, with emphasis on molecular group, rather than histologic subtyping, in providing prognostication., 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 © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Histopathologic characteristics after neoadjuvant chemotherapy (NACT) may correlate with outcome. This study evaluates histopathologic features after immunotherapy and NACT/bevacizumab, and associated clinical outcomes., Methods: Evaluable tissue from IMagyn050/GOG3015/ENGOT-ov39 patients from prespecified anatomic sites from interval cytoreductive surgery (ICS) after NACT/bevacizumab plus atezolizumab/placebo underwent central histopathologic scoring and analyzed with clinical outcomes., Results: The predefined population had 243 evaluable NACT patients, with 48.1% tumors being PD-L1-positive. No statistically significant differences in PFS (16.9 months vs. 19.2 months, p = 0.21) or OS (41.5 months vs. 45.1 months, p = 0.67) between treatment arms were seen. Substantial residual tumor (RT) (3+) was identified in 26% atezolizumab vs. 24% placebo arms (p = 0.94). Most showed no (1+) necrosis (82% vs. 96%, respectively, p = 0.69), moderate (2+) to severe (3+) fibrosis (71% vs. 75%, respectively, p = 0.82), and extensive (2+) inflammation (53% vs. 47% respectively, p = 0.48). No significant histopathologic differences were identified by tissue site or by arm. Multivariate analyses showed increased risk for progression with moderate and substantial RT (13.6 mon vs. 21.1 mon, hazard ratio 2.0, p < 0.01; 13.6 mon vs. 21.1 mon, HR 1.9, p < 0.01, respectively); but decreased risk for death with extensive inflammation (46.9 mon vs. 36.3 mon, HR 0.65, p = 0.02). Inflammation also correlated with greater likelihood of response to NACT/bevacizumab plus immunotherapy (odds ratio 2.9, p < 0.01). Modeling showed inflammation as a consistent but modest predictor for OS., Conclusions: Detailed histologic assessment of ICS specimens appear to identify characteristics, such as inflammation and residual tumor, that may provide insight to certain clinical outcomes. Future work potentially leveraging emerging tools may provide further insight into outcomes., Competing Interests: Declaration of competing interest GS reports grant/research support from MSD Italia S.r.l.; consultancy for TESARO Bio Italy S.r.l. and Johnson & Johnson; and speaker bureau/honoraria from Clovis Oncology Italy S.r.l. YG reports fees from advisory boards from GlaxoSmithKline and AstraZeneca; and fees from travel grants and speaker's bureau from Roche, AstraZeneca, MSD, and GlaxoSmithKline. PD reports advisory board honoraria and speaking fees from Novartis, Janssen-Cilag, Amgen, Merck Sharp and Dohme, Roche, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Merck. KNM reports research funding from PTC Therapeutics, Lilly, Genentech/Roche, GlaxoSmithKline, Verastem, and Clovis; advisory Board/Consultant role with Aadi, AstraZeneca, Aravive, Alkemeres, Blueprint pharma, Clovis, Caris, Duality, Eisai, EMD Serono, Gilead, GSK, Genentech/Roche, Immunogen, IMab, Janssen, Merck, Mersana, Myriad, Novartis, OncXerna, OncoNova, Panavance, VBL Therapeutics, Verastem, Zentalis, and Tubulis; and Associate Director GOG Partners with GOG Foundation BOD (uncompensated) and ASCO BOD (uncompensated). GCS reports conflicts with AstraZeneca, GlaxoSmithKine, and Clovis. MB reports participation in ad-hoc advisory boards for Genentech-Roche, Merck Sharp & Dohme, AstraZeneca, Clovis Oncology, Seattle Genetics, Aravive, and AbbVie; and consulting fees paid to institution. FS reports honoraria from Astra Zeneca, MSD, Clovis Oncology, Sandoz, and GlaxoSmithKine-Tesaro; consulting or advisory role for AstraZeneca, MSD, and GlaxoSmithKine-Tesaro; speaker's bureau from AstraZeneca, MSD, and GlaxoSmithKline-Tesaro; and travel, accommodation, and/or expenses from AstraZeneca, MSD, GlaxoSmithKline-Tesaro, and Roche. LM reports employment by Genentech and is a stockholder in Roche. YH reports employment by Parexel to provide statistical service for Roche. VK reports employment by Genentech and is a stockholder in Roche. CL reports research funding (institution) from Roche. YGL reports employment by Genentech and is a stockholder in Roche. PM-F reports consulting fees for Genentech-Roche. DM, AT, AMM, SS, LB and SKS report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Endometrial somatically derived yolk sac tumors are characterized by yolk sac morphology with AFP, SALL-4, and/or Glypican-3 immunoexpression. Yolk sac marker expression, however, is not limited to tumors with overt yolk sac histology. Three hundred consecutive endometrial malignancies were assessed for immunomarkers of yolk sac differentiation. Of these, 9% expressed ≥1 yolk sac marker, including 29% of high-grade tumors. Only 3 (1%) met morphologic criteria for yolk sac differentiation; these were originally diagnosed as serous, high-grade NOS, and dedifferentiated carcinoma. Two were MMR-intact and comprised exclusively of yolk sac elements, while the dedifferentiated case was MMR deficient and had a background low-grade endometrioid carcinoma; this case also showed BRG1 loss. All 3 were INI1 intact. Nonspecific yolk sac marker expression was seen in 14 carcinosarcomas, 4 endometrioid, 2 serous, 1 clear cell, 1 dedifferentiated, 1 mixed serous/clear cell, and 1 mesonephric-like carcinoma. INI1 was intact in all cases; one showed BRG1 loss. Twenty were MMR-intact, and 4 were MMR deficient. All MMR-deficient cases with yolk sac marker expression, both with and without true yolk sac morphology, had no evidence of residual disease on follow-up, whereas 82% of MMR-intact cases developed recurrent/metastatic disease. In summary, endometrial somatically derived yolk sac tumors were rare but under-recognized. While AFP immunostaining was specific for this diagnosis, Glypican-3 and SALL-4 expression was seen in a variety of other high-grade carcinomas. INI1 loss was not associated with yolk sac morphology or immunomarker expression in the endometrium, and BRG1 loss was rare. All patients with MMR-deficient carcinomas with yolk sac immunoexpression +/- morphology were disease-free on follow-up, whereas the majority of MMR-intact cancers showed aggressive disease., 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 © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Doravirine and islatravir is an investigational, once-daily regimen with high antiviral potency, favourable safety and tolerability, and a low propensity for resistance. We investigated a switch from bictegravir, emtricitabine, and tenofovir alafenamide to doravirine (100 mg) and islatravir (0·75 mg) in virologically suppressed adults with HIV-1., Methods: We conducted a phase 3, multicentre, randomised, active-controlled, double-blind, double-dummy, non-inferiority trial at 89 research, community, and hospital-based clinics in 11 countries. Adults aged 18 years or older with fewer than 50 HIV-1 RNA copies per mL for at least 3 months on bictegravir (50 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) and no history of previous virological failure on any past or current regimen were randomly assigned (1:1) by a computer-generated randomisation allocation schedule, with block randomisation based on a block size of four, to switch to doravirine (100 mg) and islatravir (0·75 mg) or continue bictegravir, emtricitabine, and tenofovir alafenamide orally once daily, with matching placebos taken by all participants. Participants, investigators, study staff, and sponsor personnel involved in study drug administration or clinical evaluation of participants were masked to treatment assignment until week 48. Participants were instructed at each visit to take one tablet from each of the two bottles received, one of study drug and one of placebo, once daily, and participants were assessed at baseline and weeks 4, 12, 24, 36, and 48. The primary endpoint was the proportion of participants with greater than or equal to 50 HIV-1 RNA copies per mL at week 48 in the full analysis set (ie, all participants who received at least one dose of study drug; US Food and Drug Administration snapshot; prespecified non-inferiority margin 4%). The study is ongoing, with all remaining participants in post-treatment follow-up, and is registered with ClinicalTrials.gov, NCT04223791., Findings: We screened 726 individuals for eligibility between Feb 18 and Sept 3, 2020, of whom 643 (88·6%) participants were randomly assigned to a treatment group (183 [28·5%] women and 460 [71·5%] men). 322 participants were switched to doravirine (100 mg) and islatravir (0·75 mg) and 321 continued bictegravir, emtricitabine, and tenofovir alafenamide (two participants [one with a protocol deviation and one who withdrew] assigned to bictegravir, emtricitabine, and tenofovir alafenamide did not receive treatment). The last follow-up visit for the week 48 analysis occurred on Aug 26, 2021. At week 48, two (0·6%) of 322 participants in the doravirine and islatravir group compared with one (0·3%) of 319 participants in the bictegravir, emtricitabine, and tenofovir alafenamide group had greater than or equal to 50 HIV-1 RNA copies per mL (difference 0·3%, 95% CI -1·2 to 2·0). The per-protocol analysis showed consistent results. 25 (7·8%) participants in the doravirine and islatravir group had headache compared with 23 [7·2%] participants in the bictegravir, emtricitabine, and tenofovir alafenamide group; 101 (31·4%) compared with 98 (30·7%) had infections; and eight (2·5%) participants in each group discontinued therapy due to adverse events. 32 (9·9%) participants had treatment-related adverse events in the islatravir and doravirine group comapred with 38 (11·9%) in the bictegravir, emtricitabine, and tenofovir alafenamide group. In the islatravir and doravirine group, CD4 cell counts (mean change -19·7 cells per μL) and total lymphocyte counts (mean change -0·20 × 10 9 /L) were decreased at 48 weeks., Interpretation: Switching to daily doravirine (100 mg) and islatravir (0·75 mg) was non-inferior to bictegravir, emtricitabine, and tenofovir alafenamide at week 48. However, decreases in CD4 cell and total lymphocyte counts do not support the further development of once-daily doravirine (100 mg) and islatravir (0·75 mg)., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co., Competing Interests: Declaration of interests F-HS, SOK, KE, RMP, TC (former), and MCF are or were employees of Merck Sharp & Dohme, a subsidiary of Merck & Co, who might own stock, hold stock options, or both in the company. AMM has received research funding from AbbVie, Gilead Sciences, Merck, Taimed, GSK, and ViiV Healthcare; honoraria from Gilead Sciences, ViiV Healthcare, and EMD Serono; and served on advisory boards for Gilead Sciences and ViiV Healthcare. GR has received honoraria from MSD, Gilead Sciences, GSK, and ViiV Healthcare and meeting or travel support from Gilead Sciences. MNR has received consulting fees from Gilead Sciences, Merck, and ViiV Healthcare and honoraria from AbbVie, Gilead Sciences, Janssen, and ViiV Healthcare. OOO has received honoraria from Gilead Sciences and ViiV Healthcare. JRB has received consulting fees from Gilead Sciences, MSD, Pfizer, and ViiV Healthcare and honoraria from AbbVie, Gilead Sciences, MSD, Pfizer, AstraZeneca, GSK, Janssen, ViiV Healthcare, and NovoNordisk. DPH has received research funding from Gilead Sciences, MSD, ViiV Healthcare, GSK, Janssen; honoraria for speakers bureau from Gilead Sciences and ViiV Healthcare; meeting or travel support from Gilead Sciences, ViiV Healthcare, GSK, and MSD; and served on advisory boards for and received consulting fees from Gilead Sciences, ViiV Healthcare, and Janssen. RP has served on advisory boards for and received consulting fees from Pfizer, MSD, Gilead Sciences, ViiV Healthcare, GSK, Roche, Atea, and Lilly and has received research funds (awarded to institution) from MSD, Gilead Sciences, and ViiV Healthcare. JR has received honoraria from MSD, Gilead Sciences, ViiV Healthcare, and Theratechnologies, outside the submitted work; meeting or travel support from Gilead Sciences; and has served on advisory boards for MSD, Gilead Sciences, and ViiV Healthcare. JKR has received consulting fees from AbbVie, Boehringer, Gilead Sciences, Merck, and ViiV Healthcare; honoraria from Gilead, Merck, Janssen, and ViiV; has served on advisory board for Abivax; and is a member of the governing board of the European AIDS Clinical Society. AC has received research funding from MSD and ViiV Healthcare; lecture and travel sponsorships from Gilead Sciences and ViiV Healthcare; and has served on advisory boards for Gilead Sciences, MSD, and ViiV Healthcare., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Objectives: Earlier electrocardiogram (ECG) acquisition for ST-elevation myocardial infarction (STEMI) is associated with earlier percutaneous coronary intervention (PCI) and better patient outcomes. However, the exact relationship between timely ECG and timely PCI is unclear., Methods: We quantified the influence of door-to-ECG (D2E) time on ECG-to-PCI balloon (E2B) intervention in this three-year retrospective cohort study, including patients from 10 geographically diverse emergency departments (EDs) co-located with a PCI center. The study included 576 STEMI patients excluding those with a screening ECG before ED arrival or non-diagnostic initial ED ECG. We used a linear mixed-effects model to evaluate D2E's influence on E2B with piecewise linear terms for D2E times associated with time intervals designated as ED intake (0-10 min), triage (11-30 min), and main ED (>30 min). We adjusted for demographic and visit characteristics, past medical history, and included ED location as a random effect., Results: The median E2B interval was longer (76 vs 68 min, p  < 0.001) in patients with D2E >10 min than in those with timely D2E. The proportion of patients identified at the intake, triage, and main ED intervals was 65.8%, 24.9%, and 9.7%, respectively. The D2E and E2B association was statistically significant in the triage phase, where a 1-minute change in D2E was associated with a 1.24-minute change in E2B (95% confidence interval [CI]: 0.44-2.05, p  = 0.003)., Conclusion: Reducing D2E is associated with a shorter E2B. Targeting D2E reduction in patients currently diagnosed during triage (11-30 min) may be the greatest opportunity to improve D2B and could enable 24.9% more ED STEMI patients to achieve timely D2E., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Background: Delayed intervention for ST-segment elevation myocardial infarction (STEMI) is associated with higher mortality. The association of door-to-ECG (D2E) with clinical outcomes has not been directly explored in a contemporary US-based population. Methods: This was a three-year, 10-center, retrospective cohort study of ED-diagnosed patients with STEMI comparing mortality between those who received timely (<10 min) vs. untimely (>10 min) diagnostic ECG. Among survivors, we explored left ventricular ejection fraction (LVEF) dysfunction during the STEMI encounter and recovery upon post-discharge follow-up. Results: Mortality was lower among those who received a timely ECG where one-week mortality was 5% (21/420) vs. 10.2% (26/256) among those with untimely ECGs ( p = 0.016), and in-hospital mortality was 6.0% (25/420) vs. 10.9% (28/256) ( p = 0.028). Data to compare change in LVEF metrics were available in only 24% of patients during the STEMI encounter and 46.5% on discharge follow-up. Conclusions: D2E within 10 min may be associated with a 50% reduction in mortality among ED STEMI patients. LVEF dysfunction is the primary resultant morbidity among STEMI survivors but was infrequently assessed despite low LVEF being an indication for survival-improving therapy. It will be difficult to assess the impact of STEMI care interventions without more consistent LVEF assessment., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article.

Background: Emergency care workforce concerns have gained national prominence given recent data suggesting higher than previously estimated attrition. With little known regarding characteristics of physicians leaving the workforce, we sought to investigate the age and number of years since residency graduation at which male and female emergency physicians (EPs) exhibited workforce attrition., Methods: We performed a repeated cross-sectional analysis of EPs reimbursed by Medicare linked to date of birth and residency graduation date data from the American Board of Emergency Medicine for the years 2013-2020. Stratified by gender, our primary outcomes were the median age and number of years since residency graduation at the time of attrition, defined as the last year during the study time frame that an EP provided clinical services. We constructed a multivariate logistic regression model to examine the association between gender and EP workforce attrition., Results: A total of 25,839 (70.2%) male and 10,954 (29.8%) female EPs were included. During the study years, 5905 male EPs exhibited attrition at a median (interquartile range [IQR]) age of 56.4 (44.5-65.4) years, and 2463 female EPs exhibited attrition at a median (IQR) age of 44.0 (38.0-53.9) years. Female gender (adjusted odds ratio 2.30, 95% confidence interval 1.82-2.91) was significantly associated with attrition from the workforce. Male and female EPs had respective median (IQR) post-residency graduation times in the workforce of 17.5 (9.5-25.5) years and 10.5 (5.5-18.5) years among those who exhibited attrition and one in 13 males and one in 10 females exited clinical practice within 5 years of residency graduation., Conclusions: Female physicians exhibited attrition from the EM workforce at an age approximately 12 years younger than male physicians. These data identify widespread disparities regarding EM workforce attrition that are critical to address to ensure stability, longevity, and diversity in the EP workforce., (© 2023 Society for Academic Emergency Medicine.)

Immunostaining of endometrial carcinomas for mismatch repair (MMR) protein loss is standard-of-care for Lynch syndrome screening, but also identifies MMR-deficient tumors without germline pathogenic variants. While the majority show MLH1 hypermethylation ( MLH1hm ), somatic MMR pathogenic variants are increasingly recognized drivers of immunohistochemistry-germline discordance. Because MMR abnormalities with both germline and somatic origins have prognostic significance and impart susceptibility to immune checkpoint inhibitors, it is important to understand how frequently tumors with MMR immunohistochemical loss and normal germline testing ("Lynch-like" tumors) have underlying somatic MMR pathogenic variants. Somatic tumor sequencing±microsatellite instability (MSI) testing was performed on 18 endometrial cancers with MMR immunohistochemical loss but negative MMR germline results and negative MLH1hm where relevant. Tumor sequencing and MSI testing were successful in 94%. Where successful, 80% were MSI-high and 94% had a molecular correlate for the initial immunohistochemical interpretation. The single case without an identified somatic pathogenic variant was MSI-low and initially showed loss of MSH6 by immunohistochemistry but with extremely limited internal control staining. On review, MSH6 immunohistochemistry was reclassified as equivocal, and repeat staining revealed improved control expression with intact MSH6. Following reclassification of this case, 100% tumors with MMR deficiency by immunohistochemistry had at least 1 confirmed somatic MMR pathogenic variant, and 86% were MSI-high. These results demonstrate that when correctly interpreted immunohistochemistry is a strong surrogate for somatic MMR pathogenic variants and support its use as the frontline MMR biomarker in endometrial cancer for heritable screening, molecular prognostic classification, and immunotherapeutic biomarker testing purposes., Competing Interests: Conflicts of Interest and Source of Funding: Funding support was provided by the UVA Department of Pathology Faculty Research Stipend. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The anti-programmed cell death (PD-1) checkpoint inhibitor pembrolizumab is approved for the treatment of cervical carcinoma with a programmed cell death-ligand 1 (PD-L1) Combined Positive Score (CPS) of ≥1. We assessed interobserver agreement in cervical carcinoma PD-L1 CPS to identify whether it may affect patient selection for immunotherapeutic candidacy. Twenty-nine cervical carcinomas were stained for PD-L1 (Dako 22C3), and slides were interpreted by 5 subspecialty-trained gynecologic pathologists with experience reading PD-L1 immunohistochemistry. Expression was scored using CPS and read out as positive (≥1) or negative (<1); in positive cases, a final score was assigned (1 to 100). There was consensus agreement across all 5 pathologists for 90% (26/29) (Fleiss Kappa value for interobserver agreement: 0.799). The 3 cases with disagreement were composed of 2 squamous cell carcinomas and 1 small cell carcinoma. Of the 26 with unanimous agreement, 88% (23/26) were positive and 12% (3/26) were negative. All (16/16) pure squamous cell carcinomas with full consensus were interpreted as positive, whereas tumors with glandular components were commonly consensus negative (33%, 3/9); this difference was significant ( P =0.037). Disagreements were attributable to low CPS versus negative reads (2 cases) and difficulty discerning glandular involvement from pushing invasion (1 case). In summary, experienced gynecologic pathologists showed substantial interobserver agreement in the interpretation of PD-L1 CPS at the Food and Drug Administration-approved treatment threshold, with the majority of tumors being classified as positive. Pure squamous histology was strongly associated with a consensus-positive read, whereas a subset of tumors with glandular differentiation was negative by all readers. Disagreements occurred in tumors with low versus negative CPS values and in the setting of limited invasion., 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 © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Immune-modulating therapies targeting the programmed cell death-1/programmed cell death ligand-1 (PD-L1) immunosuppressive system have been used successfully in many solid tumor types. There is evidence that biomarkers such as PD-L1 and major histocompatibility complex (MHC) class I help identify candidates for anti-programmed cell death-1/PD-L1 checkpoint inhibition, though the evidence is limited in ovarian malignancies. PD-L1 and MHC Class I immunostaining was performed on pretreatment whole tissue sections in 30 cases of high-grade ovarian carcinoma. The PD-L1 combined positive score was calculated (a score of ≥1 is considered positive). MHC class I status was categorized as an intact or subclonal loss. In patients who received immunotherapy, drug response was assessed using RECIST criteria. PD-L1 was positive in 26 of 30 cases (87%; combined positive score: 1 to 100). Seven of 30 patients showed subclonal loss of MHC class I (23%), and this occurred in both PD-L1 negative (3/4; 75%) and PD-L1 positive (4/26; 15%) cases. Only 1 of 17 patients who received immunotherapy in the setting of a platinum-resistant recurrence responded to the addition of immunotherapy, and all 17 died of disease. In the setting of recurrent disease, patients did not respond to immunotherapy regardless of PD-L1/MHC class I status, suggesting that these immunostains may not be effective predictive biomarkers in this setting. Subclonal loss of expression of MHC class I occurs in ovarian carcinoma, including in PD-L1 positive cases, suggesting that the 2 pathways of immune evasion may not be mutually exclusive and that it may be important to interrogate MHC class I status in PD-L1 positive tumors to identify additional immune evasion mechanisms in these tumors., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The College of American Pathologists (CAP) has developed a guideline on testing for mismatch repair (MMR) and microsatellite instability (MSI) for patients considered for immune checkpoint inhibitor therapy. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations., Methods: The CAP guideline was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations., Results: The ASCO Endorsement Panel determined that the recommendations from the CAP guideline, published on August 3, 2022, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer ., Recommendations: Within the guideline, MMR immunohistochemistry (IHC), MSI polymerase chain reaction, and MSI next-generation sequencing are all recommended testing options for colorectal cancer, MMR-IHC and MSI-polymerase chain reaction for gastroesophageal and small bowel cancer, and only MMR-IHC for endometrial cancer. No recommendation in favor of any testing method over another could be made for any other cancer. Tumor mutational burden was not recommended as a surrogate for DNA MMR deficiency. If MMR deficiency consistent with Lynch syndrome is detected, it should be communicated to the treating physician.Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines.

Purpose: Actionable incidental findings (AIFs) are common in radiologic imaging. Imaging is commonly performed in emergency department (ED) visits, and AIFs are frequently encountered, but the ED presents unique challenges for communication and follow-up of these findings. The authors formed a multidisciplinary panel to seek consensus regarding best practices in the reporting, communication, and follow-up of AIFs on ED imaging tests., Methods: A 15-member panel was formed, nominated by the ACR and American College of Emergency Physicians, to represent radiologists, emergency physicians, patients, and those involved in health care systems and quality. A modified Delphi process was used to identify areas of best practice and seek consensus. The panel identified four areas: (1) report elements and structure, (2) communication of findings with patients, (3) communication of findings with clinicians, and (4) follow-up and tracking systems. A survey was constructed to seek consensus and was anonymously administered in two rounds, with a priori agreement requiring at least 80% consensus. Discussion occurred after the first round, with readministration of questions where consensus was not initially achieved., Results: Consensus was reached in the four areas identified. There was particularly strong consensus that AIFs represent a system-level issue, with need for approaches that do not depend on individual clinicians or patients to ensure communication and completion of recommended follow-up., Conclusions: This multidisciplinary collaboration represents consensus results on best practices regarding the reporting and communication of AIFs in the ED setting., (Copyright © 2023 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Preferentially expressed antigen in melanoma (PRAME) is a cancer testes antigen initially employed as a diagnostic marker for melanoma. Although negative in most normal tissues, its expression has been reported in benign endometrial glands. Additionally, PRAME expression has been identified in a growing list of solid and hematologic malignancies and is of interest as a predictive biomarker, as cancer vaccination strategies and adoptive T-cell transfer targeting this molecule are under clinical investigation; additionally, PRAME may identify candidates for retinoid therapy. However, expression of PRAME has not been well-studied in endometrial cancers. We herein evaluate PRAME expression in endometrial carcinomas to better characterize its limitations as a diagnostic melanoma marker as well as its potential as a predictive biomarker in endometrial carcinomas. PRAME expression was evaluated in 256 endometrioid (n=235) and serous (n=21) endometrial carcinomas via tissue microarray. In all, 89% (227/256) demonstrated some degree of nuclear PRAME expression, including 88% (207/235) of endometrioid carcinomas and 95% (20/21) of serous carcinomas. Diffuse (>50%) expression was observed in 70% (179/256) of all cases, including 69% (163/235) of endometrioid carcinomas and 76% (16/21) of serous carcinomas. There was no association between degree of expression and grade, mismatch repair protein status, or stage. The widespread expression of PRAME in endometrial carcinomas suggests this marker should not be interpreted as specific for melanoma in this context. However PRAME may have utility as a predictive biomarker in endometrial cancer, and expansion of testing of PRAME-based therapies to endometrioid and serous endometrial carcinomas may lead to new therapeutic options for these endometrial cancer subtypes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

The objectives of this Clinical Expert Series on endometrial hyperplasia are to review the etiology and risk factors, histologic classification and subtypes, malignant progression risks, prevention options, and to outline both surgical and nonsurgical treatment options. Abnormal uterine and postmenopausal bleeding remain the hallmark of endometrial pathology, and up to 10-20% of postmenopausal bleeding will be either hyperplasia or cancer; thus, immediate evaluation of any abnormal bleeding with either tissue procurement for pathology or imaging should be undertaken. Although anyone with a uterus may develop atypical hyperplasia, also known as endometrial intraepithelial neoplasia (EIN), genetic predispositions (eg, Lynch syndrome), obesity, chronic anovulation, and polycystic ovarian syndrome all markedly increase these risks, whereas use of oral contraceptive pills or progesterone-containing intrauterine devices will decrease the risk. An EIN diagnosis carries a high risk of concomitant endometrial cancer or eventual progression to cancer in the absence of treatment. The definitive and curative treatment for EIN remains hysterectomy; however, the obesity epidemic, the potential desire for fertility-sparing treatments, the recognition of varying rates of malignant transformation, medical comorbidities, and an aging population all may factor into decisions to employ nonsurgical treatment modalities., Competing Interests: Financial Disclosure Susan C. Modesitt reports receiving payment from Elsevier for an editor-in-chief position. The other authors did not report any potential conflicts of interest., (Copyright © 2022 by the American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Cervical carcinoma remains one of the most common cancers affecting women worldwide, despite effective screening programs being implemented in many countries for several decades. The International Collaboration on Cancer Reporting (ICCR) dataset for cervical carcinoma was first developed in 2017 with the aim of developing evidence-based standardized, consistent and comprehensive surgical pathology reports for resection specimens. This 4th edition update to the ICCR dataset on cervical cancer was undertaken to incorporate major changes based upon the updated International Federation of Obstetricians and Gynecologists (FIGO) staging for carcinoma of the cervix published in 2018 and the 5th Edition World Health Organization (WHO) Classification of Female Genital Tumors published in 2020 and other significant developments in pathologic aspects of cervical cancer. This updated dataset was developed by a panel of expert gynecological pathologists and an expert gynecological oncologist, with a period of open consultation. The revised dataset includes "core" and "noncore" elements to be reported; these are accompanied by detailed explanatory notes and references providing the rationale for the updates. Standardized reporting using datasets such as this helps facilitate consistency and accuracy, data collection across different sites and comparison of epidemiological and pathologic parameters for quality and research purposes., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 by the International Society of Gynecological Pathologists.)

Proper plant growth and development require spatial coordination of cell divisions. Two unrelated microtubule-binding proteins, TANGLED1 (TAN1) and AUXIN-INDUCED IN ROOT CULTURES9 (AIR9), are together required for normal growth and division plane orientation in Arabidopsis (Arabidopsis thaliana). The tan1 air9 double mutant has synthetic growth and division plane orientation defects, while single mutants lack obvious defects. Here we show that the division site-localized protein, PHRAGMOPLAST ORIENTING KINESIN1 (POK1), was aberrantly lost from the division site during metaphase and telophase in the tan1 air9 mutant. Since TAN1 and POK1 interact via the first 132 amino acids of TAN1 (TAN11-132), we assessed the localization and function of TAN11-132 in the tan1 air9 double mutant. TAN11-132 rescued tan1 air9 mutant phenotypes and localized to the division site during telophase. However, replacing six amino-acid residues within TAN11-132, which disrupted the POK1-TAN1 interaction in the yeast-two-hybrid system, caused loss of both rescue and division site localization of TAN11-132 in the tan1 air9 mutant. Full-length TAN1 with the same alanine substitutions had defects in phragmoplast guidance and reduced TAN1 and POK1 localization at the division site but rescued most tan1 air9 mutant phenotypes. Together, these data suggest that TAN1 and AIR9 are required for POK1 localization, and yet unknown proteins may stabilize TAN1-POK1 interactions., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Cell-division-plane orientation is critical for plant and animal development and growth. TANGLED1 (TAN1) and AUXIN-INDUCED IN ROOT CULTURES 9 (AIR9) are division-site-localized microtubule-binding proteins required for division-plane positioning. The single mutants tan1 and air9 of Arabidopsis thaliana have minor or no noticeable phenotypes, but the tan1 air9 double mutant has synthetic phenotypes including stunted growth, misoriented divisions and aberrant cell-file rotation in the root differentiation zone. These data suggest that TAN1 plays a role in non-dividing cells. To determine whether TAN1 is required in elongating and differentiating cells in the tan1 air9 double mutant, we limited its expression to actively dividing cells using the G2/M-specific promoter of the syntaxin KNOLLE (pKN:TAN1-YFP). Unexpectedly, in addition to rescuing division-plane defects, expression of pKN:TAN1-YFP rescued root growth and cell file rotation defects in the root-differentiation zone in tan1 air9 double mutants. This suggests that defects that occur in the meristematic zone later affect the organization of elongating and differentiating cells., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Context.—: The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status., Objective.—: To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy., Design.—: The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. Using the National Academy of Medicine-endorsed Grading of Recommendations Assessment, Development and Evaluation approach, the recommendations were derived from available evidence, strength of that evidence, open comment feedback, and expert panel consensus. Mismatch repair immunohistochemistry, microsatellite instability derived from both polymerase chain reaction and next-generation sequencing, and tumor mutation burden derived from large panel next-generation sequencing were within scope., Results.—: Six recommendations and 3 good practice statements were developed. More evidence and evidence of higher quality were identified for colorectal cancer and other cancers of the gastrointestinal (GI) tract than for cancers arising outside the GI tract., Conclusions.—: An optimal assay depends on cancer type. For most cancer types outside of the GI tract and the endometrium, there was insufficient published evidence to recommend a specific clinical assay. Absent published evidence, immunohistochemistry is an acceptable approach readily available in most clinical laboratories., Competing Interests: Authors' disclosures of potential conflicts of interest and author contributions are found in the Appendix at the end of this article.

The coronavirus disease (COVID-19) pandemic has stressed the US health care system in unprecedented ways. In March and April 2020, emergency departments (EDs) throughout New York City experienced high volumes and acuity related to the pandemic. Here, we present a structured after-action report of a coalition of 9 EDs within a hospital system in the New York City metropolitan area, with an emphasis on best practices developed during the prolonged surge as well as specific opportunities for growth. We report our experience in 6 key areas using a framework built around lessons learned. This report represents the most salient concepts related to our institutional after-action report, and those seemingly most relevant to our peer institutions dealing with similar circumstances.

Introduction: To address persistent gender inequities in academic medicine, women professional development groups (PDG) have been developed to support the advancement of women in medicine. While these programs have shown promising outcomes, long-term evaluative metrics do not currently exist. The objective of this study was to establish metrics to assess women's PDGs., Methods: This was a modified Delphi study that included an expert panel of current and past emergency department (ED) chairs and Academy for Women in Academic Emergency Medicine (AWAEM) presidents. The panel completed three iterative surveys to develop and rank metrics to assess women PDGs. Metrics established by the expert panel were also distributed for member-checking to women EM faculty., Results: The expert panel ranked 11 metrics with high to moderate consensus ranking with three metrics receiving greater than 90% consensus: gender equity strategy and plan; recruitment; and compensation. Members ranked 12 metrics with high consensus with three metrics receiving greater than 90% consensus: gender equity strategy and plan; compensation; and gender equity in promotion rates among faculty. Participants emphasized that departments should be responsible for leading gender equity efforts with PDGs providing a supportive role., Conclusion: In this study, we identified metrics that can be used to assess academic EDs' gender equity initiatives and the advisory efforts of a departmental women's PDG. These metrics can be tailored to individual departmental/institutional needs, as well as to a PDG's mission. Importantly, PDGs can use metrics to develop and assess programming, acknowledging that many metrics are the responsibility of the department rather than the PDG.

Study Objective: We sought to identify longitudinal trends in workforce entry and attrition among rural and urban emergency physicians, nonemergency physicians, and advanced practice providers., Methods: We performed a repeated cross-sectional analysis, from 2013 to 2019, of emergency clinicians who received reimbursement for at least 50 Evaluation and Management services [99281-99285] from Medicare part B within any study year. We calculated the emergency workforce's entry and attrition rates annually. Entry was defined as clinicians newly entering or re-entering the workforce, and attrition was defined as clinicians leaving permanently or temporarily. We stratified the analyses by rural designation and assessed the proportions and state-level changes in clinician density., Results: In total, 82,499 unique clinicians performed at least 50 Evaluation and Management services within any of the 7 study years examined, including 47,000 emergency physicians, 9,029 nonemergency physicians, and 26,470 advanced practice providers. Emergency physicians made up a decreasing proportion of the workforce (68.1% in 2013; 65.5% in 2019), and advanced practice providers made up an increasing proportion of the workforce (20.9% in 2013; 26.1% in 2019). Annually, 5.9% to 6.8% (2,186 to 2,407) of emergency physicians newly entered and 0.8% to 1.4% (264 to 515) re-entered the workforce, whereas 3.8% to 4.9% (1,241 to 1,793) permanently left and 0.8% to 1.6% (276 to 521) temporarily left. Additionally, the total proportion of clinicians practicing in rural designations decreased, and advanced practice providers separately made up a substantially increasing proportion of the rural workforce (23.0% in 2013; 32.7% in 2019). Substantial state-level variation existed in the supply and demand of emergency clinician densities per 100,000 population., Conclusion: The annual rate of emergency physician attrition was collectively more than 5%, well above the 3% assumed in a recently publicized projection, suggesting a potential overestimation of the anticipated future clinician surplus. Notably, the attrition of emergency physicians has disproportionately affected vulnerable rural areas. This work can inform emergency medicine workforce decisions regarding residency training, advanced practice provider utilization, and clinician employment., (Copyright © 2022 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Mesonephric-like endometrial carcinoma is a rare but frequently misclassified and aggressive malignancy. KRAS mutations, limited estrogen receptor (ER) expression, and TTF-1, GATA3, and luminal CD10 expression are described in these tumors, but an immunohistochemistry-based screening approach has not been studied. We assessed 300 endometrial carcinomas/carcinosarcomas to ascertain the specificity of TTF-1/GATA3/luminal CD10 expression with or without ER staining for this diagnosis. Next-generation sequencing and morphologic review were performed on screen-positive cases. In all, 3% (9/300) were TTF-1+; 2 coexpressed GATA3. No cases expressed luminal CD10 or GATA3 in isolation. Two TTF-1+/ER- cases, one of which was also GATA3+, were reclassified as mesonephric-like based on morphology and molecular results (KRAS mutations without mismatch repair deficiency, TP53 mutations, or PTEN mutations): these represented 0.7% of all cases (2/300). The reclassified cases were originally diagnosed as grade 1 and 2 endometrioid carcinoma, and the latter had pulmonary metastases and pelvic recurrences. Six TTF-1+ cases retained their original serous (3) and endometrioid (3) diagnoses; 1 was reclassified as dedifferentiated. All had negative or low ER. KRAS mutations were identified in 4 TTF-1+ non-mesonephric-like cases, including 1 serous and 1 grade 3 endometrioid with p53 abnormalities, 1 mismatch repair-deficient endometrioid with a complex molecular profile, and 1 endometrioid with mucinous differentiation. These findings suggest that TTF-1 and ER are good first-line screens for mesonephric-like carcinoma, but caution that a TTF-1+/ER- immunoprofile is not specific, even in the setting of KRAS mutations. A final diagnosis of mesonephric-like carcinoma requires integration of morphologic and immunohistochemical features, with molecular support when relevant., Competing Interests: Conflicts of Interest and Source of Funding: Supported by the UVA Department of Obstetrics & Gynecologic Peyton Taylor Endowed Research Scholarship Fund as well as the UVA Department of Pathology and Stanford Department of Pathology Faculty Research Funds. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The vertical rectus abdominis myocutaneous (VRAM) flap is one of the options for soft-tissue reconstruction in the groin and thigh. The aim of this study is to evaluate the clinical outcomes, risk factors for complications, and the utility of using mesh to prevent abdominal hernia., Methods: A retrospective review of patients who underwent VRAM flap reconstruction to reconstruct proximal thigh and groin defects from 1997 to 2018 was performed. Data regarding patient demographics, surgical characteristics, and postoperative outcomes were collected. Proportional hazard regression analysis was performed to assess the association of the risk of recipient site complications. A systematic review was performed to assess the outcomes and summarize the evidence from published studies., Results: Fifty-three patients were identified and included in this study. In most of the cases, the procedures were performed after tumor resection (77%) and in the rest of the cases, they were performed for chronic complicated wounds (23%). Twenty-five (47.2%) patients developed complications. Intraoperative and postoperative radiotherapy, chronic kidney disease, history of prior tumor resection, and reconstructions of chronic complicated wounds were associated with an increased risk of recipient site complications. A systematic review identified 9 articles, for a total of 189 reconstructions. The pooled complications and failure rates were 31.2% and 2.1%, respectively. Stratified analysis showed that the rate of abdominal hernia was similar in patients with mesh (16.7%) and in patients with primary closure only (15.1%; p = 0.761)., Conclusion: Defects in the groin or proximal thigh can be treated successfully with the VRAM flap. Although wound complications and hernia rates are high, the reconstruction failure rate is low., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier Ltd.)

Sodium-glucose co-transporter type 2 (SGLT2) inhibitor therapy to treat type 2 diabetes unexpectedly reduced all-cause mortality and hospitalization due to heart failure in several large-scale clinical trials, and has since been shown to produce similar cardiovascular disease-protective effects in patients without diabetes. How SGLT2 inhibitor therapy improves cardiovascular disease outcomes remains incompletely understood. Metabolic flexibility refers to the ability of a cell or organ to adjust its use of metabolic substrates, such as glucose or fatty acids, in response to physiological or pathophysiological conditions, and is a feature of a healthy heart that may be lost during diabetic cardiomyopathy and in the failing heart. We therefore undertook studies to determine the effects of SGLT2 inhibitor therapy on cardiac metabolic flexibility in vivo in obese, insulin resistant mice using a [U 13 C]-glucose infusion during fasting and hyperinsulinemic euglycemic clamp. Relative rates of cardiac glucose versus fatty acid use during fasting were unaffected by EMPA, whereas insulin-stimulated rates of glucose use were significantly increased by EMPA, alongside significant improvements in cardiac insulin signaling. These metabolic effects of EMPA were associated with reduced cardiac hypertrophy and protection from ischemia. These observations suggest that the cardiovascular disease-protective effects of SGLT2 inhibitors may in part be explained by beneficial effects on cardiac metabolic substrate selection., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Background ST-segment elevation myocardial infarction (STEMI) guidelines recommend screening arriving emergency department (ED) patients for an early ECG in those with symptoms concerning for myocardial ischemia. Process measures target median door-to-ECG (D2E) time of 10 minutes. Methods and Results This 3-year descriptive retrospective cohort study, including 676 ED-diagnosed patients with STEMI from 10 geographically diverse facilities across the United States, examines an alternative approach to quantifying performance: proportion of patients meeting the goal of D2E≤10 minutes. We also identified characteristics associated with D2E>10 minutes and estimated the proportion of patients with screening ECG occurring during intake, triage, and main ED care periods. We found overall median D2E was 7 minutes (IQR:4-16; range: 0-1407 minutes; range of ED medians: 5-11 minutes). Proportion of patients with D2E>10 minutes was 37.9% (ED range: 21.5%-57.1%). Patients with D2E>10 minutes, compared to those with D2E≤10 minutes, were more likely female (32.8% versus 22.6%, P =0.005), Black (23.4% versus 12.4%, P =0.005), non-English speaking (24.6% versus 19.5%, P =0.032), diabetic (40.2% versus 30.2%, P =0.010), and less frequently reported chest pain (63.3% versus 87.4%, P <0.001). ECGs were performed during ED intake in 62.1% of visits, ED triage in 25.3%, and main ED care in 12.6%. Conclusions Examining D2E>10 minutes can identify opportunities to improve care for more ED patients with STEMI. Our findings suggest sex, race, language, and diabetes are associated with STEMI diagnostic delays. Moving the acquisition of ECGs completed during triage to intake could achieve the D2E≤10 minutes goal for 87.4% of ED patients with STEMI. Sophisticated screening, accounting for differential risk and diversity in STEMI presentations, may further improve timely detection.

This second Guideline for Reasonable and Appropriate Care in the Emergency Department (GRACE-2) from the Society for Academic Emergency Medicine is on the topic "low-risk, recurrent abdominal pain in the emergency department." The multidisciplinary guideline panel applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the certainty of evidence and strength of recommendations regarding four priority questions for adult emergency department patients with low-risk, recurrent, undifferentiated abdominal pain. The intended population includes adults with multiple similar presentations of abdominal signs and symptoms recurring over a period of months or years. The panel reached the following recommendations: (1) if a prior negative computed tomography of the abdomen and pelvis (CTAP) has been performed within 12 months, there is insufficient evidence to accurately identify populations in whom repeat CTAP imaging can be safely avoided or routinely recommended; (2) if CTAP with IV contrast is negative, we suggest against ultrasound unless there is concern for pelvic or biliary pathology; (3) we suggest that screening for depression and/or anxiety may be performed during the ED evaluation; and (4) we suggest an opioid-minimizing strategy for pain control. EXECUTIVE SUMMARY: The GRACE-2 writing group developed clinically relevant questions to address the care of adult patients with low-risk, recurrent, previously undifferentiated abdominal pain in the emergency department (ED). Four patient-intervention-comparison-outcome-time (PICOT) questions were developed by consensus of the writing group, who performed a systematic review of the literature and then synthesized direct and indirect evidence to formulate recommendations, following GRADE methodology. The writing group found that despite the commonality and relevance of these questions in emergency care, the quantity and quality of evidence were very limited, and even fundamental definitions of the population and outcomes of interest are lacking. Future research opportunities include developing precise and clinically relevant definitions of low-risk, recurrent, undifferentiated abdominal pain and determining the scope of the existing populations in terms of annual national ED visits for this complaint, costs of care, and patient and provider preferences., (© 2022 Society for Academic Emergency Medicine.)

Magnetic-core/gold-shell nanoparticles (MAuNPs) are of interest for enabling rapid and portable detection of trace adulterants in complex media. Gold coating provides biocompatibility and facile functionalization, and a magnetic core affords analyte concentration and controlled deposition onto substrates for surface-enhanced Raman spectroscopy. Iron oxide cores were synthesized and coated with gold by reduction of HAuCl 4 by NH 2 OH. MAuNPs were grafted with polyethylene glycol (PEG) and/or functionalized with 4-mercaptobenzoic acid (4-MBA) and examined using a variety of microscopic, spectroscopic, magnetometric, and scattering techniques. For MAuNPs grafted with both PEG and 4-MBA, the order in which they were grafted impacted not only the graft density of the individual ligands, but also the overall graft density. Significant Raman signal enhancement of the model analyte, 4-MBA, was observed. This enhancement demonstrates the functionality of MAuNPs in direct detection of trace contaminants. The magnetic deposition rate of MAuNPs in chloroform and water was explored. The presence of 4-MBA slowed the mass deposition rate, and it was postulated that the rate disparity originated from differing NP-substrate surface interactions. These findings emphasize the importance of ligand choice in reference to the medium, target analyte, and substrate material, as well as functionalization procedure in the design of similar sensing platforms.

Uterine carcinosarcoma (UCS) is an aggressive malignancy with few treatment options. A recent clinical trial has shown an increase in progression-free survival in patients with human epidermal growth factor receptor 2 (HER2)-positive serous endometrial carcinomas treated with anti-HER2-targeted therapies. Few studies have evaluated HER2 expression/amplification in UCS. Similar to serous endometrial carcinoma, the majority of UCS have TP53 mutations and a serous epithelial component, suggesting that UCS may show similar rates of HER2 positivity and therapeutic response. Therefore, we evaluated HER2 expression/amplification in a cohort of UCS over a 5-year period. HER2 immunohistochemistry (IHC) and chromogenic in situ hybridization were performed on tissue microarray and whole tissue sections and scored according to the most recent clinical trial recommendations. Three of 48 UCS (6%) had strong (3+) HER2 IHC expression, and 3 cases (6%) were equivocal (2+). Seven cases (15%) had HER2 amplification by chromogenic in situ hybridization, including all 3 with overexpression and 2 that were equivocal by IHC. Mismatch repair (MMR) protein, p53, and programmed cell death-ligand 1 (PD-L1) expression status was obtained from prior whole section analyses. All HER2-positive cases had a serous morphology and aberrant p53 expression. Only minimal PD-L1 expression was seen in the HER2-positive cases, and none had MMR loss. A subset of UCS with serous morphology have overexpression and/or amplification of HER2, which may predict response to HER2-targeted therapies. HER2-positive UCS may be less susceptible to immune checkpoint inhibition as they uncommonly show MMR deficiency and/or strong PD-L1 expression. Thus, HER2-targeted therapies could be of clinical utility in a subset of UCS without other adjuvant treatment options., 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 © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Vulvar squamous cell carcinoma (vSCC), although rare, carries significant morbidity and a high rate of recurrence. Treatment options beyond surgical excision remain limited. Lymphocyte activation gene-3 (LAG-3) and its binding partner galectin-3 (GAL-3) are an immuno-inhibitory checkpoint pair that represent potential immunotherapy targets for the treatment of vSCC. This study examined the expression of LAG-3 and GAL-3 alongside programmed cell death ligand-1 expression in invasive SCC and vulvar intraepithelial neoplasia (VIN) by immunohistochemical analysis of formalin-fixed paraffin-embedded tissue. A total of 35 cases were selected for evaluation: 13 VIN3 [human papillomavirus (HPV)-associated VIN/usual-type VIN], 2 differentiated VIN (dVIN), 16 HPV-associated vSCC, and 4 dVIN-associated vSCC. LAG-3+ tumor-infiltrating lymphocytes were identified in 91% (32/35) of cases of vulvar squamous neoplasia. Tumor cells were positive for GAL-3 in 71% of the vulvar neoplasia cases. HPV-associated vSCC was more likely to demonstrate GAL-3 tumoral positivity when compared with dVIN-associated vSCC (24/29 vs. 1/6, P=0.004). We observed co-expression of all 3 immunomarkers in 40% (14/35) of cases evaluated. In light of these findings, use of immunomodulatory drugs that target the LAG-3/GAL-3 pathway may be potentially beneficial in vSCC and efficacy may be increased when combined with anti-programmed cell death ligand-1 therapy., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

Checkpoint inhibitor-based immunotherapy is increasingly used in the treatment of gynecologic cancers, and most often targets the PD-1/PD-L1 axis. Pathologists should be familiar with the biomarkers required to determine candidacy for these treatments based on existing FDA approvals, including mismatch repair protein immunohistochemistry, microsatellite instability testing, tumor mutation burden testing, and PD-L1 immunohistochemistry. This review summarizes the rationale behind these treatments and their associated biomarkers and delivers guidance on how to utilize and readout these tests. It also introduces additional biomarkers which may provide information regarding immunotherapeutic vulnerability in the future such as neoantigen load; POLE mutation status; and immunohistochemical expression of immunosuppressive checkpoints like LAG-3, TIM-3, TIGIT, and VISTA; immune-activating checkpoints such as CD27, CD40, CD134, and CD137; enzymes such as IDO-1 and adenosine-related compounds; and MHC class I., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Background: The Society for Academic Emergency Medicine Board of Directors convened a task force to elucidate the current state of workforce, operational, and educational issues being faced by academic medical centers related to advanced practice providers (APPs). The task force surveyed academic emergency department (ED) chairs and residency program directors (PDs)., Methods: The survey was distributed to the Association of Academic Chairs of Emergency Medicine (AACEM)-member chairs and their respective residency PDs in 2021. We surveyed 125 chairs with their self-identified PDs. The survey sampled hiring, state-independent practice laws, scope of practice, teaching and supervision, training opportunities, delegation of procedures between physician learners and APPs, and perceptions of the impact on resident and medical student education., Results: Of the AACEM-member chairs identified, 73% responded and 47% of PDs responded. Most (98%) employ either physician assistants or nurse practitioners. Among responding departments, 86% report APPs working in fast-track settings, 80% work in the main ED, and 54% work in the waiting room. In 44% of departments, APPs and residents evaluate patients concurrently, and 2% of respondents reported that APPs manage high-acuity patients without attending involvement. Two-thirds of chairs believe that APPs contribute positively to the quality of patient care, while 44% believe that APPs contribute to the academic environment. One-third of PDs believe that the presence of APPs interferes with resident education. Although 75% of PDs believe that residents require training to work effectively with APPs in the ED, almost half (49%) report zero hours of training around APP supervision or collaborative skills., Conclusions: APPs are ubiquitous across academic EDs. Future research is required for academic ED leaders to balance physician and APP deployment across the academic ED within the context of patient care, resident education, institutional resources, professional development opportunities for APP staff, and standardization of APP EM training., (© 2021 by the Society for Academic Emergency Medicine.)

MLH1/PMS2 loss due to epigenetic hypermethylation of the MLH1 promoter is the most common cause of mismatch repair deficiency in endometrial carcinoma, and typically provides reassurance against an associated germline mutation. To further characterize the genetic features of MLH1/PMS2-deficient endometrial cancers, the departmental database was searched for cases with dual MLH1/PMS2 loss and retained MSH2/6 expression which underwent MLH1 hypermethylation testing. Genetic testing results were obtained when available. One hundred seventeen endometrial cancers met inclusion criteria: 100 (85%) were MLH1-hypermethylated, 3 (3%) were low-level/borderline, 7 (6%) were nonmethylated, and 7 (6%) were insufficient for testing. Sixteen cases (12 MLH1-hypermethylated, 3 nonmethylated, and 1 insufficient for testing) underwent germline testing, 6 of which (37.5%) demonstrated germline variants of unknown significance (VUS) (MSH6, PMS2, POLD1, BRIP1, RAD51D, CHEK2) but no known deleterious mutations. Notably, however, the patients harboring the MSH6 and PMS2 germline VUS had clinical features concerning for Lynch syndrome. One nonmethylated, germline-normal case underwent somatic tumor testing, and demonstrated a somatic MLH1 mutation. In summary, MLH1-hypermethylation accounts for the vast majority of MLH1/PMS2-deficient cancers in a universally screened population, although MLH1 somatic and germline mutations can occur. Occasionally, patients with MLH1-hypermethlated tumors also bear germline VUS in other mismatch repair genes as well as genes implicated in other hereditary cancer syndromes, but their clinical relevance is unclear. Family and personal cancer histories must always be evaluated to determine the need for germline testing in women with loss of MLH1/PMS2, even in the setting of hypermethylation., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 by the International Society of Gynecological Pathologists.)

Introduction: Loss of kidney function is a common feature of COVID-19 infection, but serum creatinine (SCr) is not a sensitive or specific marker of kidney injury. We tested whether molecular biomarkers of tubular injury measured at hospital admission were associated with acute kidney injury (AKI) in those with COVID-19 infection., Methods: This is a prospective cohort observational study consisting of 444 consecutive patients with SARS-CoV-2 enrolled in the Columbia University emergency department (ED) at the peak of the pandemic in New York (March 2020-April 2020). Urine and blood were collected simultaneously at hospital admission (median time: day 0, interquartile range: 0-2 days), and urine biomarkers were analyzed by enzyme-linked immunosorbent assay (ELISA) and a novel dipstick. Kidney biopsies were probed for biomarker RNA and for histopathologic acute tubular injury (ATI) scores., Results: Admission urinary neutrophil gelatinase-associated lipocalin (uNGAL) level was associated with AKI diagnosis (267 ± 301 vs. 96 ± 139 ng/ml, P  < 0.0001) and staging; uNGAL levels >150 ng/ml had 80% specificity and 75% sensitivity to diagnose AKI stages 2 to 3. Admission uNGAL level quantitatively associated with prolonged AKI, dialysis, shock, prolonged hospitalization, and in-hospital death, even when admission SCr level was not elevated. The risk of dialysis increased almost 4-fold per SD of uNGAL independently of baseline SCr, comorbidities, and proteinuria (odds ratio [OR] [95% CI]: 3.59 [1.83-7.45], P  < 0.001). In the kidneys of those with COVID-19, NGAL mRNA expression broadened in parallel with severe histopathologic injury (ATI). Conversely, low uNGAL levels at admission ruled out stages 2 to 3 AKI (negative predictive value: 0.95, 95% CI: 0.92-0.97) and the need for dialysis (negative predictive value: 0.98, 95% CI: 0.96-0.99). Although proteinuria and urinary (u)KIM-1 were implicated in tubular injury, neither was diagnostic of AKI stages., Conclusion: In the patients with COVID-19, uNGAL level was quantitatively associated with histopathologic injury (ATI), loss of kidney function (AKI), and severity of patient outcomes., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Uterine carcinosarcomas have few adjuvant treatment options. Programmed cell death ligand-1 (PD-L1) expression in these tumors may predict response to checkpoint inhibitor therapies. An increase in PD-L1 expression has been shown in endometrial carcinomas with mismatch repair (MMR) deficiencies; however, few studies have evaluated PD-L1 expression in uterine carcinosarcomas. We examined PD-L1 expression in 41 cases of uterine carcinosarcoma using combined positive scores (CPS) and tumor proportion scores (TPS), and correlated with MMR status, p53 expression, and epithelial histotype. In addition to confirming the diagnosis of carcinosarcoma, the epithelial components were stratified based on endometrioid versus serous histology. Thirty-three cases (80%) were positive for PD-L1, defined as a CPS score of ≥1 or a TPS score of ≥1%. Twelve cases (29%) showed high expression of PD-L1, defined as a CPS score of ≥10 or a TPS score of ≥10%. The majority of the morphologically adjudicated carcinosarcomas had a serous epithelial component (83%) rather than endometrioid (17%), which was reinforced by aberrant p53 staining predominantly within cases with serous morphology. The majority of carcinosarcomas showed at least focal PD-L1 expression, predominantly in tumor-associated immune cells. Carcinosarcomas with endometrioid morphology were significantly more likely to have high-level PD-L1 (5/7 vs. 7/34; P=0.015). MMR-deficient carcinosarcomas were also more likely to have high-level PD-L1 (2/3 vs. 10/28); however, this did not reach statistical significance (P=0.2) and overall MMR-deficiency was uncommon (3 cases, 7%). These findings suggest that PD-L1 may be additive to MMR testing as a predictive biomarker for checkpoint inhibitor vulnerability in carcinosarcomas., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 by the International Society of Gynecological Pathologists.)

Introduction: Bans of menthol characterizing flavor in cigarettes have been implemented in some localities and have been proposed more broadly. One proposed benefit of such a ban is to increase cessation rates among current menthol smokers. There is currently relatively limited data regarding how smoking behavior changes if menthol smokers switch to non-menthol cigarettes., Aims and Methods: African American menthol smokers interested in quitting smoking were randomized to either continue smoking menthol (n = 60) or switch to non-menthol cigarettes (n = 62) for 1 month prior to a cessation attempt. Cessation results were reported previously; this analysis reports the results from the pre-cessation visits at which amount smoked, exhaled carbon monoxide (CO) concentration, urinary cotinine concentrations, and subjective measures were assessed., Results: Over the 4-week study period, those switching to non-menthol (vs. continuing to smoke menthol) cigarettes smoked fewer cigarettes per day (mean ratio: 0.86; 95% confidence interval [CI]: 0.76, 0.98; p = .02), reported lower withdrawal symptom severity (mean difference -1.29; 95% CI: -2.6 to -0.01; p = .05) and higher perceived effectiveness of their skills for quitting smoking (mean difference 0.56; 95% CI: 0.02-1.10; p = .05). No significant differences were found between groups in exhaled CO, urinary cotinine concentrations, or most other subjective effects including support for a ban on menthol characterizing flavor in cigarettes., Conclusions: These results suggest that were menthol cigarettes no longer available, those that switch to non-menthol cigarettes would not change their smoking behavior in a way that is likely to be more hazardous, with some indicators suggesting that there may be some benefit.Clinicaltrials.gov # NCT02342327., Implications: A ban on menthol characterizing flavor in cigarettes has been proposed as a potential means by which to increase smoking cessation rates among current menthol cigarette smokers. This study evaluated how African American menthol cigarette smokers adjusted their smoking behavior after switching to non-menthol cigarettes. Although the overall differences between groups were modest, they were in a direction consistent with decreased smoking suggesting that current smokers would not adjust their behavior in a way that is likely to be more hazardous, with some indicators suggesting that there may be some benefits., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.For permissions, please e-mail: journals.permissions@oup.com.)

Autoimmune and systemic inflammatory diseases represent a heterogeneous group of immune-mediated conditions with a wide range of clinical presentations and various affected organs. Autoimmune diseases can present in the breast as localized disease or as part of systemic involvement. Although breast involvement is uncommon, the spectrum of imaging findings can include breast masses, axillary adenopathy, calcifications, and skin changes, the appearance of which can mimic breast cancer. Common etiologies include diabetic mastopathy, systemic lupus erythematosus, scleroderma, rheumatoid arthritis, idiopathic granulomatous mastitis, sarcoidosis, and Immunoglobulin-G4 related mastopathy. This educational review will present multimodality imaging findings of breast manifestations of systemic inflammatory and autoimmune diseases and coexisting complications. It will also review how these disorders may affect breast cancer risk and breast cancer treatment options, including radiation therapy., (© Society of Breast Imaging 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Small recalcitrant defects of the mandible and maxilla may be secondary to tumor, trauma, infection, and congenital origin. Vascularized bone grafting has been shown to effectively manage these defects; however, donor sites are limited. The vascularized medial femoral condyle (MFC) provides adequate cortical cancellous bone with the option of a skin island, consistent anatomy, and minimal donor site morbidity. This article outlines the use of the MFC flap for maxillomandibular reconstruction., Methods: A retrospective chart review of patients who required segmental maxillomandibular reconstruction with the MFC flap was conducted. A total of 9 patients (5 men and 5 women) with an average age of 45.3 years were identified. The etiology of the defects, flap sizes, and postoperative outcomes were recorded., Results: Three patients had osteoradionecrosis of the neomandible after irradiation of the free fibula reconstruction, 3 patients had defects after cancer extirpation (1 mandible, 2 maxillary), 1 patient had a maxillary defect from trauma, and 2 patients had a residual cleft palate defect. All defects failed initial treatment with nonvascularized bone grafts. The average dimensions of the MFC flaps were 1.2 × 2.5 × 4 cm. Two of 9 flaps included a skin island. Eight flaps survived completely, but 1 patient suffered from flap failure requiring debridement and resulted in an oroantral fistula. Four patients received endosseous dental implants. Average time to union was 6.7 months, and average time to implant was 6.75 months. The average follow-up time was 24.9 months., Conclusions: The MFC flap is useful in the reconstruction of small segmental maxillomandibular defects and for the salvage of a neomandible after osteoradionecrosis. The MFC flap provides a reliable platform for endosseous dental implants and serves as an alternative source of vascularized bone reconstruction in the head and neck., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)