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Abstract Primary lung myoepithelial carcinomas are rare neoplasms arising from the salivary glands of the respiratory epithelium. Given the rare occurrences and reports of these tumors, appropriate recommendations for resection are difficult to formulate. Although classified as low-grade neoplasms, these tumors have a significant rate of recurrence and distant metastasis.

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Objective: Gynecologic cancers are traditionally managed according to their presumed site of origin, without regard to the underlying histologic subtype. Clear cell histology is associated with chemotherapy refractoriness and poor survival. Mutations in SWI/SNF chromatin remodeling complex member ARID1A, which encodes for BAF250a protein, are common in clear cell and endometriosis-associated endometrioid carcinomas. High-throughput cell-based drug screening predicted activity of dasatinib, a tyrosine kinase inhibitor, in ARID1A-mutant clear cell carcinoma., Methods: We conducted a phase 2 clinical trial of dasatinib 140 mg once daily by mouth in patients with recurrent or persistent ovarian and endometrial clear cell carcinoma. Patients with measurable disease were enrolled and then assigned to biomarker-defined populations based on BAF250a immunohistochemistry. The translational endpoints included broad next-generation sequencing to assess concordance of protein expression and treatment outcomes., Results: Twenty-eight patients, 15 of whom had tumors with retained BAF250a and 13 with loss of BAF250a were evaluable for treatment response and safety. The most common grade 3 adverse events were anemia, fatigue, dyspnea, hyponatremia, pleural effusion, and vomiting. One patient had a partial response, eight (28%) had stable disease, and 15 (53.6%) had disease progression. Twenty-three patients had next-generation sequencing results; 13 had a pathogenic ARID1A alteration. PIK3CA mutations were more prevalent in ARID1A-mutant tumors, while TP53 mutations were more prevalent in ARID1A wild-type tumors., Conclusions: Dasatinib was not an effective single-agent treatment for recurrent or persistent ovarian and endometrial clear cell carcinoma. Studies are urgently needed for this rare gynecologic subtype., Competing Interests: Conflicts of interest Roisin O'Cearbhaill - reports personal fees from once off advisory boards from Tesaro/GSK, Regeneron, Seattle Genetics, Fresenius Kabi, Immunogen, R-Pharm, Miltenyi, 2seventybio and Bayer, outside the submitted work; received honoraria for lectures from Gynecologic Oncology Foundation, Curio, PER/MJH, SITC, Gynecologic Oncology Canada and support to attend meetings from Hitech Health, Gathering Around Cancer, Ireland, GOG Foundation and SGO. Non-compensated steering committee member for the PRIMA, Moonstone (Tesaro/GSK) and DUO-O (AstraZeneca) studies and non-compensated advisor for Carina Biotech, Acrivon, Link Therapeutics and Transgene. NRG representative for the ComboMATCH and iMATCH studies. Her institute receives funding for clinical research from Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Gynecologic Oncology Foundation, Acrivon and Lyell Immunopharma. Robert Soslow is a co-editor for the journal Modern Pathology. Dmitriy Zamarin has grants/contracts from AstraZeneca, Merck, Plexxikon, Synthekine and Genentech. He has patient licensng fees through Merck. He has received consulting fees from AstraZeneca, Synthekine, Astellas, Tessa Therapeutics, Memgen, Celldex, Crown Biosciences, Hookipa, Kalivir, Xencor and GSK. Patents planned, issued or pending include Merck for use of oncoltic NDV for cancer therapy. He also has stock options for Accurius, Immunos and Calidi Biotherapeutics. Kathleen Moore's institution receives research funding from PTC Therapeutics, Lilly, Clovis, Genentech, GSK and Verastem. Her Royalties/licenses are up to date. She received consulting fees from AstraZeneca, Aravive, Alkemeres, Aadi, Blueprint pharma, Clovis, Caris Eisai, GSK, Genentech/Roche, Hengrui, Immunogen, Inxmed, Imab, Iovance, Lilly, Mereo, Mersana, Merck, Myriad, Novartis, Novocure, Pannavance, OncXerna, Onconova, Tarveda, VBL Therapeutics and Verastem. She has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from PRIME, RTP, Medscape, Great Debates and Updates. She has received support for attending meetings and/or travel from AstraZeneca. She has a Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid through GOG P Associate Director. Mark Shahin received grants or contracts from GSK, AstraZeneca and Merck. He also received consulting fees from GSK, AstraZeneca and Immunogen. He received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GSK, AstraZeneca, Merck, Eisai, Immunogen and SeaGen. He has a leadership or fiduciary role with UniteForHer. Premal Thaker's institution received grants/contracts from Merck and GSK. He has received consulting fees from Novartis for endometrial cancer, Merck, AstraZeneca, Clovis Oncology, GSK, Novocure, R-Pharm, Immunon, Zentalis and Aadi Bioscience. Andrea E. Wahner-Hendrickson has an NCI grant (P50 CA 136393) for Mayo Ovarian Cancer SORE (Co-project leader), TORL – Site PI Clinical Trial and Prolynx – IIT. She ha received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from George Washington University for Medical Oncology Board Review (CME) – ovary and uterine. She participates on a Data Safety Monitoring Board or Advisory Board at Mayo Clinic DSMB NCI CIRB (early emphasis). She has unpaid Leadership or fiduciary roles in other board, society, committee or advocacy group with Oxcia Advisory Board and MN ovarian cancer advisory board. Carol Aghajanian received clinical trial funding to institution (MSK): Abbvie – MSK PI, GOG 3005, AstraZeneca – MSK PI, SOLO1/GOG 3004; National Coordinating Investigator & MSK PI, DO81RC00001; ENGOT – ov46; AGO-OVAR 23; GOG-3025; Clovis – MSK PI, ARIEL 2 & 3; Genentech/Roche – MSI PI, GOG 3015 (Imagyn050). She has received consulting fees from Abbvie – Advisory Board 5/8/20; Roche/Genentech – Advisory Board 8/21/20; Eisai/Merck – Advisory Board 9/12/20; AstraZeneca/Merck – Advisory Boards 9/30/20 & 10/14/20; and Repare Therapeutics – Advisory Board 10/15/20. She has participated on an Advisory Board – 6/30/21 (no consulting fee) for Blueprint Medicine. She also served as Leadership or fiduciary role in other board, society, committee or advocacy group for GOG Foundation, Board of Directors (travel cost reimbursement for attending meetings) and NRG Oncology Board of Directors (unpaid). Austin Miller, Heather Lankes, Deborah Delair, Sheila Segura, Shweta S. Chavan, Robert DeBernardo, and John Moroney have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background Pulmonary embolism (PE) is the third leading cause of cardiovascular death after myocardial infarction and stroke. The ideal therapeutic approach for these patients remains undetermined. We report our single-center outcome data for using a catheter-based pulmonary artery thrombectomy using the FlowTriever (Inari Medical, Irvine, CA) device as management for patients with submassive PE. Methods We retrospectively collected data from a single center of patients who underwent thrombectomy using INARI FlowTriever device. The data on baseline characteristics, procedural and clinical outcomes was collected and analysed Results A total of 38 patients with PE treated endovascularly with the FlowTriever device were identified: 33 with submassive PE and five with massive PE. The mean age was 65.9 years (95% CI 61.9 - 69.8), and most patients were male (73.7%). All patients had right heart strain as the main indication for thrombectomy. Four patients (10.53%) required pressor support before the procedure. In 31 patients, pre- and post-thrombectomy average mean pulmonary artery pressure (mPAP) was improved significantly by 22% (p < 0.01). Two patients had significant adverse events at 48 hours (5.26%). One patient experienced procedure-related access site hematoma and life-threatening bleeding, while another developed intraprocedural-related massive hemoptysis and cardiopulmonary arrest. Overall post-procedural length of stay was 7.7 ± 5.6 days; 52.63% of patients (n = 20) required intensive care. Three patients (7.89%) required pressor support before the procedure, and 78.9% of patients (n = 30 of 38) survived hospital discharge. Thirty patients who survived were discharged with oral anticoagulation. There were no device-related complications. Conclusion Randomized trials of interventional devices for submassive PE are warranted to either support or alert the medical community of the safety and efficacy of their use for patients with submassive and massive PE. In time, pulmonary embolism response team (PERT) may generate outcome data that better inform treatment decisions., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Elmoghrabi et al.)

Objective: Treatment options and associated biomarkers for advanced and recurrent disease are limited. Endometrial cancers (ECs) with CTNNB1 exon 3 mutations appear to have preferential response to bevacizumab, an anti-angiogenesis treatment, though the mechanism of action is unknown. We aim to identify mediators of bevacizumab-responsive endometrial cancers., Methods: We analyzed RNA expression from TCGA and protein expression from CPTAC to identify likely targets for β-catenin overactivity. We then transiently and stably overexpressed β-catenin in EC cells to confirm the results suggested by our in silico analysis. We performed corroborative experiments by silencing CTNNB1 in mutated cell lines to demonstrate functional specificity. We implanted transduced cells into xenograft models to study microvessel density., Results: CTNNB1-mutated ECs were associated with increased β-catenin and MMP7 protein abundance (P < 0.001), but not VEGF-A protein abundance. Overexpressing β-catenin in EC cells did not increase VEGF-A abundance but did increase expression and secretion of MMP7 (P < 0.03). Silencing CTNNB1 in CTNNB1-mutated cells decreased MMP7 gene expression in EC (P < 0.0001). Microvessel density was not increased., Conclusions: These data provide a mechanistic understanding for bevacizumab-response in CTNNB1-mutated ECs demonstrated in GOG-86P. We hypothesize that overexpressed and secreted MMP7 potentially digests VEGFR-1, releasing VEGF-A, and increasing its availability. These activities may drive the formation of permeable vessels, which contributes to tumor progression, metastasis, and immune suppression. This mechanism is unique to EC and advocates for further clinical trials evaluating this treatment-related biomarker., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The determination of endometrial carcinoma histological subtypes, molecular subtypes, and mutation status is critical for the diagnostic process, and directly affects patients' prognosis and treatment. Sequencing, albeit slower and more expensive, can provide additional information on molecular subtypes and mutations that can be used to better select treatments. Here, we implement a customized multi-resolution deep convolutional neural network, Panoptes, that predicts not only the histological subtypes but also the molecular subtypes and 18 common gene mutations based on digitized H&E-stained pathological images. The model achieves high accuracy and generalizes well on independent datasets. Our results suggest that Panoptes, with further refinement, has the potential for clinical application to help pathologists determine molecular subtypes and mutations of endometrial carcinoma without sequencing., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Background: The relative safety of percutaneous left ventricular assist device (pVAD) and intra-aortic balloon pump (IABP) in patients with cardiogenic shock after acute myocardial infarction remain unknown., Methods: Multiple databases were searched to identify articles comparing pVAD and IABP. An unadjusted OR was used to calculate hard clinical outcomes and mortality differences on a random effect model., Results: Seven studies comprising 26 726 patients (1110 in the pVAD group and 25 616 in the IABP group) were included. The odds of all-cause mortality (OR 0.57, 95% CI 0.47 to 0.68, p=<0.00001) and need for revascularisation (OR 0.16, 95% CI, 0.07 to 0.38, p=<0.0001) were significantly reduced in patients receiving pVAD compared with IABP. The odds of stroke (OR 1.12, 95% CI 0.14 to 9.17, p=0.91), acute limb ischaemia (OR=2.48, 95% CI 0.39 to 15.66, p=0.33) and major bleeding (OR 0.36, 95% CI 0.01 to 25.39, p=0.64) were not significantly different between the two groups. A sensitivity analysis based on the exclusion of the study with the largest weight showed no difference in the mortality difference between the two mechanical circulatory support devices., Conclusions: In patients with acute myocardial infarction complicated by cardiogenic shock, there is no significant difference in the adjusted risk of all-cause mortality, major bleeding, stroke and limb ischaemia between the devices. Randomised trials are warranted to investigate further the safety and efficacy of these devices in patients with cardiogenic shock., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The outcome of transcutaneous aortic valve replacement (TAVR) in patients with kidney transplant is unknown, as majority of these patients were excluded from the major TAVR clinical trials. We sought to compare patients with severe aortic stenosis who underwent TAVR versus surgical aortic valve replacement (SAVR) with a history of kidney transplant., Methods: PubMed, Google Scholar and Cochrane databases were searched to identify relevant articles. The incidence of all-cause mortality and acute kidney injury (AKI) was calculated using relative risk on a random effect model., Results: A total of 1,538 patients (TAVR 328, SAVR 1,210) were included in the study. TAVR was associated with lower mortality as compared with SAVR at 30 days from the index procedure (odds ratio (OR) 0.48, 95% confidence interval (CI): 0.25 - 0.93; P = 0.03). One-year mortality was studied in three studies and showed comparable mortality in patients undergoing TAVR and SAVR (OR: 0.76, 95% CI: 0.10 - 5.51; P = 0.78). Compared to SAVR, TAVR carries an identical risk of AKI (OR: 0.44, 95% CI: 0.10 - 1.90; P = 0.27). A sensitivity analysis performed by exclusion of Voudris et al study showed a non-significant difference in the mortality incidence of two groups at 30 days (OR: 0.72, 95% CI: 0.27 - 1.91; P = 0.51)., Conclusions: In patients with a history of kidney transplant, TAVR was associated with a comparable risk of mortality and AKI compared to SAVR., Competing Interests: None to declare., (Copyright 2020, Mir et al.)

Background: Left ventricular assist devices (LVAD) are indicated as bridging or destination therapy for patients with advanced (Stage D) heart failure and reduced ejection fraction (HFrEF). Due to the clustering of the mutual risk factors, HFrEF patients have a high prevalence of peripheral arterial disease (PAD). This, along with the fact that continuous flow LVAD influence shear stress on the vasculature, can further deteriorate the PAD., Methods: We queried the National Inpatient Sample (NIS) database (2002-2014) to identify the burden of pre-existing PAD cases, its association with LVAD, in-hospital mortality, and other complications of LVAD. The adjusted odds ratio (aOR) and 95% confidence interval (CI) were calculated using the Cochran-Mantel-Haenszel test., Results: A total of 20,817 LVAD patients, comprising of 1,625 (7.8%) PAD and 19,192 (91.2%) non-PAD patients were included in the study. The odds of in-hospital mortality in PAD patients were significantly higher compared to non-PAD group (OR 1.29, CI, 1.07-1.55, P = 0.007). The PAD group had significantly higher adjusted odds as compared to non-PAD group for acute myocardial infarction (aOR 1.29; 95% CI, 1.07-1.55, P = 0.007), major bleeding requiring transfusion (aOR, 1.286; 95% CI, 1.136-1.456, P < 0.001), vascular complications (aOR, 2.360; 95% CI, 1.781-3.126, P < 0.001), surgical wound infections (aOR, 1.50; 95% CI, 1.17-1.94, P = 0.002), thromboembolic complications (aOR, 1.69; 95% CI, 1.36-2.10, P < 0.001), implant-related complications (aOR, 1.47; 95% CI, 1.19-1.80, P < 0.001), and acute renal failure (aOR, 1.26; 95% CI, 1.12-1.43, P < 0.001)., Conclusion: PAD patients can have high LVAD associated mortality as compared to non-PAD., (© 2020 The Authors.)

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets., Competing Interests: Declaration Of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Fumarate hydratase (FH) mutations underpin the autosomal recessive syndrome. FH deficiency and the autosomal dominant syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH c.1431&#95;1433dupAAA (p.Lys477dup) genomic alteration has been conclusively shown to contribute to FH deficiency when occurring with another FH germline alteration. However, a sufficiently large dataset has been lacking to conclusively determine its clinical significance to cancer predisposition in the heterozygous state. We reviewed a series of 7,571 patients with cancer who received germline results through MSK-IMPACT testing at the Memorial Sloan Kettering Cancer Center. The FH c.1431&#95;1433dupAAA (p.Lys477dup) variant was detected in 24 individuals, none of whom was affected with renal cancer. Eleven of the 372 patients with renal cancer were identified to carried pathogenic FH variants associated with HLRCC. None of these 372 patients with renal cancer carried the FH c.1431&#95;1433dupAAA variant. Our data indicate the FH c.1431&#95;1433dupAAA is not associated with cancer including renal cell carcinoma., (© 2019 Wiley Periodicals, Inc.)

Purpose: Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)-associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status., Methods: MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed., Results: Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases., Conclusion: MSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.

Purpose: The treatment paradigm for uterine clear cell carcinoma is often linked to serous carcinoma. This study compares oncologic outcomes between women with uterine clear cell and serous carcinoma., Methods and Materials: We reviewed 114 women with stage I-II uterine clear cell carcinoma (n = 17, 15%) or serous carcinoma (n = 97, 85%) who underwent hysterectomy and salpingo-oophorectomy at our institution from April 1992 to December 2011; 86 (76%) had stage IA, 14 (12%) had stage IB, and 14 (12%) had stage II disease. Median followup was 57 months., Results: Patients with uterine clear cell and serous carcinoma did not differ significantly by age ≥60 years, stage, or rate of lymphovascular invasion. There was no difference in the number of patients with clear cell or serous histology who received adjuvant radiotherapy (71% vs. 84%, respectively; p = 0.31); however, significantly fewer patients with clear cell histology received adjuvant chemotherapy (35% vs. 67%, respectively; p = 0.02). At 5 years, there were no significant differences in disease-free survival (94% vs. 84%, respectively; p = 0.27), disease-specific survival (100% vs. 92%, respectively; p = 0.20), or overall survival (100% vs. 89%, respectively; p = 0.34). The differences in chemotherapy utilization did not impact pattern of relapse, specifically peritoneal spread (7% vs. 6%, respectively; p = 0.92) or other distant sites (0% vs. 9%, respectively; p = 0.17)., Conclusions: Oncologic outcomes and recurrence patterns of women with stage I-II uterine clear cell carcinoma compared favorably with those of women with serous carcinoma, despite significantly less adjuvant chemotherapy use. Potential reduction in adjuvant therapy in women with clear cell carcinoma should be studied prospectively., (Copyright © 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Mutations in DNA mismatch repair (MMR) genes and PTEN, diagnostic of Lynch and Cowden syndromes, respectively, represent the only established inherited predisposition genes in endometrial cancer to date. The prevalence of other cancer predisposition genes remains unclear. We sought the prevalence of pathogenic germline variants in unselected patients with endometrial cancer attending for surgical consultation., Patients and Methods: Patients were prospectively consented (4/2016-5/2017) to an IRB-approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel (MSK-IMPACT) with return of germline results for >75 cancer predisposition genes. Tumors were assessed for microsatellite instability (MSI). Per institutional standards, all tumors underwent Lynch syndrome screening via IHC for MMR proteins., Results: Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. Tumors were endometrioid in 104 (67%), of which 60 (58%) were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%)-7 (4.5%) with highly penetrant cancer syndromes and 15 (9.6%) with variants in moderate-, low-penetrance, or recessive genes. Of these, 5 (21%) were in Lynch syndrome genes (2 MSH6, 2 PMS2, and 1 MLH1) . All 5 tumors had concordant IHC staining; 2 (40%) were definitively MSI-high by next-generation sequencing. One patient had a known BRCA1 mutation; 1 had SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in moderate- and low-penetrance variants or genes associated with recessive disease., Conclusion: In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multi-gene panel testing identifies cancer predisposition gene variants in 14%. This finding may have implications for future cancer screening and risk-reduction recommendations. Universal IHC screening for Lynch syndrome successfully identifies the majority (71%) of high-penetrance germline mutations.

Mutations in succinate dehydrogenase complex genes predispose to familial paraganglioma-pheochromocytoma syndrome (FPG) and gastrointestinal stromal tumors (GIST). Here we describe cancer patients undergoing agnostic germline testing at Memorial Sloan Kettering Cancer Center and found to harbor germline SDHA mutations. Using targeted sequencing covering the cancer census genes, we identified 10 patients with SDHA germline mutations. Cancer diagnoses for these patients carrying SDHA germline mutations included neuroblastoma ( n = 1), breast ( n = 1), colon ( n = 1), renal ( n = 1), melanoma and uterine ( n = 1), prostate ( n = 1), endometrial ( n = 1), bladder ( n = 1), and gastrointestinal stromal tumor (GIST) ( n = 2). Immunohistochemical staining and assessment of patient tumors for second hits and loss of heterozygosity in SDHA confirmed GIST as an SDHA -associated tumor and suggests SDHA germline mutations may be a driver in neuroblastoma tumorigenesis., (© 2018 Dubard Gault et al.; Published by Cold Spring Harbor Laboratory Press.)

Objective: Mucinous ovarian cancer (MOC) is a rare type of epithelial ovarian cancer resistant to standard chemotherapy regimens. We sought to characterize the repertoire of somatic mutations in MOCs and to define the contribution of massively parallel sequencing to the classification of tumors diagnosed as primary MOCs., Methods: Following gynecologic pathology and chart review, DNA samples obtained from primary MOCs and matched normal tissues/blood were subjected to whole-exome (n = 9) or massively parallel sequencing targeting 341 cancer genes (n = 15). Immunohistochemical analysis of estrogen receptor, progesterone receptor, PTEN, ARID1A/BAF250a, and the DNA mismatch (MMR) proteins MSH6 and PMS2 was performed for all cases. Mutational frequencies of MOCs were compared to those of high-grade serous ovarian cancers (HGSOCs) and mucinous tumors from other sites., Results: MOCs were heterogeneous at the genetic level, frequently harboring TP53 (75%) mutations, KRAS (71%) mutations and/or CDKN2A/B homozygous deletions/mutations (33%). Although established criteria for diagnosis were employed, four cases harbored mutational and immunohistochemical profiles similar to those of endometrioid carcinomas, and one case for colorectal or endometrioid carcinoma. Significant differences in the frequencies of KRAS, TP53, CDKN2A, FBXW7, PIK3CA and/or APC mutations between the confirmed primary MOCs (n = 19) and HGSOCs, mucinous gastric and/or mucinous colorectal carcinomas were found, whereas no differences in the 341 genes studied between MOCs and mucinous pancreatic carcinomas were identified., Conclusions: Our findings suggest that the assessment of mutations affecting TP53, KRAS, PIK3CA, ARID1A and POLE, and DNA MMR protein expression may be used to further aid the diagnosis and treatment decision-making of primary MOC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Mixed endometrioid and clear cell carcinoma of the endometrium refers to a scenario in which the tumor exhibits histologic features of both endometrioid and clear cell carcinoma. We observed a tendency for these tumors to occur in a mismatch repair (MMR) protein-deficient molecular background in a prior study that examined a small cohort of mixed-type endometrial carcinomas. The aim of this study was to determine the rate of MMR protein deficiency in a larger series of endometrial mixed endometrioid and clear cell carcinomas, through a retrospective survey of MLH1, PMS2, MSH2, and MSH6 expression in such tumors at 5 tertiary centers. A total of 41 cases were identified and 27 (66%) tumors demonstrated MMR protein deficiency with a comparable frequency across the contributing centers (ranging from 56% to 83%). Among the MMR protein-deficient cases, 59% showed concurrent MLH1 and PMS2 loss, 33% showed concurrent MSH2 and MSH6 loss, and 4% showed isolated PMS2 or MSH6 loss. Compared with a previously published series of 15 pure endometrial clear cell carcinomas, mixed endometrioid and clear cell carcinomas are associated with significantly better disease-specific survival (P=0.02). In summary, endometrial carcinomas with mixed endometrioid and clear cell histology are frequently MMR protein deficient. This finding has implications both for our understanding of its tumor biology and for the identification of patients with potential Lynch syndrome.

Purpose: No effective systemic therapy exists for patients with metastatic low-grade serous (LGS) ovarian cancers. BRAF and KRAS mutations are common in serous borderline (SB) and LGS ovarian cancers, and MEK inhibition has been shown to induce tumor regression in a minority of patients; however, no correlation has been observed between mutation status and clinical response. With the goal of identifying biomarkers of sensitivity to MEK inhibitor treatment, we performed an outlier analysis of a patient who experienced a complete, durable, and ongoing (> 5 years) response to selumetinib, a non-ATP competitive MEK inhibitor., Patients and Methods: Next-generation sequencing was used to analyze this patient's tumor as well as an additional 28 SB/LGS tumors. Functional characterization of an identified novel alteration of interest was performed., Results: Analysis of the extraordinary responder's tumor identified a 15-nucleotide deletion in the negative regulatory helix of the MAP2K1 gene encoding for MEK1. Functional characterization demonstrated that this mutant induced extracellular signal-regulated kinase pathway activation, promoted anchorage-independent growth and tumor formation in mice, and retained sensitivity to selumetinib. Analysis of additional LGS/SB tumors identified mutations predicted to induce extracellular signal-regulated kinase pathway activation in 82% (23 of 28), including two patients with BRAF fusions, one of whom achieved an ongoing complete response to MEK inhibitor-based combination therapy., Conclusion: Alterations affecting the mitogen-activated protein kinase pathway are present in the majority of patients with LGS ovarian cancer. Next-generation sequencing analysis revealed deletions and fusions that are not detected by older sequencing approaches. These findings, coupled with the observation that a subset of patients with recurrent LGS ovarian cancer experienced dramatic and durable responses to MEK inhibitor therapy, support additional clinical studies of MEK inhibitors in this disease., (© 2015 by American Society of Clinical Oncology.)

Endometrial clear cell carcinoma (CC) is an uncommon tumor and often carries a poor prognosis. It has histologic features that overlap with other endometrial carcinomas and is frequently misclassified. Accurate classification is crucial, however, to improve treatment options. The objectives of this study were (1) to assess diagnostic interobserver variability among 5 gynecologic pathologists for tumors originally diagnosed as CC or with a component of CC (n=44); (2) to determine the utility of immunohistochemical markers estrogen receptor and HNF-1β; and (3) to detect mutations in select genes. Clinical data and morphologic features were also recorded. Agreement among reviewers was only moderate: only 46% of the original CC remained classified as such. After reclassification, estrogen receptor was positive in 8% of CC, 67% of endometrioid carcinomas (EC), and 47% of serous carcinomas (SC). Sensitivities of HNF-1β in CC, SC, and EC were 62%, 27%, and 17%, respectively, whereas specificity for CC versus EC or SC was 78%. Mutations in PIK3CA, PIK3R1, PTEN, KRAS, and NRAS were detected in 41% of 37 cases that had adequate material for study. At least 1 mutation was identified in 33% of CC, 67% of EC, and 33% of SC. This group of patients had poor outcomes: 72% of the patients with follow-up information had died of disease. In summary, this study suggests that the current pool of CC is a heterogeneous group of tumors from the morphologic, immunophenotypic, and molecular point of views and that only a percentage of them represent true CC.

AT-rich interactive domain-containing protein 1A (ARID1A), a chromatin remodeling gene recently discovered to be a tumor suppressor in ovarian cancers, has been found to be mutated at low frequencies in many other tumors including colorectal carcinoma (CRC). An association between ARID1A alteration and DNA mismatch repair (MMR) deficiency has been implicated; understanding this association may facilitate the understanding of the role of ARID1A in the various tumors. In this pilot study, we analyzed the immunohistochemical expression of ARID1A in a consecutive series of 257 CRCs that fulfilled a set of relaxed criteria for Lynch syndrome screening; 59 (23%) were MMR deficient by immunohistochemistry (44 MLH1/PMS2 deficient, 9 MSH2/MSH6 deficient, 4 MSH6 deficient, and 2 PMS2 deficient). ARID1A loss was observed in 9% (22/257) of the cohort: 24% of MMR-deficient tumors (14/59, 13 of the 14 being MLH1/PMS2 deficient) and 4% of MMR-normal tumors (8/198) (P < .05). MLH1 (mutL homolog 1) promoter hypermethylation was observed in 10 of the 13 MLH1/PMS2-deficient/ARID1A-loss tumors, indicating an association between ARID1A loss and sporadic microsatellite unstable CRCs. Among the MMR-deficient cases, ARID1A loss correlated with old age (P = .04), poor tumor differentiation (P < .01), medullary histology (P < .01), and an increased rate of nodal and distant metastasis (P = .03); these patients also trended toward a worse 5-year overall survival. Among MMR-normal tumors, no differences in clinicopathological features were detected between the groups stratified by ARID1A. In conclusion, our results suggest that ARID1A loss may be linked to a specific subset of sporadic microsatellite unstable CRCs that may be medullary but is more likely to present with metastatic disease, warranting further investigation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Low-grade serous (LGS) ovarian and primary peritoneal cancer is a rare disease with limited therapeutic options. Low response rates are observed with cytotoxic chemotherapy. However, significant responses have been reported in patients treated with bevacizumab. The objective of this study was to determine the response rate to bevacizumab with or without concurrent chemotherapy in patients with recurrent serous borderline or LGS ovarian or primary peritoneal cancer., Methods: This single-institution retrospective study examined the response rate to treatment with bevacizumab in patients with serous borderline or LGS cancer. Patients were treated at the Memorial Sloan Kettering Cancer Center between 2005 and 2012. The best overall response was determined with the use of the Response Evaluation Criteria in Solid Tumors., Results: A total of 17 patients were identified, 15 of whom were evaluable for the primary end point of best overall response. Two patients were treated with bevacizumab as a single agent, and the remainder received bevacizumab in conjunction with chemotherapy (paclitaxel, topotecan, oral cyclophosphamide, gemcitabine, or gemcitabine and carboplatin). The median duration of bevacizumab administration in evaluable patients was 23 weeks (mean, 32.2 weeks; range, 6-79.4 weeks). There were no complete responses. Partial responses were observed in 6 patients (5 patients received concurrent paclitaxel, and 1 patient received concurrent gemcitabine). The overall response rate was 40%, with a response rate of 55% among the subgroup of patients with LGS cancer., Conclusions: These results indicate that bevacizumab in combination with chemotherapy is an active treatment for recurrent LGS ovarian cancer. A prospective trial of bevacizumab in combination with paclitaxel for the treatment of LGS ovarian cancer should be considered.

Objective: To evaluate overall survival (OS) and progression-free survival (PFS) after adjuvant therapy in stage I to stage IV uterine carcinosarcoma with rhabdomyosarcoma differentiation., Methods: Memorial Sloan-Kettering Cancer Center medical records from 1990 to 2012 were reviewed. Patients who received chemotherapy with or without radiation therapy (RT), or RT alone, for completely resected stage I to stage IV uterine carcinosarcoma with rhabdomyosarcoma differentiation were included., Results: Of 53 patients, International Federation of Gynecology and Obstetrics stage distribution was as follows: I, 13 (24.5%); II, 8 (15.1%); III, 13 (24.5%); and IV, 19 (35.9%). Forty-one (77.4%) of 53 patients received adjuvant chemotherapy, and 34% of the patients who received chemotherapy also received pelvic RT or intravaginal brachytherapy (IVRT). Twelve (22.6%) of the 53 patients received only pelvic RT with/without IVRT. Paclitaxel-carboplatin was the most commonly used adjuvant chemotherapy treatment. The median PFS for the entire cohort was 13.4 months (95% confidence interval [CI], 10.5-17.0). The median OS for the entire cohort was 23.0 months (95% CI, 16.9-34.3). The median PFS periods by stage were 15.9 months for stages I/II versus 11.2 months for stages III/IV (P = 0.012). Median OS was not reached in the early-stage cohort. The median OS for the late-stage cohort was 20.9 months (P = 0.004). The median PFS periods by treatment were 10.4 months for pelvic RT with/without IVRT group versus 13.1 months for chemotherapy with/without pelvic RT with/without IVRT group (P = 0.498). The median OS periods by treatment were 23.6 months for chemotherapy with/without pelvic RT with/without IVRT group versus 16.9 months for pelvic RT with/without IVRT group (P = 0.501)., Conclusion: The results suggest that chemotherapy alone or in combination with RT is associated with longer PFS and OS compared to RT alone. Only the stage of disease significantly affected PFS and OS.

Many ovarian tumors, including high-grade serous carcinoma (HGSC), show clear cell change. Accurate diagnosis is important, however, as ovarian clear cell carcinoma (OCCC) is known to be less responsive to traditional types of ovarian cancer chemotherapies. In a previous study, the clinical, morphologic, and immunohistochemical features of 32 ovarian carcinomas, which had been previously diagnosed as pure OCCC (n=11), pure HGSC (n=11), and mixed serous and clear cell (MSC) (n=10), were analyzed. The immunoreactivities of WT1, ER, and p53, as well as the mitotic indices and stages of presentation of the MSC, were similar to those of HGSC. It was consequently concluded that MSC represented HGSC with clear cell change. Hepatocyte nuclear factor-1β (HNF-1β) is a relatively new immunohistochemical marker that has been shown to be rather sensitive and specific for OCCC. We thus sought to evaluate this marker in this specific group of tumors. One block each of pure HGSC and pure OCCC were stained with HNF-1β. In the cases of MSC, 2 blocks were stained when the serous and clear cell components were not present on the same slide. None (0/11) of the pure HGSC showed immunoreactivity for HNF-1β, whereas all (11/11) of the pure OCCC were positive. In the cases of MSC, both the serous and clear cell components were negative for HNF-1β. HNF-1β seems to be a sensitive and specific marker for OCCC and is not expressed in HGSC with clear cell change. The pattern of immunoreactivity of HNF-1β in tumors with both serous and clear cell change supports the conclusion that MSC are HGSC with clear cells.

Robotic surgery is increasingly being performed for endometrial cancer. Robotic hysterectomies (RH), like traditional laparoscopic hysterectomies (LH), involve a significant amount of uterine manipulation. The use of a manipulator is thought to possibly increase the incidence of artifactual tumor displacement beyond the endometrium, including the fallopian tube. The objective of this study was to determine whether there is an association between RH and tumor present in the fallopian tube lumina. All RH and LH cases performed for endometrial cancer from May 2007 to August 2009 were reviewed. Of the cases not converted to laparotomy, 137 RH and 184 LH were identified. Age, body mass index, operative and hysterectomy time, type and grade of tumor, stage, pelvic wash results, and the presence of detached tumor fragments (contaminants) in the lumina of the fallopian tubes were recorded. Appropriate statistical tests were applied. Of the 184 LH, 4 (2.2%) were reported to have detached fragments of tumor in the lumina of the fallopian tubes compared with 16 of the 137 (11.7%) RH cases (P<0.001). The majority of the patients with RH and tumor present in the tubes had Stage I disease (9/16, 56.2%) and Grade 1 tumors (9/16, 56.2%). Four (4/16, 25%) patients had Stage IIIa disease detected by a pelvic wash. Patients with contaminants had a higher body mass index, but the difference was not statistically significant and was possibly due to small numbers. In conclusion, our data demonstrate an association between RH and tubal contamination. The clinical significance of this phenomenon remains to be determined.

Background: Low-grade serous (LGS) ovarian cancer is a chemoresistant disease that accounts for 10% of serous ovarian cancers. Prior studies have reported that 28% to 35% of serous borderline (SB)/LGS ovarian tumors harbor a BRAF mutation, suggesting that BRAF inhibitors may be a rational therapeutic approach for this disease. In the current study, the authors sought to determine whether BRAF or KRAS mutation status was associated with disease stage and/or histology in patients with SB and LGS ovarian cancer., Methods: Genetic profiles were constructed for 75 SB and LGS ovarian tumors to determine BRAF and KRAS mutation status. The incidence and identity of BRAF and KRAS mutations were defined, and the results were correlated with disease stage, response to treatment, and overall survival., Results: Of 75 samples examined, 56 tumors (75%) had SB histology, and 19 tumors (25%) had LGS histology. Fifty-seven percent of tumors harbored either a KRAS mutation (n = 17) or a BRAF mutation (a valine-to-glutamate substitution at residue 600 [V600E]; n = 26). The BRAF V600E mutation was associated significantly with early disease stage (stage I/II; P < .001) and SB histology (P = .002). KRAS mutations were not associated significantly with disease stage or histology. Of the 22 patients (29%) who required chemotherapy, 20 had tumors with wild-type KRAS/BRAF, 2 had KRAS mutant tumors, and none had tumors that harbored a BRAF mutation. All patients with BRAF tumors remained alive at a median follow-up of 3.6 years (range, 1.9-129.3 months)., Conclusions: V600E BRAF mutations were present in 35% of patients who had SB/LGS ovarian cancers. The presence of the BRAF V600E mutation in SB/LGS ovarian cancer was associated with early stage disease and improved prognosis. The authors concluded that patients with SB/LGS ovarian cancer who require systemic therapy are unlikely to have BRAF mutant tumors., (Copyright © 2012 American Cancer Society.)

Objectives: Since 1988, cervical gland involvement and stromal invasion defined stage IIA and stage IIB endometrial carcinoma. In 2009, FIGO changed the criteria for stage II disease to include only those with cervical stromal invasion. We wished to: 1) assess the reproducibility of pathologists to distinguish patterns of cervical spread, and 2) determine the prognostic significance of cervical involvement., Methods: Slides from 46 women with cervical involvement by endometrial adenocarcinoma were scored for 5 patterns of involvement by 6 experienced pathologists to determine reproducibility. To assess prognostic significance, 206 patients with FIGO 1988 stage II adenocarcinoma formed the study population with matched FIGO stage I controls., Results: At least 5 of the 6 pathologists agreed that the cervix was involved in the 46 cases. The reproducibility for cervical gland involvement and endocervical stromal invasion was slight (kappas of 0.15 and 0.28). The survival with any type of cervical involvement was not significantly different from that of matched stage I controls (p=0.18). The 5year recurrence-free survival rates were 84% for FIGO 1988 stage I, 73% for stage IIA, and 82% for stage IIB (FIGO 2009 stage II)., Conclusions: Pathologists reliably recognize cervical involvement by endometrial carcinoma. However, reproducibility for the determination of pattern of cervical spread by experienced pathologists is too low to be of clinical utility. Women with spread of carcinoma to the cervix do not have a significantly lower survival than matched stage I controls. Cervical spread should not be the basis for determination of stage II disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Key features of extrauterine pelvic serous tumours (fallopian tube, ovary, and peritoneum) Ovarian serous carcinoma (OSC) is the most common of the ovarian epithelial malignancies, and accounts for most of the mortality. Traditionally, ovarian cancer has been considered to be one disease; however, it is now apparent that it actually consists of many different entities. OSC can be further segregated into two processes: high-grade serous carcinoma (HGSC) and low-grade serous carcinoma. This classification is supported by molecular changes, morphological appearance, clinical behaviour, and distinct precursor lesions. This review will describe in detail these features of OSC, differential diagnosis, prognosis, and recent challenges to the existing hypotheses regarding the origin of these tumours. Special attention will be paid to HGSC and its relationship with BRCA abnormalities, especially those seen in hereditary breast and ovarian cancer syndrome. Finally, treatment options based on specific molecular targets will be discussed., (© 2012 Blackwell Publishing Ltd.)

Primary lung myoepithelial carcinomas are rare neoplasms arising from the salivary glands of the respiratory epithelium. Given the rare occurrences and reports of these tumors, appropriate recommendations for resection are difficult to formulate. Although classified as low-grade neoplasms, these tumors have a significant rate of recurrence and distant metastasis.

Primary percutaneous coronary intervention (PCI) of culprit lesions (CLs) is the standard of care in patients presenting with ST elevation myocardial infarction (STEMI). However, optimal revascularization strategy for significant nonculprit lesions (non-CLs) in the setting of STEMI remains controversial. The importance of defining of such a strategy lies in the fact that approximately 50% of patients with STEMI have multivessel disease (MVD). The aim of this study was to describe characteristics, therapeutic strategies, and 1-year outcomes in a cohort of patients with STEMI and MVD. We retrospectively analyzed a cohort of 63 patients with STEMI and MVD obtained from a 5-year catheterization database. MVD was defined as ≥70% stenosis of ≥2 epicardial coronary arteries. This cohort was followed for a period of 1 year for major adverse cardiac events (MACE was defined as acute coronary syndrome, new onset heart failure, or death) and all-cause mortality. PCI with stent placement was the major therapeutic procedure (87.5%) performed for CLs. Non-CLs did not undergo interventions in a majority of individuals (47.6%), while the remaining patients underwent PCI (29%) and coronary artery bypass graft surgery (22%) for non-CLs. At 1-year follow-up, prevalence of MACE events and death in the entire cohort were 30% and 15%, respectively. A trend for better outcomes (1-year cumulative MACE events but not mortality) was observed in CL-only intervention cohort compared with non-CL intervention. The PCI and Coronary artery bypass graft surgery cohorts did not show any significant difference in clinical outcomes. In this retrospective cohort of patients with MVD who presented with STEMI, no intervention of noncritical lesions was the prevalent approach, reflecting guideline recommendations. CL-only intervention strategy showed a better clinical outcome than non-CL intervention. Intervention of noncritical lesions therefore did not seem to improve MACEs or all-cause mortality at 1-year of follow-up and might in fact have had a detrimental effect on outcomes.