@article {719846,
	title = {GLI1-Altered Mesenchymal Tumors With ACTB or PTCH1 Fusion: A Molecular and Clinicopathologic Analysis},
	journal = {Mod Pathol},
	volume = {37},
	number = {2},
	year = {2024},
	month = {2024 Feb},
	pages = {100386},
	abstract = {Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (\&gt;10 years). The most common primary site was soft tissue (n~= 9); other sites included epidural tissue (n~= 1), vertebra (n~= 1), tongue (n~= 1), hard palate (n~= 1), and liver (n~= 1). Histologically, the tumors demonstrated multinodular growth of cytologically uniform, ovoid-to-epithelioid, occasionally short spindled cells with delicate intratumoral vasculature and frequent myxoid stroma. Mitotic activity ranged from 0 to 8 mitoses/2 mm2 (mean 2). Lymphovascular invasion/protrusion of tumor cells into endothelial-lined vascular spaces was present or suspected in 6 cases. Necrosis, significant nuclear pleomorphism, or well-developed, fascicular spindle-cell growth were absent. Half demonstrated features of the newly proposed subset, "distinctive nested glomoid neoplasm." Tumors were consistently positive for CD56 (n~= 5/5). A subset was stained with S100 protein (n~= 7/13), SMA (n~= 6/13), keratin (n~= 2/9), EMA (n~= 3/7), and CD99 (n~= 2/6). Tumors harbored ACTB::GLI1 (n~= 15) or PTCH1::GLI1 (n~= 1) fusions. The assays used did not capture cases defined by GLI1 amplification. We also identified recurrent cytogenetic gains (1q, 5, 7, 8, 12, 12q13.2-ter, 21, and X). For patients with available clinical follow-up (n~= 8), half were disease free. Half demonstrated distant metastases (lungs, bone, or soft tissue). Of cases without follow-up (n~= 8), 2 were known recurrences, and 1 was presumed metastasis. Our results imply a more aggressive biological potential than currently reported. Given the possibility for metastasis and disease progression, even in cytologically bland, nested tumors, close clinical surveillance, akin to that for sarcoma management, may be indicated. The term GLI1-altered mesenchymal tumor with malignant potential is proposed.},
	keywords = {Adult, Biomarkers, Tumor, Humans, Neoplasms, Connective and Soft Tissue, S100 Proteins, Sarcoma, Soft Tissue Neoplasms, Zinc Finger Protein GLI1},
	issn = {1530-0285},
	doi = {10.1016/j.modpat.2023.100386},
	author = {Kerr, Darcy A and Cloutier, Jeffrey M and Margolis, Matthew and Mata, Douglas A and Rodrigues Simoes, Nathalie J and Faquin, William C and Dias-Santagata, Dora and Chopra, Shefali and Charville, Gregory W and Wangsiricharoen, Sintawat and Lazar, Alexander J and Wang, Wei-Lien and Rosenberg, Andrew E and Tse, Julie Y}
}
@article {719836,
	title = {Liquid biopsy-based circulating tumour (ct)DNA analysis of a spectrum of myeloid and lymphoid malignancies yields clinically actionable results},
	journal = {Histopathology},
	year = {2024},
	month = {2024 Feb 29},
	abstract = {AIMS: Liquid biopsy (LBx)-based next-generation sequencing (NGS) of circulating tumour DNA (ctDNA) can facilitate molecular profiling of haematopoietic neoplasms (HNs), particularly when tissue-based NGS is infeasible.

METHODS AND RESULTS: We studied HN LBx samples tested with FoundationOne Liquid CDx, FoundationOne Liquid, or FoundationACT between July 2016 and March 2022. We identified 271 samples: 89 non-Hodgkin lymphoma (NHL), 43 plasma-cell neoplasm (PCN), 41 histiocytoses, 27 myelodysplastic syndrome (MDS), 25 diffuse large B-cell lymphoma (DLBCL), 22 myeloproliferative neoplasm (MPN), 14 Hodgkin lymphoma (HL), and 10 acute myeloid leukaemia (AML). Among 73.4\% with detectable pathogenic alterations, median maximum somatic allele frequency (MSAF) was 16.6\%, with AML (36.2\%), MDS (19.7\%), and MPN (44.5\%) having higher MSAFs than DLBCL (3.9\%), NHL (8.4\%), HL (1.5\%), PCN (2.8\%), and histiocytoses (1.8\%) (P = 0.001). LBx detected characteristic alterations across HNs, including in TP53, KRAS, MYD88, and BTK in NHLs; TP53, KRAS, NRAS, and BRAF in PCNs; IGH in DLBCL; TP53, ATM, and PDCD1LG2 in HL; BRAF and MAP2K1 in histiocytoses; TP53, SF3B1, DNMT3A, TET2, and ASXL1 in MDS; JAK2 in MPNs; and FLT3, IDH2, and NPM1 in AML. Among 24 samples, the positive percent agreement by LBx was 75.7\% for variants present in paired buffy coat, marrow, or tissues. Also, 75.0\% of pairs exhibited alterations only present on LBx. These were predominantly subclonal (clonal fraction of 3.8\%), reflecting the analytical sensitivity of LBx.

CONCLUSION: These data demonstrate that LBx can detect relevant genomic alterations across HNs, including at low clonal fractions, suggesting a potential clinical utility for identifying residual or emerging therapy-resistant clones that may be undetectable in site-specific tissue biopsies.},
	issn = {1365-2559},
	doi = {10.1111/his.15168},
	author = {Mata, Douglas A and Lee, Jessica K and Shanmugam, Vignesh and Marcus, Chelsea B and Schrock, Alexa B and Williams, Erika and Ritterhouse, Lauren L and Hickman, Richard A and Janovitz, Tyler and Patel, Nimesh R and Kroger, Benjamin R and Ross, Jeffrey S and Mirza, Kamran M and Oxnard, Geoffrey R and Vergilio, Jo-Anne and Elvin, Julia A and Benhamida, Jamal K and Decker, Brennan and Xu, Mina L}
}
@article {719841,
	title = {Pan-cancer Genomic Analysis of AXL Mutations Reveals a Novel, Recurrent, Functionally Activating AXL W451C Alteration Specific to Myxofibrosarcoma},
	journal = {Am J Surg Pathol},
	year = {2024},
	month = {2024 Feb 19},
	abstract = {Myxofibrosarcoma (MFS) is a common soft tissue sarcoma of the elderly that typically shows low tumor mutational burden, with mutations in TP53 and in genes associated with cell cycle checkpoints (RB1, CDKN2A). Unfortunately, no alterations or markers specific to MFS have been identified and, as a consequence, there are no effective targeted therapies. The receptor tyrosine kinase AXL, which drives cellular proliferation, is targetable by new antibody-based therapeutics. Expression of AXL messenger RNA is elevated in a variety of sarcoma types, with the highest levels reported in MFS, but the pathogenic significance of this finding remains unknown. To assess a role for AXL abnormalities in MFS, we undertook a search for AXL genomic alterations in a comprehensive genomic profiling database of 463,546 unique tumors (including 19,879 sarcomas, of which 315 were MFS) interrogated by targeted next-generation DNA and/or RNA sequencing. Notably, the only genomic alterations recurrent in a specific sarcoma subtype were AXL W451C (n = 8) and AXL W450C (n = 2) mutations. The tumors involved predominantly older adults (age: 44 to 81 [median: 72] y) and histologically showed epithelioid and spindle-shaped cells in a variably myxoid stroma, with 6 cases diagnosed as MFS, 3 as undifferentiated pleomorphic sarcoma (UPS), and 1 as low-grade sarcoma. The AXL W451C mutation was not identified in any non-sarcoma malignancy. A review of publicly available data sets revealed a single AXL W451C-mutant case of UPS that clustered with MFS/UPS by methylation profiling. Functional studies revealed a novel activation mechanism: the W451C mutation causes abnormal unregulated dimerization of the AXL receptor tyrosine kinase through disulfide bond formation between pairs of mutant proteins expressing ectopic cysteine residues. This dimerization triggers AXL autophosphorylation and activation of downstream ERK signaling. We further report sarcomas of diverse histologic subtypes with AXL gene amplifications, with the highest frequency of amplification identified in MFS cases without the W451C mutation. In summary, the activating AXL W451C mutation appears highly specific to MFS, with a novel mechanism to drive unregulated signaling. Moreover, AXL gene amplifications and messenger RNA overexpression are far more frequent in MFS than in other sarcoma subtypes. We conclude that these aberrations in AXL are distinct features of MFS and may aid diagnosis, as well as the selection of available targeted therapies.},
	issn = {1532-0979},
	doi = {10.1097/PAS.0000000000002191},
	author = {Williams, Erika and Vegas, Isabella and El-Senduny, Fardous F and Zhang, Jessica and Mata, Douglas A and Hiemenz, Matthew C and Hughes, Sarah R and Sa, Brianna C and Kraft, Garrett P and Gorbatov, Nicole and Foley-Peres, Kathleen and Sanchez, Edward Z and Milikowski, Clara and Williams, Kevin Jon and Ross, Jeffrey S and Kurzrock, Razelle and Montgomery, Elizabeth A and Lombard, David B and Kumar, Surinder}
}
@article {719851,
	title = {Acute myeloid leukemia with mixed phenotype is characterized by stemness transcriptomic signatures and limited lineage plasticity},
	journal = {medRxiv},
	year = {2023},
	month = {2023 Nov 03},
	abstract = {UNLABELLED: Mixed phenotype (MP) in acute leukemias poses unique classification and management dilemmas and can be seen in entities other than de novo mixed phenotype acute leukemia (MPAL). Although WHO classification empirically recommends excluding AML with myelodysplasia related changes (AML-MRC) and therapy related AML (t-AML) with mixed phenotype (AML-MP) from MPAL, there is lack of studies investigating the clinical, genetic, and biologic features of AML-MP. We report the first cohort of AML-MRC and t-AML with MP integrating their clinical, immunophenotypic, genomic and transcriptomic features with comparison to MPAL and AML-MRC/t-AML without MP. Both AML cohorts with and without MP shared similar clinical features including adverse outcomes but were different from MPAL. The genomic landscape of AML-MP overlaps with AML without MP but differs from MPAL. AML-MP harbors more frequent RUNX1 mutations than AML without MP and MPAL. RUNX1 mutations did not impact the survival of patients with MPAL. Unsupervised hierarchal clustering based on immunophenotype identified biologically distinct clusters with phenotype/genotype correlation and outcome differences. Furthermore, transcriptomic analysis showed an enrichment for stemness signature in AML-MP and AML without MP as compared to MPAL. Lastly, MPAL but not AML-MP often switched to lymphoid only immunophenotype after treatment. Expression of transcription factors critical for lymphoid differentiation were upregulated only in MPAL, but not in AML-MP. Our study for the first time demonstrates that AML-MP clinically and biologically resembles its AML counterpart without MP and differs from MPAL, supporting the recommendation to exclude these patients from the diagnosis of MPAL. Future studies are needed to elucidate the molecular mechanism of mixed phenotype in AML.

KEY POINTS: AML-MP clinically and biologically resembles AML but differs from MPAL. AML-MP shows RUNX1 mutations, stemness signatures and limited lymphoid lineage plasticity.},
	doi = {10.1101/2023.11.01.23297696},
	author = {Galera, Pallavi and Dilip, Deepika and Derkach, Andriy and Chan, Alexander and Zhang, Yanming and Persuad, Sonali and Mishera, Tanmay and Liu, Ying and Famulare, Christopher and Gao, Qi and Mata, Douglas A and Arcila, Maria and Geyer, Mark B and Stein, Eytan and Dogan, Ahmet and Levine, Ross L and Roshal, Mikhail and Glass, Jacob and Xiao, Wenbin}
}
@article {719881,
	title = {Comparing Follicular Extension Between Low-Grade and High-Grade Dysplastic Nevi},
	journal = {Am J Dermatopathol},
	volume = {45},
	number = {6},
	year = {2023},
	month = {2023 Jun 01},
	pages = {423-424},
	abstract = {Dysplastic nevi are an important subset of melanocytic nevi with atypical clinical, histopathologic, as well as genomic features compared with common acquired nevi. Dysplastic nevi are characterized histologically by both cytologic atypia and architectural disorder. The established criteria for cytologic atypia used to distinguish between low-grade and high-grade dysplastic nevi are often subjective, although there is a dearth of more objective, reproducible features of architectural disorder (eg, pagetoid scatter) that have been validated to differentiate between low-grade and high-grade dysplastic nevi. In this study, we sought to determine whether the presence and degree of follicular extension differ between low-grade and high-grade dysplastic nevi. We retrospectively examined the histopathologic features of 90 dysplastic nevi: 60 cases of low-grade dysplastic nevi (average age of 47.2 {\textpm} 18.1 years; 62.7\% female) and 30 cases of high-grade dysplastic nevi (average age of 47.4 {\textpm} 19.8 years; 60.0\% female). After examination, 50\% of the cases of dysplastic nevi (n = 45) had hair follicles within the lesion, for which the presence and degree of follicular extension was then determined. Low-grade and high-grade dysplastic nevi do not differ significantly regarding the presence of follicular extension, average depth of follicular extension, and confluence of nevus cells along the follicular epithelium. Both low-grade and high-grade dysplastic nevi in our study demonstrated follicular extension that was superficial, that is, above the level of isthmus of hair follicles (insertion of sebaceous gland into hair follicle). Future studies are warranted to confirm these preliminary findings.},
	keywords = {Adult, Aged, Dysplastic Nevus Syndrome, Female, Humans, Hyperplasia, Male, Middle Aged, Nevus, Nevus, Pigmented, Retrospective Studies, Skin Neoplasms},
	issn = {1533-0311},
	doi = {10.1097/DAD.0000000000002438},
	author = {Grube, Vanden L and Narla, Shanthi and Mata, Douglas A and Hafeez, Farhaan}
}
@article {719856,
	title = {A Drosophila model relevant to chemotherapy-related cognitive impairment},
	journal = {Sci Rep},
	volume = {13},
	number = {1},
	year = {2023},
	month = {2023 Nov 07},
	pages = {19290},
	abstract = {Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of treatment and is characterized by deficits involving multiple cognitive domains including memory. Despite the significant morbidity of CRCI and the expected increase in cancer survivors over the coming decades, the pathophysiology of CRCI remains incompletely understood, highlighting the need for new model systems to study CRCI. Given the powerful array of genetic approaches and facile high throughput screening ability in Drosophila, our goal was to validate a Drosophila model relevant to CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult Drosophila. Neurologic deficits were observed with all tested chemotherapies, with doxorubicin and in particular cisplatin also resulting in memory deficits. We then performed histologic and immunohistochemical analysis of cisplatin-treated Drosophila tissue, demonstrating neuropathologic evidence of increased neurodegeneration, DNA damage, and oxidative stress. Thus, our Drosophila model relevant to CRCI recapitulates clinical, radiologic, and histologic alterations reported in chemotherapy patients. Our new Drosophila model can be used for mechanistic dissection of pathways contributing to CRCI (and chemotherapy-induced neurotoxicity more generally) and pharmacologic screens to identify disease-modifying therapies.},
	keywords = {Adult, Animals, Antineoplastic Agents, Chemotherapy-Related Cognitive Impairment, Cisplatin, Cognitive Dysfunction, Doxorubicin, Drosophila, Humans},
	issn = {2045-2322},
	doi = {10.1038/s41598-023-46616-9},
	author = {Matthew Torre and Bukhari, Hassan and Nithianandam, Vanitha and Zanella, Camila A and Mata, Douglas A and Feany, Mel B}
}
@article {719866,
	title = {Expanding Our Knowledge of Molecular Pathogenesis in Histiocytoses: Solitary Soft Tissue Histiocytomas in Children With a Novel CLTC::SYK Fusion},
	journal = {Am J Surg Pathol},
	volume = {47},
	number = {10},
	year = {2023},
	month = {2023 Oct 01},
	pages = {1108-1115},
	abstract = {The histiocytoses comprise a histopathologically and clinically diverse group of disorders bearing recurrent genomic alterations, commonly involving the BRAF gene and mitogen-activated protein kinase pathway. In the current study, a novel CLTC :: SYK fusion in 3 cases of a histopathologically distinct histiocytic neoplasm arising as solitary soft tissue lesions in children identified by next-generation sequencing and fluorescence in situ hybridization is described. Morphologically, all 3 neoplasms were composed of sheets of cells with round-oval nuclei and vacuolated eosinophilic cytoplasm but, in contrast to classic juvenile xanthogranuloma (JXG), Touton giant cells were absent. A separate cohort of classic JXG cases subsequently profiled by fluorescence in situ hybridization were negative for the presence of a CLTC::SYK fusion suggesting that CLTC::SYK fusion-positive histiocytoma is genetically and histologically distinct from JXG. We postulate that the CLTC::SYK fusion leads to aberrant activation of the SYK kinase, which is involved in variable pathways, including mitogen-activated protein kinase. The identification of a novel CLTC::SYK fusion may pave the way for the development of targeted therapeutic options for aggressive disease.},
	keywords = {Child, Clathrin Heavy Chains, Histiocytoma, Humans, In Situ Hybridization, Fluorescence, Mitogen-Activated Protein Kinases, Syk Kinase, Xanthogranuloma, Juvenile},
	issn = {1532-0979},
	doi = {10.1097/PAS.0000000000002102},
	author = {Crowley, Helena M and Georgantzoglou, Natalia and Tse, Julie Y and Williams, Erika and Mata, Douglas A and Martin, Stuart S and Guitart, Joan and Bridge, Julia A and Linos, Konstantinos}
}
@article {719861,
	title = {Microsatellite Instability and Mismatch Repair Deficiency Define a Distinct Subset of Lung Cancers Characterized by Smoking Exposure, High Tumor Mutational Burden, and Recurrent Somatic MLH1 Inactivation},
	journal = {J Thorac Oncol},
	year = {2023},
	month = {2023 Oct 12},
	abstract = {INTRODUCTION: Microsatellite instability (MSI) and mismatch repair (MMR) deficiency represent a distinct oncogenic process and predict response to immune checkpoint inhibitors (ICIs). The clinicopathologic features of MSI-high (MSI-H) and MMR deficiency (MMR-D) in lung cancers remain poorly characterized.

METHODS: MSI status from 5171 patients with NSCLC and 315 patients with SCLC was analyzed from targeted next-generation sequencing data using two validated bioinformatic pipelines.

RESULTS: MSI-H and MMR-D were identified in 21 patients with NSCLC (0.41\%) and six patients with SCLC (1.9\%). Notably, all patients with NSCLC had a positive smoking history, including 11 adenocarcinomas. Compared with microsatellite stable cases, MSI-H was associated with exceptionally high tumor mutational burden (37.4 versus 8.5 muts/Mb, p \&lt; 0.0001), MMR mutational signatures (43\% versus 0\%, p \&lt; 0.0001), and somatic biallelic alterations in MLH1 (52\% versus 0\%, p \&lt; 0.0001). Loss of MLH1 and PMS2 expression by immunohistochemistry was found in MLH1 altered and wild-type cases. Similarly, the majority of patients with MSI-H SCLC had evidence of MLH1 inactivation, including two with MLH1 promoter hypermethylation. A single patient with NSCLC with a somatic MSH2 mutation had Lynch syndrome as confirmed by the presence of a germline MSH2 mutation. Among patients with advanced MSI-H lung cancers treated with ICIs, durable clinical benefit was observed in three of eight patients with NSCLC and two of two patients with SCLC. In NSCLC, STK11, KEAP1, and JAK1 were mutated in nonresponders but wild type in responders.

CONCLUSIONS: We present a comprehensive clinicogenomic landscape of MSI-H lung cancers and reveal that MSI-H defines a rare subset of lung cancers associated with smoking, high tumor mutational burden, and MLH1 inactivation. Although durable clinical benefit to ICI was observed in some patients, the broad range of responses suggests that clinical activity may be modulated by co-mutational landscapes.},
	issn = {1556-1380},
	doi = {10.1016/j.jtho.2023.10.004},
	author = {Yang, Soo-Ryum and Gedvilaite, Erika and Ryan Ptashkin and Chang, Jason and Ziegler, John and Mata, Douglas A and Villafania, Liliana B and Nafa, Khedoudja and Hechtman, Jaclyn F and Benayed, Ryma and Zehir, Ahmet and Benhamida, Jamal and Arcila, Maria E and Mandelker, Diana and Rudin, Charles M and Paik, Paul K and Drilon, Alexander and Schoenfeld, Adam J and Ladanyi, Marc}
}
@article {719876,
	title = {A  model of chemotherapy-related cognitive impairment},
	journal = {bioRxiv},
	year = {2023},
	month = {2023 Jun 05},
	abstract = {Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of treatment and is characterized by deficits involving multiple cognitive domains including memory. Despite the significant morbidity of CRCI and the expected increase in cancer survivors over the coming decades, the pathophysiology of CRCI remains incompletely understood, highlighting the need for new model systems to study CRCI. Given the powerful array of genetic approaches and facile high throughput screening ability in Drosophila, our goal was to validate a Drosophila model of CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult Drosophila. Neurocognitive deficits were observed with all tested chemotherapies, especially cisplatin. We then performed histologic and immunohistochemical analysis of cisplatin-treated Drosophila tissue, demonstrating neuropathologic evidence of increased neurodegeneration, DNA damage, and oxidative stress. Thus, our Drosophila model of CRCI recapitulates clinical, radiologic, and histologic alterations reported in chemotherapy patients. Our new Drosophila model can be used for mechanistic dissection of pathways contributing to CRCI and pharmacologic screens to identify novel therapies to ameliorate CRCI.},
	doi = {10.1101/2023.06.01.543297},
	author = {Matthew Torre and Bukhari, Hassan and Nithianandam, Vanitha and Zanella, Camila A and Mata, Douglas A and Feany, Mel B}
}
@article {719871,
	title = {Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs},
	journal = {Neuro Oncol},
	volume = {25},
	number = {12},
	year = {2023},
	month = {2023 Dec 08},
	pages = {2221-2236},
	abstract = {BACKGROUND: Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas.

METHODS: We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10.

RESULTS: We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs.

CONCLUSIONS: We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.},
	keywords = {Humans, INDEL Mutation, Mutation, Nerve Sheath Neoplasms, Neurilemmoma, Neuroma, Acoustic, SOXE Transcription Factors, Transcriptional Activation},
	issn = {1523-5866},
	doi = {10.1093/neuonc/noad121},
	author = {Williams, Erika and Ravindranathan, Ajay and Gupta, Rohit and Stevers, Nicholas O and Suwala, Abigail K and Hong, Chibo and Kim, Somang and Yuan, Jimmy Bo and Wu, Jasper and Barreto, Jairo and Lucas, Calixto-Hope G and Chan, Emily and Pekmezci, Melike and LeBoit, Philip E and Mully, Thaddeus and Perry, Arie and Bollen, Andrew and Van Ziffle, Jessica and Devine, W Patrick and Reddy, Alyssa T and Gupta, Nalin and Basnet, Kristen M and Macaulay, Robert J B and Malafronte, Patrick and Lee, Han and Yong, William H and Williams, Kevin Jon and Juratli, Tareq A and Mata, Douglas A and Huang, Richard S P and Hiemenz, Matthew C and Pavlick, Dean C and Frampton, Garrett M and Janovitz, Tyler and Ross, Jeffrey S and Chang, Susan M and Berger, Mitchel S and Jacques, Line and Song, Jun S and Costello, Joseph F and Solomon, David A}
}
@article {700516,
	title = {POU2AF3-rearranged sarcomas: A novel tumor defined by fusions of EWSR1 or FUS to a gene formerly designated COLCA2},
	journal = {Genes Chromosomes Cancer},
	year = {2023},
	month = {2023 Mar 02},
	abstract = {Gene fusions involving EWSR1 or FUS as the 5{\textquoteright} partner have been reported in a diverse array of sarcomas. Here, we characterize the histopathology and genomics of six tumors harboring a gene fusion between EWSR1 or FUS and POU2AF3, an understudied, putative colorectal cancer predisposition gene. Striking morphologic features reminiscent of synovial sarcoma were observed including a biphasic appearance with variable fusiform to epithelioid cytomorphology and staghorn-type vasculature. RNA sequencing demonstrated variable breakpoints in EWSR1/FUS along with similar breakpoints in POU2AF3 that encompassed a 3{\textquoteright} portion of this gene. For cases in which additional information was available, the behavior of these neoplasms was aggressive with local spread and/or distant metastases. Although further studies are needed to confirm the functional significance of our findings, POU2AF3 fusions to EWSR1 or FUS may define a novel type of POU2AF3-rearranged sarcomas with aggressive, malignant behavior.},
	issn = {1098-2264},
	doi = {10.1002/gcc.23136},
	author = {Hiemenz, Matthew C and Kaur, Jaspreet and Kuang, Zheng and Huang, Richard S P and Harries, Lukas and Metzger, Dana and Schiavone, Kelsie and Millis, Sherri Z and Douglas I Lin and Lechpammer, Mirna and Decker, Brennan and Mata, Douglas A and Reddy, Abhinav and Parke, Matthew and Lee, Eun Y and Cui, Xiaoyan and Iwenofu, O Hans and Buehler, Darya and Henderson, Les and Baldwin, Erin M and Boikos, Sosipatros A and Ramkissoon, Shakti H and Smith, Steven C}
}
@article {700511,
	title = {Sinonasal Myxoma: A Distinct Entity or a Myxoid Variant of Desmoid Fibromatosis?},
	journal = {Mod Pathol},
	year = {2023},
	month = {2023 Apr 12},
	pages = {100189},
	abstract = {Sinonasal myxoma (SNM) is a rare benign mesenchymal tumor that arises in the sinonasal cavity or maxilla and almost exclusively affects young children. Currently, it is considered a specific entity, but its molecular characteristics have not been reported. Lesions diagnosed as SNM and odontogenic myxoma/fibromyxoma (OM/OFM) were identified from the participating institutions, and the clinicopathologic features were recorded. Immunohistochemistry for β-catenin was performed on all cases with available tissue. Next-generation sequencing (NGS) was performed on all SNM cases. Five patients with SNM were identified, including 3 boys and 2 girls with an age range of 20-36 months (mean: 26 months). The tumors were well-defined, centered in the maxillary sinus, surrounded by a rim of woven bone, and composed of a moderately cellular proliferation of spindle cells oriented in intersecting fascicles in a variably myxocollagenous stroma that contained extravasated erythrocytes. Histologically, the tumors resembled myxoid desmoid fibromatosis. Three tested cases showed nuclear expression of β-catenin. In 3 tumors, NGS revealed intragenic deletions of APC exons 5-6, 9 and 15, or 16, respectively, with concurrent loss of the other wild-type copy of APC, predicted to result in biallelic inactivation. The deletions were identical to those that occur in desmoid fibromatosis, and copy-number analysis raised the possibility that they were germline. In addition, one case showed possible deletion of APC exons 12-14, and another case exhibited a CTNNB1 p.S33C mutation. Ten patients with OM/OFM were identified, including 4 women and 6 men (mean age: 42 years). Seven tumors involved the mandible, and 3 the maxilla. Histologically, the tumors differed from SNM, and all cases lacked nuclear expression of β-catenin. These findings suggest that SNM represents a myxoid variant of desmoid fibromatosis that often arises in the maxilla. Because the APC alterations might be germline, genetic testing of the affected patients should be considered.},
	issn = {1530-0285},
	doi = {10.1016/j.modpat.2023.100189},
	author = {Velez Torres, Jaylou M and Mata, Douglas A and Briski, Laurence M and Green, Donald C and Cloutier, Jeffrey M and Kerr, Darcy A and Montgomery, Elizabeth A and Rosenberg, Andrew E}
}
@article {697472,
	title = {Determining the Association Between Melanomas and Fields of Melanocytic Dysplasia},
	journal = {Am J Dermatopathol},
	volume = {45},
	number = {2},
	year = {2023},
	month = {2023 Feb 01},
	pages = {90-92},
	abstract = {Some have proposed that melanomas in situ may be associated with fields of melanocytic dysplasia, particularly on sun-damaged skin, whereas others maintain that the atypical junctional melanocytic hyperplasia (MH) at the periphery of melanomas is simply background junctional MH of sun-damaged skin. The biological potential of atypical junctional MH at the periphery of melanomas is uncertain. We examined whether atypical junctional MH was intrinsic to the melanoma itself (ie, melanoma-associated field of melanocytic dysplasia) or was simply the predictable junctional MH associated with long-standing sun exposure. We retrospectively compared 106 cutaneous melanoma excisions without residual tumor with 105 nonmelanoma cutaneous tumor excisions (ie, basal cell or squamous cell carcinomas) without residual tumor. MH with atypia occurred significantly more frequently in melanoma than in nonmelanoma cutaneous tumor excisions (55.7\% vs. 24.8\%, P \&lt; 0.001). Solar elastosis occurred significantly less frequently in melanoma than in nonmelanoma cutaneous tumor excisions; 33.0\% of melanoma excisions and 8.6\% of nonmelanoma excision samples exhibited no solar elastosis, respectively (P \&lt; 0.001). After controlling for solar elastosis using multivariable linear regression, the association between MH with atypia and melanoma excisions remained significant (P \&lt; 0.001). Our results, therefore, demonstrate that melanomas were associated with atypical junctional MH that could not solely be accounted for by the extent of sun damage as measured by solar elastosis.},
	keywords = {Humans, Hyperplasia, Melanoma, Neoplasm, Residual, Retrospective Studies, Skin Diseases, Skin Neoplasms, Sunlight},
	issn = {1533-0311},
	doi = {10.1097/DAD.0000000000002339},
	author = {Mata, Douglas A and Christine G Lian and Hafeez, Farhaan}
}
@article {697473,
	title = {Disparities According to Genetic Ancestry in the Use of Precision Oncology Assays},
	journal = {N Engl J Med},
	volume = {388},
	number = {3},
	year = {2023},
	month = {2023 Jan 19},
	pages = {281-283},
	keywords = {Healthcare Disparities, Humans, Medical Oncology, Neoplasms, Precision Medicine},
	issn = {1533-4406},
	doi = {10.1056/NEJMc2213457},
	author = {Mata, Douglas A and Rotenstein, Lisa S and Ramos, Marco A and Jena, Anupam B}
}
@article {697477,
	title = {Activating IGF1R hotspot non-frameshift insertions define a novel, potentially targetable molecular subtype of adenoid cystic carcinoma},
	journal = {Mod Pathol},
	volume = {35},
	number = {11},
	year = {2022},
	month = {2022 Nov},
	pages = {1618-1623},
	abstract = {Activation of the tyrosine kinase receptor IGF1R is targetable with existing tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, but mutations in IGF1R have not been systematically characterized. Pan-cancer analysis of 326,911 tumors identified two distinct, activating non-frameshift insertion hotspots in IGF1R, which were significantly enriched in adenoid cystic carcinomas (ACCs). IGF1R alterations from 326,911 subjects were analyzed by variant effect prediction class, position within the gene, and cancer type. 6502 (2.0\%) samples harbored one or more alterations in IGF1R. Two regions were enriched for non-frameshift insertions: codons 663-666 at the hinge region of the fibronectin type 3 domain and codons 1034-1049 in the tyrosine kinase domain. Hotspot insertions were highly enriched in ACCs (27.3-fold higher than in the remainder of the pan-cancer dataset; P = 2.3 {\texttimes} 10-17). Among salivary gland tumors, IGF1R hotspot insertions were entirely specific to ACCs. IGF1R alterations were most often mutually exclusive with other ACC drivers (9/15, 60\%). Tumors with non-frameshift hotspot IGF1R insertions represent a novel, potentially targetable subtype of ACC. Additional studies are needed to determine whether these patients respond to existing IGF1R inhibitors.},
	keywords = {Antibodies, Monoclonal, Carcinoma, Adenoid Cystic, Fibronectins, Humans, Protein Kinase Inhibitors, Receptor, IGF Type 1, Salivary Gland Neoplasms},
	issn = {1530-0285},
	doi = {10.1038/s41379-022-01126-3},
	author = {Margolis, Matthew and Janovitz, Tyler and Laird, Jason and Mata, Douglas A and Montesion, Meagan and Lee, Jessica K and Madison, Russell W and Schrock, Alexa B and Tukachinsky, Hanna and Allen, Justin M and Erlich, Rachel and Hiemenz, Matthew C and Huang, Richard S P and Elvin, Julia and Vergilio, Jo-Anne and Douglas I Lin and Ross, Jeffrey and Oxnard, Geoffrey and Decker, Brennan}
}
@article {697475,
	title = {Clear cell mesotheliomas with inactivating VHL mutations and near-haploid genomic features},
	journal = {Genes Chromosomes Cancer},
	year = {2022},
	month = {2022 Dec 14},
	abstract = {Clear cell mesothelioma is uncommon and shows predominance of clear cells with resemblance to clear cell carcinomas. Clinicopathologic and molecular descriptions of clear cell mesothelioma remained limited. In this study, we identified an index patient with clear cell mesothelioma, confirmed by immunohistochemical and ultrastructural studies. Targeted next-generation sequencing revealed the presence of an inactivating VHL mutation. We then systematically searched for VHL-mutant mesotheliomas in a comprehensive genomic profiling database of 1532 mesotheliomas. Collectively, we identified a cohort of four VHL-mutant clear cell mesotheliomas, including three peritoneal and one pleural tumors from three females and one male, with age range of 47-68 (median 63) years. Histologically, each tumor showed a microcystic to tubulopapillary architecture with prominent clear cells. By next-generation DNA sequencing, each of the four clear cell mesotheliomas harbored inactivating VHL mutations, while lacking other alterations typical of mesotheliomas such as BAP1, NF2, SETD2, CDKN2A, CDKN2B, TP53, and PTEN. By using low-pass whole genome sequencing on the index case and targeted next-generation sequencing on the remaining three cases, we identified extensive loss of heterozygosity throughout the genome but consistently sparing chromosomes 5, 7, and 20, characteristic of genomic near-haploidization. In summary, clear cell mesotheliomas were characterized by inactivating VHL mutations and genomic near-haploidization and appeared to represent a distinct clinicopathologic and molecular category of mesotheliomas. Our findings implicate VHL in the pathogenesis of a subset of mesotheliomas, particularly those with clear cell morphology.},
	issn = {1098-2264},
	doi = {10.1002/gcc.23119},
	author = {Michal, Michael and Kravtsov, Oleksandr and Ross, Jeffrey S and Skanderov{\'a}, Daniela and Mart{\'\i}nek, Petr and Mosaieby, Elaheh and Mata, Douglas A and Williams, Erika and Hung, Yin P}
}
@article {697476,
	title = {Patterns in Actions Against Physician Licenses Related to Substance Use and Psychological or Physical Impairment in the US From 2004 to 2020},
	journal = {JAMA Health Forum},
	volume = {3},
	number = {6},
	year = {2022},
	month = {2022 Jun},
	pages = {e221163},
	abstract = {This cross-sectional study examines the frequency of actions taken against physician licenses in the US because of substance use and psychological or physical impairment from 2004 to 2020.},
	keywords = {Cross-Sectional Studies, Humans, Licensure, Physicians, Substance-Related Disorders},
	issn = {2689-0186},
	doi = {10.1001/jamahealthforum.2022.1163},
	author = {Rotenstein, Lisa S and Dadlani, Akanksha and Cleary, Jennifer and Sen, Srijan and Jena, Anupam B and Mata, Douglas A}
}
@article {697474,
	title = {Proliferative actinic keratoses are associated with adverse clinical outcomes relative to actinic keratoses without a proliferative growth pattern},
	journal = {Br J Dermatol},
	year = {2022},
	month = {2022 Nov 17},
	issn = {1365-2133},
	doi = {10.1093/bjd/ljac098},
	author = {Agarwala, Saira and Mata, Douglas A and Safeer, Laraib Z and Hafeez, Farhaan}
}
@article {692070,
	title = {Method of Tissue Acquisition Affects Success of Comprehensive Genomic Profiling in Lung Cancer},
	journal = {Arch Pathol Lab Med},
	year = {2022},
	month = {2022 Jun 30},
	abstract = {CONTEXT.{\textemdash}: Multiple procedural techniques can be used to obtain tissue to create a formalin-fixed, paraffin-embedded specimen for comprehensive genomic profiling (CGP) in lung cancer. The literature is mixed on whether the procedure affects CGP success.

OBJECTIVE.{\textemdash}: To examine whether biopsy procedure affects lung cancer CGP success.

DESIGN.{\textemdash}: This was a cross-sectional study of all patients with lung cancer whose specimens were submitted for CGP between January and February 2020. Multiple quality control metrics were used to determine whether cases were successfully profiled.

RESULTS.{\textemdash}: In all, 3312 samples were identified. Overall, 67.5\% (2236 of 3312) were obtained from biopsies, 13.0\% (432 of 3312) from fine-needle aspirations (FNAs), 9.7\% (321 of 3312) from resections, 5.3\% (174 of 3312) from fluid cytology cell blocks, and 4.5\% (149 of 3312) from bone biopsies. Overall, 70.1\% (2321 of 3312) of cases passed CGP, 15.4\% (510 of 3312) of cases were released as qualified reports, and 14.5\% (481 of 3312) of cases failed CGP. Resection samples were the most likely to be successfully sequenced, failing in only 2.8\% (9 of 321) of instances, while fluid cytology specimens were the least likely, failing in 23.0\% (40 of 174) of instances. Biopsy (14.5\% [324 of 2236]), FNA (18.5\% [80 of 432]), and bone biopsy (18.8\% [28 of 149]) specimens failed at intermediate frequencies. On multivariate logistic regression analysis of CGP success on specimen type, fluid cytology (OR, 0.08; 95\% CI, 0.03-0.19), biopsy (OR, 0.25; 95\% CI, 0.11-0.52), FNA (OR, 0.14; 95\% CI, 0.06-0.32), and bone biopsy (OR, 0.07; 95\% CI, 0.03-0.17) specimens had decreased odds of CGP success relative to resection samples. Among patients with successfully sequenced samples, 48.0\% were eligible for at least 1 therapy, based on a companion diagnostic or National Comprehensive Cancer Network biomarker.

CONCLUSIONS.{\textemdash}: The method of tissue acquisition was an important preanalytic factor that determined whether a sample would be successfully sequenced and whether a clinically actionable genomic alteration would be detected.},
	issn = {1543-2165},
	doi = {10.5858/arpa.2021-0313-OA},
	author = {Mata, Douglas A and Harries, Lukas and Williams, Erika and Hiemenz, Matthew C and Decker, Brennan and Tse, Julie Y and Janovitz, Tyler and Ferguson, Donna C and Speece, Iain A and Margolis, Matthew L and Mathews, Benjamin and Fedorchak, Kyle and Killian, J Keith and Xiao, Jinpeng and Tolba, Khaled A and Ramkissoon, Shakti and Vergilio, Jo-Anne and Elvin, Julia A and Oxnard, Geoffrey R and Ross, Jeffrey S and Huang, Richard S P}
}
@article {691221,
	title = {Androgen receptor splice variant-7 in breast cancer: clinical and pathologic correlations},
	journal = {Mod Pathol},
	volume = {35},
	number = {3},
	year = {2022},
	month = {2022 03},
	pages = {396-402},
	abstract = {Androgen receptor (AR) inhibitor therapy is a developing treatment for AR-positive breast cancer (BC) with ongoing clinical trials. AR splice variant-7 (AR-V7) is a truncated variant of AR that leads to AR inhibitor therapy resistance in prostate cancer; recent studies have identified AR-V7 in BC and theorized that AR-V7 can have a similar impact. This study assessed the prevalence and clinicopathologic features associated with AR-V7 in a large BC cohort. BC samples were evaluated by MSK-Fusion targeted RNAseq for AR-V7 detection and MSK-IMPACT targeted DNAseq, including triple-negative tumors with no driver alteration and estrogen receptor-positive/ESR1 wildtype tumors progressing on therapy. Among 196 primary and metastatic/recurrent cases (196 RNAseq, 194DNAseq), 9.7\% (19/196) were AR-V7 positive and 90.3\% (177/196) AR-V7 negative. All AR-V7 positive BC were AR-positive by immunohistochemistry (19/19). The prevalence of AR-V7 by receptor subtype (N = 189) was: 18\% (12/67) in ER-/PgR-/HER2-negative BC, 3.7\% (4/109) in ER-positive/HER2-negative BC, and 15.4\% (2/13) in HER2-positive BC; AR-V7 was detected in one ER-positive/HER2-unknown BC. Apocrine morphology was observed in 42.1\% (8/19) of AR-V7 positive BC and 3.4\% (6/177) AR-V7 negative BC (P \&lt; 0.00001). Notably, AR-V7 was detected in 2 primary BC and 7 metastatic/recurrent BC patients with no prior endocrine therapy. We conclude that positive AR IHC and apocrine morphology are pathologic features that may indicate testing for AR-V7 is warranted in both primary and metastatic BC in the appropriate clinical context. The study findings further encourage the assessment of AR-V7 as a predictive biomarker for AR antagonist benefit in ongoing clinical BC trials.},
	keywords = {Breast Neoplasms, Female, Humans, Neoplasm Recurrence, Local, Protein Isoforms, Receptors, Androgen},
	issn = {1530-0285},
	doi = {10.1038/s41379-021-00924-5},
	author = {Ferguson, Donna C and Mata, Douglas A and Tay, Timothy Ky and Traina, Tiffany A and Gucalp, Ayca and Sarat Chandarlapaty and D{\textquoteright}Alfonso, Timothy M and Brogi, Edi and Mullaney, Kerry and Ladanyi, Marc and Arcila, Maria E and Benayed, Ryma and Ross, Dara S}
}
@article {691227,
	title = {Differences in Gender Representation in the Altmetric Top 100},
	journal = {J Gen Intern Med},
	volume = {37},
	number = {3},
	year = {2022},
	month = {2022 02},
	pages = {590-592},
	keywords = {Humans, Journal Impact Factor, Social Media},
	issn = {1525-1497},
	doi = {10.1007/s11606-021-06829-y},
	author = {Rotenstein, Lisa S and Matthew Torre and Cleary, Jennifer L and Sen, Srijan and Guille, Constance and Mata, Douglas A}
}
@article {691214,
	title = {DNA methylation analysis of glioblastomas harboring FGFR3-TACC3 fusions identifies a methylation subclass with better patient survival},
	journal = {Acta Neuropathol},
	volume = {144},
	number = {1},
	year = {2022},
	month = {2022 Jul},
	pages = {155-157},
	keywords = {DNA Methylation, Glioblastoma, Humans, Microtubule-Associated Proteins, Oncogene Proteins, Fusion, Receptor, Fibroblast Growth Factor, Type 3},
	issn = {1432-0533},
	doi = {10.1007/s00401-022-02430-7},
	author = {Wu, Zhichao and Lopes Abath Neto, Osorio and Bale, Tejus A and Benhamida, Jamal and Douglas Mata and Turakulov, Rust and Abdullaev, Zied and Marker, Daniel and Ketchum, Courtney and Chung, Hye-Jung and Giannini, Caterina and Quezado, Martha and Pratt, Drew and Aldape, Kenneth}
}
@article {691216,
	title = {HPV51-associated Leiomyosarcoma: A Novel Class of TP53/RB1-Wildtype Tumor With Predilection for the Female Lower Reproductive Tract},
	journal = {Am J Surg Pathol},
	volume = {46},
	number = {6},
	year = {2022},
	month = {2022 06 01},
	pages = {729-741},
	abstract = {Inactivating mutations in tumor suppressor genes TP53 and RB1 are considered central drivers in leiomyosarcomas (LMSs). In high-risk human papillomavirus (HPV)-related tumors, a similar functional outcome is achieved through oncoproteins E6 and E7, which inactivate the p53 and RB1 proteins, respectively. Here, we hypothesized that HPV infection could provide an alternative mechanism for tumorigenesis in a subset of TP53/RB1-wildtype LMS. We evaluated tumor samples from 2585 consecutive unique patients carrying a diagnosis of gynecologic or soft tissue LMS. Tumor DNA and available RNA were analyzed by hybrid-capture-based next-generation sequencing/comprehensive genomic profiling of 406 genes and transcripts (FoundationOneHeme). Of the initial 2585 cases, we excluded 16 based on the presence of molecular alterations that are considered defining for sarcomas other than LMS. In the remaining 2569 cases, we searched for LMS that were TP53/RB1-wildtype (n=486 of 2569; 18.9\%). We also searched LMS tumors for HPV sequences that we then classified into genotypes by de novo assembly of nonhuman sequencing reads followed by alignment to the RefSeq database. Among TP53/RB1-wildtype LMS, we identified 18 unique cases harboring HPV sequences. Surprisingly, most (n=11) were HPV51-positive, and these 11 represented all HPV51-positive tumors in our entire LMS database (n=11 of 2569; 0.4\%). The absence of genomic alterations in TP53 or RB1 in HPV51-positive LMS represented a marked difference from HPV51-negative LMS (n=2558; 0\% vs. 72\% [P\&lt;0.00001], 0\% vs. 53\% [P=0.0002]). In addition, compared with HPV51-negative LMS, HPV51-positive LMS were significantly enriched for genomic alterations in ATRX (55\% vs. 24\%, P=0.027) and TSC1 (18\% vs. 0.6\%, P=0.0047). All HPV51-positive LMS were in women; median age was 54 years at surgery (range: 23 to 74 y). All known primary sites were from the gynecologic tract or adjacent anogenital area, including 5 cases of vaginal primary site. Histology was heterogeneous, with evaluable cases showing predominant epithelioid (n=5) and spindle (n=5) morphology. In situ hybridization confirmed the presence of high-risk HPV E6/E7 mRNA in tumor cells in three of three evaluable cases harboring HPV51 genomic sequences. Overall, in our pan-LMS analysis, HPV reads were identified in a subset of TP53/RB1-wildtype LMS. For all HPV51-associated LMS, the striking absence of any detectable TP53 or RB1 mutations and predilection for the female lower reproductive tract supports our hypothesis that high-risk HPV can be an alternative tumorigenic mechanism in this distinct class of LMS.},
	keywords = {Female, Humans, In Situ Hybridization, Leiomyosarcoma, Middle Aged, Papillomaviridae, Papillomavirus Infections, Retinoblastoma Binding Proteins, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases},
	issn = {1532-0979},
	doi = {10.1097/PAS.0000000000001862},
	author = {Williams, Erika and Montesion, Meagan and Lincoln, Vadim and Tse, Julie Y and Hiemenz, Matthew C and Mata, Douglas A and Shah, Bhamini B and Shoroye, Adebowale and Alexander, Brian M and Werth, Adrienne J and Foley-Peres, Kathleen and Milante, Riza R and Ross, Jeffrey S and Ramkissoon, Shakti H and Williams, Kevin Jon and Adhikari, Laura J and Zuna, Rosemary E and LeBoit, Philip E and Douglas I Lin and Elvin, Julia A}
}
@article {691217,
	title = {Molecular analysis of endometrial serous carcinoma reveals distinct clinicopathologic and genomic subgroups},
	journal = {Gynecol Oncol},
	volume = {164},
	number = {3},
	year = {2022},
	month = {2022 03},
	pages = {558-565},
	abstract = {OBJECTIVES: Endometrial serous carcinoma (EMSC) is an aggressive variant of uterine cancer with limited therapeutic options. We sought to define distinct clinicopathologic and genomic EMSC subgroups.

METHODS: We retrospectively analyzed 2159 EMSC and 2346 endometrioid-type endometrial carcinomas (EEC) tissue specimens that had undergone comprehensive genomic profiling (CGP) via the FoundationOne CDx assay during routine clinical care. High tumor mutational burden (TMB) was defined as >=10mut/Mb using the FDA-approved CDx cutoff for pembrolizumab. Microsatellite instability (MSI) was determined on 95 loci. Evidence of homologous recombination deficiency (HRD) was determined via genomic loss of heterozygosity (gLOH), a validated HRD detection method for predicting PARP inhibitor effectiveness in ovarian carcinoma. High gLOH was defined as >=16\%.

RESULTS: A genomic analysis of 2159 EMSCs revealed a predominance of TP53 mutations, microsatellite stability, low tumor mutational burden (TMB), and recurrent alterations of PIK3CA, PPP2R1A, ERBB2, CCNE1, FBXW7 and MYC. Evidence of HRD via high gLOH was identified in 22\% of EMSCs. BRCA1 and BRCA2 alterations, as well as unique SET (solid, pseudo-endometrioid, and transitional cell-like) variant morphology, were enriched in HRD-EMSC. There was an increased frequency of CCNE1 amplification, a lower prevalence of PIK3CA and PPP2R1A alterations, and no differences in HRD, MSI or TMB biomarker frequencies in patients of predicted African ancestry. EMSC exhibited distinct gene mutation frequencies and MSI, TMB and gLOH biomarker signatures compared to a cohort 2346 EEC.

CONCLUSIONS: Molecularly defined subgroups provide a framework to test the susceptibility of EMSC to targeted therapies in specific genetic settings (e.g. HRD, PIK3CA, PPP2R1A, ERBB2, MYC, CCNE1).},
	keywords = {Biomarkers, Tumor, Carcinoma, Endometrioid, Class I Phosphatidylinositol 3-Kinases, Cystadenocarcinoma, Serous, Endometrial Neoplasms, Female, Humans, Microsatellite Instability, Mutation, Retrospective Studies},
	issn = {1095-6859},
	doi = {10.1016/j.ygyno.2021.12.030},
	author = {Douglas I Lin and Fine, Alexander and Danziger, Natalie A and Huang, Richard S P and Mata, Douglas A and Decker, Brennan and Killian, Jonathan K and Ramkissoon, Shakti H and Lechpammer, Mirna and Janovitz, Tyler and Ross, Jeffrey S and Sokol, Ethan S and Elvin, Julia A}
}
@article {691213,
	title = {Molecular Characterization of Mesothelioma: Impact of Histologic Type and Site of Origin on Molecular Landscape},
	journal = {JCO Precis Oncol},
	volume = {6},
	year = {2022},
	month = {2022 Jun},
	pages = {e2100422},
	abstract = {PURPOSE: Mesothelioma is an aggressive malignancy with heterogeneous outcomes that are partly driven by the differential efficacy of existing therapies across histologic types and sites of origin. Large-scale molecular analysis of mesothelioma and its subtypes has the potential to inform future therapeutic strategies.

MATERIALS AND METHODS: We analyzed 1,294 mesotheliomas {980 pleural (malignant pleural mesothelioma [MPM]) and 314 peritoneal (malignant peritoneal mesothelioma [MPeM])} using next-generation sequencing, determined programmed death ligand-1 (PD-L1) expression and histology in a subset of cases, and assessed MTAP/CDKN2A copy-number status by fluorescence in situ hybridization and T-cell infiltration in an independent cohort.

RESULTS: The molecular landscape of MPM was characterized by inactivating alterations in CDKN2A (49\%), BAP1 (44\%), CDKN2B (42\%), MTAP (34\%), and NF2 (33\%). Compared with epithelioid MPM, nonepithelioid (ie, biphasic and sarcomatoid) MPM had identical tumor mutational burden (median 1.25 mut/Mb, P = .63), more commonly expressed PD-L1 (74\% v 51\%, P = .02), and was more likely to harbor MTAP, CDKN2A, and CDKN2B copy loss (P \&lt; .05). Fluorescence in situ hybridization confirmed that homozygous MTAP loss was enriched in nonepithelioid MPM. Relative to MPM, MPeM had comparable tumor mutational burden and PD-L1 expression. The molecular profile of MPeM was similar to MPM, with the distinction that PBRM1 alterations occurred at higher frequency (16\% v 7\%, P \&lt; .01). ALK rearrangements were only observed in MPeM.

CONCLUSION: Regardless of histology and location, the molecular landscape of mesothelioma primarily consists of inactivating alterations in tumor suppressor genes, with enrichment of certain alterations in distinct subsets (eg, MTAP loss in nonepithelioid tumors). Given the limited efficacy of current therapies for this disease, novel approaches targeting recurring alterations should be explored.},
	keywords = {B7-H1 Antigen, Biomarkers, Tumor, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Lung Neoplasms, Mesothelioma, Mesothelioma, Malignant, Neoplasm Recurrence, Local, Pleural Neoplasms, Tumor Suppressor Proteins, Ubiquitin Thiolesterase},
	issn = {2473-4284},
	doi = {10.1200/PO.21.00422},
	author = {Dagogo-Jack, Ibiayi and Madison, Russell W and Lennerz, Jochen K and Chen, Kuei-Ting and Hopkins, Julia F and Schrock, Alexa B and Ritterhouse, Lauren L and Lester, Ashley and Wharton, Keith A and Mino-Kenudson, Mari and Danziger, Natalie and Hung, Yin P and Mata, Douglas A and Ross, Jeffrey S}
}
@article {691219,
	title = {A Potassium-Based Quality-of-Service Metric Reduces Phlebotomy Errors, Resulting in Improved Patient Safety and Decreased Cost},
	journal = {Am J Clin Pathol},
	volume = {157},
	number = {5},
	year = {2022},
	month = {2022 05 04},
	pages = {789-798},
	abstract = {OBJECTIVES: Poor phlebotomy technique can introduce pseudohyperkalemia without hemolysis, requiring additional workup and placing a significant burden on patients, clinical teams, and laboratories. Such preanalytical biases can be detected through systematic evaluation of potassium concentrations on a per-phlebotomist basis. We report our long-term experience with a potassium-based quality-of-service phlebotomy metric and its effects on resource utilization.

METHODS: Potassium monitoring and retraining of 26 full-time phlebotomists were piloted as a quality-of-service intervention. Changes in potassium concentrations and impact on resource utilization were assessed. An algorithm for data monitoring and phlebotomist feedback was developed, followed by institution-wide implementation.

RESULTS: Systematic intervention and retraining normalized K+ concentrations and lowered the percentage of venipunctures with K+ above 5.2 mmol/L, leading to a marked increase in phlebotomist compliance. This change resulted in resources savings of 13\% to 100\% for individual phlebotomists, reducing the total extra laboratory time required for repeat phlebotomies to determine hyperkalemia, mostly in the high-volume phlebotomist group.

CONCLUSIONS: A quality-of-service algorithm that involved monitoring potassium concentrations on a per-phlebotomist basis with feedback and retraining contributed to a concrete, data-based quality improvement plan. The institution-wide implementation of this metric allowed for significant cost savings and a reduction in critical value alerts, directly affecting the quality of patient care.},
	keywords = {bias, Humans, Laboratories, Patient Safety, Phlebotomy, Potassium},
	issn = {1943-7722},
	doi = {10.1093/ajcp/aqab194},
	author = {Lucas, Fabienne and Mata, Douglas A and Greenblatt, Matthew B and Means, Janet and Jarolim, Petr}
}
@article {691220,
	title = {Predictive Genomic Biomarkers of Hormonal Therapy Versus Chemotherapy Benefit in Metastatic Castration-resistant Prostate Cancer},
	journal = {Eur Urol},
	volume = {81},
	number = {1},
	year = {2022},
	month = {2022 Jan},
	pages = {37-47},
	abstract = {BACKGROUND: Biomarkers predicting second-generation novel hormonal therapy (NHT) benefit relative to taxanes are critical for optimized treatment decisions for metastatic castration-resistant prostate cancer (mCRPC) patients. These associations have not been reported simultaneously for common mCRPC genomic biomarkers.

OBJECTIVE: To evaluate predictive associations of common genomic aberrations in mCRPC using an established comprehensive genomic profiling (CGP) system.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study used data from a deidentified US-based clinicogenomic database comprising patients treated in routine clinical practice between 2011 and 2020, evaluated with Foundation Medicine CGP in tissue biopsies obtained around the time of treatment decision. The main cohort included 180 NHT and 179 taxane lines of therapy (LOTs) from 308 unique patients. The sequential cohort comprised a subset of the main cohort NHT LOTs immediately followed by taxane from 55 unique patients.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate-specific antigen (PSA) response, time to next treatment (TTNT), and overall survival (OS) were assessed. Main cohort analyses were adjusted for known treatment assignment biases via inverse probability of treatment weighting (IPTW) in treatment interaction models.

RESULTS AND LIMITATIONS: In the main cohort, patients with AR amplification (ARamp) or PTEN aberrations (PTENalt) had worse relative PSA response on NHT versus taxanes compared with patients without. Patients with ARamp, PTENalt, or RB1 aberrations (RB1alt) also had worse relative TTNT and OS on NHT but not on taxanes. In multivariable models for TTNT and OS adjusted via IPTW, ARamp, PTENalt, and RB1alt were shown as poor prognostic factors overall and demonstrated significant treatment interactions, indicating reduced hazards of therapy switch and death on taxanes versus NHT. Consistent associations favoring increased benefit from subsequent taxane despite prior NHT treatment line were observed only for ARamp in the sequential cohort, in which very few patients had RB1alt for assessment.

CONCLUSIONS: ARamp status is a candidate biomarker to predict poor effectiveness of NHT relative to taxanes in mCRPC in scenarios where both options are considered.

PATIENT SUMMARY: Specific alterations in the DNA of tumors may assist in choosing between novel oral hormonal therapies and standard chemotherapy in advanced prostate cancer patients.},
	keywords = {Biomarkers, Tumor, Humans, Male, Prostate-Specific Antigen, Prostatic Neoplasms, Castration-Resistant, Retrospective Studies, Taxoids, Treatment Outcome},
	issn = {1873-7560},
	doi = {10.1016/j.eururo.2021.09.030},
	author = {Graf, Ryon P and Fisher, Virginia and Mateo, Joaquin and Gjoerup, Ole V and Madison, Russell W and Raskina, Kira and Tukachinsky, Hanna and Creeden, James and Cunningham, Rachel and Huang, Richard S P and Mata, Douglas A and Ross, Jeffrey S and Oxnard, Geoffrey R and Venstrom, Jeffrey M and Zurita, Amado J}
}
@article {691215,
	title = {Prevalence of UV Mutational Signatures Among Cutaneous Primary Tumors},
	journal = {JAMA Netw Open},
	volume = {5},
	number = {3},
	year = {2022},
	month = {2022 03 01},
	pages = {e223833},
	keywords = {Humans, Mutation, Prevalence, Skin Neoplasms},
	issn = {2574-3805},
	doi = {10.1001/jamanetworkopen.2022.3833},
	author = {Mata, Douglas A and Williams, Erika and Sokol, Ethan and Oxnard, Geoffrey R and Fleischmann, Zoe and Tse, Julie Y and Decker, Brennan}
}
@article {691212,
	title = {Triggering with 1,500 IU of human chorionic gonadotropin plus follicle-stimulating hormone compared to a standard human chorionic gonadotropin trigger dose for oocyte competence in in~vitro fertilization cycles: a randomized, double-blinded, controlled n},
	journal = {Fertil Steril},
	year = {2022},
	month = {2022 Jun 12},
	abstract = {OBJECTIVE: To assess if triggering with 1,500 IU of human chorionic gonadotropin (hCG) with 450 IU of follicle-stimulating hormone (FSH) induces noninferior oocyte competence to a standard dose of hCG trigger used in in~vitro fertilization (IVF). The alternative trigger will be considered noninferior if it is at least 80\% effective in promoting oocyte competence.

DESIGN: Randomized, double-blinded, controlled noninferiority trial.

SETTING: Academic infertility practice.

PATIENTS: Women aged 18-41 undergoing IVF with antral follicle count >=8, body mass index <=30 kg/m2, and no history of >=2 IVF cycles canceled for poor response were enrolled. Participants with a serum estradiol \&gt;5,000 pg/mL on the day of trigger were excluded because of high risk of ovarian hyperstimulation syndrome.

INTERVENTIONS: Participants were randomized to receive an alternative trigger of 1,500 IU of hCG plus 450 IU of FSH or a standard trigger dose of hCG (5,000 or 10,000 IU) for final oocyte maturation.

MAIN OUTCOME MEASURES: The primary outcome was total competent proportion, defined as the probability of 2 pronuclei from an oocyte retrieved. The alternative trigger will be considered noninferior to the standard trigger if a 1-sided 95\% confidence interval (CI) of the relative risk (RR) is not \&lt;0.8. Secondary outcomes included oocyte recovery and maturity, intracytoplasmic sperm injection fertilization, embryo quality, pregnancy rates, as well as serum and follicular hormones. Secondary outcomes were compared using a 2-sided superiority test. Outcomes were analyzed by intention-to-treat and per-protocol.

RESULTS: A total of 105 women undergoing IVF were randomized from May 2015 to June 2018. The probability of the primary outcome was 0.59 with the alternative trigger and 0.65 with the standard trigger, with a RR of 0.91 and a 1-sided 95\% CI of 0.83. Noninferiority of the alternative trigger was demonstrated. Live birthrate from all fresh transfers in the alternative trigger group vs. standard trigger was 46.9 vs. 46.4\% (RR, 1.01; 95\% CI, 0.62-1.62), respectively. Live birthrate per randomized participant was 48.1\% in the alternative trigger group vs. 62.7\% with the standard trigger (RR, 0.73; 95\% CI, 0.48-1.11). No participants had a failed retrieval.

CONCLUSION: Triggering with 1,500 IU of hCG plus 450 IU of FSH promoted noninferior oocyte competence compared to a standard hCG trigger dose.

TRIAL REGISTRATION: NCT02310919.},
	issn = {1556-5653},
	doi = {10.1016/j.fertnstert.2022.05.006},
	author = {Anaya, Yanett and Cakmak, Hakan and Mata, Douglas A and Letourneau, Joseph and Zhang, Li and Lenhart, Nikolaus and Juarez-Hernandez, Flor and Jalalian, Liza and Cedars, Marcelle I and Rosen, Mitchell}
}
@article {691228,
	title = {Accuracy of a convolutional neural network for dermatological diagnosis of tumours and skin lesions in a clinical setting},
	journal = {Clin Exp Dermatol},
	volume = {46},
	number = {7},
	year = {2021},
	month = {2021 Oct},
	pages = {1310-1311},
	keywords = {Diagnosis, Computer-Assisted, Diagnosis, Differential, Humans, Neural Networks, Computer, Skin Diseases, Skin Neoplasms, Software},
	issn = {1365-2230},
	doi = {10.1111/ced.14688},
	author = {Agarwala, S and Mata, D. A. and Hafeez, F}
}
@article {691225,
	title = {Clinicopathologic and Genomic Landscape of Breast Carcinoma Brain Metastases},
	journal = {Oncologist},
	volume = {26},
	number = {10},
	year = {2021},
	month = {2021 10},
	pages = {835-844},
	abstract = {BACKGROUND: Among patients with breast carcinoma who have metastatic disease, 15\%-30\% will eventually develop brain metastases. We examined the genomic landscape of a large cohort of patients with breast carcinoma brain metastases (BCBMs) and compared it with a cohort of patients with primary breast carcinomas (BCs).

MATERIAL AND METHODS: We retrospectively analyzed 733 BCBMs tested with comprehensive genomic profiling (CGP) and compared them with 10,772 primary breast carcinomas (not-paired) specimens. For a subset of 16 triple-negative breast carcinoma (TNBC)-brain metastasis samples, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) was performed concurrently.

RESULTS: A total of 733 consecutive BCBMs were analyzed. Compared with primary BCs, BCBMs were enriched for genomic alterations in TP53 (72.0\%, 528/733), ERBB2 (25.6\%, 188/733), RAD21 (14.1\%, 103/733), NF1 (9.0\%, 66/733), BRCA1 (7.8\%, 57/733), and ESR1 (6.3\%,46/733) (p~\&lt;~.05 for all comparisons). Immune checkpoint inhibitor biomarkers such as high tumor mutational burden (TMB-high; 16.2\%, 119/733); high microsatellite instability (1.9\%, 14/733); CD274 amplification (3.6\%, 27/733); and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like mutational signature (5.9\%, 43/733) were significantly higher in the BCBM cohort compared with the primary BC cohort (p~\&lt;~.05 for all comparisons). When using both CGP and PD-L1 IHC, 37.5\% (6/16) of patients with TNBC brain metastasis were eligible for atezolizumab based on PD-L1 IHC, and 18.8\% (3/16) were eligible for pembrolizumab based on TMB-high status.

CONCLUSION: We found a high prevalence of clinically relevant genomic alterations in patients with BCBM, suggesting that tissue acquisition (surgery) and/or cerebrospinal fluid for CGP in addition to CGP of the primary tumor may be clinically warranted.

IMPLICATIONS FOR PRACTICE: This study found a high prevalence of clinically relevant genomic alterations in patients with breast carcinoma brain metastasis (BCBM), suggesting that tissue acquisition (surgery) and/or cerebrospinal fluid for comprehensive genomic profiling (CGP) in addition to CGP of the primary tumor may be clinically warranted. In addition, this study identified higher positive rates for FDA-approved immunotherapy biomarkers detected by CGP in patients with BCBM, opening a possibility of new on-label treatments. Last, this study noted limited correlation between tumor mutational burden and PD-L1 immunohistochemistry (IHC), which shows the importance of testing patients with triple-negative BCBM for immune checkpoint inhibitor eligibility with both PD-L1 IHC and CGP.},
	keywords = {Biomarkers, Tumor, Brain Neoplasms, Genomics, Humans, Retrospective Studies, Triple Negative Breast Neoplasms},
	issn = {1549-490X},
	doi = {10.1002/onco.13855},
	author = {Huang, Richard S P and Haberberger, James and McGregor, Kimberly and Mata, Douglas A and Decker, Brennan and Hiemenz, Matthew C and Lechpammer, Mirna and Danziger, Natalie and Schiavone, Kelsie and Creeden, James and Graf, Ryon P and Strowd, Roy and Lesser, Glenn J and Razis, Evangelia D and Bartsch, Rupert and Giannoudis, Athina and Bhogal, Talvinder and Lin, Nancy U and Pusztai, Lajos and Ross, Jeffrey S and Palmieri, Carlo and Ramkissoon, Shakti H}
}
@article {691222,
	title = {Clinicopathological and genomic characterization of BCORL1-driven high-grade endometrial stromal sarcomas},
	journal = {Mod Pathol},
	volume = {34},
	number = {12},
	year = {2021},
	month = {2021 12},
	pages = {2200-2210},
	abstract = {BCORL1 is a transcriptional corepressor homologous to BCOR. We describe 12 BCORL1-altered uterine sarcomas with striking resemblance to BCOR-altered endometrial stromal sarcoma (BCOR-ESS), including 5 with BCORL1 rearrangements (JAZF1-BCORL1, EP300-BCORL1, or internal BCORL1 rearrangement), 5 with inactivating BCORL1 mutations (T513fs*22, P600fs*1, R945*, R1196*, or R1265fs*4) and 2 with homozygous BCORL1 deletion. The median patient age was 57.5 years (range 33-79). An association with aggressive clinical behavior was identified. Diagnoses assigned prior to genomic testing varied: 7 tumors were previously diagnosed as ESS, 2 as high-grade uterine sarcomas, 2 as myxoid uterine leiomyosarcomas, and 1 as a uterine spindle cell neoplasm consistent with leiomyosarcoma. Tumors harbored frequent gelatinous, mucomyxoid-like appearance by gross examination and unique histology with morphological overlap with BCOR-ESS. Key microscopic features included (1) a spindle cell appearance, most often with at least focal myxoid stroma, (2) variable amounts of hypocellular fibromyxoid spindle areas with lower grade atypia and/or (3) variable amounts of epithelioid areas with higher grade atypia. Specifically, spindle and epithelioid components were present in 100 and 75\% of sarcomas, respectively; myxoid stroma was identified in 83\%, collagen plaques or fibrosis in 50\%, and high-grade nuclear atypia was present in 42\%. Like BCOR-ESS, 50\% of BCORL1-altered sarcomas exhibited CDK4 amplification or CDKN2A loss. In contrast, 33\% harbored NF1 alterations, while 25\% had other alterations in the NF2-mTOR pathway, expanding potential therapeutic targets. In conclusion, inactivating BCORL1 genomic alterations may define a distinct subset of high-grade endometrial stromal sarcomas with biological overlap with BCOR-ESS, both of which may mimic myxoid leiomyosarcomas.},
	keywords = {Adult, Aged, Biomarkers, Tumor, Databases, Factual, Endometrial Neoplasms, Female, Gene Amplification, Gene Rearrangement, Genetic Predisposition to Disease, Humans, Middle Aged, Molecular Diagnostic Techniques, Mutation, Neoplasm Grading, Phenotype, Predictive Value of Tests, Repressor Proteins, Retrospective Studies, Sarcoma, Endometrial Stromal},
	issn = {1530-0285},
	doi = {10.1038/s41379-021-00873-z},
	author = {Douglas I Lin and Huang, Richard S P and Mata, Douglas A and Decker, Brennan and Danziger, Natalie and Lechpammer, Mirna and Hiemenz, Matthew and Ramkissoon, Shakti H and Ross, Jeffrey S and Elvin, Julia A}
}
@article {691232,
	title = {Clinicopathological and molecular characteristics of prostate cancer diagnosed in young men aged up to 45~years},
	journal = {Histopathology},
	volume = {78},
	number = {6},
	year = {2021},
	month = {2021 May},
	pages = {857-870},
	abstract = {AIMS: To characterise and compare the poorly understood clinicopathological and molecular characteristics of prostatic adenocarcinoma (PCa) in very young patients.

METHODS AND RESULTS: We compared the clinicopathological and molecular characteristics of PCa diagnosed in 90 patients aged <=45~years with those of PCa diagnosed in 200 patients of typical screening age (i.e. 60-65~years). Patients diagnosed at a younger age had a higher frequency of a family history of PCa and lower prostate-specific antigen (PSA) levels than those diagnosed at regular screening age. There were no statistically significant differences in clinical stage or pathological characteristics of the core biopsy specimens between the groups. Young patients had a higher frequency of Grade Group 1 disease at radical prostatectomy. A subset of 13 aggressive PCa cases from young patients underwent successful DNA-based next-generation sequencing. In all, 46.2\% (6/13) had TMPRSS2 rearrangements and 23.1\% (3/13) had relevant pathogenic variants in DNA damage repair genes, including a mismatch repair-deficient case with biallelic inactivation of MLH1. No statistically significant differences were observed in PCa-specific recurrence/progression between the younger and older patients, including after adjustment for clinical stage, PSA level, and Grade Group.

CONCLUSIONS: In this study, the clinicopathological and molecular features of PCa diagnosed in young patients were comparable to those of PCa diagnosed in patients of screening age. Early-onset PCa cases were not enriched in any of the known molecular PCa subtypes in this small series.},
	keywords = {Adenocarcinoma, Adult, Biopsy, Large-Core Needle, Humans, Male, Middle Aged, Neoplasm Staging, Prostate, Prostate-Specific Antigen, Prostatic Neoplasms, Retrospective Studies},
	issn = {1365-2559},
	doi = {10.1111/his.14315},
	author = {Baniak, Nicholas and Sholl, Lynette M and Mata, Douglas A and D{\textquoteright}Amico, Anthony V and Hirsch, Michelle S and Acosta, Andres M}
}
@article {691223,
	title = {Enhanced specificity of clinical high-sensitivity tumor mutation profiling in cell-free DNA via paired normal sequencing using MSK-ACCESS},
	journal = {Nat Commun},
	volume = {12},
	number = {1},
	year = {2021},
	month = {2021 06 18},
	pages = {3770},
	abstract = {Circulating cell-free DNA from blood plasma of cancer patients can be used to non-invasively interrogate somatic tumor alterations. Here we develop MSK-ACCESS (Memorial Sloan Kettering - Analysis of Circulating cfDNA to Examine Somatic Status), an NGS assay for detection of very low frequency somatic alterations in 129 genes. Analytical validation demonstrated 92\% sensitivity in de-novo mutation calling down to 0.5\% allele frequency and 99\% for a priori mutation profiling. To evaluate the performance of MSK-ACCESS, we report results from 681 prospective blood samples that underwent clinical analysis to guide patient management. Somatic alterations are detected in 73\% of the samples, 56\% of which have clinically actionable alterations. The utilization of matched normal sequencing allows retention of somatic alterations while removing over 10,000 germline and clonal hematopoiesis variants. Our experience illustrates the importance of analyzing matched normal samples when interpreting cfDNA results and highlights the importance of cfDNA as a genomic profiling source for cancer patients.},
	keywords = {Biomarkers, Tumor, Circulating Tumor DNA, DNA Mutational Analysis, Gene Frequency, Genetic Markers, High-Throughput Nucleotide Sequencing, Humans, Mutation, Neoplasms},
	issn = {2041-1723},
	doi = {10.1038/s41467-021-24109-5},
	author = {Rose Brannon, A and Jayakumaran, Gowtham and Diosdado, Monica and Patel, Juber and Razumova, Anna and Hu, Yu and Meng, Fanli and Haque, Mohammad and Sadowska, Justyna and Murphy, Brian J and Baldi, Tessara and Johnson, Ian and Ryan Ptashkin and Hasan, Maysun and Srinivasan, Preethi and Rema, Anoop Balakrishnan and Rijo, Ivelise and Agarunov, Aaron and Won, Helen and Perera, Dilmi and Brown, David N and Samoila, Aliaksandra and Jing, Xiaohong and Gedvilaite, Erika and Yang, Julie L and Stephens, Dennis P and Dix, Jenna-Marie and DeGroat, Nicole and Nafa, Khedoudja and Syed, Aijazuddin and Li, Alan and Lebow, Emily S and Bowman, Anita S and Ferguson, Donna C and Liu, Ying and Mata, Douglas A and Sharma, Rohit and Yang, Soo-Ryum and Bale, Tejus and Benhamida, Jamal K and Chang, Jason C and Dogan, Snjezana and Hameed, Meera R and Hechtman, Jaclyn F and Moung, Christine and Ross, Dara S and Vakiani, Efsevia and Vanderbilt, Chad M and Yao, JinJuan and Razavi, Pedram and Smyth, Lillian M and Sarat Chandarlapaty and Iyer, Gopa and Abida, Wassim and Harding, James J and Krantz, Benjamin and O{\textquoteright}Reilly, Eileen and Yu, Helena A and Li, Bob T and Rudin, Charles M and Diaz, Luis and Solit, David B and Arcila, Maria E and Ladanyi, Marc and Loomis, Brian and Tsui, Dana and Berger, Michael F and Zehir, Ahmet and Benayed, Ryma}
}
@article {691231,
	title = {Factors Associated With Pregnancy and Perinatal Outcomes in Female Neurosurgeons: A Cross-Sectional Study},
	journal = {Neurosurgery},
	volume = {88},
	number = {4},
	year = {2021},
	month = {2021 03 15},
	pages = {884-889},
	abstract = {Neurosurgery is male dominated with women representing only 12\% of residents and 5\% of practicing neurosurgeons. The conflicting demands of training versus pregnancy and motherhood are significant deterrents to women entering the field. We examined pregnancy incidence and timing, perinatal complications, and the perceived career impact of motherhood on female neurosurgeons using an anonymous survey of 643 training, practicing, and retired female neurosurgeons from the United States. Among 260 respondents, 50.8\% (132/260) reported pregnancies, with an average age at first pregnancy that was significantly higher than the national average (32.1~vs 26.3 yr). In all, 40.1\% (53/132) of respondents reported perinatal complications in at least one of their pregnancies. Only 25\% (33/132) of respondents noted designated program maternity allowances. The most significant challenges associated with being a mother and neurosurgeon reported were issues relating to work/life balance, "mommy guilt," and sleep deprivation. A majority of respondents, 70.1\% (82/116), reported fear of backlash from co-residents, partners, and staff, as well as hindered career advancement related to childbearing. Female neurosurgeons face challenges surrounding family planning different from those faced by male practitioners. Higher perinatal and fetal complications, backlash from colleagues, and demanding workload are significant issues. Progress requires institutional support and mentorship for women to create a more diverse field of practitioners.},
	keywords = {Adult, Aged, Cross-Sectional Studies, Female, Humans, Infertility, Female, Internship and Residency, Middle Aged, Neurosurgeons, Neurosurgery, Perinatal Care, Pregnancy, Pregnancy Outcome, Surveys and Questionnaires, Treatment Outcome, United States, Workload},
	issn = {1524-4040},
	doi = {10.1093/neuros/nyaa533},
	author = {Parker, Samantha L and Conner, Christopher R and Mata, Douglas A and Zima, Laura A and Chen, Amber and McCormack, Ryan and Bindal, Shivani and Stark, Jessica R}
}
@article {691235,
	title = {Histopathologic and immunophenotypic features of idiopathic dermal hypersensitivity reaction/urticarial dermatitis: A clinicopathologic study},
	journal = {J Cutan Pathol},
	volume = {48},
	number = {4},
	year = {2021},
	month = {2021 Apr},
	pages = {592-595},
	keywords = {Antigens, CD, Biopsy, CD8 Antigens, Cross-Sectional Studies, Dermatitis, Eczema, Forkhead Transcription Factors, Humans, Immunophenotyping, Integrin alpha Chains, Retrospective Studies, T-Lymphocytes, Regulatory, Urticaria},
	issn = {1600-0560},
	doi = {10.1111/cup.13884},
	author = {Mata, Douglas A and Lian, John W and Krakowski, Andrew and Agarwala, Saira and Hafeez, Farhaan}
}
@article {691224,
	title = {Pan-cancer analysis of  (PD-L1) mutations in 314,631 patient samples and subset correlation with PD-L1 protein expression},
	journal = {J Immunother Cancer},
	volume = {9},
	number = {6},
	year = {2021},
	month = {2021 06},
	abstract = {BACKGROUND: The effects of non-amplification short variant (SV) mutations in CD274 (programmed death-ligand 1 (PD-L1)) on PD-L1 protein expression and immune checkpoint inhibitors (ICPIs) therapy are unknown. Here, we present a retrospective analysis of CD274 mutations detected by comprehensive genomic profiling (CGP) and correlate these results with tumor-cell PD-L1 immunohistochemistry (IHC)-based expression assessment to better understand the relationship between mutations and protein expression of PD-L1.

METHODS: CGP was performed on hybridization-captured, adaptor ligation-based libraries using DNA and/or RNA extracted from 314,631 tumor samples that were sequenced for up to 406 cancer-related genes and select gene rearrangements. PD-L1 IHC was performed on a subset of cases (n=58,341) using the DAKO 22C3 PD-L1 IHC assay and scored with the tumor proportion score (TPS).

RESULTS: Overall, the prevalence of CD274 SV mutations was low (0.3\%, 1081/314,631) with 577 unique variants. The most common CD274 SV mutations were R260H (n=51), R260C (n=18), R125Q (n=12), C272fs*13 (n=11), R86W (n=10), and R113H (n=10). The prevalence of CD274 mutations varied depending on tumor type with diffuse large B-cell lymphoma (1.9\%, 19/997), cutaneous squamous cell carcinoma (1.6\%, 14/868), endometrial adenocarcinoma (1.0\%, 36/3740), unknown primary melanoma (0.9\%, 33/3679), and cutaneous melanoma (0.8\%, 32/3874) having the highest frequency of mutations. Of the R260H cases concurrently tested with PD-L1 IHC, most (81.8\%, 9/11) had no PD-L1 expression, which contrasts to the five E237K cases where most (80\%, 4/5) had PD-L1 expression. In addition, we saw a significantly lower level of PD-L1 expression in samples with a clonal truncating variant (nonsense or frameshift indel) when compared with samples with a subclonal truncating variants (mean: TPS=1 vs TPS=38; p\&lt;0.001), and also in clonal versus subclonal missense mutations (mean: TPS=11 vs TPS=22, respectively; p=0.049) CONCLUSIONS: We defined the landscape of CD274 mutations in a large cohort of tumor types that can be used as a reference for examining CD274 mutations as potential resistance biomarkers for ICPI. Furthermore, we presented novel data on the correlation of CD274 mutations and PD-L1 protein expression, providing important new information on the potential functionality of these mutations and can serve as a basis for future research.},
	keywords = {B7-H1 Antigen, Humans, Immunotherapy, Mutation, Neoplasms},
	issn = {2051-1426},
	doi = {10.1136/jitc-2021-002558},
	author = {Huang, Richard S P and Decker, Brennan and Murugesan, Karthikeyan and Hiemenz, Matthew and Mata, Douglas A and Li, Gerald and Creeden, James and Ramkissoon, Shakti H and Ross, Jeffrey S}
}
@article {691226,
	title = {Pan-cancer landscape of  (PD-L1) copy number changes in 244 584 patient samples and the correlation with PD-L1 protein expression},
	journal = {J Immunother Cancer},
	volume = {9},
	number = {5},
	year = {2021},
	month = {2021 05},
	abstract = {INTRODUCTION: Several studies have shown clinical outcomes data that support the use of CD274 (PD-L1) copy-number (CN) gains and/or losses as a biomarker for immune checkpoint inhibitor (ICPI). Here, we present the landscape of CD274 CN changes across a large cohort of solid tumor cases and correlate these with PD-L1 protein expression by immunohistochemistry.

METHODS: We analyzed all cases that underwent comprehensive genomic profiling (CGP) testing at Foundation Medicine between August 2014 and June 2020. CD274 CN changes were correlated with PD-L1 expression in tumor types where there were Food and Drug Administration approved companion diagnostic (CDx) claims and the CDx assay was used to assess PD-L1 expression.

RESULTS: In all, 244 584 samples representing 290 solid tumor types were included in the study. Overall, 17.6\% (42 983/244 584) had CD274 CN gains (\&gt;specimen ploidy), 44.6\% (108 970/244 584) were CD274 CN neutral, and 37.9\% (92 631/244 584) had CD274 CN loss. Using different CN cut offs to define CD274 positivity resulted in different prevalence estimates: ploidy +1, 17.4\% (42 636/244 584); ploidy +2, 6.2\% (15 183/244 584); ploidy +3, 2.2\% (5375/244 584); ploidy +4, 1.1\% (2712/244 584); and ploidy +8, 0.2\% (434/244 584). The prevalence of CN changes and CN positivity varied based on tumor type. CD274 CN gains were significantly associated with PD-L1 positivity in NSCLC, urothelial carcinoma, breast carcinoma, cervical carcinoma, esophagus squamous cell carcinoma (SCC) and head and neck SCC (ORs 3.3, 3.0, 2.0, 4.5. 3.8, 8.4, 1.4, respectively; p\&lt;0.05) and with microsatellite instability status in only clinically relevant tumor types (gastric adenocarcinoma, colorectal adenocarcinoma, uterine endometrial adenocarcinoma, esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma (OR: 5.2, 1.9, 3.2, 3.7 and 6.5, respectively; p\&lt;0.05)). Conversely, CD274 CN changes were not significantly correlated with tumor mutational burden in almost all the tumor types.

CONCLUSION: CD274 CN changes and PD-L1 expression were highly correlated in multiple tumor types. These prevalence data on CD274 CN changes across a large cohort of different solid tumors can be used to design future clinical studies to assess whether CD274 CN changes could be a potential biomarker for ICPI.},
	keywords = {B7-H1 Antigen, Biomarkers, Tumor, Clinical Decision-Making, DNA Copy Number Variations, Female, Gene Dosage, Genetic Predisposition to Disease, Humans, Immune Checkpoint Inhibitors, Immunohistochemistry, Male, Microsatellite Instability, Molecular Diagnostic Techniques, Mutation, Neoplasms, Phenotype, Predictive Value of Tests},
	issn = {2051-1426},
	doi = {10.1136/jitc-2021-002680},
	author = {Huang, Richard S P and Murugesan, Karthikeyan and Montesion, Meagan and Pavlick, Dean C and Mata, Douglas A and Hiemenz, Matthew C and Decker, Brennan and Frampton, Garrett and Albacker, Lee A and Ross, Jeffrey S}
}
@article {691218,
	title = {Pancreatoblastomas and mixed and pure acinar cell carcinomas share epigenetic signatures distinct from other neoplasms of the pancreas},
	journal = {Mod Pathol},
	year = {2021},
	month = {2021 Dec 30},
	abstract = {Pancreatic neoplasms are heterogenous and have traditionally been classified by assessing their lines of cellular differentiation using histopathologic methods, particularly morphologic and immunohistochemical evaluation. These methods frequently identify overlapping differentiation along ductal, acinar, and neuroendocrine lines, raising diagnostic challenges as well as questions regarding the relationship of these neoplasms. Neoplasms with acinar differentiation, in particular, frequently show more than one line of differentiation based on immunolabeling. Genome methylation signatures, in contrast, are better conserved within cellular lineages, and are increasingly used to support the classification of neoplasms. We characterized the epigenetic relationships between pancreatoblastomas, acinar cell carcinomas (including mixed variants), pancreatic neuroendocrine tumors, solid pseudopapillary neoplasms, and pancreatic ductal adenocarcinomas using a genome-wide array platform. Using unsupervised learning approaches, pancreatic neuroendocrine tumors, solid pseudopapillary neoplasms, ductal adenocarcinomas, and normal pancreatic tissue samples all localized to distinct clusters based on their methylation profiles, whereas all neoplasms with acinar differentiation occupied a broad overlapping region located between the predominantly acinar normal pancreatic tissue and ductal adenocarcinoma clusters. Our data provide evidence to suggest that acinar cell carcinomas and pancreatoblastomas are similar at the epigenetic level. These findings are consistent with genomic and clinical observations that mixed acinar neoplasms are closely related to pure acinar cell carcinomas rather than to neuroendocrine tumors or ductal adenocarcinomas.},
	issn = {1530-0285},
	doi = {10.1038/s41379-021-00989-2},
	author = {Benhamida, Jamal K and Vyas, Monika and Tanaka, Atsushi and Lu Wang and Bahrami, Armita and Ozcan, Kerem and Basturk, Olca and Villafania, Liliana and Mata, Douglas A and El Jabbour, Tony and Selenica, Pier and Roehrl, Michael H A and Britta Weigelt and Reis-Filho, Jorge S and Scaltriti, Maurizio and Klimstra, David S}
}
@article {691233,
	title = {A Performance Comparison of Commonly Used Assays to Detect RET Fusions},
	journal = {Clin Cancer Res},
	volume = {27},
	number = {5},
	year = {2021},
	month = {2021 03 01},
	pages = {1316-1328},
	abstract = {PURPOSE: Selpercatinib and pralsetinib induce deep and durable responses in patients with advanced RET fusion-positive lung and thyroid cancer. RET fusion testing strategies with rapid and reliable results are critical given recent FDA approval. Here, we assess various clinical assays in a large pan-cancer cohort.

EXPERIMENTAL DESIGN: Tumors underwent DNA-based next-generation sequencing (NGS) with reflex to RNA-based NGS if no mitogenic driver or if a RET structural variant of unknown significance (SVUS) were present. Canonical DNA-level RET fusions and RNA-confirmed RET fusions were considered true fusions. Break-apart FISH and IHC performance were assessed in subgroups.

RESULTS: A total of 171 of 41,869 patients with DNA NGS harbored RET structural variants, including 139 canonical fusions and 32 SVUS. Twelve of 32 (37.5\%) SVUS were transcribed into RNA-level fusions, resulting in 151 oncogenic RET fusions. The most common RET fusion-positive tumor types were lung (65.6\%) and thyroid (23.2\%). The most common partners were KIF5B (45\%), CCDC6 (29.1\%), and NCOA4 (13.3\%). DNA NGS showed 100\% (46/46) sensitivity and 99.6\% (4,459/4,479) specificity. FISH showed 91.7\% (44/48) sensitivity, with lower sensitivity for NCOA4-RET (66.7\%, 8/12). A total of 87.5\% (7/8) of RET SVUS negative for RNA-level fusions demonstrated rearrangement by FISH. The sensitivity of IHC varied by fusion partner: KIF5B sensitivity was highest (100\%, 31/31), followed by CCDC6 (88.9\%, 16/18) and NCOA4 (50\%, 6/12). Specificity of RET IHC was 82\% (73/89).

CONCLUSIONS: Although DNA sequencing has high sensitivity and specificity, RNA sequencing of RET SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for NCOA4-RET fusions.},
	keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Child, Child, Preschool, Female, Follow-Up Studies, High-Throughput Nucleotide Sequencing, Humans, In Situ Hybridization, Fluorescence, Infant, Male, Middle Aged, Neoplasms, Oncogene Proteins, Fusion, Prognosis, Proto-Oncogene Proteins c-ret, Retrospective Studies, Young Adult},
	issn = {1557-3265},
	doi = {10.1158/1078-0432.CCR-20-3208},
	author = {Yang, Soo-Ryum and Aypar, Umut and Rosen, Ezra Y and Mata, Douglas A and Benayed, Ryma and Mullaney, Kerry and Jayakumaran, Gowtham and Zhang, Yanming and Frosina, Denise and Drilon, Alexander and Ladanyi, Marc and Jungbluth, Achim A and Rekhtman, Natasha and Hechtman, Jaclyn F}
}
@article {691229,
	title = {Statistical Methods in Experimental Pathology: A Review and Primer},
	journal = {Am J Pathol},
	volume = {191},
	number = {5},
	year = {2021},
	month = {2021 05},
	pages = {784-794},
	abstract = {Correct use of statistical methods is important to ensure the reliability and value of the published experimental pathology literature. Considering increasing interest in the quality of statistical reporting in pathology, the statistical methods used in 10 recent issues of the American Journal of Pathology were reviewed. The statistical tests performed in the articles were summarized, with attention to their implications for contemporary pathology research and practice. Among the 195 articles identified, 93\% reported using one or more statistical tests. Retrospective statistical review of the articles revealed several key findings. First, tests for normality were infrequently reported, and parametric hypothesis tests were overutilized. Second, studies reporting multisample hypothesis tests (eg, analysis of variance) infrequently performed post hoc tests to explore differences between study groups. Third, correlation, regression, and survival analysis techniques were underutilized. On the basis of these findings, a primer on relevant statistical concepts and tests is presented, including issues related to optimal study design, descriptive and comparative statistics, and regression, correlation, survival, and genetic data analysis.},
	keywords = {Humans, Pathology, Periodicals as Topic, Reproducibility of Results, Research Design, Retrospective Studies, Statistics as Topic},
	issn = {1525-2191},
	doi = {10.1016/j.ajpath.2021.02.009},
	author = {Mata, Douglas A and Milner, Danny A}
}
@article {691239,
	title = {Substantial Overlap Between Factors Predicting Symptoms of Depression and Burnout Among Medical Interns},
	journal = {J Gen Intern Med},
	volume = {36},
	number = {1},
	year = {2021},
	month = {2021 01},
	pages = {240-242},
	keywords = {Burnout, Professional, Burnout, Psychological, Depression, Humans},
	issn = {1525-1497},
	doi = {10.1007/s11606-020-05664-x},
	author = {Rotenstein, Lisa S and Zhao, Zhuo and Mata, Douglas A and Guille, Constance and Sen, Srijan}
}
@article {691234,
	title = {Genetic and epigenetic landscape of IDH-wildtype glioblastomas with FGFR3-TACC3 fusions},
	journal = {Acta Neuropathol Commun},
	volume = {8},
	number = {1},
	year = {2020},
	month = {2020 11 09},
	pages = {186},
	abstract = {A subset of glioblastomas (GBMs) harbors potentially druggable oncogenic FGFR3-TACC3 (F3T3) fusions. However, their associated molecular and clinical features are poorly understood. Here we analyze the frequency of F3T3-fusion positivity, its associated genetic and methylation profiles, and its impact on survival in 906 IDH-wildtype GBM patients. We establish an F3T3 prevalence of 4.1\% and delineate its associations with cancer signaling pathway alterations. F3T3-positive GBMs had lower tumor mutational and copy-number alteration burdens than F3T3-wildtype GBMs. Although F3T3 fusions were predominantly mutually exclusive with other oncogenic RTK pathway alterations, they did rarely co-occur with EGFR amplification. They were less likely to harbor TP53 alterations. By methylation profiling, they were more likely to be assigned the mesenchymal or RTK II subclass. Despite being older at diagnosis and having similar frequencies of MGMT promoter hypermethylation, patients with F3T3-positive GBMs lived about 8~months longer than those with F3T3-wildtype tumors. While consistent with IDH-wildtype GBM, F3T3-positive GBMs exhibit distinct biological features, underscoring the importance of pursuing molecular studies prior to clinical trial enrollment and targeted treatment.},
	keywords = {Aged, Brain Neoplasms, Chemoradiotherapy, Adjuvant, Cohort Studies, DNA Copy Number Variations, DNA Methylation, DNA Modification Methylases, DNA Repair Enzymes, Female, Glioblastoma, Humans, Isocitrate Dehydrogenase, Kaplan-Meier Estimate, Male, Microtubule-Associated Proteins, Middle Aged, Neurosurgical Procedures, Oncogene Fusion, Promoter Regions, Genetic, Receptor, Fibroblast Growth Factor, Type 3, Retrospective Studies, Tumor Suppressor Proteins},
	issn = {2051-5960},
	doi = {10.1186/s40478-020-01058-6},
	author = {Mata, Douglas A and Benhamida, Jamal K and Lin, Andrew L and Vanderbilt, Chad M and Yang, Soo-Ryum and Villafania, Liliana B and Ferguson, Donna C and Jonsson, Philip and Miller, Alexandra M and Tabar, Viviane and Brennan, Cameron W and Moss, Nelson S and Sill, Martin and Benayed, Ryma and Mellinghoff, Ingo K and Rosenblum, Marc K and Arcila, Maria E and Ladanyi, Marc and Bale, Tejus A}
}
@article {691240,
	title = {Racial and Ethnic Diversity and Depression in Residency Programs: a Prospective Cohort Study},
	journal = {J Gen Intern Med},
	volume = {35},
	number = {4},
	year = {2020},
	month = {2020 04},
	pages = {1325-1327},
	keywords = {Cultural Diversity, Depression, ethnicity, Humans, Internship and Residency, Minority Groups, Prospective Studies, Racial Groups, United States},
	issn = {1525-1497},
	doi = {10.1007/s11606-019-05570-x},
	author = {Elharake, Jad A and Frank, Elena and Kalmbach, David A and Mata, Douglas A and Sen, Srijan}
}
@article {691236,
	title = {RAS/MAPK Pathway Driver Alterations Are Significantly Associated With Oncogenic KIT Mutations in Germ-cell Tumors},
	journal = {Urology},
	volume = {144},
	year = {2020},
	month = {2020 10},
	pages = {111-116},
	abstract = {OBJECTIVE: To report the mutational profile and clinical outcomes of a cohort of patients with KIT-mutant seminomas and nonseminomatous germ-cell tumors (SGCT/NSGCTs).

PATIENTS AND METHODS: Retrospective cohort study of all patients with KIT-mutant GCTs sequenced at Memorial Sloan Kettering between March 2014 and March 2020. Tumors were assessed with MSK-IMPACT, a DNA next-generation sequencing assay for targeted sequencing of up to 468 key cancer genes.

RESULTS: Among 568 patients with GCTs, 8.1\% had somatic KIT mutations, including 28 seminomas and 18 mixed/NSGCTs. Exons 17 (67.3\%), 11 (22.4\%), and 13 (6.1\%) were most commonly affected. KIT-mutant cases were enriched for oncogenic RAS/MAPK pathway alterations compared to KIT-wildtype cases (34.8\% vs 19.2\%, P~=~.02). Among KIT-mutant cases, concurrent mutations were noted in KRAS (21.7\%), RRAS2 (11.8\%), CBL (6.5\%), NRAS (4.3\%), MAP2K1 (2.2\%), and RAC1 (2.2\%). Mutations in KRAS, RRAS2, and NRAS were mutually exclusive. In all, 73.9\% of patients developed metastases and 95.7\% received chemotherapy. No patients received KIT-directed tyrosine kinase inhibitors (TKIs). Classification as a NSGCT rather than a SGCT was associated with an increased risk of death (hazard ratio 9.1, 95\% confidence interval 1.1-78.4, P~=~.04) while the presence of a concurrent RAS/MAPK pathway alteration was not (hazard ratio 0.8, 95\% confidence interval 0.1-4.3, P~=~.76).

CONCLUSION: Mitogenic driver alterations can co-occur with activating KIT mutations, which may explain the lack of efficacy of KIT-directed TKIs in prior trials. Novel KIT-directed TKIs that target exon 17 mutations may benefit chemotherapy-refractory patients with KIT-mutant GCTs without RAS/MAPK alterations. Dual MEK/KIT inhibitor therapy in KIT-mutant GCTs with concurrent RAS/MAPK alterations could also be a plausible therapeutic strategy.},
	keywords = {Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols, Child, DNA Mutational Analysis, Female, Follow-Up Studies, Humans, Male, MAP Kinase Kinase 1, MAP Kinase Signaling System, Middle Aged, Mutation, Neoplasms, Germ Cell and Embryonal, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-kit, ras Proteins, Retrospective Studies, Seminoma, Testicular Neoplasms, Young Adult},
	issn = {1527-9995},
	doi = {10.1016/j.urology.2020.07.027},
	author = {Mata, Douglas A and Yang, Soo-Ryum and Ferguson, Donna C and Liu, Ying and Sharma, Rohit and Benhamida, Jamal K and Al-Ahmadie, Hikmat A and Chakravarty, Debyani and Solit, David B and Tickoo, Satish K and Gupta, Sounak and Arcila, Maria E and Ladanyi, Marc and Feldman, Darren R and Reuter, Victor E and Vanderbilt, Chad M}
}
@article {691237,
	title = {Significance of Paneth cell-like differentiation in prostatic adenocarcinoma: a retrospective cohort study of 80 cases},
	journal = {Hum Pathol},
	volume = {102},
	year = {2020},
	month = {2020 08},
	pages = {7-12},
	abstract = {The grading and prognosis of prostatic adenocarcinoma with Paneth cell-like differentiation (PanEC) is controversial with limited available data. We identified 80 cases, not previously published, of PanEC first identified on biopsy (n~=~69), transurethral resection of the prostate (n~=~1), and radical prostatectomy (RP) (n~=~10). Of 69 biopsies, 22 did not have a grade assigned. In the remaining 47 biopsies, the Grade Groups (GGs) of the associated usual prostatic adenocarcinoma were GG1-2 (n~=~34) and GG3-5 (n~=~13). Of 10 RPs, the GGs were as follows: GG1-2 (n~=~8), GG4 (n~=~1), and no grade due to treatment effect (n~=~1); pathological stages were pT2 (n~=~8)~and pT3a (n~=~2), all with negative lymph nodes. We analyzed 19 cases with available follow-up only associated with GG1-2 conventional cancer; 9 underwent RP, and GGs at RP were as follows: GG1-2 (n~=~7), no grade due to treatment effect (n~=~1), and missing data (n~=~1); pathologic stages were pT2 (n~=~6) and pT3a (n~=~3); there were no positive regional lymph nodes; 3 were managed with active surveillance, without follow-up progression; 5 patients underwent radiation therapy with or without hormone therapy; none showed follow-up progression; 2 (10.5\%) patients were recommended to undergo radiotherapy, with no further follow-up. Of the cases with available follow-up, 9 were not associated with conventional adenocarcinoma; the majority of these cases were treated with radiation therapy or active surveillance without evidence of progression. In summary, although a minority of PanECs are associated with conventional higher grade adenocarcinoma and have progression after treatment, the majority have favorable findings, justifying the consideration of them as more indolent tumors despite cases in which PanEC resembles Gleason pattern 5 adenocarcinoma.},
	keywords = {Adenocarcinoma, Aged, Aged, 80 and over, Cell Differentiation, Cohort Studies, Humans, Male, Middle Aged, Neoplasm Grading, Paneth Cells, Prognosis, Prostatic Neoplasms, Retrospective Studies},
	issn = {1532-8392},
	doi = {10.1016/j.humpath.2020.05.003},
	author = {Salles, Daniela C and Mata, Douglas A and Epstein, Jonathan I}
}
@article {691230,
	title = {Ultrarapid  Mutation Screening Followed by Comprehensive Next-Generation Sequencing: A Feasible, Informative Approach for Lung Carcinoma Cytology Specimens With a High Success Rate},
	journal = {JTO Clin Res Rep},
	volume = {1},
	number = {3},
	year = {2020},
	month = {2020 Sep},
	abstract = {INTRODUCTION: For patients with advanced NSCLC, cytologic samples may be the only diagnostic specimen available for molecular profiling. Although both rapid and comprehensive assessment are essential in this setting, an integrated multitest approach remains an important strategy in many laboratories, despite the risks and challenges when working with scant samples. In this study, we describe our experience and high success rate in using a multitest approach, focusing on the clinical validation and incorporation of ultrarapid EGFR testing using the Idylla system followed by comprehensive next-generation sequencing (NGS).

METHODS: Cytology samples received for routine molecular testing were included in this study. The performance characteristics of the EGFR Idylla assay were assessed; tissue suitability parameters and interpretation criteria to supplement automated mutation calling were established. The assay performance was monitored for 1 year, comparing the results with those of concurrent NGS testing by MSK-IMPACT (primarily) or MSK-AmpliSeq and MSK-Fusion solid panel in a subset of cases.

RESULTS: Overall, 301 samples were studied; 83 samples were included in validation (60.2\% [50 of 83] were positive for EGFR mutations). Concordance with the reference method was 96.4\% (80 of 83) of the samples with excellent reproducibility. The limit of detection was variable depending on the total tissue input and the specific mutation tested. Unextracted tissue inputs that maintained total EGFR cycle of quantification at less than 23 allowed all mutations to be detected if present at greater than 5\% variant allele frequency. Mutations could be detected at 1\% variant allele frequency with total EGFR cycle of quantification of 18. During the clinical implementation phase, 218 NSCLC samples were tested by Idylla (24.3\% [53 of 218] were EGFR mutation positive). Concurrent NGS testing was requested on 165 samples and successfully performed on 96.4\% (159 of 165) of the samples. The Idylla automated results were concordant with those obtained by NGS in 96.2\% (153 of 159) of cases and improved to 98.7\% (157 of 159) after incorporation of manual review criteria to supplement automated calling, resulting in a diagnostic sensitivity of 95.6\% (95\% confidence interval: 84.9\%-99.5\%). In general, 9\% (14 of 159) of the cases tested by NGS had EGFR mutations not covered by the Idylla assay, primarily insertions in exon 19 and 20 and minor mutations cooccurring with canonical sensitizing mutations.

CONCLUSIONS: Comprehensive molecular testing is feasible and has a high success rate in NSCLC cytology samples when using a multitest approach. Testing with the Idylla system enables rapid and accurate determination of the EGFR status without compromising subsequent NGS testing.},
	issn = {2666-3643},
	doi = {10.1016/j.jtocrr.2020.100077},
	author = {Arcila, Maria E and Yang, Soo-Ryum and Momeni, Amir and Mata, Douglas A and Salazar, Paulo and Chan, Roger and Elezovic, Daniela and Benayed, Ryma and Zehir, Ahmet and Buonocore, Darren J and Rekhtman, Natasha and Lin, Oscar and Ladanyi, Marc and Nafa, Khedoudja}
}
@article {691238,
	title = {Volume of Gleason pattern 4 stratifies risk of metastasis and death in patients with Gleason score 3+5=8/5+3=8 positive prostate core biopsies},
	journal = {Hum Pathol},
	volume = {99},
	year = {2020},
	month = {2020 05},
	pages = {62-74},
	abstract = {Implementation of Grade Groups (GrGrs) has been widely accepted for reporting prostate cancer grade since the 2014 International Society of Urological Pathology consensus meeting. Despite their undisputed value for risk stratification, some GrGr are, a priori, quite heterogeneous in that they contain multiple Gleason patterns (GPs). In this regard, the prognostic significance of GP5 in biopsies with highest GrGr4 is uncertain and evaluated in this study. A search of all core biopsies positive for prostate cancer reviewed after 2005 was performed, and 71 cases with highest GrGr4 containing GP5 (i.e., 3~+~5~=~8 or 5~+~3~=~8; referred to as GrGr4/GP5pos) eligible for inclusion were identified. In addition, 95 core biopsy cases with highest GrGr4 and no GP5 (i.e, 4~+~4~=~8; referred to as GrGr4/GP5neg) were selected for comparison. Multiple pathologic parameters, including volume and amount of GP4, and clinical variables were collected to evaluate the influence of GP5 on disease recurrence, development of metastases, and disease-specific death. GrGr4/GP5pos cases did not show, as a group, statistically significant differences in prostatectomy findings, disease recurrence, metastases, and disease-specific mortality when compared with GrGr4/GP5neg cases. In addition, the risk of all outcomes evaluated in the study did not differ between the whole GrGr4/GP5pos and GrGr4/GP5neg groups. However, Kaplan-Meier analysis found that GrGr4/GP5pos cases with a significant amount of GP4 did show a higher risk of prostate cancer-specific death as well as bone and visceral metastases. Univariate Cox regression demonstrated that preoperative prostate specific antigen (PSA), total number of positive cores, and global GrGr5 were also associated with a higher chance of disease-specific death. In a multivariate model, only global GrGr5 and PSA \&gt;20~ng/dL remained statistically significant. This study suggests that the mere presence of GP5 in core biopsies with highest GrGr4 disease may not portend a worse prognosis. In these cases, accounting for the case-wide volume of GP4 by reporting a global GrGr appears to be more relevant as it identifies a subset of GrGr4/GP5pos patients with global GrGr5 who have a higher risk of metastases and prostate cancer-specific mortality.},
	keywords = {Adenocarcinoma, Aged, Aged, 80 and over, Biopsy, Large-Core Needle, Disease Progression, Humans, Kallikreins, Male, Middle Aged, Neoplasm Grading, Neoplasm Recurrence, Local, Predictive Value of Tests, Prostate-Specific Antigen, Prostatectomy, Prostatic Neoplasms, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome},
	issn = {1532-8392},
	doi = {10.1016/j.humpath.2020.03.001},
	author = {Acosta, Andres M and Taplin, Mary-Ellen and Mata, Douglas A and D{\textquoteright}Amico, Anthony V and Hirsch, Michelle S}
}
@article {644934,
	title = {Association Between Physician Depressive Symptoms and Medical Errors: A Systematic Review and Meta-analysis},
	journal = {JAMA Netw Open},
	volume = {2},
	number = {11},
	year = {2019},
	month = {2019 Nov 01},
	pages = {e1916097},
	abstract = {Importance: Depression is highly prevalent among physicians and has been associated with increased risk of medical errors. However, questions regarding the magnitude and temporal direction of these associations remain open in recent literature.

Objective: To provide summary relative risk (RR) estimates for the associations between physician depressive symptoms and medical errors.

Data Sources: A systematic search of Embase, ERIC, PubMed, PsycINFO, Scopus, and Web of Science was performed from database inception to December 31, 2018.

Study Selection: Peer-reviewed empirical studies that reported on a valid measure of physician depressive symptoms associated with perceived or observed medical errors were included. No language restrictions were applied.

Data Extraction and Synthesis: Study characteristics and RR estimates were extracted from each article. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were estimated using subgroup meta-analysis and metaregression. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was followed.

Main Outcomes and Measures: Relative risk estimates for the associations between physician depressive symptoms and medical errors.

Results: In total, 11 studies involving 21 517 physicians were included. Data were extracted from 7 longitudinal studies (64\%; with 5595 individuals) and 4 cross-sectional studies (36\%; with 15 922 individuals). The overall RR for medical errors among physicians with a positive screening for depression was 1.95 (95\% CI, 1.63-2.33), with high heterogeneity across the studies (χ2 = 49.91; P ,
	issn = {2574-3805},
	doi = {10.1001/jamanetworkopen.2019.16097},
	author = {Pereira-Lima, Karina and Mata, Douglas A and Loureiro, Sonia R and Crippa, Jos{\'e} A and Bolsoni, L{\'\i}via M and Sen, Srijan}
}
@article {644935,
	title = {Prominent Transepidermal Melanin Deposition Is a Distinguishing Histopathological Feature of Melasma: A Clinicopathologic Study},
	journal = {Dermatology},
	year = {2019},
	month = {2019 Nov 20},
	pages = {1-3},
	issn = {1421-9832},
	doi = {10.1159/000504408},
	author = {Hafeez, Farhaan and Mata, Douglas A and Christine G Lian and Poulos, Evangelos G}
}
@article {637649,
	title = {Physician-Training Stress and Accelerated Cellular Aging},
	journal = {Biol Psychiatry},
	year = {2019},
	month = {2019 May 09},
	abstract = {BACKGROUND: Stress is a key precipitant for many common diseases, but established biological markers to track stress and guide investigations into mechanisms linking stress and disease are lacking. Cross-sectional studies have identified correlations between stress and telomere attrition, but no large, longitudinal studies examining the impacts of chronic stress on telomere length exist. Residency training for physicians is a well-established stressful experience and can be used as a prospective stress model.

METHODS: In a longitudinal cohort study of 250 interns (first-year residents) at 55 United States hospital systems serving during the 2015-2016 academic year, we examined associations between measures of the residency experience and saliva-measured telomere attrition.

RESULTS: Telomere length shortened significantly over the course of internship year, from mean {\textpm} SD of 6465.1 {\textpm} 876.8 base pairs before internship to 6321.5 {\textpm} 630.6 base pairs at the end of internship (t~= 2.69; p~= .008). Stressful early family environments and neuroticism were significantly associated with shorter preinternship telomere length. Longer work hours were associated with greater telomere intern telomere loss over the year (p~= .002). Of note, the mean telomere attrition during internship year was six times greater than the typical annual attrition rate identified in a recent meta-analysis.

CONCLUSIONS: This work implicates telomere attrition as a biologically measurable consequence of physician training, with the magnitude of attrition associated with workload. Identification of an objective, biological sequela of residency stress may help to facilitate the development of effective interventions. Further, the findings implicate telomere attrition as an objective biomarker to follow the pathologic effects of stress, in general.},
	issn = {1873-2402},
	doi = {10.1016/j.biopsych.2019.04.030},
	author = {Ridout, Kathryn K and Ridout, Samuel J and Guille, Constance and Mata, Douglas A and Akil, Huda and Sen, Srijan}
}
@article {635601,
	title = {Are historical studies relevant in the setting of grade migration?},
	journal = {BJU Int},
	volume = {123},
	number = {3},
	year = {2019},
	month = {2019 Mar},
	pages = {375-376},
	issn = {1464-410X},
	doi = {10.1111/bju.14656},
	author = {Szymaniak, Julie A and Mata, Douglas A and Cole, Alexander P}
}
@article {626657,
	title = {Development of a Commercial Reference Laboratory Elective Rotation for Residents in Clinical Pathology},
	journal = {Am J Clin Pathol},
	volume = {150},
	number = {6},
	year = {2018},
	month = {2018 Oct 24},
	pages = {485-490},
	abstract = {Objectives: To develop a curriculum for a commercial reference laboratory clinical pathology training elective.

Methods: A 4-day elective at Quest Diagnostics was developed. The elective included 32 sessions composed of interactive didactic sessions and laboratory tours/demonstrations. Ten residents who attended the elective completed a written evaluation and scored each component of the curriculum.

Results: Written comments were very positive and demonstrated the goals of the elective were achieved. Laboratory tours and one-on-one sessions with the medical directors were especially well received. Most of the residents stated that the rotation gave them exposure to an area of laboratory medicine that they were not familiar with.

Conclusions: The elective provided a resident training experience that was highly regarded and exposed residents to an area of laboratory medicine not encountered in most pathology training programs. Our curriculum could serve as a model for establishing a similar elective in other training programs.},
	issn = {1943-7722},
	doi = {10.1093/ajcp/aqy070},
	author = {Lewandrowski, Kent and Keegan, Alissa and Makarenko, Vladislav and Maryamchak, Elena and Mata, Douglas A and Palte, Michael J and Rudolf, Joseph W and Safdar, Nida and Schmidt, Ryan J and Stuart, Lena and Xiong, Yiqin and Rao, Lokinendi and Melanson, Stacy E F and Michael Snyder, L}
}
@article {626656,
	title = {Prevalence of Burnout Among Physicians: A Systematic Review},
	journal = {JAMA},
	volume = {320},
	number = {11},
	year = {2018},
	month = {2018 09 18},
	pages = {1131-1150},
	abstract = {Importance: Burnout is a self-reported job-related syndrome increasingly recognized as a critical factor affecting physicians and their patients. An accurate estimate of burnout prevalence among physicians would have important health policy implications, but the overall prevalence is unknown.

Objective: To characterize the methods used to assess burnout and provide an estimate of the prevalence of physician burnout.

Data Sources and Study Selection: Systematic search of EMBASE, ERIC, MEDLINE/PubMed, psycARTICLES, and psycINFO for studies on the prevalence of burnout in practicing physicians (ie, excluding physicians in training) published before June 1, 2018.

Data Extraction and Synthesis: Burnout prevalence and study characteristics were extracted independently by 3 investigators. Although meta-analytic pooling was planned, variation in study designs and burnout ascertainment methods, as well as statistical heterogeneity, made quantitative pooling inappropriate. Therefore, studies were summarized descriptively and assessed qualitatively.

Main Outcomes and Measures: Point or period prevalence of burnout assessed by questionnaire.

Results: Burnout prevalence data were extracted from 182 studies involving 109 628 individuals in 45 countries published between 1991 and 2018. In all, 85.7\% (156/182) of studies used a version of the Maslach Burnout Inventory (MBI) to assess burnout. Studies variably reported prevalence estimates of overall burnout or burnout subcomponents: 67.0\% (122/182) on overall burnout, 72.0\% (131/182) on emotional exhaustion, 68.1\% (124/182) on depersonalization, and 63.2\% (115/182) on low personal accomplishment. Studies used at least 142 unique definitions for meeting overall burnout or burnout subscale criteria, indicating substantial disagreement in the literature on what constituted burnout. Studies variably defined burnout based on predefined cutoff scores or sample quantiles and used markedly different cutoff definitions. Among studies using instruments based on the MBI, there were at least 47 distinct definitions of overall burnout prevalence and 29, 26, and 26 definitions of emotional exhaustion, depersonalization, and low personal accomplishment prevalence, respectively. Overall burnout prevalence ranged from 0\% to 80.5\%. Emotional exhaustion, depersonalization, and low personal accomplishment prevalence ranged from 0\% to 86.2\%, 0\% to 89.9\%, and 0\% to 87.1\%, respectively. Because of inconsistencies in definitions of and assessment methods for burnout across studies, associations between burnout and sex, age, geography, time, specialty, and depressive symptoms could not be reliably determined.

Conclusions and Relevance: In this systematic review, there was substantial variability in prevalence estimates of burnout among practicing physicians and marked variation in burnout definitions, assessment methods, and study quality. These findings preclude definitive conclusions about the prevalence of burnout and highlight the importance of developing a consensus definition of burnout and of standardizing measurement tools to assess the effects of chronic occupational stress on physicians.},
	keywords = {Burnout, Professional, Compassion Fatigue, Depersonalization, Humans, Job Satisfaction, Physicians, Prevalence, Surveys and Questionnaires},
	issn = {1538-3598},
	doi = {10.1001/jama.2018.12777},
	author = {Rotenstein, Lisa S and Matthew Torre and Ramos, Marco A and Rosales, Rachael C and Guille, Constance and Sen, Srijan and Mata, Douglas A}
}
@article {608957,
	title = {A Comparison of the Expectations and Experiences of Medical Students From High-, Middle-, and Low-Income Countries Participating in Global Health Clinical Electives},
	journal = {Teach Learn Med},
	volume = {30},
	number = {1},
	year = {2018},
	month = {2018 Jan-Mar},
	pages = {45-56},
	abstract = {Phenomenon: Global health education (GHE) is expanding to include socioculturally and resource-different settings, with the goal of developing a workforce with members who can promote health equity locally and globally. GHE is also no longer limited to students from high-income countries (HICs). However, it is unknown whether the motivations and experiences of medical students from HICs and from low- and middle-income countries (LMICs) participating in GHE clinical electives through institutional partnerships are similar or different. Such an understanding is needed to design programs that meet the needs of participants and effectively train them in the principles and practice of global health.

APPROACH: This was a cross-sectional, mixed-methods survey of LMIC students from partner sites rotating at one U.S. medical school, and U.S. students from one medical school rotating at partner sites, between 2010 and 2015. Variables included demographic characteristics of participants, components of the curriculum at the home institution, and components of the away rotation, including perceptions of its content and impact. Content analysis was used to identify themes in the responses provided to open-ended questions.

FINDINGS: In all, 63 of 84 (75\%) LMIC and 61 of 152 (40\%) U.S. students participated. Recall of predeparture training was low for both LMIC and U.S. students (44\% and 55\%, respectively). Opportunities to experience different healthcare systems, resource-different settings, and cultural exposure emerged as motivators for both groups. Both groups noted differences in doctor-patient relationships, interactions between colleagues, and use of diagnostic testing. U.S. respondents were more likely to perceive differences in the impact of social determinants of health and ethical issues. Both groups felt that their experience affected their interactions with patients and perspectives on education, but U.S. students were more likely to mention perspectives on healthcare delivery and social determinants of health, whereas LMIC respondents noted impacts on career goals. Insights: These results argue that GHE is not restricted to resource-constrained settings and that students from LMICs have similar reasons for participation as those from HICs. LMIC students also identified a lack of emphasis on GHE topics like social determinants of health during GH electives, which could diminish the effectiveness of these experiences. Both U.S. and LMIC students emphasized the cultural component of their GHE experience but had different perceptions regarding core tenets of GHE, such as the social determinants of health and health equity, during these experiences.},
	issn = {1532-8015},
	doi = {10.1080/10401334.2017.1347510},
	author = {Peluso, Michael J and Rodman, Adam and Mata, Douglas A and Kellett, Anne T and van Schalkwyk, Susan and Rohrbaugh, Robert M}
}
@article {608958,
	title = {A novel oocyte maturation trigger using 1500~IU of human chorionic gonadotropin plus 450~IU of follicle-stimulating hormone may decrease ovarian hyperstimulation syndrome across all in vitro fertilization stimulation protocols},
	journal = {J Assist Reprod Genet},
	volume = {35},
	number = {2},
	year = {2018},
	month = {2018 Feb},
	pages = {297-307},
	abstract = {PURPOSE: Modification of the trigger used to induce final oocyte maturation in in vitro fertilization (IVF) is a major strategy used to reduce the risk of ovarian hyperstimulation syndrome (OHSS). A novel trigger composed of 1500~IU of human chorionic gonadotropin (hCG) plus 450~IU of follicle-stimulating hormone (FSH) has been developed to reduce OHSS risk. This study compares outcomes of the novel trigger to conventional triggers used in high-risk OHSS patients undergoing IVF.

METHODS: In this retrospective cohort study, IVF cycles at high risk for OHSS based on a serum estradiol >~5000~pg/ml on trigger day conducted between January 2008 and February 2016 were evaluated. Oocyte maturation was induced with the novel trigger (1500~IU hCG plus 450~IU FSH) or a conventional trigger [3300~IU hCG, gonadotropin-releasing hormone agonist (GnRHa) alone, or GnRHa plus 1500~IU hCG]. IVF cycle outcomes were compared. Trigger strategies were examined for associations with OHSS development using logistic regression.

RESULTS: Among 298 eligible IVF cycles identified, there were no differences in oocyte maturation, fertilization, embryo quality, or pregnancy outcomes among all triggers. After adjusting for serum estradiol level and number of follicles, the novel trigger was associated with lower odds of OHSS symptom development compared to the 3300~IU hCG and GnRHa plus hCG 1500~IU triggers (p~=~0.007 and 0.04, respectively).

CONCLUSIONS: This study suggests that 1500~IU hCG plus 450~IU FSH may be associated with decreased OHSS symptoms compared to conventional triggers, while producing similar IVF and pregnancy outcomes. More important, this novel trigger may provide a superior alternative in down-regulated cycles and in patients with hypothalamic dysfunction where GnRHa triggers cannot be utilized.},
	issn = {1573-7330},
	doi = {10.1007/s10815-017-1074-4},
	author = {Anaya, Yanett and Mata, Douglas A and Letourneau, Joseph and Cakmak, Hakan and Cedars, Marcelle I and Rosen, Mitchell P}
}
@article {608961,
	title = {Improving undergraduate pathology teaching: medical students{\textquoteright} perspective-reply},
	journal = {Hum Pathol},
	volume = {68},
	year = {2017},
	month = {2017 10},
	pages = {203-204},
	keywords = {Curriculum, Education, Medical, Undergraduate, Humans, Students, Medical, Teaching},
	issn = {1532-8392},
	doi = {10.1016/j.humpath.2017.03.030},
	author = {Chu, YunXiang and Richard N. Mitchell and Mata, Douglas A}
}
@article {608960,
	title = {Passport to pathology: transforming the medical student pathology elective from a passive educational experience to an exciting, immersive clinical rotation},
	journal = {Hum Pathol},
	volume = {68},
	year = {2017},
	month = {2017 10},
	pages = {34-39},
	keywords = {Curriculum, Education, Medical, Undergraduate, Humans, Pathology, Clinical, Students, Medical, United States},
	issn = {1532-8392},
	doi = {10.1016/j.humpath.2017.08.031},
	author = {Minhas, Paras S and Enogieru, Imarhia E and Richard N. Mitchell and Mata, Douglas A}
}
@article {608959,
	title = {Work-Family Conflict and the Sex Difference in Depression Among Training Physicians},
	journal = {JAMA Intern Med},
	volume = {177},
	number = {12},
	year = {2017},
	month = {2017 Dec 01},
	pages = {1766-1772},
	abstract = {Importance: Depression is common among training physicians and may disproportionately affect women. The identification of modifiable risk factors is key to reducing this disease burden and its negative impact on patient care and physician career attrition.

Objective: To determine the presence and magnitude of a sex difference in depressive symptoms and work-family conflict among training physicians; and if work-family conflict impacts the sex difference in depressive symptoms among training physicians.

Design, Setting, and Participants: A prospective longitudinal cohort study of medical internship in the United States during the 2015 to 2016 academic year in which 3121 interns were recruited across all specialties from 44 medical institutions.

Main Outcomes and Measures: Prior to and during their internship year, participants reported the degree to which work responsibilities interfered with family life using the Work Family Conflict Scale and depressive symptoms using the Patient Health Questionnaire-9 (PHQ-9).

Results: Mean (SD) participant age was 27.5 (2.7) years, and 1571 participants (49.7\%) were women. Both men and women experienced a marked increase in depressive symptoms during their internship year, with the increase being statistically significantly greater for women (men: mean increase in PHQ-9, 2.50; 95\% CI, 2.26-2.73 vs women: mean increase, 3.20; 95\% CI, 2.97-3.43). When work-family conflict was accounted for, the sex disparity in the increase in depressive symptoms decreased by 36\%.

Conclusions and Relevance: Our study demonstrates that depressive symptoms increase substantially during the internship year for men and women, but that this increase is greater for women. The study also identifies work-family conflict as an important potentially modifiable factor that is associated with elevated depressive symptoms in training physicians. Systemic modifications to alleviate conflict between work and family life may improve physician mental health and reduce the disproportionate depression disease burden for female physicians. Given that depression among physicians is associated with poor patient care and career attrition, efforts to alleviate depression among physicians has the potential to reduce the negative consequences associated with this disease.},
	keywords = {Adult, Depression, Family Conflict, Female, Humans, Internship and Residency, Longitudinal Studies, Male, Physicians, Physicians, Women, Prospective Studies, Sex Factors, Surveys and Questionnaires, United States},
	issn = {2168-6114},
	doi = {10.1001/jamainternmed.2017.5138},
	author = {Guille, Constance and Frank, Elena and Zhao, Zhuo and Kalmbach, David A and Nietert, Paul J and Mata, Douglas A and Sen, Srijan}
}
@article {559316,
	title = {Ambient Temperature and Sudden Infant Death Syndrome in the United States},
	journal = {Epidemiology},
	volume = {28},
	number = {5},
	year = {2017},
	month = {2017 Sep},
	pages = {728-734},
	abstract = {BACKGROUND: Sudden infant death syndrome (SIDS) is a leading cause of infant mortality in the United States. While thermal stress is implicated in many risk factors for SIDS, the association between ambient temperature and SIDS remains unclear.

METHODS: We obtained daily individual-level infant mortality data and outdoor temperature data from 1972 to 2006 for 210 US cities. We applied a time-stratified case-crossover analysis to determine the effect of ambient temperature on the risk of SIDS by season. We stratified the analysis by race, infant age, and climate.

RESULTS: There were a total of 60,364 SIDS cases during our study period. A 5.6{\textdegree}C (10{\textdegree}F) higher daily temperature on the same day was associated with an increased SIDS risk of 8.6\% (95\% confidence interval [CI] = 3.6\%, 13.8\%) in the summer, compared with a 3.1\% decrease (95\% CI = -5.0\%, -1.3\%) in the winter. Summer risks were greater among black infants (18.5\%; 95\% CI = 9.3\%, 28.5\%) than white infants (3.6\%; 95\% CI = -2.3\%, 9.9\%), and among infants 3-11 months old (16.9\%; 95\% CI = 8.9\%, 25.5\%) than infants 0-2 months old (2.7\%; 95\% CI = -3.5\%, 9.2\%). The temperature-SIDS association was stronger in climate clusters in the Midwest and surrounding northern regions.

CONCLUSIONS: Temperature increases were associated with an elevated risk of SIDS in the summer, particularly among infants who were black, 3 months old and older, and living in the Midwest and surrounding northern regions.},
	issn = {1531-5487},
	doi = {10.1097/EDE.0000000000000703},
	author = {Jhun, Iny and Mata, Douglas A and Nordio, Francesco and Mihye Lee and Schwartz, Joel and Antonella Zanobetti}
}
@article {559321,
	title = {Utility of Clinical Risk Stratification in the Selection of Muscle-Invasive Bladder Cancer Patients for Neoadjuvant Chemotherapy: A Retrospective Cohort Study},
	journal = {Bladder Cancer},
	volume = {3},
	number = {1},
	year = {2017},
	month = {2017 Jan 27},
	pages = {35-44},
	abstract = {Introduction: Level I evidence supports the use of cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer prior to radical cystectomy (RC). On average, 30-40\% of patients achieve a complete pathologic response (i.e., stage pT0) after receiving NAC. Some centers risk-stratify patients, suggesting that there may be a higher-risk population that would derive the most benefit from NAC. Recently, a risk-stratification model developed at M.D. Anderson Cancer Center (MDACC) specified criteria for clinical staging and patient selection for NAC. We applied this model to our own RC patient cohort and evaluated our own experience with clinical risk stratification and the effect of NAC on post treatment risk categories. Methods: We retrospectively reviewed the charts of consecutive patients who underwent RC at two institutions between 2004 and 2014 and noted whether or not they received NAC. We determined the clinical stage by reviewing the exam under anesthesia, transurethral resection biopsy (TURBT) pathology, and preoperative imaging. Patients with cT2-T4a node-negative disease were included. Those with sarcomatoid features or adenocarcinoma were excluded. Patients were classified as high risk if they had tumor-associated hydronephrosis, clinical stage>=T3b-T4a disease, variant histology (i.e., micropapillary or small cell), or lymphovascular invasion (LVI), as specified by the MDACC model. Variables were examined for associations with cancer-specific survival (CSS), overall survival (OS), and risk-category reclassification. Results: We identified 166 patients with a median follow-up time of 22.2 months. In all, 117 patients (70.5\%) did not receive NAC, 68 (58.1\%) of whom we classified as high risk. Among patients not receiving NAC, CSS and OS were significantly decreased in high-risk patients (log-rank test p = 0.01 for both comparisons). The estimated age-adjusted hazard ratios of high-risk classification for cancer-specific and overall death were 3.2 (95\% CI: 1.2 to 8.6) and 2.2 (95\% CI: 1.1 to 4.4), respectively. On post-RC final pathology, 23 (46.9\%) low-risk patients were up-classified to high risk and 17 (25.0\%) high-risk patients were down-classified. Complete pathologic responses (pT0) were achieved in 7 (6.0\%) patients and partial responses (pT1, pTa, pTis) were achieved in 28 (23.9\%) patients. Of the 49 patients who did receive NAC, 43 (87.8\%) received cisplatin-based and six (12.2\%) received carboplatin-based regimens. Applying the MDACC model, we categorized 41 (83.7\%) patients as high risk prior to NAC treatment. On final pathology, 3 (37.5\%) low-risk patients were up-classified and 17 (41.5\%) high-risk patients were down-classified. Complete pathologic responses (pT0) were seen in 13 (26.5\%) patients and partial responses were seen in 10 (20.4\%) patients. Although the utilization of NAC was not statistically significantly associated with CSS or OS (log-rank test p > 0.05 for both comparisons), it was associated with a 1.2 times increased odds (95\% CI: 0.4 to 2.1) of post-RC reclassification from high to low risk on age-adjusted logistic regression. Conclusions: We found similar results using the clinical risk-stratification model in our cohort and showed that the high-risk category was associated with lower CSS and OS. NAC was associated with a higher probability of risk reclassification from high to low risk.},
	issn = {2352-3727},
	doi = {10.3233/BLC-160062},
	author = {von Rundstedt, Friedrich-Carl and Mata, Douglas A and Kryvenko, Oleksandr N and Shah, Anup A and Jhun, Iny and Lerner, Seth P}
}
@book {457961,
	title = {Statistics for Pathologists},
	year = {2016},
	pages = {250},
	publisher = {Demos Medical Publishing},
	organization = {Demos Medical Publishing},
	edition = {1},
	address = {New York},
	url = {http://www.demosmedical.com/statistics-for-pathologists.html},
	author = {Danny A. Milner and Emily E.K. Meserve and T. Rinda Soong and Douglas A. Mata}
}
@article {423261,
	title = {Testosterone Treatment in Older Men.},
	journal = {N Engl J Med},
	volume = {375},
	number = {1},
	year = {2016},
	month = {2016 Jul 7},
	pages = {89},
	keywords = {fatigue, Hormone Replacement Therapy, Humans, Male, Sexual Behavior, Testosterone, Walking},
	issn = {1533-4406},
	doi = {10.1056/NEJMc1603665$\#$SA3},
	author = {Mata, Douglas A and Ranjith Ramasamy and Lipshultz, Larry I}
}
@article {408046,
	title = {Resident Physicians With Depression or Depressive Symptoms--In Reply.},
	journal = {JAMA},
	volume = {315},
	number = {21},
	year = {2016},
	month = {2016 Jun 7},
	pages = {2347-8},
	issn = {1538-3598},
	doi = {10.1001/jama.2016.1724},
	author = {Mata, Douglas A and Ramos, Marco A and Sen, Srijan}
}
@article {401891,
	title = {In Their Own Words: An Analysis of the Experiences of Medical Interns Participating in a Prospective Cohort Study of Depression.},
	journal = {Acad Med},
	year = {2016},
	month = {2016 May 10},
	abstract = {PURPOSE: To compare the subjective experiences of interns with and without symptoms of depression using a mixed-methods approach.

METHOD: In 2007-2008, interns from six institutions were screened for depression before and during internship using an online survey that included the Patient Health Questionnaire (PHQ-9). At the end of internship, participants were asked what made the year difficult, easy, and memorable, and how they had changed. Computerized lexical and qualitative thematic analyses were performed to analyze their free-text responses.

RESULTS: Sixty-three percent (244/388) of invited interns participated in the original cohort study. Of those, 42\% (103/244) answered the open-ended questions for this analysis. Thirty-five percent (36/103) screened positive for clinically significant depression (i.e., PHQ-9 score >= 10) during their intern year. Respondents with symptoms of depression were more likely to report problems with cynicism, exhaustion, and stress, while those without them were more likely to mention positive patient care and educational experiences. Respondents with symptoms of depression preferentially described experiences that "broke" their confidence, sense of well-being, and belief in the medical profession, while those who did not described profoundly positive, life-changing experiences regarding interactions with patients and supportive colleagues, through which they grew personally and professionally.

CONCLUSIONS: Depression during internship affects not only objective outcomes like medical errors but also how interns value the profession and themselves, with potentially profound consequences for their future career decisions. Residency programs should implement reactive interventions targeting depression and proactive interventions promoting resilience and well-being to address the issues that lead to depression.},
	issn = {1938-808X},
	doi = {10.1097/ACM.0000000000001227},
	author = {Mata, Douglas A and Ramos, Marco A and Kim, Michelle M and Guille, Constance and Sen, Srijan}
}
@article {386566,
	title = {Student-run free clinics: the USA{\textquoteright}s psychiatry recruitment solution?},
	journal = {Lancet Psychiatry},
	volume = {3},
	number = {4},
	year = {2016},
	month = {2016 Apr},
	pages = {321-2},
	issn = {2215-0374},
	doi = {10.1016/S2215-0366(16)00099-7},
	author = {Ramos, Marco A and Rotenstein, Lisa S and Mata, Douglas A}
}
@article {379741,
	title = {A review of molecular predictors of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer.},
	journal = {Mini Rev Med Chem},
	year = {2016},
	month = {2016 Mar 15},
	abstract = {Locally advanced, muscle-invasive urothelial carcinoma of the bladder (MIBC) may be definitively treated with either radiotherapy or radical cystectomy (RC) with urinary diversion. Neoadjuvant chemotherapy (NAC) is typically administered prior to treatment with either modality. Receiving NAC prior to RC might confer a survival advantage compared to undergoing RC alone. However, its usefulness has been questioned due to concerns about overtreatment and toxicity. Having the ability to predict whether individual patients would benefit from or be harmed by NAC would be an important tool in precision medicine. Unfortunately, to date no prognostic or predictive molecular markers have been validated for this purpose. In this manuscript, we review the current state of molecular markers in MIBC treatment and outline how recent advances in whole-genome sequencing may soon improve the selection of precisely targeted therapeutics for the benefit of individual patients.},
	issn = {1875-5607},
	author = {Degener, Stephan and Mata, Douglas A and Youssef, Ramy and G{\"o}dde, Daniel and Tandogdu, Zafer and Roth, Stephan and von Rundstedt, Friedrich-Carl}
}
@article {373181,
	title = {Diagnostic Accuracy of Renal Mass Biopsy: An Ex Vivo Study of 100 Nephrectomy Specimens.},
	journal = {Int J Surg Pathol},
	year = {2016},
	month = {2016 Jan 25},
	abstract = {We investigated the diagnostic accuracy of renal mass biopsy in an ex vivo model, as well as compared the agreement of the preoperative radiological diagnosis with the final pathologic diagnosis. Two 18-gauge needle-core and 2 vacuum-needle biopsies were performed ex vivo from the tumors of 100 consecutive patients undergoing radical nephrectomy between 2006 and 2010. The median tumor size was 5.5 cm. There was no significant difference with regard to cylinder length or tissue quality between the sampling methods. At least 1 of 4 needle cores contained diagnostic tissue in 88\% of patients. Biopsy specimens identified clear cell (54\%), papillary (13\%), or chromophobe (5\%) renal cell carcinoma; urothelial carcinoma (6\%); oncocytoma (5\%); liposarcoma (1\%); metastatic colorectal carcinoma (1\%); squamous cell carcinoma (1\%); unclassified renal cell neoplasm (1\%); and no tumor sampled (12\%). The sensitivity of the biopsy for accurately determining the diagnosis was 88\% (95\% CI: 79\% to 93\%). The specificity was 100\% (95\% CI: 17\% to 100\%). Biopsy grade correlated strongly with final pathology (83.5\% agreement). There was no difference in average tumor size in cases with the same versus higher grade on final pathology (5.87 vs 5.97; P = .87). Appraisal of tumor histology by radiology agreed with the pathologic diagnosis in 68\% of cases. Provided that the biopsy samples the tumor tissue in a renal mass, pathologic analysis is of great diagnostic value in respect of grade and tumor type and correlates well with excisional pathology. This constitutes strong ground for increasingly used renal mass biopsy in patients considering active surveillance or ablation therapy.},
	issn = {1940-2465},
	doi = {10.1177/1066896915625178},
	author = {von Rundstedt, Friedrich-Carl and Mata, Douglas Alexander and Kryvenko, Oleksandr N and Roth, Stephan and Degener, Stephan and Dreger, Nici Markus and Goedde, Daniel and Assaid, Ahmed and Kamper, Lars and Haage, Patrick and Stoerkel, Stephan and Lazica, David A}
}
@article {373171,
	title = {Effects of Testosterone Replacement Therapy on Lower Urinary Tract Symptoms: A Systematic Review and Meta-analysis.},
	journal = {Eur Urol},
	year = {2016},
	month = {2016 Feb 10},
	abstract = {CONTEXT: There is a potential risk that testosterone replacement therapy (TRT) may exacerbate lower urinary tract symptoms (LUTS) among aging men with late-onset hypogonadism (LOH) because of testosterone{\textquoteright}s growth-promoting effects on the prostate.

OBJECTIVE: To compare the change in LUTS severity as assessed using the International Prostate Symptom Score (IPSS) between men receiving TRT versus placebo for the treatment of LOH.

EVIDENCE ACQUISITION: Systematic search of MEDLINE, Embase, ClinicalTrials.gov, and The Cochrane Library for randomized controlled trials of TRT for LOH published between January 1992 and September 2015. Studies were eligible for inclusion if they were a randomized control trial, used TRT, and assessed LUTS outcomes using the IPSS. Estimates were pooled using random effects meta-analysis. Differences by study-level characteristics were estimated using meta-regression.

EVIDENCE SYNTHESIS: Data were extracted from 14 trials involving 2029 participants. The average age was 64.5 yr and the average follow-up was 34.4 mo. Seven studies used topical, five used injectable, and two used oral testosterone. There was no statistically significant difference in pooled changes in IPSS from baseline to follow up in men treated with TRT compared with those receiving placebo (-0.41 points [95\% confidence interval: -0.89 to 0.07; I(2)=0\%, p=0.28] vs. 0.12 points [95\% confidence interval: -0.32 to 0.55; I(2)=0\%, p=0.81], between-group difference p>0.05). No between-group differences were noted in subanalyses that controlled for potential confounders such as type of testosterone, change in testosterone, aging male symptom scale, or prostate-specific antigen levels (p>0.05 for all comparisons).

CONCLUSIONS: In this meta-analysis of 14 clinical trials of TRT for LOH, the change in IPSS was similar among men receiving TRT versus placebo, suggesting that TRT treatment does not worsen LUTS among men with LOH.

PATIENT SUMMARY: In this analysis of 14 clinical trials, testosterone replacement therapy did not worsen lower urinary tract symptoms among men being treated for late-onset hypogonadism.},
	issn = {1873-7560},
	doi = {10.1016/j.eururo.2016.01.043},
	author = {Kohn, Taylor P and Mata, Douglas A and Ranjith Ramasamy and Lipshultz, Larry I}
}
@article {373176,
	title = {Neuropathology: bridging psychiatry and neurology in medical education.},
	journal = {Lancet Psychiatry},
	volume = {3},
	number = {2},
	year = {2016},
	month = {2016 Feb},
	pages = {98-100},
	issn = {2215-0374},
	doi = {10.1016/S2215-0366(15)00517-9},
	author = {Minhas, Paras and Chu, YunXiang and Mata, Douglas A}
}
@inbook {457956,
	title = {The Role of Imaging in Urology},
	booktitle = {The Role of Imaging Technology in Current Surgical Practice},
	year = {2015},
	publisher = {Nova Science Publishers},
	organization = {Nova Science Publishers},
	edition = {1},
	address = {Hauppauge, NY},
	url = {https://www.novapublishers.com/catalog/product_info.php?products_id=55742},
	author = {Michelle M. Kim and Douglas A. Mata and Dicken S.C. Ko}
}
@article {357091,
	title = {Prevalence of Depression and Depressive Symptoms Among Resident Physicians: A Systematic Review and Meta-analysis.},
	journal = {JAMA},
	volume = {314},
	number = {22},
	year = {2015},
	month = {2015 Dec 8},
	pages = {2373-83},
	abstract = {IMPORTANCE: Physicians in training are at high risk for depression. However, the estimated prevalence of this disorder varies substantially between studies.

OBJECTIVE: To provide a summary estimate of depression or depressive symptom prevalence among resident physicians.

DATA SOURCES AND STUDY SELECTION: Systematic search of EMBASE, ERIC, MEDLINE, and PsycINFO for studies with information on the prevalence of depression or depressive symptoms among resident physicians published between January 1963 and September 2015. Studies were eligible for inclusion if they were published in the peer-reviewed literature and used a validated method to assess for depression or depressive symptoms.

DATA EXTRACTION AND SYNTHESIS: Information on study characteristics and depression or depressive symptom prevalence was extracted independently by 2 trained investigators. Estimates were pooled using random-effects meta-analysis. Differences by study-level characteristics were estimated using meta-regression.

MAIN OUTCOMES AND MEASURES: Point or period prevalence of depression or depressive symptoms as assessed by structured interview or validated questionnaire.

RESULTS: Data were extracted from 31 cross-sectional studies (9447 individuals) and 23 longitudinal studies (8113 individuals). Three studies used clinical interviews and 51 used self-report instruments. The overall pooled prevalence of depression or depressive symptoms was 28.8\% (4969/17,560 individuals, 95\% CI, 25.3\%-32.5\%), with high between-study heterogeneity (Q = 1247, τ2 = 0.39, I2 = 95.8\%, P ,
	issn = {1538-3598},
	doi = {10.1001/jama.2015.15845},
	author = {Mata, Douglas A and Ramos, Marco A and Bansal, Narinder and Khan, Rida and Guille, Constance and Di Angelantonio, Emanuele and Sen, Srijan}
}
@article {343301,
	title = {A 25-Year-Old Man with Exudative Retinal Detachments and Infiltrates without Hematological or Neurological Findings Found to Have Relapsed Precursor T-Cell Acute Lymphoblastic Leukemia.},
	journal = {Case Rep Ophthalmol},
	volume = {6},
	number = {3},
	year = {2015},
	month = {2015 Sep-Dec},
	pages = {321-7},
	abstract = {BACKGROUND: Precursor T-cell acute lymphoblastic leukemia (pre-T-ALL) may cause ocular pathologies such as cotton-wool spots, retinal hemorrhage, and less commonly, retinal detachment or leukemic infiltration of the retina itself. However, these findings are typically accompanied by the pathognomonic hematological signs of acute leukemia.

CASE PRESENTATION: In this case report and review of the literature, we describe a particularly unusual case of a 25-year-old man who presented to our hospital with bilateral exudative retinal detachments associated with posterior pole thickening without any hematological or neurological findings. The patient, who had a history of previously treated pre-T-ALL in complete remission, was found to have leukemia cell infiltration on retinal biopsy.

CONCLUSION: Our case underscores the fact that the ophthalmologist may be the first provider to detect the relapse of previously treated leukemia, and that ophthalmic evaluation is critical for detecting malignant ocular infiltrates.},
	issn = {1663-2699},
	doi = {10.1159/000439375},
	author = {Johnson, Jordan S and Lopez, James S and Kavanaugh, Arthur Scott and Liang, Chanping and Mata, Douglas A}
}
@article {343306,
	title = {Using exit competencies to integrate pathology into the undergraduate clinical clerkships.},
	journal = {Hum Pathol},
	year = {2015},
	month = {2015 Sep 21},
	issn = {1532-8392},
	doi = {10.1016/j.humpath.2015.08.018},
	author = {Chu, YunXiang and Richard N. Mitchell and Mata, Douglas A}
}
@article {312641,
	title = {Comparison of microdissection testicular sperm extraction, conventional testicular sperm extraction, and testicular sperm aspiration for nonobstructive azoospermia: a systematic review and meta-analysis.},
	journal = {Fertil Steril},
	year = {2015},
	month = {2015 Aug 8},
	abstract = {OBJECTIVE: To investigate the relative differences in outcomes among microdissection testicular sperm extraction (micro-TESE), conventional testicular sperm extraction (cTESE), and testicular sperm aspiration (TESA) in men with nonobstructive azoospermia.

DESIGN: Systematic review and meta-analysis.

SETTING: A variety of outpatient academic and private urology clinics.

PATIENTS(S): Men with nonobstructive azoospermia.

INTERVENTION(S): Micro-TESE, cTESE, or TESA.

MAIN OUTCOME MEASURE(S): Sperm retrieval (SR).

RESULT(S): Fifteen studies with a total of 1,890 patients were identified. The weighted average age of the patients was 34.4~years, the follicular stimulating hormone level was 20.5 mIU/mL, the T was 373~ng/dL, and the testicular volume was 13.5~mL. In a direct comparison, performance of micro-TESE was 1.5 times more likely (95\% confidence interval 1.4-1.6) to result in successful SR as compared with cTESE. Similarly, in a direct comparison, performance of cTESE was 2.0 times more likely (95\% confidence interval 1.8-2.2) to result in successful SR as compared with TESA. Because of inconsistent reporting, evaluation of other procedural characteristics and pregnancy outcomes was not possible.

CONCLUSION(S): Sperm retrieval was higher for micro-TESE compared with cTESE and for cTESE compared with TESA. Standardization of reported outcomes as well as combining all available SR data would help to further elucidate the SRs of these procedures.},
	issn = {1556-5653},
	doi = {10.1016/j.fertnstert.2015.07.1136},
	author = {Bernie, Aaron M and Mata, Douglas A and Ranjith Ramasamy and Schlegel, Peter N}
}
@article {312636,
	title = {Infertility, Sexual Dysfunction, and Depression: Recommendations for Future Studies.},
	journal = {Urology},
	year = {2015},
	month = {2015 Aug 14},
	issn = {1527-9995},
	doi = {10.1016/j.urology.2015.07.035},
	author = {Jain, Lakshay and Tilak, Gaurie and Mata, Douglas A}
}
@article {282791,
	title = {Precision Medicine and Men{\textquoteright}s Health.},
	journal = {Am J Mens Health},
	year = {2015},
	month = {2015 Jul 17},
	abstract = {Precision medicine can greatly benefit men{\textquoteright}s health by helping to prevent, diagnose, and treat prostate cancer, benign prostatic hyperplasia, infertility, hypogonadism, and erectile dysfunction. For example, precision medicine can facilitate the selection of men at high risk for prostate cancer for targeted prostate-specific antigen screening and chemoprevention administration, as well as assist in identifying men who are resistant to medical therapy for prostatic hyperplasia, who may instead require surgery. Precision medicine-trained clinicians can also let couples know whether their specific cause of infertility should be bypassed by sperm extraction and in vitro fertilization to prevent abnormalities in their offspring. Though precision medicine{\textquoteright}s role in the management of hypogonadism has yet to be defined, it could be used to identify biomarkers associated with individual patients{\textquoteright} responses to treatment so that appropriate therapy can be prescribed. Last, precision medicine can improve erectile dysfunction treatment by identifying genetic polymorphisms that regulate response to medical therapies and by aiding in the selection of patients for further cardiovascular disease screening.},
	issn = {1557-9891},
	doi = {10.1177/1557988315595693},
	author = {Mata, Douglas A and Katchi, Farhan M and Ranjith Ramasamy}
}
@article {270476,
	title = {Addressing Depression and Suicide Among Physician Trainees.},
	journal = {JAMA Psychiatry},
	year = {2015},
	month = {2015 Jun 24},
	issn = {2168-6238},
	doi = {10.1001/jamapsychiatry.2015.0643},
	author = {Khan, Rida and Lin, Jamie S and Mata, Douglas A}
}
@article {267946,
	title = {Can we predict future depression in residents before the start of clinical training?},
	journal = {Med Educ},
	volume = {49},
	number = {7},
	year = {2015},
	month = {2015 Jul},
	pages = {741-2},
	issn = {1365-2923},
	doi = {10.1111/medu.12742},
	author = {Mata, Douglas A and Lin, Jamie S and Ramos, Marco A}
}
@article {263056,
	title = {Self-Treatment and Informal Treatment for Depression Among Resident Physicians.},
	journal = {Fam Med},
	volume = {47},
	number = {6},
	year = {2015},
	month = {2015 Jun},
	pages = {487-488},
	issn = {1938-3800},
	author = {Mata, Douglas A and Ramos, Marco A}
}
@article {255091,
	title = {Microscopic visualization of intravasal spermatozoa is positively associated with patency after bilateral microsurgical vasovasostomy.},
	journal = {Andrology},
	year = {2015},
	month = {2015 Apr 24},
	abstract = {We evaluated pre-operative and intraoperative factors associated with successful patency following bilateral microsurgical vasovasostomy (VV). We retrospectively reviewed the charts of 1331 men who underwent bilateral VV by two surgeons between 2006 and 2013. Vasal fluid was examined intraoperatively for gross quality (i.e., clear or opaque and creamy/thick) and for the presence of spermatozoa on microscopy (i.e., whole spermatozoa, sperm fragments, or azoospermia). Post-operative patency was assessed by semen analysis or patient report of conception. Perioperative factors were explored using descriptive statistics and examined in logistic regression models for associations with post-operative patency. The median age at VV was 39~years [interquartile range (IQR): 35-44] and the median obstructive interval (OI) was 7~years (IQR: 4-11). Overall, 1307 patients achieved post-operative patency (98\%) while 24 remained obstructed (2\%). Among those who became patent, 410 reported conception. After adjustment for potential confounders, only microscopic examination of the intravasal fluid for the presence of spermatozoa (bilateral or unilateral whole spermatozoa vs. sperm parts/azoospermia) at the time of VV was significantly associated with post-operative patency with an odds ratio (OR) of 14.2 (95\% CI: 5.8-34.9; p~=~,
	issn = {2047-2927},
	doi = {10.1111/andr.12033},
	author = {Ramasamy, R. and Mata, D. A. and Jain, L. and Perkins, A. R. and Marks, S. H. and Lipshultz, L. I.}
}
@article {250321,
	title = {Variability in surgical quality in a phase III clinical trial of radical cystectomy in patients with organ-confined, node-negative urothelial carcinoma of the bladder.},
	journal = {J Surg Oncol},
	year = {2015},
	month = {2015 Apr 14},
	abstract = {BACKGROUND AND OBJECTIVES: Previous studies have shown that variability in surgical technique can affect the outcomes of cooperative group trials. We analyzed measures of surgical quality and clinical outcomes in patients enrolled in the p53-MVAC trial.

METHODS: We performed a post-hoc analysis of patients with pT1-T2N0M0 urothelial carcinoma of the bladder following radical cystectomy (RC) and bilateral pelvic and iliac lymphadenectomy (LND). Measures of surgical quality were examined for associations with time to recurrence (TTR) and overall survival (OS).

RESULTS: We reviewed operative and/or pathology reports for 440 patients from 35 sites. We found that only 31\% of patients met all suggested trial eligibility criteria of having >=15 lymph nodes identified in the pathologic specimen (LN$\#$) and having undergone both extended and presacral LND. There was no association between extent of LND, LN$\#$, or presacral LND and TTR or OS after adjustment for confounders and multiple testing.

CONCLUSIONS: We demonstrated that there was substantial variability in surgical technique within a cooperative group trial. Despite explicit entry criteria, many patients did not undergo per-protocol LNDs. While outcomes were not apparently affected, it is nonetheless evident that careful attention to study design and quality monitoring will be critical to successful future trials. J. Surg. Oncol. {\textcopyright} 2015 Wiley Periodicals, Inc.},
	issn = {1096-9098},
	doi = {10.1002/jso.23903},
	author = {Mata, Douglas A and Groshen, Susan and von Rundstedt, Friedrich-Carl and Skinner, Donald G and Stadler, Walter M and Cote, Richard J and Stein, John P and Lerner, Seth P}
}
@article {235706,
	title = {Association Between the Presence of Sperm in the Vasal Fluid During Vasectomy Reversal and Postoperative Patency: A Systematic Review and Meta-analysis.},
	journal = {Urology},
	year = {2015},
	month = {2015 Feb 16},
	abstract = {OBJECTIVE: To investigate the association between the presence of sperm in the vasal fluid during vasectomy reversal (VR) and postoperative patency.

METHODS: We performed a systematic review and meta-analysis of the English-language literature reporting on the association between the presence of sperm in the intraoperative vasal fluid (ie, whole or parts vs none) and patency (ie, patent or not) after microsurgical vasovasostomy for men with obstructive azoospermia due to vasectomy. Odds ratios (OR) and 95\% confidence intervals were calculated to quantify the strength of the association reported by each study. Meta-analysis was performed using a random-effects model.

RESULTS: Four case series and 2 retrospective cohort studies of a total of 1293 eligible patients were identified. The mean age at VR was 37.8~years, and the mean obstructive interval was 7.1~years. The unadjusted OR of postoperative patency was 4.1 times higher (95\% confidence interval, 2.3-7.3) given the presence of intravasal sperm or sperm parts as opposed to their absence at the time of VR (Q~= 3.4; df~= 5; P~= .6; I(2)~= 22\%). The pooled OR should be interpreted with caution as only the 2 retrospective cohort studies reported meaningful data on this association. Because of inconsistent reporting, analysis of other vasal fluid characteristics (eg, consistency) and outcomes (eg, pregnancy) was not possible.

CONCLUSION: The presence of whole sperm or sperm parts in the vasal fluid during VR is positively associated with postoperative patency. Our review highlights the poor methodological quality of existing evidence and underscores the need for more thorough follow up and higher standards of reporting in future studies.},
	issn = {1527-9995},
	doi = {10.1016/j.urology.2014.09.005},
	author = {Jason M. Scovell and Mata, Douglas A and Ranjith Ramasamy and Lindsey A. Herrel and Wayland Hsiao and Lipshultz, Larry I}
}
@article {228316,
	title = {Reply.},
	journal = {Urology},
	volume = {84},
	number = {6},
	year = {2014},
	month = {2014 Dec},
	pages = {1341},
	issn = {1527-9995},
	doi = {10.1016/j.urology.2014.06.083},
	author = {Coward, Robert M and Mata, Douglas A and Smith, Ryan P and Kovac, Jason R and Lipshultz, Larry I}
}
@article {228311,
	title = {Significance of lymphovascular invasion in organ-confined, node-negative urothelial cancer of the bladder: data from the prospective p53-MVAC trial.},
	journal = {BJU Int},
	year = {2014},
	month = {2014 Nov 21},
	abstract = {OBJECTIVES: {\textbullet} To investigate the association between lymphovascular invasion (LVI) and clinical outcome in organ-confined, node-negative urothelial cancer of the bladder (UCB) in a post-hoc analysis of a prospective clinical trial. {\textbullet} To explore the effect of adjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) on outcome in the subset of patients whose tumors exhibited LVI.

PATIENTS AND METHODS: {\textbullet} Surgical and tumor factors were extracted from the operative and pathology reports of 499 patients who had undergone radical cystectomy (RC) for pT1-T2 N0 UCB in the p53-MVAC trial (SWOG 4B951/NCT00005047). {\textbullet} The presence or absence of LVI was determined by pathologic examination of transurethral resection or RC specimens. {\textbullet} Variables were examined in univariate and multivariate Cox proportional hazards models for associations with time to recurrence (TTR) and overall survival (OS).

RESULTS: {\textbullet} Among 499 patients with a median follow-up of 4.9 years, a subset of 102 (20\%) had LVI-positive tumors. Of these, 34 patients had pT1 and 68 had pT2 disease. {\textbullet} LVI was significantly associated with TTR with a hazard ratio (HR) of 1.78 (95\% confidence interval [CI]: 1.15 to 2.77; number of events [EV] = 95; p = 0.01) and with OS with a HR of 2.02 (95\% CI: 1.31 to 3.11; EV = 98; p = 0.001) after adjustment for pathologic stage. {\textbullet} Among 27 patients with LVI-positive tumors who were randomized to receive adjuvant chemotherapy, receiving MVAC was not significantly associated with TTR (HR 0.70; 95\% CI: 0.16 to 3.17; EV = 7; p = 0.65) or with OS (HR: 0.45; 95\% CI: 0.11 to 1.83; EV = 9; p = 0.26).

CONCLUSIONS: {\textbullet} Our post-hoc analysis of the p53-MVAC trial revealed an association between LVI and shorter TTR and OS in patients with pT1-T2N0 disease. {\textbullet} The analysis did not demonstrate a statistically significant benefit of adjuvant MVAC chemotherapy in patients with LVI, although a possible benefit was not ruled out.},
	issn = {1464-410X},
	doi = {10.1111/bju.12997},
	author = {von Rundstedt, Friedrich-Carl and Mata, Douglas A and Groshen, Susan and Stein, John P and Skinner, Donald G and Stadler, Walter M and Cote, Richard J and Kryvenko, Oleksandr N and Godoy, Guilherme and Lerner, Seth P}
}
@article {228321,
	title = {Vasectomy reversal outcomes in men previously on testosterone supplementation therapy.},
	journal = {Urology},
	volume = {84},
	number = {6},
	year = {2014},
	month = {2014 Dec},
	pages = {1335-40},
	abstract = {OBJECTIVE: To report considerations for preoperative management and outcomes of vasectomy reversal (VR) in men with a history of testosterone supplementation therapy (TST).

METHODS: A retrospective review of men on TST before VR from 2010 to 2013 was performed. For inclusion, patients were required to have baseline and follow-up hormone levels as well as postoperative semen analyses. Preoperative use of medical testicular salvage therapy and testicular sperm aspiration (TESA), intraoperative findings, and pregnancies were also analyzed.

RESULTS: Six of 265 men who underwent VR had prior TST and met inclusion criteria. Median age was 39 years with a median obstructive interval of 7.5 years. Median duration of TST was 9 months before discontinuation and transition to testicular salvage therapy with clomiphene citrate with or without human chorionic gonadotropin for a median of 2.8 months. At baseline, decreased luteinizing hormone (median, 2 mIU/mL), follicle stimulating hormone (median, 5 mIU/mL), and total testosterone (median, 249 ng/dL) were observed. Two men (33\%) with uncertain recovery of spermatogenesis based on physical examination and hormone response underwent preoperative testicular sperm aspiration confirming the presence of sperm. Nine vasovasostomies and 3 epididymovasostomies were performed. Patency was 83\% after a median follow-up of 6.4 months and was 100\% in men undergoing at least 1 vasovasostomy. Spontaneous pregnancy was achieved by 50\% during the follow-up period.

CONCLUSION: Testicular salvage medical therapy may play a role in the preoperative management of VR in men with prior TST. VR after TST can have outcomes comparable to those in the general population.},
	issn = {1527-9995},
	doi = {10.1016/j.urology.2014.06.081},
	author = {Coward, Robert M and Mata, Douglas A and Smith, Ryan P and Kovac, Jason R and Lipshultz, Larry I}
}
@article {228331,
	title = {Biochemical and structural evidence in support of a coherent model for the formation of the double-helical influenza A virus ribonucleoprotein.},
	journal = {MBio},
	volume = {4},
	number = {1},
	year = {2012},
	month = {2012},
	pages = {e00467-12},
	abstract = {Influenza A virions contain eight ribonucleoproteins (RNPs), each comprised of a negative-strand viral RNA, the viral polymerase, and multiple nucleoproteins (NPs) that coat the viral RNA. NP oligomerization along the viral RNA is mediated largely by a 28-amino-acid tail loop. Influenza viral RNPs, which serve as the templates for viral RNA synthesis in the nuclei of infected cells, are not linear but rather are organized in hairpin-like double-helical structures. Here we present results that strongly support a coherent model for the assembly of the double-helical influenza virus RNP structure. First, we show that NP self-associates much more weakly in the absence of RNA than in its presence, indicating that oligomerization is very limited in the cytoplasm. We also show that once NP has oligomerized, it can dissociate in the absence of bound RNA, but only at a very slow rate, indicating that the NP scaffold remains intact when viral RNA dissociates from NPs to interact with the polymerase during viral RNA synthesis. In addition, we identify a previously unknown NP-NP interface that is likely responsible for organizing the double-helical viral RNP structure. This identification stemmed from our observation that NP lacking the oligomerization tail loop forms monomers and dimers. We determined the crystal structure of this NP dimer, which reveals this new NP-NP interface. Mutation of residues that disrupt this dimer interface does not affect oligomerization of NPs containing the tail loop but does inactivate the ability of NPs containing the tail loop to support viral RNA synthesis in minigenome assays. IMPORTANCE: Influenza A virus, the causative agent of human pandemics and annual epidemics, contains eight RNA gene segments. Each RNA segment assumes the form of a rod-shaped, double-helical ribonucleoprotein (RNP) that contains multiple copies of a viral protein, the nucleoprotein (NP), which coats the RNA segment along its entire length. Previous studies showed that NP molecules can polymerize via a structural element called the tail loop, but the RNP assembly process is poorly understood. Here we show that influenza virus RNPs are likely assembled from NP monomers, which polymerize through the tail loop only in the presence of viral RNA. Using X-ray crystallography, we identified an additional way that NP molecules interact with each other. We hypothesize that this new interaction is responsible for organizing linear, single-stranded influenza virus RNPs into double-helical structures. Our results thus provide a coherent model for the assembly of the double-helical influenza virus RNP structure.},
	keywords = {Crystallography, X-Ray, Influenza A virus, Models, Molecular, Protein Binding, Protein Multimerization, Protein Structure, Quaternary, Ribonucleoproteins, RNA, Viral},
	issn = {2150-7511},
	doi = {10.1128/mBio.00467-12},
	author = {Ye, Qiaozhen and Guu, Tom S Y and Mata, Douglas A and Kuo, Rei-Lin and Smith, Bartram and Krug, Robert M and Tao, Yizhi J}
}
@webarticle {228336,
	title = {Seminar on the European Union and NATO: A Fulbright Grantee{\textquoteright}s Perspective},
	journal = {Spanish Fulbright Commission Official Website},
	year = {2012},
	abstract = {Between February 29th and March 7th, 2012, a group of 37 American Fulbright Scholars based in Europe participated in a week-long conference on the European Union and NATO held in Luxembourg and Belgium. The primary purpose of the seminar was to educate American Fulbright grantees on the structure and functions of European institutions. By exposing grantees to these institutions firsthand, the seminar served to encourage grantees to think about how their future careers might relate to international diplomacy, law, and policy.},
	url = {http://elblogdefulbright.es/index.php/2012/03/seminar-on-the-european-union-and-nato-a-fulbright-grantees-perspective/},
	author = {Mata, Douglas A}
}
@article {228326,
	title = {Structure of the hepatitis E virus-like particle suggests mechanisms for virus assembly and receptor binding.},
	journal = {Proc Natl Acad Sci U S A},
	volume = {106},
	number = {31},
	year = {2009},
	month = {2009 Aug 4},
	pages = {12992-7},
	abstract = {Hepatitis E virus (HEV), a small, non-enveloped RNA virus in the family Hepeviridae, is associated with endemic and epidemic acute viral hepatitis in developing countries. Our 3.5-A structure of a HEV-like particle (VLP) shows that each capsid protein contains 3 linear domains that form distinct structural elements: S, the continuous capsid; P1, 3-fold protrusions; and P2, 2-fold spikes. The S domain adopts a jelly-roll fold commonly observed in small RNA viruses. The P1 and P2 domains both adopt beta-barrel folds. Each domain possesses a potential polysaccharide-binding site that may function in cell-receptor binding. Sugar binding to P1 at the capsid protein interface may lead to capsid disassembly and cell entry. Structural modeling indicates that native T = 3 capsid contains flat dimers, with less curvature than those of T = 1 VLP. Our findings significantly advance the understanding of HEV molecular biology and have application to the development of vaccines and antiviral medications.},
	keywords = {Amino Acid Sequence, Binding Sites, Capsid Proteins, Dimerization, Hepatitis E virus, Models, Molecular, Molecular Sequence Data, Polysaccharides, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Virus, Virion, Virus Assembly},
	issn = {1091-6490},
	doi = {10.1073/pnas.0904848106},
	author = {Guu, Tom S Y and Liu, Zheng and Ye, Qiaozhen and Mata, Douglas A and Li, Kunpeng and Yin, Changcheng and Zhang, Jingqiang and Tao, Yizhi Jane}
}
