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Deepika Sirohi,1 Steven C Smith,2,3 Neeraj Agarwal,4 Benjamin L Maughan4 1Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, UT, USA; 2Department of Pathology, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; 3Department of Urology, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA; 4Division of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA Abstract: Over the past few decades, the classification system of renal cell carcinoma (RCC) variants has witnessed tremendous and ongoing refinement driven by genomic profiling and morphological correlation that have provided valuable insights into tumor biology and characterization of this heterogeneous subset of tumors. The importance of accurate classification cannot be understated given the downstream impact on treatment decisions, risk stratification, and need for genetic testing. While the morphologic heterogeneity across these tumors is increasingly being recognized, all non-clear-cell RCCs are commonly categorized under one therapeutic category with management strategies that largely derive from clear-cell RCCs. As research in metastatic RCC progresses, there is a growing focus on rare subtypes and unclassified tumors, which is rapidly changing the treatment paradigm for non-clear-cell RCC. This review focuses on the histomorphologic diagnostic challenges of unclassified RCCs discussing the utility of contemporary diagnostic tools. It further discusses the current state of knowledge and guidelines for management of this class of tumors. Keywords: pathology, classification, morphology, management

Staphylococcus aureus is a rare cause of pneumonia, though in recent times methicillin-resistant strains are emerging increasingly as causative pathogens. Methicillin resistant Staphylococcus aureus (MRSA) has been reported to cause rapidly fatal hemorrhagic pneumonia. Most of these strains have been found to produce a lethal exotoxin called Panton-Valentine leukocidin. The finding of an underlying asymptomatic multisystem sarcoidosis was unusual in the case being reported here.

Gangliocytic paragangliomas are rare benign neoplastic lesions of neuroendocrine origin occurring primarily in peri-ampullary region. Commonly occurring as small submucosal lesions, presentation as a large polyp with acute ileo-ileal intussusception in a 62-year-old woman is rare and is described in this case report.

Aims: Urothelial carcinoma (UC) demonstrates significant molecular and histologic heterogeneity. The WHO 2022 classification has hinted at adding molecular signatures to the morphologic diagnosis. As morphology and associated molecular repertoire may potentially translate to choices of and response to therapy and relapse rate, broader acceptability of recognizing these key features among uropathologists is needed. This prompted an international survey to ascertain the practice patterns in classical/subtype UC among uropathologists across the globe., Methods and Results: A survey instrument was shared among 98 uropathologists using SurveyMonkey software. Anonymized respondent data were analysed. The response rate was 85%. A majority were in concordance with the profiles of luminal (93%) and basal (82%) types. Opinion on the FGFR3 testing platform was variable. While 95% concurred that TERT promoter mutation is the key driver in UC, 72% had the opinion that APOBEC mutagenesis is the main signature in muscle invasive bladder cancer (MIBC). Uropathologists have divergent opinions on MIBC and ERCC2 mutations. Among the participants, 94% would quantify aggressive micropapillary and sarcomatoid histology, while 88% would reevaluate another transurethral resection of the bladder tumour specimen in nonmuscle invasive tumour with micropapillary, small cell, or sarcomatoid histology. A leading number agreed to specific molecular signatures of micropapillary (93%), plasmacytoid (97%), and small cell (86%) subtypes. Ninety-six percent of participants agreed that a small-cell component portends a more aggressive course and should be treated with neoadjuvant chemotherapy and 63% would perform HER2/neu testing only on oncologist's request in advanced tumours. Ninety percent agreed that microsatellite instability testing, although not a standard protocol, should be considered in young patients with upper tract UC. Eighty-six percent agreed that UC with high tumour mutational burden would be a better candidate for immunotherapy., Conclusion: In the era of precision medicine, enhanced understanding of molecular heterogeneity of UC will contribute to better therapeutic options, novel biomarker discovery, innovative management protocols, and outcomes. Our survey provides a broad perspective of pathologists' perceptions and experience regarding incorporation of histomolecular approaches to "personalize" therapy. Due to variable clinical adoption, there is a need for additional data using uniform study criteria. This will drive generation of best practice guidelines in this area for widespread and consistent clinical utility., (© 2024 John Wiley & Sons Ltd.)

Oncocytic renal neoplasms are a major source of diagnostic challenge in genitourinary pathology; however, they are typically nonaggressive in general, raising the question of whether distinguishing different subtypes, including emerging entities, is necessary. Emerging entities recently described include eosinophilic solid and cystic renal cell carcinoma (ESC RCC), low-grade oncocytic tumor (LOT), eosinophilic vacuolated tumor (EVT), and papillary renal neoplasm with reverse polarity (PRNRP). A survey was shared among 65 urologic pathologists using SurveyMonkey.com (Survey Monkey, Santa Clara, CA, USA). De-identified and anonymized respondent data were analyzed. Sixty-three participants completed the survey and contributed to the study. Participants were from Asia (n = 21; 35%), North America (n = 31; 52%), Europe (n = 6; 10%), and Australia (n = 2; 3%). Half encounter oncocytic renal neoplasms that are difficult to classify monthly or more frequently. Most (70%) indicated that there is enough evidence to consider ESC RCC as a distinct entity now, whereas there was less certainty for LOT (27%), EVT (29%), and PRNRP (37%). However, when combining the responses for sufficient evidence currently and likely in the future, LOT and EVT yielded > 70% and > 60% for PRNRP. Most (60%) would not render an outright diagnosis of oncocytoma on needle core biopsy. There was a dichotomy in the routine use of immunohistochemistry (IHC) in the evaluation of oncocytoma (yes = 52%; no = 48%). The most utilized IHC markers included keratin 7 and 20, KIT, AMACR, PAX8, CA9, melan A, succinate dehydrogenase (SDH)B, and fumarate hydratase (FH). Genetic techniques used included TSC1/TSC2/MTOR (67%) or TFE3 (74%) genes and pathways; however, the majority reported using these very rarely. Only 40% have encountered low-grade oncocytic renal neoplasms that are deficient for FH. Increasing experience with the spectrum of oncocytic renal neoplasms will likely yield further insights into the most appropriate work-up, classification, and clinical management for these entities., (© 2024. The Author(s).)

Context.—: The American Society of Clinical Oncology/College of American Pathologists 2018 update of the human epidermal growth factor receptor 2 (HER2) testing guideline includes a fluorescence in situ hybridization (FISH) group with a HER2 to chromosome 17 centromere (CEP17) ratio less than 2.0 and HER2 copy number 6.0 or greater (group 3), which requires integrated review of HER2 immunohistochemistry (IHC)., Objective.—: To assess the clinicopathologic features of group 3 patients and determine features associated with HER2-positive status after workup., Design.—: Cases submitted for HER2 FISH between January 2019 and June 2022 were identified, and relevant clinicopathologic information was obtained., Results.—: One hundred forty-two HER2 FISH cases (1.6%) were group 3. In 52 cases (36.6%) IHC was negative (0/1+), in 3 (2.8%) IHC was positive (3+), and in 86 (60.6%) IHC was 2+. Annotated IHC 2+ slides were recounted by a second reviewer in targeted areas, where 16 of 86 (18.6%) had a HER2:CEP17 ratio less than 2.0 and a HER2 copy number of 4.0 or greater to less than 6.0 (HER2 negative). After combined IHC/FISH review, 74 of 142 (52.1%) were classified as HER2 positive. HER2 copy number/cell was higher in HER2-positive compared with HER2-negative cases after the workup. The extent and intensity of staining in IHC 2+ cases did not correlate with the level of gene amplification. Twenty percent of HER2-positive patients achieved pathologic complete response., Conclusions.—: About half of group 3 cases were classified as HER2 positive after additional workup. Pathologic complete response rates in HER2-positive cases were lower than expected for group 1 (HER2:CEP17 ratio ≥2.0; HER2 copy number ≥4.0) patients. IHC-targeted FISH recounts may be redundant and may potentially lead to classification of some patients as HER2 negative, resulting in withholding of targeted therapy., (© 2024 College of American Pathologists.)

Morphological features are critical in evaluation of renal tumors and directing molecular workup. The objective of this study was to review histomorphology of renal tumors with molecular alterations of known subtypes. Renal tumors in The Cancer Genome Atlas were reviewed to identify tumors with defining molecular alterations. Single representative digital slides and pathology reports were reviewed and morphologic features recorded. Sixty tumors were identified with molecular alterations in genes characteristic of defined renal cell carcinoma (RCC) subtypes. Findings included the presence of both low- and high-grade histology in TFE3 rearranged RCCs, TFEB amplified RCCs, succinate dehydrogenase ( SDH ) mutated RCCs and RCCs with mutations in mismatch repair genes. Three ELOC mutated RCCs were identified, one of which demonstrated infiltrative features. Pseudostratification of nuclei in fumarate hydratase mutated RCCs and nuclear grooves in SDH mutated RCCs were intriguing findings not previously reported. Mucinous features were noted in NF2, KRAS, and SDH mutated and ALK rearranged tumors. Significant morphologic overlap was noted across most categories with limited clues for subclassification. Whereas the number of diagnostic entities for kidney tumors continues to increase, many of these have overlapping features, highlighting the significant role molecular characterization currently plays and will continue to play in the future., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Objectives: Artificial intelligence (AI)-based chatbots have demonstrated accuracy in a variety of fields, including medicine, but research has yet to substantiate their accuracy and clinical relevance. We evaluated an AI chatbot's answers to questions posed during a treatment planning conference., Methods: Pathology residents, pathology faculty, and an AI chatbot (OpenAI ChatGPT [January 30, 2023, release]) answered a questionnaire curated from a genitourinary subspecialty treatment planning conference. Results were evaluated by 2 blinded adjudicators: a clinician expert and a pathology expert. Scores were based on accuracy and clinical relevance., Results: Overall, faculty scored highest (4.75), followed by the AI chatbot (4.10), research-prepared residents (3.50), and unprepared residents (2.87). The AI chatbot scored statistically significantly better than unprepared residents (P = .03) but not statistically significantly different from research-prepared residents (P = .33) or faculty (P = .30). Residents did not statistically significantly improve after research (P = .39), and faculty performed statistically significantly better than both resident categories (unprepared, P < .01; research prepared, P = .01)., Conclusions: The AI chatbot gave answers to medical questions that were comparable in accuracy and clinical relevance to pathology faculty, suggesting promise for further development. Serious concerns remain, however, that without the ability to provide support with references, AI will face legitimate scrutiny as to how it can be integrated into medical decision-making., (© American Society for Clinical Pathology, 2024.)

Background: In the digital age, search engines and social media platforms are primary sources for health information, yet their commercial interests-focused algorithms often prioritize irrelevant content. Web-based health applications by reputable sources offer a solution to circumvent these biased algorithms. Despite this advantage, there remains a significant gap in research on the effective integration of content-ranking algorithms within these specialized health applications to ensure the delivery of personalized and relevant health information., Objective: This study introduces a generic methodology designed to facilitate the development and implementation of health information recommendation features within web-based health applications., Methods: We detail our proposed methodology, covering conceptual foundation and practical considerations through the stages of design, development, operation, review, and optimization in the software development life cycle. Using a case study, we demonstrate the practical application of the proposed methodology through the implementation of recommendation functionalities in the EndoZone platform, a platform dedicated to providing targeted health information on endometriosis., Results: Application of the proposed methodology in the EndoZone platform led to the creation of a tailored health information recommendation system known as EndoZone Informatics. Feedback from EndoZone stakeholders as well as insights from the implementation process validate the methodology's utility in enabling advanced recommendation features in health information applications. Preliminary assessments indicate that the system successfully delivers personalized content, adeptly incorporates user feedback, and exhibits considerable flexibility in adjusting its recommendation logic. While certain project-specific design flaws were not caught in the initial stages, these issues were subsequently identified and rectified in the review and optimization stages., Conclusions: We propose a generic methodology to guide the design and implementation of health information recommendation functionality within web-based health information applications. By harnessing user characteristics and feedback for content ranking, this methodology enables the creation of personalized recommendations that align with individual user needs within trusted health applications. The successful application of our methodology in the development of EndoZone Informatics marks a significant progress toward personalized health information delivery at scale, tailored to the specific needs of users., (©Wenhao Li, Rebecca O'Hara, M Louise Hull, Helen Slater, Diksha Sirohi, Melissa A Parker, Niranjan Bidargaddi. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 29.05.2024.)

TFEB -amplified renal cell carcinoma (RCC), which belongs to the MITF family of RCC, is characterized by genomic amplification at the 6p21.1 locus where the TFEB gene is located. The vascular endothelial growth factor A and cyclin D3 genes are also located at this same locus. When tumors lack classic morphologic features, they may be classified as "RCC not otherwise specified (NOS)." However, it is increasingly important to accurately diagnose the RCC subtype to define the patient's individual prognosis and select the subsequent therapeutic modalities, which now include targeted agents. Therefore, knowledge of the diagnostic features of TFEB -altered RCCs, such as t(6;11) RCCs and TFEB -amplified RCCs, is critical for identifying these tumors. Herein, we present an interesting case of TFEB -amplified RCC that was initially diagnosed as RCC NOS on biopsy of a renal tumor in a community practice setting with available molecular findings demonstrating CCND3 amplification. The genetic abnormality was "accidentally" detected due to the amplification of the colocated CCND3 gene at the 6p21 locus of the TFEB gene on a limited genetic sequencing panel. This case highlights the importance of molecular tests in accurately diagnosing RCC and carefully interpreting molecular findings in the context of histomorphologic features., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

EGFR amplification in gliomas is commonly defined by an EGFR/CEP7 ratio of ≥2. In testing performed at a major reference laboratory, a small subset of patients had ≥5 copies of both EGFR and CEP7 yet were not amplified by the EGFR/CEP7 ratio and were designated high polysomy cases. To determine whether these tumors are more closely related to traditionally defined EGFR-amplified or nonamplified gliomas, a retrospective search identified 22 out of 1143 (1.9%) gliomas with an average of ≥5 copies/cell of EGFR and CEP7 with an EGFR/CEP7 ratio of <2 displaying high polysomy. Of these cases, 4 had insufficient clinicopathologic data to include in additional analysis, 15 were glioblastomas, 2 were IDH-mutant astrocytomas, and 1 was a high-grade glial neoplasm, NOS. Next-generation sequencing available on 3 cases demonstrated one with a TERT promoter mutation, TP53 mutations in all cases, and no EGFR mutations or amplifications, which most closely matched the nonamplified cases. The median overall survival times were 42.86, 66.07, and 41.14 weeks for amplified, highly polysomic, and nonamplified, respectively, and were not significantly different (p =  0.3410). High chromosome 7 polysomic gliomas are rare but our data suggest that they may be biologically similar to nonamplified gliomas., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)

Somatic or germline homologous recombination repair (HRR) pathway gene mutations are commonly detected in prostate cancer, especially in advanced disease, and are associated with response to poly (ADP-ribose) polymerase (PARP) inhibitors. In this study, we evaluated whether histological patterns are predictive of HRR pathway gene mutations. The study population comprised 130 patients with advanced prostate carcinoma who underwent comprehensive genomic profiling (CGP) of tumor tissue at a CLIA-certified laboratory. HRR genes in the study included BRCA1, BRCA2, ATM, BARD1, BRIP, CHEK2, MRE11A, NBN, PALB2, RAD51C, RAD51D, EMSY, ATR, CHEK1, and FAM175A. Overall, 38 patients had mutations in BRCA1/2, 36 in other HRR genes, and 56 were negative for HRR mutations. All cases were re-reviewed and quantified by two genitourinary pathologists blinded to mutational status for the following histological patterns of prostate carcinoma: cribriform, ductal, intraductal carcinoma (IDC), small cell carcinoma, signet ring-like pattern, and lobular carcinoma-like pattern. Discordances were resolved by consensus review. Histologic patterns were analyzed for any correlation with mutations in HRR pathway genes (grouped as BRCA1/2 mutated or non-BRCA1/2 mutated) compared to tumors without mutations in HRR genes by Chi-square testing. Patterns with >20 % and >30 % of tumor volume were additionally evaluated for correlation with mutational status. We found no significant association between HRR pathway mutations and cribriform pattern, IDC, ductal carcinoma, small cell carcinoma, signet ring-like pattern, or lobular carcinoma-like patterns. Tumors with >20 % or >30 % histologic patterns by volume also demonstrated no significant association with mutational status. This study suggests that histopathologic examination alone is insufficient to distinguish prostate cancer with germline or somatic mutations in HRR pathway genes, highlighting the continuing importance of ancillary molecular diagnostics in guiding therapy selection for prostate cancer patients who may benefit from PARP inhibitors., Competing Interests: Declaration of competing interest N. A. (lifetime disclosures): Consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. Research funding to Neeraj Agarwal's institution: Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol-Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon.U.S. reports consultancy to Astellas, Exelixis, Seattle Genetics, Imvax, Sanofi, AstraZeneca, and Gilead. Reports research funding to institute from Janssen, Exelixis, and Astellas/Seattle Genetics. Other authors have not conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Refinement of the risk classification for localized prostate cancer is warranted to aid in clinical decision making. A systematic analysis was undertaken to evaluate the prognostic ability of three genomic classifiers, Decipher, GPS, and Prolaris, for biochemical recurrence, development of metastases and prostate cancer-specific mortality in patients with localized prostate cancer., Methods: Data sources: MEDLINE, Embase, and Web of Science were queried for reports published from January 2010 to April 2022., Study Selection: prospective or retrospective studies reporting prognosis for patients with localized prostate cancer., Data Extraction: relevant data were extracted into a customized database by one researcher with a second overreading. Risk of bias was assessed using a validated tool for prognostic studies, Quality in Prognosis Studies (QUIPS). Disagreements were resolved by consensus or by input from a third reviewer. We assessed the certainty of evidence by GRADE incorporating adaptation for prognostic studies., Results: Data synthesis: a total of 39 studies (37 retrospective) involving over 10,000 patients were identified. Twenty-two assessed Decipher, 5 GPS, and 14 Prolaris. Thirty-four studies included patients who underwent prostatectomy. Based on very low to low certainty of evidence, each of the three genomic classifiers modestly improved upon the prognostic ability for biochemical recurrence, development of metastases, and prostate cancer-specific mortality compared to standard clinical risk-classification schemes., Limitations: downgrading of confidence in the evidence stemmed largely from bias due to the retrospective nature of the studies, heterogeneity in treatment received, and era in which patients were treated (i.e., prior to the 2000s)., Conclusions: Genomic classifiers provide a small but consistent improvement upon the prognostic ability of clinical classification schemes, which may be helpful when treatment decisions are uncertain. However, evidence from current management-era data and of the predictive ability of these tests is needed., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: eHealth websites are increasingly being used by community members to obtain information about endometriosis. Additionally, clinicians can use these websites to enhance their understanding of the condition and refer patients to these websites. However, poor-quality information can adversely impact users. Therefore, a critical evaluation is needed to assess and recommend high-quality endometriosis websites., Objective: This study aimed to evaluate the quality and provide recommendations for high-quality endometriosis eHealth websites for the community and clinicians., Methods: PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines informed 2 Google searches of international and Australian eHealth websites. The first search string used the terms "endometriosis," "adenomyosis," or "pelvic pain," whereas "Australia" was added to the second search string. Only free eHealth websites in English were included. ENLIGHT, a validated tool, was used to assess the quality across 7 domains such as usability, visual design, user engagement, content, therapeutic persuasiveness, therapeutic alliance, and general subjective evaluation. Websites with a total score of 3.5 or more were classified as "good" according to the ENLIGHT scoring system and are recommended as high-quality eHealth websites for information on endometriosis., Results: In total, 117 eHealth websites were screened, and 80 were included in the quality assessment. Four high-quality eHealth websites (ie, those that scored 3.5 or more) were identified (Endometriosis Australia Facebook Page, Endometriosis UK, National Action Plan for Endometriosis on EndoActive, and Adenomyosis by the Medical Republic). These websites provided easily understood, engaging, and accurate information. Adenomyosis by the Medical Republic can be used as a resource in clinical practice. Most eHealth websites scored well, 3.5 or more in the domains of usability (n=76, 95%), visual design (n=64, 80%), and content (n=63, 79%). However, of the 63 websites, only 25 provided references and 26 provided authorship details. Few eHealth websites scored well on user engagement (n=18, 23%), therapeutic persuasiveness (n=2, 3%), and therapeutic alliance (n=22, 28%). In total, 30 (38%) eHealth websites scored well on general subjective evaluation., Conclusions: Although geographical location can influence the search results, we identified 4 high-quality endometriosis eHealth websites that can be recommended to the endometriosis community and clinicians. To improve quality, eHealth websites must provide evidence-based information with appropriate referencing and authorship. Factors that enhance usability, visual design, user engagement, therapeutic persuasiveness, and therapeutic alliance can lead to the successful and long-term uptake of eHealth websites. User engagement, therapeutic persuasiveness, and therapeutic alliance can be strengthened by sharing lived experiences and personal stories and by cocreating meaningful content for both the community and clinicians. Reach and discoverability can be improved by leveraging search engine optimization tools., Trial Registration: PROSPERO CRD42020185475; https://www.crd.york.ac.uk/PROSPERO/display&#95;record.php?RecordID=185475&VersionID=2124365., (©Diksha Sirohi, Cecilia Hoi Man Ng, Niranjan Bidargaddi, Helen Slater, Melissa A Parker, Mary Louise Hull, Rebecca O'Hara. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 10.01.2024.)

Context.—: Quantitative imaging is a promising tool that is gaining wide use across several areas of pathology. Although there has been increasing adoption of morphologic and immunohistochemical analysis, the adoption of evaluation of fluorescence in situ hybridization (FISH) on formalin-fixed, paraffin-embedded tissue has been limited because of complexity and lack of practice guidelines., Objective.—: To perform human epidermal growth factor receptor 2 (HER2) FISH validation in breast carcinoma in accordance with the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2018 guideline., Design.—: Clinical validation of HER2 FISH was performed using the US Food and Drug Administration-approved dual-probe HER2 IQFISH (Dako, Carpinteria, California) with digital scanning performed on a PathFusion (Applied Spectral Imaging, Carlsbad, California) system. Validation parameters evaluated included z-stacking, classifier, accuracy, precision, software, and hardware settings. Finally, we evaluated the performance of digital enumeration on clinical samples in a real-world setting., Results.—: The accuracy samples showed a final concordance of 95.3% to 100% across HER2 groups 1 to 5. During clinical implementation for HER2 groups 2, 3, and 4, we achieved a final concordance of 76% (95 of 125). Of these cases, only 8% (10 of 125) had discordances with clinical impact that could be identified algorithmically and triaged for manual review., Conclusions.—: Digital FISH enumeration is a useful tool to improve the efficacy of HER2 FISH enumeration and capture genetic heterogeneity across HER2 signals. Excluding cases with high background or poor image quality and manual review of cases with ASCO/CAP group discordances can further improve the efficiency of digital HER2 FISH enumeration., (© 2023 College of American Pathologists.)

Background: There is a lack of evidence that pregnancy reduces endometriotic lesions or symptoms, however studies indicate that people with endometriosis are commonly advised to get pregnant to manage or treat endometriosis. This study sought to examine the impact of this advice on patients with endometriosis when the advice was provided by healthcare professionals., Methods: The Endometriosis Patient Experience Survey was a self-reported, community-based, cross-sectional online survey of people who had been medically diagnosed with endometriosis. Descriptive statistics were used to analyse the quantitative survey data and thematic analysis was undertaken for the qualitative survey data., Results: 1892 participants had received the advice to get pregnant or have a baby to manage or treat their endometriosis, with 89.4% of participants receiving this advice from healthcare professionals. In exploring the qualitative data, seven themes were contextualised relating to the impact of this advice in terms of health literacy, accepting the advice, rejecting the advice, major life decisions, healthcare interactions, mental health and relationships., Conclusions: This study demonstrates profound and often negative patient impacts of the advice from healthcare professionals to get pregnant to manage or treat endometriosis. Impacts ranged from planning for pregnancy, hastening the making of major life decisions, eroding trust with healthcare professionals, worsening mental health and straining relationships. Providing evidence-based information on the treatment and management of endometriosis is essential. Pregnancy or having a baby should not be suggested as a treatment for endometriosis and the provision of this advice by healthcare professionals can have negative impacts on those who receive it., (© 2023. The Author(s).)

Background. Neuroendocrine differentiation in the prostate gland ranges from clinically insignificant neuroendocrine differentiation detected with markers in an otherwise conventional prostatic adenocarcinoma to a lethal high-grade small/large cell neuroendocrine carcinoma. The concept of neuroendocrine differentiation in prostatic adenocarcinoma has gained considerable importance due to its prognostic and therapeutic ramifications and pathologists play a pivotal role in its recognition. However, its awareness, reporting, and resource utilization practice patterns among pathologists are largely unknown. Methods. Representative examples of different spectrums of neuroendocrine differentiation along with a detailed questionnaire were shared among 39 urologic pathologists using the survey monkey software. Participants were specifically questioned about the use and awareness of the 2016 WHO classification of neuroendocrine tumors of the prostate, understanding of the clinical significance of each entity, and use of different immunohistochemical (IHC) markers. De-identified respondent data were analyzed. Results. A vast majority (90%) of the participants utilize IHC markers to confirm the diagnosis of small cell neuroendocrine carcinoma. A majority (87%) of the respondents were in agreement regarding the utilization of type of IHC markers for small cell neuroendocrine carcinoma for which 85% of the pathologists agreed that determination of the site of origin of a high-grade neuroendocrine carcinoma is not critical, as these are treated similarly. In the setting of mixed carcinomas, 62% of respondents indicated that they provide quantification and grading of the acinar component. There were varied responses regarding the prognostic implication of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and for Paneth cell-like differentiation. The classification of large cell neuroendocrine carcinoma was highly varied, with only 38% agreement in the illustrated case. Finally, despite the recommendation not to perform neuroendocrine markers in the absence of morphologic evidence of neuroendocrine differentiation, 62% would routinely utilize IHC in the work-up of a Gleason score 5 + 5 = 10 acinar adenocarcinoma and its differentiation from high-grade neuroendocrine carcinoma. Conclusion. There is a disparity in the practice utilization patterns among the urologic pathologists with regard to diagnosing high-grade neuroendocrine carcinoma and in understanding the clinical significance of focal neuroendocrine cells in an otherwise conventional acinar adenocarcinoma and Paneth cell-like neuroendocrine differentiation. There seems to have a trend towards overutilization of IHC to determine neuroendocrine differentiation in the absence of neuroendocrine features on morphology. The survey results suggest a need for further refinement and development of standardized guidelines for the classification and reporting of neuroendocrine differentiation in the prostate gland.

Opinion Statement: PRCC is a unique histologic entity compared to other forms of renal cell carcinoma, harboring distinct molecular drivers. The WHO 2022 classification is further emphasizing the molecular biology by making molecular classifications of PRCC subclassifications and discontinuing the morphologic type 1 and type 2 classification system. We agree with this functional classification system and encourage all future clinical trials to only include patients with similar diagnosis instead of conducting basket trials (including all nccRCC together) which limits the scientific value of those conclusions. Based on recent disease-specific clinical trial (S1500, PAPMET), the current standard of care for patients with treatment naïve PRCC is cabozantinib. Prospective clinical trials clearly establish that immune checkpoint inhibitor therapy has meaningful activity in PRCC. The data to date include only single-arm clinical trials of combination immune therapy. Despite the positive and encouraging results, we need validation through randomized studies because of the overestimation of effect size seen in single-arm trials. These randomized trials are currently underway and enrolling. We strongly encourage all physicians to support these studies and enroll patients with PRCC to these trials in order to continue improving the standard of care., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Combination immunotherapy is now considered the standard first-line therapy for patients with metastatic clear cell renal cell carcinoma (mccRCC) after multiple clinical trials demonstrated improved overall survival compared with single-agent tyrosine kinase inhibitors. Cabozantinib modulates critical components of the immune system, such as decreasing regulatory T cells and increasing T-effector cell populations, and is approved for the treatment of mRCC. Avelumab is a human IgG1 monoclonal antibody that binds to programmed death-ligand 1 protein and inhibits the interaction with PD-1. This phase I trial assessed the safety and clinical activity of avelumab and cabozantinib combination therapy in mccRCC., Methods: This study was a phase I, 3+3 dose escalation clinical trial. The primary endpoint was the safety and identification of the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR) and radiographic progression-free survival (rPFS). There were 3 dose cohorts: cabozantinib 20, 40, and 60 mg/day, each combined with avelumab (10 mg/kg intravenously every 2 weeks). An additional 3 patients were included in the final dose cohort as a confirmation of the RP2D. No dose modifications were allowed for avelumab, but dose delays were permitted. Both dose reductions and holds were allowed for cabozantinib. Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was used to determine ORR, and treatment beyond progression was allowed., Results: Twelve patients with newly diagnosed mccRCC were enrolled from July 2018 until March 2020. Three patients were enrolled in the 20 and 40 mg cohorts each, and 6 were enrolled in the 60 mg cohort. The International Metastatic RCC Database Consortium (IMDC) risk categories for these patients were: 4 patients (favorable risk), 6 patients (intermediate risk), and 2 patients (poor risk). No dose-limiting toxicities (DLTs) were observed in any cohort. Six patients developed serious adverse events related to study treatment after the DLT window period. Immune-related adverse events (iRAEs) were reported in 11 patients; fatigue and diarrhea were the most common (each with n = 4, 33.3%), followed by maculopapular rash and hand-foot syndrome (each with n = 3, 25%). Dose reductions were required in 5 of 6 patients in the cabozantinib 60 mg cohort after the DLT period. One patient discontinued avelumab due to irAE (nephritis), while none discontinued cabozantinib due to toxicity. The ORR was 50%, with one complete response (CR) and 5 partial responses (PR). The disease control rate (CR + PR + stable disease) was noted in 92% of the patients. Radiological PFS survival rate at 6 and 12 months was reported in 67.7% and 33.5% of patients, respectively., Conclusion: Combination therapy with avelumab and cabozantinib is safe and showed preliminary clinical activity in mccRCC. Even though the DLT was not met in any of the 3 cohorts, the recommended RP2D dose for the combination is cabozantinib 40 mg/day due to a high incidence of grade 2 toxicity for cabozantinib 60 mg/day after the DLT period. (ClinicalTrials.gov Identifier: NCT03200587)., (© The Author(s) 2023. Published by Oxford University Press.)

Inferring transient molecular structural dynamics from diffraction data is an ambiguous task that often requires different approximation methods. In this paper, we present an attempt to tackle this problem using machine learning. Although most recent applications of machine learning for the analysis of diffraction images apply only a single neural network to an experimental dataset and train it on the task of prediction, our approach utilizes an additional generator network trained on both synthetic and experimental data. Our network converts experimental data into idealized diffraction patterns from which information is extracted via a convolutional neural network trained on synthetic data only. We validate this approach on ultrafast electron diffraction data of bismuth samples undergoing thermalization upon excitation via 800 nm laser pulses. The network was able to predict transient temperatures with a deviation of less than 6% from analytically estimated values. Notably, this performance was achieved on a dataset of 408 images only. We believe that employing this network in experimental settings where high volumes of visual data are collected, such as beam lines, could provide insights into the structural dynamics of different samples., (© 2023 Author(s). Published under an exclusive license by AIP Publishing.)

Triple-negative apocrine carcinomas (TNACs) are rare breast tumors with limited studies evaluating their molecular characteristics and clinical behavior. We performed a histologic, immunohistochemical, genetic, and clinicopathologic assessment of 42 invasive TNACs (1 with a focal spindle cell component) from 41 patients, 2 pure apocrine ductal carcinomas in situ (A-DCIS), and 1 A-DCIS associated with spindle cell metaplastic carcinoma (SCMBC). All TNACs had characteristic apocrine morphology and expressed androgen receptor (42/42), gross cystic disease fluid protein 15 (24/24), and CK5/6 (16/16). GATA3 was positive in most cases (16/18, 89%), and SOX10 was negative (0/22). TRPS1 was weakly expressed in a minority of tumors (3/14, 21%). Most TNACs had low Ki67 proliferation (≤10% in 67%, 26/39), with a median index of 10%. Levels of tumor infiltrating lymphocytes were low (≤10% in 93%, 39/42, and 15% in 7%, 3/42). Eighteen percent of TNACs presented with axillary nodal metastasis (7/38). No patients treated with neoadjuvant chemotherapy achieved pathologic complete response (0%, 0/10). Nearly all patients with TNAC (97%, n = 32) were without evidence of disease at the time of study (mean follow-up of 62 months). Seventeen invasive TNACs and 10 A-DCIS (7 with paired invasive TNAC) were profiled by targeted capture-based next-generation DNA sequencing. Pathogenic mutations in phosphatidylinositol 3-kinase pathway genes PIK3CA (53%) and/or PIK3R1 (53%) were identified in all TNACs (100%), including 4 (24%) with comutated PTEN. Ras-MAPK pathway genes, including NF1 (24%), and TP53 were mutated in 6 tumors each (35%). All A-DCIS shared mutations, such as phosphatidylinositol 3-kinase aberrations and copy number alterations with paired invasive TNACs or SCMBC, and a subset of invasive carcinomas showed additional mutations in tumor suppressors (NF1, TP53, ARID2, and CDKN2A). Divergent genetic profiles between A-DCIS and invasive carcinoma were identified in 1 case. In summary, our findings support TNAC as a morphologically, immunohistochemically, and genetically homogeneous subgroup of triple-negative breast carcinomas and suggest overall favorable clinical behavior., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Selection and development of monoclonal antibody (mAb) therapeutics against pathogenic viruses depends on certain functional characteristics. Neutralization potency, or the half-maximal inhibitory concentration (IC 50 ) values, is an important characteristic of candidate therapeutic antibodies. Structural insights into the bases of neutralization potency differences between antiviral neutralizing mAbs are lacking. In this report, we present cryo-electron microscopy (EM) reconstructions of three anti-Eastern equine encephalitis virus (EEEV) neutralizing human mAbs targeting overlapping epitopes on the E2 protein, with greater than 20-fold differences in their respective IC 50 values. From our structural and biophysical analyses, we identify several constraints that contribute to the observed differences in the neutralization potencies. Cryo-EM reconstructions of EEEV in complex with these Fab fragments reveal structural constraints that dictate intravirion or intervirion cross-linking of glycoprotein spikes by their IgG counterparts as a mechanism of neutralization. Additionally, we describe critical features for the recognition of EEEV by these mAbs including the epitope-paratope interaction surface, occupancy, and kinetic differences in on-rate for binding to the E2 protein. Each constraint contributes to the extent of EEEV inhibition for blockade of virus entry, fusion, and/or egress. These findings provide structural and biophysical insights into the differences in mechanism and neutralization potencies of these antibodies, which help inform rational design principles for candidate vaccines and therapeutic antibodies for all icosahedral viruses.

Machine learning (ML) and Deep learning (DL) models are popular in many areas, from business, medicine, industries, healthcare, transportation, smart cities, and many more. However, the conventional centralized training techniques may not apply to upcoming distributed applications, which require high accuracy and quick response time. It is mainly due to limited storage and performance bottleneck problems on the centralized servers during the execution of various ML and DL-based models. However, federated learning (FL) is a developing approach to training ML models in a collaborative and distributed manner. It allows the full potential exploitation of these models with unlimited data and distributed computing power. In FL, edge computing devices collaborate to train a global model on their private data and computational power without sharing their private data on the network, thereby offering privacy preservation by default. But the distributed nature of FL faces various challenges related to data heterogeneity, client mobility, scalability, and seamless data aggregation. Moreover, the communication channels, clients, and central servers are also vulnerable to attacks which may give various security threats. Thus, a structured vulnerability and risk assessment are needed to deploy FL successfully in real-life scenarios. Furthermore, the scope of FL is expanding in terms of its application areas, with each area facing different threats. In this paper, we analyze various vulnerabilities present in the FL environment and design a literature survey of possible threats from the perspective of different application areas. Also, we review the most recent defensive algorithms and strategies used to guard against security and privacy threats in those areas. For a systematic coverage of the topic, we considered various applications under four main categories: space, air, ground, and underwater communications. We also compared the proposed methodologies regarding the underlying approach, base model, datasets, evaluation matrices, and achievements. Lastly, various approaches' future directions and existing drawbacks are discussed in detail., (© The Author(s), under exclusive licence to Springer Nature B.V. 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Objectives: Fumarate hydratase (FH)-deficient tumors can occur due to germline or somatic mutations and have distinctive morphologic features. The aims of this study are to refine morphologic criteria and identify mutations in FH-deficient smooth muscle tumors (SMTs)., Methods: The morphology of SMTs and kidney tumors submitted to a national reference laboratory for FH immunohistochemistry (IHC) was reviewed by two gynecologic and two genitourinary pathologists, respectively. Fisher exact test was used for analysis. Fourteen SMTs were sequenced using the Illumina TruSight Oncology 500 Assay., Results: Twenty-two kidney tumors (5 FH deficient) and 51 SMTs (27 FH deficient) were reviewed. FH-deficient kidney tumors exclusively showed cord-like growth, rhabdoid change, and absence of coagulative tumor necrosis and psammoma bodies. FH-deficient SMTs were significantly more likely to have staghorn vessels, eosinophilic cytoplasmic inclusions, schwannoma-like areas, or hereditary leiomyomatosis and renal cell cancer-like nuclei (P < .05 for each). Seven of 14 sequenced SMTs showed mutations of the FH gene and no other driver mutations., Conclusions: FH-deficient SMTs submitted for FH immunohistochemistry (IHC) showed distinct morphology. Although FH IHC is used for screening of FH-deficient tumors, FH mutations were identified in only 50% of FH-deficient SMTs. This highlights the need for additional exploration of mechanisms of FH protein loss in tumors lacking FH mutations., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Immunohistochemistry (IHC) highlights specific cell types in tissues and traditionally involves antibody staining together with a hematoxylin counterstain. The intensity and pattern of hematoxylin staining differs between cell types and reveals morphological characteristics of cells. Here, we propose that features in the hematoxylin stain can be used to predict IHC labels, such as Neurofibromin (encoded by the gene NF1 ). The dataset consists of 7.2 million cells from benign and kidney cancer cores in a tissue microarray. Morphology and hematoxylin (H&M) features defined within QuPath are subjected to a clustering analysis in CytoMap. H&M features are also used to train 4 different XGBoost models to predict high, low, and negative NF1 stain classes in benign renal tubules, clear cell (ccRCC), papillary (PRCC), and chromophobe (ChRCC) renal carcinoma. The prediction accuracies of NF1 staining classes in benign, ccRCC, ChRCC, and PRCC range between 70% and 90% with areas under the precision recall curve PRAUC NF1-high = 0.82+0.12, PRAUC NF1-low = 0.62+0.25, and PRAUC NF1-negative = 0.83+0.16. The most important feature for predicting the NF1 class involves the minimum cellular hematoxylin staining intensity. Together, these results demonstrate the feasibility to predict NF1 expression solely from features in hematoxylin staining using open source software. Since the hematoxylin features can be obtained from regular H&E and IHC slides, the proposed workflow has broad applicability., Competing Interests: The author(s) declare they have no competing interests, (© 2023 The Authors.)

Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis during primary infection is unknown. To investigate this question, we characterized the functional properties of newly-generated dengue virus (DENV) prM-reactive monoclonal antibodies (mAbs) in vitro and using a mouse model of DENV disease. Anti-prM mAbs neutralized DENV infection in a virion maturation state-dependent manner. Alanine scanning mutagenesis and cryoelectron microscopy of anti-prM mAbs in complex with immature DENV defined two modes of attachment to a single antigenic site. In vivo, passive transfer of intact anti-prM mAbs resulted in an antibody-dependent enhancement of disease. However, protection against DENV-induced lethality was observed when the transferred mAbs were genetically modified to inhibit their ability to interact with Fcγ receptors. These data establish that in addition to mature forms of the virus, partially mature infectious prM + virions can also contribute to pathogenesis during primary DENV infections.

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for patients with metastatic castration-resistant prostate cancer harboring deleterious or suspected deleterious BRCA1 and/or 2 mutations. Identifying patients with prostate cancer harboring these mutations may be challenging. Circulating cell-free DNA (cfDNA) provides an avenue for an easier detection of these mutations. Herein, we aimed to evaluate the concordance of BRCA mutations in the tumor tissue and cfDNA in patients with metastatic prostate cancer in the real-world setting., Methods: Somatic genomic profiling results were obtained from a clinical cohort of patients at our institution who had at least two samples tested. One of the samples needed to be from either primary or metastatic tissue. Concordance was adjusted to not include mutation types that the cfDNA platforms were not designed to detect., Results: The presence or absence of mutations in the BRCA gene was assessed in a total of 589 samples, including 327 cfDNA samples, from 260 patients with metastatic prostate cancer. The median time between the first test and any subsequent test was 22.8 (0.0-232) months. BRCA mutation was present in the patient's original prostate tissue in 23 samples (3.9%) of patients. The adjusted concordance between prostate tumor tissue and cfDNA was 97.9% [95% CI, 95.3-99.1%]. The adjusted concordance between metastatic samples and cfDNA was 93.5% [95% CI, 86.4-97.3%]. Of the patients who had a BRCA mutation detected in their prostate tissue, there was a 70% probability of detecting a BRCA mutation in the patient's cfDNA as well. For patients who did not have a detectable BRCA mutation in their primary prostate tissue, the probability of detecting a subsequent one later in the disease course was less than 0.9%., Conclusion: There is a high level of concordance between tissue and blood for BRCA mutations. Testing cfDNA can provide reliable information on BRCA mutational status and is a viable alternative to solid tissue sequencing when unavailable. The development of a new BRCA mutation later in the disease course is a rare event.

Approximately 20% of men with metastatic castration-sensitive prostate cancer (mCSPC) progress within 1 year of treatment, and biomarkers to identify them up front are lacking. In a randomized phase III trial in men with mCSPC (SWOG S1216), higher baseline circulating tumor cells (CTCs) were prognostic of inferior outcomes. We aimed to validate these findings and interrogate corresponding tumor genomic profiles. Consecutively seen men with newly diagnosed mCSPC undergoing systemic therapy and baseline CTC enumeration by CellSearch assay were included. Gene alterations were determined by comprehensive genomic profiling of tumor tissue by Clinical Laboratory Improvement Amendments-certified lab. The relationship between categorized CTC counts and both progression-free survival (PFS) and overall survival (OS) was assessed in the context of Cox proportional hazards models, both unadjusted and adjusted for age, Gleason score, PSA at androgen-deprivation therapy initiation, disease volume, de novo status, treatment intensification, and number of altered genes. Overall, 103 patients were included in the analysis. On multivariate analysis high CTCs (≥ 5 vs. 0) were associated with poorer PFS [HR, 4.52; 95% confidence interval (CI), 1.84-11.11; P = 0.001) and OS (HR, 3.59; 95% CI, 0.95-13.57; P = 0.060). Patients with higher CTC counts had a greater number of altered genes and total number of alterations (all P < 0.02). In this article, for the first time, we externally validate the association of higher CTC counts with inferior survival outcomes in men with mCSPC and show a distinct associated tumor genomic landscape. These findings may improve prognostication, patient counseling, and treatment selection in men with mCSPC., (©2022 American Association for Cancer Research.)

The tumor suppressor gene PTEN is the second most commonly deleted gene in cancer. Such deletions often include portions of the chromosome 10q23 locus beyond the bounds of PTEN itself, which frequently disrupts adjacent genes. Coincidental loss of PTEN -adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here, we describe how the loss of ATAD1 , which is adjacent to and frequently co-deleted with PTEN , predisposes cancer cells to apoptosis triggered by proteasome dysfunction and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic protein BIM from mitochondria to inactivate it. Cultured cells and mouse xenografts lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which activate BIM and trigger apoptosis. This work furthers our understanding of mitochondrial protein homeostasis and could lead to new therapeutic options for the hundreds of thousands of cancer patients who have tumors with chromosome 10q23 deletion., Competing Interests: JW, CC, PW, HK, JB, AB, TY, JR, DS, ST, PB, NA, AL, DS, MW, JR No competing interests declared, HF has filed a patent related to this work. Reference: WO2021/257910, (© 2022, Winter et al.)

Background: Urothelial carcinoma with squamous differentiation (UCS) is the most common variant differentiation of urothelial carcinoma (UC). Although treatment is usually similar to pure UC, there is paucity of data regarding its genomic landscape and putative molecular drivers. In this study, we compared the mutational profile of tumors with UCS and UC histology., Methods: In this IRB-approved retrospective study, patients with advanced UCS and UC undergoing tumor based comprehensive genomic profiling from a CLIA-certified laboratory were included. An independent genitourinary pathologist reviewed all cases. Patients were determined to have UCS based on presence of any component of squamous differentiation. Patients with UC having any other secondary histology variant were excluded. Genes with alterations (GA) in less than 5% of patients and variants of unknown significance were excluded from the analysis. Chi-square test was used to compare gene aberration frequency and the p-values were adjusted for false using Benjamini-Hochberg (BH) correction., Results: Among the 87 eligible patients with UCS (n=31) and UC (n=56), patients with UCS were more likely to be female (32.3% vs. 14.3%, p=0.047) with no significant differences in other clinicopathological features. Most common genomic alterations seen in UCS were TP53 (67.7%), KMT2D (48.4%) and ARID1A (32.3%). KMT2D mutations were significantly enriched in UCS (48.4% vs. 0%, FDR adj p <0.001, p = <0.001) compared to UC. Prevalence of CUL4A mutations was numerically higher in UCS vs. UC (12.9% vs. 1.8%, FDR adj p = 0.43, p = 0.03). Tumor mutation burden and the number of genomic aberrations per patient were not significantly different between the two groups., Conclusion: These findings highlight significant enrichment of KMT2D mutations in UCS and potential role of chromatin remodeling genes as drivers and potential therapeutic targets., Competing Interests: Conflict of interest Neeraj Agarwal reports consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. His institution receives research funding from Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Umang Swami reports consultancy to Astellas, Exelixis and Seattle Genetics and research funding to institute from Janssen, Exelixis and Astellas/Seattle Genetics. Abhishek Tripathi reports consultancy to Foundation Medicine, Pfizer, Genzyme, EMD Sorono, Exelixis, Deka Biosciences, Seattle Genetics, Urology Times honorarium), Cardinal health (honorarium). His institution receives research funding from Clovis Oncology, Corvus Pharmaceuticals, Bayer, EMD Serono, Aravive, WindMIL, Exact Sciences, Pfizer. Benjamin Haaland reports consultancy to Value Analytics and the National Kidney Foundation. Sumati Gupta reports research funding from BMS, Rexahn, Incyte, Novartis, LSK, Five Prime, Mirati, QED, Debiopharm, Merck, Pfizer, Astra Zeneca, MedImmune, Clovis; travel fund from QED; spouse has stock ownership in Salarius Pharmaceuticals. Benjamin Maughan reports consultancy to Abbive, Pfizer, AVEO oncology, Janssen, Astellas, Bristol-Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology and Peloton Therapeutics. His institution receives research funding from Exelixis, Bavarian-Nordic, Clovis, Genentech and Bristol-Myers Squibb. Petros Grivas reports consulting fees from AstraZeneca, Astellas Pharma, Bayer, Bristol Myers Squibb, Dyania Health, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, GlaxoSmithKline, Guardant Health, Gilead Sciences, Infinity Pharmaceuticals, Janssen, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics, Regeneron Pharmaceuticals, Seattle Genetics, UroGen, SilverBack Therapeutics, 4D Pharma PLC. His institution has received grants from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm, EMD Serono, GlaxoSmithKline, Gilead Sciences, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics, G1 Therapeutics. Roberto Nussenzveig has consulted for Tempus, Nishita Tripathi, Yeonjung Jo, Nicolas Sayegh, Haoran Li, Vinay Mathew Thomas, Sumanta Pal and Deepika Sirohi have no conflict of interest to disclose., (Published by Elsevier Inc.)