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Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8 + T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses., Competing Interests: Declaration of interests Z.B.: research funding from Bristol-Myers Squibb & Genentech/imCORE; honoraria from UpToDate. X.G.: advisory board for Exelixis, Bayer and Guardant Health. D.A.B.: non-financial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, advisory board fees from Exelixis and Aveo, and consulting/personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy outside of the submitted work. N.I.V.: advisory board to Sanofi/Genzyme, Oncocyte, and Lilly. M.S.H.: consultant, Janssen Pharmaceuticals and UpToDate. R.H.: research funding from Novartis. B.A.M.: consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, Dendreon, Bristol Myers Squibb, Calithera, and EMD Serono; research funding to the institution from Bristol Myers Squibb, Calithera, Exelixis, and Seattle Genetics. A.S.F.: consultant, Olympus America, Inc.; honoraria, Roche, Janssen; advisory board, Vessi Medical. C.J.W.: equity holder of BioNTech, Inc; research funding from Pharmacyclics. D.F.M.: honoraria from BMS, Pfizer, Merck, Alkermes, Inc., EMD Serono, Eli Lilly and Company, Iovance, Eisai, Inc., Werewolf Therapeutics, and Calithera Biosciences; research support from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes, Inc. D.Y.C.H.: consultancies and research funding from Pfizer, Novartis, BMS, Merck, Eisai, Ipsen, and Exelixis. S.S.: grants from Exelixis, grants from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, personal fees from CRISPR Therapeutics, personal fees from NCI, and personal fees from AACR; a patent for Biogenex with royalties paid. E.M.V.A.: advisory/consulting, Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio, Monte Rosa; research support, Novartis, BMS; equity, Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa; patents, institutional patents filed on chromatin mutations and immunotherapy response and methods for clinical interpretation. T.K.C.: research (institutional and personal), Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and Sons, LLC, Calithera, Cerulean, Corvus, Eisai, Exelixis, F. Hoffmann-La Roche, Foundation Medicine, Inc., Genentech, GlaxoSmithKline, Ipsen, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, and Tracon; consulting/honoraria or advisory role, Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, Bristol Myers-Squibb/ER Squibb and Sons, LLC, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, Foundation Medicine, Inc., Genentech, GlaxoSmithKline, Heron Therapeutics, Infinity Pharma, Ipsen, Jansen Oncology, IQVIA, Lilly, Merck, NCCN, Novartis, Nuscan, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Sanofi/Aventis, Surface Oncology, Tempest, and Up-to-Date; CME-related events (e.g., OncLIve, PVI, MJH Life Sciences); NCI GU Steering Committee; stock ownership, Pionyr and Tempest; patents filed, royalties, or other intellectual properties, related to biomarkers of immune checkpoint blockers and ctDNA; travel, accommodations, expenses, medical writing in relation to consulting, advisory roles, or honoraria; no speaker’s bureau. S.R.V.: consulting, MPM Capital and Vida Ventures; spouse is an employee of and holds equity in Kojin Therapeutics. All other authors report no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Microglia, the resident brain immune effectors cells, show dynamic activation level changes for most neuropsychiatric diseases, reflecting their complex regulatory function and potential as a therapeutic target. Emerging single-cell molecular biology studies are used to investigate the genetic modification of individual cells to better understand complex gene regulatory pathways. Although multiple protocols for microglia isolation from adult mice are available, it is always challenging to get sufficient purified microglia from a single brain for simultaneous DNA and RNA extraction for subsequent downstream analysis. Moreover, for data comparison between treated and untreated groups, standardized cell isolation techniques are essential to decrease variability. Here, we present a combined method of microglia isolation from a single adult mouse brain, using a magnetic bead-based column separation technique, and a column-based extraction of purified DNA-RNA from the isolated microglia for downstream application. Our current method provides step-by-step instructions accompanied by visual explanations of important steps for isolating DNA-RNA simultaneously from a highly purified microglia population.

Objectives: To evaluate outcomes of patients achieving a post-treatment pathological stage of

A major challenge in drug development is safety and toxicity concerns due to drug side effects. One such side effect, drug-induced liver injury (DILI), is considered a primary factor in regulatory clearance. The Critical Assessment of Massive Data Analysis (CAMDA) 2020 CMap Drug Safety Challenge goal was to develop prediction models based on gene perturbation of six preselected cell-lines (CMap L1000), extended structural information (MOLD2), toxicity data (TOX21), and FDA reporting of adverse events (FAERS). Four types of DILI classes were targeted, including two clinically relevant scores and two control classifications, designed by the CAMDA organizers. The L1000 gene expression data had variable drug coverage across cell lines with only 247 out of 617 drugs in the study measured in all six cell types. We addressed this coverage issue by using Kru-Bor ranked merging to generate a singular drug expression signature across all six cell lines. These merged signatures were then narrowed down to the top and bottom 100, 250, 500, or 1,000 genes most perturbed by drug treatment. These signatures were subject to feature selection using Fisher's exact test to identify genes predictive of DILI status. Models based solely on expression signatures had varying results for clinical DILI subtypes with an accuracy ranging from 0.49 to 0.67 and Matthews Correlation Coefficient (MCC) values ranging from -0.03 to 0.1. Models built using FAERS, MOLD2, and TOX21 also had similar results in predicting clinical DILI scores with accuracy ranging from 0.56 to 0.67 with MCC scores ranging from 0.12 to 0.36. To incorporate these various data types with expression-based models, we utilized soft, hard, and weighted ensemble voting methods using the top three performing models for each DILI classification. These voting models achieved a balanced accuracy up to 0.54 and 0.60 for the clinically relevant DILI subtypes. Overall, from our experiment, traditional machine learning approaches may not be optimal as a classification method for the current data., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Adeluwa, McGregor, Guo and Hur.)

Synucleinopathy disorders are characterized by aggregates of α-synuclein (α-syn), which engage microglia to elicit a neuroinflammatory response. Here, we determined the gene expression and DNA methylation changes in microglia induced by aggregate α-syn. Transgenic murine Thy-1 promoter (mThy1)-Asyn mice overexpressing human α-syn are a model of synucleinopathy. Microglia from 3 and 13-month-old mice were used to isolate nucleic acids for methylated DNA and RNA-sequencing. α-Syn-regulated changes in gene expression and genomic methylation were determined and examined for functional enrichment followed by network analysis to further elucidate possible connections within the data. Microglial DNA isolated from our 3-month cohort had 5315 differentially methylated gene (DMG) changes, while RNA levels demonstrated a change in 119 differentially expressed genes (DEGs) between mThy1-Asyn mice and wild-type littermate controls. The 3-month DEGs and DMGs were highly associated with adhesion and migration signaling, suggesting a phenotypic transition from resting to active microglia. We observed 3742 DMGs and 3766 DEGs in 13-month mThy1-Asyn mice. These genes were often related to adhesion, migration, cell cycle, cellular metabolism, and immune response. Network analysis also showed increased cell mobility and inflammatory functions at 3 months, shifting to cell cycle, immune response, and metabolism changes at 13 months. We observed significant α-syn-induced methylation and gene expression changes in microglia. Our data suggest that α-syn overexpression initiates microglial activation leading to neuroinflammation and cellular metabolic stresses, which is associated with disease progression., Competing Interests: Conflict of Interests The authors declare no competing interests for this work., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Limited data exist on the clinical effectiveness of second-line (2L) vascular endothelial growth factor (receptor) targeted inhibitor (VEGF(R)i) sunitinib after first-line (1L) immuno-oncology (IO) therapy for patients with metastatic renal cell carcinoma (mRCC) in real-world settings., Methods: A retrospective cohort study among adult patients with mRCC treated with 2L sunitinib following 1L IO was conducted from select International mRCC Database Consortium (IMDC) centers. All analyses were performed overall and by 1L ipilimumab + nivolumab (IPI+NIVO) or 1L IO+VEGF(R)i. Median overall survival (mOS) and time-to-treatment discontinuation (mTTD) in 2L were estimated using Kaplan-Meier analysis. The 2L objective response rate (ORR) (complete/partial response) was reported., Results: Among 102 patients on 2L sunitinib, mean age was 61.3 years. IMDC risk scores at 2L initiation was available for 83 patients: 8 (9.6%) were favorable, 45 (54.2%) were intermediate, and 30 (36.1%) were poor risk. The 1L consisted of IPI+NIVO in 62 (60.8%), IO+VEGF(R)i therapy in 27 (26.5%), and IO monotherapy in 13 (12.7%) patients. Among all patients, mOS was 15.6 months (95% confidence interval [CI], 9.8-21.7), with a 1-year OS rate of 57.5% (95% CI, 45.2-68.0). mTTD was 5.4 months (95% CI, 4.2-7.2) and ORR was 22.5%., Conclusion: Despite availability of effective 1L therapies in recent years, 2L sunitinib continues to have clinical activity after failure of 1L IO. Further studies on optimal treatment sequencing after 1L IO progression are needed., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: The therapeutic landscape for urothelial carcinoma has changed significantly over the past few years with the addition of immunotherapy to platinum-based chemotherapy. Targeted therapy against FGFR (fibroblast growth factor receptor) is now also approved for the minority of patients with FGFR aberrations. Antibody-drug conjugates (ADCs) are of great interest in urothelial carcinoma, with a recent FDA approval for enfortumab vedotin (EV) and others in development., Areas Covered: This review will provide an overview of treatment of advanced urothelial carcinoma and detail the various ADCs being studied in this disease., Expert Opinion: ADCs are an important therapeutic option for urothelial carcinoma. Responses to EV exceeded 40% in heavily pre-treated patients, while the response rate to EV combined with pembrolizumab in a phase 1b trial was ~70% in treatment-naïve patients. EV has already been approved in the United States and we await randomized data to confirm a survival benefit with EV. Meanwhile, studies of other ADCs, including in biomarker-selected populations, are ongoing. ADCs will undoubtedly play an increasing role in the management of urothelial carcinoma and will likely be offered earlier in the disease course, resulting in significant changes to treatment algorithms in urothelial cancer in the coming years.

Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB., Competing Interests: Declaration of interests M.X.H. has consulted for Amplify Medicines and Ikena Oncology. Z.B. reports research support from Bristol-Meyers Squibb (BMS) and Genentech/imCORE unrelated to this study. D.A.B. reports non-financial support from BMS, honoraria from LM Education/Exchange Services, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of this work. B.A.M. has consulted for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, and EMD Serono. He received research support to Dana-Farber Cancer Institute from BMS, Calithera, Exelixis, and Seattle Genetics. J.L.G. is a consultant for and/or receives sponsored research support from GlaxoSmithKline (GSK), Array BioPharma, Codagenix, Verseau, Kymera, and Eli Lilly. A. Rotem is an employee of AstraZeneca and an equity holder in NucleAI and Celsius Therapeutics. A. Regev is a founder and equity holder of Celsius Therapeutics, holds equity in Immunitas Therapeutics, and, until August 31, 2020, was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and Thermo Fisher Scientific; since August 1, 2020, she has been an employee of Genentech. E.M.V.A. reports advisory/consulting with Tango Therapeutics, Genome Medical, Invitae, Monte Rosa, Enara Bio, Manifold Bio, and Janssen; research support from Novartis and BMS; equity in Tango Therapeutics, Genome Medical, Syapse, Manifold Bio, Monte Rosa, and Enara Bio. T.K.C. reports research support/honoraria from, consulting/advisory relationships with, and/or equity stakes in Alexion, Analysis Group, AstraZeneca, Aveo, Bayer, BMS, Calithera, Cerulean, Corvus, Eisai, EMD Serono, Exelixis, F. Hoffmann-La Roche, Foundation Management, Genentech, GSK, Heron Therapeutics, Infinity Pharma, Janssen Oncology, IQVIA, Ipsen, Lilly, Merck, NCCN, Novartis, Peloton, Pfizer, Pionyr, Prometheus Labs, Roche, Roche Products Limited, Sanofi/Aventis, Takeda, Tracon, Surface Oncology, Tempest, Up-to-Date, OncLIve, PVI, and MJH Life Sciences; patents filed, royalties, or other intellectual properties related to biomarkers of immune checkpoint blockers; and support from the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The tumor immune microenvironment plays a critical role in cancer progression and response to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the composition and phenotypic states of immune cells in this tumor are incompletely characterized. We performed single-cell RNA and T cell receptor sequencing on 164,722 individual cells from tumor and adjacent non-tumor tissue in patients with ccRCC across disease stages: early, locally advanced, and advanced/metastatic. Terminally exhausted CD8 + T cells were enriched in metastatic disease and were restricted in T cell receptor diversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased, and suppressive M2-like macrophages were increased in advanced disease. Terminally exhausted CD8 + T cells and M2-like macrophages co-occurred in advanced disease and expressed ligands and receptors that support T cell dysfunction and M2-like polarization. This immune dysfunction circuit is associated with a worse prognosis in external cohorts and identifies potentially targetable immune inhibitory pathways in ccRCC., Competing Interests: Declaration of interests D.A.B. reports nonfinancial support from Bristol Myers Squibb, honoraria from LM Education/Exchange Services, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of the submitted work. S.H.G. has patents licensed to Novalgen Inc, outside of the submitted work. Z.B. reports nonfinancial support from Bristol Myers Squibb and Genentech/imCore. D.B.K. has acted as an advisor to and has received consulting fees from Neon Therapeutics and owns equity in Agenus, Armata pharmaceuticals, Breakbio, Biomarin Pharmaceutical, Bristol Myers Squibb, Celldex Therapeutics, Chinook Therapeutics, Editas Medicine, Exelixis, Gilead Sciences, IMV, Lexicon Pharmaceuticals, Moderna, and Regeneron Pharmaceuticals. K.M.M. reports research support from Bristol Myers Squibb. B.A.M. reports consulting fees from Bayer, Astellas, Astra Zeneca, Seattle Genetics, Dendreon, Calithera, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, and EMD Serono, and research support to DFCI from Bristol Myers Squibb, Calithera, Exelixis, Seattle Genetics. D.F.M. has received consulting fees from Bristol Myers Squibb, Pfizer, Merck, Alkermes, EMD Serono, Eli Lilly, Iovance, and Eisai, and research support from Bristol Myers Squibb, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, and Alkermes. S.A.S. reports nonfinancial support from Bristol Myers Squibb outside the submitted work. S.A.S. previously advised and has received consulting fees from Neon Therapeutics. S.A.S. reports nonfinancial support from Bristol Myers Squibb, and equity in Agenus Inc., Agios Pharmaceuticals, Breakbio Corp., Bristol Myers Squibb, and Lumos Pharma, outside the submitted work. S.S. reported personal fees from Merck, AstraZeneca, Bristol Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI, grants from Bristol Myers Squibb, AstraZeneca, Novartis, and Exelixis, and royalties from Biogenex. A.H.S. has patents/pending royalties on the PD-1 pathway from Roche and Novartis. A.H.S. is on advisory boards for Bicara, Janssen Immunology, Surface Oncology, Elstar, SQZ Biotechnologies, Elpiscience, Selecta, and Monopteros, and consults for Novartis. A.H.S. has received research funding from AbbVie, Novartis, Roche, UCB, Ipsen, Quark, and Merck. D.F.M. reports personal fees from Bristol Myers Squibb, Pfizer, Merck, Novartis, Exelixis, Array BioPharm, Genentech, Alkermes, Jounce Therapeutics, X4 Pharma, Peloton, EMD Serono, and Eli Lilly, and research support from Bristol Myers Squibb, Prometheus Laboratories, Merck, Genentech, Pfizer, Exelixis, Novartis, X4 Pharma, Alkermes, and Peloton. T.K.C. reports grants and personal fees from Astra Zeneca; personal fees from Bayer; grants and personal fees from Bristol Myers Squibb; personal fees from Cerulean; grants and personal fees from Eisai; personal fees from Foundation Medicine Inc.; grants and personal fees from Exelixis; grants and personal fees from Genentech; personal fees from Roche; grants and personal fees from GlaxoSmithKline; grants and personal fees from Merck, from Novartis, Peloton, and Pfizer; personal fees from Prometheus Labs; grants and personal fees from Corvus; personal fees from Ipsen; grants from Tracon; and grants from Astellas outside the submitted work. The other authors declare no potential conflicts of interest. C.J.W. is an equity holder of BioNTech., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Genomic alterations in penile squamous cell carcinoma (PSCC) appear similar to squamous cell carcinomas of the head and neck and esophagus but not lung, skin, bladder, and cervix. PSCCs display genomic heterogeneity, low mutation burden, and potentially actionable alterations in the Notch, DNA repair, kinase, and cell-cycle pathways. See related article by Chahoud et al., p. 2560 ., (©2021 American Association for Cancer Research.)

Prior studies of the renal cell carcinoma (RCC) germline landscape investigated predominantly patients of European ancestry. We examine the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 1,829 patients with RCC from various ancestries. Overall, P/LP variants are found in 17% of patients, among whom 10.3% harbor one or more clinically actionable variants with potential preventive or therapeutic utility. Patients of African ancestry with RCC harbor significantly more P/LP variants in FH compared to patients of non-African ancestry with RCC and African controls from the Genome Aggregation Database (gnomAD). Patients of non-African ancestry have significantly more P/LP variants in CHEK2 compared to patients of African ancestry with RCC and non-Finnish Europeans controls. Non-Africans with RCC have more actionable variants compared to Africans with RCC. This work helps understand the underlying biological differences in RCC between Africans and non-Africans and paves the way to more comprehensive genomic characterization of underrepresented populations., Competing Interests: Declaration of interests S.Y., E.D.E., K.H., V.F., and S.N. are employees of Invitae Corporation, a testing laboratory that furnished the diagnostic test results used in this study. S.Y. reported other support from Invitae during the conduct of the study. E.D.E., K.H., and S.N. reported being shareholders of Invitae. J.E.G.: Astra-Zeneca, Helix Genetics, Ambry Genetics, Invitae Genetics, Myriad Genetics, Konica-Minolta, and Novartis Pharmaceuticals. H.Q.R. received honoraria from Ambry Genetics. David J. Kwiatkowski reports serving as a consultant for Novartis. B.A.M. discloses payment for consulting with Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai, and EMD Serono. He also received research support to the Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis, and Seattle Genetics. G.S.: consultant for BMS, Exelixis, Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, AstraZeneca, Merck, Genentech, EMD Serono, and Astellas/Agensys; research support to institution from AstraZeneca, Bayer, Amgen, Boehringer-Ingelheim, Janssen, Merck, Sanofi, and Pfizer; author for UpToDate; Steering Committee for AstraZeneca, BMS, Bavarian Nordic, and Astellas; speaker for OncLive, Research to Practice, and Physician Education Resource (PER). T.K.C. reported receiving institutional and personal funds from Analysis Group, AstraZeneca, Alexion, Bayer, Bristol Myers Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine, Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products, Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Sanofi/Aventis, and Takeda; reported receiving honoraria from the Analysis Group, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers Squibb/E.R. Squibb and Sons LLC, Cerulean, Eisai, Foundation Medicine, Inc., Exelixis, Genentech, Roche, Roche Products, Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Heron Therapeutics, Lilly, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, UpToDate, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc. (Healthcare Communications Company with several brands such as OnClive, PeerView, and PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, and Lancet Oncology; having a consulting or advisory role at Analysis Group, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers Squibb/E.R. Squibb and Sons LLC, Cerulean, Eisai, Foundation Medicine, Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, UpToDate, and NCCN; Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber, member of NCCN Kidney Panel and the GU Steering Committee, and past Chairman of the Kidney Cancer Association Medical and Scientific Steering Committee; medical writing and editorial assistance support may have been funded by communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, and Parexel, among others); the institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies and/or royalties potentially involved in research around the subject matter; CV provided upon request for scope of clinical practice and research. T.K.C. is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School, the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI, and various National Cancer Institute (NCI), Department of Defense (DOD), and foundations and industry grants. A.G. is supported by R01 CA227237, R01 CA244569, and the Louis B. Mayer Foundation. The remaining authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In this multicenter, single-arm, multicohort, phase 2 trial, the efficacy of nivolumab and ipilimumab was evaluated in patients with advanced rare genitourinary cancers, including bladder and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, platinum-refractory germ cell tumors, penile carcinoma, and prostate cancer of variant histology (NCT03333616)., Methods: Patients with rare genitourinary malignancies and no prior immune checkpoint inhibitor exposure were enrolled. Patients received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg intravenously every 3 weeks for 4 doses, and this was followed by 480 mg of nivolumab intravenously every 4 weeks. The primary endpoint was the objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors (version 1.1)., Results: Fifty-five patients were enrolled at 6 institutions between April 2018 and July 2019 in 3 cohorts: BUTCVH (n = 19), adrenal tumors (n = 18), and other tumors (n = 18). The median follow-up was 9.9 months (range, 1 to 21 months). Twenty-eight patients (51%) received 4 doses of nivolumab and ipilimumab; 25 patients received nivolumab maintenance for a median of 4 cycles (range, 1-18 cycles). The ORR for the entire study was 16% (80% confidence interval, 10%-25%); the ORR in the BUTCVH cohort, including 2 complete responses, was 37%, and it was 6% in the other 2 cohorts. Twenty-two patients (40%) developed treatment-related grade 3 or higher toxicities; 24% (n = 13) required high-dose steroids (≥40 mg of prednisone or the equivalent). Grade 5 events occurred in 3 patients; 1 death was treatment related., Conclusions: Nivolumab and ipilimumab resulted in objective responses in a subset of patients with rare genitourinary malignancies, especially those with BUTCVH. An additional cohort exploring their activity in genitourinary tumors with neuroendocrine differentiation is ongoing., Lay Summary: Patients with rare cancers are often excluded from studies and have limited treatment options. Fifty-five patients with rare tumors of the genitourinary system were enrolled from multiple sites and were treated with nivolumab and ipilimumab, a regimen used for kidney cancer. The regimen showed activity in some patients, particularly those with bladder or upper tract cancers of unusual or variant histology; 37% of those patients responded to therapy. Additional studies are ongoing to better determine who benefits the most from this combination., (© 2020 American Cancer Society.)

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.

Purpose: In this phase II response-adaptive trial, we investigated the rational application of immune checkpoint blockade in renal cell carcinoma (RCC; ClinicalTrials.gov identifier: NCT03203473)., Methods: We enrolled patients with metastatic RCC with no prior checkpoint inhibitor exposure. All patients received nivolumab alone with subsequent arm allocation based on response. Patients with a confirmed partial response (PR) or complete response (CR) within 6 months discontinued nivolumab and were observed (arm A). Patients with stable disease or progressive disease (PD) after no more than 6 months of nivolumab received two doses of ipilimumab (arm B). The primary endpoints were the proportion of patients with PR/CR at 1 year after nivolumab discontinuation (arm A) and proportion of nivolumab nonresponders who converted to PR/CR after ipilimumab (arm B)., Results: Overall, 83 patients initiated treatment, of whom 96% had clear-cell histology, 51% were treatment naïve, and 67% had intermediate/poor-risk disease. Median follow-up was 19.5 months. Within 6 months, induction nivolumab resulted in a confirmed PR in 12% of patients (n = 10). Fourteen patients were not allocated to a study arm (seven because of toxicity, seven because of PD). Twelve patients (14%) were allocated to arm A and discontinued nivolumab, of whom five (42%; 90% CI, 18% to 68%) remained off nivolumab at ≥ 1 year. Of 57 patients (69%) allocated to arm B, two patients converted to a confirmed PR (4%; 90% CI, 1% to 11%), and no CRs were observed., Conclusion: In this study, nivolumab followed by two doses of ipilimumab resulted in no CRs and a low PR/CR conversion. The number of patients evaluated for nivolumab discontinuation was too small to assess the value of this approach. Currently, our data do not support a response-adaptive strategy for checkpoint blockade in advanced RCC.

CDX-014 is an antibody-drug conjugate directed against TIM-1, a surface marker highly expressed in renal cell carcinoma (RCC) and ovarian carcinoma. This phase I, first-in-human trial was conducted to evaluate the safety and preliminary activity of CDX-014 in patients with advanced refractory RCC, following a dose-escalation and dose expansion design. CDX-014 was administered intravenously at doses ranging from 0.15 to 2.0 mg/kg every 2 or 3 weeks until progression or unacceptable toxicity. Sixteen patients received at least one dose of CDX-014. The maximum tolerated dose was not identified. Most frequent adverse grade 1 or 2 adverse events included nausea (38%), fatigue, alopecia, elevation of AST and decreased appetite (25% each). Adverse events of grade 3 or more included hyperglycemia (19%), urosepsis (6%), and one multi-organ failure (6%) responsible for one treatment-related death. Two patients discontinued therapy for adverse events including fatigue grade 2 and urosepsis grade 4. CDX-014 showed antitumor activity with one prolonged partial response and a clinical benefit rate (objective response or stable disease >6 months) of 31%. The two patients that exhibited the most marked tumor shrinkage had high TIM-1 expression on tumor tissue. Overall, CDX-014 exhibited a manageable toxicity profile and early signs of activity, supporting further evaluation of antibody-drug conjugates in patients with advanced RCC and potentially other TIM-1 expressing cancers. Trial registration https://clinicaltrials.gov/ct2/show/NCT02837991 NCT02837991; July 20, 2016.

Background: Prolonged androgen deprivation therapy (ADT) is favored over short-term use in patients with localized high-risk prostate cancer (PC)., Objectives: This study sought to compare cardiorespiratory fitness (CRF) and cardiovascular (CV) mortality among patients with PC with and without ADT exposure and to explore how duration of ADT exposure influences CRF and CV mortality., Methods: Retrospective cohort study of patients referred for exercise treadmill testing (ETT) after a PC diagnosis. PC risk classification was based on Gleason score (GS): high risk if GS ≥8; intermediate risk if GS = 7; and low risk if GS <7. CRF was categorized by metabolic equivalents (METs): METs >8 defined as good CRF and METs ≤8 as reduced CRF. ADT exposure was categorized as short term (≤6 months) versus prolonged (>6 months)., Results: A total of 616 patients underwent an ETT a median of 4.8 years (interquartile range: 2.0, 7.9 years) after PC diagnosis. Of those, 150 patients (24.3%) received ADT prior to the ETT; 99 with short-term and 51 with prolonged exposure. 504 patients (81.8%) had ≥2 CV risk factors. Prolonged ADT was associated with reduced CRF (odds ratio [OR]: 2.71; 95% confidence interval [CI]: 1.31 to 5.61; p = 0.007) and increased CV mortality (hazard ratio [HR]: 3.87; 95% CI: 1.16 to 12.96; p = 0.028) in adjusted analyses. Although the association between short-term ADT exposure and reduced CRF was of borderline significance (OR: 1.71; 95% CI: 1.00 to 2.94; p = 0.052), there was no association with CV mortality (HR: 1.60; 95% CI: 0.51 to 5.01; p = 0.420) in adjusted Cox regression models., Conclusions: Among patients with PC and high baseline CV risk, prolonged ADT exposure was associated with reduced CRF and increased CV mortality., Competing Interests: This work was supported by the Goodman Master Clinician Award from Brigham and Women’s Hospital (to Dr. Groarke) and by the Gelb Master Clinician Award and the Catherine Fitch Fund form Brigham and Women’s Hospital (to Dr. Nohria). Dr. McGregor has served as a consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, and Genentech; and has received research support paid to his institution from Bristol Myers Squibb. Dr. Neilan was supported in part through a gift from A. Curt Greer, Pamela Greer, and Kohlberg Foundation, National Institutes of Health/National Heart, Lung, and Blood Institute (grants 1R01HL130539-01A1, 1R01HL137562-01A1, K24HL113128-06), and National Institutes of Health/Harvard Center for AIDS Research (grant P30 AI060354). Dr. Nohria has served as a consultant for Takeda Oncology and Triple Gene Therapy; and has received research support from Amgen, Inc. Dr. Groarke has received research support from Amgen, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2020 The Authors.)

Background: CD73-adenosine signaling in the tumor microenvironment is immunosuppressive and may be associated with aggressive renal cell carcinoma (RCC). We investigated the prognostic significance of CD73 protein expression in RCC leveraging nephrectomy samples. We also performed a complementary analysis using The Cancer Genome Atlas (TCGA) dataset to evaluate the correlation of CD73 (ecto-5'-nucleotidase ( NT5E ), CD39 (ectonucleoside triphosphate diphosphohydrolase 1 ( ENTPD1 )) and A2 adenosine receptor (A2AR; ADORA2A ) transcript levels with markers of angiogenesis and antitumor immune response., Methods: Patients with RCC with available archived nephrectomy samples were eligible for inclusion. Tumor CD73 protein expression was assessed by immunohistochemistry and quantified using a combined score (CS: % positive cells×intensity). Samples were categorized as CD73 negative (CS=0), CD73 low or CD73 high (< and ≥median CS, respectively). Multivariable Cox regression analysis compared disease-free survival (DFS) and overall survival (OS) between CD73 expression groups. In the TCGA dataset, samples were categorized as low, intermediate and high NT5E , ENTPD1 and ADORA2A gene expression groups. Gene expression signatures for infiltrating immune cells, angiogenesis, myeloid inflammation, and effector T-cell response were compared between NT5E , ENTPD1 and ADORA2A expression groups., Results: Among the 138 patients eligible for inclusion, 'any' CD73 expression was observed in 30% of primary tumor samples. High CD73 expression was more frequent in patients with M1 RCC (29% vs 12% M0), grade 4 tumors (27% vs 13% grade 3 vs 15% grades 1 and 2), advanced T-stage (≥T3: 22% vs T2: 19% vs T1: 12%) and tumors with sarcomatoid histology (50% vs 12%). In the M0 cohort (n=107), patients with CD73 high tumor expression had significantly worse 5-year DFS (42%) and 10-year OS (22%) compared with those in the CD73 negative group (DFS: 75%, adjusted HR: 2.7, 95% CI 1.3 to 5.9, p=0.01; OS: 64%, adjusted HR: 2.6, 95% CI 1.2 to 5.8, p=0.02) independent of tumor stage and grade. In the TCGA analysis, high NT5E expression was associated with significantly worse 5-year OS (p=0.008). NT5E and ENTPD1 expression correlated with higher regulatory T cell (Treg) signature, while ADORA2A expression was associated with increased Treg and angiogenesis signatures., Conclusions: High CD73 expression portends significantly worse survival outcomes independent of stage and grade. Our findings provide compelling support for targeting the immunosuppressive and proangiogenic CD73-adenosine pathway in RCC., Competing Interests: Competing interests: AT: advisory role for Foundation Medicine, Pfizer; research funding to institution from EMD Serono, Bayer, Clovis Oncology, Aravive Inc, WindMIL therapeutics, Corvus Pharmaceuticals; EL, WX, AF, JAS, ESG, GB, JHF, CG, CM and LT: none; NM-C: support for research travel from Pfizer and Ipsen, and consulting fees from BMS and Bayer; XXW: research funding to institution from Bristol-Myers Squibb (BMS); MG: research funding from BMS and Merck; BAM: payment for consulting with Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech, Eisai and EMD Serono, and received research support to Dana Farber Cancer Institute (DFCI) from BMS, Calithera, Exelixis, Seattle Genetics. TKC: supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at DFCI. Research (institutional and personal): AstraZeneca, Alexion, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda. Honoraria: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, BMS/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc, Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly Oncology. Consulting or advisory Role: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest, Lilly Ventures. Stock ownership: Pionyr, Tempest. Other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee), KidneyCan Advisory board, Kidney cancer Research Summit co-chair (2019-). Patents, royalties or other intellectual properties: related to biomarkers of immune checkpoint blockers. Travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others).The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. CV provided upon request for scope of clinical practice and researchMentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. NA: consultancy to Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Janssen, Merck, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. Research funding to my institution: Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. DFM: Honorarium for consultancy from BMS, Pfizer, Merck, Alkermes Inc, EMD Serono, Eli Lilly, Iovance and Eisai. Research support from BMS, Merck, Genentech, Pfizer, Exelixis, X4 Pharma, Alkermes. SS: reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Exelixis and Novartis; is a consultant/advisory board member for Merck, AstraZeneca, Bristol-Myers Squibb, CRISPR Therapeutics AG, AACR, and NCI; and receives royalties from Biogenex. LCH: Reports consulting fees from Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, BMS, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano, ASIM CME, and Ology Medical Education. Research funding from Bayer, Sotio, BMS, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, Endocyte (Novartis). Support for research travel from Bayer and Genentech. Currently employed by Surface Oncology., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Cell-free circulating DNA (cfDNA) can be used for noninvasive profiling of tumor genomic aberrations. We hypothesized that molecular alterations may inform prognostication in advanced urothelial carcinoma (aUC). We evaluated 124 aUC patients who underwent cfDNA analysis using a 73-gene sequencing panel (Guardant360). The association of molecular alterations and clinical factors with overall survival (OS) and failure-free-survival (FFS) was evaluated using the Kaplan-Meier method and Cox proportional-hazards regression. The median age was 72yr, and 65 patients (52.4%) received prior therapy with platinum, 21 (17.1%) with a taxane, and ten (8.1%) with a PD-1/PD-L1 inhibitor. At least one genomic alteration was detected in 112 patients (90.3%). The median number of alterations per sample was four (range 0-80). Commonly altered genes included TP53 (54.8%), PIK3CA (24.2%), ARID1A (22.6%), ERBB2 (19.4%), EGFR (16.1%), NF1 (13.7%), RB1 (12.9%), FGFR3 (11.3%), BRAF (10.5%), BRCA1 (10.5%), and RAF1 (8.9%). BRCA1 and RAF1 alterations were associated with worse OS (hazard ratio [HR] 2.48; p=0.07; HR 4.87; p=0.007) and FFS (HR 2.35; p=0.016; HR 2.40; p=0.047). Poor Eastern Cooperative Oncology Group performance status and the presence of visceral metastasis were associated with shorter OS; genomic evolution was observed. In conclusion, cfDNA molecular alterations were detected in most aUC patients. BRCA1 and RAF1 alterations were negatively prognostic, supporting further evaluation of DNA damage response and RAF kinase inhibitors. PATIENT SUMMARY: Noninvasive testing of cell-free circulating DNA in advanced urothelial carcinoma identifies clinically relevant molecular aberrations. Alterations in BRCA1 and RAF1 genes appear to be negatively associated with clinical outcomes, supporting further study of DNA damage response and RAF kinase inhibitors in selected patients., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Importance: Several immune checkpoint inhibitors (ICIs) are approved for use in patients with metastatic renal cell carcinoma (mRCC), but the efficacy and safety of ICI rechallenge in mRCC is unknown., Objective: To evaluate the safety and efficacy of ICI rechallenge in patients with mRCC., Design, Setting, and Participants: This multicenter, retrospective cohort study included consecutive patients with mRCC from 9 institutions in the US who received at least 2 separate lines of ICI (ICI-1, ICI-2) between January 2012 and December 2019., Exposure: Receipt of an ICI (anticytotoxic T-lymphocyte-associated protein 4, anti-programmed cell death protein 1, or anti-programmed cell death ligand 1), alone or in combination with other therapies, in at least 2 separate lines of therapy for mRCC., Main Outcomes and Measures: Investigator-assessed best overall response and immune-related adverse events., Results: A total of 69 patients were included. Median (range) age at diagnosis of mRCC was 61 (36-86) years. Of these, 50 were men and 19 were women. The most common therapies received at ICI-1 were single-agent ICI (n = 27 [39%]) or ICI in combination with targeted therapy (n = 29 [42%]), while at ICI-2, the most common therapies were single-agent ICI (n = 26 [38%]) or dual ICI (n = 22 [32%]). Most patients discontinued ICI-1 owing to disease progression (n = 50 [72%]) or toxic effects (n = 16 [23%]). The overall response rates at ICI-1 and ICI-2 were 37% and 23%, respectively. The likelihood of a response at ICI-2 was greatest among patients who had previously responded to ICI-1 (7 of 24 [29%]), although responses at ICI-2 were seen in those who had progressive disease as their best response following ICI-1 (3 of 14 [21%]) as well as in those who received single-agent ICI at ICI-2 (7 of 23 [30%]). Grade 3 or higher immune-related adverse events were seen in 18 patients (26%) and 11 patients (16%) at ICI-1 and ICI-2, respectively. There were no treatment-related deaths., Conclusions and Relevance: The findings of this multicenter cohort study suggest that ICI rechallenge in patients with mRCC may be safe and reasonably efficacious, with an overall response rate of 23%. Data from prospective studies are needed to validate these findings and determine the role of sequential ICI regimens in treatment of mRCC.

Cancer patients frequently develop tumor and treatment-related complications, leading to diminished quality of life, shortened survival, and overutilization of emergency department and hospital services. Outpatient oncology treatment has potential to leave cancer patients unmonitored for long periods while at risk of clinical deterioration which has been exaggerated during the COVID19 pandemic. Visits to cancer clinics and hospitals risk exposing immunocompromised patients to infectious complications. Remote patient reported outcomes monitoring systems have been developed for use in cancer treatment, showing benefits in economic and survival outcomes. While advanced devices such as pulmonary artery pressure monitors and implantable loop recorders have proven benefits in cardiovascular care, similar options do not exist for oncology. Here we review the current literature around remote patient monitoring in cancer care and propose the use of reliable devices for capturing and reporting patient symptoms and physiology., Competing Interests: Dr. Mitchell is a named inventor on six patent applications related to this work., (Copyright © 2020, McGregor et al.)

Background: Cabozantinib is approved for the first and subsequent line treatment of metastatic clear-cell renal cell carcinoma (ccRCC) based on trials in which most patients were immune checkpoint blockade (ICB) naive. With an expanding role of ICB in earlier lines of therapy, we assessed activity of cabozantinib in patients with metastatic ccRCC after progressing on anti-PD-1/PD-L1-based ICBs., Methods: We retrospectively analysed the clinical outcomes of 86 patients from 2 academic centres who received cabozantinib after progression on ICB alone, ICB in combination with vascular endothelial growth factor inhibitors (VEGFis) or ICB in combination with other therapies. Overall response rate (ORR, investigator assessed), time to treatment failure (TTF), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated., Results: Eighty-six patients were included in the analysis; the median age was 63 years (range 33-84) and the median number of prior therapies was 2 (range 1-10). The type of prior ICB therapy was ICBs alone (64%), an ICB in combination with a VEGFi (29%) or ICBs in combination with other therapies (7%). At the time of cabozantinib treatment, 71% of patients were in the International Metastatic RCC Database Consortium good- or intermediate-risk groups. Approximately half of patients (52%) were started on cabozantinib at the full 60 mg daily dose. The ORR was 36% (95% confidence interval [CI] = 26-47%) with no complete response and 43% achieving stable disease; 21% had primary progressive disease. The median TTF was 6.5 months (95% CI = 5.3-8.5.). The median OS was 13.1 months (95% CI = 8.7-NR) with 55% (95% CI = 41-66%) OS rate at 12 months. Most common reasons for dose reductions were fatigue (27%), palmar-plantar erythrodysesthesia (16%) and diarrhoea (10%)., Conclusions: Cabozantinib is active in patients treated with prior ICB-based therapies, with no new safety signals. This study supports the use of cabozantinib after ICB-based therapies., Competing Interests: Conflict of interest statement B.A.M. is reports serving as a consultant for Bayer, Astellas, AstraZeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech and EMD Serono and reports receiving research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis andSeattle Genetics. A.-K.AL. reports serving as a consultant for AbbVie, Astellas, Bristol-Myers Squibb, Eisai, Ipsen, Janssen, Merck, Novartis, Pfizer, Roche and TerSera and reports receiving research grants (institution or personal) from Bristol-Myers Squibb, Novartis, Roche andIpsen. D.A.B. reports receiving non-financial support from Bristol-Myers Squibb and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group and Insight Strategy, outside the submitted work. X.X.W. reports receiving research support to DFCI from Bristol Myers Squibb. L.C.H. reports serving as a consultant for Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano and Ology Medical Education; reports receiving research funding to the institution (DFCI) from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer and Endocyte (Novartis) and reports receiving financial support for research travel from Bayer and Genentech. M.A.B. reports serving as a consultant for Exelixis, Seattle Genetics, EMD Serono, Nektar and Sanofi and receiving institutional research funding from Bayer, Bristol-Myers Squibb, Genentech/Roche, Xencor, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton and Pfizer. T.K.C. reports serving as a consultant for Analysis Group, AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Heron Therapeutics, Lilly, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology and receiving research support to DFCI from Analysis Group, AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Sanofi/Aventis andTakeda. All remaining authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Variant histology renal cell carcinoma (vRCC) encompasses rare non-clear cell subtypes that have long been associated with poor prognosis and minimal response to therapies targeting vascular endothelial growth factor and its receptor. Molecular advances have helped classify vRCC into distinct entities and identify putative targetable driver alterations, such as MET in papillary subtypes. More have since been identified in other vRCC subtypes, including alterations of tumor metabolism, chromatin remodeling genes, cell-cycle genes, and inactivation of tumor suppressors such as TP53 or NF2. New targeted therapies, as well as immune checkpoint inhibitors, have been in development and yielded encouraging results. Collaborative clinical trials will be an essential step toward better implementation of these regimens in clinical practice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Antibiotic use alters commensal gut microbiota, which is a key regulator of immune homeostasis., Objective: To investigate the impact of antibiotic use on clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with systemic agents., Design, Setting, and Participants: We analyzed two cohorts: an institutional cohort (n=146) receiving programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-based immune checkpoint inhibitors (ICIs) and a trial-database cohort (n=4144) receiving interferon-α (n=510), mammalian target of rapamycin (mTOR) inhibitors (n=660), and vascular endothelial growth factor targeted therapies (VEGF-TT; n=2974) on phase II/III clinical trials., Outcomes Measurements and Statistical Analysis: The association of antibiotic use (defined as use from 8 wk before to 4 wk after the initiation of anticancer therapy) with progression-free survival (PFS) and overall survival (OS) was evaluated using Cox regression, adjusted for known prognostic factors including International Metastatic RCC Database Consortium risk factors., Results and Limitations: Most patients were male, had clear cell histology, and were at an intermediate risk. Overall, in the institutional cohort, objective response rate (ORR) was 30%, PFS was 7.2 mo, and 1-yr OS was 77%. Antibiotic users (n=31, 21%) had a lower ORR (12.9% vs 34.8%, p=0.026) and shorter PFS (adjusted hazard ratio [HR]=1.96, 95% confidence interval [CI] 1.20-3.20, p=0.007) than antibiotic nonusers. In the trial-database cohort, antibiotic use (n=709, 17%) adversely impacted OS in patients treated with interferon (HR=1.62, 95% CI 1.13-2.31, p=0.008) or with VEGF-TT and prior cytokines (HR=1.65, 95% CI 1.04-2.62, p=0.033), but not patients treated with mTOR inhibitors or VEGF-TT without prior cytokines. Limitations include retrospective design, and limited details regarding concomitant medications and antibiotic indication/duration., Conclusions: Antibiotic use appears to reduce the efficacy of immunotherapy-based regimens in mRCC. The modulation of gut microbiota may play an important role in optimizing outcomes of patients treated with ICIs., Patient Summary: We evaluated metastatic renal cell carcinoma patients and found that those who were treated with immunotherapy had worse outcomes if they also received antibiotics at the start of treatment. This study highlights the importance of judicious antibiotic use., (Copyright © 2019. Published by Elsevier B.V.)

Background: International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium (IMDC) risk groups are important when considering therapeutic options for first-line treatment., Materials and Methods: Adult patients with clear cell mRCC initiating first-line sunitinib between 2010 and 2018 were included in this retrospective database study. Median time to treatment discontinuation (TTD) and overall survival (OS) were estimated using Kaplan-Meier analysis. Outcomes were stratified by IMDC risk groups and evaluated for those in the combined intermediate and poor risk group and separately for those in the intermediate risk group with one versus two risk factors., Results: Among 1,769 patients treated with first-line sunitinib, 318 (18%) had favorable, 1,031 (58%) had intermediate, and 420 (24%) had poor IMDC risk. Across the three risk groups, patients had similar age, gender, and sunitinib initiation year. Median TTD was 15.0, 8.5, and 4.2 months in the favorable, intermediate, and poor risk groups, respectively, and 7.1 months in the combined intermediate and poor risk group. Median OS was 52.1, 31.5, and 9.8 months in the favorable, intermediate, and poor risk groups, respectively, and 23.2 months in the combined intermediate and poor risk group. Median OS (35.1 vs. 21.9 months) and TTD (10.3 vs. 6.6 months) were significantly different between intermediate risk patients with one versus two risk factors., Conclusion: This real-world study found a median OS of 52 months for patients with favorable IMDC risk treated with first-line sunitinib, setting a new benchmark on clinical outcomes of clear cell mRCC. Analysis of intermediate risk group by one or two risk factors demonstrated distinct clinical outcomes., Implications for Practice: This analysis offers a contemporary benchmark for overall survival (median, 52.1 months; 95% confidence interval, 43.4-61.2) among patients with clear cell metastatic renal cell carcinoma who were treated with sunitinib as first-line therapy in a real-world setting and classified as favorable risk according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification. This study demonstrates that clinical outcomes differ between IMDC risk groups as well as within the intermediate risk group based on the number of risk factors, thus warranting further consideration of risk group when counseling patients about therapeutic options and designing clinical trials., (© AlphaMed Press 2020.)

Background: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Although the incidence and prevalence of irAEs have been well characterized in the literature, less is known about the cumulative incidence rate of irAEs. We studied the cumulative incidence of irAEs, defined as the probability of irAE occurrence over time and the risk factors for irAE development in metastatic urothelial carcinoma (mUC) and renal cell carcinoma (mRCC) patients treated with ICIs., Methods: We identified a cohort of patients who received ICIs for mUC and mRCC. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) V.5.0 guidelines. The monthly incidence of irAEs over time was reported after landmark duration of therapy. Cumulative incidence of irAEs was calculated to evaluate the time to the first occurrence of an irAE accounting for the competing risk of death. Prognostic factors for irAE were assessed using the Fine and Gray method., Results: A total of 470 patients were treated with ICIs between July 2013 and October 2018 (mUC: 199 (42.3%); mRCC: 271 (57.7%)). 341 (72.6%) patients received monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received dual ICI therapy. Overall, 186 patients (39.5%) experienced an irAE at any time point. Common irAEs included hypothyroidism (n=42, 22.6%), rush and pruritus (n=36, 19.4%), diarrhea/colitis (n=35, 18.8%), transaminitis (n=32, 17.2%), and pneumonitis (n=14, 7.5%). Monthly incidence rates decreased over time; however, 17 of 109 (15.6%, 95% CI: 9.4% to 23.8%) experienced their first irAE at least 1 year after treatment initiation. No differences in cumulative incidence were observed based on cancer type, agent, or irAE grade. On multivariable analysis, combined ICI therapy with another ICI or with targeted therapy (p<0.001), first-line ICI therapy (p=0.011), and PD-1 inhibitor therapy (p=0.007) were all significantly associated with irAE development., Conclusions: This study quantitates the incidence of developing irAEs due to ICI conditioned on time elapsed without irAE development. Although the monthly incidence of irAEs decreased over time on therapy, patients can still develop delayed irAEs beyond ICI discontinuation, and thus, continuous vigilant monitoring is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Immune checkpoint inhibitors (ICI) induce a range of immune-related adverse events (irAEs) with various degrees of severity. While clinical experience with ICI retreatment following clinically significant irAEs is growing, the safety and efficacy are not yet well characterized., Methods: This multicenter retrospective study identified patients with metastatic renal cell carcinoma treated with ICI who had >1 week therapy interruption for irAEs. Patients were classified into retreatment and discontinuation cohorts based on whether or not they resumed an ICI. Toxicity and clinical outcomes were assessed descriptively., Results: Of 499 patients treated with ICIs, 80 developed irAEs warranting treatment interruption; 36 (45%) of whom were restarted on an ICI and 44 (55%) who permanently discontinued. Median time to initial irAE was similar between the retreatment and discontinuation cohorts (2.8 vs 2.7 months, p=0.59). The type and grade of irAEs were balanced across the cohorts; however, fewer retreatment patients required corticosteroids (55.6% vs 84.1%, p=0.007) and hospitalizations (33.3% vs 65.9%, p=0.007) for irAE management compared with discontinuation patients. Median treatment holiday before reinitiation was 0.9 months (0.2-31.6). After retreatment, 50% (n=18/36) experienced subsequent irAEs (12 new, 6 recurrent) with 7 (19%) grade 3 events and 13 drug interruptions. Median time to irAE recurrence after retreatment was 2.8 months (range: 0.3-13.8). Retreatment resulted in 6 (23.1%) additional responses in 26 patients whose disease had not previously responded. From first ICI initiation, median time to next therapy was 14.2 months (95% CI 8.2 to 18.9) and 9.0 months (5.3 to 25.8), and 2-year overall survival was 76% (95%CI 55% to 88%) and 66% (48% to 79%) in the retreatment and discontinuation groups, respectively., Conclusions: Despite a considerable rate of irAE recurrence with retreatment after a prior clinically significant irAE, most irAEs were low grade and controllable. Prospective studies are warranted to confirm that retreatment enhances survival outcomes that justify the safety risks., Competing Interests: Competing interests: WX reports consulting role with Bayer. NM-C reports support for research travel from Pfizer and Ipsen, and consulting fees for BMS. BAM reports advisory roles for Astellas/Seattle Genetics, Astra Zeneca, Nektar, Exelixis, Pfizer and consultant roles for Astellas, Bayer, Genentech, Janssen and EMD Serono. DYCH reports consulting roles with BMS, Novartis, Pfizer, Ipsen and Exelixis. MAB has a consulting/advisory role with Exelixis, Seattle Genetics, EMD Serono, Nektar and Sanofi and receives institutional research funding from Bayer, Bristol-Myers Squibb, Genentech/Roche, Xencor, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Peleton and Pfizer. TKC reports research (institutional and personal) funds from AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takedal Honoraria from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly; consulting or advisory Role for AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest; stock ownership in Pionyr, Tempest; no leadership or employment in for-profit companies; other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee); patents, royalties or other intellectual properties: International Patent Application No. PCT/US2018/12209, entitled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response,” filed January 3, 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed January 11, 2017 and International Patent Application No. PCT/US2018/058430, entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy,” filed October 31, 2018, claiming priority to U.S. Provisional Patent Application No. 62/581,175, filed November 3, 2017; travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria; medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others).The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. CV provided upon request for scope of clinical practice and research. He reports mentoring several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components. LCH reports consulting fees from Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano, Ology Medical Education; Research funding from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, Endocyte (Novartis), and support for research travel from Bayer and Genentech., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Treatment options for rare genitourinary malignancies, including adrenocortical carcinoma, bladder/upper tract cancers of variant histology, penile squamous cell carcinoma, and chemotherapy-refractory germ cell tumors, are limited, often with a poor response to systemic therapy. Given preclinical data and efficacy across multiple malignancies, immunotherapy has been and continues to be explored in this challenging setting. In this report, we explore the data for immunotherapy in these tumors and highlight ongoing clinical trials. International collaborations and innovative trials will be critical to advancing treatment for these rare tumors. PATIENT SUMMARY: In this report, we explore the data for immunotherapy in rare genitourinary malignancies and highlight ongoing clinical trials. International collaborations and innovative trials will be critical to advancing treatment for these rare tumors., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: In this multicenter phase II trial, we evaluated atezolizumab combined with bevacizumab in patients with advanced renal cell carcinoma (RCC) with variant histology or any RCC histology with ≥ 20% sarcomatoid differentiation., Patients and Methods: Eligible patients may have received previous systemic therapy, excluding prior bevacizumab or checkpoint inhibitors. Patients underwent a baseline biopsy and received atezolizumab 1,200 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. The primary end point was overall response rate (ORR) by RECIST version 1.1. Additional end points were progression-free survival (PFS), toxicity, biomarkers of response as determined by programmed death-ligand 1 (PD-L1) status, and on-therapy quality-of-life (QOL) metrics using the Functional Assessment of Cancer Therapy Kidney Symptom Index-19 and the Brief Fatigue Inventory., Results: Sixty patients received at least 1 dose of either study agent; the majority (65%) were treatment naïve. The ORR for the overall population was 33% and 50% in patients with clear cell RCC with sarcomatoid differentiation and 26% in patients with variant histology RCC. Median PFS was 8.3 months (95% CI, 5.7 to 10.9 months). PD-L1 status was available for 36 patients; 15 (42%) had ≥ 1% expression on tumor cells. ORR in PD-L1-positive patients was 60% (n = 9) v 19% (n = 4) in PD-L1-negative patients. Eight patients (13%) developed treatment-related grade 3 toxicities. There were no treatment-related grade 4-5 toxicities. QOL was maintained throughout therapy., Conclusion: In this study, atezolizumab and bevacizumab demonstrated safety and resulted in objective responses in patients with variant histology RCC or RCC with ≥ 20% sarcomatoid differentiation. This regimen warrants additional exploration in patients with rare RCC, particularly those with PD-L1-positive tumors.

Purpose: Locally advanced or metastatic urothelial carcinoma is an incurable disease with limited treatment options, especially for patients who were previously treated with platinum and anti-programmed death 1 or anti-programmed death ligand 1 (PD-1/L1) therapy. Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, which is highly expressed in urothelial carcinoma., Methods: EV-201 is a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti-PD-1/L1 therapy. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review. Key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability., Results: Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma. Median follow-up was 10.2 months (range, 0.5 to 16.5 months). Confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses. Similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy. Median duration of response was 7.6 months (range, 0.95 to 11.30+ months). The most common treatment-related adverse events were fatigue (50%), any peripheral neuropathy (50%), alopecia (49%), any rash (48%), decreased appetite (44%), and dysgeusia (40%). No single treatment-related adverse events grade 3 or greater occurred in 10% or more of patients., Conclusion: Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies.

Introduction : The conventional management of most patients with metastatic urothelial carcinoma (UC) is platinum-based chemotherapy followed by immunotherapy. Erdafitinib is an option in post-platinum patients with activating mutations in fibroblast growth factor receptor (FGFR)-3 and -2. Salvage therapy with taxanes or vinflunine has demonstrated minimal efficacy. Enfortumab Vedotin (EV), a monoclonal antibody-drug conjugate (ADC) targeting nectin-4 is under investigation in patients with advanced UC. Areas covered : This review describes the epidemiology and unmet needs of patients with metastatic UC and is focused specifically on heavily treated patients. We explore the rationale for targeting nectin 4 and the clinical development of EV; efficacy and safety data from the completed phase I and II studies are examined. Ongoing trials to definitively assess clinical outcomes in comparison to current therapy and trials exploring EV in combination are also highlighted. Expert opinion : There is an unmet need for new therapies in most patients with advanced UC and who progress after platinum and immunotherapy. EV has shown promising efficacy and safety in this population in phase 1 and 2 trials including those with poor prognostic factors such as liver metastases. Ongoing trials exploring this agent in combination will continue to advance the treatment of UC.

Introduction: Obesity at the time of diagnosis has been associated with better outcomes in some metastatic cancers such as renal-cell cancer. The association between body mass index (BMI) and germ-cell tumor (GCT) outcomes has not been reported. We sought to assess the association between BMI and outcomes in men with GCT in a large hospital registry., Patients and Methods: Electronic medical records for 1161 GCT patients treated at Dana-Farber Cancer Institute between 1997 and 2012 were reviewed. Information regarding BMI, histology, stage, treatment, and patient characteristics was obtained. We separately evaluated patients with clinical stage 1 and metastatic disease. Using logistic regression analysis, we investigated the association between BMI and clinical features, such as International Germ Cell Consensus Classification (IGCCC) and stage at diagnosis. We used Cox proportional hazards regression to assess the association between BMI and risk of relapse and GCT-specific death., Results: Among men diagnosed with clinical stage 1 GCT, BMI ≥ 25 kg/m 2 was not associated with an increased risk of relapse (hazard ratio = 0.83; 95% confidence interval, 0.53-1.30) compared to those with BMI < 25 kg/m 2 . In the metastatic disease setting, men with BMI < 25 kg/m 2 were less likely to present with good-risk disease; however, BMI was not associated with risk of relapse (hazard ratio = 1.00; 95% confidence interval, 0.63-1.59, P = .99)., Conclusion: There was no evidence for an association between BMI and GCT outcomes. A lower BMI was associated with adverse prognostic variables at presentation per IGCCC risk groups for metastatic GCT, but this was not associated with relapse., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Drug-induced peripheral neuropathy is a side effect of a variety of therapeutic agents that can affect therapeutic adherence and lead to regimen modifications, impacting patient quality of life. The molecular mechanisms involved in the development of this condition have yet to be completely described in the literature. We used a computational network pharmacology approach to explore the Connectivity Map, a large collection of transcriptional profiles from drug perturbation experiments to identify common genes affected by peripheral neuropathy-inducing drugs. Consensus profiles for 98 of these drugs were used to construct a drug-gene perturbation network. We identified 27 genes significantly associated with neuropathy-inducing drugs. These genes may have a potential role in the action of neuropathy-inducing drugs. Our results suggest that molecular mechanisms, including alterations in mitochondrial function, microtubule and cytoskeleton function, ion channels, transcriptional regulation including epigenetic mechanisms, signal transduction, and wound healing, may play a critical role in drug-induced peripheral neuropathy., (© 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Background: Aggregation of high-throughput biological data using pathway-based approaches is useful to associate molecular results to functional features related to the studied phenomenon. Biological pathways communicate with one another through the crosstalk phenomenon, forming large networks of interacting processes., Results: In this work, we present the pathway crosstalk perturbation network (PXPN) model, a novel model used to analyze and integrate pathway perturbation data based on graph theory. With this model, the changes in activity and communication between pathways observed in transitions between physiological states are represented as networks. The model presented here is agnostic to the type of biological data and pathway definition used and can be implemented to analyze any type of high-throughput perturbation experiments. We present a case study in which we use our proposed model to analyze a gene expression dataset derived from experiments in a BKS-db/db mouse model of type 2 diabetes mellitus-associated neuropathy (DN) and the effects of the drug pioglitazone in this condition. The networks generated describe the profile of pathway perturbation involved in the transitions between the healthy and the pathological state and the pharmacologically treated pathology. We identify changes in the connectivity of perturbed pathways associated to each biological transition, such as rewiring between extracellular matrix, neuronal system, and G-protein coupled receptor signaling pathways., Conclusion: The PXPN model is a novel, flexible method used to integrate high-throughput data derived from perturbation experiments; it is agnostic to the type of data and enrichment function used, and it is applicable to a wide range of biological phenomena of interest.

Cytoreductive nephrectomy (CRN) has long been considered a standard of care in the management of mRCC. This is largely based on randomized trials in the era of interferon (IFN) that demonstrate an improvement in overall survival (OS). With the advent of targeted therapies, the role of CRN has been questioned and multiple retrospective analyses have shown a potential benefit, particularly in intermediate-risk disease. Two long-awaited prospective trials have been published in the past year that explore the role of CRN. The CARMENA trial randomly assigned patients to therapy with sunitinib with or without CRN, showing noninferiority of sunitinib alone versus sunitinib plus CRN with a median OS of 18.4 months versus 13.9 months, respectively (hazard ratio [HR] for mortality, 0.89; 95% CI, 0.71-1.1). The SURTIME trial randomly assigned patients to immediate CRN followed by sunitinib versus a deferred CRN after three cycles of sunitinib. Analysis is limited by early termination as a result of low accrual. Although there was no difference in progression-free survival (PFS), median OS was significantly improved among patients in the deferred CRN arm (HR, 0.57; 95% CI, 0.34-0.95; p = .032). Early systemic therapy is paramount, but there are patients who may derive benefit by incorporating the removal of the primary tumor in their multimodal therapy, perhaps in a deferred setting. As systemic treatment paradigms shift and immunotherapy again moves to the frontline setting with the potential for novel therapeutic approaches, the role of CRN will continue to evolve with the potential to offer surgical interventions with minimal, if any, delay in systemic treatment.

Context: Systemic therapy for metastatic clear cell renal cell carcinoma (mccRCC) has greatly evolved over the last 15yr. More recently, combination strategies involving contemporary immunotherapy have emerged as key opportunities to further shift the treatment landscape., Objective: To review the evidence regarding the efficacy and safety of standard therapeutic options in mccRCC as well as combination immunotherapy options on the horizon., Evidence Acquisition: PubMed/Medline, Embase, Web of Knowledge, and Cochrane Library databases were searched up to February 2018 and according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. A narrative review of studies was performed., Evidence Synthesis: Twenty-six studies were included regarding therapies for metastatic RCC including vascular endothelial growth factor (VEGF)-directed therapy (n=9), mTOR inhibitors (n=2), cytokines (n=3), vaccines (n=3), and immune checkpoint inhibitors (ICIs, n=9). VEGF tyrosine kinase inhibitor monotherapy had been the standard therapy, and its use is evolving in the front-line setting with ICIs; cabozantinib provides superior progression-free survival versus sunitinib in intermediate- and poor-risk patients, by International Metastatic RCC Database Consortium criteria. The mTOR therapy is largely inferior to VEGF-directed therapy, although it has a role in combination strategies. Cytokines have largely been replaced in current practice throughout most regions, and vaccines have failed to show improved survival in phase III studies to date. ICIs have now become standard care in untreated patients with intermediate and poor risks, given overall survival benefit seen with CheckMate-214 study; survival data from IMmotion 151 are not yet mature. Several ongoing phase III combination trials, with promising early-phase data, are due to be read out., Conclusions: The treatment landscape for mccRCC has evolved since the introduction of VEGF inhibitors. Combination therapies involving checkpoint inhibitors could be the next standard of care., Patient Summary: With the expanding role of immune checkpoint inhibitors in metastatic renal cell carcinoma, the treatment paradigm has shifted to include combination therapy in the untreated setting. As the field advances, the bar has been raised in evaluating ongoing combination strategies., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes. In this study, we employed a systems biology approach to identify DPN-related transcriptional pathways conserved across human and various murine models. Eight microarray datasets on peripheral nerve samples from murine models of type 1 (streptozotocin-treated) and type 2 (db/db and ob/ob) diabetes of various ages and human subjects with non-progressive and progressive DPN were collected. Differentially expressed genes (DEGs) were identified between non-diabetic and diabetic samples in murine models, and non-progressive and progressive human samples using a unified analysis pipeline. A transcriptional network for each DEG set was constructed based on literature-derived gene-gene interaction information. Seven pairwise human-vs-murine comparisons using a network-comparison program resulted in shared sub-networks including 46 to 396 genes, which were further merged into a single network of 688 genes. Pathway and centrality analyses revealed highly connected genes and pathways including LXR/RXR activation, adipogenesis, glucocorticoid receptor signalling, and multiple cytokine and chemokine pathways. Our systems biology approach identified highly conserved pathways across human and murine models that are likely to play a role in DPN pathogenesis and provide new possible mechanism-based targets for DPN therapy.

We examined food consumption in response to a laboratory-induced stressor (two challenging neuropsychological tasks) among non-Hispanic White women categorized as lower or higher in socioeconomic status based on education. The two socioeconomic status groups did not differ with respect to current hunger or baseline dietary habits. Perceived stress was measured pre- and post-challenge. Snacks were offered post-challenge; food consumption was measured by weighing snack bowls pre- and post-offering. Perceived stress increased pre- to post-challenge for both groups, but this effect was stronger for women lower in socioeconomic status. In addition, women lower versus higher in socioeconomic status consumed more food overall and more high-fat sweet food in particular (large effect sizes). These findings provide evidence of socioeconomic status differences in food consumption following an acute stressor.

Purpose: FGFR3-TACC3 (fibroblast growth factor receptor 3-transforming acidic coiled coil-containing protein 3) fusions have recently been identified as driver mutations that lead to the activation of FGFR3 in bladder cancer and other tumor types and are associated with sensitivity to tyrosine kinase inhibitors. We examined the clinical and molecular characteristics of patients with FGFR3-TACC3 fusions and hypothesized that they are enriched in a subset of patients with bladder cancer., Materials and Methods: We correlated somatic FGFR3-TACC3 fusions with clinical and molecular features in two cohorts of patients with bladder cancer. The first cohort consisted of the muscle-invasive bladder cancer (MIBC) data set (n = 412) from The Cancer Genome Atlas. The second cohort consisted of patients with MIBC or high-grade non-MIBC at the Dana-Farber Cancer Institute that had targeted capture sequencing of a selected panel of cancer genes (n = 356). All statistical tests were two sided. The clinical response of one patient with FGFR3-TACC3 bladder cancer to an FGFR3 inhibitor was investigated., Results: Overall, 751 patients with high-grade bladder cancer without FGFR3-TACC3 fusions and 17 with FGFR3-TACC3 fusions were identified in the pooled analysis of the data sets from The Cancer Genome Atlas and the Dana-Farber Cancer Institute. FGFR3-TACC3 fusions were enriched in patients age ≤ 50 years versus age 51 to 65 years versus those older than 65 years (pooled, P = .002), and were observed in four (12%) of 33 patients age ≤ 50 years in the pooled analysis. Similarly, FGFR3-TACC3 fusions were significantly more common in Asians (13%) compared with African Americans (4%) and whites (2%; pooled, P < .001), as well as in never smokers (5.6%) compared with ever smokers (1.1%; pooled, P < .001). One patient with the fusion who was treated with an FGFR3 inhibitor achieved complete remission for 10 months., Conclusion: Clinical testing to identify FGFR3 fusions should be prioritized for patients with bladder cancer who are younger, never smokers, and/or Asian., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Amin H. NassarNo relationship to discloseKevin LundgrenNo relationship to discloseMark PomerantzHonoraria: BayerEliezer Van AllenStock and Other Ownership Interests: Synapse, Tango Therapeutics, Genome Medical Consulting or Advisory Role: Synapse, Roche, Third Rock Ventures, Takeda, Novartis, Genome Medical, InVitae Speakers' Bureau: Illumina Research Funding: Bristol-Myers Squibb, NovartisLauren HarshmanConsulting or Advisory Role: Medivation, Astellas Pharma, Pfizer, Genentech, Theragene, KEW, Corvus Pharmaceuticals, Merck, Exelixis, Bayer Research Funding: Medivation, Astellas Pharma (Inst), Bayer (Inst), Sotio (Inst), Genentech (Inst), Dendreon (Inst), Bristol-Myers Squibb (Inst), Takeda (Inst), Merck (Inst), Janssen Oncology (Inst), Pfizer (Inst) Travel, Accommodations, Expenses: BayerAtish D. ChoudhuryEmployment: LeMaitre Vascular (I) Honoraria: Bayer, Astellas Pharma Research Funding: Janssen Pharmaceuticals (Inst)Mark A. PrestonNo relationship to discloseGraeme S. SteeleNo relationship to discloseKent W. MouwConsulting or Advisory Role: Pfizer, EMD SeronoXiao X. WeiNo relationship to discloseBradley A. McGregorConsulting or Advisory Role: Bayer, Seattle Genetics, Astellas Pharma, Exelixis, AstraZeneca, Genentech, NextarToni K. ChoueiriHonoraria: National Comprehensive Cancer Network, UpToDate Consulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Peloton Therapeutics, Exelixis, Prometheus Laboratories, Alligent, Ipsen, Corvus Pharmaceuticals Research Funding: Pfizer (Inst), Novartis (Inst), Merck (Inst), Exelixis (Inst), TRACON Pharma (Inst), GlaxoSmithKline (Inst), Bristol-Myers Squibb (Inst), AstraZeneca (Inst), Peloton Therapeutics (Inst), Genentech (Inst), Celldex (Inst), Agensys (Inst), Eisai (Inst)Joaquim BellmuntHonoraria: UpToDate Consulting or Advisory Role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca, MedImmune, Bristol-Myers Squibb Research Funding: Millennium Pharmaceuticals (Inst), Sanofi (Inst) Travel, Accommodations, Expenses: Pfizer, MSD OncologyDavid J. KwiatkowskiConsulting or Advisory Role: AstraZeneca, Genentech Research Funding: AADiGuru P. SonpavdeHonoraria: UpToDate Consulting or Advisory Role: Bayer, Genentech, Sanofi, Merck, Novartis, Pfizer, Argos Therapeutics, Agensys, Eisai, AstraZeneca, Janssen Pharmaceuticals, Amgen, Bristol-Myers Squibb, Exelixis Speakers' Bureau: Clinical Care Options, National Comprehensive Cancer Network, Physician Education Resource, Onclive, Research to Practice Research Funding: Onyx Pharmaceuticals (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Celgene (Inst), Merck (Inst), Pfizer (Inst) Other Relationship: Boehringer Ingelheim, AstraZeneca, (© 2018 by American Society of Clinical Oncology.)

The quintessential biological response to disease is inflammation. It is a driver and an important element in a wide range of pathological states. Pharmacological management of inflammation is therefore central in the clinical setting. Anti-inflammatory drugs modulate specific molecules involved in the inflammatory response; these drugs are traditionally classified as steroidal and non-steroidal drugs. However, the effects of these drugs are rarely limited to their canonical targets, affecting other molecules and altering biological functions with system-wide effects that can lead to the emergence of secondary therapeutic applications or adverse drug reactions (ADRs). In this study, relationships among anti-inflammatory drugs, functional pathways, and ADRs were explored through network models. We integrated structural drug information, experimental anti-inflammatory drug perturbation gene expression profiles obtained from the Connectivity Map and Library of Integrated Network-Based Cellular Signatures, functional pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases, as well as adverse reaction information from the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The network models comprise nodes representing anti-inflammatory drugs, functional pathways, and adverse effects. We identified structural and gene perturbation similarities linking anti-inflammatory drugs. Functional pathways were connected to drugs by implementing Gene Set Enrichment Analysis (GSEA). Drugs and adverse effects were connected based on the proportional reporting ratio (PRR) of an adverse effect in response to a given drug. Through these network models, relationships among anti-inflammatory drugs, their functional effects at the pathway level, and their adverse effects were explored. These networks comprise 70 different anti-inflammatory drugs, 462 functional pathways, and 1,175 ADRs. Network-based properties, such as degree, clustering coefficient, and node strength, were used to identify new therapeutic applications within and beyond the anti-inflammatory context, as well as ADR risk for these drugs, helping to select better repurposing candidates. Based on these parameters, we identified naproxen, meloxicam, etodolac, tenoxicam, flufenamic acid, fenoprofen, and nabumetone as candidates for drug repurposing with lower ADR risk. This network-based analysis pipeline provides a novel way to explore the effects of drugs in a therapeutic space.

Background: An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB., Methods: We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6 weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR., Results: Median follow up was 16.6 months (range: 0.7-67.8). Median duration on therapy was 5.1 months (<1-61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3-42.4) at baseline and 4.1 (1.1-96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ≥25% from baseline to 6 weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS (p < 0.001) and OS (p = 0.004), whereas a decrease in NLR by ≥25% was associated with improved outcomes., Conclusions: Early decline and NLR at 6 weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation.

Background: Development of psychosocial group interventions for ovarian cancer survivors has been limited. Drawing from elements of cognitive-behavioral stress management (CBSM), mindfulness-based stress reduction (MBSR), and acceptance and commitment therapy (ACT), we developed and conducted preliminary testing of an Internet-based group intervention tailored specifically to meet the needs of ovarian cancer survivors. The Internet-based platform facilitated home delivery of the psychosocial intervention to a group of cancer survivors for whom attending face-to-face programs could be difficult given their physical limitations and the small number of ovarian cancer survivors at any one treatment site., Objective: The aim of this study was to develop, optimize, and assess the usability, acceptability, feasibility, and preliminary intended effects of an Internet-based group stress management intervention for ovarian cancer survivors delivered via a tablet or laptop., Methods: In total, 9 ovarian cancer survivors provided feedback during usability testing. Subsequently, 19 survivors participated in 5 waves of field testing of the 10-week group intervention led by 2 psychologists. The group met weekly for 2 hours via an Internet-based videoconference platform. Structured interviews and weekly evaluations were used to elicit feedback on the website and intervention content. Before and after the intervention, measures of mood, quality of life (QOL), perceived stress, sleep, and social support were administered. Paired t tests were used to examine changes in psychosocial measures over time., Results: Usability results indicated that participants (n=9) performed basic tablet functions quickly with no errors and performed website functions easily with a low frequency of errors. In the field trial (n=19), across 5 groups, the 10-week intervention was well attended. Perceived stress (P=.03) and ovarian cancer-specific QOL (P=.01) both improved significantly during the course of the intervention. Trends toward decreased distress (P=.18) and greater physical (P=.05) and functional well-being (P=.06) were also observed. Qualitative interviews revealed that the most common obstacles participants experienced were technical issues and the time commitment for practicing the techniques taught in the program. Participants reported that the intervention helped them to overcome a sense of isolation and that they appreciated the ability to participate at home., Conclusions: An Internet-based group intervention tailored specifically for ovarian cancer survivors is highly usable and acceptable with moderate levels of feasibility. Preliminary psychosocial outcomes indicate decreases in perceived stress and improvements in ovarian cancer-specific QOL following the intervention. A randomized clinical trial is needed to demonstrate the efficacy of this promising intervention for ovarian cancer survivors., (©Ellen M Kinner, Jessica S Armer, Bonnie A McGregor, Jennifer Duffecy, Susan Leighton, Marya E Corden, Janine Gauthier Mullady, Frank J Penedo, Susan K Lutgendorf. Originally published in JMIR Cancer (http://cancer.jmir.org), 15.01.2018.)

Context: Immunotherapy has historic and contemporary presence in prostate, urothelial (UC), and renal cell (RCC) carcinomas. However, robust data on utility and generalizability of these treatments in older patients are lacking., Objective: To systematically evaluate evidence regarding the efficacy and safety of immunotherapy in elderly patients with prostate cancer, UC, or RCC., Evidence Acquisition: PubMed/Medline, Embase, Web of Knowledge, and Cochrane Library databases were searched up to October 2017 and according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. A narrative review of studies was performed., Evidence Synthesis: Twenty-one reports were included regarding prostate cancer (four studies), UC (eight), and RCC (nine). In prostate cancer, sipuleucel-T improves survival (median age >70 yr) and similar results were seen in the PROSTVAC phase 2 trial. Ipilimumab has not improved survival independent of age; data for programmed cell death 1 inhibition is evolving. In metastatic UC, ≥50% of patients enrolled in pivotal checkpoint inhibitor studies were aged ≥65 yr. Three studies reported similar objective response rates (ORRs) in patients aged <65 versus ≥65 yr, whereas one study reported comparable ORRs in patients <80 versus ≥80 yr. In metastatic RCC, cytokine studies showed no efficacy difference by age; one study reported more ≥grade 3 toxicity in patients aged ≥65 yr. One vaccine-based study suggests that older age was associated with shorter survival. The benefit of nivolumab in second-line therapy was more apparent for patients aged 65-<75 yr than for those aged ≥75 yr. Across tumor subtypes, immunotherapy was well tolerated with minimal data stratifying toxicity by age., Conclusions: Contemporary immunotherapy has informed practice in genitourinary malignancies independent of patient age. Trial reporting of outcomes by age will be important to understand the generalizability of ongoing investigations for elderly patients., Patient Summary: With the growing use of immunotherapy in genitourinary malignancies, benefits appear to apply independent of age. As the field advances, detailed reporting on outcomes and toxicities by age will be informative for both patients and physicians when discussing treatment options., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Treatment of metastatic renal cell carcinoma (mRCC) typically entails mechanistically distinct agents across the first- and second-line setting. Activity of these agents may be predicated on selective pressure that modulates RCC biology. Circulating tumor DNA (ctDNA) is a platform to noninvasively ascertain temporal changes in genomic profile., Objective: To assess the ctDNA profile in a large cohort of mRCC patients, and to assess changes across patients receiving first-line and later lines of therapy., Design, Setting, and Participants: We obtained the ctDNA profile in mRCC patients who received ctDNA profiling as part of routine clinical care at progression using a 73-gene Clinical Laboratory Improvement Amendments-certified ctDNA platform., Outcome Measurements and Statistical Analysis: Genomic alterations (GAs) were pooled for the entire cohort. A comparison of first- and postfirst-line was performed with grouping based on conventional practice patterns (first-line regimens included sunitinib, pazopanib, and bevacizumab, and postfirst-line regimens included everolimus, axitinib, cabozantinib, and nivolumab)., Results and Limitations: ctDNA clinical results from a nationwide cohort of 220 consecutive patients with mRCC were assessed (145 men, 75 women; median age: 63 yr, interquartile range: 57-70). GAs were detected in 78.6% of patients. The most frequent GAs in the overall cohort included TP53 (35%), VHL (23%), EGFR (17%), NF1 (16%), and ARID1A (12%). Thirty-eight and 64 patients were coded as receiving first-line and later line agents, respectively. The highest disparity in GA frequencies in postfirst-line versus first-line were in TP53 (49% vs 24%), VHL (29% vs 18%), NF1 (20% vs 3%), EGFR (15% vs 8%), and PIK3CA (17% vs 8%) while ARID1A was equivalent (13% vs 11%). Restricting the analysis to later lines versus first-line vascular endothelial growth factor inhibitors, these differences were even more prominent, particularly for TP53 (64% vs 31%) and NF1 (29% vs 4%)., Conclusions: In the largest assessment of ctDNA-detected GAs prevalence in mRCC to date, the majority of patients demonstrated clinically and biologically relevant GAs. Increasing p53 and mechanistic target of rapamycin pathway (eg, NF1, PIK3CA) alterations in postfirst-line patients with first-line vascular endothelial growth factor-directed therapy may underlie mechanisms of resistance. Routine ctDNA assessment during the clinical course of mRCC patients may have therapeutic implications., Patient Summary: Collection of circulating tumor DNA is feasible in patients with metastatic renal cell carcinoma, and analysis of a large cohort demonstrates significant changes in circulating tumor DNA profile across patients' clinical course which may have therapeutic implications., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Emerging evidence suggests a positive association of diet and obesity with depression. Researchers have examined several diet-mood hypotheses, including investigating the extent to which carbohydrates may impact mood. There is limited research on how glycemic load, a characteristic of carbohydrates, impacts mood in healthy adults. Eighty-two healthy weight and overweight/obese, but otherwise healthy, adults enrolled in a randomized, crossover controlled feeding study testing low-compared to high-glycemic load diets. All participants completed self-report mood and energy level questionnaires during each arm of the intervention. Diets were isocaloric and were matched by macronutrient content as a percent of total energy. Mood was assessed with the Profile of Mood States (POMS) subscales; tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment, total mood disturbance (TMD), and negative affect (NA) in addition to the Center for Epidemiological Studies - Depression (CES-D) scale at baseline and end of both 28-day feeding periods. Linear mixed models tested the intervention effect on mood, controlling for baseline POMS and CES-D scores, diet type, diet sequence, feeding period, sex, and percent body fat classification. The consumption of the high-glycemic load diet resulted in a 38% higher score for depressive symptoms on the CES-D (P = 0.002) compared to the low-glycemic load diet as well as 55% higher score for TMD (P = 0.05), and 26% higher score for fatigue/inertia (P = 0.04). In subgroup analyses, the overweight/obese participants had 40% higher scores on the CES-D scale compared to healthy weight participants (P = 0.05). In conclusion, a high-glycemic load diet was associated with higher depression symptoms, total mood disturbance, and fatigue compared to a low-glycemic load diet especially in overweight/obese, but otherwise healthy, adults. This trial was registered at clinicaltrials.gov: NCT00622661., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The mean fibre diameter (MFD) of wool is the primary determinant of price, processing performance and textile quality. This study determines the primary influences on MFD as Saxon Merino sheep age, by allometrically relating MFD to fleece-free liveweight (FFLwt). In total, 79 sheep were grazed in combinations of three stocking rates and two grazing systems (GS: sheep only; mixed with Angora goats) and studied over 3 years. Measurements were made over 14 consecutive periods (Segments), including segments of FFLwt gain or FFLwt loss. Using shearing and liveweight records and dye-bands on wool, the FFLwt and average daily gain (ADG) of each sheep were determined for each segment. The mean and range in key measurements were as follows: FFLwt, 40.1 (23.1 to 64.1) kg; MFD, 18.8 (12.7 to 25.8) μm. A random coefficient restricted maximum likelihood (REML) regression mixed model was developed to relate the logarithm of MFD to the logarithm of FFLwt and other effects. The model can be written in the form of ${\rm MFD}\,{\equals}\,\rkappa \left( {{\rm GS,}\,{\rm A}{\rm ,}\,{\rm Segment}{\rm .Plot,}\,{\rm Segment,}\,{\rm ADG}} \right){\times}{\rm FFLwt}^{{\left( {\ralpha \left( {{\rm GS}} \right){\plus}\rbeta \left(\rm A \right){\plus}\rgamma \left( {{\rm Segment}{\rm .Plot}} \right)} \right)}} $ , where $\ralpha \left( {{\rm GS}} \right)\,{\equals}\,\;\left\{ {\matrix{\!\! {0.32\left( {{\rm SE}\,{\equals}\,{\rm 0}{\rm .038}} \right)\,{\rm when}\,{\rm sheep}\,{\rm are}\,{\rm grazed}\,{\rm alone}} \hfill \cr \!\!\!\!{0.49\left( {{\rm SE}\,{\equals}\,{\rm 0}{\rm .049}} \right)\,{\rm when}\,{\rm sheep}\,{\rm are}\,{\rm mixed}\,{\rm with}\,{\rm goats}} \hfill \cr } } \right.$ β(A) is a random animal effect, γ(Segment.Plot) a random effect associated with Segment.plot combinations, and κ a constant that depends on GS, random animal effects, random Segment.plot combination effects, Segment and ADG. Thus, MFD was allometrically related to the cube root of FFLwt over seasons and years for sheep, but to the square root of FFLwt for sheep grazed with goats. The result for sheep grazed alone accords with a primary response being that the allocation of nutrients towards the cross-sectional growth of wool follicles is proportional to the changes in the skin surface area arising from changes in the size of the sheep. The proportionality constant varied systematically with ADG, and in sheep only grazing, was about 5 when sheep lost 100 g/day and about 6 when sheep gained 100 g/day. The proportionality constant did not systematically change with chronological age. The variation in the allometric coefficient between individual sheep indicates that some sheep were more sensitive to changes in FFLwt than other sheep. Key practical implications include the following: (a) the reporting of systematic increases in MFD with age is likely to be a consequence of allowing sheep to increase in size during shearing intervals as they age; (b) comparisons of MFD between sheep are more likely to have a biological basis when standardised to a common FFLwt and not just to a common age;, ((c) wool quality (MFD, staple strength) are most likely to be optimised in management systems that maintain constant FFLwt of adult sheep within and between years.)