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Hormone therapy following surgery reduces the risk of breast cancer (BC) recurrence and progression of hormone-sensitive BC, especially in postmenopausal women. Despite the antitumor efficacy of hormone therapy, particularly of aromatase inhibitors, they cause long-term side effects, mainly bone density reduction. Exercise can slow the rate of bone loss, which reduces the risk of fractures from osteoporosis, and could be an integrative treatment able to mitigate the BC treatment side effects positively impacting bone health. This narrative review aims to discuss studies on the effect of exercise on bone health in BC women undergoing aromatase inhibitors, highlighting the possible role of exercise as complementary to conventional therapies. Additionally, according to the literature revision, exercise practical applications to improve bone health in these patients are summarized.

Transcranial magnetic stimulation (TMS) evokes neuronal activity in the targeted cortex and connected brain regions. The evoked brain response can be measured with electroencephalography (EEG). TMS combined with simultaneous EEG (TMS−EEG) is widely used for studying cortical reactivity and connectivity at high spatiotemporal resolution. Methodologically, the combination of TMS with EEG is challenging, and there are many open questions in the field. Different TMS−EEG equipment and approaches for data collection and analysis are used. The lack of standardization may affect reproducibility and limit the comparability of results produced in different research laboratories. In addition, there is controversy about the extent to which auditory and somatosensory inputs contribute to transcranially evoked EEG. This review provides a guide for researchers who wish to use TMS−EEG to study the reactivity of the human cortex. A worldwide panel of experts working on TMS−EEG covered all aspects that should be considered in TMS−EEG experiments, providing methodological recommendations (when possible) for effective TMS−EEG recordings and analysis. The panel identified and discussed the challenges of the technique, particularly regarding recording procedures, artifact correction, analysis, and interpretation of the transcranial evoked potentials (TEPs). Therefore, this work offers an extensive overview of TMS−EEG methodology and thus may promote standardization of experimental and computational procedures across groups.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans.Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject’s age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be “safe” where they are applying stimulation beyond that examined in published studies that also investigated potential side effects.Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.

It has been theorized that hemispheric dominance and more segregated information processing have evolved to overcome long conduction delays through the corpus callosum (transcallosal conduction delay - TCD) but that this may still impact behavioral performance, mostly in tasks requiring high timing accuracy. Nevertheless, a thorough understanding of the temporal features of interhemispheric communication is lacking.Here, we aimed to assess the relationship between TCD and behavioral performance with a noninvasive directional cortical measure of TCD obtained from transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) in the motor system.Twenty-one healthy right-handed subjects were tested. TEPs were recorded during an ipsilateral silent period (iSP) paradigm and integrated with diffusion tensor imaging (DTI) and an in-phase bimanual thumb-opposition task. Linear mixed models were applied to test relationships between measures.We found TEP indexes of transcallosal communication at ∼15 ms both after primary motor cortex stimulation (M1-P15) and after dorsal premotor cortex stimulation (dPMC-P15). Both M1-and dPMC-P15 were predicted by mean diffusivity in the callosal body. Moreover, M1-P15 was positively related to iSP. Importantly, M1-P15 latency was linked to bimanual coordination with direction-dependent effects, so that asymmetric TCD was the best predictor of bimanual coordination.Our findings support the idea that transcallosal timing in signal transmission is essential for interhemispheric communication and can impact the final behavioral outcome. However, they challenge the view that a short conduction delay is always beneficial. Rather, they suggest that the effect of the conduction delay may depend on the direction of information flow.

The treatment of Alzheimer’s disease (AD) in the field of non-pharmacological interventions is a challenging issue, given the limited benefits of the available drugs. Cognitive training (CT) represents a commonly recommended strategy in AD. Recently, repetitive transcranial magnetic stimulation (rTMS) has gained increasing attention as a promising therapeutic tool for the treatment of AD, given its ability of enhancing neuroplasticity. In the present randomized, double-blind, sham-controlled study, we aimed at investigating the add-on effect of a high frequency rTMS protocol applied over the left dorsolateral prefrontal cortex (DLPFC) combined with a face-name associative memory CT in the continuum of AD pathology. Fifty patients from a very early to a moderate phase of dementia were randomly assigned to one of two groups: CT plus real rTMS or CT plus placebo rTMS. The results showed that the improvement in the trained associative memory induced with rTMS was superior to that obtained with CT alone. Interestingly, the extent of the additional improvement was affected by disease severity and levels of education, with less impaired and more educated patients showing a greater benefit. When testing for generalization to non-trained cognitive functions, results indicated that patients in CT-real group showed also a greater improvement in visuospatial reasoning than those in the CT-sham group. Interestingly, this improvement persisted over 12 weeks after treatment beginning.The present study provides important hints on the promising therapeutic use of rTMS in AD.

Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) allow one to assess cortical excitability and effective connectivity in clinical and basic research. However, obtaining clean TEPs is challenging due to the various TMS-related artifacts that contaminate the electroencephalographic (EEG) signal when the TMS pulse is delivered. Different preprocessing approaches have been employed to remove the artifacts, but the degree of artifact reduction or signal distortion introduced in this phase of analysis is still unknown. Knowing and controlling this potential source of uncertainty will increase the inter-rater reliability of TEPs and improve the comparability between TMS–EEG studies. The goal of this study was to assess the variability in TEP waveforms due to of the use of different preprocessing pipelines. To accomplish this aim, we preprocessed the same TMS–EEG data with four different pipelines and compared the results. The dataset was obtained from 16 subjects in two identical recording sessions, each session consisting of both left dorsolateral prefrontal cortex and left inferior parietal lobule stimulation at 100% of the resting motor threshold. Considerable differences in TEP amplitudes and global mean field power (GMFP) were found between the preprocessing pipelines. Topographies of TEPs from the different pipelines were all highly correlated (ρ>0.8) at latencies over 100 ms. By contrast, waveforms at latencies under 100 ms showed a variable level of correlation, with ρ ranging between 0.2 and 0.9. Moreover, the test–retest reliability of TEPs depended on the preprocessing pipeline. Taken together, these results take us to suggest that the choice of the preprocessing approach has a marked impact on the final TEP, and that further studies are needed to understand advantages and disadvantages of the different approaches.

Elastin microfibril interface-located proteins (EMILINs) are extracellular matrix glycoproteins implicated in elastogenesis and cell proliferation.Recently, a missense mutation in the EMILIN1 gene has been associated with autosomal dominant connective tissue disorder and motor-sensory neuropathy in a single family.We identified by whole exome sequencing a novel heterozygous EMILIN1 mutation c.748C>T [p.R250C] located in the coiled coil forming region of the protein, in four affected members of an autosomal dominant family presenting a distal motor neuropathy phenotype.In affected patient a sensory nerve biopsy showed slight and unspecific changes in the number and morphology of myelinated fibers. Immunofluorescence study of a motor nerve within a muscle biopsy documented the presence of EMILIN-1 in nerve structures. Skin section and skin derived fibroblasts displayed a reduced extracellular deposition of EMILIN-1 protein with a disorganized network of poorly ramified fibers in comparison with controls.Downregulation of emilin1a in zebrafish displayed developmental delay, locomotion defects, and abnormal axonal arborization from spinal cord motor neurons. The phenotype was complemented by wild-type zebrafish emilin1a, and partially the human wild-type EMILIN1 cRNA, but not by the cRNA harboring the novel c.748C>T [p.R250C].These data suggest a role of EMILIN-1 in the pathogenesis of diseases affecting the peripheral nervous system.

Vascular mural cells (vMCs) are essential components of the vertebrate vascular system, controlling blood vessel maturation and homeostasis. Discrete molecular mechanisms have been associated with vMC development and differentiation. The function of hemodynamic forces in controlling vMC recruitment is unclear. Using transgenic lines marking developing vMCs in zebrafish embryos, we find that vMCs are recruited by arterial-fated vessels and that the process is flow dependent. We take advantage of tissue-specific CRISPR gene targeting to demonstrate that hemodynamic-dependent Notch activation and the ensuing arterial genetic program is driven by endothelial primary cilia. We also identify zebrafish foxc1b as a cilia-dependent Notch-specific target that is required within endothelial cells to drive vMC recruitment. In summary, we have identified a hemodynamic-dependent mechanism in the developing vasculature that controls vMC recruitment.

Modern advances in systemic and localized therapies for patients with renal cell carcinoma (RCC) have significantly improved patients' outcomes. If disease progression occurs after initial treatment, clinicians often have multiple options for a first salvage therapy. Because salvage and initial treatments both may affect overall survival time, and they may interact in unanticipated ways, there is a growing need to determine sequences of initial therapy and first salvage therapy that maximize overall survival while maintaining quality of life. The complexity of this problem grows if a second salvage therapy must be chosen for patients with treatment-resistant disease or a second progression occurs following first salvage. On November 9, 2023, a think tank was convened during the International Kidney Cancer Symposium (IKCS) North America to discuss challenges in accounting for postprogression therapies when estimating overall survival (OS) time based on randomized controlled trial (RCT) data. The present manuscript summarizes the topics discussed, with the aim to encourage adoption of statistical methods that account for salvage therapy effects to obtain scientifically valid OS estimation. We highlight limitations of traditional methods for estimating OS that account for initial treatments while ignoring salvage therapy effects and discuss advantages of applying more sophisticated statistical methods for estimation and trial design. These include identifying multistage treatment strategies, correcting for confounding due to salvage therapy effects, and conducting Sequentially Multiple Assignment Randomized Trials (SMARTs) to obtain unbiased comparisons between multistage strategies. We emphasize the critical role of patient input in trial design, and the potential for information technology (IT) advances to support complex trial designs and real-time data analyses. By addressing these challenges, future RCTs can better inform clinical decision-making and improve patient outcomes in RCC., Competing Interests: Declaration of competing interest Pavlos Msaouel reports honoraria for scientific advisory board membership for Mirati Therapeutics, Bristol Myers Squibb, and Exelixis; consulting fees from Axiom Healthcare; nonbranded educational programs supported by Exelixis, Pfizer, and DAVA Oncology; leadership or fiduciary roles as a Medical Steering Committee member for the Kidney Cancer Association and a Kidney Cancer Scientific Advisory Board member for KCCure; and research funding from Takeda, Bristol Myers Squibb, Mirati Therapeutics, Regeneron Pharmaceuticals, and Gateway for Cancer Research. Eric A. Singer reports honoraria for data safety monitoring board membership for Aura Biosciences and leadership or fiduciary roles as a Medical Steering Committee member for the Kidney Cancer Association. Kathryn E Beckermann received funding to the institution for preclinical awards including BMS-IASLC-LCFA, Pionyr, Arsenal Bio, and Aravive, as well as funds as a consultant to Aravive, Aveo, Arcus, Alpine Bioscience, BMS, Exelixis, Merck, Eisai, Nimbus, and Adicet. Bradley A. McGregor reports consulting fees from Arcus, BMS, Daiichi, Eisai, Exelixis, Gilead, Lily, Pfizer as well as research funding to institution from BMS, Exelixis, Gilead, and Pfizer. Ulka N. Vaishampayan reports consulting fees from BMS. Novartis, Merck, Exelixis, Pfizer, Glilead and Alkermes, as well as speaker fees from Bayes and Exelixis. Eric Jonasch reports research support from Abbvie, Arrowhead, Aveo, BMS, Corvus, Merck, NiKang, ProFoundBio, Telix, honoraria from Aveo, Clinical Care Options, DAVA, EBSCO, Eisai, Exelixis, GSK, IDEO Oncology, i3 Health, Ipsen, Kaplan, Merck, Novartis, NiKang, Petra Drugstore, Plexus, leadership position in NCCN Guidelines (Vice-Chair Kidney Cancer Panel), member of the NCI RCC Steering Committee, and board Member of the International Kidney Cancer Coalition. Katie Coleman is employed by the Rare Cancer Research Foundation and has received honoraria from Exelixis for a speaking engagement related to patient advocacy. Nizar M. Tannir reported receiving and personal fees (honoraria) from Calithera Biosciences during the conduct of the study; and grants (sponsored trial) from Calithera Biosciences, Bristol Myers Squibb (BMS), Nektar Therapeutics, Arrowhead Pharmaceuticals, and Novartis, as well as personal fees (honoraria) from Calithera Biosciences, BMS, Eisai Medical Research, Merck Sharp & Dohme (MSD), Deka Biosciences, Neoleukin Therapeutics, Exelixis, and Ono Pharmaceutical outside the submitted work. Daniel M Geynisman reports honoraria from Targeted Oncology, consulting fees from Pfizer, Exelixis, AstraZeneca, Seattle Genetics/Astellas, Merck, and Bristol-Myers Squibb, as well as research funding to institution from Merck, Astellas Pharma, Harpoon Therapeutics, Arvinas, and CG Oncology. Walter M. Stadler reports consulting fees for participation in Data and Safety Monitoring Board from Astra-Zeneca, Merck, Pfizer, and Treadwell Therapeutics, other consulting fees from Astra-Zeneca, Aveo, Caremark/CVS, EMA Wellness, Fortress Biotech, and Xencor, speakers bureau for CME programs from Dava Oncology, Global Academyc for Medical Education, OncLive, PeerView, Research to Practice, and Vindico, research funding to institution from Abbvie, Amgen, Astra-Zeneca, Astellas (Medivation), Bayer, Bristol-Myers-Squibb, Boehringer-Ingelheim, Calithera, Corvus, Eisai, Exilixis, Genentech (Roche), Johnson & Johnson (Janssen), Merck, Novartis, Pfizer, Seattle Genetics, X4Pharmaceuticals, Xencor, stock holdings from Fortress Biotech, Expert Witness for Sandoz, as well as miscellaneous fees from Cancer (ACS), Up-To-Date, and the Kidney Cancer Journal. Yousef Zakharia reports advisory board / consulting fees from Bristol Myers Squibb, Amgen, Janssen, Eisai, Exelixis, Genzyme Corporation, Pfizer, EMD Serono, Astellas, and Seagen, Grant/research institutional support from Pfizer, Exelixis, and Eisai, as well as honoraria for data safety monitoring board membership from Janssen Research and Development. Daniel D. Shapiro has no disclosures., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The use of systemic immune checkpoint blockade before surgery is increasing in patients with metastatic renal cell carcinoma, however, the safety and feasibility of performing consolidative cytoreductive nephrectomy after the administration of systemic therapy are not well described., Patients and Methods: A retrospective review of patients undergoing nephrectomy was performed using our prospectively maintained institutional database. Patients who received preoperative systemic immunotherapy were identified, and the risk of postoperative complications were compared to those who underwent surgery without upfront systemic treatment. Perioperative characteristics and surgical complications within 90 days following surgery were recorded., Results: Overall, we identified 220 patients who underwent cytoreductive nephrectomy from April 2015 to December 2022, of which 46 patients (21%) received systemic therapy before undergoing surgery. Unadjusted rates of surgical complications included 20% (n = 35) in patients who did not receive upfront systemic therapy and 20% (n = 9) in those who received upfront systemic immunotherapy. In our propensity score analysis, there was no statistically significant association between receipt of upfront immunotherapy and 90-day surgical complications [odds ratio (OR): 1.82, 95% confidence interval (CI): 0.59-5.14; P = 0.3]. This model, however, demonstrated an association between receipt of upfront immunotherapy and an increased odds of requiring a blood transfusion [OR: 4.53, 95% CI: 1.83-11.7; P = 0.001]., Conclusion: In our cohort, there was no significant difference in surgical complications among patients who received systemic therapy before surgery compared to those who did not receive upfront systemic therapy. Cytoreductive nephrectomy is safe and with low rates of complications following the use of systemic therapy., Competing Interests: Declaration of Competing Interest Maria Carlo has no conflicts of interest to disclose. Jonathan Coleman has no conflicts of interest to disclose. Lennert Eismann has no conflicts of interest to disclose. Darren Feldman reports research funding from Telix, BioNTech, Astellas, and Decibel Therapeutics; is a consultant for Telix and BioNTech; and reports royalties from UpToDate. Alvin Goh is a consultant for Medtronic. A. Ari Hakimi is on the Merck Advisory board. Sari Khaleel (KhaleelS@mskcc.org) has no conflicts of interest to disclose. Ritesh Kotecha reports advisory board consultation for Eisai; receives institutional research funding from Pfizer, Novartis, Takeda, and Allogene Therapeutics; and is supported in part by the Academy of Kidney Cancer Investigators of the CDMRP/DOD (KC200127). Chung-Han Lee reports honoraria from Ideology Health, Intellisphere, Research to Practice, American Institute of Continuing Medical Education, and Medscape; has a consulting or advisory role for Aveo, Cardinal Health, Eisai, Bristol Myers Squibb, Merck, Pfizer/EMD Serono, and Exelixis; and reports research funding from Eisai, Bristol Myers Squibb, Calithera Biosciences, Exelixis, Merck, and AstraZeneca. Richard Matulewicz has no conflicts of interest to disclose. Robert Motzer reports grants from Bristol Myers Squibb and Pfizer; grants and personal fees from Eisai, Exelixis, Merck, and Genentech/Roche; and personal fees from EMD Serono Research. Irina Ostrovnaya has no conflicts of interest to disclose. Stephen Reese has no conflicts of interest to disclose. Katiana Vazquez-Rivera has no conflicts of interest to disclose. Paul Russo has no conflicts of interest to disclose. Juan Arroyave Villada has no conflicts of interest to disclose. Martin Voss reports receiving commercial research grants from Bristol Myers Squibb, Pfizer, and Genentech/Roche; honoraria from Novartis and Bristol Myers Squibb; and travel/accommodation from AstraZeneca, Eisai, Novartis, and Takeda; and serving as a consultant/advisory board member for Alexion Pharmaceuticals, Aveo, Bayer, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai, Genentech, GlaxoSmithKline, Merck, Natera, Onquality Pharmaceuticals, Novartis, and Pfizer. Charlie White has no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: This study aimed to characterize MSH6/PMS2-associated mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) tumors, given revised guidelines suggesting more modest phenotypes., Methods: Patients who consented to Institutional Review Board-approved protocols of tumor/germline sequencing or Lynch syndrome registry at a single institution from February 2005 to January 2021 with germline, heterozygous MSH6/PMS2 pathogenic/likely pathogenic variants were identified. Clinical data were abstracted and correlated with MMR/microsatellite instability status using nonparametric tests., Results: We identified 243 patients (133 sequencing, 110 registry) with germline MSH6/PMS2 pathogenic/likely pathogenic variants; 186 (77%) had >1 cancer. Of 261 pooled tumors, colorectal cancer (CRC) and endometrial cancer (EC) comprised 55% and 43% of cancers in MSH6 and PMS2, respectively; 192 tumors underwent molecular assessments and 122 (64%) were MMR-D/MSI-H (77 in MSH6, 45 in PMS2). MMR-D/MSI-H cancers included CRC (n = 56), EC (n = 35), small bowel cancer (n = 6), ovarian cancer (n = 6), urothelial cancer (n = 5), pancreas/biliary cancer (n = 4), gastric/esophageal cancer (n = 3), nonmelanoma skin tumors (n = 3), prostate cancer (n = 2), breast cancer (n = 1), and central nervous system/brain cancer (n = 1). Among MMR-D/MSI-H CRC and EC, median age of diagnosis was 51.5 (range = 27-80) and 55 (range = 39-74) years, respectively; 9 of 56 (16%) MMR-D/MSI-H CRCs were diagnosed at age <35 years., Conclusion: MSH6/PMS2 heterozygotes remain at risk for a broad spectrum of cancers, with 16% of MMR-D/MSI-H CRCs presenting before upper threshold of initiation of colonoscopy per guidelines., Competing Interests: Conflict of Interest Ying L. Liu reports research funding from AstraZeneca, REPARE, and GSK unrelated to this work. Karen A. Cadoo reports participating in advisory boards and/or consulting for AstraZeneca, MJH Life Sciences, MSD Ireland, GSK Ireland, and NextCure; institutional funding from MSD Ireland and Immunogen; and educational support from Pfizer and Roche Ireland, all unrelated to this work. Jinru Shia serves as a consultant for Paige AI unrelated to this work. Zsofia K. Stadler’s immediate family member serves as a consultant in Ophthalmology for Alcon, Adverum Biotechnologies, Gyroscope Therapeutics Limited, Neurogene, and RegenexBio outside the submitted work. All other authors declare no conflicts of interest, (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: Tumor-only sequencing, implemented for the identification of somatic variants, is oftentimes used for the detection of actionable germline variants. We sought to determine whether tumor-only sequencing assays are suitable for detection of actionable germline variants, given their importance for the delivery of targeted therapies and risk-reducing measures., Patients and Methods: The detection of germline variants affecting moderate- and high-penetrance cancer susceptibility genes (CSGs) by tumor-only sequencing was compared to clinical germline testing in 21 333 cancer patients who underwent tumor and germline testing using the Food and Drug Administration (FDA)-authorized Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay. Seven homologous recombination deficiency (HRD), two DNA damage response (DDR) and four mismatch repair (MMR) genes, as well as NF1, RB1 and TP53 were included in the analysis. FDA-authorized and New York State Department of Health-approved sequencing methods for germline, tumor/normal and tumor-only sequencing assays and analytical pipelines were employed., Results: In patients who underwent tumor and germline sequencing, as compared to clinical genetic testing, tumor-only sequencing failed to detect 10.5% of clinically actionable pathogenic germline variants in CSGs, including 18.8%, 12.8% and 7.3% of germline variants in MMR, DDR and HRD genes, respectively. The sensitivity for detection of pathogenic germline variants by tumor-only sequencing was 89.5%. Whilst the vast majority of pathogenic germline exonic single-nucleotide variants (SNVs) and small indels were detected by tumor-only sequencing, large percentages of germline copy number variants, intronic variants and repetitive element insertions were not detected., Conclusions: Tumor-only sequencing is adequate for the detection of clinically actionable germline variants, particularly for SNVs and small indels; however, a small subset of alterations affecting HRD, DDR and MMR genes may not be detected optimally. Therefore, for high-risk patients with negative tumor-only sequencing results, clinical genetic testing could be considered given the impact of these variants on therapy and genetic counseling., Competing Interests: Disclosure JSR-F reports receiving personal/consultancy fees from Goldman Sachs, REPARE Therapeutics, Paige.AI and Eli Lilly; membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics, Paige.AI and Personalis; membership of the Board of Directors of Grupo Oncoclinicas; and ad hoc membership of the scientific advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis, Genentech and InVicro, outside the scope of this study. The remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To address demands for timely germline information to guide treatments, we evaluated experiences of patients with ovarian, pancreatic, and prostate cancer with a mainstreaming genetic testing model wherein multigene panel testing was ordered by oncologists with standardized pretest patient education, and genetic counselors delivered results and post-test genetic counseling via telephone., Methods: Among 1,203 eligible patients, we conducted a prospective single-arm study to examine patient uptake and acceptability (via self-report surveys at baseline and three weeks and three months following result return) of this mainstreaming model., Results: Only 10% of eligible patients declined participation. Among 1,054 tested participants, 10% had pathogenic variants (PV), 16% had variants of uncertain significance (VUS), and 74% had no variant identified (NV). Participants reported high initial acceptability, including high satisfaction with their testing decision. Variability over time in several outcomes existed for participants with PV or NV: those with NV experienced a temporary increase in depression (p Time  < 0.001; p Time2  < 0.001), and those with PV experienced a small increase in genetic testing distress (p = 0.03). Findings suggested that result type, sex, and cancer type were also associated with outcomes including clinical depression and uncertainty., Conclusion: This mainstreaming model may offer a feasible approach for extending access to germline genetic information., (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)

Urothelial carcinoma (UC) of the bladder and upper tract (ureter, renal pelvis) is one of the most frequently occurring malignancies. While the majority of UC are chemically induced by smoking, accumulating evidence from genetic studies have demonstrated a small, but consistent impact of heritable gene variants and family history of UC on the development of the disease. Beyond the established association between upper tract UC and germline mismatch DNA repair defects as a defining feature of Lynch syndrome, newer investigations focusing on moderate- and high-risk cancer-related gene variants in DNA damage repair and other signaling pathways are expanding our knowledge on the heritable genetic basis of UC, opening new avenues in the breadth of genetic testing and in clinical counseling of these patients. Overcoming existing challenges in the interpretation of uncertain findings and family cascade testing may help expand our testing approach and guidelines. Following the paradigm of other tumor types, such as breast and ovarian cancers, germline genetic testing, particularly when combined with somatic testing, has the potential to directly benefit affected UC patients and their families in the future through therapeutic targeting (i.e. with poly(ADP-ribose)) polymerase inhibitors, immune checkpoint inhibitors) and genetically informed screening/surveillance, respectively., Competing Interests: Declaration of Competing Interest No other conflicts of interest to declare by rest authors., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To report the overall survival (OS) outcomes of patients with nonclear cell renal cell carcinoma (nccRCC) treated at our institution with a cytoreductive nephrectomy (CN) and better understand the clinical and pathological characteristics of the patients that respond best., Material and Methods: We queried our prospectively maintained database for patients who underwent CN for nccRCC between 1989 and 2018. Histology was reviewed by an expert genitourinary pathologist, and nccRCC tumors were subdivided into papillary, unclassified, chromophobe, and other histology. Baseline clinicopathology, treatments, and survival outcomes were recorded. Preoperative hematological parameters including the neutrophil-to-lymphocyte ratio (NLR) were analyzed. Significant univariate predictors of OS were tested in a multivariate model., Results: There were 100 nccRCC patients treated with CN. Median age was 61 years (IQR: 48-69) and 65% were male. There were 79 patient deaths with a median OS of 13.7 months (10.8-27.2). Estimated 2- and 5-year survival was 40.1% and 12.2%, respectively. Median follow-up of survivors was 13 months (IQR: 3-30). On multivariate analysis, increasing NLR (hazard ratio [HR] 1.27; 95% confidence interval [CI] 1.14-1.40, P < 0.001) and sarcomatoid features (HR 2.18; 95% CI 1.19-3.97, P = 0.014) conferred worse OS and the presence of papillary features were a favorable prognostic feature (HR 0.37; 95% CI 0.21-0.65, P < 0.001)., Conclusions: OS outcomes in patients with nccRCC who underwent a CN are consistently modest throughout the study period. Patients with papillary features and a lower preoperative NLR may be better candidates for a CN., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Mucinous tubular and spindle-cell carcinoma (MTSCC) is a rare kidney cancer subtype with limited cases reported in the literature. We report on outcomes of 25 patients with this variant who were managed at our institution., Materials and Methods: The institution database was queried, and clinical data extracted for patients with MTSCC. Molecular features examined included next-generation sequencing with Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets and allele-specific copy number analysis using the Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) algorithm in a subset of patients., Results: All patients underwent primary tumor-directed therapy (nephrectomy = 23, cryoablation = 2). Metastases were diagnosed in 6 patients (24%), 3 (12%) of whom had de novo metastatic disease. Five of 6 patients with metastatic disease had high-grade histological features compared with 0 of 19 nonmetastatic patients (83% vs. 0%; P < .001, Fisher exact test). Three-year overall survival from diagnosis was 84.8% (95% confidence interval, 59.6-94.9) with a median follow-up time of 3.9 years (range, 1 month to 10.3 years). Three deaths occurred, all from metastatic disease. Four patients received systemic therapy with time to treatment failure ≤6 months across different agents with the exception of 1 patient with prolonged response with sunitinib treatment (30.6 months). The most frequent molecular alterations were neurofibromin 2 mutations (n = 2; 40%), germline alterations (n = 2; 40%) including checkpoint kinase 2 and BRCA2 DNA repair associated mutations, multiple chromosomal copy number losses, and mismatch repair deficiency in 1 patient., Conclusion: MTSCC is characterized by localized tumors treated successfully with primary tumor-directed therapy. However, patients with high-grade histological features were more likely to develop metastatic disease with limited responses to standard therapies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Germline genetic testing increasingly identifies advanced prostate cancer (PCa) patients who are candidates for precision therapies. The Prostate Cancer Clinical Trials Consortium (PCCTC) established the Germline Genetics Working Group to provide guidance and resources to expand effective use of germline genetic testing., Materials and Methods: A 14-item questionnaire was e-mailed to academic oncologists at 43 PCCTC sites to collect information on germline genetic testing patterns, including patients considered, choice of assays, barriers slowing adoption, and actions to overcome barriers., Results: Twenty-six genitourinary oncologists from 19 institutions responded. Less than 40% (10 of 26) reported referring patients to a genetics department, whereas the remainder take personal responsibility for genetic testing and counseling; 16 (62%) consider testing all metastatic PCa patients, whereas 3 (12%) consider testing all patients with high-risk local disease; and 7 (27%) use multigene comprehensive pan-cancer panels, and 14 (54%) use smaller or targeted cancer gene panels. Barriers to widespread use are: (1) delayed or limited access to genetic counseling; (2) no insurance coverage; (3) lack of effective workflows; (4) insufficient educational materials; and (5) time and space constraints in busy clinics. The primary limitation was the <50% (19 of 43) response from PCCTC sites and no coverage of nonacademic cancer treatment facilities., Conclusion: Joint efforts by urologists, oncologists, genetics counselors, insurers, and cancer centers can accelerate implementation of integrated germline genetic services for personalized treatment and clinical trial eligibility for PCa patients., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Sarcomatoid features (SF) in renal cell carcinoma (RCC) denote poor prognosis. Data for metastatic chromophobe RCC (ChRCC) with SF are limited. We studied clinical outcomes and genomic features in this setting., Patients and Methods: We performed a retrospective review of newly diagnosed metastatic ChRCC patients; end points included overall survival (OS), time to treatment failure (TTF), and time to metastatic recurrence (TTR) after nephrectomy for localized disease. A subset of patients underwent next-generation sequencing (NGS). Outcomes were compared using nonparametric tests., Results: One hundred nine patients with metastatic ChRCC were identified including 29 with SF. Median TTR after nephrectomy was shorter for patients with versus without SF (2.7 months [95% confidence interval (CI), 0.7-6.9] versus 48.8 months [95% CI, 30.8-80.7], log rank P < .001). Median TTF during first-line therapy was shorter for patients with versus without SF (1.8 months [95% CI, 0.9-2.7] vs. 8.0 months [95% CI, 5.1-13.0]; log rank P < .001). No responses were observed in 6 patients treated with nivolumab including 4 with SF. Median OS was inferior for patients with versus without SF (38 months vs.7.5 months; hazard ratio, 4.7 [95% CI, 2.7-8.2]; P < .001). NGS, performed in 22 patients, showed that 64% and 45% harbored tumor protein P53 and phosphatase and tensin homolog alterations, respectively. Microsatellite instability high status was identified in 3 patients., Conclusion: Metastatic ChRCC patients with SF had worse outcomes compared with those without SF. Median TTR < 3 months for this subgroup supports close surveillance after nephrectomy for localized tumors. Lack of benefit with various systemic regimens warrants studying underlying biology and investigating novel agents., (Published by Elsevier Inc.)

Introduction: Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance., Methods: We identified patients who had SRMs (4cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC. Patients were selected from 3 publicly available cohorts, The Cancer Genome Atlas (n = 110), University of Tokyo (n = 37), The International Cancer Genome Consortium (n = 31), and from our own institutional prospective database (n = 25). Among this cohort we analyzed mutations present in at least 5% of tumors, assessing for the enrichment of mutations and progression-free survival using the composite endpoint of recurrence or death of disease. Analysis was adjusted for multiple testing. A Cox regression model was used to assess clinical variables with significant mutations., Results: In total, 203 patients were available for analysis. Median follow-up was 43.1 months among survivors. Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C, and MTOR were present in more than 5% of tumors. Twenty-three patients (11.3%) had recurrence or died of their disease. Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P 0.033., Conclusions: We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality. The strongest association was seen in those with KDM5C mutations. Use of these genomic biomarkers may improve stratification of patients with SRMs and for those who may be appropriate for active surveillance. Prospective evaluation of these markers is needed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Renal medullary carcinoma (RMC) is a rare and aggressive type of kidney cancer that primarily affects young adults with sickle cell trait; outcomes are poor despite treatment. Identifying molecular features of this tumor could provide biologic rationale for novel targeted therapies. The objective was to report on clinical outcomes with systemic therapy and characterize molecular features., Patients and Methods: This was a retrospective analysis on 36 patients given a pathologic diagnosis of RMC at one institution from 1995 to 2015. Tumors were analyzed for expression of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) through immunohistochemistry and for genomic alterations with fluorescence in situ hybridization for SMARCB1, and targeted next-generation sequencing. Time from initiation of therapy to progression of disease and overall survival were calculated using the Kaplan-Meier method., Results: The median age in the cohort was 28 (range, 12-72) years, and all patients tested had sickle cell trait. Overall survival was 5.8 months (95% confidence interval [CI], 4.1-10.9) and for 12 patients who received platinum-based therapy, median progression-free survival was 2.5 months (95% CI, 1.2-not reached). A total of 10 available tumors underwent analysis with fluorescence in situ hybridization for SMARCB1; this revealed loss of heterozygosity with concurrent translocation in 8, and biallelic loss in 2. Next-generation targeted sequencing showed no recurring mutations., Conclusions: Outcome was generally poor in this cohort of patients with RMC. Uniform loss of SMARCB1 is a key molecular feature in this tumor and mechanism of loss appears to be mostly through translocations and deletions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To establish prognostic genomic biomarkers for patients with metastatic clear cell renal cell carcinoma (ccRCC)., Materials and Methods: We identified 60 patients who presented with metastatic ccRCC at our institution between 2001 and 2015 and had genomic sequencing on their primary tumor. We pooled these patients with 107 other patients with the same inclusion criteria from three well-known public databases. Five commonly mutated genes were chosen for analysis: VHL, PBRM1, BAP1, SETD2, and KDM5C. Overall survival (OS) was estimated using the Kaplan-Meier method and the log-rank test was used for comparisons between groups., Results: Median OS in the cohort was 2.5 years. Higher Fuhrman grade was associated with decreased median OS (P<0.001). Mutations in SETD2 (P = 0.027) and KDM5C (P = 0.019) were associated with reduced risk of death (hazard ratio [HR] = 0.58 [95% CI: 0.35-0.94] and HR = 0.43 [95% CI: 0.22-0.85], respectively). BAP1 mutations (P = 0.008) were associated with increased risk of death (HR = 1.81 [95% CI: 1.16-2.83]). There were significantly more female patients with a BAP1 mutation than females in the overall cohort (P = 0.001)., Conclusions: Mutations in BAP1 negatively affected OS, whereas SETD2 and KDM5C mutations were associated with prolonged OS in our pooled cohort of 167 patients with metastatic ccRCC. Our results expand upon efforts at understanding genomic biomarkers in localized disease. Those efforts set the stage for our novel investigation examining associations of select recurrent somatic mutations in stage IV patients with ccRCC., (Copyright © 2017 Elsevier Inc. All rights reserved.)