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Background: Enfortumab vedotin (EV) has been approved for the treatment of patients with locally advanced/metastatic urothelial carcinoma (la/mUC) who previously received platinum-based chemotherapy followed by immune checkpoint inhibitors. However, the pivotal clinical trials did not include patients previously treated with avelumab maintenance therapy., Objective: The aim of the present retrospective analysis was to assess the effectiveness of EV following avelumab in patients with mUC enrolled in the ARON-2 EV study., Patients and Methods: The study included 182 patients with mUC treated with EV following avelumab maintenance. The primary objective was to assess clinical outcomes, including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and duration of response (DoR). Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models., Results: Median OS and PFS were 12.7 (95% CI 10.2-14.1) and 7.9 (95% CI 6.4-9.9) months, respectively. Complete response (CR) was achieved in 5% and partial response (PR) in 34% of patients, with an ORR of 39%. The DoR in patients who achieved CR/PR was 10.9 months (95% CI 8.1-11.4). The incidence of grade ≥ 3 peripheral neuropathy and skin rash was 9%, followed by 8% of grade ≥ 3 diarrhea and 4% of grade ≥ 3 hyperglycemia., Conclusions: The results of our large international retrospective study confirm the effectiveness of EV and endorse its use in the population of patients with mUC treated with EV following the frontline platinum-based chemotherapy and subsequent maintenance treatment with avelumab., Competing Interests: Declarations Funding No external funding was used in the preparation of this manuscript. Conflicts of Interest Ondřej Fiala received honoraria from Roche, Janssen, GSK, and Pfizer for consultations and lectures unrelated to this project. Francesco Massari has received research support and/or honoraria from Advanced Accelerator Applications, Astellas, Astra Zeneca, Bayer, BMS, Janssen, Ipsen, MSD, and Pfizer outside the submitted work. Umberto Basso received honoraria for Bristol-Myers Squibb, Novartis, and Astra Zeneca; research funding from Ipsen; and travel grants from Bristol-Myers Squibb, Janssen Oncology, Astellas Pharma, MSD Oncology, Merck/Pfizer, and Bayer, all unrelated to this project. Sebastiano Buti received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis, Merck, Gentili, and Astellas, all unrelated to the present paper. Yüksel Ürün has served on advisory board for Abdi-İbrahim, Astellas, AstraZeneca, Bristol Myers-Squibb, Deva, Eczacıbaşı, Gen ilaç, Gilead, GSK, Janssen, Merck, MSD, Novartis, Pfizer, and Roche and received travel grants, honoraria, or consultation fees from Abdi-İbrahim, Astellas, Bristol Myers-Squibb, Deva, Eczacıbaşı, Gen İlaç, Gilead, GSK, Janssen, Merck, Novartis, Pfizer, and Roche, all unrelated to the present paper. Maria T. Bourlon is a consultant of Bristol Myers Squibb, Merck, MSD, Gilead, Astellas, and Asofarma and a speaker for Janssen Pharmaceuticasl, MSD, Merck, and Astellas, all unrelated to the present paper. Mimma Rizzo has received honoraria as a speaker/consultant by MSD, Merck Serono, Astrazeneca, Bristol Myers Squibb, Eisai, and Gilead, all unrelated to the present paper. Linda Cerbone has received honoraria for advisory boards, speaker engagements, and scientific consultancy for educational purposes from AstraZeneca, EISAI, MSD, Ipsen, BMS, and A.A.A.; and is a past MSD employee in Medical Affairs. Javier Molina-Cerrillo reports research funding from Roche, Ipsen, Pfizer, and Janssen; travel support from Pfizer, Janssen, Ipsen, and BMS; and a consulting or advisory role with Ipsen, Roche, BMS, Pfizer, Sanofi, Janssen, Astellas, Eisai, Adium, and MSD, all unrelated to the present paper. Álvaro Pinto is a member of advisory boards of Pfizer, Novartis, Ipsen, BMS, Janssen, Astellas, Sanofi, Bayer, Clovis, Roche, MSD, Pierre Fabre, and Merck; has received research support from Pfizer and BMS; clinical trial payments from Pfizer, Bayer, Janssen, MSD, Clovis, Pharmacyclics, BMS, Sanofi, Astra Zeneca, Roche, Eisai, and Aveo; and travel arrangements from Janssen, Roche, Pfizer, BMS, and Ipsen, all unrelated to the present paper. Andrey Soares reports honoraria from Janssen, Pfizer, Bayer, AstraZeneca, Astellas Pharma, Merck Serono, Sanofi, Ipsen, and Adium; consulting or advisory role from Astellas Pharma, Janssen, Roche, Bayer, AstraZeneca, MSD, Bristol-Myers Squibb, Adium, Ipsen, Pfizer, and Novartis; research funding from Bristol-Myers Squibb (Inst), Astellas (Inst), and AstraZeneca (Inst); travel, accommodations, and expenses from Bayer, Janssen, Ipsen, Adium, MSD, and Merck Serono; and ownership in BIO, Brazilian Information Oncology; all unrelated to this study. Alexandr Poprach has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from BMS, Ipsen, Roche, Astellas, Merck, Eisai, MSD, Novartis, and Pfizer, unrelated to this project. Gian Paolo Spinelli has received payment or honoraria for advidory boards from Novartis, Roche, and Bayer, unrelated to this project. Martin Angel received honoraria from Roche, Johnson & Johnson, Raffo, and Pfizer for consultations and lectures unrelated to this project. Fernando Sabino M. Monteiro reports research support provided by Merck Sharp Dome; honoraria from Janssen, Ipsen, Bristol Myers Squibb, and Merck Sharp Dome; and ownership in BIO, Brazilian Information Oncology, all unrelated to this study. Camillo Porta acted as a remunerated consultant and/or speaker for Angelini Pharma, AstraZeneca, BMC, Eisai, Exilixis, Genenta, Ipsen, Merck Serono, and MSD; as a protocol steering committee member for Eisai and MSD; and as an Independent Review Board member for Genenta. Shilpa Gupta is a consultant for Bristol Myers Squibb, Merck, Pfizer, Gilead, Bayer, and Seattle Genetics; is a speaker for Bristol Myers Squibb; and has institutional research funding from Seatte Genetics, Pfizer, Merck, Bristol Myers Squibb, Roche, Novartis, and Tyra Biosciences. Matteo Santoni has received research support and honoraria from Janssen, Bristol Myers Squibb, Ipsen, MSD, Astellas, and Bayer, all unrelated to the present paper. Patrizia Giannatempo, Enrique Grande, Zin W. Myint, Ugo De Giorgi, Renate Pichler, Francesco Grillone, Fabio Calabrò, Luca Galli, Ravindran Kanesvaran, Giandomenico Roviello, Jakub Kucharz, Se Hoon Park, Emmanuel Seront, Carlo Messina, Daniele Santini, Akihiro Yano, Lorena Incorvaia, Martina Catalano, Luigi Formisano, Gaetano Facchini, Giuseppe Fornarini, Sara Elena Rebuzzi, Cecilia Nasso, Marco Stellato, Deniz Tural, Gaetano Aurilio, Ilana Epstein, Francesco Carrozza, Giovanni Benedetti, Tomáš Büchler, Cinzia Ortega, Roubini Zakopoulou, Nicola Battelli, and Joaquin Bellmunt declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. Tomáš Büchler and Camillo Porta are Editorial Board members of Targeted Oncology. Tomáš Büchler and Camillo Porta were not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethics Approval The study protocol was approved on 28 September 2023, by the Ethical Committee of the coordinating center (Marche Region – Italy – no. 2022 39/7875, Study Protocol “ARON 2 Study” NCT05290038) and by the Institutional Review Boards of participating centers. Consent to Participate Informed consent with subsequent analysis of the follow-up data was obtained from all participants. Consent for Publication Not applicable. Availability of Data and Material The datasets generated and/or analyzed during the current study are not publicly available due to patient data security but are available from the corresponding author on reasonable request. Code Availability Not applicable. Author Contributions Study concept and design: all authors; acquisition of data: all authors; analysis and interpretation of data: all authors; drafting of the manuscript: Fiala, Massari, Gupta, and Santoni; critical revision of the manuscript for important intellectual content: all authors; statistical analysis: Santoni; obtaining funding: none; administrative, technical, or material support: none; and supervision: Gupta and Santoni., (© 2024. The Author(s).)

Background: Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, "primary refractory" (P ref ), face dismal outcomes., Objective: Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of P ref patients., Methods: This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan-Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve., Results: In our study, the P ref rate was 19%. Nivolumab/ipilimumab showed the highest P ref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-P ref patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for P ref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of P ref . This study presents limitations, mainly because of its retrospective design., Conclusions: The ARON-1 study provides valuable insights into P ref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches., Competing Interests: Declarations Funding No external funding was used in the preparation of this article. Conflicts of Interest/Compting Interests Ondrej Fiala received honoraria from Novartis, Janssen, Merck, BMS, MSD, Pierre Fabre, and Pfizer for consultations and lectures unrelated to this project. Sebastiano Buti has received honoraria for speaking at scientific events and advisory roles from Astra Zeneca, BMS, Ipsen, Merck, Eisai, MSD, Novartis, and Pfizer and research funding from Novartis and Pfizer unrelated to this project. He has also been on the advisory board for Gentili. Francesco Massari has received research support and/or honoraria from Astellas, BMS, Janssen, Ipsen, MSD, and Pfizer outside the submitted work. Enrique Grande has received honoraria for speaker engagements and advisory roles or received funding for continuous medical education from Adacap, Amgen, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, Ipsen, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, and Thermo Fisher Scientific and research grants from Pfizer, Astra Zeneca, Astellas, and Lexicon Pharmaceuticals. All of the above are unrelated to the present paper. Alexandr Poprach has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from BMS, Ipsen, Roche, Astellas, Merck, Eisai, MSD, Novartis, and Pfizer, unrelated to this project. Javier Molina-Cerrillo declares consultant, advisory, or speaker roles for Ipsen, Roche, Pfizer, Sanofi, Janssen, and BMS unrelated to this project. Zin W. Myint has received research support from Merck unrelated to the present paper. Ray Manneh Kopp has received research support and/or honoraria from Amgen, Astellas, Astra Zeneca, Bayer, BMS, Eli Lilly, Janssen, MSD, Pfizer, Tecnofarma and Roche, unrelated to this project. Jakub Kucharz has received honoraria from Angelini, Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, IPSEN, Janssen, Merck MSD, Novartis, and Pfizer, and research funding from Novartis, all unrelated to the present paper. Fernando Sabino M. Monteiro has received research support from Janssen and Merck Sharp Dome and honoraria from Janssen, Ipsen, Bristol Myers Squibb, and Merck Sharp Dome, all unrelated to the present paper. Ravindran Kanesvaran has received fees for speaker bureau and advisory board activities from the following companies; Pfizer, MSD, BMS, Eisai, Ipsen, Johnson and Johnson, Merck, Amgen, Astellas, and Bayer, unrelated to this project. Tomáš Büchler has received research support from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Merck KGaA, MSD, and Novartis; consulting fees from Bristol Myers Squibb, Astellas, Janssen, and Sanofi/Aventis; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol Myers Squibb, AstraZeneca, Roche, Servier, Accord, MSD, and Pfizer, all unrelated to the present paper. Andrey Soares has received honoraria from Janssen, Pfizer, Bayer, AstraZeneca, Astellas Pharma, Merck Serono, Sanofi, Ipsen, Adium. Consulting or Advisory Role from Astellas Pharma, Janssen, Roche, Bayer, AstraZeneca, MSD, Bristol-Myers Squibb, Adium, Ipsen, and Pfizer, research Funding from Bristol-Myers Squibb (Inst), Astellas (Inst), and AstraZeneca (Inst), travel, accommodations, and expenses from Bayer, Janssen, Ipsen, Adium, MSD, and Merck Serono, and ownership in BIO, Brazilian Information Oncology. All are unrelated to this study. Camillo Porta has received honoraria from Angelini Pharma, AstraZeneca, BMS, Eisai, Exelixis, Genenta, Ipsen, Merck Serono, and MSD and acted as a Protocol Steering Committee Member for Eisai and MSD, unrelated to this project. Matteo Santoni has received research support and honoraria from Janssen, Bristol Myers Squibb, Ipsen, MSD, Astellas, A.A.A. and Bayer, all unrelated to the present paper. Daniele Santini, Haoran Li, Giandomenico Roviello, Se Hoon Park, Umberto Basso, Martina Catalano, Emmanuel Seront, Jawaher Ansari, Marwan Ghosn, Fabio Calabrò, Dipen Bhuva, Maria T. Bourlon, Michela Roberto, Mattia Alberto Di Civita, Veronica Mollica, Andrea Marchetti, Nicola Battelli, Marco Ricci, and Aristotelis Bamias have no conflicts of interest that are directly relevant to the content of this article. Tomas Buchler and Camillo Porta are Editorial Board members of Targeted Oncology. Tomas Buchler and Camillo Porta were not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethics Approval The “ARON-1” project obtained approved from the Ethics Committee of the Marche Region (2021-492) and adhered to the principles outlined in the Declaration of Helsinki. Consent to Participate Informed consent was obtained from all individual participants included in the study. Consent for Publication Not applicable. Availability of Data and Material The datasets generated during and/or analyzed in the current study are available from the corresponding author on reasonable request. Code Availability Not applicable. Authors’ Contributions Conception and design: DS, MS, FM; acquisition of data: DS, MS, FM; analysis and interpretation of data: DS, MS, FM; drafting of the manuscript: DS, MS, FM; critical revision of the manuscript for important intellectual content: all authors; statistical analysis: MS; supervision: MS, FM., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Upper tract urothelial carcinoma (UTUC) accounts for the 5-10% of all urothelial carcinomas (UCs). In this analysis, we reported the real-world data from the ARON-2 study (NCT05290038) on the efficacy of pembrolizumab in patients with UTUC who recurred or progressed after platinum-based chemotherapy. Medical records of patients with metastatic UTUC treated with pembrolizumab as second-line therapy were reviewed from 34 institutions in 14 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. 235 patients were included in our analysis. Median OS was 8.6 months (95% CI 6.6-12.1), the 1 year OS rate was 43% while the 2 years OS rate 29%. The median PFS was 5.1 months (95% CI 3.9-6.9); 46% of patients were alive at 6 months, 34% at 12 months and 25% at 24 months. According to RECIST 1.1, 18 patients (8%) experienced complete response (CR), 57 (24%) partial response (PR), 44 (19%) stable disease (SD), and 116 (49%) progressive disease (PD), with an ORR of 32%. Our study confirms the effectiveness of pembrolizumab in patients pretreated with a platinum-based combination, irrespective of their sensitivity to the first-line treatment and of their histology. In addition, we emphasized the limited benefit of the treatment with pembrolizumab in patients with hepatic metastases and poor ECOG performance status., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background and Objective: Papillary renal cell carcinoma (pRCC) is the most frequent histological subtype of non-clear cell RCC (nccRCC). Owing to the heterogeneity of nccRCC, patients are often excluded from large phase 3 trials focused on clear cell RCC, so treatment options for nccRCC remain limited. Our aim was to investigate the efficacy of first-line treatment with tyrosine kinase inhibitors (TKIs) or immuno-oncology (IO)-based combinations in patients with pRCC., Methods: We performed a multicenter retrospective analysis of real-world data collected for patients with advanced pRCC treated in 40 centers in 12 countries as part of the ARON-1 project (NCT05287464). The primary endpoints were overall survival (OS), progression-free survival (PFS), the overall response rate (ORR), and time to second progression (PFS2). OS, PFS, and PFS2 were estimated using the Kaplan-Meier method and results were compared between the treatment groups using a log-rank test. Univariate and multivariable analyses were carried out using Cox proportional-hazard models., Key Findings and Limitations: We included 200 patients with metastatic pRCC, of whom 73 were treated with IO-based combinations and 127 with TKIs. Median OS was 22.5 mo in the TKI group 28.8 mo in the IO group (p = 0.081). Median PFS was 6.4 mo in the TKI group and 17.4 mo in the IO group (p < 0.001). The ORR was higher in the IO group than in the TKI group (41% vs 27%; p = 0.037)., Conclusions and Clinical Implications: Our results show that IO-based combinations have superior efficacy outcomes to TKIs for first-line treatment of metastatic pRCC., Patient Summary: The ARON-1 project collects clinical data for patients with kidney cancer treated in multiple centers worldwide to assess outcomes in the real-world setting. We analyzed data for patients with metastatic kidney cancer of a specific subtype to evaluate the efficacy of different first-line treatments. Patients treated with immune-based combinations had better outcomes than patients treated with tyrosine kinase inhibitors., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Brain metastatic carcinoma is a rare occurrence among prostate cancer metastases. 68 Gallium prostate-specific membrane antigen PET-CT ([ 68 Ga]PSMA PET/CT) is commonly used for prostate cancer staging and detection of biochemical recurrences. However, various CNS tumors exhibit activity on [ 68 Ga]PSMA PET/CT and may often be included in the differential diagnosis. Herein, we present a case of brain metastatic prostate cancer successfully treated with surgical resection and adjuvant stereotactic Gamma Knife radiosurgery (GKRS) followed by androgen deprivation therapy (ADT) to emphasize the need for histologic confirmation. A 70-year-old male with a history of very high-risk prostatic adenocarcinoma presented with biochemical recurrence following radical prostatectomy and irradiation of the prostatic fossa. [ 68 Ga]PSMA PET/CT and MRI identified a solitary lesion in the left occipital lobe; differential diagnosis included prostate metastasis, meningioma, or a new metastatic primary lesion. The patient underwent surgical resection, and immunohistochemical staining confirmed the lesion as brain metastatic prostate adenocarcinoma. One month after resection, the patient underwent GKRS to the tumor bed and two additional metastases, followed by ADT. Repeated imaging 15 months after GKRS revealed stable posttreatment changes with no evidence of new metastases, thus demonstrating durable, effective local and systemic control. Brain metastatic prostate adenocarcinoma without nodal or osseous metastases is a rare phenomenon. The affinity of [ 68 Ga]PSMA PET/CT for non-prostate histologies such as meningioma introduces uncertainty into the diagnostic process. This case demonstrates the durable local control conferred by GKRS toward these lesions and emphasizes the need for clinical, radiographic, and histopathologic data to identify disease presentations and facilitate appropriate treatment regimens., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Knight et al.)

Importance: The presence of bone pain is significantly associated with worse overall survival (OS) in patients with castration-resistant prostate cancer. However, there are few data regarding bone pain and survival outcomes in the context of metastatic, hormone-sensitive prostate cancer (MHSPC)., Objective: To compare survival outcomes among patients with MHSPC by presence or absence of baseline bone pain at diagnosis., Design, Setting, and Participants: This post hoc secondary analysis, conducted from September 1 to December 31, 2023, used patient-level data from SWOG-1216, a phase 3, prospective randomized clinical trial that enrolled patients with newly diagnosed MHSPC from 248 academic and community centers across the US from March 1, 2013, to July 15, 2017. All patients in the intention-to-treat population who had available bone pain status were eligible and included in this secondary analysis., Interventions: In the SWOG-1216 trial, patients were randomized (1:1) to receive either androgen deprivation therapy (ADT) with orteronel, 300 mg orally twice daily (experimental group), or ADT with bicalutamide, 50 mg orally daily (control group), until disease progression, unacceptable toxic effects, or patient withdrawal., Main Outcomes and Measures: Overall survival was the primary end point; progression-free survival (PFS) and prostate-specific antigen (PSA) response were secondary end points. Cox proportional hazards regression models were used for both univariable and multivariable analyses adjusting for age, treatment type, Gleason score, disease volume, Zubrod performance status, and PSA level., Results: Of the 1279 male study participants, 301 (23.5%) had baseline bone pain at MHSPC diagnosis and 896 (70.1%) did not. Bone pain status was unavailable in 82 patients (6.4%). The median age of the 1197 patients eligible and included in this secondary analysis was 67.6 years (IQR, 61.8-73.6 years). Compared with patients who did not experience bone pain, those with baseline bone pain were younger (median age, 66.0 [IQR, 60.1-73.4] years vs 68.2 [IQR, 62.4-73.7] years; P = .02) and had a higher incidence of high-volume disease (212 [70.4%] vs 373 [41.6%]; P < .001). After adjustment, bone pain was associated with shorter PFS and OS. At a median follow-up of 4.0 years (IQR, 2.5-5.4 years), patients with bone pain had median PFS of 1.3 years (95% CI, 1.1-1.7 years) vs 3.7 years (95% CI, 3.3-4.2 years) in patients without initial bone pain (adjusted hazard ratio [AHR], 1.46; 95% CI, 1.22-1.74; P < .001) and OS of 3.9 years (95% CI, 3.3-4.8 years) vs not reached (NR) (95% CI, 6.6 years to NR) in patients without initial bone pain (AHR, 1.66; 95% CI, 1.34-2.05; P < .001)., Conclusions and Relevance: In this post hoc secondary analysis of the SWOG-1216 randomized clinical trial, patients with baseline bone pain at MHSPC diagnosis had worse survival outcomes than those without bone pain. These data suggest prioritizing these patients for enrollment in clinical trials, may aid patient counseling, and indicate that the inclusion of bone pain in prognostic models of MHSPC may be warranted., Trial Registration: ClinicalTrials.gov Identifier: NCT01809691.

Background: About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care., Objective: This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy., Methods: The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models., Results: Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively)., Conclusions: Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management., (© 2024. The Author(s).)

Background: There is an ongoing debate as to whether sex could be associated with immune checkpoint inhibitor (ICI) benefit. Existing literature data reveal contradictory results, and data on first-line immune combinations are lacking., Method: This was a real-world, multicenter, international, observational study to determine the sex effects on the clinical outcomes in metastatic renal cell carcinoma (mRCC) patients treated with immuno-oncology combinations as first-line therapy., Results: A total of 1827 mRCC patients from 71 cancer centers in 21 countries were included. The median OS was 38.7 months (95% CI 32.7-44.2) in the overall study population: 40.0 months (95% CI 32.7-51.6) in males and 38.7 months (95% CI 26.4-41.0) in females (p = 0.202). The median OS was higher in males vs. females in patients aged 18-49y (36.9 months, 95% CI 29.0-51.6, vs. 24.8 months, 95% CI 16.8-40.4, p = 0.426, with + 19% of 2y-OS rate, 72% vs. 53%, p = 0.006), in the clear cell histology subgroup (44.2 months, 95% CI 35.8-55.7, vs. 38.7 months, 95% CI 26.0-41.0, p = 0.047), and in patients with sarcomatoid differentiation (34.4 months, 95% CI 26.4-59.0, vs. 15.3 months, 95% CI 8.9-41.0, p < 0.001). Sex female was an independent negative prognostic factor in the sarcomatoid population (HR 1.72, 95% CI 1.15 - 2.57, p = 0.008)., Conclusions: Although the female's innate and adaptive immunity has been observed to be more active than the male's, women in the subgroup of clear cell histology, sarcomatoid differentiation, and those under 50 years of age showed shorter OS than males., (© 2024. The Author(s).)

Background: Patients with advanced chronic kidney disease (ACKD) are at an increased risk of developing renal cell carcinoma (RCC), but molecular alterations in RCC specimens arising from ACKD and overall survival (OS) in affected patients are not well defined., Patients and Methods: Using the Oncology Research Information Exchange Network (ORIEN) Total Cancer Care ® protocol, 296 consented adult patients with RCC and somatic tumor whole exome sequencing were included. Patients with ACKD were defined as those with serum creatinine ≥1.5 mg/dL prior to RCC diagnosis., Results: Of 296 patients with RCC, 61 met the criteria for ACKD. The most common somatic mutations in the overall cohort were in VHL (126, 42.6%), PBRM1 (102, 34.5%), and SETD2 (54, 18.2%). BAP1 had a decreased mutational frequency in RCC specimens from patients without ACKD as compared to those with ACKD (10.6% versus 1.6%), but this was not statistically significant in univariable (OR 0.14, p = 0.056) or multivariable (OR 0.15, p = 0.067) analysis. Median OS was not reached in either cohort., Conclusions: Using the clinicogenomic ORIEN database, our study found lower rates of BAP1 mutations in RCC specimens from patients with ACKD, which may reflect a BAP1 -independent mutational driver of RCC in patients with ACKD.

Background: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy., Patients and Methods: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors., Results: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001)., Conclusions: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy., (© 2024. The Author(s).)

Background: Systemic treatment with immune combinations is the gold standard for metastatic renal cell carcinoma (mRCC) worldwide. The systemic immune-inflammation index (SII) is a prognostic marker for several types of malignant neoplasms, including mRCC, in the era of tyrosine kinase inhibitor (TKI) treatment. Data regarding the prognostic value of the SII in patients with mRCC treated with immunotherapy are scarce and controversial.  METHODS: We retrospectively collected the data of patients with mRCC from 56 centers in 18 countries. SII (Platelet × Neutrophil/Lymphocyte count) was calculated prior to the first systemic treatment and cut-off was defined by a survival receiver operating characteristic (ROC) analysis. The primary objective of our retrospective study was to assess the outcomes of patients treated with first-line immunotherapy.  RESULTS: Data from 1034 mRCC patients was collected and included in this analysis. The SII cut-off value was 1265. After a follow-up of 26.7 months, and the overall survival (OS) and progression-free survival (PFS) were 39.8 and 15.7 months, respectively. According to SII (low vs. high), patients with low-SII had longer OS (55.7 vs. 22.2 months, P < .001), better PFS (20.8 vs. 8.5 months, P < .001), and higher overall response rate (52 vs. 37%, P = .033)., Conclusion: A high SII is associated with poor oncological outcomes in patients with mRCC. SII could be an easily accessible prognostic indicator for use in clinical practice., Competing Interests: Disclosure Fernando Sabino M. Monteiro: Research support was provided by Janssen (Merck Sharp Dome). Honoraria from Janssen, Ipsen, Bristol Myers Squibb, and Merck Sharp Dome. Ownership: BIO, Brazilian Information Oncology; Ondrej Fiala: Received honoraria from Roche, Janssen, MSD, Pierre Fabre, GSK, and Pfizer for consultations and lectures unrelated to this project; Francesco Massari: Personal fees from Astellas, BMS, Janssen, Ipsen, MSD, and Pfizer; Jindrich Kopecky: Consulting fees from Bristol Myers Squibb, Ipsen, Novartis, MSD; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol-Myers Squibb, MSD, Pfizer, Merck, and Novartis; Jakub Kuchartz: Honoraria: Angelini, Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, IPSEN, Janssen, Merck MSD, Novartis, Pfizer, Research Funding: Novartis; Enrique Grande: Honoraria: Adacap, AMGEN, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, IPSEN, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, NanoString Technologies, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, and Thermo Fisher Scientific. Funding: Pfizer, Astra Zeneca, Astellas, and Lexicon Pharmaceuticals; Maria T. Bourlon: Honoraria/advisory board: Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, Eisai, IPSEN, Janssen, Merck, MSD, Novartis, Pfizer, Roche. Funding: Pfizer; Javier Molina-Cerrillo: Consultant, advisory, or speaker roles for IPSEN, Roche, Pfizer, Sanofi, Janssen, Eisai, MSD, and BMS. JMC has received research grants from Pfizer, IPSEN, Janssen, and Roche; Tomas Buchler: Research support: AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Merck KGaA, MSD, and Novartis; consulting fees from Bristol Myers Squibb, Astellas, Janssen, and Sanofi/Aventis; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol-Myers Squibb, AstraZeneca, Roche, Servier, Accord, MSD, and Pfizer; Emmanuel Seront: Consultancy: MSD, BMS, Pfizer, Ipsen; Aristotelis Bamias: Honoraria, Advisory, Research support: Pfizer, Roche, MSD, BMS, and Ipsen; Camillo Porta: Honoraria: Angelini Pharma, Astra Zeneca, Bristol Myers Squibb, Eisai, Ipsen, MSD; Andre Poisl Fay: Honoraria: Pfizer, Astellas, BMS, Novartis, Roche, Astra-Zeneca, Janssen, MSD, Ipsen. Scientific Advisory Board: Janssen, Novartis, Roche, Ipsen, Pfizer, Bayer, MSD. Research Grant: CAPES - CNPq, BMS, Roche, Astra-Zeneca, MSD, Foundation Medicine, Ipsen. Ownership: BIO, Brazilian Information Oncology. All other authors do not have relationships to disclose. All authors except Ondrej Fiala are unrelated to this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Renal c carcinoma (RCC) is one of the most common urinary cancers worldwide, with a predicted increase in incidence in the coming years. Immunotherapy, as a single agent, in doublets, or in combination with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has rapidly become a cornerstone of the RCC therapeutic scenario, but no head-to-head comparisons have been made. In this setting, real-world evidence emerges as a cornerstone to guide clinical decisions., Objective: The objective of this retrospective study was to assess the outcome of patients treated with first-line immune combinations or immune oncology (IO)-TKIs for advanced RCC., Design, Setting, and Participants: Data from 930 patients, 654 intermediate risk and 276 poor risk, were collected retrospectively from 58 centers in 20 countries. Special data such as sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localization, in addition to biochemical data such as hemoglobin, platelets, calcium, lactate dehydrogenase, neutrophils, and radiological response by investigator's criteria, were collected., Outcome Measurements and Statistical Analysis: Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The median follow-up was calculated by the inverse Kaplan-Meier method., Results and Limitations: The median follow-up time was 18.7 mo. In the 654 intermediate-risk patients, the median OS and PFS were significantly longer in patients with the intermediate than in those with the poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (38.9 vs 17.3 mo, 95% confidence interval [CI] p < 0.001, and 17.3 vs 11.6 mo, 95% CI p < 0.001, respectively). In the intermediate-risk subgroup, the OS was 55.7 mo (95% CI 31.4-55.7) and 40.2 mo (95% CI 29.6-51.6) in patients treated with IO + TKI and IO + IO combinations, respectively (p = 0.047). PFS was 30.7 mo (95% CI 16.5-55.7) and 13.2 mo (95% CI 29.6-51.6) in intermediate-risk patients treated with IO + TKI and IO + IO combinations, respectively (p < 0.001). In the poor-risk subgroup, the median OS and PFS did not show a statistically significant difference between IO + IO and IO + TKI. Our study presents several limitations, mainly due to its retrospective nature., Conclusions: Our results showed differences between the IO + TKI and IO + IO combinations in intermediate-risk patients. A clear association with longer PFS and OS in favor of patients who received the IO + TKI combinations compared with the IO-IO combination was observed. Instead, in the poor-risk group, we observed no significant difference in PFS or OS between patients who received different combinations., Patient Summary: Renal cancer is one of the most frequent genitourinary tumors. Treatment is currently based on immunotherapy combinations or immunotherapy with tyrosine kinase inhibitors, but there are no comparisons between these.In this study, we have analyzed the clinical course of 930 patients from 58 centers in 20 countries around the world. We aimed to analyze the differences between the two main treatment strategies, combination of two immunotherapies versus immunotherapy + antiangiogenic therapy, and found in real-life data that intermediate-risk patients (approximately 60% of patients with metastatic renal cancer) seem to benefit more from the combination of immunotherapy + antiangiogenic therapy than from double immunotherapy. No such differences were found in poor-risk patients. This may have important implications in daily practice decision-making for these patients., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Trichorhinophalangeal syndrome type 1 (TRPS1) has been reported to be a sensitive and specific immunohistochemical (IHC) marker for breast carcinomas, especially when determining primary site of origin. However, there is limited data on TRPS1 expression in prostate and bladder cancers. A two-phase study was performed with 1) an exploratory cohort analyzing TRPS1 gene alterations in prostate, bladder, and breast carcinoma and TPRS1 mRNA expression data in prostate and bladder carcinoma; and 2) TRPS1 and GATA3 IHC in a confirmatory cohort in prostate, bladder, and breast carcinoma samples. Gene alterations were identified in a subset of breast, bladder, and prostate carcinomas and mRNA was consistently detected. In the IHC cohort, 183/210 (87.1 %) of breast, 22/69 (31.9 %) of prostate, and 20/73 (27.4 %) of urothelial carcinomas showed staining with TRPS1. Intermediate to high expression of TRPS1 was observed in 173/210 (82.8 %) of breast, 17/69 (24.6 %) of prostate, and 15/73 (20.5 %) of urothelial carcinomas. Furthermore, in prostate cancer, 26.9 % of pelvic lymph node metastases and 50 % in sites of distant metastases showed expression. Increased TRPS1 mRNA expression (p = 0.032) and IHC expression (p = 0.040) correlated with worse overall survival in bladder cancer. By comparison, GATA3 IHC stained 136/210 (64.8 %) of breast, 0/69 (0 %) of prostate, and 63/73 (93 %) of bladder carcinomas. Intermediate to high expression of GATA3 was seen in 131/210 (62.4 %) of breast and 63/73 (93 %) of bladder carcinomas. This study shows there is significant staining of TRPS1 in bladder and prostate cancers. As a result, comprehensive studies are needed to establish the true specificity of TRPS1 IHC stain across various tumor types before its widespread clinical adoption., Competing Interests: Declaration of competing interest The authors have no relevant conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Tumor thrombus (TT) is a complication of renal cell carcinoma (RCC) for which favorable medical management remains undefined. While radical nephrectomy has been shown to increase overall survival in RCC patients, surgical interventions such as cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) utilized to perform TT resection carry high mortality rates. While it has been documented that RCC with TT is associated with venous thromboembolism (VTE) development, anticoagulation use in these patients remains controversial in clinical practice. Whether anticoagulation is associated with improved survival outcomes remains unclear. Furthermore, if anticoagulation is initiated, there is limited evidence for whether direct oral anticoagulants (DOACs), heparin, or warfarin serve as the most advantageous choice. While the combination of immunotherapy and tyrosine kinase inhibitors (TKIs) has been shown to improve the outcomes of RCC, the clinical benefits of this combination are not well studied prospectively in cases with TT. In this literature review, we explore the challenges of treating RCC-associated TT with special attention to anticoagulation. We provide a comprehensive overview of current surgical and medical approaches and summarize recent studies investigating anticoagulation in RCC patients undergoing surgery, targeted therapy, and/or immunotherapy. Our goal is to provide clinicians with updated clinical insight into anticoagulation for RCC-associated TT patients.

Background: Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab., Methods: We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model., Results: A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3 months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2 months, p = 0.002) and OS (8.7 vs. 14.1 months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival., Conclusions: Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC)., Patients and Methods: Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival., Results: A total of 675 patients were included; BMI was >25 kg/m 2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m 2 versus those with BMI ≤25 kg/m 2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P = .044). In the BMI ≤25 kg/m 2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002)., Conclusion: Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC., Methods: Data from patients aged ≥ 18 years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study., Results: Our analysis included 162 patients. The median follow-up time was 18.9 months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8 months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD., Conclusions: Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The upfront treatment of metastatic renal cell carcinoma (mRCC) has been revolutionized by the introduction of immune-based combinations. The role of cytoreductive nephrectomy (CN) in these patients is still debated. The ARON-1 study (NCT05287464) was designed to globally analyze real-world data of mRCC patients receiving first-line immuno-oncology combinations. This sub-analysis is focused on the role of upfront or delayed partial or radical CN in three geographical areas (Western Europe, Eastern Europe, America/Asia)., Methods: We conducted a multicenter retrospective observational study in mRCC patients treated with first-line immune combinations from 55 centers in 19 countries. From 1152 patients in the ARON-1 dataset, we selected 651 patients with de novo mRCC. 255 patients (39%) had undergone CN, partial in 14% and radical in 86% of cases; 396 patients (61%) received first-line immune-combinations without previous nephrectomy., Results: Median overall survival (OS) from the diagnosis of de novo mRCC was 41.6 months and not reached (NR) in the CN subgroup and 24.0 months in the no CN subgroup, respectively (P<0.001). Median OS from the start of first-line therapy was NR in patients who underwent CN and 22.4 months in the no CN subgroup (P<0.001). Patients who underwent CN reported longer OS compared to no CN in all the three geographical areas., Conclusions: No significant differences in terms of patients' outcome seem to clearly emerge, even if the rate CN and the choice of the type of first-line immune-based combination varies across the different Cancer Centers participating in the ARON-1 project.

Background: Immuno-oncology combinations have achieved survival benefits in patients with metastatic renal cell carcinoma (mRCC)., Objective: The ARON-1 study (NCT05287464) was designed to globally collect real-world data on the use of immuno-combinations as first-line therapy for mRCC patients., Patients and Methods: Patients aged ≥ 18 years with a cytologically and/or histologically confirmed diagnosis of mRCC treated with first-line immuno-combination therapies were retrospectively included from 47 International Institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall clinical benefit (OCB)., Results: A total of 729 patients were included; tumor histology was clear-cell RCC in 86% of cases; 313 patients received dual immuno-oncology (IO + IO) therapy while 416 were treated with IO-tyrosine kinase inhibitor (IO + TKI) combinations. In the overall study population, the median OS and PFS were 36.5 and 15.0 months, respectively. The median OS was longer with IO+TKI compared with IO+IO therapy in the 616 patients with intermediate/poor International mRCC Database Consortium (IMDC) risk criteria (55.7 vs 29.7 months; p = 0.045). OCB was 84% for IO+TKI and 72% for IO + IO combination (p < 0.001)., Conclusions: Our study may suggest that immuno-oncology combinations are effective as first-line therapy in the mRCC real-world context, showing outcome differences between IO + IO and IO + TKI combinations in mRCC subpopulations., Clinical Trial Registration: NCT05287464., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: CD47 is an antiphagocytic molecule that plays a critical role in immune surveillance. A variety of malignancies have been shown to evade the immune system by increasing the expression of CD47 on the cell surface. As a result, anti-CD47 therapy is under clinical investigation for a subset of these tumors. Interestingly, CD47 overexpression is associated with negative clinical outcomes in lung and gastric cancers; however, the expression and functional significance of CD47 in bladder cancer is not fully understood., Materials and Methods: We retrospectively studied patients with muscle invasion bladder cancer (MIBC) who underwent a transurethral resection of bladder tumor (TURBT) and subsequently underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). CD47 expression was examined by IHC in both TURBT and matched RC specimens. The difference in CD47 expression levels between TURBT and RC was also compared. The association of CD47 levels (TURBT) with clinicopathological parameters and survival outcomes was evaluated by Pearson's chi-squared tests and the Kaplan-Meier method, respectively., Results: A total of 87 MIBC patients were included. The median age was 66 (39-84) years. Most patients were Caucasian (95%), male (79%), and aged >60 (63%) and most often (75%) underwent NAC prior to RC. Of those who received NAC, 35.6% were responders and 64.4% were non-responders. The final reported stages as per AJCC for all patients were as follows: stage 0 (32%), stage 1 (1%), stage 2 (20%), stage 3 (43%), and stage 4a (5%). A total of 60% of patients were alive; of those, 30% had disease recurrence and 40% died from bladder cancer at a median follow-up of 3.1 (0.2-14.2) years. CD47 levels were detectable in 38 (44%) TURBT samples. There was no association between CD47 levels and clinicopathological parameters such as age, gender, race, NAC, final stage, disease recurrence, and overall survival (OS). Patients aged >60 ( p = 0.006), non-responders ( p = 0.002), and at stage ≥ 3 ( p < 0.001) were associated with worse OS by a univariate analysis and stage ≥ 3 remained significant even after a multivariate analysis. In patients managed with NAC, there were decreased CD47 levels in RC specimens compared to the TURBT specimens, but this did not reach statistical significance., Conclusion: CD47 expression was not a predictive nor prognostic marker for MIBC patients. However, expression of CD47 was detected in nearly half of MIBCs, and future studies are needed to explore the potential role of anti-CD47 therapy in these patients. Furthermore, there was a slight positive trend in decreased CD47 levels (from TURBT to RC) in patients receiving NAC. As a result, more research is needed to understand how NAC may modify immune surveillance mechanisms in MIBC.

Purpose: Cannabinoids (CBD) have anti-tumor activity against prostate cancer (PCa). Preclinical studies have demonstrated a significant decrease in prostate specific antigen (PSA) protein expression and reduced tumor growth in xenografts of LNCaP and DU-145 cells in athymic mice when treated with CBD. Over-the-counter CBD products may vary in activity without clear standardization, and Epidiolex is a standardized FDA-approved oral CBD solution for treatment of certain types of seizures. We aimed to assess the safety and preliminary anti-tumor activity of Epidiolex in patients with biochemically recurrent (BCR) PCa., Experimental Design: This was an open-label, single center, phase I dose escalation study followed by a dose expansion in BCR patients after primary definitive local therapy (prostatectomy +/- salvage radiotherapy or primary definitive radiotherapy). Eligible patients were screened for urine tetrahydrocannabinol prior to enrollment. The starting dose level of Epidiolex was 600 mg by mouth once daily and escalated to 800 mg daily with the use of a Bayesian optimal interval design. All patients were treated for 90 days followed by a 10-day taper. The primary endpoints were safety and tolerability. Changes in PSA, testosterone levels, and patient-reported health-related quality of life were studied as secondary endpoints., Results: Seven patients were enrolled into the dose escalation cohort. There were no dose-limiting toxicities at the first two dose levels (600 mg and 800 mg). An additional 14 patients were enrolled at the 800 mg dose level into the dose expansion cohort. The most common adverse events were 55% diarrhea (grade 1-2), 25% nausea (grade 1-2), and 20% fatigue (grade 1-2). The mean PSA at baseline was 2.9 ng/mL. At the 12-week landmark time-point, 16 out of 18 (88%) had stable biochemical disease, one (5%) had partial biochemical response with the greatest measurable decline being 41%, and one (5%) had PSA progression. No statistically significant changes were observed in patient-reported outcomes (PROs), but PROs changed in the direction of supporting the tolerability of Epidiolex (e.g., emotional functioning improved)., Conclusion: Epidiolex at a dose of 800 mg daily appears to be safe and tolerable in patients with BCR prostate cancer supporting a safe dose for future studies.

BACKGROUND Prostate cancer growth is primarily driven by testosterone and 5a-dihydrotestosterone. Abiraterone is an irreversible inhibitor of CYP17, and CYP17 inhibition is a required step in testosterone biosynthesis. Previous studies have shown that abiraterone trough levels are predictive of prostate-specific antigen (PSA) response in metastatic castrate-resistant prostate cancer (mCRPC). It has not been demonstrated if this association exists for patients with metastatic hormone-sensitive prostate cancer (mHSPC). In this study, we aimed to explore the correlation and association between abiraterone trough levels and PSA levels in patients with mHSPC. MATERIAL AND METHODS This was a single-center, prospective, observational study of patients with mHSPC being treated with abiraterone acetate (AA) 1000 mg once daily. Abiraterone trough levels (22-26 h after drug administration) were drawn at 1, 3, and 7 months after treatment initiation. RESULTS Thirteen patients with mHSPC were enrolled, and complete pharmacokinetic data were available for 8 patients. The mean trough levels at 1 month, 3 months, and 7 months were 34.49 ng/mL (3.36-240.46), 13.82 ng/mL (2.91-29.96), and 15.7 ng/mL (3.58-26.86), respectively. The correlation between the 1-month abiraterone trough level and 1-month PSA level was 0.29 (P=0.38), between 3-month abiraterone trough and 3-month PSA was -0.61 (P=0.08), and between 7-month abiraterone trough and 7-month PSA was -0.31 (P=0.54). CONCLUSIONS This study demonstrated a trend toward a negative correlation between 3-month abiraterone trough levels and PSA levels, but the correlation was not statistically significant. A study with a larger prospective sample size is needed to validate these findings.

Background: Drug-drug interactions are a major concern in oncology and may potentially affect the outcome of patients with cancer., Objective: In this study, we aimed to determine whether the concomitant use of statins, metformin, or proton pump inhibitors affects survival in patients with metastatic renal cell carcinoma treated with first-line combination therapies., Methods: Medical records of patients with documented metastatic renal cell carcinoma between January 2016 and November 2021 were reviewed at 17 participating centers. This research was conducted in ten institutions, including both referral centers and local hospitals. Patients were assessed for overall survival, progression-free survival, and overall clinical benefit. Univariate and multivariate analyses were conducted to explore the association of variables of interest with overall survival and progression-free survival., Results: A total of 304 patients receiving dual immunotherapy (51%) or immunotherapy/vascular endothelial growth factor-tyrosine kinase inhibitor (49%) combinations were eligible for inclusion in this retrospective study. Statin use was a significant prognostic factor for longer overall survival in a univariate analysis (hazard ratio 0.48, 95% confidence interval 0.26-0.87; p = 0.016) and a multivariate analysis (hazard ratio 0.48, 95% confidence interval 0.31-0.74; p < 0.001) and was significantly associated with an overall clinical benefit (83% in statin users vs 71% in non-users; p = 0.045). Otherwise, the use of metformin or proton pump inhibitors did not affect the outcome of these patients., Conclusions: Our study suggests a prognostic impact of statin use in patients receiving first-line immuno-oncology combinations. The mechanism of this interaction warrants further elucidation., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Adjuvant treatment has always been a cornerstone in the therapeutic approach of many cancers, considering its role in reducing the risk of relapse and, in some cases, increasing overall survival. Adjuvant immune checkpoint inhibitors have been tested in different malignancies., Methods: We performed a meta-analysis aimed to explore the impact of adjuvant PD-1 and PD-L1 inhibitors on relapse-free survival (RFS) in cancer patients enrolled in randomized controlled clinical trials. We retrieved all phase III trials published from 15 June 2008 to 15 May 2022, evaluating PD-1/PD-L1 inhibitors monotherapy as an adjuvant treatment by searching on EMBASE, Cochrane Library, and PubMed/ Medline, and international oncological meetings' abstracts. The outcome of interest was RFS. We also performed subgroup analyses focused on age and gender., Results: Overall, 8 studies, involving more than 6000 patients, were included in the analysis. The pooled results highlighted that the use of adjuvant PD-1/PD-L1 inhibitors may reduce the risk of relapse compared to control treatments (hazard ratio, 0.72; 95% confidence intervals, 0.67-0.78). In addition, the subgroup analyses observed that this benefit was consistent in different patient populations, including male, female, younger, and older patients., Conclusions: Adjuvant anti-PD-1/PD-L1 treatment is associated with an increased RFS in the overall population and in subgroups divided according to age and gender.

Statins are commonly prescribed to reduce plasma cholesterol levels and risk of cardiovascular events and mortality. Statin exposure may have cancer-preventive properties in some solid tumors, including Renal Cell Carcinoma (RCC). Emerging evidences show that statins can inhibit RCC cell growth by inducing cell cycle arrest and apoptosis in a dose- and time-dependent manner. In addition, statins inhibit the phosphorylation of AKT, mammalian target of rapamycin (mTOR), and ERK leading to reduced motility of RCC cells. Interestingly, the potential impact of concomitant statin intake has been recently evaluated in RCC patients treated by targeted therapy or immunotherapy. In this review, we illustrate the most recent data on the preclinical activity of statins in Renal Cell Carcinoma models and discuss the impact of their use on the prevention and survival of patients affected by this tumor., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Several bone-seeking radionuclides have been developed for palliation of metastatic bone pain since 1956, however, so far radium-223 dichloride is the first and only Food and Drug Administration (FDA) approved targeted alpha therapy for metastatic castration-resistant prostate cancer (mCRPC) based on ALSYMPCA phase 3 study. While radium-223 does improve pain and overall survival outcomes, the improvement can come at the expense of side effects such as bone marrow toxicity. The development of new and better treatment with long-standing pain relief is clearly an unmet medical need., Methods: The study is a non-randomized phase II study. The study population consists of 25 patients with CRPC who had progressed on any lines of prior therapies and whose serum testosterone level is less than 50 ng/dl and have metastatic lesions to at least two bone sites, with at least one site that has clinically meaningful pain at baseline (≥ 4 on an 11-point intensity scale). Eligible patients will be given two cycles of Sn-117 m-DTPA every 8 weeks or 56 days. Treatment will be administered by slow IV injection over 5-10 min. Retreatment after two cycles is allowed if patients meet the following retreatment criteria. The primary objective is to evaluate the efficacy of Sn-117 m-DTPA on sustained pain response in patients with CRPC metastatic to at least two bone sites and at least one with clinically meaningful pain at baseline (≥ 4 on an 11-point pain intensity scale). Sustained pain response is defined as: 1) achieving pain index ≤ 3 within a 12-week period and 2) maintaining pain index ≤ 3 over a 16-week period. The secondary objectives are: safety and tolerability, measurement of Sn-117 m-DTPA activity by gamma-camera dosimetry scans, therapeutic efficacy, time to the first symptomatic skeletal event, duration of pain response, changes in PSA and ALP levels, patient-reported outcomes and progression free survival and overall survival., Discussion: Sn-117 m-DTPA is a unique bone-targeting theranostic radiopharmaceutical agent that selectively binds most heavily to bone metastases sites. This study will be the first prospective phase II trial to assess the pain efficacy and anti-tumor activity of Sn-117 m-DTPA in mCRPC with at least one clinically meaningful pain at baseline., Trial Registration: ClincialTrials.gov Identifier: NCT04616547., (© 2022. The Author(s).)

Background: Hematological adverse events (HAEs) are common during treatment for glioblastoma (GBM), usually associated with temozolomide (TMZ). Their clinical value is uncertain, as few investigations have focused on outcomes for HAEs during GBM treatment., Methods: We combined data from two randomized clinical trials, RTOG 0525 and RTOG 0825, to analyze HAEs during treatment for GBM. We investigated differences between chemoradiation and adjuvant therapy, and by regimen received during adjuvant treatment., Results: 1454 patients participated in these trials, of which 1154 (79.4%) developed HAEs. During chemoradiation, 44.4% of patients developed HAEs (54% involving more than one cell line), and were most commonly lymphopenia (50.6%), and thrombocytopenia (47.5%). During adjuvant treatment, 45% of patients presented HAEs (78.6% involving more than one cell line), and were more commonly leukopenia (62.7%), and thrombocytopenia (62.3%). Median overall survival (OS) and progression free survival (PFS) were longer in patients with HAEs (OS 19.4 months and PFS 9.9 months) compared to those with other or no adverse events (OS 14.1 months and PFS 5.9 months). There was no significant difference in survival between grade 1 and/or 2 versus grade 3 and/or 4 HAEs. History of HAEs during chemoradiation was a protective factor for presentation of HAEs during adjuvant therapy., Conclusion: HAEs are common during GBM treatment, and often involve more than one cell line (more likely during adjuvant therapy). HAEs may be associated with prolonged OS and PFS, particularly during adjuvant therapy. HAEs during chemoradiation was a protective factor for HAEs during adjuvant therapy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists-enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.

Objective: We aimed to review of literature on the clinical presentation, management and outcomes of pituitary apoplexy following gonadotrophic release hormone (GnRH) agonist administration for the treatment of prostate cancer., Methods: We used PRISMA guidelines for our systematic review and included all English language original articles on pituitary apoplexy following GnRH agonist administration among prostate cancer patients from Jan 1, 1995 to Dec 31, 2020. Data on patient demographics, prostate cancer type, Gleason score at diagnosis, history of pituitary adenoma, clinical presentation, GnRH agonist, interval to pituitary apoplexy, laboratory evaluation at admission, radiologic findings, treatment of pituitary apoplexy, time to surgery if performed, pathology findings, and clinical/hormonal outcomes were collected and analyzed., Results: Twenty-one patients with pituitary apoplexy met our inclusion criteria. The mean age of patients was 70 (60-83) years. Leuprolide was the most common used GnRH agonist, used in 61.9% of patients. Median duration to symptom onset was 5 h (few minutes to 6 months). Headache was reported by all patients followed by ophthalmoplegia (85.7%) and nausea/vomiting (71.4%). Three patients had blindness at presentation. Only 8 cases reported complete anterior pituitary hormone evaluation on presentation and the most common endocrine abnormality was FSH elevation. Tumor size was described only in 15 cases and the mean tumor size was 26.26 mm (18-48 mm). Suprasellar extension was the most common imaging finding seen in 7 patients. 71.4% of patients underwent pituitary surgery, while 23.8% were managed conservatively. Interval between symptoms onset to pituitary surgery was 7 days (1-90 days). Gonadotroph adenoma was most common histopathologic finding. Clinical resolution was comparable, while endocrine outcomes were variable among patients with conservative vs surgical management., Conclusion: Although the use of GnRH agonists is relatively safe, it can rarely lead to pituitary apoplexy especially in patients with pre-existing pituitary adenoma. Physicians should be aware of this complication as it can be life threatening. A multidisciplinary team approach is recommended in treating individuals with pituitary apoplexy.

High Glutaminase (GLS1) expression may have prognostic implications in colorectal and breast cancers; however, high quality data for expression in prostate cancer (PCa) are lacking. The purpose of this study is to investigate the status of GLS1 expression in PCa and correlated expression levels with clinicopathologic parameters. This study was conducted in two phases: an exploratory cohort analyzing RNA-Seq data for GLS1 from The Cancer Genome Atlas (TCGA) data portal (246 PCa samples) and a GLS1 immunohistochemical protein expression cohort utilizing a tissue microarray (TMA) (154 PCa samples; 41 benign samples) for correlation with clinicopathologic parameters. In the TCGA cohort, GLS1 mRNA expression did not show a statistically significant difference in disease-free survival (DFS) but did show a small significant difference in overall survival (OS). In the TMA cohort, there was no correlation between GLS1 expression and stage, Gleason score, DFS and OS. GLS1 expression did not significantly correlate with the clinical outcomes measured; however, GLS1 expression was higher in PCa cells compared to benign epithelium. Future studies are warranted to evaluate expression levels in greater numbers of high-grade and advanced PCa samples to investigate whether there is a rational basis for GLS1 targeted therapy in a subset of patients with prostate cancer.

BACKGROUND Prostate adenocarcinoma rarely metastasize to the brain. The aim of this study was to understand the risk association and survival outcomes comparing prostate cancer with brain metastasis (group 1) with prostate cancer without brain metastasis (group 2) at the time of initial diagnosis. MATERIAL AND METHODS We searched the Surveillance, Epidemiology, and End Results (SEER) statewide cancer registries for all cases of stage IV prostate cancer adenocarcinoma diagnosed between 2010 and 2015. We used the Kaplan-Meier method and Cox regression to analyze survival outcomes and logistic regression to study the association between the presence of brain metastasis and potential risk variables. Exclusion criteria were the presence of neuroendocrine and small cell histology. RESULTS The study included 14 753 patients. Of these, 187 patients were in group 1 (with brain metastasis) and 14 566 were in group 2 (without brain metastasis). When comparing the metastases distribution at the time of initial presentation between group 1 and group 2, the occurrence of bone metastasis was similar in the 2 groups (87% vs 90%); however, liver metastasis (13% vs 4%) and lung metastasis (29% vs 7%) were significantly higher in group 1. We found a strong association between brain metastasis and visceral metastasis. There was no association between age, race, and grade and having brain metastasis. CONCLUSIONS Our analysis shows that visceral metastasis is associated with a higher risk of brain metastasis. Presence of a visceral metastasis can be a useful parameter to consider early magnetic resonance imaging of the brain to facilitate diagnosis of asymptomatic brain metastasis.

Radiopharmaceuticals are reemerging as attractive anticancer agents, but there are no universally adopted guidelines or standardized procedures for evaluating agent validity before early-phase trial implementation. To validate a radiopharmaceutical, it is desirous for the radiopharmaceutical to be specific, selective, and deliverable against tumors of a given, molecularly defined cancer for which it is intended to treat. In this article, we discuss four levels of evidence-target antigen immunohistochemistry, in vitro and in vivo preclinical experiments, animal biodistribution and dosimetry studies, and first-in-human microdose biodistribution studies-that might be used to justify oncology therapeutic radiopharmaceuticals in a drug-development sequence involving early-phase trials. We discuss common practices for validating radiopharmaceuticals for clinical use, everyday pitfalls, and commonplace operationalizing steps for radiopharmaceutical early-phase trials. We anticipate in the near-term that radiopharmaceutical trials will become a larger proportion of the National Cancer Institute Cancer Therapy Evaluation Program (CTEP) portfolio., 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 Kunos, Howells, Chauhan, Myint, Bernard, El Khouli and Capala.)

Importance: A high incidence of fall and fracture in a subset of patients treated with androgen receptor inhibitors (ARIs) has been reported, although the relative risk (RR) of fall and fracture for patients who receive ARI treatment is unknown., Objective: To evaluate whether treatment with ARIs is associated with an elevated relative risk for fall and fracture in patients with prostate cancer., Data Sources: Cochrane, Scopus, and MedlinePlus databases were searched from inception through August 2019., Study Selection: Randomized clinical trials comparing patients with prostate cancer treated with any ARI or placebo were included., Data Extraction and Synthesis: Two independent reviewers used a standardized data extraction and quality assessment form. A mixed effects model was used to estimate the effects of ARI on relative risk, with included studies treated as random effects and study groups treated as fixed effects in the pooled analysis. Sample size for each study was used to weight the mixed model. Statistical analysis was performed from August to October 2019., Main Outcomes and Measures: The primary outcome was RR of fall and fractures for patients receiving ARI treatment., Results: Eleven studies met this study's inclusion criteria. The total population was 11 382 men (median [range] age: 72 [43-97] years), with 6536 in the ARI group and 4846 in the control group. Participants in the ARI group could have received enzalutamide, apalutamide, or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations; patients in the control group could have received placebo, bicalutamide, or abiraterone. The reported incidence of fall was 525 falls (8%) in the ARI group and 221 falls (5%) in the control group. The incidence of fracture was 242 fractures (4%) in the ARI group and 107 fractures (2%) in the control group. Use of an ARI was associated with an increased risk of falls and fractures: all-grade falls (RR, 1.8; 95% CI, 1.42-2.24; P < .001); grade 3 or greater fall (RR, 1.6; 95% CI, 1.27-2.08; P < .001); all-grade fracture (RR, 1.59; 95% CI, 1.35-1.89; P < .001), and likely grade 3 or greater fracture (RR, 1.71; 95% CI, 1.12-2.63; P = .01)., Conclusions and Relevance: Use of ARI was associated with an increase in falls and fractures in patients with prostate cancer as assessed by a retrospective systematic review and meta-analysis. Further studies are warranted to identify and understand potential mechanisms and develop strategies to decrease falls and fractures associated with ARI use.

Introduction: Androgen deprivation therapy (ADT) is a primary treatment option for patients diagnosed with locally advanced-stage or metastatic prostate cancer. Androgen deprivation can be achieved either by radical orchiectomy or by medical castration using a gonadotropin-releasing hormone agonist. ADT has been linked to an initial 12-month loss of bone mineral density, a risk factor for weight-bearing bone fracture, and therefore, a confounding hazard for adverse event when patients are enrolled on early phase trials. To better understand the frequency of ADT-investigational agent-related bone fracture, we conducted a retrospective study of National Cancer Institute Cancer Therapy Evaluation Program (CTEP)-sponsored early phase trials to determine the number of fractures observed among enrolled prostate cancer patients. Patients and Methods: 464 locally advanced-stage or metastatic prostate cancer patients were identified among seven ADT-investigational agent trials conducted between 2006 and 2013. Demographic, co-morbidity, treatment, and adverse event variables were abstracted from CTEP databases and descriptive statistics were used. Results: 464 men had a median age of 64 years, were mostly white (90%), and had a performance status of 0 or 1 (98%). The number of new bone fractures occurring on or after ADT-investigational agent treatment was very low (4.6 per 1000 person-years). The median pretrial prostate specific antigen level was 29 ng/mL and most men (71%) had prostate cancer histopathology Gleason 7 score or higher. In these trials, 43 percent of men had bone only and 35 percent had bone and visceral metastatic disease. The most frequent grade 1 or 2 adverse events were fatigue (36%), hot flashes (27%), and anemia (17%). Grade 3 or higher adverse events were rare, with hypertension (3%) and hyperglycemia (3%) observed. Conclusions: Identifying bone health factors may still be relevant in selected early phase ADT-investigational agent trial patients, emphasizing the need for improved methods for capturing baseline bone health and studying ADT-investigational agent and concurrent medication interactions on bone health., (Copyright © 2020 Myint and Kunos.)

Objective/background: Early stage classical Hodgkin lymphoma (cHL) has an excellent outcome. Recent studies focus on decreasing toxicity related to the addition of radiation along with chemotherapy. Real-life reporting of the addition of radiation to chemotherapy is lacking. This study investigates the outcomes obtained from a statewide cancer registry for early stage cHL patients treated with chemotherapy alone (CT) versus patients treated with the combined modality of chemotherapy and radiation (CMT)., Methods: A retrospective study of cHL patients diagnosed and treated was identified using a statewide cancer registry from 2005 to 2014. Patients with early stage disease (I, II) were then grouped on the basis of the presence of B symptoms into favorable and unfavorable groups. Baseline characteristics (age, gender, extranodal involvement, and histology) as well as overall survival were compared for both groups depending on whether they received CT or CMT as first line therapy for their cHL., Results: A total of 961 patients were identified; of those, 127 were excluded as they received only radiation or another form of treatment. Of the remaining patients, 293 were categorized as early stage favorable cHL (Group 1) and 130 adults were in the unfavorable cHL (Group 2). There were 335 patients with advanced stage cHL (Group 3) and 76 patients in an unknown stage. The 10-year overall survival for Group 1 was 81.3% versus 76.3% for Group 2 and 52.7% for Group 3. For Group 1, 10-year overall survival was 86.7% with CMT versus 75.1% for those receiving CT only (p = .004). For Group 2, there was no difference in 10-year overall survival between the CMT group (80.0%) and CT (72.5%) (p = .73)., Conclusion: While radiation therapy might increase long-term toxicity in cHL, in our large data cohort, radiotherapy consolidation as part of the initial therapy for early stage disease provides superior survival at 10 years, especially in favorable risk cHL., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Published by Elsevier Ltd.)

Purpose: To provide an overview of fibroblast growth factor receptor (FGFR) gene alterations and the pharmacology, clinical effectiveness, dosage and administration, cost, and place in therapy of erdafitinib in bladder cancer., Summary: Erdafitinib (Balversa, Janssen Pharmaceuticals) is a novel pan-FGFR inhibitor recently approved for the treatment of patients with advanced urothelial cancer with specific FGFR genetic alterations who have received at least one prior platinum-containing regimen. Erdafitinib binding to the FGFR2 and FGFR3 receptors inhibits FGF activity, resulting in cell death. Erdafitinib is available in tablet form, and the current recommended daily dosing is 8 mg, with dose escalation to 9 mg after 14 to 21 days of therapy if tolerated. A phase 2 clinical trial demonstrated that patients who received erdafitinib experienced on average 5.5 months of progression-free survival (95% confidence interval [CI], 4.2-6.0 months). In addition, 40% (95% CI, 31-50%) of patients responded to erdafitinib therapy. Patients receiving erdafitinib therapy should be monitored specifically for elevations in serum phosphate levels and changes in vision. Other adverse effects include anemia, thrombocytopenia, and electrolyte abnormalities., Conclusion: Erdafitinib is the first small-molecule FGFR inhibitor approved for use in advanced bladder cancer., (© American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Prostate cancer (PC) is the most common male cancer in the USA. When comparing the incidence and mortality rates of PC, the Surveillance Epidemiology and End Results data of 2005-2014 show that Appalachian Kentucky had a lower incidence (113/100 000 v 137/100 000) but a higher mortality rate (23.8% v 21.8%) when compared to non-Appalachian Kentucky. The aim of this study was to further characterize the survival disparities of PC between Appalachian and non-Appalachian Kentucky., Methods: All stages of PC patients diagnosed between 2007 and 2011 were collected through the Kentucky Cancer Registry. Baseline characteristics and survival outcomes were compared between Appalachian Kentucky and non-Appalachian Kentucky, using Pearson χ2 and Cox regression analyses in this population-based analysis., Results: Of 12 871 patients studied, 3482 (26.8%) were from Appalachian Kentucky whereas 8489 (73.2%) were from non-Appalachian Kentucky. Caucasians predominated in both groups. Most Appalachian Kentucky patients were aged 65-74 years. Appalachian Kentucky patients had a higher Gleason score, higher prostate specific antigen (PSA), more aggressive histologic grade, more distant disease, higher comorbidity score, lower education, and higher poverty compared to patients from non-Appalachian Kentucky. There was a 5-year survival difference between Appalachian Kentucky and non-Appalachian Kentucky in unadjusted analysis (p<0.001) that disappeared after adjusting with Cox regression analysis (p=0.4). However, worsened survival was still seen with higher Gleason score, higher PSA, distant stage disease, higher Charlson comorbidity index, and very low high school education (p<0.001)., Conclusion: In this population-based analysis, this study shows a significant difference in PC survival between Appalachian and non-Appalachian Kentucky. The difference was not related to geographic location, but rather to high comorbidity score, high poverty rate, and low education. Additional research is needed to understand the healthcare restraints for Appalachian Kentucky.

Background: Neuroendocrine tumors (NETs) are rare tumors that can originate from any part of the body. Often, imaging or exploratory surgery can assist in the identification of the tumor primary site, which is critical to the management of the disease. Neuroendocrine tumors (NETs) of unknown primary constitute approximately 10-15% of all NETs. Determining the original site of the tumor is critical to providing appropriate and effective treatment. Methods: We performed a retrospective review of neuroendocrine tumors at our institution between 2012 and 2016 using a 92-gene cancer ID analysis. Results: 56 patients with NETs of unknown primary were identified. Samples for 38 of the 56 underwent the 92-gene cancer ID analysis. The primary site of the tumor was identified with >95% certainty in 35 of the 38 patients. Conclusion: The 92-gene cancer ID analysis identified a primary site in 92% of our NETs study cohort that previously had been unknown. The results have direct implications on management of patients with regard to FDA-approved treatment options., (Creative Commons Attribution License)

Background: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare pulmonary condition, characterized by diffuse proliferation of neuroendocrine cells in the respiratory epithelium. DIPNECH lesions are less than 5 mm in size and are limited to the basement membrane with no invasion. There is limited information regarding epidemiology, natural history of disease progression, or the management of this rare entity. We present the experience of a center with extensive expertise in neuroendocrine disease., Methods: A cohort of patients (N = 13) with DIPNECH treated and followed at our institution was identified. We describe the our approach to their care, our disease management and also provide a review of DIPNECH pathophysiology., Results: Our patient cohort consisted of twelve females and one male with a mean age of 63 years at the time of diagnosis. Dyspnea on exertion and dry cough were the most common presenting symptoms. Two patients were under surveillance without treatment; three patients were treated with a short-acting somatostatin analog; three patients were treated with azithromycin alone; four were treated with a combination of long-acting monthly somatostatin analogs and azithromycin; one patient received a combination of long-acting somatostatin analog and everolimus. Five patients had concomitant bronchial carcinoids., Conclusions: DIPNECH is a rare pathology that can profoundly affect a patient's quality of life. Paroxysmal coughing episodes can be difficult to treat. Our limited single center experience shows encouraging response to use of somatostatin analogs, azithromycin, and everolimus in the management of debilitating DIPNECH associated symptoms.

Copper is a crucial micronutrient needed by animals and humans for proper organ function and metabolic processes such as hemoglobin synthesis, as a neurotransmitter, for iron oxidation, cellular respiration, and antioxidant defense peptide amidation, and in the formation of pigments and connective tissue. Multiple factors, either hereditary or acquired, contribute to the increase in copper deficiency seen clinically over the past decades. The uptake of dietary copper into intestinal cells is via the Ctr1 transporter, located at the apical membrane aspect of intestinal cells and in most tissues. Copper is excreted from enterocytes into the blood via the Cu-ATPase, ATP7A, by trafficking the transporter towards the basolateral membrane. Zinc is another important micronutrient in animals and humans. Although zinc absorption may occur by direct interaction with the Ctr1 transporter, its absorption is slightly different. Copper deficiency affects physiologic systems such as bone marrow hematopoiesis, optic nerve function, and the nervous system in general. Detailed pathophysiology and its related diseases are explained in this manuscript. Diagnosis is made by measuring serum copper, serum ceruloplasmin, and 24-h urine copper levels. Copper deficiency anemia is treated with oral or intravenous copper replacement in the form of copper gluconate, copper sulfate, or copper chloride. Hematological manifestations are fully reversible with copper supplementation over a 4- to 12-week period. However, neurological manifestations are only partially reversible with copper supplementation.

Background: Pernicious Anemia (PA), the most common cause of cobalamin deficiency anemia worldwide, is an autoimmune disease of multifactorial etiologies involving complex environmental and immunological factors. Although it was first reported by Addison in 1849 with subsequent advances in understanding of pathogenesis and molecular biology, diagnosis of PA is still challenging for clinicians because of its complexity and diverse clinical presentations., Conclusion: Herein, we provide an overview of PA, mainly focusing on its scientific and practical aspects in diagnosis. We also discuss the limitations of currently available diagnostic tools for the evaluation of cobalamin deficiency and PA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Gastrointestinal (GI) cancers are a group of highly aggressive malignancies with a huge disease burden worldwide. There is clearly a significant unmet need for new drugs and therapies to further improve the treatment outcomes of GI malignancies. Immunotherapy is a novel treatment strategy that is emerging as an effective and promising treatment option against several types of cancers. CTLA-4 and PD-1 are critical immune checkpoint molecules that negatively regulate T cell activation via distinct mechanisms. Immune checkpoint blockade with antibodies directed against these pathways has already shown clinical efficacy that has led to their FDA approval in the treatment of several solid tumors including melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and head and neck cancer. This review will summarize the current clinical progress of modern immunotherapy in the field of GI tumors, with a special focus on immune checkpoint blockade.

Cancer-associated thrombosis (CAT) accounts for about 20% of all thrombosis worldwide. It is the second leading cause of death in cancer patients. The risk of venous thromboembolism (VTE) is 4 -7 times higher and the risk of recurrent VTE three times higher in the cancer patients, compared to the non-cancer patients. The survival of cancer patients with VTE is lower than that of patients without VTE. In the last two decades, the incidence of CAT has risen in the ambulatory patients than in the inpatient setting. While the role of pharmacologic thromboprophylaxis (PTP) is established in the hospitalized cancer patients, ambulatory PTP is not, except in patients with multiple myeloma and myeloproliferative neoplasms. In the last decade, the low-molecular-weight heparin (LMWH) has emerged as the standard of care for the treatment of acute cancer-associated VTE. Many questions remain unanswered with regards to the optimal duration of LMWH therapy in the CAT, the role of direct oral anticoagulants (DOACs) in CAT, and the optimal anticoagulation management in thrombocytopenic cancer patients. Research trials are necessary to define a subset of ambulatory solid tumor patients who may benefit from PTP and to define the role of DOACs in the prevention and treatment of CAT.