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Background: The urinary microbiota of patients with benign prostatic hyperplasia (BPH) has been associated with lower urinary tract symptoms (LUTS), however, little is known about urinary microbiota correlations with clinicopathological parameters associated with BPH. Here, we investigate associations between the urinary microbiota and clinical parameters of patients with BPH undergoing surgery., Methods: Forty-one patients with BPH undergoing surgery were recruited from two medical centers. Catheterized urine specimens were collected and the microbiota was characterized by 16S rRNA gene sequencing. Patients were segregated into two groups according to each clinical parameter and differences in urinary microbiota diversity and composition were evaluated., Results: Higher prostate weight and prostate-specific antigen (PSA) levels were associated with higher alpha diversity in the urinary microbiota of BPH patients. At the specific microbe level, we found that the greater the prostatic weight, the lower the relative abundance of Streptococcus, while the greater the PSA levels, the higher the abundance of Lactobacillus. Treatment with 5-α-reductase inhibitor was associated with overall urinary microbiota composition, in part due to a higher abundance of Corynebacterium and Anaerococcus in this group., Conclusions: We demonstrated that the urinary microbiota of BPH patients is associated with clinicopathological features, paving the way for larger studies in which causality between urinary microbiota and BPH can be appropriately explored., (© 2023 Wiley Periodicals LLC.)

Background: Cyclin pathway gene alterations are frequent in urothelial tumors and may co-exist with other important aberrations, leading to therapeutic opportunities. We characterized the landscape of cyclin gene alterations in urothelial and non-urothelial urinary tract (UT) malignancies., Patients and Methods: Overall, 6842 urothelial and 897 non-urothelial UT cancers were analyzed (hybrid-capture-based comprehensive genomic profile (Foundation Medicine)). Alteration frequency in cyclin-sensitizing and -resistance genes, and co-occurrence with fibroblast growth factor receptor (FGFR) gene abnormalities were evaluated., Results: Cyclin-activating gene alterations were detected in 47.3% of urothelial and 37.9% of non-urothelial UT cancers. Frequency varied by histology and tumor site. CDKN2A and CDKN2B loss were the most frequent alterations in urothelial tumors (present in 38.5% and 30.4% of patients, respectively). Both genes were less frequently altered in adenocarcinomas (15.2% and 8.9%), but commonly altered in squamous cell carcinomas (74.4% and 39%). Tumors of neuroendocrine origin were relatively silent in activating cyclin alterations, but frequently displayed Rb1 alterations (86% and 83.7% of neuroendocrines and small cell carcinomas). Urachal tumors (n = 79) presented a distinct landscape of cyclin alterations relative to other UT cancers, with less frequent alterations overall. FGF/FGFR genes were altered in 34.9% of urothelial (22.1% in FGFR3), and 19.4% of non-urothelial urinary tract tumors (6.8% FGFR3). Cyclin-activating alterations frequently co-occurred with FGF/FGFR alterations but were in general mutually exclusively with cyclin resistance alterations (RB1/CCNE1)., Conclusions: Cyclin pathway activating alterations are common in urinary tract tumors, but frequency varies with histology and tumors sites. Co-occurrence of cyclin and FGFR pathway alterations may inform therapeutic opportunities., (© The Author(s) 2022. Published by Oxford University Press.)

Accessibility to next-generation sequencing (NGS) technologies has enabled the profiling of microbial communities living in distinct habitats. 16S ribosomal RNA (rRNA) gene sequencing is widely used for microbiota profiling with NGS technologies. Since most used NGS platforms generate short reads, sequencing the full-length 16S rRNA gene is impractical. Therefore, choosing which 16S rRNA hypervariable region to sequence is critical in microbiota profiling studies. All nine 16S rRNA hypervariable regions are taxonomically informative, but due to variability in profiling performance for specific clades, choosing the ideal 16S rRNA hypervariable region will depend on the bacterial composition of the habitat under study. Recently, NGS allowed the identification of microbes in the urinary tract, and urinary microbiota has become an active research area. However, there is no current study evaluating the performance of different 16S rRNA hypervariable regions for male urinary microbiota profiling. We collected urine samples from male volunteers and profiled their urinary microbiota by sequencing a panel of six amplicons encompassing all nine 16S rRNA hypervariable regions. Systematic comparisons of their performance indicate V1V2 hypervariable regions better assess the taxa commonly present in male urine samples, suggesting V1V2 amplicon sequencing is more suitable for male urinary microbiota profiling. We believe our results will be helpful to guide this crucial methodological choice in future male urinary microbiota studies., 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 © 2022 Heidrich, Inoue, Asprino, Bettoni, Mariotti, Bastos, Jardim, Arap and Camargo.)

Purpose: Li-Fraumeni syndrome (LFS) is rare in the worldwide population, but it is highly prevalent in the Brazilian population because of a founder mutation, TP53 p.R337H, accounting for 0.3% of south and southeastern population. Clinical criteria for LFS may not identify all individuals at risk of carrying the Brazilian founder mutation because of its lower penetrance and variable expressivity. This variant is rarely described in databases of somatic mutations. Somatic findings in tumor molecular profiling may give insight to identify individuals who might be carriers of LFS and allow the adoption of risk reduction strategies for cancer., Materials and Methods: We determined the frequency of the TP53 p.R337H variant in tumor genomic profiling from 755 consecutive Brazilian patients with pan-cancer. This is a retrospective cohort from January 2013 to March 2020 at a tertiary care center in Brazil., Results: The TP53 p.R337H variant was found in 2% (15 of 755) of the samples. The mutation allele frequency ranged from 30% to 91.7%. A total of seven patients were referred for genetic counseling and germline testing after tumor genomic profiling results were disclosed. All the patients who proceeded with germline testing (6 of 6) confirmed the diagnosis of LFS. Family history was available in 12 cases. Nine patients (9 of 12) did not meet LFS clinical criteria., Conclusion: The identification of the TP53 p.R337H variant in tumor genomic profiling should be a predictive finding of LFS in the Brazilian population and should prompt testing for germline status confirmation., Competing Interests: Maurício Fernando Silva Almeida RibeiroTravel, Accommodations, Expenses: Foundation Medicine Rodrigo Medeiros BovolinStock and Other Ownership Interests : Abbott Laboratories (ABT), Johnson & Johnson (JNJ), Novo Nordisk A/S (NVO), Edwards Lifesciences (EW), Zoetis Inc (ZTS), Gilead Sciences (GILD), Varian Medical Systems Inc. (VAR), Varex Imaging Corporation (VREX) Fernando Costa SantiniHonoraria: Merck Sharp & Dohme, Roche, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, Wyeth, AmgenConsulting or Advisory Role: Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Roche, Bayer, Lilly, AmgenSpeakers' Bureau: Roche, Merck Sharp & Dohme, AstraZeneca, BayerTravel, Accommodations, Expenses: Bayer, Merck Sharp & Dohme, Bristol Myers Squibb Rodrigo Ramella MunhozHonoraria: Bristol Myers Squibb, MSD, Roche, Novartis, Sanofi, Merck SeronoConsulting or Advisory Role: Roche, Merck Serono, Sanofi, Bristol Myers SquibbSpeakers' Bureau: Bristol Myers Squibb, MSD, Novartis, RocheResearch Funding: Lilly, Roche, Bristol Myers Squibb, Novartis, MSDTravel, Accommodations, Expenses: Bristol Myers Squibb, MSD, Roche, Sanofi Denis Leonardo Fontes JardimHonoraria: Janssen-Cilag, Roche/Genentech, Astellas Pharma, MSD Oncology, BMS Brazil, Pfizer, Libbs, MerckConsulting or Advisory Role: Janssen-Cilag, Pfizer, MSDTravel, Accommodations, Expenses: MSD, BMS Brazil, Janssen-Cilag Gustavo dos Santos FernandesHonoraria: Roche, MSD Oncology, BayerResearch Funding: Roche, Memorial Sloan-Kettering Cancer Center, BMS BrazilTravel, Accommodations, Expenses: Roche Maria Isabel AchatzConsulting or Advisory Role: RocheSpeakers' Bureau: AstraZeneca, MSD Oncology, Merck Sharpe & DohmeNo other potential conflicts of interest were reported.

Purpose: To present a summary of the recommendations for the treatment and follow-up for metastatic castration-resistant prostate cancer (mCRPC) as acquired through a questionnaire administered to 99 physicians working in the field of prostate cancer in developing countries who attended the Prostate Cancer Consensus Conference for Developing Countries., Methods: A total of 106 questions out of more than 300 questions addressed the use of imaging in staging mCRPC, treatment recommendations across availability and response to prior drug treatments, appropriate drug treatments, and follow-up, and those same scenarios when limited resources needed to be considered. Responses were compiled and the percentages were presented by clinicians to support each response. Most questions had five to seven relevant options for response including abstain and/or unqualified to answer, or in the case of yes or no questions, the option to abstain was offered., Results: Most of the recommendations from this panel were in line with prior consensus, including the preference of a new antiandrogen for first-line therapy of mCRPC. Important aspects highlighted in the scenario of limited resources included the option of docetaxel as treatment preference as first-line treatment in several scenarios, docetaxel retreatment, consideration for reduced doses of abiraterone, and alternative schedules of an osteoclast-targeted therapy., Conclusion: There was wide-ranging consensus in the treatment for men with mCRPC in both optimal and limited resource settings., Competing Interests: Fernando Cotait MalufHonoraria: Janssen Oncology, Astellas Pharma, Bayer Schering Pharma, Merck Sharp & Dohme, Roche/Genentech, BMS Brazil, Ipsen, Sanofi/Aventis, Merck Serono, AstraZenecaConsulting or Advisory Role: Janssen Oncology, Astellas Pharma, Bayer Schering Pharma, Merck Sharp & Dohme, Roche/Genentech, BMS Brazil, Ipsen, Merck Serono, AstraZenecaResearch Funding: Janssen-Cilag, Merck Sharp & DohmeTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bayer Schering Pharma Felipe MoraesHonoraria: Janssen, Zodiac Pharma, MSD, Libbs, Bayer, AmgenConsulting or Advisory Role: Janssen Adriano Gonçalves SilvaHonoraria: MSD Oncology, Janssen Oncology, Astellas Pharma, Roche, Pfizer/EMD Serono, Bayer, BMS BrazilConsulting or Advisory Role: Janssen Oncology, Astellas Pharma, Pfizer/EMD Serono, MSD OncologyResearch Funding: MSD Oncology, Janssen OncologyTravel, Accommodations, Expenses: Janssen Oncology, Astellas Pharma, MSD Oncology, Roche Aldo Lourenço Abbade DettinoHonoraria: Janssen-Cilag, Bayer, Astellas Pharma, RocheConsulting or Advisory Role: NovartisResearch Funding: Janssen, RocheTravel, Accommodations, Expenses: MSD Oncology Ana Paula Garcia CardosoConsulting or Advisory Role: Janssen Oncology, Pfizer, Astellas PharmaSpeakers' Bureau: Janssen Oncology, Novartis, MSD Oncology, Astellas Pharma, AstraZeneca, BayerTravel, Accommodations, Expenses: Ipsen, Janssen Oncology, Bristol-Myers Squibb André Seeke SasseHonoraria: Roche, Astellas Pharma, Janssen-Cilag, Bristol-Myers Squibb, Merck KGaA, MSD Oncology, NovartisConsulting or Advisory Role: Astellas Pharma, Janssen-Cilag, Merck KGaA, Novartis, RocheResearch Funding: Bristol-Myers SquibbTravel, Accommodations, Expenses: MSD Oncology, Janssen-Cilag Andrey SoaresHonoraria: Janssen, Pfizer, Bayer, Novartis, AstraZeneca, Astellas Pharma, Pierre Fabre, Merck Serono, Sanofi, Roche, MSDConsulting or Advisory Role: Astellas Pharma, Janssen, Roche, Bayer, Lilly, AstraZeneca, Novartis, MSD, Bristol-Myers SquibbResearch Funding: Bristol-Myers SquibbTravel, Accommodations, Expenses: AstraZeneca, Pfizer, Astellas Pharma, Bristol-Myers Squibb, Bayer, Roche, Janssen, Merck Serono, Sanofi, Ipsen, MSD Ariel Galapo KannConsulting or Advisory Role: Janssen OncologySpeakers' Bureau: Janssen Oncology, GlaxoSmithKline, Roche Daniel HerchenhornConsulting or Advisory Role: Janssen-Cilag Denis Leonardo Fontes JardimHonoraria: Janssen-Cilag, Roche/Genentech, Astellas Pharma, MSD Oncology, BMS Brazil, Pfizer, Libbs, MerckConsulting or Advisory Role: Janssen-Cilag, Pfizer, MSDTravel, Accommodations, Expenses: MSD, BMS Brazil, Janssen-Cilag Diego Emilio Lopera CortésConsulting or Advisory Role: Bristol-Myers Squibb, Pfizer, NovartisSpeakers' Bureau: Dr Reddy's Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, PfizerTravel, Accommodations, Expenses: MSD Oncology Fábio Roberto KaterConsulting or Advisory Role: Janssen-Cilag, PfizerTravel, Accommodations, Expenses: Janssen-Cilag Igor A. Protzner MorbeckHonoraria: Janssen-Cilag, BMS Brazil, AstraZeneca, MSD Oncology, Astellas PharmaConsulting or Advisory Role: BMS Brazil, Janssen-Cilag, TakedaTravel, Accommodations, Expenses: Astellas Pharma, BMS Brazil Juan Jose ZarbáConsulting or Advisory Role: Pfizer/EMD Serono, Astellas PharmaResearch Funding: MSD Oncology, Lilly, Exelixis, Astellas PharmaExpert Testimony: LillyTravel, Accommodations, Expenses: Roche, Pfizer Karine Martins da TrindadeHonoraria: BMS Brazil, Janssen-Cilag, MSD OncologyConsulting or Advisory Role: MSD Oncology, Janssen-Cilag, Astellas PharmaResearch Funding: BMS Brazil, Roche/Genentech, MSD Oncology, Janssen-CilagTravel, Accommodations, Expenses: Janssen-Cilag, BMS Brazil, Ipsen Leonardo Atem G. A. CostaHonoraria: Janssen Oncology, Astellas Pharma, AstraZenecaConsulting or Advisory Role: Janssen Oncology, Astellas Pharma, AstraZenecaTravel, Accommodations, Expenses: Janssen Oncology, Boehringer Ingelheim, Astellas Pharma, AstraZeneca Lucas V. dos SantosStock and Other Ownership Interests: Merck Sharp & Dohme, Eisai, Fleury GroupHonoraria: BMS Brazil, United Medical, Roche/GenentechConsulting or Advisory Role: Lilly, Bristol-Myers Squibb, MSD, Roche/GenentechSpeakers' Bureau: BMS Brazil, United MedicalResearch Funding: Roche/Genentech, Janssen Oncology, Novartis, GlaxoSmithKline, Amgen, Boston Scientific, Takeda, BMS Brazil, MSD, Exelixis Manuel Caitano MaiaConsulting or Advisory Role: AstraZeneca, Janssen OncologySpeakers' Bureau: Janssen Oncology, AstraZeneca, Bayer, MSD Oncology, Pfizer, Astellas PharmaExpert Testimony: MSD OncologyTravel, Accommodations, Expenses: Astellas Pharma, Janssen Oncology Mariana Bruno SiqueiraConsulting or Advisory Role: Novartis, Janssen-CilagSpeakers' Bureau: Novartis, MSD Oncology, Bayer, Janssen-CilagTravel, Accommodations, Expenses: Roche, Pfizer, Ipsen Silke GillessenConsulting or Advisory Role: Astellas Pharma, Advanced Accelerator Applications, Roche, Janssen, Bayer, Orion Pharma GmbH, Menarini Silicon Biosystems, Tolero Pharmaceuticals, MSD Oncology, Amgen, PfizerSpeakers' Bureau: Janssen-CilagPatents, Royalties, Other Intellectual Property: Method for biomarker (WO 3752009138392 A1)Travel, Accommodations, Expenses: ProteoMedixOther Relationship: ProteoMediX, Aranda PharmaNo other potential conflicts of interest were reported.

Purpose: To present a summary of the recommendations for the treatment and follow-up for the biochemical recurrence of castration-resistant prostate cancer (PCa) as acquired through a questionnaire administered at the Prostate Cancer Consensus Conference for Developing Countries., Methods: A total of 27 questions were identified as relating to this topic. Responses from the clinician were tallied and are presented in percentage format. Topics included the use of imaging in staging, treatment recommendations across different patient scenarios of life expectancy and prostate-specific antigen (PSA) doubling time, and follow-up for nonmetastatic castration-resistant PCa., Results: A consensus agreed that in optimal conditions, positron emission tomography-computed tomography with prostate-specific membrane antigen would be used although in limited resource situations the combined use of CT of the abdomen and pelvic (or pelvic MRI), a bone scan, and a CT of the thorax or chest x-ray was recommended. In cases when PSA levels double in < 10 months, more than 90% of clinicians agreed on the use of apalutamide or enzalutamide, regardless of life expectancy. With a doubling time of more than 10 months, > 54% of experts recommended no treatment independent of life expectancy. More than half of the experts, regardless of resources, recommended follow-up with a physical examination and PSA levels every 3-6 months and imaging only in the case of symptoms., Conclusion: The voting results and recommendations presented in this document can be used by physicians to support management for biochemical recurrence of castration-resistant PCa in areas of limited resources. Individual clinical decision making should be supported by available data., Competing Interests: Felipe Moraes Toledo PereiraHonoraria: Janssen, Zodiac Pharma, MSD, Libbs, Bayer, AmgenConsulting or Advisory Role: Janssen Adriano Gonçalves e SilvaHonoraria: MSD Oncology, Janssen Oncology, Astellas Pharma, Roche, Pfizer/EMD Serono, Bayer, Bristol-Myers Squibb BrazilConsulting or Advisory Role: Janssen Oncology, Astellas Pharma, Pfizer/EMD Serono, MSD OncologyResearch Funding: MSD Oncology, Janssen OncologyTravel, Accommodations, Expenses: Janssen Oncology, Astellas Pharma, MSD Oncology, Roche Aldo Lourenço Abbade DettinoHonoraria: Janssen-Cilag, Bayer, Astellas Pharma, RocheConsulting or Advisory Role: NovartisResearch Funding: Janssen, RocheTravel, Accommodations, Expenses: MSD Oncology Ana Paula Garcia CardosoConsulting or Advisory Role: Janssen Oncology, Pfizer, Astellas PharmaSpeakers' Bureau: Janssen Oncology, Novartis, MSD Oncology, Astellas Pharma, AstraZeneca, BayerTravel, Accommodations, Expenses: Ipsen, Janssen Oncology, Bristol-Myers Squibb Andre Deeke SasseHonoraria: Roche, Astellas Pharma, Janssen-Cilag, Bristol-Myers Squibb, Merck KGaA, MSD Oncology, NovartisConsulting or Advisory Role: Astellas Pharma, Janssen-Cilag, Merck KGaA, Novartis, RocheResearch Funding: Bristol-Myers SquibbTravel, Accommodations, Expenses: MSD Oncology, Janssen-Cilag Ariel Galapo KannConsulting or Advisory Role: Janssen OncologySpeakers' Bureau: Janssen Oncology, GlaxoSmithKline, Roche Carlos DzikConsulting or Advisory Role: Janssen-Cilag, IPSEN, NovartisSpeakers' Bureau: Janssen OncologyTravel, Accommodations, Expenses: Astellas Pharma, Janssen Oncology Daniel HerchenhornConsulting or Advisory Role: Janssen-Cilag Denis Leonardo Fontes JardimHonoraria: Janssen-Cilag, Roche/Genentech, Astellas Pharma, MSD Oncology, Bristol-Myers Squibb Brazil, Pfizer, Libbs, MerckConsulting or Advisory Role: Janssen-Cilag, Pfizer, MSDTravel, Accommodations, Expenses: MSD, Bristol-Myers Squibb Brazil, Janssen-Cilag Diego LoperaConsulting or Advisory Role: Bristol-Myers Squibb, Pfizer, NovartisSpeakers' Bureau: Dr Reddy's Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, PfizerTravel, Accommodations, Expenses: MSD Oncology Pamela SalmanConsulting or Advisory Role: Roche/Genentech, Novartis, Lilly, Merck SeronoSpeakers' Bureau: Roche/Genentech, Novartis, Lilly Ray Antonio Manneh KoppHonoraria: Astellas Scientific and Medical Affairs Inc, Janssen-Cilag, Bayer, Merck Sharp & Dohme, Roche, Bristol-Myers Squibb, Sanofi, AstraZeneca, PfizerConsulting or Advisory Role: Astellas Pharma, Janssen-Cilag, Roche, Merck Serono, Merck Sharp & Dohme, AstraZeneca, Sanofi, PfizerSpeakers' Bureau: San Jorge Foundation, ACHOResearch Funding: Pfizer, Merck Sharp & Dohme, NovartisTravel, Accommodations, Expenses: Merck Sharp & Dohme Sandro Roberto De Araujo CavalleroHonoraria: Pfizer, Astellas Pharma, Janssen Oncology, AstraZenecaConsulting or Advisory Role: Janssen Oncology, MSD Oncology, Astellas PharmaSpeakers' Bureau: Pfizer, Janssen-Cilag, Astellas PharmaTravel, Accommodations, Expenses: Pfizer, Roche/Genentech, Janssen-Cilag, Astellas Pharma Vinicius Carrera SouzaConsulting or Advisory Role: Janssen, Astellas Pharma, Bayer, Bristol-Myers Squibb BrazilResearch Funding: JanssenTravel, Accommodations, Expenses: Janssen Andrey SoaresHonoraria: Janssen, Pfizer, Bayer, Novartis, AstraZeneca, Astellas Pharma, Pierre Fabre, Merck Serono, Sanofi, Roche, MSDConsulting or Advisory Role: Astellas Pharma, Janssen, Roche, Bayer, Lilly, AstraZeneca, Novartis, MSD, Bristol-Myers SquibbResearch Funding: Bristol-Myers SquibbTravel, Accommodations, Expenses: AstraZeneca, Pfizer, Astellas Pharma, Bristol-Myers Squibb, Bayer, Roche, Janssen, Merck Serono, Sanofi, Ipsen, MSDNo other potential conflicts of interest were reported.

Background: Non-metastatic castration resistant prostate cancer (M0 CRPC) has seen important developments in drugs and diagnostic tools in the last two years. New hormonal agents have demonstrated improvement in metastasis free survival in M0 CRPC patients and have been approved by regulatory agencies in Brazil. Additionally, newer and more sensitive imaging tools are able to detect metastasis earlier than before, which will impact the percentage of patients staged as M0 CRPC. Based on the available international guidelines, a group of Brazilian urology and medical oncology experts developed and completed a survey on the diagnosis and treatment of M0 CRPC in Brazil. These results are reviewed and summarized and associated recommendations are provided., Objective: To present survey results on management of M0 CRPC in Brazil., Design, Setting, and Participants: A panel of six Brazilian prostate cancer experts determined 64 questions concerning the main areas of interest: 1) staging tools, 2) treatments, 3) side effects of systemic treatment/s, and 4) osteoclast-targeted therapy. A larger panel of 28 Brazilian prostate cancer experts answered these questions in order to create country-specific recommendations discussed in this manuscript. Outcome measurements and statistical analysis: The panel voted publicly but anonymously on the predefined questions. These answers are the panelists' opinions, not a literature review or meta-analysis. Therapies not yet approved in Brazil were excluded from answer options. Each question had five to seven relevant answers including two non-answers. Results were tabulated in real time., Conclusions: The results and recommendations presented can be used by Brazilian physicians to support the management of M0 CRPC patients. Individual clinical decision making should be supported by available data, however, for Brazil, guidelines for diagnosis and management of M0 CRPC patients have not been developed. This document will serve as a point of reference when confronting this disease stage., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

Purpose: Over the last decades, cytotoxic chemotherapy has been the cornerstone of metastatic pancreatic adenocarcinoma treatment. In late-stage disease, a range of treatment regimens still offers minor benefits. Molecular profiling studies have shown that pancreatic adenocarcinoma (PDAC) is a mutation-driven tumor type, with KRAS mutations found in approximately 90% of cases, which could partially explain the resistance to chemotherapy. Preclinical data on selective targeting of a downstream point of the RAF-MEK-ERK pathway with a MEK inhibitor along with the concurrent use of an autophagy inhibitor such as hydroxychloroquine appears to be one alternative approach to overcome resistance and inhibit cell proliferation., Methods: We herein aim to investigate the rationale of autophagy inhibitors use and describe the outcomes of patients who received this experimental treatment., Results: Two patients have received this experimental regimen from January 2020 to the present date, achieving disease stabilization that is clinically meaningful, considering the chemoresistance scenario of the included patients., Conclusions: Our real-life data regarding KRAS-mutated PDAC patients who received treatment with the MEK inhibitor trametinib combined with hydroxychloroquine after experiencing disease progression are consistent with the preclinical data, pointing to the clinical benefits of this regimen.

Purpose of Review: The aim of this review is to highlight the clinical development of PD-1 and PD-L1 inhibitors in cancer therapy. We focus on detailing the registration trials that have led to FDA-approved indications of anti-PD-1 and anti-PD-L1 therapies and future strategies., Recent Findings: The number of PD-1/PD-L1 inhibitors approved and in studies continues to grow, in different scenarios. Although the first wave of approvals included advanced cancers, localized disease is under growing interest in recent trials and approvals. Several of these agents are migrating from a monotherapy strategy to combinations (especially with targeted agents and chemotherapy). To date, several studies are being conducted for a better understanding of predictive biomarkers, mechanisms of resistance, optimal treatment duration, and immune-related toxicities. This article summarizes the recent history of modern cancer immunotherapy, provides an overview of novel drug-development considerations, and thus, illustrates the opportunities these new generations of immunotherapies represent.

Purpose: Evaluate the association between the use of phase I expansion cohorts (ECs) and drug performance in phase II as well as time to approval by the FDA. Experimental Design: We performed a systematic search of MEDLINE for single-agent dose-finding adult oncology phase I trials published in 2006 to 2011 and subsequent phase II trials. Successful phase II trials were those that met their primary endpoints. Dates of approval were obtained from the Drugs@FDA website in April 2014. A logistic regression model was used to determine the associations between variables and success in phase II. Results: We identified 533 phase I trials evaluating 381 drugs; 112 drugs had at least one phase I trial with an expansion cohort. Phase I trials with expansion cohorts of two to 20 patients were associated with a higher rate of successful phase II trials than those with no expansion cohort [48% vs. 27%; OR, 2.1; 95% confidence interval (CI), 1.1-4.0; P = 0.037]. Phase II success rates were the same for expansion cohort with two to 20 and more than 20 patients (48% vs. 52%). Other positive associations were disease-specific trials (OR, 1.7; 95% CI, 1.0-2.9; P = 0.037), industry sponsorship (OR, 2.9; 95% CI, 1.5-5.7; P = 0.0024), and response rate of 6% to 20% (OR, 2.89; 95% CI, 1.6-5.2; P = 0.0007). Drugs tested in phase I trials with expansion cohorts had a higher rate of 5-year approval (19% vs. 5%; HR, 4.4; 95% CI, 2.2-8.8; P < 0.001). Conclusions: The use of expansion cohorts in phase I trials was associated with success of subsequent phase II trials. However, confounders may play a role in this association. Clin Cancer Res; 23(15); 4020-6. ©2017 AACR ., (©2017 American Association for Cancer Research.)