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Urothelial carcinoma of the bladder comprises a spectrum of illnesses ranging from nonmuscle-invasive to muscle-invasive to advanced/metastatic disease. Each of these clinical states is characterized by a unique pathogenesis, prognosis and approach to treatment. However, given the heterogeneity of urothelial carcinoma, differences in biology and outcomes exist not only among these clinical states but also within each state. Personalized medicine, also commonly referred to as individualized or stratified medicine, offers the potential to optimize treatment for a given patient, based on the ability to accurately predict prognosis, response to treatment and tolerability of treatment. This review will discuss recent efforts, current challenges and future opportunities, for the personalized management of urothelial carcinoma. [ABSTRACT FROM AUTHOR]

Background: Treatment of high-risk localized prostate cancer remains inadequate. The authors performed a phase 2 multicenter trial of neoadjuvant docetaxel plus bevacizumab before radical prostatectomy.Methods: Eligibility included any of the following: prostate-specific antigen (PSA) >20 ng/mL or PSA velocity >2 ng/mL/y, cT3 disease, any biopsy Gleason score 8 to 10, and Gleason score 7 with T3 disease by endorectal magnetic resonance imaging (MRI) at 1.5 T. Also, those with ≥50% biopsy cores involved and either Gleason score 7, PSA >10, or cT2 disease were eligible. Patients were treated with docetaxel 70 mg/m(2) every 3 weeks for 6 cycles and bevacizumab 15 mg/m(2) every 3 weeks for 5 cycles. The primary endpoint was partial response by endorectal MRI.Results: Forty-one patients were treated. Median age was 55 years (range, 40-66 years). Baseline characteristics included: median PSA, 10.1 ng/mL; cT2, 49%, cT3, 32%; and Gleason score 8 to 10, 73%. Thirty-eight of 41 (93%) patients completed all 6 cycles. Grade ≥3 adverse events were rare, although 3 of 41 (7%) experienced febrile neutropenia. Twelve patients (29%; 95% confidence interval [CI], 16%-45%) achieved a >50% reduction in tumor volume, and 9 patients (22%; 95% CI, 11%-38%) achieved a >50% post-treatment decline in PSA. Thirty-seven of the 41 patients underwent radical prostatectomy; there were no complete pathologic responses.Conclusions: Neoadjuvant docetaxel and bevacizumab is safe, and results in reductions in both tumor volume and serum PSA, in men with high-risk localized prostate cancer. The role of neoadjuvant chemotherapy in prostate cancer, and perioperative antiangiogenic therapy in general, requires further elucidation through ongoing and planned trials. [ABSTRACT FROM AUTHOR]

There have been more drugs approved by the US Food and Drug Administration for the treatment of castration-resistant prostate cancer in the past 3 years than in the prior 3 decades, with additional drugs on the verge of approval based on the results of recently reported randomized trials. While an improvement in the understanding of the pathogenesis of castration-resistant prostate cancer has undeniably accelerated the transition of novel approaches from "bench to bedside," the recent successes in the treatment of prostate cancer are also a result of the efforts of clinical investigators to redefine the framework in which drugs for castration-resistant disease are evaluated. This review will explore the shifting paradigm in drug development for castration-resistant prostate cancer over the past several decades, and highlight how new definitions, trial designs, and endpoints have facilitated the emergence of new therapies for this challenging disease. [ABSTRACT FROM AUTHOR]

Background: The Veterans Health Administration (VHA) is the largest integrated health care system in the United States. Studies suggest that the VHA provides better preventive care and care for some chronic illnesses than does the private sector. Objective: To assess the quality of cancer care for older patients provided by the VHA versus fee-for-service Medicare. Design: Observational study of patients with cancer that was diagnosed between 2001 and 2004 who were followed through 2005. Setting: VHA and non-VHA hospitals and office-based practices. Patients: Men older than 65 years with incident colorectal, lung, or prostate cancer; lymphoma; or multiple myeloma. Measurements: Rates of processes of care for colorectal, lung, or prostate cancer; lymphoma; or multiple myeloma. Rates were adjusted by using propensity score weighting. Results: Compared with the fee-for-service Medicare population, the VHA population received diagnoses of colon (P < 0.001) and rectal (P = 0.007) cancer at earlier stages and had higher adjusted rates of curative surgery for colon cancer (92.7% vs. 90.5%; P < 0.010), standard chemotherapy for diffuse large B-cell non-Hodgkin lymphoma (71.1% vs. 59.3%; P < 0.001), and bisphosphonate therapy for multiple myeloma (62.1% vs. 50.4%; P < 0.001). The VHA population had lower adjusted rates of 3-dimensional conformal or intensity-modulated radiation therapy for prostate cancer treated with external-beam radiation therapy (61.6% vs. 86.0%; P < 0.001). Adjusted rates were similar for 9 other measures. Sensitivity analyses suggest that if patients with cancer in the VHA system have more severe comorbid illness than other patients, rates for most indicators would be higher in the VHA population than in the fee-for-service Medicare population. Limitation: This study included only older men and did not include information about performance status, severity of comorbid illness, or patient preferences. Conclusion: Care for older men with cancer in the VHA system was generally similar to or better than care for fee-for-service Medicare beneficiaries, although adoption of some expensive new technologies may be delayed in the VHA system. Primary Funding Source: Department of Veterans Affairs. [ABSTRACT FROM AUTHOR]

BACKGROUND:: Vinorelbine (VRL) in combination with estramustine has known efficacy in the initial chemotherapeutic management of hormone-refractory prostate cancer (HRPC). However, little is known about the efficacy of VRL as second-line chemotherapy in HRPC. METHODS:: We retrospectively identified patients with HRPC treated in a single institution with VRL as second-line chemotherapy with or without estramustine. Patient baseline characteristics, declines in prostate-specific antigen, performance status, toxicities, and survival were assessed. RESULTS:: Thirty-nine patients were treated with VRL between 1999 and 2005. Twenty-one patients (54%) received single-agent VRL and 18 patients (46%) had concomitant estramustine. Seven patients (17.9%, 95% confidence interval 7.5%-33.6%) treated with VRL experienced prostate-specific antigen declines >/=50%. Median duration of therapy was 1.4 months (range 0.2-14.0 months). Median overall survival was 6.9 months (range 1.4-29.9 months); it was 16.1 month in responders and 5.5 months in nonresponders. Median survival was significantly longer in patients with VRL and estramustine than in patients who received VRL alone (8.5 months versus 4.1 months, P = 0.05). The most common reversible adverse effect of VRL was grade 1 or 2 fatigue observed in 36% of patients. CONCLUSIONS:: As a second-line chemotherapy, VRL demonstrated moderate activity and was well tolerated in patients with HRPC. Patients treated with the combination of VRL and estramustine experienced a longer survival than those receiving VRL alone. [ABSTRACT FROM AUTHOR]

Docetaxel (Taxotere); Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com) is the first agent to significantly extend survival in hormone-refractory prostate cancer. Because agents active in advanced cancers tend to be beneficial in earlier stage disease, docetaxel is now to be assessed, along with hormonal therapy, in the adjuvant setting among patients whose localized prostate cancer has features that put them at particular risk for recurrence and cancer-specific mortality. Data from a pilot study suggest that neo-adjuvant treatment with docetaxel may be appropriate for selected high-risk patients and that such treatment can be undertaken without increasing surgical morbidity. Gene-expression profiling of tissue before and after docetaxel treatment is providing further insight into its effects. A randomized trial, conducted by the Cancer and Leukemia Group B, will evaluate neoadjuvant docetaxel in high-risk patients, whereby patients will be randomized to either immediate radical prostatectomy or surgery preceded by hormonal therapy plus docetaxel. Another large randomized trial will be evaluating the effect of adjuvant hormonal therapy with or without docetaxel in high-risk men after radical prostatectomy. [ABSTRACT FROM AUTHOR]

High-risk localized prostate cancer remains a vexing problem for clinicians. Definitive local treatments such as surgery and radiation therapy cure only a minority of these patients. As a result, efforts are being made to reduce the risk of recurrence by using chemotherapy and new agents before, during or after definitive local therapy. Neoadjuvant androgen deprivation therapy has yielded disappointing results when combined with surgery. Chemotherapy in the management of localized disease is evolving, and preliminary studies are just now being completed. Although these agents have established activity and acceptable toxicity in the hormone-refractory setting, more extensive use of them in patients with androgen-dependent disease will require data from randomized studies to determine overall efficacy. New molecular-targeted therapies are promising and hold the greatest hope that outcomes in early disease may be improved with early use of systemic therapy. The neoadjuvant surgical model also has promise in assessing the activity of new drugs, because it provides a means to determine molecular effects of specific agents, along with standard pathologic and clinical parameters of efficacy. [ABSTRACT FROM AUTHOR]

Inhibition of protein tyrosine phosphatase 1B (PTP1B) has been proposed as one of the drug targets for treating type 2 diabetes and obesity. Bioassay-guided fractionation of a MeOH extract of the semen of Myristica fragrans Houtt. (Myristicaceae) afforded PTP1B inhibitory compounds, meso-dihydroguaiaretic acid (1) and otobaphenol (2). Compounds 1 and 2 inhibited PTP1B with IC(50) values of 19.6 +/- 0.3 and 48.9 +/- 0.5 microM, respectively, in the manner of non-competitive inhibitors. Treatment with compound 1 on 32D cells overexpressing the insulin receptor (IR) resulted in a dose-dependent increase in the tyrosine phosphorylation of IR. These results indicate that compound 1 can act as an enhancing agent in intracellular insulin signaling, possibly through the inhibition of PTP1B activity. [ABSTRACT FROM AUTHOR]

Background: Survival for patients with castration-resistant prostate cancer is highly variable. We assessed the effectiveness of a whole-blood RNA transcript-based model as a prognostic biomarker in castration-resistant prostate cancer.Methods: Peripheral blood was prospectively collected from 62 men with castration-resistant prostate cancer on various treatment regimens who were enrolled in a training set at the Dana-Farber Cancer Institute (Boston, MA, USA) from August, 2006, to June, 2008, and from 140 patients with castration-resistant prostate cancer in a validation set from Memorial Sloan-Kettering Cancer Center (New York, NY, USA) from August, 2006, to February, 2009. A panel of 168 inflammation-related and prostate cancer-related genes was assessed with optimised quantitative PCR to assess biomarkers predictive of survival.Findings: A six-gene model (consisting of ABL2, SEMA4D, ITGAL, and C1QA, TIMP1, CDKN1A) separated patients with castration-resistant prostate cancer into two risk groups: a low-risk group with a median survival of more than 34·9 months (median survival was not reached) and a high-risk group with a median survival of 7·8 months (95% CI 1·8-13·9; p<0·0001). The prognostic utility of the six-gene model was validated in an independent cohort. This model was associated with a significantly higher area under the curve compared with a clinicopathological model (0·90 [95% CI 0·78-0·96] vs 0·65 [0·52-0·78]; p=0·0067).Interpretation: Transcriptional profiling of whole blood yields crucial prognostic information about men with castration-resistant prostate cancer. The six-gene model suggests possible dysregulation of the immune system, a finding that warrants further study.Funding: Source MDX. [ABSTRACT FROM AUTHOR]

Background and Objective: Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024., Methods: Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists")., Key Findings and Limitations: Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis., Conclusions and Clinical Implications: The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Black men consistently have higher rates of prostate cancer (PCA)- related mortality. Advances in PCA treatment, screening, and hereditary cancer assessment center around germline testing (GT). Of concern is the significant under-engagement of Black males in PCA GT, limiting the benefit of precision therapy and tailored cancer screening despite longstanding awareness of these disparities. To address these critical disparities, the Socioecological Model (SEM) was employed to develop comprehensive recommendations to overcome barriers and implement equitable strategies to engage Black males in PCA GT., Methods: Clinical/research experts, national organization leaders, and community stakeholders spanning multiple regions in US and Africa participated in developing a framework for equity in PCA GT grounded in the SEM. A novel mixed-methods approach was employed to generate key areas to be addressed and informed statements for consensus consideration utilizing the modified Delphi model. Statements achieving strong consensus (> =75% agreement) were included in final equity frameworks addressing clinical/community engagement and research engagement., Results: All societal levels of the SEM (interpersonal, institutional, community, and policy/advocacy) must deliver information about PCA GT to Black males that address benefits/limitations, clinical impact, hereditary cancer implications, with acknowledgment of mistrust (mean scores [MS] 4.57-5.00). Interpersonal strategies for information delivery included engagement of family/friends/peers/Black role models to improve education/awareness and overcome mistrust (MS 4.65-5.00). Institutional strategies included diversifying clinical, research, and educational programs and integrating community liaisons into healthcare institutions (MS 4.57-5.00). Community strategies included partnerships with healthcare institutions and visibility of healthcare providers/researchers at community events (MS 4.65-4.91). Policy/advocacy included improving partnerships between advocacy and healthcare/community organizations while protecting patient benefits (MS 4.57-5.00). Media strategies were endorsed for the first time at every level (MS 4.56-5.00)., Conclusion: The SEM-based equity frameworks proposed provide the first multidisciplinary strategies dedicated to increase engagement of Black males in PCA GT, which are critical to reduce disparities in PCA-mortality through informing tailored screening, targeted therapy, and cascade testing in families., (© 2024. The Author(s).)

As part of our ongoing research on new anti-diabetic compounds from ethnopharmacologically consumed plants, two previously undescribed lupane-type triterpenoids ( 1 and 2 ) with dicarboxylic groups, an undescribed nor-taraxastane-type triterpenoid ( 3 ), and 14 known compounds ( 4 - 17 ) were isolated from the leaves of Cleistocalyx operculatus . Extensive spectroscopic analysis (IR, HRESIMS, 1D, and 2D NMR) was used for structure elucidation, while the known compounds were compared to reference data reported in the scientific literature. All the isolates ( 1 - 17 ) were evaluated for their inhibitory effects on the protein tyrosine phosphatase 1B (PTP1B) enzyme. Compounds 6 , 9 , and 17 showed strong PTP1B inhibitory activities. The mechanism of PTP1B inhibition was studied through enzyme kinetic experiments. A non-competitive mechanism of inhibition was determined using Lineweaver-Burk plots for compounds 6 , 9 , and 17 . Additionally, Dixon plots were employed to determine the inhibition constant. Further insights were gained through a structure-activity relationship study and molecular docking analysis of isolated compounds with the PTP1B crystal structure. Moreover, all isolates ( 1 - 17 ) were tested for their stimulatory effects on the uptake of 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl) amino]-D-glucose (2-NBDG) in differentiated 3T3-L1 adipocyte cells. Compounds 6 , 13 , and 17 exhibited strong glucose absorption stimulation activity in a dose-dependent manner.

Four new compounds, racemic chalcone-monoterpene hybrids ( 1 - 3 ) and a chalcone ( 9 ), along with nine known compounds ( 4 - 8 , 10 - 13 ), have been isolated from the buds of Cleistocalyx operculatus . The chemical structures of the isolated compounds were identified through NMR data analysis and confirmed by computational methods, including electronic circular dichroism (ECD) calculations, and further synthetic approaches. Compounds 1 - 5 were synthesized via a Diels-Alder reaction, a process informed by biomimetic condensation studies that combined chalcones and monoterpenes. These synthetic approaches also yielded various unnatural chalcone-monoterpene derivatives ( 14 - 23 ). The inhibitory effects on protein tyrosine phosphatase 1B (PTP1B) of both naturally isolated and synthetically obtained compounds were evaluated. Compounds 4 , 9 , 13 , and 16b exhibited potent PTP1B inhibitory activity, with IC 50 values ranging from 0.9 ± 0.2 to 3.9 ± 0.7 μM. The enantiomers (+)- 4 and (-)- 16b showed enhanced activity compared to their respective enantiomers. Kinetic studies indicate that all active compounds inhibit PTP1B through mixed mechanisms, and molecular docking simulations agree with the experimental assays on PTP1B. Our results suggest that chalcone-meroterpene adducts from the buds of C. operculatus exhibit potential as antidiabetic agents, partly due to their PTP1B enzyme inhibition.

Background: There is currently limited literature assessing the real-world treatment patterns and clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) mutations., Methods: Medical charts were abstracted for mCRPC patients with ≥ 1 of 12 HRR somatic gene alterations treated at US oncology centers participating in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange. Treatment patterns and clinical outcomes were assessed from the initiation of first-line or later (1L+) mCRPC therapy received on or after July 1, 2014., Results: Among 138 patients included in the study, the most common somatic HRR mutations were CDK12 (47.8%), BRCA2 (22.5%), and ATM (21.0%). Novel hormonal therapy and taxane chemotherapy were most commonly used in 1L; taxane use increased in later lines. Median overall survival (95% confidence interval [CI]) was 36.3 (30.7-47.8) months from initiation of 1L therapy and decreased for subsequent lines. Similarly, there was a trend of decreasing progression-free survival and prostate-specific antigen response from 1L to 4L+ therapy., Conclusions: Treatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature., Competing Interests: Disclosure PJ Bobbili, M DerSarkissian, A Muthukumar, T Guo, M Mohan, A Zhang, and MS Duh are employees of Analysis Group, Inc.; a consulting company that has provided paid consulting services to Pfizer, Inc., which funded the development and conduct of this study and manuscript. J Ivanova, B Arondekar, J Chang, and A Niyazov are employees and shareholders of Pfizer, Inc. DB Solit is an employee of Memorial Sloan Kettering Cancer Center; has received payment or honoraria for participation in an advisory board for BridgeBio, Elsie Biotechnologies Inc, Fog Pharma, FORE Therapeutics, Function Oncology, PaigeAI, Pfizer Inc, Rain Therapeutics, Scorpion Therapeutics, and Vividion Therapeutics; has participated on a data safety monitoring board or advisory board for Rain Therapeutics; and is a shareholder in Elsie Biotechnologies Inc, FORE therapeutics, Function Oncology, and Scorpion Therapeutics. R Huq is an employee of Memorial Sloan Kettering Cancer Center. NB Mettu is an employee of Duke Cancer Institute; and has received research funding paid to their institution from Amgen, Amphivena Therapeutics, Aravive Inc, AstraZeneca, BioMed Valley Discoveries, Bristol-Myers Squibb Company, Erytech Pharma, Genentech-Roche, Incyte, Merck, Mereo Biopharma, Repare Therapeutics, and Syros. SJ McCall is an employee of Duke Cancer Institute; has received consulting fees from AstraZeneca; speaker fees from Takeda Pharmaceuticals; and is a part investor in Frameshift MRT software, owned by Duke University and licensed to SciMed Solutions. M Green is a former employee of Duke Cancer Institute and a current employee of Labcop. M Dhawan is an employee of Genentech. M Turski is an employee of UCSF Hellen Diller Cancer Center; and has received speaking fees from Bayer. P Lam is an employee of UCSF Hellen Diller Cancer Center. J Lee is an employee of the American Association for Cancer Research, and has received grants or contracts from AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, BMS, Genentech, Janssen, Novartis, Merck, and Pfizer Inc. WK Oh is an employee of Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai; is the Chief Medical Officer of the Prostate Cancer Foundation; has received consulting fees from Genetic Chemistry Therapeutics and Pfizer Inc; has equity in Sema4/GeneDx, and is an author and editor for UpToDate., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The isolation of previously undescribed 12 compounds from the MeOH extract of Jacobaea vulgaris whole plants is disclosed, comprising 11 dihydrostilbenes (1-11) and one flavanone (12), and eight known compounds (six flavonoids, one dihydrostilbene, and one caffeoylquinic acid). Structural elucidation employed spectroscopic methods, including 1D and 2D NMR spectroscopy, HRESIMS, and ECD calculations. Evaluation of the compounds' effects on PCSK9 and LDLR mRNA expression revealed that compounds 1 and 3 downregulated PCSK9 mRNA while increasing LDLR mRNA expression, suggesting potential cholesterol-lowering properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)