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1.
Clin Cancer Res ; 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568346

RESUMO

PURPOSE: Dose-dense methotrexate-vinblastine-adriamycin-cisplatin (ddMVAC) and gemcitabine-cisplatin (GC) are accepted neoadjuvant regimens for muscle-invasive bladder cancer. The aim of this study was to validate the score from a coexpression extrapolation (COXEN) algorithm-generated gene expression model (GEM) as a biomarker in patients undergoing radical cystectomy. PATIENTS AND METHODS: Eligibility included cT2-T4a N0 M0, urothelial bladder cancer, ≥ 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy; 237 patients were randomized between ddMVAC, given every 14 days for four cycles, and GC, given every 21 days for four cycles. The primary objective assessed prespecified dichotomous treatment-specific COXEN score as predictive of pT0 rate or ≤ pT1 (downstaging) at surgery. RESULTS: Among 167 evaluable patients, the OR for pT0 with the GC GEM score in GC-treated patients was 2.63 [P = 0.10; 95% confidence interval (CI), 0.82-8.36]; for the ddMVAC COXEN GEM score with ddMVAC treatment, the OR was 1.12 (P = 0.82, 95% CI, 0.42-2.95). The GC GEM score was applied to pooled arms (GC and ddMVAC) for downstaging with an OR of 2.33 (P = 0.02; 95% CI, 1.11-4.89). In an intention-to-treat analysis of eligible patients (n = 227), pT0 rates for ddMVAC and GC were 28% and 30% (P = 0.75); downstaging was 47% and 40% (P = 0.27), respectively. CONCLUSIONS: Treatment-specific COXEN scores were not significantly predictive for response to individual chemotherapy treatment. The COXEN GEM GC score was significantly associated with downstaging in the pooled arms. Additional biomarker development is planned.

2.
Lancet ; 397(10275): 695-703, 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33592176

RESUMO

BACKGROUND: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC. METHODS: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057. FINDINGS: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group. INTERPRETATION: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC. FUNDING: National Institutes of Health and National Cancer Institute.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33514567

RESUMO

No approved medical therapies prevent progression of low-grade prostate cancer (PCa). Rapamycin inhibits cell proliferation and augments immune responses, producing an antitumor effect. Encapsulated rapamycin (eRapa) incorporates rapamycin into a pH-sensitive polymer, ensuring consistent dosing. Here, we present results from a phase I trial evaluating the safety and tolerability of eRapa in patients with PCa. Patients with Gleason <=7 (3+4) disease (low- and intermediate-risk) under active surveillance were enrolled in a 3+3 study with three eRapa dosing cohorts (cohort 1: 0.5mg/week; cohort 2: 1.0 mg/week; and cohort 3: 0.5mg/day). Patients were treated for three months and followed for an additional three months to assess safety, pharmacokinetics, quality of life (QoL), immune response, and disease progression. Fourteen patients (cohort 1: n=3; cohort 2: n=3; cohort 3: n=8) were enrolled. In cohort 3, one dose-limiting toxicity (DLT; neutropenia) and two non-DLT grade 1-2 adverse events (AEs) occurred that resulted in patient withdrawal. All AEs in cohorts 1-2 were grade 1. Peak serum rapamycin concentration was 7.1ng/mL after a 1mg dose. Stable trough levels (~2.0ng/mL) developed after 48-72 hours. Daily dosing mildly worsened QoL, though QoL recovered after treatment cessation in all categories except fatigue. Weekly dosing increased naïve T-cell populations. Daily dosing increased central memory cell populations and exhaustion markers. No disease progression was observed. In conclusion, treatment with eRapa was safe and well-tolerated. Daily dosing produced higher frequencies of lower-grade toxicities and transient worsening of QoL, while weekly dosing impacted immune response. Future studies will verify clinical benefit and long-term tolerability.

4.
Nutr Cancer ; : 1-8, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33511883

RESUMO

Non-supplemental carotenoids and retinol may potentiate antioxidant and anti-inflammatory mechanisms. Chronic intraprostatic inflammation is linked to prostate carcinogenesis. We investigated the association of circulating carotenoids and retinol with intraprostatic inflammation in benign tissue. We included 235 men from the Prostate Cancer Prevention Trial placebo arm who had a negative end-of-study biopsy, most (92.8%) done without clinical indication. α-carotene, ß-carotene, ß-cryptoxanthin, lycopene, and retinol were assessed by high-performance liquid chromatography using pooled year 1 and 4 serum. Presence and extent of intraprostatic inflammation in benign tissue was assessed in 3 (of 6-10) biopsy cores. Logistic (any core with inflammation vs none) and polytomous logistic (some or all cores with inflammation vs none) regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) of intraprostatic inflammation by concentration tertile adjusting for age, race, prostate cancer family history, and serum cholesterol. None of the carotenoids or retinol was associated with intraprostatic inflammation, except ß-cryptoxanthin, which appeared to be positively associated with any core with inflammation [vs none, T2: OR (95% CI) = 2.67 (1.19, 5.99); T3: 1.80 (0.84, 3.82), P-trend = 0.12]. These findings suggest that common circulating carotenoids and retinol are not useful dietary intervention targets for preventing prostate cancer via modulating intraprostatic inflammation.

5.
Int J Cancer ; 148(1): 99-105, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32930425

RESUMO

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

6.
J Geriatr Oncol ; 2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32739353

RESUMO

OBJECTIVES: Studies of local stage prostate cancer survivors suggest that treatments carry risk of persistent impotence, incontinence, and bowel dysfunction. To examine impacts of cancer type and side effects on health-related quality of life (HRQoL) in long-term cancer survivorship, we evaluated 5-year follow-up of patients with prostate cancer and compared results with a matched group of male long-term survivors of other local-stage cancers. MATERIALS AND METHODS: We examined genitourinary, bowel and sexual symptoms, and general quality of life. Matched survivors of colorectal, lung, and bladder cancers were recruited via registries in 3 different regions in the United States. Patients were surveyed 3-5 years after diagnosis with the SF-12 and EPIC to evaluate general mental and physical health-related quality of life (HRQoL) and patient function and bother. RESULTS: We analyzed responses from long-term prostate (n = 77) and bladder, colorectal, and lung cancer (n = 124) patients. In multivariate analysis, long-term local stage prostate cancer survivors had significantly higher SF-12 physical component scores but did not differ from long-term survivors of other cancers in terms of their SF-12 mental summary scores. Prostate survivors had similar mental, urinary, bowel, and sexual HRQoL compared to long-term survivors of other local stage cancers. CONCLUSION: Long-term general and prostate-specific HRQoL was similar between local stage prostate and bladder, colorectal, and lung patients with cancer. Future research focusing on factors other than initial treatment and the cancer type per se may provide more meaningful information regarding factors that predict disparities on HRQoL among longer-term survivors of early stage male cancers.

7.
JAMA Oncol ; 6(10): e203187, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32852532

RESUMO

Importance: Active surveillance is increasingly recognized as the preferred standard of care for men with low-risk prostate cancer. However, active surveillance requires repeated assessments, including prostate-specific antigen tests and biopsies that may increase anxiety, risk of complications, and cost. Objective: To identify and validate clinical parameters that can identify men who can safely defer follow-up prostate cancer assessments. Design, Setting, and Participants: The Canary Prostate Active Surveillance Study (PASS) is a multicenter, prospective active surveillance cohort study initiated in July 2008, with ongoing accrual and a median follow-up period of 4.1 years. Men with prostate cancer managed with active surveillance from 9 North American academic medical centers were enrolled. Blood tests and biopsies were conducted on a defined schedule for least 5 years after enrollment. Model validation was performed among men at the University of California, San Francisco (UCSF) who did not enroll in PASS. Men with Gleason grade group 1 prostate cancer diagnosed since 2003 and enrolled in PASS before 2017 with at least 1 confirmatory biopsy after diagnosis were included. A total of 850 men met these criteria and had adequate follow-up. For the UCSF validation study, 533 active surveillance patients meeting the same criteria were identified. Exclusion criteria were treatment within 6 months of diagnosis, diagnosis before 2003, Gleason grade score of at least 2 at diagnosis or first surveillance biopsy, no surveillance biopsy, or missing data. Exposures: Active surveillance for prostate cancer. Main Outcomes and Measures: Time from confirmatory biopsy to reclassification, defined as Gleason grade group 2 or higher on subsequent biopsy. Results: A total of 850 men (median [interquartile range] age, 64 [58-68] years; 774 [91%] White) were included in the PASS cohort. A total of 533 men (median [interquartile range] age, 61 [57-65] years; 422 [79%] White) were included in the UCSF cohort. Parameters predictive of reclassification on multivariable analysis included maximum percent positive cores (hazard ratio [HR], 1.30 [95% CI, 1.09-1.56]; P = .004), history of any negative biopsy after diagnosis (1 vs 0: HR, 0.52 [95% CI, 0.38-0.71]; P < .001 and ≥2 vs 0: HR, 0.18 [95% CI, 0.08-0.4]; P < .001), time since diagnosis (HR, 1.62 [95% CI, 1.28-2.05]; P < .001), body mass index (HR, 1.08 [95% CI, 1.05-1.12]; P < .001), prostate size (HR, 0.40 [95% CI, 0.25-0.62]; P < .001), prostate-specific antigen at diagnosis (HR, 1.51 [95% CI, 1.15-1.98]; P = .003), and prostate-specific antigen kinetics (HR, 1.46 [95% CI, 1.23-1.73]; P < .001). For prediction of nonreclassification at 4 years, the area under the receiver operating curve was 0.70 for the PASS cohort and 0.70 for the UCSF validation cohort. This model achieved a negative predictive value of 0.88 (95% CI, 0.83-0.94) for those in the bottom 25th percentile of risk and of 0.95 (95% CI, 0.89-1.00) for those in the bottom 10th percentile. Conclusions and Relevance: In this study, among men with low-risk prostate cancer, heterogeneity prevailed in risk of subsequent disease reclassification. These findings suggest that active surveillance intensity can be modulated based on an individual's risk parameters and that many men may be safely monitored with a substantially less intensive surveillance regimen.

9.
Cancer Prev Res (Phila) ; 13(10): 853-862, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32581009

RESUMO

Aspirin and statin use may lower the risk of advanced/fatal prostate cancer, possibly by reducing intraprostatic inflammation. To test this hypothesis, we investigated the association of aspirin and statin use with the presence and extent of intraprostatic inflammation, and the abundance of specific immune cell types, in benign prostate tissue from a subset of men from the placebo arm of the Prostate Cancer Prevention Trial. Men were classified as aspirin or statin users if they reported use at baseline or during the 7-year trial. Presence and extent of inflammation were assessed, and markers of specific immune cell types (CD4, CD8, FoxP3, CD68, and c-KIT) were scored, in slides from end-of-study prostate biopsies taken irrespective of clinical indication, per trial protocol. Logistic regression was used to estimate associations between medication use and inflammation measures, adjusted for potential confounders. Of 357 men included, 61% reported aspirin use and 32% reported statin use. Prevalence and extent of inflammation were not associated with medication use. However, aspirin users were more likely to have low FoxP3, a T regulatory cell marker [OR, 5.60; 95% confidence interval (CI), 1.16-27.07], and statin users were more likely to have low CD68, a macrophage marker (OR, 1.63; 95% CI, 0.81-3.27). If confirmed, these results suggest that these medications may alter the immune milieu of the prostate, which could potentially mediate effects of these medications on advanced/fatal prostate cancer risk.

10.
Prostate ; 80(11): 895-905, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32506665

RESUMO

BACKGROUND: Intraprostatic inflammation is an emerging prostate cancer risk factor. Estrogens are pro-inflammatory while androgens are anti-inflammatory. Thus, we investigated whether serum sex steroid hormone concentrations are associated with intraprostatic inflammation to inform mechanistic links among hormones, inflammation, and prostate cancer. METHODS: We conducted a cross-sectional study among 247 men in the placebo arm of the Prostate Cancer Prevention Trial who had a negative end-of-study biopsy, most (92.7%) performed without clinical indication per trial protocol. Serum estradiol, estrone, and testosterone were previously measured by immunoassay in pooled baseline and Year 3 serum. Free estradiol and free testosterone were calculated. Inflammation was visually assessed (median of three prostate biopsy cores per man). Polytomous or logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of some or all cores inflamed (both vs none) or any core inflamed (vs none) by hormone tertile, adjusting for age, race, and family history. We evaluated effect modification by waist circumference and body mass index (BMI). RESULTS: In all, 51.4% had some and 26.3% had all cores inflamed. Free (P-trend = .11) but not total estradiol was suggestively inversely associated with all cores inflamed. In men with waist circumference greater than or equal to 102 cm (P-trend = .021) and BMI ≥ 27.09 kg/m2 (P-trend = .0037) free estradiol was inversely associated with any core inflamed. Estrone was inversely associated with all cores inflamed (T3: OR = 0.36, 95% CI 0.14-0.95, P-trend = .036). Total (T3: OR = 1.91, 95% CI 0.91-4.02, P-trend = .11) and free (T3: OR = 2.19, 95% CI 1.01-4.74, P-trend = .05) testosterone were positively associated with any core inflamed, especially free testosterone in men with waist circumference less than 102 cm (T3: OR = 3.51, 95% CI 1.03-12.11, P-trend = .05). CONCLUSIONS: In this first study in men without prostate cancer and irrespective of clinical indication for biopsy, contrary to the hypothesis, circulating estrogens appeared to be inversely associated, especially in heavy men, whereas androgens appeared to be positively associated with intraprostatic inflammation.


Assuntos
Hormônios Esteroides Gonadais/sangue , Prostatite/sangue , Idoso , Biópsia , Peso Corporal , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Neoplasias da Próstata/prevenção & controle , Prostatite/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
JNCI Cancer Spectr ; 4(2): pkaa003, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32368717

RESUMO

There are few data regarding disparities in overall survival (OS) between Asian and white men with metastatic castration-resistant prostate cancer (mCRPC). We compared OS of Asian and white mCRPC men treated in phase III clinical trials with docetaxel and prednisone (DP) or a DP-containing regimen. Individual participant data from 8820 men with mCRPC randomly assigned on nine phase III trials to receive DP or a DP-containing regimen were combined. Men enrolled in these trials had a diagnosis of prostate adenocarcinoma. The median overall survival was 18.8 months (95% confidence interval [CI] = 17.4 to 22.1 months) and 21.2 months (95% CI = 20.8 to 21.7 months) for Asian and white men, respectively. The pooled hazard ratio for death for Asian men compared with white men, adjusted for baseline prognostic factors, was 0.95 (95% CI = 0.84 to 1.09), indicating that Asian men were not at increased risk of death. This large analysis showed that Asian men did not have shorter OS duration than white men treated with docetaxel.

12.
J Urol ; 204(4): 701-706, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32343189

RESUMO

PURPOSE: We investigated the ability of prostate magnetic resonance imaging to detect Gleason Grade Group 2 or greater cancer in a standardized, multi-institutional active surveillance cohort. MATERIALS AND METHODS: We evaluated men enrolled in Canary Prostate Active Surveillance Study with Gleason Grade Group less than 2 and who underwent biopsy within 12 months of multiparametric magnetic resonance imaging. Our primary outcome was biopsy reclassification to Gleason Grade Group 2 or greater. We evaluated the performance of magnetic resonance imaging PI-RADS® score and clinical factors. Multivariable logistic regression models were fit with magnetic resonance imaging and clinical factors and used to perform receiver operating curve analyses. RESULTS: There were 361 participants with 395 prostate magnetic resonance imaging studies with a median followup of 4.1 (IQR 2.0-7.6) years. Overall 108 (27%) biopsies showed reclassification. Defining positive magnetic resonance imaging as PI-RADS 3-5, the negative predictive value and positive predictive value for detecting Gleason Grade Group 2 or greater cancer was 83% (95% CI 76-90) and 31% (95% CI 26-37), respectively. PI-RADS was significantly associated with reclassification (PI-RADS 5 vs 1 and 2 OR 2.71, 95% CI 1.21-6.17, p=0.016) in a multivariable model but did not improve upon a model with only clinical factors (AUC 0.768 vs 0.762). In 194 fusion biopsies higher grade cancer was found in targeted cores in 21 (11%) instances, while 25 (13%) had higher grade cancer in the systematic cores. CONCLUSIONS: This study adds the largest cohort data to the body of literature for magnetic resonance imaging in active surveillance, recommending systematic biopsy in patients with negative magnetic resonance imaging and the inclusion of systematic biopsy in patients with positive magnetic resonance imaging.


Assuntos
Imagem por Ressonância Magnética , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estudos Prospectivos , Neoplasias da Próstata/terapia , Conduta Expectante
13.
J Clin Oncol ; 38(14): 1549-1557, 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32130059

RESUMO

PURPOSE: The 17-gene Oncotype DX Genomic Prostate Score (GPS) test predicts adverse pathology (AP) in patients with low-risk prostate cancer treated with immediate surgery. We evaluated the GPS test as a predictor of outcomes in a multicenter active surveillance cohort. MATERIALS AND METHODS: Diagnostic biopsy tissue was obtained from men enrolled at 8 sites in the Canary Prostate Active Surveillance Study. The primary endpoint was AP (Gleason Grade Group [GG] ≥ 3, ≥ pT3a) in men who underwent radical prostatectomy (RP) after initial surveillance. Multivariable regression models for interval-censored data were used to evaluate the association between AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Predictiveness curves were used to evaluate how models stratified risk of AP. Association between GPS and time to upgrade on surveillance biopsy was evaluated using Cox proportional hazards models. RESULTS: GPS results were obtained for 432 men (median follow-up, 4.6 years); 101 underwent RP after a median 2.1 years of surveillance, and 52 had AP. A total of 167 men (39%) upgraded at a subsequent biopsy. GPS was significantly associated with AP when adjusted for diagnostic GG (hazards ratio [HR]/5 GPS units, 1.18; 95% CI, 1.04 to 1.44; P = .030), but not when also adjusted for prostate-specific antigen density (PSAD; HR, 1.85; 95% CI, 0.99 to 4.19; P = .066). Models containing PSAD and GG, or PSAD, GG, and GPS may stratify risk better than a model with GPS and GG. No association was observed between GPS and subsequent biopsy upgrade (P = .48). CONCLUSION: In our study, the independent association of GPS with AP after initial active surveillance was not statistically significant, and there was no association with upgrading in surveillance biopsy. Adding GPS to a model containing PSAD and diagnostic GG did not significantly improve stratification of risk for AP over the clinical variables alone.

14.
Prostate Cancer Prostatic Dis ; 23(3): 486-493, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32055002

RESUMO

BACKGROUND: Cixutumumab, a monoclonal antibody targeting insulin-like growth factor I receptor, did not improve undetectable prostate-specific antigen (PSA) rate at 28 weeks when combined with androgen deprivation in the randomized phase II SWOG S0925 trial for patients with new metastatic hormone-sensitive prostate cancer. We now present mature survival analyses, along with pre-specified secondary and exploratory endpoints. METHODS: We randomized 210 patients to androgen deprivation with or without cixutumumab, 105 per treatment arm. We used Kaplan-Meier curves to analyze overall survival, radiographic progression-free survival, and castration resistance-free survival by treatment arm, disease volume, and risk group. We explored differences in survival by treatment arm via covariate-adjusted Cox proportional hazards models adjusted for disease volume and risk. RESULTS: No difference was seen between treatment arms in overall survival (HR 1.01 [0.70-1.45]; p = 0.97), radiographic progression-free survival (HR 1.17 [0.85-1.60]; p = 0.35), or castration resistance-free survival (HR 1.02 [0.75-1.41]; p = 0.88). At baseline, 105/198 (53.0%) patients had high-risk features and 119/210 (56.7%) had high-volume disease; 16.7% of patients had discordant classifications of high or low category for risk and volume. Adjusting for risk or volume yielded no differences in overall survival between arms. Inferior survival was observed in high-risk (HR 1.89 [1.29-2.80]; p = 0.001) and high-volume (HR 2.75 [1.84-4.10]; p < 0.0001) disease. Disease volume was a better fit to survival data than risk group (AIC 878.3 vs. 889.2). Compared to patients achieving undetectable PSA at 28 weeks, inferior survival was observed in patients whose PSA was >0.2 to ≤4.0 ng/mL (HR 3.72 [1.99-6.95]; p < 0.0001) or >4.0 ng/mL (HR 7.13 [4.24-11.9]; p < 0.0001). CONCLUSIONS: In new metastatic hormone-sensitive prostate cancer, addition of cixutumumab to androgen deprivation did not improve survival. Baseline risk and disease volume carried prognostic value for this distinct trial population, although disease volume added more prognostic information. PSA treatment response was a strong intermediate endpoint for survival.

15.
Cancer Prev Res (Phila) ; 13(6): 521-530, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32102946

RESUMO

Vitamin D may influence prostate cancer risk, but evidence is inconsistent. We conducted a nested case-control study in the Prostate Cancer Prevention Trial (PCPT). Cases (n = 1,128) and controls (n = 1,205) were frequency matched on age, first-degree relative with prostate cancer, and PCPT treatment arm (finasteride/placebo); African-Americans were oversampled and case/control status was biopsy confirmed. We selected 21 SNPs in vitamin D-related genes (VDR, GC, C10orf88, CYP2R1, CYP24A1, CYP27B1, DHCR7, and NADSYN1) to test genotype and genotype-treatment interactions in relation to prostate cancer. We also tested mean serum 25(OH)D differences by minor allele distributions and tested for serum 25(OH)D-genotype interactions in relation to prostate cancer risk. Log-additive genetic models (Bonferroni-corrected within genes) adjusted for age, body mass index, PSA, and family history of prostate cancer revealed a significant interaction between treatment arm and GC/rs222016 (finasteride OR = 1.37, placebo OR = 0.85; P interaction < 0.05), GC/rs222014 (finasteride OR = 1.36, placebo OR = 0.85; P interaction < 0.05), and CYP27B1/rs703842 (finasteride OR = 0.76, placebo OR = 1.10; P interaction < 0.05) among Caucasians, and C10orf88/rs6599638 (finasteride OR = 4.68, placebo OR = 1.39; P interaction < 0.05) among African-Americans. VDR/rs1544410 and CYP27B1/rs703842 had significant treatment interactions for high-grade disease among Caucasians (finasteride OR = 0.81, placebo OR = 1.40; P interaction < 0.05 and finasteride OR = 0.70, placebo OR = 1.28; P interaction < 0.05, respectively). Vitamin D-related SNPs influenced serum 25(OH)D, but gene-serum 25(OH)D effect modification for prostate cancer was marginally observed only for CYP24A1/rs2248359. In conclusion, evidence that vitamin D-related genes or gene-serum 25(OH)D associations influence prostate cancer risk is modest. We found some evidence for gene-finasteride interaction effects for prostate cancer in Caucasians and African-Americans. Results suggest only minimal associations of vitamin D with total or high-grade prostate cancer.

17.
Br J Gen Pract ; 70(690): e20-e28, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31848198

RESUMO

BACKGROUND: Electronic care coordination systems, known as the Key Information Summary (KIS) in Scotland, enable the creation of shared electronic records available across healthcare settings. A KIS provides clinicians with essential information to guide decision making for people likely to need emergency or out-of-hours care. AIM: To estimate the proportion of people with an advanced progressive illness with a KIS by the time of death, to examine when planning information is documented, and suggest improvements for electronic care coordination systems. DESIGN AND SETTING: This was a mixed-methods study involving 18 diverse general practices in Scotland. METHOD: Retrospective review of medical records of patients who died in 2017, and semi-structured interviews with healthcare professionals were conducted. RESULTS: Data on 1304 decedents were collected. Of those with an advanced progressive illness (79%, n = 1034), 69% (n = 712) had a KIS. These were started a median of 45 weeks before death. People with cancer were most likely to have a KIS (80%, n = 288), and those with organ failure least likely (47%, n = 125). Overall, 68% (n = 482) of KIS included resuscitation status and 55% (n = 390) preferred place of care. People with a KIS were more likely to die in the community compared to those without one (61% versus 30%). Most KIS were considered useful/highly useful. Up-to-date free-text information within the KIS was valued highly. CONCLUSION: In Scotland, most people with an advanced progressive illness have an electronic care coordination record by the time of death. This is an achievement. To improve further, better informal carer information, regular updating, and a focus on generating a KIS for people with organ failure is warranted.


Assuntos
Plantão Médico/organização & administração , Continuidade da Assistência ao Paciente/organização & administração , Registros Eletrônicos de Saúde/estatística & dados numéricos , Serviços Médicos de Emergência/organização & administração , Cuidados Paliativos/organização & administração , Atenção Primária à Saúde/organização & administração , Doente Terminal , Tomada de Decisões , Humanos , Disseminação de Informação , Satisfação do Paciente , Estudos Retrospectivos , Escócia/epidemiologia
18.
Int J Cancer ; 146(7): 1819-1826, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31226226

RESUMO

Latinos represent <1% of samples analyzed to date in genome-wide association studies of cancer. The clinical value of genetic information in guiding personalized medicine in populations of non-European ancestry will require additional discovery and risk locus characterization efforts across populations. In the present study, we performed a GWAS of prostate cancer (PrCa) in 2,820 Latino PrCa cases and 5,293 controls to search for novel PrCa risk loci and to examine the generalizability of known PrCa risk loci in Latino men. We also conducted a genetic admixture-mapping scan to identify PrCa risk alleles associated with local ancestry. Genome-wide significant associations were observed with 84 variants all located at the known PrCa risk regions at 8q24 (128.484-128.548) and 10q11.22 (MSMB gene). In admixture mapping, we observed genome-wide significant associations with local African ancestry at 8q24. Of the 162 established PrCa risk variants that are common in Latino men, 135 (83.3%) had effects that were directionally consistent as previously reported, among which 55 (34.0%) were statistically significant with p < 0.05. A polygenic risk model of the known PrCa risk variants showed that, compared to men with average risk (25th-75th percentile of the polygenic risk score distribution), men in the top 10% had a 3.19-fold (95% CI: 2.65, 3.84) increased PrCa risk. In conclusion, we found that the known PrCa risk variants can effectively stratify PrCa risk in Latino men. Larger studies in Latino populations will be required to discover and characterize genetic risk variants for PrCa and improve risk stratification for this population.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hispano-Americanos , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Idoso , Alelos , Biomarcadores Tumorais , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Razão de Chances , Polimorfismo de Nucleotídeo Único
19.
J Urol ; 203(4): 727-733, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31651227

RESUMO

PURPOSE: In a large, prospective, multi-institutional active surveillance cohort we evaluated whether African American men are at higher risk for reclassification. MATERIALS AND METHODS: The Canary PASS (Prostate Active Surveillance Study) is a protocol driven, active surveillance cohort with a prespecified prostate specific antigen and surveillance biopsy regimen. Men included in this study had Gleason Grade Group 1 or 2 disease at diagnosis and fewer than 5 years between diagnosis and enrollment, and had undergone 1 or more surveillance biopsies. The reclassification risk, defined as an increase in the Gleason score on subsequent biopsy, was compared between African American and Caucasian American men using Cox proportional hazards models. In the subset of men who underwent delayed prostatectomy the rate of adverse pathology findings, defined as pT3a or greater disease, or Gleason Grade Group 3 or greater, was compared in African American and Caucasian American men. RESULTS: Of the 1,315 men 89 (7%) were African American and 1,226 (93%) were Caucasian American. There was no difference in the treatment rate in African American and Caucasian American men. In multivariate models African American race was not associated with the risk of reclassification (HR 1.16, 95% CI 0.78-1.72). Of the 441 men who underwent prostatectomy after a period of active surveillance the rate of adverse pathology was similar in those who were African American and Caucasian American (46% vs 47%, p=0.99). CONCLUSIONS: Of men on active surveillance who followed a standardized protocol of regular prostate specific antigen testing and biopsy those who were African American were not at increased risk for pathological reclassification while on active surveillance, or for adverse pathology findings at prostatectomy. Active surveillance appears to be an appropriate management strategy for African American men with favorable risk prostate cancer.


Assuntos
Afro-Americanos/estatística & dados numéricos , Próstata/patologia , Neoplasias da Próstata/diagnóstico , Conduta Expectante/estatística & dados numéricos , Idoso , Biópsia com Agulha de Grande Calibre/normas , Biópsia com Agulha de Grande Calibre/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Humanos , Calicreínas/sangue , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Prostatectomia/estatística & dados numéricos , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Estados Unidos , Conduta Expectante/normas
20.
J Urol ; 203(3): 522-529, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31549935

RESUMO

PURPOSE: The RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for 3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival. MATERIALS AND METHODS: We analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis. RESULTS: Estimated progression-free survival at 36 months was 68.4% (95% CI 60.1-75.3) and 65.4% (95% CI 56.8-72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5-80.5) and 68.5% (95% CI 59.8-75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome. CONCLUSIONS: This analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.


Assuntos
Cistectomia/métodos , Procedimentos Cirúrgicos Robóticos/métodos , Neoplasias da Bexiga Urinária/cirurgia , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Taxa de Sobrevida , Estados Unidos , Neoplasias da Bexiga Urinária/mortalidade
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