Effects of protein restriction on insulin-like growth factor (IGF)-1 in men with prostate cancer: results from a randomized clinical trial.

BACKGROUND: Insulin-like growth factor (IGF)-1 and its binding proteins are important in cancer growth, especially in prostate cancer. Observational studies suggest that protein restriction can lower IGF-1 levels. However, it is unclear whether an isocaloric protein-restricted diet affects IGF-1 and IGFBPs in men with prostate cancer. METHODS: In this academic, single-center, parallel-group, prospective, randomized, open-label, blinded end-point trial, 38 consenting overweight (BMI 30.5 ± 5.5 kg/m2) men with localized prostate cancer, aged 43-72 years, were randomized (1:1) with permuted blocks to 4-6 weeks of customized isocaloric PR diets (0.8 g protein/kg lean body mass) or their usual diet. Biomarkers influencing cancer biology, including serum IGF-1 and its binding proteins were measured longitudinally. RESULTS: Contrary to our hypothesis, feeding individuals an isocaloric protein-restricted diet did not result in a significant reduction in serum IGF-1. Moreover, there was no observed increase in serum IGFBP-1 or IGFBP-3 concentration. CONCLUSION: These findings demonstrate that protein restriction without calorie restriction does not reduce serum IGF-1 concentration or increase IGFBP-1 and IGFBP-3 in men with localized prostate cancer. Further research is needed to identify dietary interventions for safely and effectively reducing IGF-1 in this patient group.

A propensity analysis comparing definitive chemo-radiotherapy for muscle-invasive squamous cell carcinoma of the bladder vs. urothelial carcinoma of the bladder using the National Cancer Database.

INTRODUCTION: Squamous cell carcinoma (SqCC) is the second most common histology of primary bladder cancer, but still very limited information is known about its treatment outcomes. Most bladder cancer trials have excluded SqCC, and the current treatment paradigm for localized SqCC is extrapolated from results in urothelial carcinoma (UC). In particular, there is limited data on the efficacy of definitive chemo-radiotherapy (CRT). In this study, we compare overall survival outcomes between SqCC and UC patients treated with definitive CRT. MATERIALS/METHODS: We queried the National Cancer Database (NCDB) for muscle-invasive (cT2-T4 N0 M0) bladder cancer patients diagnosed from 2004 to 2013 who underwent concurrent CRT. Propensity matching was performed to match patients with SqCC to those with UC. OS was analyzed using the Kaplan-Meier survival method, and the log-rank test and Cox regression were used for analyses. RESULTS: 3332 patients met inclusion criteria of which 79 (2.3%) had SqCC. 73.4% of SqCC patients had clinical T2 disease compared to 82.5% of UC patients. Unadjusted median OS for SqCC patients was 15.6 months (95% CI, 11.7-19.6) versus 29.1 months (95% CI, 27.5-30.7) for those with UC (P < 0.0001). On multivariable analysis, factors associated with worse OS included: SqCC histology [HR: 1.53 (95% CI, 1.19-1.97); P = 0.001], increasing age [HR: 1.02 (95% CI, 1.02-1.03); P < 0.0001], increasing clinical T-stage [HR: 1.21 (95% CI, 1.13-1.29); P < 0.0001], and Charlson-Deyo comorbidity index [HR: 1.26 (95% CI, 1.18-1.33); P < 0.0001]. Seventy-seven SqCC patients were included in the propensity-matched analysis (154 total patients) with a median OS for SqCC patients of 15.1 months (95% CI, 11.1-18.9) vs. 30.4 months (95% CI, 19.4-41.4) for patients with UC (P = 0.013). CONCLUSIONS: This is the largest study to-date assessing survival outcomes for SqCC of the bladder treated with CRT. In this study, SqCC had worse overall survival compared to UC patients. Histology had a greater impact on survival than increasing T-stage, suggesting that histology should be an important factor when determining a patient's treatment strategy and that treatment intensification in this subgroup may be warranted.

Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms.

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Dietary interventions based on protein restriction (PR) reduce circulating triglycerides (TGs), but underlying mechanisms and clinical relevance remain unclear. Here, we show that 1 week of a protein-free diet without enforced calorie restriction significantly lowered circulating TGs in both lean and diet-induced obese mice. Mechanistically, the TG-lowering effect of PR was due, in part, to changes in very low-density lipoprotein (VLDL) metabolism both in liver and peripheral tissues. In the periphery, PR stimulated VLDL-TG consumption by increasing VLDL-bound APOA5 expression and promoting VLDL-TG hydrolysis and clearance from circulation. The PR-mediated increase in Apoa5 expression was controlled by the transcription factor CREBH, which coordinately regulated hepatic expression of fatty acid oxidation-related genes, including Fgf21 and Ppara. The CREBH-APOA5 axis activation upon PR was intact in mice lacking the GCN2-dependent amino acid-sensing arm of the integrated stress response. However, constitutive hepatic activation of the amino acid-responsive kinase mTORC1 compromised CREBH activation, leading to blunted APOA5 expression and PR-recalcitrant hypertriglyceridemia. PR also contributed to hypotriglyceridemia by reducing the rate of VLDL-TG secretion, independently of activation of the CREBH-APOA5 axis. Finally, a randomized controlled clinical trial revealed that 4-6 weeks of reduced protein intake (7%-9% of calories) decreased VLDL particle number, increased VLDL-bound APOA5 expression, and lowered plasma TGs, consistent with mechanistic conservation of PR-mediated hypotriglyceridemia in humans with translational potential as a nutraceutical intervention for dyslipidemia.

Surgical Management for Prostate Cancer.

For prostate cancer, radical prostatectomy remains the gold standard for surgical management. Given the side effects associated with surgery, patients at low risk of prostate cancer-specific mortality should consider active surveillance under the guidance of a urologist to safely delay intervention. For patients with an intermediate risk of cancer-specific mortality and otherwise healthy life expectancy, radical prostatectomy has been demonstrated to improve survival. Finally, even for select patients with advanced prostate cancer-metastatic disease to the lymph nodes or distant sites-radical prostatectomy may provide a survival benefit.

Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health.

Protein-restricted (PR), high-carbohydrate diets improve metabolic health in rodents, yet the precise dietary components that are responsible for these effects have not been identified. Furthermore, the applicability of these studies to humans is unclear. Here, we demonstrate in a randomized controlled trial that a moderate PR diet also improves markers of metabolic health in humans. Intriguingly, we find that feeding mice a diet specifically reduced in branched-chain amino acids (BCAAs) is sufficient to improve glucose tolerance and body composition equivalently to a PR diet via metabolically distinct pathways. Our results highlight a critical role for dietary quality at the level of amino acids in the maintenance of metabolic health and suggest that diets specifically reduced in BCAAs, or pharmacological interventions in this pathway, may offer a translatable way to achieve many of the metabolic benefits of a PR diet.

Update on male urinary stress incontinence.

Urinary incontinence after prostate surgery is a rare, but potentially devastating problem. Guidelines for the evaluation and treatment of male stress urinary incontinence have evolved over the years. A review of current behavioral, medical and surgical approaches (male sling, artificial urinary sphincter) for post prostatectomy incontinence is reviewed in this manuscript.

Prostate-specific antigen density predicts adverse pathology and increased risk of biochemical failure.

OBJECTIVES: To determine whether the prostate-specific antigen (PSA) density (PSAD), measured using either ultrasound (US) or prostatic weight (PW), is an independent predictor of adverse pathologic findings or biochemical-free survival and whether it outperformed PSA. METHODS: The data were obtained prospectively from 1327 patients undergoing radical prostatectomy from 1990 to 2003. The US PSAD was calculated by dividing the preoperative PSA level in nanograms per milliliter by the US measured prostate volume in cubic centimeters. The PW PSAD was calculated by dividing the PSA value in nanograms per milliliter by the measured PW of the prostatectomy specimen in grams. Logistic regression analysis was performed to determine whether the US or PW PSAD was more accurate than the PSA level in predicting for adverse pathologic findings. A proportional hazards model was used to determine whether PSAD more accurately predicted for biochemical failure (PSA level greater 0.2 ng/mL). RESULTS: Multivariate analysis demonstrated that US and PW PSAD were independent predictors of positive margins (odds ratio [OR] 5.00, 95% confidence interval [CI] 2.65 to 9.47 and OR 29.75, 95% CI 10.18 to 86.96, respectively), extracapsular disease (OR 10.89, 95% CI 5.32 to 22.32 and OR 126.62, 95% CI 37.99 to 422.07, respectively), seminal vesical invasion (OR 6.06, 95% CI 2.96 to 12.41 and OR 33.72, 95% CI 9.79 to 116.15, respectively), and biochemical failure (hazard ratio 3.32, 95% CI 2.38 to 4.63 and hazard ratio 8.70, 95% CI 5.21 to 14.52, respectively). The C-index demonstrated that both US and PW PSAD appeared more discriminant for adverse pathologic findings and biochemical failure than did the PSA level. CONCLUSIONS: The US and PW PSAD are strong predictors of advanced pathologic features and biochemical failure after radical prostatectomy. The incorporation of PSAD into the risk assessment could provide additional prognostic information beyond grade, stage, and PSA level; therefore, the inclusion of PSAD into nomograms should be considered.