Impact of Weight Management on Obesity-Driven Biomarkers of Prostate Cancer Progression.

PURPOSE: Excess body and visceral fat increase the risk of death from prostate cancer (PCa). This phase II study aimed to test whether weight reduction by > 5% total body weight counteracts obesity-driven PCa biomarkers. MATERIALS AND METHODS: Forty men scheduled for prostatectomy were randomized into intervention (n = 20) or control (n = 20) arms. Intervention participants followed a weight management program for 4 to 16 weeks before and 6 months after surgery. Control participants received standardized educational materials. All participants attended visits at baseline, 1 week before surgery, and 6 months after surgery. Circulating immune cells, cytokines, and chemokines were evaluated. Weight loss, body composition/distribution, quality of life, and nutrition literacy were assessed. Prostate tissue samples obtained from biopsy and surgery were analyzed. RESULTS: From baseline to surgery (mean = 5 weeks), the intervention group achieved 5.5% of weight loss (95% CI, 4%-7%). Compared to the control, the intervention also reduced insulin, total cholesterol, LDL cholesterol, leptin, leptin:adiponectin ratio, and visceral adipose tissue. The intervention group had reduced c-peptide, plasminogen-activator-inhibitor-1, and T cell count from baseline to surgery. Myeloid-derived suppressor cells were not statistically different by group. Intervention group anthropometrics improved, including visceral and overall fat loss. No prostate tissue markers changed significantly. Quality of life measures of general and emotional health improved in the intervention group. The intervention group maintained or kept losing to a net loss of 11% initial body weight (95% CI, 8%-14%) at the study end. CONCLUSIONS: Our study demonstrated improvements in body composition, PCa biomarkers, and quality of life with a weight management intervention.

Feasibility of a Weight Management Program Tailored for Overweight Men with Localized Prostate Cancer - A Pilot Study.

BACKGROUND: Overweight men with prostate cancer are more likely to suffer from recurrence and death following prostatectomy compared with healthy weight men. This study tested the feasibility of delivering a comprehensive program to foster weight loss before and weight maintenance after surgery in overweight men with localized prostate cancer. METHODS: Twenty overweight men scheduled for prostatectomy elected either the intervention (n = 15) or the nonintervention (n = 5). Anthropometrics, biomarkers, diet quality, nutrition literacy, quality of life, and long-term follow-up were assessed in both groups. RESULTS: The intervention led to 5.55 kg of weight loss including 3.88 kg of fat loss from baseline to surgery (mean = 8.3 weeks). The intervention significantly increased fiber, protein, fruit, nut, and vegetable intake; and decreased trans fats intake during weight loss. The intervention significantly reduced insulin, C-peptide, systolic blood pressure, leptin:adiponectin ratio, and visceral adiposity compared to the nonintervention. Post-surgically, weight loss was maintained. Changes in lipid profiles, nutrition literacy, and follow-up were not statistically significant in either group. CONCLUSION: Significant weight loss (≥5%) is feasible with a coaching intervention in overweight men preparing for prostatectomy and is associated with favorable cardiometabolic effects. This study is registered under NCT02252484 (www.clinicaltrials.gov).

Glycemic impact of a diet and lifestyle intervention on diabetics and prediabetics during treatment for non-muscle invasive bladder cancer.

Introduction: Patients with Type II Diabetes Mellitus (DM2) have increased risk of recurrence and progression of non-muscle invasive bladder cancer (NMIBC). Glucose control through lifestyle intervention is an uninvestigated, attractive strategy to decrease risk of cancer recurrence. We test the feasibility of a diet and exercise program and its glycemic impact in patients with DM2 and NMIBC.Materials/methods: Five participants with NMIBC and pre-diabetes or DM2 were recruited for a pilot, prospective clinical trial. Each participant received dietary counseling for 16 sessions during clinical visits. The intervention included a carbohydrate-restricted (CR) diet (<130 grams per day), 30 min, walking 5×/wk, and 5000 steps daily. Diet compliance was measured with 24-hour diet recall. Exercise was monitored with accelerometer and self-report.Results: Five participants enrolled and two participants completed the 12-month intervention. Adherence was 60% to CR diet and 84% to exercise goals. Participants reduced carbohydrate consumption by 44%. Participants showed reductions in fasting blood glucose, HbA1c, glucosuria, fasting blood insulin, and body weight, and increased euglycemia on continuous glucose monitoring.Conclusions: Adherence to a CR diet and exercise goals is feasible in patients with NMIBC and DM2 and also leads improved glucose control. A phase-II trial on bladder cancer-specific outcomes is warranted.

The Feasibility of a Health Care Application in the Treatment of Patients Undergoing Radical Cystectomy.

PURPOSE: Patients who undergo radical cystectomy of bladder cancer are at high risk for complications and hospital readmissions. Studies indicate insufficient preoperative education and perioperative monitoring. The aim of this study was to demonstrate the feasibility of implementing a health care application to provide more patient education and more thorough monitoring perioperatively. MATERIALS AND METHODS: Participants with home Wi-Fi access who were undergoing radical cystectomy were recruited for this pilot trial. Each subject was provided a tablet preloaded with the m.Care (LifeScience Technologies, Leawood, Kansas) health care application, an accelerometer and vital sign equipment. Participants were asked to watch educational videos, use the provided accelerometer and perform vital sign monitoring. RESULTS: In 1 year 20 participants enrolled in the study and 15 completed it. The most frequently viewed videos were "Ileal Conduit versus Neobladder" and "Comprehensive Care Pathway." All participants used the accelerometer and 60% kept up with syncing the data regularly. The average step count preoperatively was 5,679 reflecting a sedentary population. Step counts decreased during the inpatient stay (1,351 steps) and trended toward baseline during the postoperative period (3,156 steps). Vital signs were recorded on 85% of assigned days and generated 33 triggers for intervention. While most triggers led to repeat assessment, education and encouragement, 4 participants underwent outpatient treatment, including cultures, intravenous fluids, antibiotics or dronabinol prescription, without the need for hospital readmission. CONCLUSIONS: Providing more education and monitoring perioperatively is feasible using a health care application. Testing is warranted to determine the extent to which implementation will improve patient triaging and reduce readmissions.

Perioperative Immunonutrition Modulates Inflammatory Response after Radical Cystectomy: Results of a Pilot Randomized Controlled Clinical Trial.

PURPOSE: Poor preoperative nutritional status is associated with a higher complication rate after radical cystectomy in patients with bladder cancer. Given the short interval between diagnosis and radical cystectomy, we compared the effect of short-term specialized immunonutrition to that of a standard oral nutritional supplement on the acute inflammatory response and arginine status in patients treated with radical cystectomy. MATERIALS AND METHODS: In this prospective, randomized study in 29 men 14 received specialized immunonutrition and 15 received oral nutritional supplement. Each group drank 3 cartons per day for 5 days before and 5 days after radical cystectomy. The Th1-Th2 balance, plasma interleukin-6 and plasma amino acids were measured at baseline, intraoperatively and on postoperative days 2, 14 and 30. Body composition was measured by dual energy x-ray absorptiometry at baseline and on postoperative days 14 and 30. Differences in outcomes were assessed using the generalized linear mixed model. RESULTS: In the specialized immunonutrition group there was a 54.3% average increase in the Th1-Th2 balance according to the tumor necrosis factor-α-to-interleukin-13 ratio from baseline to intraoperative day, representing a shift toward a Th1 response. In the oral nutritional supplement group the Th1-Th2 balance decreased 4.8%. The change in the Th1-Th2 balance between the specialized immunonutrition and oral nutritional supplement groups significantly differed (p <0.027). Plasma interleukin-6 was 42.8% lower in the specialized immunonutrition group compared to the oral nutritional supplement group on postoperative day 2 (p = 0.020). In the specialized immunonutrition group plasma arginine was maintained from baseline to postoperative day 2 and yet the oral nutritional supplement group showed a 26.3% reduction from baseline to postoperative day 2 (p = 0.0003). The change in appendicular muscle loss between the groups was not statistically significant. CONCLUSIONS: Th1-to-Th2 ratios, peak interleukin-6 levels and plasma arginine suggest that consuming specialized immunonutrition counteracts the disrupted T-helper balance, lowers the inflammatory response and prevents arginine depletion due to radical cystectomy.

Effects of gangliosides on the activity of the plasma membrane Ca2+-ATPase.

Control of intracellular calcium concentrations ([Ca(2+)]i) is essential for neuronal function, and the plasma membrane Ca(2+)-ATPase (PMCA) is crucial for the maintenance of low [Ca(2+)]i. We previously reported on loss of PMCA activity in brain synaptic membranes during aging. Gangliosides are known to modulate Ca(2+) homeostasis and signal transduction in neurons. In the present study, we observed age-related changes in the ganglioside composition of synaptic plasma membranes. This led us to hypothesize that alterations in ganglioside species might contribute to the age-associated loss of PMCA activity. To probe the relationship between changes in endogenous ganglioside content or composition and PMCA activity in membranes of cortical neurons, we induced depletion of gangliosides by treating neurons with d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (d-PDMP). This caused a marked decrease in the activity of PMCA, which suggested a direct correlation between ganglioside content and PMCA activity. Neurons treated with neuraminidase exhibited an increase in GM1 content, a loss in poly-sialoganglioside content, and a decrease in PMCA activity that was greater than that produced by d-PDMP treatment. Thus, it appeared that poly-sialogangliosides had a stimulatory effect whereas mono-sialogangliosides had the opposite effect. Our observations add support to previous reports of PMCA regulation by gangliosides by demonstrating that manipulations of endogenous ganglioside content and species affect the activity of PMCA in neuronal membranes. Furthermore, our studies suggest that age-associated loss in PMCA activity may result in part from changes in the lipid environment of this Ca(2+) transporter.

Decreases in plasma membrane Ca²âº-ATPase in brain synaptic membrane rafts from aged rats.

Precise regulation of free intracellular Ca(2+) concentrations [Ca(2+) ](i) is critical for normal neuronal function, and alterations in Ca(2+) homeostasis are associated with brain aging and neurodegenerative diseases. One of the most important proteins controlling [Ca(2+) ](i) is the plasma membrane Ca(2+) -ATPase (PMCA), the high-affinity transporter that fine tunes the cytosolic nanomolar levels of Ca(2+) . We previously found that PMCA protein in synaptic plasma membranes (SPMs) is decreased with advancing age and the decrease in enzyme activity is much greater than that in protein levels. In this study, we isolated raft and non-raft fractions from rat brain SPMs and used quantitative mass spectrometry to show that the specialized lipid microdomains in SPMs, the rafts, contain 60% of total PMCA, comprised all four isoforms. The raft PMCA pool had the highest specific activity and this decreased progressively with age. The reduction in PMCA protein could not account for the dramatic activity loss. Addition of excess calmodulin to the assay did not restore PMCA activity to that in young brains. Analysis of the major raft lipids revealed a slight age-related increase in cholesterol levels and such increases might enhance membrane lipid order and prevent further loss of PMCA activity.

Milk intake enhances cerebral antioxidant (glutathione) concentration in older adults: A randomized controlled intervention study.

Background: A major antioxidant, glutathione (GSH), is a key factor in the antioxidant defense mechanism against oxidative stress and aging-related functional declines. Our previous observational study showed positive correlations between brain GSH concentrations and dairy food consumption, particularly milk (p < 0.001), in older adults. Objective: To investigate whether a recommended amount of milk intake (3 cups/day) in low dairy consumers enhances brain GSH concentrations through an intervention trial. Methods: Seventy-three older adults (60-89 years) with a low dairy intake (≤1.5 servings/day) were randomized (5:2 ratio) in this 3-month randomized clinical trial. The intervention group was provided 1% milk weekly and instructed to consume 3 cups of milk/day for 3 months while the control group continued their habitual intake of total dairy ≤ 1.5 servings/day (<1 cup of milk/day). Brain GSH concentrations were measured in the fronto-parietal region using our unique 3 T magnetic resonance chemical shift imaging technique at baseline and 3 months. Results: Among 73 randomized participants, 66 participants (49 intervention; 17 controls) completed the study. Milk intake in the intervention group increased from 0.2 ± 0.3 cups/day to 3.0 ± 0.6 cups/day (p < 0.001) between baseline and the end of the study, while milk intake in the control group did not differ throughout the study duration (0.4 ± 0.4 cups/day). The intervention group showed increases in brain GSH concentrations by 7.4 ± 11.7% (p < 0.001) in parietal and 4.7 ± 9.8% (p = 0.003) in fronto-parietal regions, and 4.6 ± 8.7% (p < 0.001) in overall brain concentration after the intervention compared with baseline, while the control group showed no changes. Conclusion: This study provides evidence that milk serves as a good dietary source to increase and/or restore brain GSH concentrations in older adults. Identifying dietary sources that effectively enhance antioxidant defenses and neuroprotection could lead to the development of new strategies to promote brain health in the aging population. Clinical trial registration: [https://ClinicalTrials.gov], identifier [NCT02957422].

Exploration of biomarkers from a pilot weight management study for men undergoing radical prostatectomy.

BACKGROUND: Several biologic mechanisms, including inflammation and immune changes, have been proposed to explain the role of obesity in prostate cancer (CaP) progression. Compared to men of a healthy weight, overweight and obese men are more likely to have CaP recurrence post-prostatectomy. Obesity is related to inflammation and immune dysregulation; thus, weight loss may be an avenue to reduce inflammation and reverse these immune processes. OBJECTIVES: This study explores the reversibility of the biological mechanisms through intentional weight loss using a comprehensive weight management program in men undergoing prostatectomy. Outcomes include blood and tissue biomarkers, microtumor environment gene expression, inflammation markers and Dietary Inflammatory Index (DII) scores. METHODS: Twenty overweight men undergoing prostatectomy participated in this study. Fifteen men chose the intervention and 5 men chose the nonintervention group. The intervention consisted of a comprehensive weight loss program prior to prostatectomy and a weight maintenance program following surgery. Prostate tissue samples were obtained from diagnostic biopsies before the intervention and prostatectomy samples after weight loss. Blood samples and diet records were collected at baseline, pre-surgery after weight loss and at study end after weight maintenance. Immunohistochemistry and NanoString analysis were used to analyze the tissue samples. Flow cytometry was used to assess circulating immune markers. Inflammation markers were measured using Luminex panels. RESULTS: The intervention group lost >5% body weight prior to surgery. DII scores improved during the weight loss intervention from baseline to pre-surgery (P = 0.002); and between group differences were significant (P = 0.02). DII scores were not associated with IL-6 nor hsCRP. In the intervention, CXCL12, CXCR7, and CXCR4 (C-X-C motif chemokine ligand/receptor) and Ki67 expression decreased in the prostate tissue from biopsy to surgery (P = 0.06), yet plasma CXCL12 increased during the same timeframe (P = 0.009). The downregulation of several genes (FDR<0.001) was observed in the intervention compared to the non-intervention. Changes in immune cells were not significant in either group. CONCLUSION: This feasibility study demonstrates that in overweight men with localized CaP, weight loss alters blood, and tissue biomarkers, as well as tumor gene expression. More research is needed to determine the biological and clinical significance of these findings.

Effects of Immunonutrition for Cystectomy on Immune Response and Infection Rates: A Pilot Randomized Controlled Clinical Trial.

UNLABELLED: After radical cystectomy (RC), patients are at risk for complications including infections. The expansion of myeloid-derived suppressor cells (MDSCs) after surgery may contribute to the lower resistance to infection. Immune response and postoperative complications were compared in men consuming either specialized immunonutrition (SIM; n=14) or an oral nutrition supplement (ONS; n=15) before and after RC. MDSC count (Lin- CD11b+ CD33+) was significantly different between the groups over time (p=0.005) and significantly lower in SIM 2 d after RC (p<0.001). MDSC count expansion from surgery to 2 d after RC showed a weak association with an increase in infection rate 90 d after surgery (p=0.061). Neutrophil:lymphocyte ratio was significantly lower in SIM compared with ONS 3h after the first incision (p=0.039). Participants receiving SIM had a 33% reduction in postoperative complication rate (95% confidence interval [CI], 1-64; p=0.060) and a 39% reduction in infection rate (95% CI, 8-70; p=0.027) during late-phase recovery. The small sample size limits the study findings. PATIENT SUMMARY: Results show that the immune response to surgery and late infection rates differ between radical cystectomy patients receiving specialized immunonutrition versus oral nutrition supplement in the perioperative period. TRIAL REGISTRATION: ClinicalTrials.gov NCT01868087.