Challenges and Opportunities in Establishing Appropriate Intermediate Endpoints Reflecting Patient Benefit: A Roadmap for Research and Clinical Application in Nonmetastatic Prostate Cancer.

Defining meaningful endpoints for research of early-stage high-risk prostate cancer is challenging, with established measures such as overall survival and metastasis-free survival facing limitations related to feasibility and adequate reflection of patient relevance. Developing endpoints must cater to diverse perspectives across scientific, clinical, regulatory, and patient viewpoints. Endpoints such as pathological complete response, no evidence of disease, and prevention of prostate-specific antigen relapse may reflect patient benefit by accounting for diagnostic and treatment burdens.

Early Endpoints in High-risk Localized Prostate Cancer: Exploratory Analysis of Three Radiation Therapy Oncology Group Phase 3 Studies.

BACKGROUND: Early endpoints in clinical trials of high-risk localized prostate cancer (HRLPC) that resemble those monitored in real-world practice could expedite clinical development. OBJECTIVE: To assess the association of prostate-specific antigen (PSA) recurrence (PSA-R)-based early endpoints with metastasis-free survival (MFS), overall survival (OS), and prostate cancer (PC)-specific survival (PCSS), and to identify clinically undetectable disease. DESIGN, SETTING, AND PARTICIPANTS: A post hoc analysis of patients with HRLPC from Radiation Therapy Oncology Group studies 9202, 9902, and 0521 was performed. INTERVENTION: Long-term adjuvant androgen-deprivation therapy (ADT) and post-primary definitive radiotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Event-free survival (EFS; PSA-R, locoregional recurrence [LRR], distant metastasis [DM], or death), biochemical failure (PSA-R), general clinical failure (PSA-R, LRR, DM, ADT initiation, or death), and no evidence of disease (NED; alive patients without PSA-R, LRR, DM, and subsequent PC therapy, and with testosterone recovery) were assessed for association with MFS, OS, and PCSS using correlation and landmark analyses, Kaplan-Meier method, and Cox proportional-hazard model. PSA-R was defined as PSA nadir + 2 ng/ml; PSA nadir + 2 ng/ml and rising; PSA >5, 10, and 25 ng/ml; or PSA doubling time (PSADT) <6 mo. RESULTS AND LIMITATIONS: Among assessed early endpoints, EFS with PSA nadir + 2 ng/ml and rising, or with PSA >5 ng/ml was associated with MFS, OS, and PCSS. No development of EFS with PSADT <6 mo or ADT initiation event or achievement of NED at 3 yr was associated with prolonged OS, MFS, and PCSS (hazard ratio [95% confidence interval], 0.53 [0.45-0.64], 0.63 [0.52-0.76], and 0.26 [0.18-0.36], or 0.56 [0.48-0.66], 0.62 [0.52-0.74], and 0.26 [0.19-0.37]) after the landmark time. Older studies performed before the current guidance should be interpreted with caution. CONCLUSIONS: We identified EFS with PSA nadir + 2 ng/ml and rising, PSA >5 ng/ml, or PSADT <6 mo ± ADT initiation and NED as potentially promising early endpoints in HRLPC that should be validated further. PATIENT SUMMARY: We identified novel clinical measures that may expedite the development of new medicines for patients with localized prostate cancer at a high risk of progression. These measures, which took into account prostate-specific antigen assessments and other clinical characteristics, should be confirmed in future studies. We also defined a novel measure of no evidence of disease that can help treating physicians identify patients with clinically undetectable disease.

Randomized, Open-Label Phase 2 Study of Apalutamide plus Androgen Deprivation Therapy versus Apalutamide Monotherapy versus Androgen Deprivation Monotherapy in Patients with Biochemically Recurrent Prostate Cancer.

Purpose: This randomized phase 2 study sought to assess the treatment effect of a finite duration of apalutamide with and without androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BCR PC). Materials and Methods. Patients with BCR PC after primary definitive therapy and prostate-specific antigen (PSA) doubling time ≤12 months were randomized to open-label apalutamide (240 mg/d) alone, apalutamide plus ADT, or ADT alone (1 : 1:1 ratio) for 12 months followed by a 12-month observation period (NCT01790126). Mean changes from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) at 12 months (primary endpoint) and other prespecified assessments of health-related quality of life (HRQoL), PSA nadir, time to PSA progression, time to testosterone recovery, recovered testosterone >150 ng/dL without PSA progression at 24 months, and molecular markers were evaluated. Results: In 90 enrolled patients (apalutamide plus ADT (n = 31), apalutamide (n = 29), ADT (n = 30)), FACT-P at 12 months was not significantly different between apalutamide, ADT and apalutamide, and ADT groups. Addition of apalutamide to ADT prolonged time to PSA progression but this change did not reach statistical significance (hazard ratio (HR): 0.56, 95% confidence interval (CI): 0.23-1.36, P=0.196); time to testosterone recovery was similar in the ADT-containing groups. In apalutamide plus ADT, apalutamide, and ADT groups, 37.9%, 37.0%, and 19.2% of patients, respectively, had testosterone >150 ng/dL at 24 months without confirmed PSA progression. Of the few biomarkers expressed in blood, EPHA3 was significantly associated with shorter time to PSA progression (P=0.02) in the overall population. Conclusions: HRQoL was similar in patients treated with apalutamide alone, ADT alone, or their combination, although apalutamide plus ADT did not demonstrate statistically significant noninferiority in change from baseline in overall HRQoL. The aggregated efficacy and safety outcomes support further evaluation of apalutamide plus ADT in BCR PC.

Apalutamide plus Androgen Deprivation Therapy for Metastatic Castration-Sensitive Prostate Cancer: Analysis of Pain and Fatigue in the Phase 3 TITAN Study.

PURPOSE: We performed an exploratory analysis of prostate cancer-related pain and fatigue on health-related quality of life in patients with metastatic castration-sensitive prostate cancer receiving apalutamide (240 mg/day) or placebo, with continuous androgen deprivation therapy (ADT), in the phase 3, randomized, double-blind, placebo controlled TITAN trial (NCT02489318). MATERIALS AND METHODS: Patient-reported outcomes for pain and fatigue were evaluated using the Brief Pain Inventory-Short Form and Brief Fatigue Inventory. Time to deterioration (TTD) was estimated by Kaplan-Meier method; hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards model. General estimating equations for logistic regression estimated treatment-related differences in the likelihood of worsening pain or fatigue. RESULTS: Compliance for completing the Brief Pain Inventory-Short Form and Brief Fatigue Inventory was high (96% to 97%) in the first year. Median followup times were similar between treatments (19 to 22 months). Median pain TTD was longer with apalutamide than placebo for "pain at its least in the last 24 hours" (28.7 vs 21.8 months, respectively; p=0.0146), "pain interfered with mood" (not estimable vs 22.4 months; p=0.0017), "pain interfered with walking ability" (28.7 vs 20.2 months; p=0.0027), "pain interfered with relations" (not estimable vs 23.0 months; p=0.0139) and "pain interfered with sleep" (28.7 vs 20.9 months; p=0.0167). Likelihood for fatigue and worsening fatigue were similar between groups. CONCLUSIONS: Patients with metastatic castration-sensitive prostate cancer receiving apalutamide plus ADT vs placebo plus ADT reported consistently favorable TTD of pain. No difference for change in fatigue was observed with apalutamide vs placebo.

Effect of in-office samples on dermatologists' prescribing habits: a retrospective review.

The relationship between physicians and pharmaceutical companies has caused the medical community to question the degree to which pharmaceutical interactions and incentives can influence physicians' prescribing habits. Our study aimed to analyze whether a change in institutional policy that restricted the availability of in-office samples for patients resulted in any measurable change in the prescribing habits of faculty physicians in the Department of Dermatology and Cutaneous Surgery at the University of South Florida (USF)(Tampa, Florida). Medical records were retrospectively reviewed for common dermatology diagnoses-acne vulgaris, atopic dermatitis, onychomycosis, psoriasis, and rosacea-before and after the pharmaceutical policy changes, and the prescribed medications were recorded. These medications were then categorized as brand name, generic, and over-the-counter (OTC). Statistical analysis using a mixed effects ordinal logistic regression model accounting for baseline patient characteristics was conducted to determine if a difference in prescribing habits occurred.

Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study.

BACKGROUND: In the phase 3 TITAN study, the addition of apalutamide to androgen deprivation therapy (ADT) significantly improved the primary endpoints of overall survival and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer. We aimed to assess health-related quality of life (HRQOL) in TITAN, including pain and fatigue. METHODS: In this randomised, placebo-controlled, double-blind, phase 3 study, patients with metastatic castration-sensitive prostate cancer (defined as not receiving ADT at the time of metastatic disease progression) aged 18 years and older, receiving continuous ADT (selected at the investigator's discretion), and with an Eastern Cooperative Oncology Group performance status score of 0 or 1 were randomly assigned (1:1), using an interactive web response system, to receive oral apalutamide (four 60 mg tablets, once daily) or matching placebo. Previous localised disease treatment or previous docetaxel for metastatic castration-sensitive prostate cancer were allowed. Randomisation was stratified by Gleason score at diagnosis, region, and previous docetaxel treatment. Randomisation was done using randomly permuted blocks (block size of four). Investigators, research staff, sponsor study team, and patients were masked to the identities of test and control treatments. Patient-reported outcomes were prespecified exploratory endpoints and were the Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and EuroQoL 5D questionnaire 5 level (EQ-5D-5L). BPI and BFI were completed for 7 consecutive days (days -6 to 1 inclusive of each cycle visit), then at months 4, 8, and 12 in follow-up. FACT-P and EQ-5D-5L were completed during cycles 1-7, then every other cycle until the end of treatment, and at months 4, 8, and 12 in follow-up. Analyses were based on the intention-to-treat population. Missing patient-reported outcome assessments were calculated as the expected number of assessments for a visit minus the actual number of assessments received for that visit. For time-to-event endpoints, when median values could not be calculated because less than 50% of patients had degradation, 25th percentiles were compared. This study is registered with ClinicalTrials.gov, number NCT02489318, and is ongoing. FINDINGS: Between Dec 9, 2015, and July 25, 2017, 1052 eligible patients were enrolled randomly assigned to apalutamide (n=525) or placebo (n=527). Data cutoff for this analysis of patient-reported outcomes was Nov 23, 2018. Median follow-up for time to pain-related endpoints ranged from 19·4 to 22·1 months. Patients were mostly asymptomatic at baseline: on the BPI-SF pain severity scale of 0-10, median pain scores (indicating worst pain in the past 24 h) were 1·14 (IQR 0-3·17) in the apalutamide group and 1·00 (0-2·86) in the placebo group, and median worst fatigue scores on the BFI were 1·29 (IQR 0-3·29) in the apalutamide group and 1·43 (0·14-3·14) in the placebo group. Patient experience of pain and fatigue (intensity and interference) did not differ between the groups for the duration of treatment. Median time to worst pain intensity progression was 19·09 months (95% CI 11·04-not reached) in the apalutamide group versus 11·99 months (8·28-18·46) in the placebo group (HR 0·89 [95% CI 0·75-1·06]; p=0·20). Median time to pain interference progression was not reached in either group (95% CI 28·58-not reached in the apalutamide group; not reached-not reached in the placebo group). 25th percentiles for time to pain interference progression were 9·17 months (5·55-11·96) in the apalutamide group and 6·24 months (4·63-7·43) in the placebo group (HR 0·90 [95% CI 0·73-1·10]; p=0·29). FACT-P total scores and EQ-5D-5L data showed preservation of HRQOL in both groups. The median time to deterioration as determined by FACT-P total score was 8·87 months (95% CI 4·70-11·10) in the apalutamide group and 9·23 months (7·39-12·91) in the placebo group (HR 1·02 [95% CI 0·85-1·22]; p=0·85). INTERPRETATION: Apalutamide with ADT is a well-tolerated and effective option for men with metastatic castration-sensitive prostate cancer. The combination significantly improves survival outcomes compared with ADT alone while maintaining HRQOL despite additive androgen blockade. FUNDING: Janssen Research & Development.

Pulmonary Artery Systolic Pressure Measured Intraoperatively by Right Heart Catheterization Is a Predictor of Kidney Transplant Recipient Survival.

BACKGROUND The effect of pulmonary artery systolic pressure (PASP) measured by Swan-Ganz right heart catheter (SG-RHC) on kidney transplant recipient survival has not been previously studied. The objective of this study was to assess the relationships between PASP measured via SG-RHC, done intraoperatively at the time of initiating anesthesia at the beginning of kidney transplant surgery, and patient survival. Multiple comorbidities, time on dialysis before the transplantation, and graft function were also analyzed in our study. MATERIAL AND METHODS This was a retrospective cohort study using data from all consecutive patients undergoing kidney transplant between January 1, 2005 and December 31, 2009 at Tampa General Hospital. Kidney transplant recipients were divided into 2 groups: Group 1 with PASP <35 mmHg and group 2 with PASP ≥35 mmHg. Patients and graft survival data, time on dialysis before transplant, and comorbidities were compared between the 2 groups. RESULTS Only 363 patients were found to have a documented PASP measurement at the time of anesthesia induction for the transplant surgery, and were included in the specific analysis of our study. Patients with PASP ≥35 mmHg showed a significant decrease in survival in comparison to patients having PASP values <35 mmHg (HR 1.88; 95% CI 1.012 to 3.47, P=0.04). There was a significant positive correlation between time on dialysis and PASP (rho 0.20; 95% CI 0.09 to 0.30, p<0.001), as well as a significant difference in median time on dialysis between PASP <35 vs. PASP ≥35 (22 vs. 29 months, p=0.004). There were no significant differences in graft failure between the 2 PASP groups (HR 0.34; 95% CI 0.12 to 1.01, P=0.05). CONCLUSIONS Patients with PASP ≥35 mmHg, measured intraoperatively by SG-RHC, showed significantly shorter survival in comparison to patients having PASP values <35 mmHg. This result suggests the need for a randomized controlled trial to address the importance of post-transplant pulmonary hypertension management in patient survival.

Efficacy of Laparoscopic Nissen Fundoplication vs Transoral Incisionless Fundoplication or Proton Pump Inhibitors in Patients With Gastroesophageal Reflux Disease: A Systematic Review and Network Meta-analysis.

BACKGROUND & AIMS: The effects of transoral incisionless fundoplication (TIF) and laparoscopic Nissen fundoplication (LNF) have been compared with those of proton pump inhibitors (PPIs) or a sham procedure in patients with gastroesophageal reflux disease (GERD), but there has been no direct comparison of TIF vs LNF. We performed a systematic review and network meta-analysis of randomized controlled trials to compare the relative efficacies of TIF vs LNF in patients with GERD. METHODS: We searched publication databases and conference abstracts through May 10, 2017 for randomized controlled trials that compared the efficacy of TIF or LNF with that of a sham procedure or PPIs in patients with GERD. We performed a network meta-analysis using Bayesian methods under random-effects multiple treatment comparisons. We assessed ranking probability by surface under the cumulative ranking curve. RESULTS: Our search identified 7 trials comprising 1128 patients. Surface under the cumulative ranking curve ranking indicated TIF had highest probability of increasing patients' health-related quality of life (0.96), followed by LNF (0.66), a sham procedure (0.35), and PPIs (0.042). LNF had the highest probability of increasing percent time at pH <4 (0.99), followed by PPIs (0.64), TIF (0.32), and the sham procedure (0.05). LNF also had the highest probability of increasing LES pressure (0.78), followed by TIF (0.72) and PPIs (0.01). Patients who underwent the sham procedure had the highest probability for persistent esophagitis (0.74), followed by those receiving TIF (0.69), LNF (0.38), and PPIs (0.19). Meta-regression showed a shorter follow-up time as a significant confounder for the outcome of health-related quality of life in studies of TIF. CONCLUSIONS: In a systematic review and network meta-analysis of trials of patients with GERD, we found LNF to have the greatest ability to improve physiologic parameters of GERD, including increased LES pressure and decreased percent time pH <4. Although TIF produced the largest increase in health-related quality of life, this could be due to the shorter follow-up time of patients treated with TIF vs LNF or PPIs. TIF is a minimally invasive endoscopic procedure, yet based on evaluation of benefits vs risks, we do not recommend it as a long-term alternative to PPI or LNF treatment of GERD.

Bisphosphonates in multiple myeloma: an updated network meta-analysis.

BACKGROUND: Bisphosphonates are specific inhibitors of osteoclastic activity and are used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010 and 2012. OBJECTIVES: To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus non-aminobisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression-free survival (PFS), and decreases skeletal-related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate-related gastrointestinal toxicities, osteonecrosis of jaw (ONJ) and hypocalcemia. SEARCH METHODS: We searched MEDLINE, Embase (September 2011 to July 2017) and the CENTRAL (2017, Issue 7) to identify all randomized controlled trial (RCT) in MM up to July 2017 using a combination of text and MeSH terms. SELECTION CRITERIA: Any randomized controlled trial (RCT) comparing bisphosphonates versus placebo/no treatment/bisphosphonates and observational studies or case reports examining bisphosphonate-related ONJ in patients with MM were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) using a random-effects model. We used meta-regression to explore statistical heterogeneity. Network meta-analysis using Bayesian approach was conducted. MAIN RESULTS: In this update, we included four new studies (601 participants), resulting in a total of 24 included studies.Twenty RCTs compared bisphosphonates with either placebo or no treatment and four RCTs involved another bisphosphonate as a comparator. The 24 included RCTs enrolled 7293 participants. Pooled results showed that there was moderate-quality evidence of a reduction in mortality with on OS from 41% to 31%, but the confidence interval is consistent with a larger reduction and small increase in mortality compared with placebo or no treatment (HR 0.90, 95% CI 0.76 to 1.07; 14 studies; 2706 participants). There was substantial heterogeneity among the included RCTs (I2 = 65%) for OS. To explain this heterogeneity we performed a meta-regression assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate but limited evidence of an effect on PFS. This provided a further rationale for performing a network meta-analyses of the various types of bisphosphonates that were not compared head-to-head in RCTs. Results from network meta-analyses showed evidence of a benefit for OS with zoledronate compared with etidronate (HR 0.56, 95% CI 0.29 to 0.87) and placebo (HR 0.67, 95% CI 0.46 to 0.91). However, there was no evidence for a difference between zoledronate and other bisphosphonates.The effect of bisphosphonates on disease progression (PFS) is uncertain. Based on the HR of 0.75 (95% CI 0.57 to 1.00; seven studies; 908 participants), 47% participants would experience disease progression without treatment compared with between 30% and 47% with bisphosphonates (low-quality evidence). There is probably a similar risk of non-vertebral fractures between treatment groups (RR 1.03, 95% CI 0.68 to 1.56; six studies; 1389 participants; moderate-quality evidence). Pooled analysis demonstrated evidence for a difference favoring bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; seven studies; 1116 participants; moderate-quality evidence) and skeletal-related events (SREs) (RR 0.74, 95% CI 0.63 to 0.88; 10 studies; 2141 participants; moderate-quality evidence). The evidence for less pain with bisphosphonates was of very low quality (RR 0.75, 95% CI 0.60 to 0.95; eight studies; 1281 participants).Bisphosphonates may increase ONJ compared with placebo but the confidence interval is very wide (RR 4.61, 95% CI 0.99 to 21.35; P = 0.05; six studies; 1284 participants; low-quality evidence). The results from the network meta-analysis did not show any evidence for a difference in the incidence of ONJ (eight RCTs, 3746 participants) between bisphosphonates. Data from nine observational studies (1400 participants) reported an incidence of 5% to 51% with combination of pamidronate and zoledronate, 3% to 11% with zoledronate alone, and 0% to 18% with pamidronate alone.The pooled results showed no evidence for a difference in increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.59; seven studies; 1829 participants; low-quality evidence).The pooled results showed no evidence for a difference in increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74; three studies; 1090 participants; low-quality evidence). The results from network meta-analysis did not show any evidence for differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used. AUTHORS' CONCLUSIONS: Use of bisphosphonates in participants with MM reduces pathological vertebral fractures, SREs and pain. Bisphosphonates were associated with an increased risk of developing ONJ. For every 1000 participants treated with bisphosphonates, about one patient will suffer from the ONJ. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or non-aminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate was found to be better than placebo and first-generation bisposphonate (etidronate) in pooled direct and indirect analyses for improving OS and other outcomes such as vertebral fractures. Direct head-to-head trials of the second-generation bisphosphonates are needed to settle the issue if zoledronate is truly the most efficacious bisphosphonate currently used in practice.

Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: A systematic review and meta-analysis.

BACKGROUND: There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT. METHODS: Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis. FINDINGS: We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 × 10-10), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 × 10-36) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death. INTERPRETATION: Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom.

Levator Ani Muscle Defects in Patients With Surgical Failure.

INTRODUCTION: The objective of the study was to use a well-described system of measuring levator ani (LA) muscle defects from magnetic resonance images to evaluate whether major defects are correlated to an increased risk of surgical failure. METHODS: A retrospective cohort study performed on patients who underwent laparoscopic uterosacral ligament suspension from 2010 to 2012. Surgical failure was defined as a composite score of anatomic bulge beyond the hymen with sensation of bulge or repeat treatment of prolapse via pessary or surgery by 1-year follow-up. Levator ani muscle defects were graded by a score of 0 (no defect), 1 (<50% muscle bulk missing), 2 (>50% muscle bulk missing), or 3 (complete loss of muscle). Total score is the sum from both graded sides, with 0 classified as having no defect, 1 to 3 classified as having minor defects, and 4 to 6 classified as having major defects. Dichotomous values of LA major defects were compared against dichotomous values of surgical outcomes via a contingency table. Fisher exact test was then performed to correlate major defects to surgical success/failure. P value of less than 0.05 was considered statistically significant. RESULTS: Sixty-six women met the inclusion criteria. Thirteen (19.6%) patients met the criteria for surgical failure at 1 year. Of the 13, 54% (7) had a major defect, and 46% (6) had a minor or no defect (odds ratio, 1.31; 95% confidence interval, 0.39-4.41; P = 0.762). CONCLUSIONS: We did not find a statistical correlation to surgical failure after a laparoscopic uterosacral ligament suspension with LA muscle defects on preoperative magnetic resonance images within this specific patient population.

Eliciting regret improves decision making at the end of life.

INTRODUCTION: Management choices at the end of life are high-stake decisions fraught with emotions, chief among is regret. Our objective in this paper is to test the utility of a regret-based model to facilitate referral to hospice care while helping patients clarify their preferences on how they wish to spend the remaining days of their lives. METHODS: A prospective cohort study that enrolled consecutive adult patients (n = 178) aware of the terminal nature of their disease. The patients were at the point in care where they had to decide between continuing potentially 'curative/life-prolonging' treatment (Rx) versus hospice care. Preferences were elicited using a Dual Visual Analog Scale regarding the level of regret of omission versus commission (RgO/RgC) towards hospice care and Rx. Each patient's RgO/RgC was contrasted against the predictive probability of death to suggest a management plan, which was then compared with the patient's actual choice. The probability of death was estimated using validated Palliative Performance Scale predictive model. RESULTS: Eighty-five percent (151/178) of patients agreed with the model's recommendations (p < 0.000001). Model predicted the actual choices for 72% (128/178) of patients (p < 0.00001). Logistic regression analysis showed that people who were initially inclined to be referred to hospice and were predicted to choose hospice over disease-directed treatment by the regret model have close to 98% probability of choosing hospice care at the end of their lives. No other factors (age, gender, race, educational status and pain level) affected their choice. CONCLUSIONS: Using regret to elicit choices in the end-of-life setting is both descriptively and prescriptively valid. People with terminal disease who are initially inclined to choose hospice and do not regret such a choice will select hospice care with high level of certainty.

Nonfluorodeoxyglucose-Avid Persistent Splenomegaly at Time of Transplantation Delays Neutrophil and Platelets Engraftment without Affecting Survival in Patients with Lymphomas Undergoing Allogeneic Hematopoietic Cell Transplantation.

It is unclear if persistent splenomegaly in the presence of a negative positron emission tomography (PET) scan before allogeneic hematopoietic cell transplantation (HCT) influences post-transplantation outcomes in patients with lymphoma. We retrospectively reviewed records of 152 patients who underwent allogeneic HCT for various lymphomas. Centralized review of pretransplantation computed tomography (CT) and PET images was performed. Spleen volume (SV) was measured using the freehand volume segmentation tool in AW Workstation software (General Electric, Waukesha, WI). Splenic index (SI) was calculated as a product of width, thickness, and length of the spleen. Normal SV was defined as SV < 314.5 cm3 and normal SI was defined as SI ≤ 480 cm3, as described in the literature. Among the study population, 42.8% received an allogeneic HCT from an HLA-matched related donor, 36.2% from a matched unrelated donor, 12.5% from a mismatched unrelated donor, and 8.6% received a double umbilical cord blood transplantation. Most (61.8%) received myeloablative conditioning. Median age at transplantation was 52 (range, 21 to 68) years. Pre-allogeneic HCT spleen CT and PET images were available on 88% and 70.3% patients, respectively. SV ranged from 90 cm3 to 4684 cm3 with a median of 290.5 cm3 and a mean of 400.3 cm3. SI calculation showed a range from 50.3 cm3 to 8276.4 cm3 with a median of 582.1 cm3 and a mean of 771.2 cm3. The majority of patients (83.1%) had PET-negative spleen before allogeneic transplantation. Engraftment was delayed in PET-negative patients with persistent splenomegaly, with median days to neutrophil engraftment of 17 versus 16 (P = .03) and median days to platelet engraftment of 16 versus 14 (P = .04) when using SV. However, persistent splenomegaly did not appear to impact progression-free survival (P = .11) or overall survival (P = .37). Splenomegaly in the setting of a PET-negative study before allogeneic HCT delays neutrophil and platelet engraftment but does not appear to affect survival. Future studies using registry data or larger multicenter studies would be required to evaluate the impact of splenomegaly and its fluorodeoxyglucose avidity on allogeneic HCT outcomes in specific subtypes of lymphomas.

Examination of Broad Symptom Improvement Resulting From Mindfulness-Based Stress Reduction in Breast Cancer Survivors: A Randomized Controlled Trial.

PURPOSE: The purpose of this randomized trial was to evaluate the efficacy of the Mindfulness-Based Stress Reduction for Breast Cancer (MBSR[BC]) program in improving psychological and physical symptoms and quality of life among breast cancer survivors (BCSs) who completed treatment. Outcomes were assessed immediately after 6 weeks of MBSR(BC) training and 6 weeks later to test efficacy over an extended timeframe. PATIENTS AND METHODS: A total of 322 BCSs were randomly assigned to either a 6-week MBSR(BC) program (n = 155) or a usual care group (n = 167). Psychological (depression, anxiety, stress, and fear of recurrence) and physical symptoms (fatigue and pain) and quality of life (as related to health) were assessed at baseline and at 6 and 12 weeks. Linear mixed models were used to assess MBSR(BC) effects over time, and participant characteristics at baseline were also tested as moderators of MBSR(BC) effects. RESULTS: Results demonstrated extended improvement for the MBSR(BC) group compared with usual care in both psychological symptoms of anxiety, fear of recurrence overall, and fear of recurrence problems and physical symptoms of fatigue severity and fatigue interference (P < .01). Overall effect sizes were largest for fear of recurrence problems (d = 0.35) and fatigue severity (d = 0.27). Moderation effects showed BCSs with the highest levels of stress at baseline experienced the greatest benefit from MBSR(BC). CONCLUSION: The MBSR(BC) program significantly improved a broad range of symptoms among BCSs up to 6 weeks after MBSR(BC) training, with generally small to moderate overall effect sizes.

The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are commonly used to treat chemotherapy-induced anemia (CIA). However, about half of patients do not benefit. OBJECTIVES: To evaluate the benefits and harms related to the use of iron as a supplement to ESA and iron alone compared with ESA alone in the management of CIA. SEARCH METHODS: We searched for relevant trials from the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 1 January 2016), MEDLINE (1950 to February 2016), and www.clinicaltrials.gov without using any language limits. SELECTION CRITERIA: All randomized controlled trials (RCTs) comparing 'iron plus ESA' or 'iron alone' versus 'ESA alone' in people with CIA were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included eight RCTs (12 comparisons) comparing ESA plus iron versus ESA alone enrolling 2087 participants. We did not find any trial comparing iron alone versus ESAs alone in people with CIA. None of the included RCTs reported overall survival. There was a beneficial effect of iron supplementation to ESAs compared with ESAs alone on hematopoietic response (risk ratio (RR) 1.17, 95% confidence interval (CI) 1.09 to 1.26; P < 0.0001; 1712 participants; 11 comparisons; high-quality evidence). Assuming a baseline risk of 35% to 80% for hematopoietic response without iron supplementation, between seven and 16 patients should be treated to achieve hematopoietic response in one patient. In subgroup analyses, RCTs that used intravenous (IV) iron favored ESAs and iron (RR 1.20 (95% CI 1.10 to 1.31); P < 0.00001; 1321 participants; eight comparisons), whereas we found no evidence for a difference in hematopoietic response in RCTs using oral iron (RR 1.04 (95% CI 0.87 to 1.24); P = 0.68; 391 participants; three comparisons). There was no evidence for a difference between the subgroups of IV and oral iron (P = 0.16). There was no evidence for a difference between the subgroups of types of iron (P = 0.31) and types of ESAs (P = 0.16) for hematopoietic response.The iron supplementation to ESAs might be beneficial as fewer participants treated with iron supplementation required red blood cell (RBC) transfusions compared to the number of participants treated with ESAs alone (RR 0.74 (95% CI 0.60 to 0.92); P = 0.007; 1719 participants; 11 comparisons; moderate-quality evidence). Assuming a baseline risk of 7% to 40% for RBC transfusion without iron supplementation, between 10 and 57 patients should be treated to avoid RBC transfusion in one patient.We found no evidence for a difference in the median time to hematopoietic response with addition of iron to ESAs (hazard ratio (HR) 0.93 (95% CI 0.67 to 1.28); P = 0.65; 1042 participants; seven comparisons; low-quality evidence). In subgroup analyses, RCTs in which dextran (HR 0.95 (95% CI 0.36 to 2.52); P = 0.92; 340 participants; three comparisons), sucrose iron (HR 1.15 (95% CI 0.60 to 2.21); P = 0.67; 102 participants; one comparison) and sulfate iron (HR 1.24 (95% CI 0.99 to 1.56); P = 0.06; 55 participants; one comparison) were used showed no evidence for difference between iron supplementation versus ESAs alone compared with RCTs in which gluconate (HR 0.78 (95% CI 0.65 to 0.94); P = 0.01; 464 participants; two comparisons) was used for median time to hematopoietic response (P = 0.02). There was no evidence for a difference between the subgroups of route of iron administration (P = 0.13) and types of ESAs (P = 0.46) for median time to hematopoietic response.Our results indicated that there could be improvement in the hemoglobin (Hb) levels with addition of iron to ESAs (mean difference (MD) 0.48 (95% CI 0.10 to 0.86); P = 0.01; 827 participants; seven comparisons; low-quality evidence). In RCTs in which IV iron was used there was evidence for a difference (MD 0.84 (95% CI 0.21 to 1.46); P = 0.009; 436 participants; four comparisons) compared with oral iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) for mean change in Hb level (P = 0.03). RCTs in which dextran (MD 1.55 (95% CI 0.62 to 2.47); P = 0.001; 102 participants; two comparisons) was used showed evidence for a difference with iron supplementation versus ESAs alone compared with RCTs in which gluconate (MD 0.54 (95% CI -0.15 to 1.22); P = 0.12; 334 participants; two comparisons) and sulfate iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) were used for mean change in Hb level (P = 0.007). RCTs in which epoetin was used showed evidence for a difference with iron supplementation versus ESAs alone (MD 0.77 (95% CI 0.25 to 1.29); P = 0.004; 337 participants; five comparisons) compared with darbepoetin use (MD 0.10 (95% CI -0.13 to 0.33); P = 0.38; 490 participants; two comparisons) for mean change in Hb level (P = 0.02).We found no evidence for a difference in quality of life with addition of iron to ESAs (standardized mean difference 0.01 (95% CI -0.10 to 0.12); P = 0.88; 1124 participants; three RCTs; high-quality evidence).We found no evidence for a difference in risk of grade III-IV thromboembolic events (RR 0.95 (95% CI 0.54 to 1.65); P = 0.85; 783 participants; three RCTs; moderate-quality evidence). The incidence of treatment-related mortality (TRM) was 0% (997 participants; four comparisons; high-quality evidence).Other common adverse events included vomiting, asthenia, and leukopenia, and were similar in both arms.Overall the risk of bias across outcomes was high to low. Since the included RCTs had shorter follow-up duration (up to 20 weeks), the long-term effects of iron supplementation are unknown. Our main reasons for downgrading the quality of evidence were inconsistency across the included studies and imprecision of results. AUTHORS' CONCLUSIONS: Our systematic review shows that addition of iron to ESAs offers superior hematopoietic response, reduces the risk of RBC transfusions, and improves Hb levels, and appears to be well tolerated. None of the included RCTs reported overall survival. We found no evidence for a difference in quality of life with iron supplementation.

Association between Fellowship Training, Surgical Volume, and Laparoscopic Suturing Techniques among Members of the American Association of Gynecologic Laparoscopists.

Study Objective. To compare surgical volume and techniques including laparoscopic suturing among members of the American Association of Gynecologic Laparoscopists (AAGL) according to fellowship training status. Design. A web-based survey was designed using Qualtrics and sent to AAGL members. Results. Minimally invasive gynecologic surgery (FMIGS) trained surgeons were more likely to perform more than 8 major conventional laparoscopic cases per month (63% versus 38%, P < 0.001, OR [95% CI] = 2.78 [1.54-5.06]) and were more likely to perform laparoscopic suturing during these cases (32% versus 16%, P < 0.004, OR [95% CI] = 2.44 [1.25-4.71]). The non-fellowship trained (NFT) surgeons in private practice were less likely to perform over 8 conventional laparoscopic cases (34% versus 51%, P = 0.03, OR [95% CI] = 0.50 [0.25-0.99]) and laparoscopic suturing during these cases (13% versus 27%, P = 0.01, OR [95% CI] = 0.39 [0.17-0.92]) compared to NFT surgeons in academic practice. Conclusion. The surgical volume and utilization of laparoscopic suturing of FMIGS trained surgeons are significantly increased compared to NFT surgeons. Academic practice setting had a positive impact on surgical volume of NFT surgeons but not on FMIGS trained surgeons.

Estimated levator ani subtended volume: a novel assay for predicting surgical failure after uterosacral ligament suspension.

BACKGROUND: Levator ani muscle complex plays an important role in pelvic support and defects or laxity in this muscle complex contributes to pelvic organ prolapse and recurrence after surgical repair. OBJECTIVE: The purpose of this study was to determine whether estimated levator ani subtended volume can predict surgical outcomes for laparoscopic bilateral uterosacral ligament suspension. STUDY DESIGN: A retrospective cohort study was performed in patients who underwent laparoscopic uterosacral ligament suspension from 2010-2012. Only patients with a preoperative pelvic magnetic resonance image were included. Surgical failure was defined as a composite score that included the presence of anatomic bulge beyond the hymen with sensation of vaginal bulge or repeat treatment for prolapse via pessary or surgery by 1-year follow-up evaluation. Standard protocol pelvic magnetic resonance imaging measurements pubococcygeal line, H-line, and M-line were collected along with the calculation of the width of the levator ani hiatus. Estimated levator ani subtended volume was calculated for each subject. An optimal cutoff point was calculated and compared against categoric values of surgical success/failure. A Fisher exact test, an area under receiver operating characteristics curve, and logistic regression analysis were performed. A probability value of <.05 was considered statistically significant. RESULTS: Ninety-three women underwent laparoscopic bilateral uterosacral ligament suspension during study period. Of these, 66 women had a standardized preoperative pelvic magnetic resonance image per institutional protocol. Thirteen patients (19.6%) met the criteria for surgical failure by 1 year. An optimal cutoff point of 38.5 was calculated by Liu's method for optimization. Among the patients with defined surgical failures, 84.6% (11/13) had an estimated levator ani subtended volume above cutoff point of 38.5. Among the patients with defined surgical success, 39.6% (21/53) had an estimated levator ani subtended volume above the cutoff point (84.6% vs 39.6%; P = .0048) with a significant odds ratio of 8.38 (95% confidence interval, 1.69-41.68; P = .009). An area under receiver operating characteristics curve of 0.725 (95% confidence interval, 0.603-0.847), sensitivity of 84.6% (95% confidence interval, 54.6%-98.1%), and specificity of 60.4% (95% confidence interval, 46%-73.5%) at 38.5 were predictors of surgical success/failure by 1 year. Logistic regression analysis demonstrated no significant confounders among age, body mass index, stage, or parity. CONCLUSIONS: Estimated levator ani subtended volume may predict surgical failure for laparoscopic bilateral uterosacral ligament suspension. Patients with a calculated estimated levator ani subtended volume above 38.5 on a preoperative pelvic magnetic resonance imaging were associated with an increased risk for surgical failure by 1 year, regardless of age, body mass index, stage, or parity. Future investigation that will include repeatability, reliability analysis, and a prospective study is warranted.

Safety of Gastrointestinal Endoscopy With Conscious Sedation in Patients With and Without Obstructive Sleep Apnea.

BACKGROUND AND STUDY AIMS: Patients with obstructive sleep apnea (OSA) undergoing endoscopy with sedation are considered by practitioners to be at a higher risk for cardiopulmonary complications. The aim of the present study was to evaluate the safety of conscious sedation in patients with OSA undergoing gastrointestinal endoscopy. PATIENTS AND METHODS: This is an IRB-approved prospective cohort study performed at the James A. Haley VA. A total of 248 patients with confirmed moderate or severe OSA by polysomnography and 252 patients without OSA were enrolled. Cardiopulmonary variables such as heart rate, blood pressure, and level of blood oxygen saturation were recorded at 3-minute intervals throughout the endoscopic procedure. RESULTS: In total, 302 colonoscopies, 119 esophagogastroduodenoscopies, 6 flexible sigmoidoscopies, and 60 esophagogastroduodenoscopy/colonoscopies were performed. None of the patients in the study required endotracheal intubation, pharmacologic reversal, or experienced an adverse outcome as a result of changes in blood pressure, heart rate, or blood oxygen saturation. There were no significant differences in the rate of tachycardia (P=0.749), bradycardia (P=0.438), hypotension (systolic/diastolic, P=0.460; mean arterial pressure, P=0.571), or hypoxia (P=0.787) between groups. The average length of time spent in each procedure and the average dose of sedation administered also did not differ significantly between the groups. CONCLUSIONS: Despite the presumed increased risk of cardiopulmonary complications, patients with OSA who undergo endoscopy with conscious sedation have clinically insignificant variations in cardiopulmonary parameters that do not differ from those without OSA. Costly preventative measures in patients with OSA are not warranted.

Circulating long noncoding RNA GAS5 levels are correlated to prevalence of type 2 diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM), a metabolic disease, is characterized by impaired fasting glucose levels. Type 2 DM is adult onset diabetes. Long non-coding RNAs (lncRNAs) regulate gene expression and multiple studies have linked lncRNAs to human diseases. METHODS: Serum samples obtained from 96 participating veterans at JAH VA were deposited in the Research Biospecimen Repository. We used a two-stage strategy to identify an lncRNA whose levels correlated with T2DM. Initially we screened five serum samples from diabetic and non-diabetic individuals using lncRNA arrays. Next, GAS5 lncRNA levels were analyzed in 96 serum samples using quantitative PCR. Receiver operating characteristic (ROC) analysis was performed to determine the optimal cutoff GAS5 for diagnosis of DM. RESULTS: Our results demonstrate that decreased GAS5 levels in serum were associated with diabetes in a cohort of US military veterans. The ROC analysis revealed an optimal cutoff GAS5 value of less than or equal to 10. qPCR results indicated that individuals with absolute GAS5 < 10 ng/µl have almost twelve times higher odds of having diabetes (Exact Odds Ratio [OR] = 11.79 (95% CI: 3.97, 37.26), p < 0.001). Analysis indicated area under curve (AUC) of ROC of 0.81 with 85.1% sensitivity and 67.3% specificity in distinguishing non-diabetic from diabetic subjects. The positive predictive value is 71.4%. CONCLUSION: lncRNA GAS5 levels are correlated to prevalence of T2DM. GENERAL SIGNIFICANCE: Assessment of GAS5 in serum along with other parameters offers greater accuracy in identifying individuals at-risk for diabetes.

Association between obesity and the trends of routes of hysterectomy performed for benign indications.

OBJECTIVE: To estimate the association between obesity and the recent trends of routes chosen for hysterectomy performed for benign indications in the United States. MATERIALS AND METHODS: Using the American College of Surgeons-National Surgical Quality Improvement Project's database, patients who underwent hysterectomy for benign indications from 2005 to 2011 were identified by International Classification of Diseases, 9th Revision codes and were categorized into total abdominal hysterectomy (TAH), total vaginal hysterectomy (TVH), laparoscopically assisted vaginal hysterectomy (LAVH), and total laparoscopic hysterectomy (TLH). The patients were divided into four subgroups according to body mass index (BMI) (less than 25, 25-29.9, 30-39.9, and 40 or greater). The data were analyzed using Student's t test or χ2 and Fisher's exact test. RESULTS: A total of 18,810 patients underwent hysterectomy for benign indications during the study period: 9,852 (52.4%) were TAH, 5,146 (27.4%) TVH, 2,296 (12.2%) LAVH, and 1,516 (8.0%) TLH. The rates of TAH increased from 45.7% in patients with ideal body weight to 62% in morbidly obese patients (P<.001). The rate of TVH and LAVH decreased from 32.7% and 13.3% in patients with ideal body weight to 17.1% and 11.7% in morbidly obese patients, respectively (P<.001 and 0.04). The rate of TLH performed was independent of BMI (P=.61). Higher BMI was associated with longer operative time (P<.001) in all routes of hysterectomy. The rates of superficial and deep wound infections were higher with increasing BMI in patients undergoing TAH (P<.001) but not with TVH (P=.26), LAVH (P=1.0), or TLH (P=.48). CONCLUSION: Regarding hysterectomy performed for benign indications, increasing BMI was associated with increased rate of TAH and decreased rate of TVH and LAVH, but not the rate of TLH. Increasing BMI was associated with increased operative time for all subgroups and increased surgical site infection in the TAH group.