Discovery of Potent, Dual-Inhibitors of Diacylglycerol Kinases Alpha and Zeta Guided by Phenotypic Optimization.

We describe a phenotypic screening and optimization strategy to discover compounds that block intracellular checkpoint signaling in T-cells. We identified dual DGKα and ζ inhibitors notwithstanding the modest similarity between α and ζ relative to other DGK isoforms. Optimized compounds produced cytokine release and T-cell proliferation consistent with DGK inhibition and potentiated an immune response in human and mouse T-cells. Additionally, lead inhibitor BMS-502 demonstrated dose-dependent immune stimulation in the mouse OT-1 model, setting the stage for a drug discovery program.

Discovery of Orally Active Isofuranones as Potent, Selective Inhibitors of Hematopoetic Progenitor Kinase 1.

While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer.

Design, synthesis and SAR study of novel C2-pyrazolopyrimidine amides and amide isosteres as allosteric integrase inhibitors.

The design, synthesis and structure-activity relationships associated with a series of C2-substituted pyrazolopyrimidines as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) are described. Structural modifications to these molecules were made in order to examine the effect on potency and, for select compounds, pharmacokinetic properties. We examined a variety of C2-substituted pyrazolopyrimidines and found that the C2-amide derivatives demonstrated the most potent antiviral activity of this class against HIV-1 infection in cell culture.

Aspirin Use and Lethal Prostate Cancer in the Health Professionals Follow-up Study.

BACKGROUND: Aspirin use probably protects against some malignancies but its effects on lethal prostate cancer (PC) are unclear. OBJECTIVE: To investigate the association between regular aspirin use and lethal PC. DESIGN, SETTING, AND PARTICIPANTS: Participants were aged 40-75 yr at baseline in 1986 and have been followed with biennial questionnaires. The risk analysis includes 49 409 men. The survival analysis includes 5980 PC patients without metastatic disease at diagnosis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used Cox proportional hazards regression to examine the association between current, past, or never regular aspirin use (≥2 d/wk) in relation to lethal (metastatic or fatal) PC. We also examined years of use among current users and years since stopping among past users. In the risk analysis, aspirin was updated throughout follow-up. In the survival analysis, aspirin use after diagnosis was assessed. RESULTS AND LIMITATIONS: Some 29% of participants used aspirin regularly at baseline, which increased to 60% by 2010. In the risk analysis, 804 men were diagnosed with lethal PC. Current regular aspirin was associated with a lower risk of lethal prostate cancer (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.66-0.96) compared to never users. In the survival analysis, 451 of the men diagnosed with nonmetastatic PC later developed lethal disease. Current postdiagnostic aspirin was associated with a lower risk of lethal PC (HR 0.80, 95% CI 0.64-1.00) and overall mortality (HR 0.79, 95% CI 0.69-0.90). When restricted to highly screened men, the risk analysis associations were stronger and survival analysis associations remained statistically significant. Reverse causation and residual confounding remain concerns, as demonstrated by the attenuated results in sensitivity analyses. CONCLUSIONS: Regular aspirin use was associated with a lower risk of lethal PC. Postdiagnostic use was associated with better survival after diagnosis. PATIENT SUMMARY: We found that it may be advisable for prostate cancer patients to take aspirin to improve their survival for both prostate cancer mortality and other mortality outcomes.

5,6,7,8-Tetrahydro-1,6-naphthyridine Derivatives as Potent HIV-1-Integrase-Allosteric-Site Inhibitors.

A series of 5,6,7,8-tetrahydro-1,6-naphthyridine derivatives targeting the allosteric lens-epithelium-derived-growth-factor-p75 (LEDGF/p75)-binding site on HIV-1 integrase, an attractive target for antiviral chemotherapy, was prepared and screened for activity against HIV-1 infection in cell culture. Small molecules that bind within the LEDGF/p75-binding site promote aberrant multimerization of the integrase enzyme and are of significant interest as HIV-1-replication inhibitors. Structure-activity-relationship studies and rat pharmacokinetic studies of lead compounds are presented.

High-Intensity Focused Ultrasound (HIFU) as salvage therapy for radio-recurrent prostate cancer: predictors of disease response

ABSTRACT Background Some men with localized radio-recurrent prostate cancer may benefit from salvage high-intensity focused ultrasound (HIFU). Herein, we describe oncologic outcomes and predictors of disease response after salvage whole gland HIFU from our prospective cohort. Materials and Methods Patients with localized radio-recurrent prostate cancer were prospectively enrolled from January 2005 to December 2014. Participants had to meet both biochemical and histological definitions of recurrence. Exclusion criteria included the receipt of prior salvage therapy, presence of metastatic disease, and administration of ADT in the 6-months prior to enrollment. Participants were treated with a single session of whole-gland HIFU ablation with the AblathermTM device (EDAP, France). The primary endpoint was recurrence-free survival (RFS), defined as a composite endpoint of PSA progression (Phoenix criteria), receipt of any further salvage therapy, receipt of ADT, clinical progression, or death. Kaplan-Meier survival analysis was used to determine the primary end-point and stratifications were used to determine the significance of 6 pre-specified predictors of improved RFS (TRUS biopsy grade, number of study entry TRUS biopsy cores positive, palpable disease at study enrollment, pre-HIFU PSA, an undetectable post-HIFU PSA nadir, and receipt of prior hormone therapy). Survival analysis was performed on participants with a minimum of 1-year follow-up. Results Twenty-four participants were eligible for study inclusion with a median follow-up of 31.0 months. Median PSA at study entry was 4.02ng/ml. Median time to PSA nadir was 3 months after treatment and median post-HIFU PSA nadir was 0.04ng/ml. Median 2-year and 5-year RFS was 66.3% and 51.6% respectively. Of our 6 prespecified predictors, an undetectable PSA nadir was the only significant predictor of improved RFS (HR 0.07, 95% CI 0.02-0.29, log-rank P<0.001). One participant underwent an intervention for a urethral stricture. No participants developed osteitis pubis or rectourethral fistulae. Conclusions Salvage HIFU allows for disease control in selected patients with localized radio-recurrent prostate cancer. An undetectable PSA nadir serves as an early predictor of disease response.

Prostate cancer screening among family physicians in Ontario: An update on attitudes and current practice.

INTRODUCTION: This study serves as an update of prostate cancer screening practices among family physicians in Ontario, Canada. Since this population was first surveyed in 2010, the Canadian Task Force on Preventive Health Care (CTFPHC) and the United States Preventive Services Task Force (USPSTF) released recommendations against prostate cancer screening. METHODS: An online survey was developed through input from urologists and family practitioners. It was distributed via email to all members of the Ontario Medical Association's Section on General and Family practice (11 657 family physicians). A reminder email was sent at two weeks and the survey remained active for one month. RESULTS: A total of 1880 family physicians completed surveys (response rate 16.1%). Overall, 80.4% offered prostate cancer screening compared to 91.7% when surveyed in 2010. Physicians new to practice (two years or less) were the most likely to not offer screening (24.6%). A combination of digital rectal exam (DRE) and prostate-specific antigen (PSA) remained the most common form of screening (58.3%). Following the release of the CTFPHC recommendations, 45.6% of respondents said they now screen fewer patients. Participants were less familiar with national urological society guidelines compared to task force recommendations. The majority (72.6%) of respondents feel PSA screening leads to overdiagnosis and treatment. Those surveyed remained split with respect to PSA utility. CONCLUSIONS: Data suggest a decline in screening practices since 2010, with newer graduates less likely to offer screening. CFTPHC and USPSTF recommendations had the greatest impact on clinical practice. Those surveyed were divided with respect to PSA utility. Some additional considerations to PSA screening in the primary care setting, including patient-driven factors, were not captured by our concise survey.

High-intensity Focused Ultrasound (HIFU) as salvage therapy for radio-recurrent prostate cancer: predictors of disease response.

BACKGROUND: Some men with localized radio-recurrent prostate cancer may benefit from salvage high-intensity focused ultrasound (HIFU). Herein, we describe oncologic outcomes and predictors of disease response after salvage whole gland HIFU from our prospective cohort. MATERIALS AND METHODS: Patients with localized radio-recurrent prostate cancer were prospectively enrolled from January 2005 to December 2014. Participants had to meet both biochemical and histological definitions of recurrence. Exclusion criteria included the receipt of prior salvage therapy, presence of metastatic disease, and administration of ADT in the 6-months prior to enrollment. Participants were treated with a single session of whole-gland HIFU ablation with the AblathermTM device (EDAP, France). The primary endpoint was recurrence-free survival (RFS), defined as a composite endpoint of PSA progression (Phoenix criteria), receipt of any further salvage therapy, receipt of ADT, clinical progression, or death. Kaplan-Meier survival analysis was used to determine the primary end-point and stratifications were used to determine the significance of 6 pre-specified predictors of improved RFS (TRUS biopsy grade, number of study entry TRUS biopsy cores positive, palpable disease at study enrollment, pre-HIFU PSA, an undetectable post-HIFU PSA nadir, and receipt of prior hormone therapy). Survival analysis was performed on participants with a minimum of 1-year follow-up. RESULTS: Twenty-four participants were eligible for study inclusion with a median follow-up of 31.0 months. Median PSA at study entry was 4.02ng/ml. Median time to PSA nadir was 3 months after treatment and median post-HIFU PSA nadir was 0.04ng/ ml. Median 2-year and 5-year RFS was 66.3% and 51.6% respectively. Of our 6 pre-specified predictors, an undetectable PSA nadir was the only significant predictor of improved RFS (HR 0.07, 95% CI 0.02-0.29, log-rank P<0.001). One participant underwent an intervention for a urethral stricture. No participants developed osteitis pubis or rectourethral fistulae. CONCLUSIONS: Salvage HIFU allows for disease control in selected patients with localized radio-recurrent prostate cancer. An undetectable PSA nadir serves as an early predictor of disease response.

Management of pelvic fracture-associated urethral injuries: A survey of Canadian urologists.

INTRODUCTION: The management of pelvic fracture-associated urethral injuries (PFUI) is not standardized and optimal management is controversial. We surveyed Canadian urologists about their experiences and opinions regarding optimal management of PFUI. METHODS: Canadian urologists were surveyed via an anonymous, bilingual, web-based, 12-item questionnaire. A total of 735 Canadian urologists were invited to participate via email distributed by the Canadian Urological Association. RESULTS: Of the 146 urologists who participated (19.9% response rate), the majority practice at a trauma centre (53.2%), but manage only 1-5 PFUI/year (71.5%). Most participants (82.6%) favour primary realignment compared to suprapubic (SP) tube with delayed repair (15.3%) and immediate reconstruction (2.1%). Compared to SP diversion and delayed repair, the majority of participants believe primary realignment is associated with equivocal incontinence (61.2%) and erectile dysfunction rates (75.8%), but has lower stricture rates (73.0%). Among respondents who perform primary realignment, 45.4% concurrently place a SP tube, while 54.6% do not. While 91% believe SP tubes do not increase the risk of pelvic hardware infections, 31.6% report that orthopedic surgeons alter their management of pelvic fractures in the presence of a SP tube. CONCLUSIONS: Most Canadian urologist respondents - even those practicing at trauma centres - manage very few PFUIs/year. There is reasonable consensus among respondents that primary realignment is favourable to delayed or immediate reconstruction, but discordance on whether or not to place concurrent SP tubes. The urological and orthopedic consequences of SP tubes in the management of traumatic urological injuries warrant further investigation.

Pathologic correlation of transperineal in-bore 3-Tesla magnetic resonance imaging-guided prostate biopsy samples with radical prostatectomy specimen.

PURPOSE: To determine the accuracy of in-bore transperineal 3-Tesla (T) magnetic resonance (MR) imaging-guided prostate biopsies for predicting final Gleason grades in patients who subsequently underwent radical prostatectomy (RP). METHODS: A retrospective review of men who underwent transperineal MR imaging-guided prostate biopsy (tpMRGB) with subsequent radical prostatectomy within 1 year was conducted from 2010 to 2015. All patients underwent a baseline 3-T multiparametric MRI (mpMRI) with endorectal coil and were selected for biopsy based on MR findings of a suspicious prostate lesion and high degree of clinical suspicion for cancer. Spearman correlation was performed to assess concordance between tpMRGB and final RP pathology among patients with and without previous transrectal ultrasound (TRUS)-guided biopsies. RESULTS: A total of 24 men met all eligibility requirements, with a median age of 65 years (interquartile range [IQR] 11.7). The median time from biopsy to RP was 85 days (IQR 50.5). Final pathology revealed Gleason 3 + 4 = 7 in 12 patients, 4 + 3 = 7 in 10 patients, and 4 + 4 = 8 in 2 patients. A strong correlation (ρ: +0.75, p < 0.001) between tpMRGB and RP results was observed, with Gleason scores concordant in 17 cases (71%). 16 of the 24 patients underwent prior TRUS biopsies. Subsequent tpMRGB revealed Gleason upgrading in 88% of cases, which was concordant with RP Gleason scores in 69% of cases (ρ: +0.75, p < 0.001). CONCLUSION: Final Gleason scores diagnosed by tpMRGB at 3-T correlate strongly with final RP surgical pathology. This may facilitate prostate cancer diagnosis, particularly in patients with negative or low-grade TRUS biopsy results in whom clinically significant cancer is suspected or detected on mpMRI.

Regular Aspirin Use and the Risk of Lethal Prostate Cancer in the Physicians' Health Study.

BACKGROUND: Regular aspirin use probably protects against some malignancies including prostate cancer (PC), but its impact on lethal PC is particularly unclear. OBJECTIVE: To investigate the association between regular aspirin and (1) the risk of lethal PC in a large prospective cohort and (2) survival after PC diagnosis. DESIGN, SETTING, AND PARTICIPANTS: In 1981/82, the Physicians' Health Study randomized 22 071 healthy male physicians to aspirin, ß-carotene, both, or placebo. After the trial ended in 1988, annual questionnaires have obtained data on aspirin use, cancer diagnoses, and outcomes up to 2009 for the whole cohort, and to 2015 for PC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated the relationship between regular aspirin (>3 tablets/week) and lethal PC (metastases or PC death). Cox proportional-hazards models estimated hazard ratios (HRs) for the risk of lethal PC in the whole cohort and postdiagnosis survival among men initially diagnosed with nonlethal PC. RESULTS AND LIMITATIONS: Risk analysis revealed that 502 men developed lethal PC by 2009. Current and past regular aspirin was associated with a lower risk of lethal PC (current: HR 0.68, 95% confidence interval [CI] 0.52-0.89; past: HR 0.54, 95% CI 0.40-0.74) compared to never users. In the survival analysis, 407/3277 men diagnosed with nonlethal PC developed lethal disease by 2015. Current postdiagnostic aspirin was associated with lower risks of lethal PC (HR 0.68, 95% CI 0.52-0.90) and overall mortality (HR 0.72, 95% CI 0.61-0.9). We could not assess aspirin dose, and inconsistencies were observed in some sensitivity analyses. CONCLUSIONS: Current regular aspirin use was associated with a lower risk of lethal PC among all participants. Current postdiagnostic use was associated with improved survival after diagnosis, consistent with a potential inhibitory effect of aspirin on PC progression. A randomized trial is warranted to confirm or refute these findings. PATIENT SUMMARY: We examined the potential effect of regular aspirin use on lethal prostate cancer. We found that taking aspirin was associated with a lower risk of lethal prostate cancer, and taking it after diagnosis may help to prevent prostate cancer from becoming fatal.

A prospective evaluation of obesometric parameters associated with renal stone recurrence.

INTRODUCTION: Our aim was to evaluate whether obesometric serum hormones and body fat distribution are associated with renal stone recurrence. METHODS: We conducted a prospective cohort study of participants undergoing renal stone (RS) intervention at a single institution from November 2009-June 2010 and followed them for a median 62 months. Obesometric parameters were measured at baseline, including body mass index (BMI), fasting serum leptin and adiponectin, and proportion of visceral adipose tissue (%VAT) averaged from three fixed axial computed tomography (CT) slices. The primary study outcome was stone recurrence. RESULTS: A total of 110 participants were enrolled. Elevated %VAT was associated RS recurrence; participants with %VAT in the highest quartile had a five-year stone-free rate of 47.1% compared to 72.2% among other participants (p=0.004). Adjusting for gender, elevated %VAT was independently predictive of renal stone recurrence among initial stone formers (n=74; hazard ratio [HR] 4.53, 95% confidence interval [CI] 1.08-19.02), but not among recurrent stone formers (n=19; HR 0.51, 95% CI 0.054-4.72). Other obesometric factors, including leptin, adiponectin, and BMI, were not significantly predictive of recurrence. CONCLUSIONS: We report a novel association between an elevated %VAT and stone recurrence. These findings may inform patient counselling and followup regimens. The metabolic basis for these findings requires further investigation.

Data on Medicare eligibility and cancer screening utilization.

Health insurance is associated with increased utilization of cancer screening services. Data on breast, prostate and colorectal cancer screening were abstracted from the 2012 Behavioral Risk Factor and Surveillance System. This data in brief includes two sets of analyses: (i) the use of cancer screening in individuals within the low-income bracket and (ii) determinants for each of the three approaches to colorectal cancer screening (fecal occult blood test, colonoscopy and sigmoidoscopy+fecal occult blood test). Covariates included education attainment, residency, and access to health care provider. The data supplement our original research article on the effect of Medicare eligibility on cancer screening utilization "The impact of Medicare eligibility on cancer screening behaviors" [1].

Impact of resident involvement in endoscopic bladder cancer surgery on pathological outcomes.

OBJECTIVE: Transurethral resection of bladder tumor (TURBT) pathology specimens which lack muscle are associated with clinical upstaging and may necessitate repeat resections, potentially delaying curative treatment. This study evaluated whether resident involvement in TURBT is associated with suboptimal perioperative outcomes. MATERIALS AND METHODS: All TURBTs performed at a Canadian healthcare institution from November 2011 to June 2014 were reviewed. Multivariable logistic regression models assessed associations between intraoperative resident involvement and TURBT muscle presence. Among high-risk patients (high grade, ≥ T1 or carcinoma in situ) who underwent cystectomy, time from TURBT to cystectomy was compared between resident and attending urologists with the log-rank test. RESULTS: In total, 463 TURBTs were identified. In multivariable analyses, residents were less likely to obtain muscle in specimens for all TURBTs [adjusted odds ratio (aOR) 0.59, p = 0.03] and the subset of 275 high-risk TURBTs (aOR 0.41, p = 0.006). Among patients who underwent cystectomy, time to cystectomy was delayed by a median of 23 days when residents were involved in the initial high-risk TURBT compared with attending urologists only (p = 0.024). CONCLUSIONS: In this single academic center series, intraoperative resident involvement was associated with a decreased rate of muscle presence in TURBT specimens and a prolonged time to cystectomy.

Transurethral Resection of the Prostate Biopsy of Suspected Anterior Prostate Cancers Identified by Multiparametric Magnetic Resonance Imaging: A Pilot Study of a Novel Technique.

OBJECTIVE: To describe a novel biopsy technique that involves performing a cognitively directed transurethral resection of the prostate (TURP) to diagnose suspected anterior prostate cancers (APCs) detected by multiparametric magnetic resonance imaging (mpMRI) in patients with prior negative transrectal ultrasound (TRUS)-guided biopsies. METHODS: This is a prospective study in which participants aged 50-75 were offered inclusion if they had an elevated prostate-specific antigen level, a lesion suspicious for APC on mpMRI, and at least one prior negative TRUS-guided prostate biopsy. Prostatic mpMRI was acquired with a 3-Tesla machine without endorectal coil. Preoperative review of the mpMRI images was used to target the suspected APC on TURP biopsy. The primary outcome was the detection rate of clinically significant prostate cancer, defined as the presence of any Gleason pattern ≥ 4 in the specimen. Secondary outcomes included biopsy-related complications including 30-day readmissions. RESULTS: A total of 16 consecutive participants were enrolled. Median age was 64 years, median prostate-specific antigen was 12.4 ng/mL, and participants had a median of 2 prior negative TRUS-guided biopsies. Thirteen (81.3%) participants had clinically significant APCs detected by TURP biopsy. One participant was readmitted within 30-days postprocedure for continuous bladder irrigation. Seven participants (43.8%) underwent radical prostatectomy that confirmed clinically significant disease in all 7 participants. CONCLUSION: Among participants with anterior prostate lesions on mpMRI and prior negative TRUS-guided biopsy, TURP biopsy does detect some clinically significant cancers. This study serves as a proof of concept and further comparative trials are needed prior to widespread adoption.

Primary genitourinary melanoma: Epidemiology and disease-specific survival in a large population-based cohort.

BACKGROUND: Primary genitourinary (GU) melanoma is a rare disease, which is poorly characterized. OBJECTIVE: To examine clinical characteristics and survival outcomes of primary GU melanoma among men and women. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study using the Surveillance, Epidemiology, and End Results database (1973-2010) was used to identify primary GU melanoma cases by tumor site and histology codes. We examined associations of GU melanoma with demographic, clinical, and pathologic characteristics, as well as disease-specific survival (DSS). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: DSS was calculated using the Kaplan-Meier method. Cox-proportional hazard models were used to calculate hazard ratios and 95% CI for factors associated with worse DSS. RESULTS AND LIMITATIONS: A total of 1,586 histologically confirmed cases of primary GU melanoma were identified with a median age of 66.1 years (IQR: 55-80). Incidence of primary GU melanoma was 0.2cases/million among men and 1.80cases/million among women. Overall, 60.1% of patients had localized disease at presentation and 90.5% of patients had cancer-directed surgery. Patients with urothelial melanoma had the worst 5- and 10-year DSS (39% and 29%, respectively). Women with vulvar/vaginal melanoma had worse 5- and 10-year DSS compared to men with penile/scrotal melanoma. In multivariate analysis, decreased survival was associated with increasing age, distant stage, and lymph node involvement. Results are limited by the lack of standardized staging for primary GU melanoma and the retrospective design of our study. CONCLUSIONS: Patients with primary GU melanoma present with advanced stage and have a poor prognosis. Women have worse DSS compared to men. DSS is negatively associated with advanced age at diagnosis, higher stage, and lymph node involvement. PATIENT SUMMARY: Clinicians and patients must be aware of the poor disease-specific outcomes associated with primary GU melanoma. Most importantly, women fare worse than men and mucosal melanomas have worse outcomes compared to cutaneous melanomas.

The impact of Medicare eligibility on cancer screening behaviors.

INTRODUCTION: Lack of health insurance limits access to preventive services, including cancer screening. We examined the effects of Medicare eligibility on the appropriate use of cancer screening services in the United States. METHODS: We performed a cross-sectional analysis of the 2012 Behavioral Risk Factor and Surveillance System (analyzed in 2014). Univariable and logistic regression analyses were performed for participants aged 60-64 and 66-70 to examine the effects of Medicare eligibility on prevalence of self-reported screening for colorectal, breast, and prostate cancers. Sub-analyses were performed among low-income (<$25,000 annual/household) individuals. RESULTS: Medicare-eligible individuals were significantly more likely to undergo all examined preventive services (colorectal cancer OR: 1.90; 95% CI 1.79-2.04; prostate cancer OR: 1.29; 95% CI 1.17-1.43; breast cancer OR: 1.23; 95% CI 1.10-1.37) and the effect was most pronounced among low-income individuals (colorectal cancer OR: 2.04; 95% CI 1.8-2.32; prostate cancer OR: 1.39; 95% CI 1.12-1.72; breast cancer OR: 1.42, 95% CI 1.20-1.67). Access to a healthcare provider was the strongest independent predictor of undergoing appropriate screening, ranging from OR 2.73 (95% CI 2.20-3.39) for colorectal cancer screening in the low-income population to OR 4.79 (95% CI 3.95-5.81) for breast cancer screening in the overall cohort. The difference in screening prevalence was most pronounced when comparing Medicare-eligible participants to uninsured Medicare-ineligible participants (+33.2%). CONCLUSIONS: Medicare eligibility impacts the prevalence of cancer screening, likely as a result of increased access to primary care. Low-income individuals benefit most from Medicare eligibility. Expanded public insurance coverage to these individuals may improve access to preventive services.

Trends in utilisation, perioperative outcomes, and costs of nephroureterectomies in the management of upper tract urothelial carcinoma: a 10-year population-based analysis.

OBJECTIVE: To perform a population-based study to evaluate contemporary utilisation trends, morbidity, and costs associated with nephroureterectomies (NUs), as contemporary data for NUs are largely derived from single academic institution series describing the experience of high-volume surgeons and it is unclear if the same favourable results occur at a national level. PATIENTS AND METHODS: Using the Premier Hospital Database, we captured patients undergoing a NU with diagnoses of renal pelvis or ureteric neoplasms from 2004 to 2013. We fitted regression models, adjusting for clustering by hospitals and survey weighting to evaluate 90-day postoperative complications, operating-room time (OT), prolonged length of stay (pLOS), and direct hospital costs among open (ONU), laparoscopic (LNU) and robotic (RNU) approaches. RESULTS: After applying sampling and propensity weights, we derived a final study cohort of 17 254 ONUs, 13 317 LNUs and 3774 RNUs for upper tract urothelial carcinoma (UTUC) in the USA between 2004 and 2013. During that period, minimally invasive NU (miNU) increased from 36% to 54%, while the total number of NUs decreased by nearly 20%. No differences were noted in perioperative outcomes between the three surgical approaches, including when the analysis was restricted to the highest-volume hospitals and highest-volume surgeons. The OT was longer for LNU and RNU (P < 0.001), while the pLOS rates were decreased (P < 0.001). Adjusted 90-day median direct hospital costs were higher for LNU and RNU (P < 0.001), which disappeared when adjusting for the highest-volume groups, except for RNUs performed by high-volume surgeons. CONCLUSIONS: During this contemporary 10-year study, miNU has been replacing ONU for UTUC with a recent surge in RNU, along with a concurrent reduction in total NUs performed. Despite not being associated with a clinically significant improvement in perioperative outcomes, the costs for miNUs were consistently higher. However, higher hospital volumes suggest a potential cost containment strategy when performing miNUs.

The Contemporary Incidence and Sequelae of Rhabdomyolysis Following Extirpative Renal Surgery: A Population Based Analysis.

PURPOSE: We evaluate the contemporary incidence and consequences of postoperative rhabdomyolysis after extirpative renal surgery. MATERIALS AND METHODS: We conducted a population based, retrospective cohort study of patients who underwent extirpative renal surgery with a diagnosis of a renal mass or renal cell carcinoma in the United States between 2004 and 2013. Regression analysis was performed to evaluate 90-day mortality (Clavien grade V), nonfatal major complications (Clavien grade III-IV), hospital readmission rates, direct costs and length of stay. RESULTS: The final weighted cohort included 310,880 open, 174,283 laparoscopic and 69,880 robotic extirpative renal surgery cases during the 10-year study period, with 745 (0.001%) experiencing postoperative rhabdomyolysis. The presence of postoperative rhabdomyolysis led to a significantly higher incidence of 90-day nonfatal major complications (34.7% vs 7.3%, p <0.05) and higher 90-day mortality (4.4% vs 1.02%, p <0.05). Length of stay was twice as long for patients with postoperative rhabdomyolysis (incidence risk ratio 1.83, 95% CI 1.56-2.15, p <0.001). The robotic approach was associated with a higher likelihood of postoperative rhabdomyolysis (vs laparoscopic approach, OR 2.43, p <0.05). Adjusted 90-day median direct hospital costs were USD 7,515 higher for patients with postoperative rhabdomyolysis (p <0.001). Our model revealed that the combination of obesity and prolonged surgery (more than 5 hours) was associated with a higher likelihood of postoperative rhabdomyolysis developing. CONCLUSIONS: Our study confirms that postoperative rhabdomyolysis is an uncommon complication among patients undergoing extirpative renal surgery, but has a potentially detrimental impact on surgical morbidity, mortality and costs. Male gender, comorbidities, obesity, prolonged surgery (more than 5 hours) and a robotic approach appear to place patients at higher risk for postoperative rhabdomyolysis.