Comparison of Hospitals Affiliated With PPS-Exempt Cancer Centers, Other Hospitals Affiliated With NCI-Designated Cancer Centers, and Other Hospitals That Provide Cancer Care.

IMPORTANCE: Congress has exempted 11 specialized cancer centers in the United States from the Prospective Payment System (PPS). These centers are also exempt from reporting many of the process-of-care and outcome measures to the Centers for Medicare & Medicaid Services that are required for hospitals in the PPS. It is not known how hospitals affiliated with PPS-exempt cancer centers differ from other hospitals affiliated with National Cancer Institute cancer centers (NCI-CCs) or other US hospitals that provide cancer care. OBJECTIVE: To examine differences between hospitals affiliated with PPS-exempt cancer centers, other hospitals affiliated with NCI-CCs, and other hospitals that provide cancer care on metrics that could be used in public reporting. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study compared hospital characteristics and cancer-related services using data from the American Hospital Association Annual Survey and US News Best Hospitals rankings. With a 100% sample of Medicare beneficiaries who underwent 1 of 9 cancer operations (brain tumor resection, colorectal resection, cystectomy, esophagectomy, gastrectomy, liver resection, lung resection, pancreatic resection, prostatectomy) from January 1, 2011, to May 31, 2015, we used hierarchical logistic regression methods to compare differences in 18 postoperative outcomes. Data analysis was conducted from February 2018 to August 2018. MAIN OUTCOMES AND MEASURES: This study evaluated hospital characteristics, including cancer-specific services, patient comorbidity burden, and cancer surgery postoperative outcomes, from PPS-exempt cancer centers, NCI-affiliated cancer centers, and other US hospitals that provide cancer care. RESULTS: Hospitals affiliated with PPS-exempt cancer centers (n = 15) and NCI-CCs (n = 54) were similar in hospital characteristics, basic cancer-related services, and patient comorbidity burden. Compared with NCI-CCs, PPS-exempt cancer centers had significantly higher US News reputation scores (mean [SD], 17.5 [24.0] vs 2.6 [4.8]; P < .001) but no differences in oncology patient volume, patient safety ratings, comorbidity burden, nurse staffing, US News total cancer scores, or US News survival scores. Hospitals affiliated with PPS-exempt cancer centers and NCI-CCs had similar adjusted postoperative outcomes for 15 of 18 measures, including mortality, readmission, and surgical site infections. Compared with hospitals affiliated with PPS-exempt cancer centers, patients treated at NCI-CCs were more likely to have postoperative sepsis (3.1% vs 1.7%; P = .002), acute renal failure (6.2% vs 3.9%; P = .01), and urinary tract infection (6.4% vs 4.0%; P = .002). Compared with the other hospitals that provide cancer care (n = 3578), PPS-exempt cancer center status was associated with improved outcomes for 7 of 18 measures, including mortality, sepsis, acute renal failure, pulmonary failure, and failure to rescue. CONCLUSIONS AND RELEVANCE: Hospitals affiliated with PPS-exempt cancer centers and NCI-CCs had generally similar hospital characteristics, patient comorbidity burden, and cancer surgery outcomes. These findings raise questions about why some cancer centers are designated as PPS-exempt and why most hospitals are not required to publicly report cancer-specific quality metrics.

Evaluation of readmissions due to surgical site infections: A potential target for quality improvement.

INTRODUCTION: Readmissions have become a focus of pay-for-performance programs. Surgical site infections (SSI) are the reason for most readmissions. Readmissions for SSI could be a unique target for quality improvement. METHODS: Readmission risk for SSI were evaluated for patients undergoing colectomies from 2013 to 2014. Hazard models were developed to examine factors associated with and hospital-level variation in risk-adjusted rates of readmission for SSI. RESULTS: Among 59,088 patients at 525 hospitals, the rate of readmissions for SSI ranged from 1.45% to 6.34%. Characteristics associated with a greater likelihood of SSI readmissions include male gender, smoking, open surgery and hospitals with increased socioeconomically-disadvantaged patients. After risk adjustment, there was little correlation between hospital performance with SSI readmission rate and performance with overall SSI or total readmission rate (r2 = 0.29, r2 = 0.14). CONCLUSIONS: Readmission for SSI represents a unique aspect of quality beyond that offered by measuring only SSI or readmission rates alone, and may provide actionable quality improvement.

Relationship Between State Malpractice Environment and Quality of Health Care in the United States.

BACKGROUND: One major intent of the medical malpractice system in the United States is to deter negligent care and to create incentives for delivering high-quality health care. A study was conducted to assess whether state-level measures of malpractice risk were associated with hospital quality and patient safety. METHODS: In an observational study of short-term, acute-care general hospitals in the United States that publicly reported in the Centers for Medicaid & Medicare Services Hospital Compare in 2011, hierarchical regression models were used to estimate associations between state-specific malpractice environment measures (rates of paid claims, average Medicare Malpractice Geographic Practice Cost Index [MGPCI], absence of tort reform laws, and a composite measure) and measures of hospital quality (processes of care, imaging utilization, 30-day mortality and readmission, Agency for Healthcare Research and Quality Patient Safety Indicators, and patient experience from the Hospital Consumer Assessment of Healthcare Providers and Systems [HCAHPS]). RESULTS: No consistent association between malpractice environment and hospital process-of-care measures was found. Hospitals in areas with a higher MGPCI were associated with lower adjusted odds of magnetic resonance imaging overutilization for lower back pain but greater adjusted odds of overutilization of cardiac stress testing and brain/sinus computed tomography (CT) scans. The MGPCI was negatively associated with 30-day mortality measures but positively associated with 30-day readmission measures. Measures of malpractice risk were also negatively associated with HCAHPS measures of patient experience. CONCLUSIONS: Overall, little evidence was found that greater malpractice risk improves adherence to recommended clinical standards of care, but some evidence was found that malpractice risk may encourage defensive medicine.

Dipstick Urinalysis as a Test for Microhematuria and Occult Bladder Cancer.

Introduction: There is a lack of evidence supporting the routine use of laboratory tests to detect bladder cancer. Identifying a cost-effective and widely available diagnostic aid may improve bladder cancer outcomes. We sought to evaluate the utility of dipstick urinalysis to detect microhematuria and diagnose bladder cancer in a large, diverse, contemporary cohort. Methods: All non-pregnant women and men 35 and older with a new diagnosis of microhematuria (≥3 RBC/hpf) were identified via a multi-center electronic medical record data warehouse query. Negative controls with no history of hematuria were randomly chosen and included to complete our cohort. Comparison between dipstick urinalysis and microscopic urinalysis on self-matched patients for the detection of microhematuria and diagnosis of bladder cancer was performed via Spearman's rank correlation coefficient, sensitivity/specificity testing, and ROC curve analysis. Results: A total of 46,842 patients were included. Spearman's rank order correlation (rho = 0.66) between degree of microhematuria on dipstick urinalysis and microscopic urinalysis indicated a strong positive relationship. The ROC curve for dipstick urinalysis to identify microhematuria had an AUC of 0.80 (95% CI 0.79-0.81). No difference (p = 0.83) in diagnostic accuracy between dipstick urinalysis (AUC 0.74, 95% CI 0.70-0.78) and microscopic urinalysis (AUC 0.73, 95% CI 0.69-0.78) as a test for bladder cancer was found. Conclusion: Dipstick urinalysis provides a highly specific test for microhematuria and similar accuracy to microscopic urinalysis when used as a diagnostic tool to detect bladder cancer.

Nationwide Assessment of Robotic Lobectomy for Non-Small Cell Lung Cancer.

BACKGROUND: Robotic lobectomy has been described for non-small cell lung cancer (NSCLC). Our objectives were to (1) evaluate the use of robotic lobectomy over time, (2) identify factors associated with its use, and (3) assess outcomes after robotic lobectomy compared with other surgical approaches. METHODS: Stage I to IIIA NSCLC patients were identified from the National Cancer Data Base (2010 to 2012). Trends in robotic lobectomy were assessed over time, and multivariable logistic regression models were developed to identify factors associated with its use. Propensity-matched cohorts were constructed to compare postoperative outcomes after robotic lobectomy with thoracoscopic and open lobectomy. RESULTS: Lobectomy was performed in 62,206 patients by open (n = 45,527), thoracoscopic (n = 12,990), or robotic (n = 3,689) procedures at 1,215 hospitals. Between 2010 and 2012, robotic lobectomy significantly increased, from 3.0% to 9.1% (p < 0.001). Academic (odds ratio, 1.55; 95% confidence interval, 1.04 to 2.33) and high-volume hospitals (odds ratio, 1.49; 95% confidence interval, 1.04 to 2.14) were associated with increased use of robotic lobectomy. Length of stay was shorter in robotic lobectomy compared with open lobectomy (6.1 vs 6.9 days; p < 0.001). Fewer lymph nodes (9.9 vs 10.9; p < 0.001) and 12 or more nodes were examined less frequently (32.0% vs 35.6%; p = 0.005) in robotic resections than in thoracoscopic resections. There was no difference between robotic and open or robotic and thoracoscopic lobectomy patients in margin positivity, 30-day readmission, and deaths at 30 and 90 days. CONCLUSIONS: Robotic lobectomies have significantly increased in stage I to IIIA NSCLC patients, with outcomes similar to other approaches. Additional studies are needed to determine if this technology offers potential advantages compared with video-assisted thoracoscopic operations.

Association Between State Medical Malpractice Environment and Postoperative Outcomes in the United States.

BACKGROUND: The US medical malpractice system assumes that the threat of liability should deter negligence, but it is unclear whether malpractice environment affects health care quality. We sought to explore the association between state malpractice environment and postoperative complication rates. STUDY DESIGN: This observational study included Medicare fee-for-service beneficiaries undergoing one of the following operations in 2010: colorectal, lung, esophageal, or pancreatic resection, total knee arthroplasty, craniotomy, gastric bypass, abdominal aortic aneurysm repair, coronary artery bypass grafting, or cystectomy. The state-specific malpractice environment was measured by 2010 medical malpractice insurance premiums, state average award size, paid malpractice claims/100 physicians, and a composite malpractice measure. Outcomes of interest included 30-day readmission, mortality, and postoperative complications (eg sepsis, myocardial infarction [MI], pneumonia). Using Medicare administrative claims data, associations between malpractice environment and postoperative outcomes were estimated using hierarchical logistic regression models with hospital random-intercepts. RESULTS: Measures of malpractice environment did not have significant, consistent associations with postoperative outcomes. No individual tort reform law was consistently associated with improved postoperative outcomes. Higher-risk state malpractice environment, based on the composite measure, was associated with higher likelihood of sepsis (odds ratio [OR] 1.22; 95% CI 1.07 to 1.39), MI (OR 1.14; 95% CI 1.06 to 1.23), pneumonia (OR 1.09; 95% CI 1.03 to 1.16), acute renal failure (OR 1.15; 95% CI 1.08 to 1.22), deep vein thrombosis/pulmonary embolism (OR 1.22; 95% CI 1.13 to 1.32), and gastrointestinal bleed (OR 1.18; 95% CI 1.08 to 1.30). CONCLUSIONS: Higher risk malpractice environments were not consistently associated with a lower likelihood of surgical postoperative complications, bringing into question the ability of malpractice lawsuits to promote health care quality.

Effect of Flexible Duty Hour Policies on Length of Stay for Complex Intra-Abdominal Operations: A Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) Trial Analysis.

BACKGROUND: Changes to resident duty hour policies in the Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) trial could impact hospitalized patients' length of stay (LOS) by altering care coordination. Length of stay can also serve as a reflection of all complications, particularly those not captured in the FIRST trial (eg pneumothorax from central line). Programs were randomized to either maintaining current ACGME duty hour policies (Standard arm) or more flexible policies waiving rules on maximum shift lengths and time off between shifts (Flexible arm). Our objective was to determine whether flexibility in resident duty hours affected LOS in patients undergoing high-risk surgical operations. STUDY DESIGN: Patients were identified who underwent hepatectomy, pancreatectomy, laparoscopic colectomy, open colectomy, or ventral hernia repair (2014-2015 academic year) at 154 hospitals participating in the FIRST trial. Two procedure-stratified evaluations of LOS were undertaken: multivariable negative binomial regression analysis on LOS and a multivariable logistic regression analysis on the likelihood of a prolonged LOS (>75th percentile). RESULTS: Before any adjustments, there was no statistically significant difference in overall mean LOS between study arms (Flexible Policy: mean [SD] LOS 6.03 [5.78] days vs Standard Policy: mean LOS 6.21 [5.82] days; p = 0.74). In adjusted analyses, there was no statistically significant difference in LOS between study arms overall (incidence rate ratio for Flexible vs Standard: 0.982; 95% CI, 0.939-1.026; p = 0.41) or for any individual procedures. In addition, there was no statistically significant difference in the proportion of patients with prolonged LOS between study arms overall (Flexible vs Standard: odds ratio = 1.028; 95% CI, 0.871-1.212) or for any individual procedures. CONCLUSIONS: Duty hour flexibility had no statistically significant effect on LOS in patients undergoing complex intra-abdominal operations.

Nationwide Assessment of Trends in Choledocholithiasis Management in the United States From 1998 to 2013.

Importance: There are currently 2 widely accepted treatment strategies for patients presenting to the hospital with choledocholithiasis. However, the rate of use for each strategy in the United States has not been evaluated, and their trends over time have not been described. Furthermore, an optimal management strategy for choledocholithiasis has yet to be defined. Objective: To evaluate secular trends in the management of choledocholithiasis in the United States and to compare hospital length of stay between patients with choledocholithiasis treated with endoscopic retrograde cholangiopancreatography with laparoscopic cholecystectomy (ERCP+LC) vs laparoscopic common bile duct exploration with laparoscopic cholecystectomy (LCBDE+LC). Design, Setting, and Participants: In this cohort study, we studied patients with a primary diagnosis of choledocholithiasis that were included in the National Inpatient Sample between 1998 and 2013 from a representative sample of acute care hospitals in the United States. Patients with cholangitis or pancreatitis were excluded. Main Outcomes and Measures: Unadjusted and risk-adjusted median hospital length of stay. Results: Of the 37 207 patients included in our analysis, 36 048 (96.9%) were treated with ERCP+LC and 1159 (3.1%) were treated with LCBDE+LC. The mean (SD) age of patients treated with ERCP+LC was 50.7 (21.1) years and was 51.9 (20.9) years for those treated with LCBDE+LC; 25 788 (69.3%) were female. Analysis of the National Inpatient Sample data indicates that there are an average of 26 158 patients with choledocholithiasis admitted in the United States each year. The overall use of CBDE for patients with choledocholithiasis decreased from 39.8% of admissions in 1998 to 8.5% in 2013 (P < .001). A decrease was also seen for open CBDE (30.6% vs 5.5%; P < .001) and laparoscopic CBDE (9.2% vs 3.0%; P < .001) independently. Rates of management with LCBDE+LC decreased from 5.3% to 1.5% (P < .001), while rates of ERCP+LC increased from 52.8% to 85.7% (P < .001). The unadjusted median hospital length of stay was shorter for patients treated with LCBDE+LC than for those treated with ERCP+LC (3.0 vs 4.0 days; P < .001). After risk-adjustment, the median length of stay remained 0.5 days shorter for patients treated with LCBDE+LC than with ERCP+LC (3.5 vs 4.0 days; P < .001). Conclusions and Relevance: This study highlights the marked decline in the use of both open and laparoscopic CBDE in the United States as well as the benefit to the length of stay LCBDE+LC has over ERCP+LC. Despite a persistent need for CBDE and the potential benefits of LCBDE+LC over ERCP+LC for managing choledocholithiasis, if current trends continue, CBDE may be at risk of disappearing from the surgical armamentarium.

Association Between State Medical Malpractice Environment and Surgical Quality and Cost in the United States.

CONTEXT: The US medical malpractice system is designed to deter negligence and encourage quality of care through threat of liability. OBJECTIVE: To examine whether state-level malpractice environment is associated with outcomes and costs of colorectal surgery. DESIGN, SETTING, AND PATIENTS: Observational study of 116,977 Medicare fee-for-service beneficiaries who underwent colorectal surgery using administrative claims data. State-level malpractice risk was measured using mean general surgery malpractice insurance premiums; paid claims per surgeon; state tort reforms; and a composite measure. Associations between malpractice environment and postoperative outcomes and price-standardized Medicare payments were estimated using hierarchical logistic regression and generalized linear models. MAIN OUTCOME MEASURES: thirty-day postoperative mortality; complications (pneumonia, myocardial infarction, venous thromboembolism, acute renal failure, surgical site infection, postoperative sepsis, any complication); readmission; total price-standardized Medicare payments for index hospitalization and 30-day postdischarge episode-of-care. RESULTS: Few associations between measures of state malpractice risk environment and outcomes were identified. However, analyses using the composite measure showed that patients treated in states with greatest malpractice risk were more likely than those in lowest risk states to experience any complication (OR: 1.31; 95% CI: 1.22-1.41), pneumonia (OR: 1.36; 95%: CI, 1.16-1.60), myocardial infarction (OR: 1.44; 95% CI: 1.22-1.70), venous thromboembolism (OR:2.11; 95% CI: 1.70-2.61), acute renal failure (OR: 1.34; 95% CI; 1.22-1.47), and sepsis (OR: 1.38; 95% CI: 1.24-1.53; all P < 0.001). There were no consistent associations between malpractice environment and Medicare payments. CONCLUSIONS: There were no consistent associations between state-level malpractice risk and higher quality of care or Medicare payments for colorectal surgery.

Hospital Characteristics Associated With Penalties in the Centers for Medicare & Medicaid Services Hospital-Acquired Condition Reduction Program.

IMPORTANCE: In fiscal year (FY) 2015, the Centers for Medicare & Medicaid Services (CMS) instituted the Hospital-Acquired Condition (HAC) Reduction Program, which reduces payments to the lowest-performing hospitals. However, it is uncertain whether this program accurately measures quality and fairly penalizes hospitals. OBJECTIVE: To examine the characteristics of hospitals penalized by the HAC Reduction Program and to evaluate the association of a summary score of hospital characteristics related to quality with penalization in the HAC program. DESIGN, SETTING, AND PARTICIPANTS: Data for hospitals participating in the FY2015 HAC Reduction Program were obtained from CMS' Hospital Compare and merged with the 2014 American Hospital Association Annual Survey and FY2015 Medicare Impact File. Logistic regression models were developed to examine the association between hospital characteristics and HAC program penalization. An 8-point hospital quality summary score was created using hospital characteristics related to volume, accreditations, and offering of advanced care services. The relationship between the hospital quality summary score and HAC program penalization was examined. Publicly reported process-of-care and outcome measures were examined from 4 clinical areas (surgery, acute myocardial infarction, heart failure, pneumonia), and their association with the hospital quality summary score was evaluated. EXPOSURES: Penalization in the HAC Reduction Program. MAIN OUTCOMES AND MEASURES: Hospital characteristics associated with penalization. RESULTS: Of the 3284 hospitals participating in the HAC program, 721 (22.0%) were penalized. Hospitals were more likely to be penalized if they were accredited by the Joint Commission (24.0% accredited, 14.4% not accredited; odds ratio [OR], 1.33; 95% CI, 1.04-1.70); they were major teaching hospitals (42.3%; OR, 1.58; 95% CI, 1.09-2.29) or very major teaching hospitals (62.2%; OR, 2.61; 95% CI, 1.55-4.39; vs nonteaching hospitals, 17.0%); they cared for more complex patient populations based on case mix index (quartile 4 vs quartile 1: 32.8% vs 12.1%; OR, 1.98; 95% CI, 1.44-2.71); or they were safety-net hospitals vs non-safety-net hospitals (28.3% vs 19.9%; OR, 1.36; 95% CI, 1.11-1.68). Hospitals with higher hospital quality summary scores had significantly better performance on 9 of 10 publicly reported process and outcomes measures compared with hospitals that had lower quality scores (all P ≤ .01 for trend). However, hospitals with the highest quality score of 8 were penalized significantly more frequently than hospitals with the lowest quality score of 0 (67.3% [37/55] vs 12.6% [53/422]; P < .001 for trend). CONCLUSIONS AND RELEVANCE: Among hospitals participating in the HAC Reduction Program, hospitals that were penalized more frequently had more quality accreditations, offered advanced services, were major teaching institutions, and had better performance on other process and outcome measures. These paradoxical findings suggest that the approach for assessing hospital penalties in the HAC Reduction Program merits reconsideration to ensure it is achieving the intended goals.

Long-Term Outcome of IPAA in Patients Presenting with Fulminant Ulcerative Colitis: A Matched Cohort Study.

BACKGROUND: Studies reveal that ileal pouch-anal anastomosis (IPAA) has long-term success. These reports, however, use well-selected cohorts and exclude patients presenting with fulminant colitis (FC). Herein, we aimed to characterize long-term functional outcomes in patients with fulminant ulcerative colitis (UC) undergoing IPAA. METHODS: A prospective database identified patients who underwent IPAA between 1998 and 2008. Patients with FC and chronic UC were matched by age, gender, date of surgery, and follow-up duration. Clinical and laboratory parameters, immunomodulator use at the time of surgery, and functional outcomes were compared. RESULTS: Forty patients with FC and 73 patients with chronic UC were identified. Preoperative albumin, hemoglobin, leukocyte count, and steroid dose were significantly different for those with FC. Average survey follow-up was 5.2 years for FC and 6.7 years for chronic UC patients. Functional outcomes were not significantly different. The 3-year fistula-free rate was 91.4 versus 98.6 % and the 3-year stricture-free rate was 79.3 versus 87.2 % for FC versus chronic UC patients, respectively. CONCLUSION: Patients undergoing colectomy for FC secondary to UC have similar long-term functional outcomes after IPAA despite significantly worse presentation. This study confirms that IPAA is an appropriate and durable treatment for patients with FC.

Long-term outcomes of ileal pouch-anal anastomosis for pediatric chronic ulcerative colitis.

BACKGROUND: Ileal pouch-anal anastomosis (IPAA) is the surgical treatment of choice for patients with chronic ulcerative colitis (CUC). In the pediatric population, short-term outcomes of IPAA are excellent but long-term data limited. The purpose of this study is to report long-term functional and quality of life outcomes of IPAA in pediatric patients. METHODS: Functional outcomes and quality of life (QoL) following IPAA in patients ≤ 18 years of age were prospectively assessed by survey over a 30 year period. Preoperative information, chronic pouchitis and pouch loss were retrospectively reviewed. RESULTS: Over 30 years, 202 children with CUC underwent IPAA. Questionnaires were returned by 87% and median (range) survey follow-up was 181.5 (7.8-378.5) months. Postoperative day and night-time stool frequency did not increase over time though incontinence increased slightly. Quality of life (QoL) was generally excellent and stable over time. Crohn's disease (CD) was diagnosed in 33 (16%) patients during the follow-up period. Chronic pouchitis occurred in 22 patients and pouch failure in 13 patients. Kaplan Meier estimates of pouch survival at 20 years were 61% for patients with CD and 92% for CUC. CONCLUSIONS: Ileal pouch-anal anastomosis has long-term durability as a cure for pediatric chronic ulcerative colitis, with most patients reporting stable bowel function and QoL. Chronic pouchitis and pouch failure affect a minority of patients and require further study.

Prognostic Value of Molecular Detection of Lymph Node Metastases After Curative Resection of Stage II Colon Cancer: A Systematic Pooled Data Analysis.

BACKGROUND: We aimed to clarify the prognostic value of guanylyl cyclase C (GCC) lymph node ratio (LNR) status as a predictor of recurrence in untreated stage IIA colon cancer on the basis of pooled individual data from previous studies. METHODS: Patients were classified according to predefined GCC LNR risk groups (low, LNR ≤ 0.1; intermediate, 0.1 < LNR ≤ 0.2; high, LNR > 0.2). Outcomes included time to recurrence, disease-free survival, and overall survival. Stratified log-rank tests and multivariate Cox models assessed the association between outcomes and GCC lymph node status. RESULTS: The final data set contained 553 patients with stage IIA colon cancer with a median of 18 lymph nodes examined after resection; 65 patients (11.8%) had recurrence. Overall, 109 patients (19.7%) were classified high risk on the basis of GCC LNR. In multivariate analysis, high GCC LNR value (> 0.2) was a significant predictor of cancer recurrence (hazard ratio [HR], 3.18; 95% confidence interval [CI], 1.77-5.71; P < .001) and lower disease-free survival (HR, 2.40; 95% CI, 1.60-3.62; P < .001) and overall survival (HR, 2.12; 95% CI, 1.35-3.33; P = .001). CONCLUSION: Patients considered at high risk on the basis of their GCC LNR status have significantly inferior outcomes compared to those with low GCC LNR values, particularly among those traditionally considered to be at low risk for recurrence.

DPYD variants as predictors of 5-fluorouracil toxicity in adjuvant colon cancer treatment (NCCTG N0147).

BACKGROUND: Previous studies have suggested the potential importance of three DPYD variants (DPYD*2A, D949V, and I560S) with increased 5-FU toxicity. Their individual associations, however, in 5-FU-based combination therapies, remain controversial and require further systematic study in a large patient population receiving comparable treatment regimens with uniform clinical data. METHODS: We genotyped 2886 stage III colon cancer patients treated adjuvantly in a randomized phase III trial with FOLFOX or FOLFIRI, alone or combined with cetuximab, and tested the individual associations between functionally deleterious DPYD variants and toxicity. Logistic regressions were used to assess univariate and multivariable associations. All statistical tests were two-sided. RESULTS: In 2594 patients with complete adverse event (AE) data, the incidence of grade 3 or greater 5FU-AEs in DPYD*2A, I560S, and D949V carriers were 22/25 (88.0%), 2/4 (50.0%), and 22/27 (81.5%), respectively. Statistically significant associations were identified between grade 3 or greater 5FU-AEs and both DPYD*2A (odds ratio [OR] = 15.21, 95% confidence interval [CI] = 4.54 to 50.96, P < .001) and D949V (OR = 9.10, 95% CI = 3.43 to 24.10, P < .001) variants. Statistical significance remained after adjusting for multiple variables. The DPYD*2A variant statistically significantly associated with the specific AEs nausea/vomiting (P = .007) and neutropenia (P < .001), whereas D949V statistically significantly associated with dehydration (P = .02), diarrhea (P = .003), leukopenia (P = .002), neutropenia (P < .001), and thrombocytopenia (P < .001). Although two patients with I560S had grade≥3 5FU-AEs; a statistically significant association could not be demonstrated because of its low frequency (P = .48). CONCLUSION: In the largest study to date, statistically significant associations were found between DPYD variants (DPYD*2A and D949V) and increased incidence of grade 3 or greater 5FU-AEs in patients treated with adjuvant 5-FU-based combination chemotherapy.

Interactions between beta-2 adrenoceptor gene variation, cardiovascular control and dietary sodium in healthy young adults.

Dietary sodium affects function of the beta-2 adrenoceptor (ADRB2). We tested the hypothesis that haplotype variation in the ADRB2 gene would influence the cardiovascular and regional vasodilator responses to sympathoexcitatory manoeuvres following low, normal and high sodium diets, and ADRB2-mediated forearm vasodilation in the high sodium condition. Seventy-one healthy young adults were grouped by double homozygous haplotypes: Arg16+Gln27 (n = 31), the rare Gly16+Gln27 (n = 10) and Gly16+Glu27 (n = 30). Using a randomized cross-over design, subjects were studied following 5 days of controlled low, normal and high sodium with 1 month or longer between diets (and low hormone phase of the menstrual cycle). All three visits utilized ECG and finger plethysmography for haemodynamic measures, and the high sodium visit included a brachial arterial catheter for forearm vasodilator responses to isoprenaline with plethysmography. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. We found a main effect of haplotype on ADRB2 density (P = 0.03) with the Gly16+Glu27 haplotype having the greatest density (low, normal, high sodium: 12.9 ± 0.9, 13.5 ± 0.9 and 13.6 ± 0.8 fmol mg(-1) protein, respectively) and Arg16+Gln27 having the least (9.3 ± 0.6, 10.1 ± 0.5 and 10.3 ± 0.6  fmol mg(-1) protein, respectively), but there were no sodium or haplotype effects on receptor binding conformation. In the mental stress trial, there was a main effect of haplotype on cardiac output (P = 0.04), as Arg16+Gln27 had the lowest responses. Handgrip and forearm vasodilation yielded no haplotype differences, and no correlations were present for ADRB2 density and haemodynamics. Our findings support cell-based evidence that ADRB2 haplotype influences ADRB2 protein expression independent of dietary sodium, yet the haemodynamic consequences appear modest in healthy humans.

Randomized trial of drain antisepsis after mastectomy and immediate prosthetic breast reconstruction.

BACKGROUND: In this 2-site randomized trial, we investigated the effect of antiseptic drain care on bacterial colonization of surgical drains and infection after immediate prosthetic breast reconstruction. METHODS: With IRB approval, we randomized patients undergoing bilateral mastectomy and reconstruction to drain antisepsis (treatment) for one side, with standard drain care (control) for the other. Antisepsis care included both: chlorhexidine disc dressing at drain exit site(s) and irrigation of drain bulbs twice daily with dilute sodium hypochlorite solution. Cultures were obtained from bulb fluid at 1 week and at drain removal, and from the subcutaneous drain tubing at removal. Positive cultures were defined as ≥1+ growth for fluid and >50 CFU for tubing. RESULTS: Cultures of drain bulb fluid at 1 week (the primary endpoint) were positive in 9.9 % of treatment sides (10 of 101) versus 20.8 % (21 of 101) of control sides (p = 0.02). Drain tubing cultures were positive in 0 treated drains versus 6.2 % (6 of 97) of control drains (p = 0.03). Surgical site infection occurred within 30 days in 0 antisepsis sides versus 3.8 % (4 of 104) of control sides (p = 0.13), and within 1 year in three of 104 (2.9 %) of antisepsis sides versus 6 of 104 (5.8 %) of control sides (p = 0.45). Clinical infection occurred within 1 year in 9.7 % (6 of 62) of colonized sides (tubing or fluid) versus 1.5 % (2 of 136) of noncolonized sides (p = 0.03). CONCLUSIONS: Simple and inexpensive local antiseptic interventions with a chlorhexidine disc and hypochlorite solution reduce bacterial colonization of drains, and reduced drain colonization was associated with fewer infections.

Molecular testing for lymph node metastases as a determinant of colon cancer recurrence: results from a retrospective multicenter study.

PURPOSE: Recurrence risk assessment to make treatment decisions for early-stage colon cancer patients is a major unmet medical need. The aim of this retrospective multicenter study was to evaluate the clinical utility of guanylyl cyclase C (GCC) mRNA levels in lymph nodes on colon cancer recurrence. METHODS: The proportion of lymph nodes with GCC-positive mRNA (LNR) was evaluated in 463 untreated T3N0 patients, blinded to clinical outcomes. One site's (n = 97) tissue grossing method precluded appropriate lymph node assessment resulting in post hoc exclusion. Cox regression models tested the relationship between GCC and the primary endpoint of time to recurrence. Assay methods, primary analyses, and cut points were all prespecified. RESULTS: Final dataset contained 366 patients, 38 (10%) of whom had recurrence. Presence of four or more GCC-positive lymph nodes was significantly associated with risk of recurrence [hazard ratio (HR) = 2.46, 95% confidence interval (CI), 1.07-5.69, P = 0.035], whereas binary GCC LNR risk class (HR = 1.87, 95% CI, 0.99-3.54, P = 0.054) and mismatch repair (MMR) status (HR = 0.77, 95% CI, 0.36-1.62, P = 0.49) were not. In a secondary analysis using a 3-level GCC LNR risk group classification of high (LNR > 0.20), intermediate (0.10 < LNR ≤ 0.20), and low (LNR ≤ 0.10), high-risk patients had a 2.5 times higher recurrence risk compared with low-risk patients (HR = 2.53, 95% CI, 1.24-5.17, P = 0.011). CONCLUSIONS: GCC status is a promising prognostic factor independent of traditional histopathology risk factors in a contemporary population of patients with stage IIa colon cancer not treated with adjuvant therapy, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique.

Adjuvant GM-CSF improves survival in high-risk stage iiic melanoma: a single-center Study.

OBJECTIVES: Stage III melanoma is associated with an increased risk of recurrence and death. Complete surgical resection remains the best chance for cure. Unfortunately, no adjuvant therapy has demonstrated a consistent improvement in melanoma-specific survival (MSS). We hypothesize that adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) may improve clinical outcomes. PATIENTS AND METHODS: Retrospective cohort study of 317 surgically resected stage III melanoma patients managed with observation or adjuvant GM-CSF at a single institution from 2001 to 2010. RESULTS: Of the 317 stage III patients, 165 (52%) were observed and 152 (48%) were treated with GM-CSF, with a median follow-up of 34 months. Patients treated with GM-CSF tended to be younger (P < 0.0001), had more advanced stage disease (P = 0.002), and were more likely to have had a recurrence before initiation of adjuvant therapy than the observation group (P < 0.0001). Adjuvant GM-CSF seemed to be associated with improved MSS, but this did not reach statistical significance (P = 0.08). Patients with stage IIIC melanoma derived a substantial benefit from adjuvant GM-CSF, with a 52% risk reduction in melanoma-specific death (hazard ratio 0.48; 95% confidence interval, 0.27-0.87; P = 0.02). CONCLUSIONS: Despite selecting patients with more advanced stage and a higher incidence of regional relapse, adjuvant GM-CSF was associated with an improved MSS but not disease-free survival in patients with stage IIIC disease. In patients not otherwise eligible for clinical trials, adjuvant GM-CSF treatment is a reasonable option for individuals with resected high-risk melanoma.

Bonferroni-based correction factor for multiple, correlated endpoints.

Multiple testing and its impact on the type I and type II error rates are frequently discussed in the statistical and biomedical literature. The Bonferroni adjustment is one of the most widely used approaches, yet it suffers from poor statistical performance when there are correlated test statistics. For example, it is criticized to be too conservative. Nonetheless, part of the strong appeal of the Bonferroni approach is the straightforward implementation and relatively intuitive explanation. In this manuscript, a novel adaptation to the traditional Bonferroni approach that accounts for correlated data is proposed. A simple correction factor based on intraclass correlation is applied to the standard Bonferroni method to overcome the shortcomings of the standard Bonferroni adjustment yet maintains its advantages. The method is motivated by an early phase clinical trial examining the effect of a study medication on marijuana craving, which is commonly quantified into four correlated constructs. A detailed simulation study demonstrated that the proposed approach is statistically sound and appropriate for a wide range of common settings.

Complement dependent cytotoxicity in chronic lymphocytic leukemia: ofatumumab enhances alemtuzumab complement dependent cytotoxicity and reveals cells resistant to activated complement.

Complement dependent cytotoxicity (CDC) is an important mechanism of action for monoclonal antibodies (mAbs) used in the treatment of chronic lymphocytic leukemia (CLL). We hypothesized that alemtuzumab (ALM) mediated CDC would be increased by the addition of ofatumumab (OFA). CLL cells from 21 previously untreated patients with progressive disease were tested in vitro for mAb binding, complement activation and CDC. The subpopulation of CDC resistant CLL cells was examined for levels of C3b and C5b-9 binding, and expression of complement regulatory proteins. OFA significantly increased complement activation and CDC in ALM-treated CLL cells, suggesting that combining ALM and OFA could improve clinical outcome in patients with CLL. Approximately 10% of CLL cells were resistant to CDC because of lower levels of complement activation or decreased cytotoxicity of activated complement. Improvement of clinical responses will require determining the mechanisms of CDC resistance and developing methods to overcome this problem.