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**Background:** Approximately 60% of hospitalized children undergoing surgery experience at least 1 day of moderate-to-severe pain after surgery. Pain following spine surgery may affect opioid exposure, length of stay (LOS), and costs in hospitalized pediatric patients. This is a retrospective cohort analysis of pediatric patients undergoing inpatient primary spine surgery. **Objectives:** To examine the association of opioid-related and economic outcomes with postsurgical liposomal bupivacaine (LB) or non-LB analgesia in pediatric patients who received spine surgery. **Methods:** Premier Healthcare Database records (January 2015–September 2019) for patients aged 1–17 years undergoing inpatient primary spine surgery were retrospectively analyzed. Outcomes included in-hospital postsurgical opioid consumption (morphine milligram equivalents [MMEs]), opioid-related adverse events (ORAEs), LOS (days), and total hospital costs. A generalized linear model adjusting for baseline characteristics was used. **Results:** Among 10 189 pediatric patients, the LB cohort (n=373) consumed significantly fewer postsurgical opioids than the non-LB cohort (n=9816; adjusted MME ratio, 0.53 [95% confidence interval (CI), 0.45–0.61]; P

Background and Purpose— Although exogenous hormone therapy (HT) use has been associated with increased risk of ischemic stroke in postmenopausal women, it remains unknown whether sex hormone levels contribute to ischemic stroke risk. We aimed to estimate associations between plasma sex hormone levels and ischemic stroke risk, by HT status, in a nested case-control study of postmenopausal women from the NHS (Nurses’ Health Study). Methods— Women with confirmed incident ischemic stroke (n=419) were matched with controls (n=419) by age, HT use, and other factors. Plasma estradiol and testosterone levels were measured using liquid chromatography tandem mass spectrometry; SHBG (sex hormone-binding globulin) was assayed by electrochemiluminescence immunoassay. Associations of total and free estradiol and testosterone, the estradiol/testosterone ratio, and SHBG with ischemic stroke were estimated using conditional logistic regressions stratified by HT status with adjustment for matching and cardiovascular risk factors. Results— Current HT users had different hormone profiles from never/past users. No clear linear trends were observed between estradiol (total or free) levels or the estradiol/testosterone ratio and ischemic stroke risk among either current users ( P trend >0.1) or never/past users ( P trend >0.6). For both current and never/past users, the associations between some of the sex hormones and ischemic stroke differed by body mass index categories ( P interaction ≤0.04). For women with a body mass index 2 , a higher estradiol/testosterone ratio was associated with significantly elevated ischemic stroke risk among current users ( P trend =0.01), and higher levels of total and free estradiol were significantly associated with higher ischemic stroke risk among never/past users ( P trend ≤0.04). Testosterone and SHBG were not associated with ischemic stroke in either current or never/past users. Conclusions— Our findings do not support a role of sex hormone levels in mediating ischemic stroke risk among postmenopausal women. Replications in additional larger studies are required.

Introduction Hospitalization is the largest component of health care spending in the United States. Most hospitalized patients first visit the emergency department (ED), where hospitalization decisions are made. Optimal utilization of hospital resources is critical for all stakeholders. Methods We performed a population-based, cross-sectional study evaluating ED visits and subsequent inpatient admissions for patients with coronary artery disease (CAD) and chest pain (CP) suggestive of CAD from 2006 to 2013 using the Nationwide Emergency Department Sample database weighted for national estimates. We analyzed trends using a generalized linear regression model with a Poisson distribution and Wald test. Results From 2006 to 2013, there was a 15% decrease in ED visits for CAD (p

Rivaroxaban reduces stroke compared with warfarin in patients with non-valvular atrial fibrillation (NVAF). This study compared healthcare costs before and after stroke in NVAF patients treated with rivaroxaban or warfarin. Using de-identified IBM MarketScan Commercial and Medicare databases, this retrospective cohort study (from 2011 to 2019) included patients with NVAF who initiated rivaroxaban or warfarin within 30 days after initial NVAF diagnosis. Patients who developed stroke were identified, and stroke severity was determined by the National Institutes of Health Stroke Scale (NIHSS) score, imputed by a random forest method. Total all-cause per-patient per-year (PPPY) costs of care were determined for patients: (1) who developed stroke during the pre- and post-stroke periods and (2) who remained stroke-free during the follow-up period. Treatment groups were balanced using inverse probability of treatment weighting. A total of 13,599 patients initiated rivaroxaban and 39,861 initiated warfarin, of which 272 (2.0%) and 1,303 (3.3%), respectively, developed stroke during a mean follow-up of 28 months. Among patients who developed stroke, PPPY costs increased from the pre-stroke to post-stroke period, with greater increases in the warfarin cohort relative to the rivaroxaban cohort. Overall, the costs increased by 1.78-fold for rivaroxaban vs 3.07-fold for warfarin; for less severe strokes (NIHSS < 5), costs increased 0.88-fold and 1.05-fold, respectively. Cost increases for more severe strokes (NIHSS ≥ 5) among rivaroxaban patients were half those for warfarin patients (3.19-fold vs 6.37-fold, respectively). Among patients without stroke, costs were similar during the follow-up period between the two treatment groups. Total all-cause costs of care increased in the post-stroke period, and particularly in the patients treated with warfarin relative to those treated with rivaroxaban. The lower rate of stroke in the rivaroxaban cohort suggests that greater pre- to post-stroke cost increases result from more strokes occurring in the warfarin cohort.

Background/Objective: This study evaluated emergency department (ED) visit trends, subsequent inpatient admissions for patients with inflammatory bowel disease (IBD) diagnosis and IBD-related abdominal pain (AP), and hospital-level variation in inpatient admission rates in the USA (US). Methods: This population-based, cross-sectional study included data from Nationwide Emergency Department Sample (NEDS, 2006─2013) database. Patients ≥18 years of age with primary ED diagnosis of IBD/IBD-related AP were included. Variables included demographics, insurance information, household income, Quan-Charlson comorbidity score, ED discharge disposition, and length of hospital stay (2006, 2010, and 2013). Variation between hospitals using risk-adjusted admission ratio was estimated. Results: Annual ED visits for IBD/100,000 US population increased (30 in 2006 vs 42 in 2013, p = 0.09), subsequent admissions remained stable (20 in 2006 vs 23 in 2013, p = 0.52). ED visits for IBD-related AP increased by 71% (7 in 2006 vs 12 in 2013; p = 0.12), subsequent admissions were stable (0.50 in 2006 vs 0.58 in 2013; p = 0.88). Proportion of patients with subsequent hospitalization decreased (IBD: 65.7% to 55.7%; IBD-related AP: 6.9% to 4.9%). Variation in subsequent inpatient admissions was 1.42 (IBD) and 1.96 (IBD-related AP). Conclusions: An increase in annual ED visits was observed for patients with IBD and IBD-related AP; however, subsequent inpatient admission rate remained stable.

Effective postsurgical pain management is important for pediatric patients to improve outcomes while reducing resource use and waste. The authors examined opioid consumption and economic outcomes associated with liposomal bupivacaine (LB) or non-LB analgesia use in pediatric patients undergoing cardiothoracic surgery.The authors retrospectively analyzed Premier Healthcare Database records.The data extracted from the database included patient records from hospitals across the United States in both rural and urban locations.The records included data from patients aged 12-to-18 years.The records belonged to patients undergoing video-assisted thoracoscopic procedures (VATS) who received LB or non-LB analgesia after surgery.Outcomes included in-hospital postsurgical opioid consumption in morphine milligram equivalents (MMEs), hospital length of stay (LOS), and total hospital costs; the LB and non-LB cohorts were compared using a generalized linear model with inverse probability of treatment weighting to balance the cohorts. For VATS procedures, pediatric patients receiving LB had significant reductions in in-hospital opioid consumption (632 v 991 MMEs; p0.0001), shorter LOS (5.1 v 5.6 days; p = 0.0023), and lower total hospital costs ($18,084 v $21,962; p0.0001) compared with those receiving non-LB analgesia.These results support use of LB in multimodal analgesia regimens for managing pain in pediatric patients after cardiothoracic surgery.

To describe chronic lymphocytic leukemia (CLL) treatment patterns and patient outcomes in Latin America.This chart review study (NCT02559583; 2008-2015)evaluated time to progression (TTP) and overall survival (OS) outcomes among patients with CLL who initiate done (The most commonly prescribed therapies in both LOTs were chlorambucil-, followed by fludarabine- and cyclophosphamide (C)/CHOP-based therapies. Chlorambucil- and C/CHOP-based therapies were largely prescribed to elderly patients (≥65 years) while fludarabine-based therapy was predominantly used by younger patients (≤65 years). In LOT1, relative to chlorambucil-administered patients, those prescribed fludarabine-based therapies had lower risk of disease progression (hazard ratio [HR] and 95% confidence interval [CI] 0.32 [0.19-0.54]), whereas C/CHOP-prescribed patients had higher risk (HR 95%CI 1.88 [1.17-3.04]). Similar results were observed in LOT2. There was no difference in OS between treatments in both LOTs.Novel therapies such as kinase inhibitors were rarely prescribed in LOT1 or LOT2in Latin America. The greater TTP observed forfludarabine-based therapies could be attributed to the fact that fludarabine-based therapies are predominantly administered to young and healthy patients.Chlorambucil-based therapy, which has limited benefits, is frequently prescribed in Latin America. Prescribing novel agents for fludarabine-based therapy-ineligible patients with CLL is the need of the hour.

Introduction: Healthcare expenditures remain unclear in NVAF patients initiating anticoagulation therapy. Objective: To compare total healthcare cost in pre- and post-stroke periods between rivaroxaban- and warfarin-treated NVAF patients. Methods: This retrospective study using de-identified IBM MarketScan Commercial and Medicare databases (2011-2019) included patients initiating rivaroxaban or warfarin within 30 days after a 1 st observed NVAF diagnosis who later developed ischemic or hemorrhage stroke. Patients had ≥6 months continuous health plan enrollment, CHA 2 DS 2 -VASc score ≥2 and no history of stroke or anticoagulation therapy. Inpatient stroke diagnosis was identified by ICD-9/-10 code, and stroke severity status was defined by National Institutes of Health Stroke Scale (NIHSS) score, imputed by a random forest method. Total per-patient per-year (PPPY) cost of care was calculated pre- and post-stroke (from treatment initiation to time of stroke and from stroke until end of study enrollment, respectively). Cost increases pre-/post-stroke were compared within each treatment cohort. Results: During a mean follow up of 25 and 30 months for rivaroxaban and warfarin respectively, 272 (2.0%) and 1,303 (3.3%) patients, respectively, developed stroke. For the rivaroxaban cohort, the pre-/post-stroke cost increase was lower than that for warfarin (1.79-fold vs 3.08-fold, respectively); for more severe stroke (NIHSS ≥6), the cost increase for rivaroxaban was half that of warfarin (3.19-fold increase vs 6.37-fold increase, respectively). Conclusions: The study showed a substantial increase in total cost of care following stroke, especially among patients with severe strokes. Warfarin patients had a much higher increase in post-stroke costs relative to rivaroxaban patients, suggesting a benefit of rivaroxaban in preventing strokes with poor outcomes that are costly.

Introduction: The National Institutes of Health Stroke Scale (NIHSS) scores are often not readily available in structured claims databases. We have previously demonstrated that a machine learning model can be used to determine proxies for NIHSS scores. Our current work focuses on creating a model applicable across different databases to validate our approach and enable further outcome studies. Methods: We identified 1,415 eligible hospital-admitted patients in the Optum® de-identified Integrated Claims-EMR database who were diagnosed with ischemic or hemorrhagic stroke, or a transient ischemic attack and had NIHSS scores in medical notes. These patients were split into a training (N=1,192) set for model development and a hold-out test (N=223) set to evaluate model performance. Furthermore, model performance was externally validated using the 286 eligible stroke patients in IBM’s Claims-EMR database (CED). Potential predictors for stroke severity included relevant procedures, diagnoses, patient demographics, and information about the patient hospital stay. Results: The optimal model, a random forest model, achieved a coefficient of determination (R 2 ) between the actual and predicted NIHSS scores in the hold-out Optum dataset of 0.48 and of 0.42 in the secondary CED dataset. The final model incorporated a total of 47 predictors. The strongest predictors included transient ischemic attack diagnosis, length of hospital stay, critical care procedures, patient age, and hemiplegia diagnosis. Conclusion: This study shows that machine learning can be used to determine proxies for NIHSS scores across different real-world databases. Ultimately, this will enable large claims-based outcome studies involving stroke severity to improve our understanding of how stroke severity affects healthcare utilization, total cost of care, and the financial impact on the larger community.

Supplemental Digital Content is available in the text., Background and Purpose— Oral anticoagulation therapy is standard of care for patients with nonvalvular atrial fibrillation to prevent stroke. This study compared rivaroxaban and warfarin for stroke and all-cause mortality risk reduction in a real-world setting. Methods— This retrospective cohort study (2011–2017) included de-identified patients from the Optum Clinformatics Database who started treatment with rivaroxaban or warfarin within 30 days following initial diagnosis of nonvalvular atrial fibrillation. Before nonvalvular atrial fibrillation diagnosis, patients had 6 months of continuous health plan enrollment and CHA2DS2-VASc score ≥2. Stroke severity was determined by the National Institutes of Health Stroke Scale, imputed based on machine learning algorithms. Stroke and all-cause mortality risks were compared by treatment using Cox proportional hazard regression, with inverse probability of treatment weighting to balance cohorts for baseline risk factors. Stratified analysis by treatment duration was also performed. Results— During a mean follow-up of 27 months, 175 (1.33/100 patient-years [PY]) rivaroxaban-treated and 536 (1.66/100 PY) warfarin-treated patients developed stroke. The inverse probability of treatment weighting model showed that rivaroxaban reduced stroke risk by 19% (hazard ratio [HR], 0.81 [95% CI, 0.73–0.91]). Analysis by stroke severity revealed risk reductions by rivaroxaban of 48% for severe stroke (National Institutes of Health Stroke Scale score, 16–42; HR, 0.52 [95% CI, 0.33–0.82]) and 19% for minor stroke (National Institutes of Health Stroke Scale score, 1 to

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Although previous studies have suggested a potential role of sex hormones in the etiology of colorectal cancer (CRC), no study has yet examined the associations between circulating sex hormones and survival among CRC patients. We prospectively assessed the associations of prediagnostic plasma concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone and sex hormone-binding globulin (SHBG) with CRC-specific and overall mortality among 609 CRC patients (370 men and 239 postmenopausal women not taking hormone therapy at blood collection) from four U.S. cohorts. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression. We identified 174 deaths (83 CRC-specific deaths) in men and 106 deaths (70 CRC-specific deaths) in women. In men, higher circulating level of free testosterone was associated with lower risk of overall (the highest vs. lowest tertiles, HR = 0.66, 95% CI, 0.45–0.99, p(trend) = 0.04) and possibly CRC-specific mortality (HR = 0.73, 95% CI, 0.41–1.29, p(trend) = 0.27). We generally observed nonsignificant inverse associations for other sex steroids, and a positive association for SHBG with CRC-specific mortality among male patients. In women, however, we found a suggestive positive association of estrone with overall (HR = 1.54, 95% CI, 0.92–2.60, p(trend) = 0.11) and CRC-specific mortality (HR = 1.96, 95% CI, 1.01–3.84, p(trend) = 0.06). Total estradiol, free estradiol and free testosterone were generally suggestively associated with higher risk of mortality among female patients, although not statistically significant. These findings implicated a potential role of endogenous sex hormones in CRC prognosis, which warrant further investigation.

Background Stroke severity is an important predictor of patient outcomes and is commonly measured with the National Institutes of Health Stroke Scale (NIHSS) scores. Because these scores are often recorded as free text in physician reports, structured real-world evidence databases seldom include the severity. The aim of this study was to use machine learning models to impute NIHSS scores for all patients with newly diagnosed stroke from multi-institution electronic health record (EHR) data. Methods NIHSS scores available in the Optum© de-identified Integrated Claims-Clinical dataset were extracted from physician notes by applying natural language processing (NLP) methods. The cohort analyzed in the study consists of the 7149 patients with an inpatient or emergency room diagnosis of ischemic stroke, hemorrhagic stroke, or transient ischemic attack and a corresponding NLP-extracted NIHSS score. A subset of these patients (n = 1033, 14%) were held out for independent validation of model performance and the remaining patients (n = 6116, 86%) were used for training the model. Several machine learning models were evaluated, and parameters optimized using cross-validation on the training set. The model with optimal performance, a random forest model, was ultimately evaluated on the holdout set. Results Leveraging machine learning we identified the main factors in electronic health record data for assessing stroke severity, including death within the same month as stroke occurrence, length of hospital stay following stroke occurrence, aphagia/dysphagia diagnosis, hemiplegia diagnosis, and whether a patient was discharged to home or self-care. Comparing the imputed NIHSS scores to the NLP-extracted NIHSS scores on the holdout data set yielded an R2 (coefficient of determination) of 0.57, an R (Pearson correlation coefficient) of 0.76, and a root-mean-squared error of 4.5. Conclusions Machine learning models built on EHR data can be used to determine proxies for stroke severity. This enables severity to be incorporated in studies of stroke patient outcomes using administrative and EHR databases.

Limited data are available regarding contemporary multiple myeloma (MM) treatment practices in Latin America. In this retrospective cohort study, medical records were reviewed for a multinational cohort of 1103 Latin American MM patients (median age, 61 years) diagnosed in 2008-2015 who initiated first-line therapy (LOT1). Of these patients, 33·9% underwent autologous stem cell transplantation (ASCT). During follow-up, 501 (45·4%) and 129 (11·7%) patients initiated second- (LOT2) and third-line therapy (LOT3), respectively. In the LOT1 setting, from 2008 to 2015, there was a decrease in the use of thalidomide-based therapy, from 66·7% to 42·6%, and chemotherapy from, 20·2% to 5·9%, whereas use of bortezomib-based therapy or bortezomib + thalidomide increased from 10·7% to 45·5%. Bortezomib-based therapy and bortezomib + thalidomide were more commonly used in ASCT patients and in private clinics. In non-ASCT and ASCT patients, median progression-free survival (PFS) was 15·0 and 31·1 months following LOT1 and 10·9 and 9·5 months following LOT2, respectively. PFS was generally longer in patients treated with bortezomib-based or thalidomide-based therapy versus chemotherapy. These data shed light on recent trends in the management of MM in Latin America. Slower uptake of newer therapies in public clinics and poor PFS among patients with relapsed MM point to areas of unmet therapeutic need in Latin America.

Objective: To compare total cost of care in pre- and post-stroke periods between rivaroxaban- and warfarin-treated NVAF patients. Methods: De-identified Optum Clinformatics® Database (OptumInsight, 2011-17) was used in this study of patients initiating rivaroxaban or warfarin within 30 days after a 1 st observed NVAF diagnosis. Patients had ≥6 months continuous health plan enrollment, CHA2DS2-VASc score ≥2 and no history of stroke or anticoagulation. Inpatient stroke diagnosis was identified by ICD-9/-10 code, and severity status was defined by National Institutes of Health Stroke Scale (NIHSS) score, imputed by a random forest method. For all patients who developed stroke, total per-patient per-month (PPPM) cost of care was estimated before (from treatment initiation to time of stroke) and after (from stroke until the earliest of either death or end of enrollment) stroke occurrence. Generalized linear models adjusted for confounders were used to compare PPPM cost between the 2 groups in the 2 periods, with gamma distribution, log link and weighted by follow up. Results: During a mean follow up of 27 months, 2.6% of rivaroxaban and 3.9% of warfarin patients developed stroke and were included in the analysis. During pre-stroke period, total cost of care was similar for both treatment groups (~$3400 PPPM), which increased 3-fold in the post-stroke period (Table 1). During post stroke period, total cost of care was 21% lower for rivaroxaban patients vs. warfarin. Of those with less severe stroke (NIHSS Conclusions: Total cost of care for stroke prevention was similar in rivaroxaban and warfarin treated patients, but post-stroke cost was lower in rivaroxaban patients. These findings suggest favorable long-term cost benefit with rivaroxaban, driven by significant savings in less severe stroke.

Objectives In a previous real-world study, rivaroxaban reduced the risk of stroke overall and severe stroke compared with warfarin in patients with nonvalvular atrial fibrillation (NVAF). The aim of this study was to assess the reproducibility in a different database of our previously observed results (Alberts M, et al. Stroke. 2020;51:549-555) on the risk of severe stroke among NVAF patients in a different population treated with rivaroxaban or warfarin. Material and Methods This retrospective cohort study included patients from the IBM® MarketScan® Commercial and Medicare databases (2011-2019) who initiated rivaroxaban or warfarin after a diagnosis of NVAF, had ≥6 months of continuous health plan enrollment, had a CHA2DS2-VASc score ≥2, and had no history of stroke or anticoagulant use. Patient data were assessed until the earliest occurrence of a primary inpatient diagnosis of stroke, death, end of health plan enrollment, or end of study. Stroke severity was defined by National Institutes of Health Stroke Scale (NIHSS) score, imputed by random forest model. Cox proportional hazard regression was used to compare risk of stroke between cohorts, balanced by inverse probability of treatment weighting. Results The mean observation period from index date to either stroke, or end of eligibility or end of data was 28 months. Data from 13,599 rivaroxaban and 39,861 warfarin patients were included. Stroke occurred in 272 rivaroxaban-treated patients (0.97/100 person-years [PY]) and 1,303 warfarin-treated patients (1.32/100 PY). Rivaroxaban patients had lower risk for stroke overall (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.76–0.88) and for minor (NIHSS 1 to Conclusions The results of this study in a larger population of NVAF patients align with previous real-world findings and the ROCKET-AF trial by showing improved stroke prevention with rivaroxaban versus warfarin across all stroke severities.

Background Lipid biomarkers, such as HDL-cholesterol concentrations, have been shown to have positive, inverse, and null associations with total, breast, and colorectal cancer risks. Studies of novel lipid biomarkers, such as apolipoprotein A-I (apo A-I) and apolipoprotein B-100 (apo B-100), and cancer risk have been sparse, to our knowledge. Objectives We evaluated the prospective association of total, breast, colorectal, and lung cancers and cancer mortality with circulating lipid biomarkers in 15,602 female health professionals in the Women's Health Study (aged ≥45 y, free of cardiovascular disease and cancer, and without hormone replacement therapy or lipid-lowering medications at baseline). Design Cox regression models estimated HRs of cancer endpoints (19 y median follow-up) across quartiles 1 (reference) to 4 of each lipid biomarker after adjustment for cancer risk factors. Results Confirmed cases included 2163 incident cancer cases (864 breast, 198 colorectal, and 190 lung cancers) and 647 cancer deaths. Total cancer risk was significantly lower in the highest quartile of apo A-I (adjusted HR: 0.79; 95% CI: 0.70, 0.90; P-trend = 0.0008) and HDL cholesterol (HR: 0.85; 95% CI: 0.75, 0.97; P-trend = 0.01). For site-specific cancers, significant associations included colorectal cancer risk with HDL cholesterol (HR: 0.63; 95% CI; 0.41, 0.98; P-trend = 0.03), triglycerides (HR: 1.86; 95% CI: 1.17, 2.97; P-trend = 0.02), and apo B-100 (HR: 1.60; 95% CI: 1.03, 2.49; P-trend = 0.006) and lung cancer risk with HDL cholesterol (HR: 0.59; 95% CI: 0.38, 0.93; P-trend = 0.01). LDL cholesterol was not significantly associated with risk of total cancer or any site-specific cancers. In time-dependent models that were adjusted for the use of a lipid-lowering medication after baseline, these associations remained. Conclusions Lipids were associated with total, lung, and colorectal cancer risks in women. Lifestyle interventions for heart-disease prevention, which reduce apo B-100 or raise HDL cholesterol, may be associated with reduced cancer risk. The Women's Health Study was registered at clinicaltrials.gov as NCT00000479.

Summary Objective To describe the characteristics of real‐world patients potentially eligible for adjunctive pharmacotherapy for weight loss. Methods Patients from the GE Centricity electronic medical record database were selected if they had body mass index (BMI) ≥30 or ≥27 to

Context: Ibrutinib, a once-daily inhibitor of Bruton tyrosine kinase (BTK), is approved in the US for patients with MCL with ≥1 prior therapy. Single-agent ibrutinib received accelerated approval for MCL after showing complete response (CR) rates of 19–21% and overall response rates of 68–72% (Dreyling Lancet 2016; Wang NEJM 2013). Venetoclax is a BCL2 inhibitor approved in the US for patients with CLL with ≥1 prior therapy and for patients with previously untreated AML. Single-agent venetoclax has also shown efficacy in MCL, with CR rates of 21% (Davids J Clin Oncol 2017). In preclinical models, ibrutinib + venetoclax showed synergistic antitumor activity via dual inhibition of the BTK and BCL2 pathways (Zhao Br J Haematol 2015). In the phase 2 AIM study, 71% of 24 patients with MCL treated with ibrutinib + venetoclax had a best response of CR. Notably, the CR rate was 50% in patients with TP53 mutations, a population considered chemo-insensitive; this included 1 previously untreated patient (Tam NEJM 2018). Objective: To evaluate ibrutinib + venetoclax in patients ≥65 years and patients Design: This new open-label arm of the ongoing phase 3 SYMPATICO study will be conducted in ∼75 previously untreated patients with MCL. This study is currently enrolling patients. Patients or other participants: Key inclusion criteria include age ≥65 years or 18–65 years with a TP53 mutation, pathologically confirmed treatment-naive MCL with ECOG performance status of 0–2, and measurable disease. Patients with the blastoid variant of MCL, history of CNS lymphoma, or prior treatment with a BTK or BCL-2 inhibitor are ineligible. Interventions: Patients will receive oral, once daily 560 mg ibrutinib + venetoclax in a 5-week ramp-up to 400 mg venetoclax. Patients receive ibrutinib + venetoclax for 104 weeks; afterwards, venetoclax is discontinued in all patients and single-agent ibrutinib continues until progressive disease or unacceptable toxicity. Main outcome measures: The primary objective is to evaluate the CR rate. Secondary objectives include additional efficacy evaluations, safety, and pharmacokinetics. Funding: Pharmacyclics LLC, an AbbVie Company.

Background: While several studies have evaluated healthcare costs of stroke, limited data are available on long-term costs by stroke severity. Objective: To assess healthcare costs in relation to stroke severity over 3 years following stroke diagnosis. Methods: Patients with newly diagnosed stroke were assessed using OPTUM de-identified Integrated Claims-Medical Record Database (2007-2016). The National Institutes of Health Stroke Scale (NIHSS) score, imputed by 100 clinically relevant predictors selected by a random forest method, was used to group patients by severity: no impairment (5-16, Mod), moderately severe (>16-21, MS), severe (>21-42, S). All-cause medical and pharmacy costs were estimated in patients for up to 3 years following diagnosis. Mean cumulative costs were evaluated by partitioning the follow-up period into 2-week intervals. The average cost incurred in each interval was then weighted by the Kaplan-Meier survival probability at the beginning of each interval, after which costs were summed across all intervals. Results: We identified 8512 patients with a mean age of 69 years at first stroke diagnosis; 1396, 4783, 1927, 215 and 191 were in the NI, Min, Mod, MS, and S cohorts, respectively. Mortality was 3%, 13%, 33%, 88% and 100% at Year 3 following stroke diagnosis in the NI, Min, Mod, MS, and S cohorts, respectively. In year 1 following diagnosis, the cumulative total healthcare costs were the highest in the Mod cohort (mean ± SE; $67365±$1234) and lowest in the S cohort ($15945±$647). Healthcare costs increased in year 3 substantially compared to year 1, with the NI cohort showing the greatest increase in healthcare costs (116% increase), followed by the Min (86%), Mod (39%), MS (9%) and S (0%) cohorts. Hospitalization was the costliest healthcare service across all cohorts and ranged in Year 3 from $62100 in the Mod cohort to $13241 in the S cohort; outpatient services were the second most costly. Conclusion: Majority of patients with severe strokes (MS and S) incurred high healthcare costs within a month whereas patients with less severe strokes (Min and NI) accrued more costs over time due to better survival outcomes, underscoring short and long-term economic burden of various degrees of stroke severity.

Background: The National Institutes of Health Stroke Scale (NIHSS) score has been used to measure initial stroke severity. However, limited data are available on the utility of NIHSS in predicting all-cause mortality risk. Objective: To assess the association between stroke severity and mortality in stroke patients, using NIHSS stroke severity scoring. Methods: This retrospective cohort study followed patients after first inpatient diagnosis of stroke using OPTUM de-identified Integrated Claims-Medical Database (2007-2016). The NIHSS score was imputed using 100 clinically relevant predictors selected by a random forest method. Patients were classified by NIHSS score into 5 severity groups: no impairment (5-16, Mod), moderately severe (>16-21, MS) or severe (>21-42, S). Patients were followed from stroke diagnosis to the earliest occurrence of either death, end of data or lost to follow-up. Time to death was assessed by Cox proportional hazard regression, comparing more severe stroke patients vs the NI patients (reference group), adjusting for age, gender, comorbidity index, and region. Results: A total of 16,554 stroke patients were studied; 17%, 57%, 22%, 2%, and 2% were in None, Min, Mod, MS and S groups, respectively. Mean age was 68 years at stroke diagnosis (ranging 64 to 79 years). Overall, 4.3% had a history of atrial fibrillation and 3.1% received anticoagulants for stroke prevention. Median follow-up was 23, 18, 10, 0.9 and 0.6 months for the None, Min, Mod, MS and S cohorts, respectively. Following stroke diagnosis, 74% of MS and 89% S patients died within 30 days of stroke onset, whereas the NI and Min patients remained alive within 30 days. When compared with the NI patients, more severe patients had significantly increased mortality risk; hazard ratios (95% confidence intervals) were 2.8 (2.2-3.6), 9.7 (7.4-12.6), 116 (86-154), and 364 (270-491) for the Min, Mod, MS and S patients, respectively. Conclusions: Mortality rates increased significantly with more severe strokes, as determined by the initial NIHSS score. Over 75% of the patients with moderately severe and severe strokes died within 1 month following stroke diagnosis.

The Women's Health Initiative (WHI) Dietary Modification (DM) trial did not show that reductions in dietary fat accompanied by increases in vegetable and fruit consumption decrease the incidence of colorectal cancer. Secondary analyses suggested that aspirin use may modify the intervention effects of DM on colorectal cancer development, although a recent reanalysis including the postintervention period confirmed no main effect of the intervention on reducing colorectal cancer incidence Methods: We analyzed data from 48,834 postmenopausal women who were randomized into the low-fat DM (N = 19,540) or comparison (N = 29,294) group for an average 8.1 years and followed for an additional 9.4 years through August 31, 2014. Exposure to specific class(es) or strength(s) of nonsteroidal anti-inflammatory drugs (NSAIDs) was modeled at baseline and as time-dependent use through the 9-year clinic visit. A Cox proportional hazard model was employed to assess the association of the DM, medication use, and their interaction with colorectal cancer events.A total of 906 incident cases of colorectal cancer were identified during the intervention and postintervention periods. By both exposure models, we found that colorectal cancer incidence was not different in the DM from the comparison group among any type of NSAID users. None of the interactions with any category of NSAID use was statistically significant; however there was most modest evidence for an interaction (p = 0.07) with aspirin use at baseline (hazard ratio [HR] = 0.81, 95% confidence interval [CI], 0.60-1.11 for users; HR = 1.12, 95% CI, 0.97-1.30 for nonusers). Strength and duration of aspirin use at baseline did not alter the associations.Extended follow-up of women in the WHI DM trial did not confirm combined protective effects of aspirin and low-fat diet on colorectal cancer risk among the postmenopausal women.

Background: Payment reforms and other policy initiatives are accelerating the shift of risk from payers to providers. As a result, population health management is playing an increasing role in decision making by providers, guided by the Medicare Triple Aim. Reducing avoidable hospitalizations is an important tool for achieving this aim, by increasing quality of care and containing hospital costs. Previous studies have examined the trends over time of emergency department (ED) visits for major diseases. However, there is very little data assessing ED visits related to the symptoms of these major diseases. This study examined the trends of ED visits for chest pain (CP), a symptom suggestive of coronary artery disease (CAD), and of shortness of breath (SOB), a symptom suggestive of congestive heart failure (CHF). Methods: We conducted a population-based cross-sectional study to estimate ED visits for CP suggestive of CAD and for SOB suggestive of CHF in the US for the years 2006 through 2013 at encounter level, using the Nationwide Emergency Department Sample (NEDS) database. We defined CP suggestive of CAD as a principal diagnosis of CP for the ED visit (ICD-9-CM code: 786.5), with a CAD code (410-414) as a secondary diagnosis but no diagnosis for other serious conditions that may trigger CP (e.g., aortic dissection). We defined SOB suggestive of CHF as a principal diagnosis of SOB (ICD-9-CM code: 786.05) for the ED visit with a CHF code (428.0-428.4) as a secondary diagnosis but no diagnosis for other conditions that may trigger SOB (e.g., pneumothorax). Outcome measures included annual number of ED visits and subsequent admissions, weighted for national estimates (2006-2013). We performed a trend analysis in rates over time, which accounted for US census population, for ED visits and subsequent admissions, using a generalized linear regression model with a Poisson distribution and a Wald test. Results: The number of ED visits for CP suggestive of CAD per 100,000 population increased 24.3% from 197 in 2006 to 245 in 2013 (p0.1). Similarly, subsequent admissions for SOB suggestive of CHF were relatively low and stable, from 0.61 admissions per 100,000 in 2006 to 0.72 admissions in 2013 (p>0.1). Conclusions: Our results showed an increasing trend for ED visits and a decreasing trend for subsequent admissions over time for CP suggestive of CAD. However, there appeared no change for ED visits and subsequent admissions over time for SOB suggestive of CHF. Future research is warranted to examine possible reasons for the different ED visit rates for symptoms associated with major diseases such as CAD and CHF.

Colorectal cancers are a group of heterogeneous disorders that involve interactions among environmental influences, germ-line susceptibility factors, and accumulated genetic and epigenetic changes in the colorectal epithelium. This review provides background on environmental exposure and molecular pathways during colorectal cancer pathogenesis. Additionally, the review discusses the interplay between these risk factors in the context of colorectal cancer development and progression. Smoking, obesity, and regular aspirin use appear to have profound effects on colorectal cancer initiation and prognosis through the activation of pathways targeting gene methylation, inflammation, insulin mitogenesis, and cell proliferation. New data on other types of exposure and molecular changes will continue to improve our understanding of the cause of colorectal cancer, leading to novel therapeutic and preventive strategies and ultimate reduction in disease burden.

Effectiveness of rivaroxaban vs warfarin in patients with non-valvular atrial fibrillation (NVAF) is not well-understood over long follow up time in real-world settings. This study compared risk for stroke by severity and post-stroke mortality between rivaroxaban and warfarin. This retrospective

Background: Soy intake is associated with a lower risk of breast cancer. However, it is unclear whether the same reduction in risk associated with high soy intake is also applicable to familial or genetic breast cancer. Objective: The aim of this study was to assess the dietary factors among carriers and noncarriers of BRCA mutations in the Korean Hereditary Breast Cancer Study (KOHBRA). Design: The KOHBRA Study is an ongoing project composed of affected breast cancer patients and familial members of breast cancer cases with BRCA mutations. To assess the association between dietary diversity and breast cancer risk, an HR was estimated by comparing affected subjects with their familial nonaffected members. To assess the interaction between the combination of BRCA mutation and diet diversity, the case-only OR (COR) was estimated by comparing BRCA mutation carriers and noncarriers only in affected subjects. Results: Soy product intake was associated with a lower risk of breast cancer in carriers (HR: 0.39; 95% CI: 0.19, 0.79 for the highest quartile). The highest quartile of meat intake was associated with a higher risk of breast cancer regardless of BRCA mutation in carriers (HR: 1.97; 95% CI: 1.13, 3.44) and noncarriers (95% CI: 1.41; 1.12, 1.78). The associations of meat intake and soybean intake for breast cancer were more prominent in BRCA2 mutation carriers. In the analysis with only cases, the highest quartile of soy intake, but not meat intake, was associated with BRCA-related breast cancer (COR: 0.57; 95% CI: 0.36, 0.91). Conclusion: Our study suggests that soy product consumption is associated with lower breast cancer risk and it had an interaction with BRCA mutation. This trial was registered at clinicaltrials.gov as NCT00595348. Am J Clin Nutr doi: 10.3945/ajcn.112.057760.

Nipple-sparing mastectomy (NSM) improves cosmetic outcome of mastectomy, but many patients are not candidates for this procedure because of concerns about nipple-areolar viability. Surgical delay is a technique that has been used for more than 400 years to improve survival of skin flaps. We used a surgical delay procedure to improve nipple viability in patients who were identified to be at high risk for nipple necrosis following NSM.Patients at high risk for nipple necrosis following NSM underwent a surgical delay procedure 7-21 days prior to mastectomy. Subareolar biopsy and sentinel node biopsy, if indicated, were performed at the time of the delay procedure. Nipple viability was assessed before and after NSM. If the subareolar biopsy revealed malignancy, the NAC was removed at the time of mastectomy.31 NAC in 20 patients underwent surgical delay. All of the NAC subjected to a surgical delay survived following the delay procedure. In 2 patients, the subareolar biopsy was positive and 3 NAC were removed at the time of mastectomy (1 for purposes of symmetry). Of the 28 delayed NAC left at the time of NSM, all survived the post-mastectomy course.A procedure to surgically delay the NAC 7-21 days prior to NSM is demonstrated to ensure viability of NAC in patients previously thought to be at high risk for nipple loss.

Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell-cycle regulators. However, epidemiologic studies evaluating hormone therapy use and colorectal cancer risk by the status of cell-cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between hormone therapy use and colorectal cancer risk differs by the molecular pathologic status of microsatellite instability (MSI) and expression of cell-cycle–related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between hormone therapy use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105,520 postmenopausal women. We found a difference between hormone therapy use and colorectal cancer risk according to CDKN1A expression (Pheterogeneity = 0.01). Current hormone therapy use was associated with a reduced risk for CDKN1A-nonexpressed [multivariate relative risk (RR), 0.61; 95% confidence interval (CI), 0.46–0.82] but not for CDKN1A-expressed (RR, 1.32; 95% CI, 0.76–2.31) tumors. The lower risk for CDKN1A-nonexpressed but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between hormone therapy use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular pathological epidemiology findings suggest a preventive effect of hormone therapy against colorectal carcinogenesis that depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A. Cancer Res; 72(12); 3020–8. ©2012 AACR.

Background : Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the US and EU for patients (pts) with CLL and allows for treatment without chemotherapy. Standard of care for first-line CLL in older pts or those with comorbidities includes single-agent ibr or chemoimmunotherapy (CIT) with chlorambucil (clb) plus anti-CD20 therapy. As no data were available from phase 3 studies directly comparing single-agent ibr with CIT, we performed a cross-trial analysis using data from two phase 3 studies to assess single-agent ibr vs clb plus obinutuzumab (G) in first-line CLL. Methods : In the ongoing PCYC-1115/1116 (RESONATE-2), pts with previously untreated CLL/SLL aged ≥65 years without del(17p) were randomized to receive ibr (420 mg once daily continuously) or clb. In PCYC-1130 (iLLUMINATE), pts with untreated CLL/SLL aged ≥65 years or Results : Primary analysis included 136 pts treated with single-agent ibr and 98 pts treated with clb-G. Median age was 73 years in both groups. High-risk genomic features were generally well balanced (54% and 58% of pts, respectively), including del(11q) (21% and 22%), TP53 mutations (9% and 5%), and unmutated IGHV (43% and 46%). Bulky disease (≥5 cm) was present in 40% and 37% of pts, respectively. Median follow-up was 48.8 mo for ibr and 31.3 mo for clb-G. Single-agent ibr significantly prolonged PFS compared with clb-G (median not reached [NR] vs 22.2 mo), with an 82% reduction in risk of progression or death (HR 0.184; P Conclusions : Despite limitations of this cross-trial analysis, results suggest that PFS with single-agent ibr was superior to clb-G, including, importantly, in patients with high-risk genomic characteristics or bulky disease. In a time-matched analysis, AE profile with single-agent ibr appeared favorable to clb-G. In comparing ibr and ibr-G, lymphocytosis was more common with ibr than ibr-G but resolved in almost all pts, and ORR was similar for ibr and ibr-G. While CR rate was higher for ibr-G vs ibr, CR was not needed to achieve long-term PFS benefit with single-agent ibr. Disclosures Tedeschi: AbbVie: Consultancy; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau. Greil:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding. Demirkan:AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Robak:Janssen: Consultancy, Honoraria; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy. Moreno:AbbVie: Consultancy; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy. Barr:AbbVie, Gilead: Consultancy. Simpson:Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Gaidano:Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Bairey:Jansen: Research Funding; AbbVie: Consultancy; ROCHE: Research Funding. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gill:Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau. Flinn:Takeda: Research Funding; Calithera: Research Funding; Agios: Research Funding; Forma: Research Funding; Trillium: Research Funding; Infinity: Research Funding; ArQule: Research Funding; Gilead: Research Funding; TG Therapeutics: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Kite: Research Funding; Curis: Research Funding; Portola: Research Funding; Novartis: Research Funding; Verastem: Consultancy, Research Funding; Merck: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Forty Seven: Research Funding; Constellation: Research Funding; Seattle Genetics: Research Funding. Kipps:Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lin:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Webb:Janssen: Employment; Johnson & Johnson: Equity Ownership. Fedorov:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Styles:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Gribben:TG Therapeutics: Honoraria; Pharmacyclics: Honoraria; NIH: Research Funding; Novartis: Honoraria; Acerta Pharma: Honoraria, Research Funding; Abbvie: Honoraria; Kite: Honoraria; Roche: Honoraria; Unum: Equity Ownership; Wellcome Trust: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Cancer Research UK: Research Funding; Medical Research Council: Research Funding.

89 Background: Although patients with CRPC frequently develop metastasis within 3 years following castration resistance, the impact of metastasis on HRU in these patients is not well understood. Methods: The Optum de-identified electronic health record database (1/1/2007 – 4/30/2016) was used in this single cohort observational study comparing HRU after metastasis with HRU before metastasis. The cohort included only non-metastatic CRPC (nmCRPC) patients who later developed metastasis. The pre-metastasis period spanned from nmCRPC identification to development of metastasis; the post-metastasis period spanned from metastasis until death or end of data availability. Per-patient per-month (PPPM) HRU was estimated during both pre- and post-metastasis periods by a generalized linear mixed model adjusted for log-transformed baseline PSA, age, testosterone levels, and Charlson Comorbidity Index. Results: With a mean time of 11 and 17 months of pre- and post-metastasis periods, respectively, 540 CRPC men were included, with a mean age at nmCRPC identification of 75 years. Higher HRU was seen across all service types during the post-metastasis period. There was a 2.5-fold increase in inpatient admissions and a 6.4-fold increase in inpatient length-of-stay in the post-metastasis period compared to the pre-metastasis period (p < 0.01). For emergency department (ED) visits, there was a 2.0-fold increase from the pre- to post-metastasis periods (p < 0.01). For observation unit visits, a 2.7-fold increase was seen in the post-metastasis period (p < 0.01). Finally, patients were 40% more likely to have an office visit after developing metastasis (p < 0.01). The PPPM use of intensive care unit, hospice or skilled nursing facility were too low for meaningful comparison between the pre- and post-metastasis periods. Conclusions: Shorter time to metastasis was observed in this cohort vs. other nmCRPC studies, likely due to delayed disease identification. CRPC patients incurred substantially higher HRU after developing metastasis, attributable to inpatient, ED, observation unit as well as office visits, suggesting that delaying metastasis may reduce or delay the increased HRU in patients with nmCRPC.

e17058Background: Real world data regarding the progression of patients with nmCRPC is limited. This study assessed association of PSA doubling time (PSADT) over disease follow-up with risk for met...

Stroke severity, as measured by the National Institutes of Health Stroke Scale (NIHSS) score, has been used to predict mortality in ischemic stroke (IS). Its ability to predict mortality in hemorrhagic stroke (HS) is unclear. This study examined the use of real-world data to assess IS and HS

27 Background: Currently there is insufficient guidance for the management of nmCRPC. This study assessed patient risk of developing metastases and death based on their PSA levels over time. Methods: This was a retrospective study using the Optum electronic health record database (1/1/2007 – 4/30/2016) in men ≥18 years. nmCRPC was defined as a PC diagnosis, 2 rising PSA levels ≥1 week apart, testosterone < 50 ng/dL (post-PC diagnosis), and no ICD-9/10 code or therapy indicating metastasis. Patients were required to have ≥1 PSA record per 3-month period for 9 months following nmCRPC diagnosis. Group Based Trajectory Modeling (GBTM) was used to group patients based on similar PSA trends over 9 months. The association of these PSA groups with metastasis/mortality risk was measured using multivariate Cox proportional hazard regression models. An overall trend for metastasis and mortality across the groups was also tested. Results: From a total of 729 patients included, 4 distinct groups were identified: Group 1 (49% of patients), 2 (32%), 3 (14%) and 4 (5%). Group 1 had the lowest PSA (7 ng/mL) at nmCRPC diagnosis and steady PSA during the 9-month follow-up. In contrast, Groups 2, 3 and 4 had higher PSA at nmCRPC diagnosis (17, 61, 513 ng/mL respectively) and rising PSA during follow-up. There was a trend of increasing metastasis and mortality risk (p < 0.001 for both trends) with the higher PSA groups. For metastasis, Hazard Ratios (HRs) and 95% confidence intervals (CIs) were 1.7 (1.3-2.2), 3.5 (2.5-5.0), 1.8 (0.7-4.7) in Groups 2, 3 and 4, respectively, vs. Group 1. For mortality, HRs (95% CIs) were 1.9 (1.4-2.5), 2.6 (1.8-3.7), 4.5 (2.4-8.4) in Groups 2, 3 and 4, respectively, vs. Group 1. Metastasis-free survival (MFS) independently predicted mortality risk. Patients developing metastasis within 1 year had 4.4-fold greater risk for mortality (95% CI = 2.2-8.8) than those who remained MFS at year 3. Conclusions: A large proportion of nmCRPC patients with PSA increases during the follow-up period had significantly increased risk for metastasis and mortality, with MFS predicting mortality risk. Periodic measurement of PSA may better inform management of nmCRPC.

Background The burden of disease due to norovirus infection has been well described in the general United States population, but studies of norovirus occurrence among persons with chronic medical conditions have been limited mostly to the immunocompromised. We assessed the impact of norovirus gastroenteritis on health care utilization in US subjects with a range of chronic medical conditions. Methods We performed a retrospective cohort study using MarketScan data from July 2002 to December 2013, comparing the rates of emergency department visits, outpatient visits and hospitalizations among patients with chronic conditions (renal, cardiovascular, respiratory, immunocompromising, gastrointestinal, hepatic/pancreatic and neurological conditions and diabetes) with those in a healthy population. We estimated the rates of these outcomes due to norovirus gastroenteritis using an indirect modelling approach whereby cases of gastroenteritis of unknown cause and not attributed to a range of other causes were assumed to be due to norovirus. Results Hospitalization rates for norovirus gastroenteritis were higher in all of the risk groups analyzed compared with data in otherwise healthy subjects, ranging from 3.2 per 10,000 person-years in persons with chronic respiratory conditions, to 23.1 per 10,000 person-years in persons with chronic renal conditions, compared to 2.1 per 10,000 among persons without chronic conditions. Over 51% of all norovirus hospitalizations occurred in the 37% of the population with some form of chronic medical condition. Outpatient visits for norovirus gastroenteritis were also increased in persons with chronic gastrointestinal or immunocompromising conditions. Conclusion Norovirus gastroenteritis leads to significantly higher rates of healthcare utilization in patients with a chronic medical condition compared to patients without any such condition.

Background: Flavonoids inhibit the growth of colon cancer cells in vitro. In a secondary analysis of a randomized controlled trial, the Polyp Prevention Trial, a higher intake of one subclass, flavonols, was statistically significantly associated with a reduced risk of recurrent advanced adenoma. Most previous prospective studies on colorectal cancer evaluated only a limited number of flavonoid subclasses and intake ranges, yielding inconsistent results. Objective: In this study, we examined whether higher habitual dietary intakes of flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols, and anthocyanins) were associated with a lower risk of colorectal cancer. Design: Using data from validated food-frequency questionnaires administered every 4 y and an updated flavonoid food composition database, we calculated flavonoid intakes for 42,478 male participants from the Health Professionals Follow-Up Study and for 76,364 female participants from the Nurses’ Health Study. Results: During up to 26 y of follow-up, 2519 colorectal cancer cases (1061 in men, 1458 in women) were documented. Intakes of flavonoid subclasses were not associated with risk of colorectal cancer in either cohort. Pooled multivariable adjusted RRs (95% CIs) comparing the highest with the lowest quintiles were 1.04 (0.91, 1.18) for flavonols, 1.01 (0.89, 1.15) for flavones, 0.96 (0.84, 1.10) for flavanones, 1.07 (0.95, 1.21) for flavan-3-ols, and 0.98 (0.81, 1.19) for anthocyanins (all P values for heterogeneity by sex >0.19). In subsite analyses, flavonoid intake was also not associated with colon or rectal cancer risk. Conclusion: Our findings do not support the hypothesis that a higher habitual intake of any flavonoid subclass decreases the risk of colorectal cancer.

Observational data on the association between circulating 25(OH)D and colorectal cancer risk are limited in women. To determine whether prediagnostic levels of 25(OH)D were associated with risk of incident colorectal cancer in the Women's Health Study (WHS), we conducted a nested case–control study using 274 colorectal cases and 274 controls. Each case was matched to a control by age, ethnicity, fasting status at the time of blood collection, time of day when blood was drawn, and month of blood draw. Conditional logistic regression was used to estimate the OR and 95% confidence interval (CI) for colorectal cancer by 25(OH)D quartiles. Mean plasma 25(OH)D was lower in cases versus controls (21.9 vs. 23.9 ng/mL, P = 0.01). In multivariable-adjusted logistic regression models, plasma 25(OH)D was significantly and inversely associated with odds of colorectal cancer (quartile 4 [Q4] vs. quartile 1 [Q1]: OR, 0.45; 95% CI, 0.25–0.81; Ptrend 0.02). In addition, we observed a somewhat lower risk of colorectal cancer-related mortality after adjustment for matching variables, randomization treatment and other risk factors (Q4:Q1 OR, 0.40; 95% CI, 0.17–0.97; Ptrend 0.05). In this cohort of healthy women, we found a significant inverse association between prediagnostic 25(OH)D levels and risk of incident colorectal cancer, and a borderline significant inverse association between prediagnostic 25(OH)D levels and colorectal cancer-related mortality. These results support a possible association between plasma 25(OH)D and risk of colorectal cancer in women. Cancer Prev Res; 8(8); 675–82. ©2015 AACR. See related commentary by Demetrius Albanes, p. 657

Adiponectin, an adipocyte-secreted hormone, has insulin-sensitizing characteristics. It remains unclear whether adiponectin may influence colorectal cancer development.To determine whether prediagnostic levels of adiponectin were associated with risk of incident colorectal cancer in the Women's Health Study, we conducted a nested case-control study of 275 colorectal cancer cases and 275 matched controls. Each case was matched to a control by age, ethnicity, fasting status at the time of blood collection, time of day when blood was drawn, and month of blood draw. Multivariable logistic regression with adjustment for colorectal cancer risk factors was used to estimate the odds ratio (OR) and 95 % confidence interval (CI) for risk of colorectal cancer incidence and mortality by adiponectin quartiles based on the control distribution.Median plasma adiponectin level was similar in cases versus controls (6.00 vs. 6.24 μg/mL). In multivariable-adjusted logistic regression models, high plasma adiponectin levels were not significantly associated with risk of colorectal cancer [quartile 4 (Q4) vs. quartile 1 (Q1): OR (95 % CI) 0.86 (0.48-1.56), p trend = 0.63].These results suggest no appreciable association between plasma adiponectin and risk of colorectal cancer in women. Confirmation of these observations in larger studies is needed.

5027 Background: Interventions in nmCRPC are the last defense against metastasis, which drives health care cost and mortality. To assess the value of such interventions we must analyze risk factors for metastasis and death. Methods: This was a retrospective study of data (Optum electronic health record database, 2007 – 2016) from men with a prostate cancer diagnosis, 2 rising PSA levels ≥1 week apart, castrate level ( < 50 ng/dL) testosterone (T) and no ICD-9/10 code or therapy indicating metastasis. Gleason grade (G) and PSA data up to and including nmCRPC index date (ie, date of 2nd PSA rise) were used to assign NCCN risk groups: Low (G ≤6 and PSA < 10 ng/mL), Intermediate (IM) (G = 7 or 10 ≤ PSA ≤ 20 ng/mL) or High (G ≥ 8 or PSA > 20 ng/mL). The LP/NG group comprised men with PSA < 10 ng/mL (LP) and missing G (NG). A Cox proportional hazard model, adjusted for age, race, comorbidity index score, T level, therapy type and bone scans was used to compare LP/NG, IM and High with the Low risk group. Results: Among 1008 men with nmCRPC (mean age 76 years; 12% African American), 553 developed metastases and 430 died during follow-up. Mean time to metastasis was 28, 22, 15, 13 months in the Low, LP/NG, IM, and High groups, respectively. In the Low group, 9 of 29 (31%) men developed metastases, vs 131/285 (46%) in the LP/NG group (hazard ratio [HR] = 1.70, 95% confidence interval [CI]: 0.86-3.35), 175/320 (55%) in the IM group (HR = 2.52, 95% CI: 1.28-4.91) and 238/374 (64%) in the High group (HR = 3.63, 95% CI: 1.85-7.10). Mean time to death was 32, 30, 24, 21 months in the Low, LP/NG, IM, High groups, respectively. There were 8 deaths in the Low group (27.6%), vs 101 (35.4%) (HR = 1.35, 95% CI: 0.65-2.79) in the LP/NG group, 124 (38.8%) (HR = 1.79, 95% CI: 0.87-3.70) in the IM group and 197 (52.7%) (HR = 2.96, 95% CI: 1.45-6.05) in the High group. The High risk group was more likely to develop metastasis during the first year and die within the first 2 years. Conclusions: Metastasis and death occurred earlier and more frequently in the Intermediate and High groups relative to the Low risk group. These findings may further inform diagnostic and management strategies for combating disease progression.