Citations

1083 Background: Pixantrone (Pix) is a novel aza-anthracenedione with structural similarities to mitoxantrone and promising activity against non-Hodgkin’s lymphoma. Due to the lack of iron binding it is theorized to exhibit less cardiotoxicity than the anthracyclines. Methods: N1031 is a phase II RCT of 2 schedules of Pix, in pts with MBC. Group A pts received 180mg/m2 IV q3 wks, and group B pts 85mg/m2 IV on days 1, 8, 15 q4 wks. Eligibility included prior exposure to anthracyclines and/or taxanes, and 1 to 3 regiments in the metastatic setting (minimum of 2 if no prior adjuvant therapy given). Due to lack of long term cardiac safety data no more than 12 cycles were allowed. Frequent cardiac imaging was performed per protocol. Primary endpoint was RR and secondary endpoints included PFS, OS, safety, and QOL. Planned sample size was 25 pts per group. Results: In total 46 pts were evaluable (23 per group), mean age 55.5 yrs (range 38-79), 37% PS 0, 52% PS 1, and 11% PS 2. 80% of pts had prior exposure to doxorubicin, 72% had prior (neo)-adjuvant therapy, 76% were ER+ and 57% received prior HT. Number of prior metastatic regiments was: 1 (28%), 2 (61%) and 3 (11%). Most common adverse events (%) of any grade were: alopecia (74), anemia (74), fatigue (85), nausea (67), ANC decrease (87), and skin disorder (41). Grade 3-4 adverse events (%) at least possibly attributed to Pix and occurring in at least 2 pts were: ANC decrease (57), fatigue (9), increased AST (4%). One pt from each group (4%) had a grade 3 decrease in EF. There were no major differences between the two groups except for more oral mucositis in group A (35% vs 4%). Median number of cycles was 3 in group A (range 1-12) and 2 in group B (range 1-8). There was only 1 confirmed tumor response per group (4%,95% CI: 0.1-22%) prompting early termination of the trial. The median PFS was 2.7 mo (95% CI: 1.8-3.8), and the median OS was 8.9 mo (95% CI: 7.5-N/A). Conclusions: Pixantrone has insufficient activity in patients with MBC exposed to prior anthracyclines and/or taxanes. Adverse events were similar to prior experience with Pix. There were no major differences between the 2 schedules of administration. There was no significant cardiac toxicity seen in this trial. Correlative studies are underway.

1048 Background: Previous trials with p plus gem show significant antitumor activity in MBC. Nab-p has lower toxicity compared to p with similar therapeutic effects. This study assessed proportion of confirmed tumor responses and toxicity profile of this combination. Methods: Single stage phase II study enrolled patients (pts) with measurable MBC eligible for 1st line chemotherapy (chemo). Pts treated (tx) with nab-p 125 mg/m2 followed by gem 1,000 mg/m2 days 1 and 8 of 21 day cycle. Dose modifications allowed for both drugs. Primary endpoint was proportion of confirmed responses; complete response (CR), partial response (PR) by RESIST criteria on two consecutive evaluations at least 6 weeks apart. 41 evaluable pts required to test the null hypothesis that the confirmed response rate was at most 40% against the alternative of at least 60%. Results: 50 pts enrolled 11/05 to 5/06. Median age 56 (29–86). 40 pts (80%) visceral disease, 34 (68%) ER positive, 28 (56%) PR positive, 1 (2%) HER2 positive, 1 (2%) prior trastuzumab treatment (tx). 25 (50%) had prior adjuvant chemo, including 15 (30%) prior taxane. Median follow-up 7 mos (3–12). Median of 6 cycles of tx completed (1–15). 41 pts discontinued tx, due to progression (41%), pt refusal (27%), adverse events (17%), alternate tx (7%). Confirmed response rate 48% (95% CI: 34–63%): 4 CR, 20 PR. Median duration of response 6.6 mos (95% CI: 5.7, not reached), median progression-free survival (PFS) 7.9 mos (95% CI: 5.3–9.3). Rate of overall survival (OS) at 6 mos 91% (95% CI: 84–100%), 6 month PFS 58% (95% CI: 45–74%). Median OS not reached. 30 pts required dose delays on total of 52 cycles, mostly due to hematologic AEs. 9 pts (19%) had grade (gr) 4 adverse event (AE), 32 (67%) had maximum gr 3 AE. Most common gr 3/4 AEs: neutropenia (52%), fatigue (26%), anemia (14%), dyspnea (14%), thrombocytopenia (12%). Four pts had gr 3 neuropathy. Conclusions: Nab-paclitaxel in combination with gem has clear activity in patients with MBC. Manageable hematologic, but no other significant toxicities. Study ongoing to correlate efficacy with caveolin-1 levels with results expected Spring 2007. Follow up study of this combination with an anti-angiogenesis agent is in development. No significant financial relationships to disclose.

Background: Bevacizumab (BEV), a monoclonal antibody against vascular endothelial growth factor-A (VEGF-A), is a standard component of medical therapy of metastatic colorectal cancer (mCRC). Activation of alternative angiogenesis pathways has been implicated in resistance to BEV. This phase II study examines the activity of combined vertical blockade of VEGF signaling with sorafenib and BEV as salvage therapy in patients with progressive disease (PD) on all standard therapy in mCRC. Methods: mCRC patients with documented PD on standard therapy, received sorafenib (200 mg orally twice daily, days 1–5 and 8–12) and BEV (5 mg/kg intravenously, day 1) every 2 weeks. Primary endpoint was 3-month progression-free survival (PFS) rate and secondary endpoints were overall survival (OS), response rate (RR), safety, and feasibility. Results: Of the 83 patients enrolled, 79 were evaluable. Of these, 42 (53%) were progression-free at 3 months. Median PFS was 3.5 months and median OS was 8.3 months. One patient had a partial response and 50 patients (63.3%) had at least one stable tumor assessment. Of 79 evaluable patients, 54 (68%) experienced grade 3/4 adverse events (AEs) at least possibly related to treatment. Most frequent grade 3/4 AEs were: fatigue (24.1%), hypertension (16.5%), elevated lipase (8.9%), hand-foot skin reaction (8.9%), diarrhea (7.6%), and proteinuria (7.6%). Reasons for treatment discontinuation were PD (72%), AEs (18%), patient refusal (8%), physician decision (1%), and death (1%). Conclusions: The combination of BEV and sorafenib as salvage therapy in heavily pretreated mCRC patients is tolerable and manageable, with evidence of promising activity. ClinicalTrials.gov identifier: NCT00826540, URL: http://clinicaltrials.gov/ct2/show/NCT00826540

Background: The effective self-management of heart failure (HF) is highly dependent on cognitive function. Dementia frequently coexists with HF, but its exact prevalence and impact on health care utilization and death is not well understood. Methods: Residents from 7 southeast Minnesota counties with a first-ever code for HF (ICD-9 428 and ICD-10 I50) between 1/1/2012 and 12/31/2017 were identified. Dementia before and after the HF diagnosis was ascertained with codes recommended by the US Department of Health and Human Services. Patients were followed through 12/31/2018 for death and hospitalizations. Cox and Andersen-Gill models were used to examine associations between dementia (prior and post HF) and death and hospitalizations, respectively. Dementia after HF was analyzed as a time-dependent variable. Results: Among 6,312 patients with HF (mean age 75 years, 49% female), 636 (10%) had a prior diagnosis of dementia. After a mean (SD) follow-up of 3.1 (1.8) years, 601 (9.5%) patients were diagnosed with dementia post HF. The median time from HF to dementia was 1.3 years, with 43% of dementia cases occurring within 1 year and 64% within 2 years post HF. During follow-up, 2,678 deaths and 15,095 hospitalizations occurred. After adjustment, patients with dementia before HF had nearly a 2-times increased risk of death and 10% increased risk of hospitalization compared to those that did not have dementia (Table). Dementia after HF was associated with a 78% increased risk of death and 63% increased risk of hospitalization compared to those that did not have dementia. Conclusions: Approximately 10% of patients had dementia prior to HF and 10% develop dementia shortly after HF diagnosis. Patients with HF and dementia have an increased risk of death and hospitalization compared to dementia-free counterparts. These data underscore the importance of recognizing the presence and impact of dementia on outcomes in HF to optimize care delivery.

Introduction: Alcohol use is common in the United States. Most studies describe a J-shaped relationship between alcohol consumption and cognitive function: frequent heavy consumption alters brain functions and decreases cognitive performance; regular light and moderate consumption may have protective impact. We are unaware of any reports utilizing longitudinally collected data to derive a cumulative exposure of alcohol use and assess its association with cognitive function. Hypothesis: Cumulative 30-year exposure to alcohol has a J-shaped association with mid-life cognitive function. Methods: We included 3,068 participants aged 18-30 years at the baseline examination (1985-86) and having up to 8 follow-up exams at 2- to 5-year intervals including at 30 years (2015-16). Cumulative “drink-years” exposure to alcohol was estimated at each exam by multiplying the usual number of drinks/day reported by the number of years since last exam, and then summing across exams. We used multivariable adjusted linear regression models to assess the independent associations of number of drink-years with 6 measures of cognitive function studied at Year 30: Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), Stroop Test, Montreal Cognitive Assessment (MoCA), Category Fluency Test, and Letter Fluency Test. We used inverse probability of censoring weighting to account for potential informative censoring. Linear regression models estimated standardized mean test scores for the cumulative alcohol use categories (drink-years: >0 and <15, 15-29.9, 30+). Too few participants were available for assessment of higher categories of use. Results: Compared with never drinking, the 3 categories of cumulative exposure were unassociated with any of the cognitive function measures. Conclusions: Cumulative 30-year alcohol use is not associated with cognitive function in middle-aged adults in the CARDIA study.

Background: Current cardiovascular disease (CVD) risk scores are derived from research cohorts and are particularly inaccurate in women, older adults, and those with missing data. To overcome these limitations, we aimed to develop a cohort to capitalize on the depth and breadth of clinical data within electronic health record (EHR) systems in order to develop next-generation sex-specific risk prediction scores for incident CVD. Methods: All individuals 30 years of age or older residing in Olmsted County, Minnesota on 1/1/2006 were identified. We developed and validated algorithms to define a variety of risk factors, thus building a comprehensive risk profile for each patient. Outcomes including myocardial infarction (MI), percutaneous intervention (PCI), coronary artery bypass graft (CABG), and CVD death were ascertained through 9/30/2017. Results: We identified 73,069 individuals without CVD (Table). We retrieved a total of 14,962,762 lab results; 14,534,466 diagnoses; 17,062,601 services/procedures; 1,236,998 outpatient prescriptions; 1,079,065 heart rate measurements; and 1,320,115 blood pressure measurements. The median number of blood pressure and heart rate measurements ascertained per individuals were 11 and 9, respectively. The five most prevalent conditions were: hypertension, hyperlipidemia, arthritis, depression, and cardiac arrhythmias. During follow-up 1,455 MIs, 1,581 PCI, 652 CABG, and 2,161 CVD-related deaths occurred. Conclusions: We developed a cohort with comprehensive risk profiles and follow-up for each patient. Using sophisticated machine learning approaches, this electronic cohort will be utilized to develop next-generation sex-specific CVD risk prediction scores. These approaches will allow us to address several challenges with use of EHR data including the ability to 1) deal with missing values, 2) assess and utilize a large number of variables without over-fitting, 3) allow non-linear relationships, and 4) use time-to-event data.

Background: The focus of most existing phenotyping algorithms based on electronic health record (EHR) data has been to accurately identify cases and non-cases of specific diseases. However, a more challenging task is to accurately identify disease incidence, as identifying the first occurrence of disease is more important for efficient and valid clinical and epidemiological research. Moreover, stroke is a challenging phenotype due to diagnosis difficulty and common miscoding. This task generally requires utilization of multiple types of EHR data (e.g., diagnoses and procedure codes, unstructured clinical notes) and a more robust algorithm integrating both natural language processing and machine learning. In this study, we developed and validated an EHR-based classifier to accurately identify stroke incidence among a cohort of atrial fibrillation (AF) patients Methods: We developed a stroke phenotyping algorithm using International Classification of Diseases, Ninth Revision (ICD-9) codes, Current Procedural Terminology (CPT) codes, and expert-provided keywords as model features. Structured data was extracted from Rochester Epidemiology Project (REP) database. Natural Language Processing (NLP) was used to extract and validate keyword occurrence in clinical notes. A window of ±30 days was considered when including/excluding keywords/codes into the input vector. Frequencies of keywords/codes were used as input feature sets for model training. Multiple competing models were trained using various combinations of feature sets and two machine learning algorithms: logistic regression and random forest. Training data were provided by two nurse abstractors and included validated stroke incidences from a previously established atrial fibrillation cohort. Precision, recall, and F-score of the algorithm were calculated to assess and compare model performances. Results: Among 4,914 patients with atrial fibrillation, 1,773 patients were screened. 3,141 patients had no stroke-related codes or keywords and were presumed to be free of stroke during follow-up. Among the screened patients, 740 had validated strokes and 1,033 did not have a stroke based on review of the EHR by trained nurse abstractors. The best performing stroke incidence phenotyping classifier utilized Keywords+ICD-9+CPT features using a random forest classifier, achieving a precision of 0.942, recall of 0.943, and F-score of 0.943. Conclusion: In conclusion, we developed and validated a stroke algorithm that performed well for identifying stroke incidence in an enriched population (AF cohort), which extends beyond the typical binary case/non-case stroke identification problem. Future work will involve testing the generalizability of this algorithm in a general population.

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

Purpose: Cystinuria is a genetic disorder with both autosomal recessive and incompletely dominant inheritance. The disorder disrupts cystine and other dibasic amino acid transport in proximal tubules of the kidney, resulting in recurrent kidney stone formation. Currently, there are no consensus guidelines on evaluation and management of this disease. This article represents the consensus of the author panel and will provide clinicians with a stepwise framework for evaluation and clinical management of patients with cystinuria based on evidence in the existing literature. Materials and Methods: A search of MEDLINE ® /PubMed ® and Cochrane databases was performed using the following key words: “cystine nephrolithiasis,” “cystinuria,” “penicillamine, cystine,” and “tiopronin, cystine.” In total, as of May 2018, these searches yielded 2335 articles, which were then evaluated for their relevance to the topic of evaluation and management of cystinuria. Evidence was evaluated by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Results: Twenty-five articles on the topic of cystinuria or cystine nephrolithiasis were deemed suitable for inclusion in this study. The literature supports a logical evaluation process and step-wise treatment approach beginning with conservative measures: fluid intake and dietary modification. If stone formation recurs, proceed to pharmacotherapeutic options by first alkalinizing the urine and then using cystine-binding thiol drugs. Conclusions: The proposed clinical pathways provide a framework for efficient evaluation and treatment of patients with cystinuria, which should improve overall outcomes of this rare, but highly recurrent, form of nephrolithiasis.