Citations

PurposeTo commission an open source Monte Carlo (MC) dose engine, “MCsquare” for a synchrotron‐based proton machine, integrate it into our in‐house C++‐based I/O user interface and our web‐based software platform, expand its functionalities, and improve calculation efficiency for intensity‐modulated proton therapy (IMPT).MethodsWe commissioned MCsquare using a double Gaussian beam model based on in‐air lateral profiles, integrated depth dose of 97 beam energies, and measurements of various spread‐out Bragg peaks (SOBPs). Then we integrated MCsquare into our C++‐based dose calculation code and web‐based second check platform “DOSeCHECK.” We validated the commissioned MCsquare based on 12 different patient geometries and compared the dose calculation with a well‐benchmarked GPU‐accelerated MC (gMC) dose engine. We further improved the MCsquare efficiency by employing the computed tomography (CT) resampling approach. We also expanded its functionality by adding a linear energy transfer (LET)‐related model‐dependent biological dose calculation.ResultsDifferences between MCsquare calculations and SOBP measurements were <2.5% (<1.5% for ~85% of measurements) in water. The dose distributions calculated using MCsquare agreed well with the results calculated using gMC in patient geometries. The average 3D gamma analysis (2%/2 mm) passing rates comparing MCsquare and gMC calculations in the 12 patient geometries were 98.0 ± 1.0%. The computation time to calculate one IMPT plan in patients’ geometries using an inexpensive CPU workstation (Intel Xeon E5‐2680 2.50 GHz) was 2.3 ± 1.8 min after the variable resolution technique was adopted. All calculations except for one craniospinal patient were finished within 3.5 min.ConclusionsMCsquare was successfully commissioned for a synchrotron‐based proton beam therapy delivery system and integrated into our web‐based second check platform. After adopting CT resampling and implementing LET model‐dependent biological dose calculation capabilities, MCsquare will be sufficiently efficient and powerful to achieve Monte Carlo‐based and LET‐guided robust optimization in IMPT, which will be done in the future studies.

AbstractObjectivesIn the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes of progression‐free survival (PFS) benefit vs placebo‐Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT).MethodsRNA sequencing data were used to investigate the basis of these differences.ResultsThe PFS benefit of IRd vs placebo‐Rd was greater in patients with tumors expressing high c‐MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c‐MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c‐MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81.ConclusionsPFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c‐MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE‐MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537

Background Social determinants of health are relevant to cardiovascular outcomes but have had limited examination in atrial fibrillation (AF). Objectives The purpose of this study was to examine the association of annual household income and cardiovascular outcomes in individuals with AF. Methods We analysed administrative claims for individuals with AF from 2009 to 2015 captured by a health claims database. We categorised estimates of annual household income as <$40 000; $40–$59 999; $60–$74 999; $75–$99 999; and ≥$100 000. Covariates included demographics, education, cardiovascular disease risk factors, comorbid conditions and anticoagulation. We examined event rates by income category and in multivariable-adjusted models in reference to the highest income category (≥$100 000). Results Our analysis included 336 736 individuals (age 72.7±11.9 years; 44.5% women; 82.6% white, 8.4% black, 7.0% Hispanic and 2.1% Asian) with AF followed for median (25th and 75th percentile) of 1.5 (95% CI 0.6 to 3.0) years. We observed an inverse association between income and heart failure and myocardial infarction (MI) with evidence of progressive risk across decreased income categories. Individuals with household income <$40 000 had the greatest risk for heart failure (HR 1.17; 95% CI 1.05 to 1.30) and MI (HR 1.18; 95% CI 0.98 to 1.41) compared with those with income ≥$100 000. Conclusions We identified an association between lower household income and adverse outcomes in a large cohort of individuals with AF. Our findings support consideration of income in the evaluation of cardiovascular risk in individuals with AF.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on the clinical presentation and workup of suspected bladder cancer, treatment of non–muscle-invasive urothelial bladder cancer, and treatment of metastatic urothelial bladder cancer because important updates have recently been made to these sections. Some important updates include recommendations for optimal treatment of non–muscle-invasive bladder cancer in the event of a bacillus Calmette-Guérin (BCG) shortage and details about biomarker testing for advanced or metastatic disease. The systemic therapy recommendations for second-line or subsequent therapies have also been revised. Treatment and management of muscle-invasive, nonmetastatic disease is covered in the complete version of the NCCN Guidelines for Bladder Cancer available at NCCN.org . Additional topics covered in the complete version include treatment of nonurothelial histologies and recommendations for nonbladder urinary tract cancers such as upper tract urothelial carcinoma, urothelial carcinoma of the prostate, and primary carcinoma of the urethra.

Introduction Severe obesity is a growing epidemic that causes significant morbidity and mortality, and is particularly difficult to reverse. Efficacious and cost-effective interventions are needed to combat this epidemic. This study hypothesized that obese people (body mass index (BMI) ≥35 kg/m 2 ) using a remote weight-loss program combining a mobile application, wireless scales, and low-calorie meal replacement would experience clinically significant weight loss. Methods This study was a retrospective observational analysis of 8275 individuals with a baseline BMI ≥35 kg/m 2 who used a remote weight-loss program combining mobile applications, frequent self-weighing, and calorie restriction via meal replacement for a minimum of 35 days. Weight changes were evaluated at multiple intervals (42, 60, 90, and 120 days), and weight loss was evaluated for all and for pre-specified subgroups based on demographic features and frequency of self-weighing. Results Mean weight loss at 42 days ( N = 6781) was 8.1 kg (margin of error (MOE) = 0.126 kg) with 73.6% of users experiencing >5% total body weight loss. Both men (9.1 kg; MOE = 0.172 kg; 7.9% from baseline) and women (7.1 kg; MOE = 0.179 kg; 7.2% from baseline) experienced significant weight loss. At the 120-day interval ( N = 2914), mean weight loss was 14 kg (MOE = 0.340 kg), 13% total body weight loss from baseline, and 82.3% of participants had lost >5% of their initial body weight. The decrease in body-fat percent correlated well with weight loss ( R = 0.92; p < 0.001). Conclusions In a large cohort of individuals with class II or III obesity, a remote weight-loss program combining mobile applications, daily self-weighing, and calorie restriction via meal replacement resulted in dramatic weight loss among subjects who were active users when evaluated through a retrospective observational analysis.

AbstractThe diagnosis of primary plasma cell leukemia (pPCL) has been made by quantifying circulating plasma cells (cPCs) morphologically on a peripheral blood (PB) smear. However, this technique is not sufficiently sensitive. Multiparametric flow cytometry (MFC) provides a readily available and highly sensitive method to identify and quantify cPCs that could complement PB smear assessment. However, an optimal quantitative cutoff for cPCs by MFC to identify pPCL has not been established. Thus, a total of 591 patients newly diagnosed multiple myeloma (NDMM) patients who had their PB samples evaluated morphologically by PB smear, and immunophenotypically by MFC prior to beginning therapy were evaluated. The presence of ≥200 cPCs/μL by MFC (N = 25 or 5% of the total population) was chosen to identify patients with ≥5% cPCs by PB smear with a specificity of 99% and a sensitivity of 77%. For patients with ≥200 cPCs/μL by MFC compared to the remainder of the cohort, the median Time to next therapy (TTNT) was 18 vs 30 months and the median OS was 38 vs 70 months respectively. Thus, MFC assessment of PB can be utilized in conjunction with the morphological assessment of a PB smear to aid in improving the identification of pPCL among NDMM patients.

Background: Polypharmacy is highly prevalent in elderly individuals with chronic conditions, including atrial fibrillation (AF). The impact of polypharmacy on adverse outcomes and on treatment effectiveness in elderly AF patients remains unaddressed. Methods: We studied 338,810 AF patients ≥75 years of age with 1,761,660 active prescriptions [mean (SD), 5.1 (3.8) per patient] enrolled in the MarketScan Medicare Supplemental database in 2007-2015. Polypharmacy was defined as ≥5 active prescriptions at AF diagnosis based on outpatient pharmacy claims. AF treatments (oral anticoagulation, rhythm and rate control) and cardiovascular endpoints (ischemic stroke, bleeding, heart failure) were defined based on inpatient, outpatient and pharmacy claims. Multivariable Cox models were used to estimate associations of polypharmacy with cardiovascular endpoints and the interaction between polypharmacy and AF treatments in relation to cardiovascular endpoints. Results: Prevalence of polypharmacy was 52% (176,007 of 338,810). Patients with polypharmacy had increased risk of major bleeding [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.12, 1.20] and heart failure (HR 1.33, 95%CI 1.29, 1.36), but not of ischemic stroke (HR 0.96, 95%CI 0.92, 1.00), compared to those not with polypharmacy (Table). Polypharmacy status did not consistently modify the effectiveness of oral anticoagulants. However, rhythm control (vs. rate control) was more effective in preventing heart failure hospitalization in patients not with polypharmacy (HR 0.87, 95%CI 0.76, 0.99) than among those with polypharmacy (HR 0.98, 95%CI 0.91, 1.07, p for interaction = 0.02). Conclusion: Polypharmacy is frequent among elderly patients with AF, associated with adverse outcomes, and potentially affecting the effectiveness of AF treatments. Optimizing management of polypharmacy in elderly AF patients may lead to improved outcomes.

Introduction: Women with atrial fibrillation (AF) experience greater symptomatology, worse quality of life, and have a higher risk of stroke as compared to men, but are less likely to receive rhythm control for the treatment of AF. Whether these differences exist in elderly patients with AF, and whether sex modifies the effectiveness of rhythm versus rate control therapy has not been assessed. Methods: We studied 135,850 men and 139,767 women 75 years or older diagnosed with AF in the MarketScan Medicare database between 2007-2015. Rate control was defined as use of rate control medication or atrioventricular node ablation. Rhythm control was defined by use of anti-arrhythmics, catheter ablation or cardioversion. Participants on both rate and rhythm were coded under rhythm control. We used multivariable logistic and Cox regression models to estimate 1) the association of sex and treatment strategy (within 30-day post AF diagnosis and entire follow-up) and, 2) the association of treatment strategy with incident heart failure, stroke and major bleeding. Results: Men were on average (SD) 82.5 (5.2) years old and women 83.8 (5.6) years, respectively. Women were less likely to receive rhythm control treatment as compared to men in the 30-day post AF diagnosis period (22% vs 27%), (OR 0.91, 95% CI 0.88, 0.94) and over the entire duration of follow-up (28% vs 32%) (HR 0.93, 95% CI 0.90, 0.96). Rhythm (vs. rate) control was associated with a higher risk of heart failure in women [HR 1.41, 95% CI 1.34, 1.49] than in men [HR, 1.21 95% CI 1.15, 1.28] (p for multiplicative interaction < 0.001, Table ). Sex did not modify associations between treatment and incident stroke or major bleeding events. Conclusion: Women aged 75 years and older were less likely to be prescribed rhythm control as compared to men, and experienced higher risk of heart failure than men when receiving rhythm (vs rate) control. Future studies will need to delve into the mechanisms underlying these differences.

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.

7006 Background: KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for adult R/R ALL. In an interim analysis of Phase 1 of ZUMA-3, we reported manageable safety and encouraging efficacy of KTE-X19; 72% of pts achieved a complete remission (CR) or CR with incomplete bone marrow (BM) recovery (CRi; Wierda et al, ASH 2018. #897). Here, we present end of Phase 1 results. Methods: Adults with R/R B cell ALL, > 5% BM blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 KTE-X19 cells/kg after conditioning chemotherapy. Revised adverse event management (rAE mgmt) was implemented for additional pts in a 1 × 106 dose cohort: corticosteroids were given earlier at onset of Grade ≥ 2 neurologic events (NEs) and tocilizumab was used only for active toxicity. The primary endpoint was the dose-limiting toxicity (DLT) rate. Key additional endpoints were KTE-X19 levels, incidence of AEs, minimal residual disease (MRD), and CR/CRi rate. Results: As of 9/27/18, 45 pts had received KTE-X19 (median follow-up [f/u], 16 mo). The median age was 46 y (range, 18–77); 30 pts (66%) had ≥ 3 prior therapies and the median pre-conditioning BM blasts was 70% (range, 0–97). Six, 23, and 16 pts received 2, 1, and 0.5 × 106 cells/kg, respectively. There were no DLTs in the DLT-evaluable pts. The most common Grade ≥ 3 AEs were hypotension (38%), pyrexia (38%) and thrombocytopenia (31%). There were 2 previously reported KTE-X19–related Grade 5 AEs of cerebral infarction and multiorgan failure, both in the context of CRS. Grade ≥ 3 CRS and NEs occurred in 13 (29%) and 17 (38%) pts, respectively. Of 41 pts with ≥ 2 mo of f/u, 68% had CR/CRi, and 73% had undetectable MRD. Of 19 pts with ≥ 2 mo of f/u treated with 1 × 106 cells/kg, 16 (84%) had a CR/CRi and the median event-free survival was 15 mo. In 9 pts treated with 1 × 106 cells/kg and rAE mgmt, 2 (22%) had Grade 3 CRS and 1 (11%) had Grade 3 NE with no Grade 4/5 events. Conclusions: KTE-X19 dosing and safety mgmt have been successfully refined by testing 3 cell doses and evaluating a new AE mgmt guideline with altered corticosteroids/tocilizumab use for NE/CRS. Pivotal Phase 2 is ongoing at the 1 × 106 dose with rAE mgmt. Clinical trial information: NCT02614066.