Citations

AbstractAlthough it is well established that human cytochrome P450 1 family enzymes are induced by cigarette smoking through activation of the Ah receptor, it is not known whether this leads to increased metabolic activation or detoxification of carcinogenic polycyclic aromatic hydrocarbons (PAH), which are present in cigarette smoke and the general environment. We gave oral doses of deuterated phenanthrene ([D10]Phe), a non-carcinogenic surrogate of carcinogenic PAH such as benzo[a]pyrene, to smokers (N = 170, 1 or 10 μg doses) and non-smokers (N = 57, 1 μg dose). Bioactivation products (dihydrodiol and tetraol) and detoxification products (phenols) of [D10]Phe were determined in 6-h urine to obtain a comprehensive metabolic profile. Cigarette smoking increased the bioactivation of [D10]Phe and decreased its detoxification resulting in significantly different metabolic patterns between smokers and non-smokers (P < 0.01), consistent with increased cancer risk in smokers. The Phe bioactivation ratios ([D10]PheT/total [D9]OHPhe) were significantly higher (2.3 (P < 0.01) to 4.8 (P < 0.001) fold) in smokers than non-smokers. With solid human in vivo evidence, our results for the first time demonstrate that cigarette smoking enhances the metabolic activation of Phe, structurally representative of carcinogenic PAH, in humans, strongly supporting their causal role in cancers caused by smoking. The results suggest potential new methods for identifying smokers who could be at particularly high risk for cancer.

Background: Microvascular dysfunction is known to play a key role in patients with angina and nonobstructive coronary artery disease. We investigated the impact of ranolazine among patients with angina and nonobstructive coronary artery disease. Methods: In this randomized, double-blinded, placebo-controlled pilot trial, 26 patients with angina once weekly or more, abnormal stress test, and nonobstructive coronary artery disease (<50% stenosis by angiography and fractional flow reserve >0.80) were randomized 1:1 to ranolazine or placebo for 12 weeks. Primary end point was ΔSeattle Angina Questionnaire (SAQ) angina frequency score. Baseline and 3 months follow-up SAQ, Duke Activity Status Index scores along with invasive fractional flow reserve, coronary flow reserve (CFR), hyperemic myocardial resistance, and cardiopulmonary exercise testing measurements were performed. Results: No significant differences in ΔSAQ angina frequency scores ( P =0.53) or Duke Activity Status Index ( P =0.76) were observed between ranolazine versus placebo, although patients on ranolazine had lesser improvement in SAQ physical limitation scores ( P =0.02) compared with placebo at 3 months. There were no significant differences in ΔCFR or Δhyperemic myocardial resistance between ranolazine and placebo groups. Patients treated with ranolazine, compared with placebo, had no significant improvement in maximum rate of oxygen consumption measured during incremental exercise (VO 2 max) and peak metabolic equivalents of task. Interestingly, in the ranolazine group, patients with baseline CFR<2.0 demonstrated greater gain in CFR compared with those with baseline CFR≥2.0 ( P =0.02). Conclusions: Ranolazine did not demonstrate improvement in SAQ angina frequency score, invasive microvascular function, or peak metabolic equivalent compared with placebo at 3 months. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02147067.

Abstract Background Heart transplant (HTx) patients can develop graft dysfunction (GD) without biopsy evidence of cell or antibody mediated rejection. Cardiac MRI (CMR) can detect inflammatory or infiltrative causes of cardiomyopathy however CMR findings in HTx recipients with GD have not been previously described. Purpose We sought to identify CMR characteristics of HTx patients with GD, and evaluate its additive value in its diagnosis and prognosis. Methods CMR has been performed routinely to evaluate GD at our institutions. There were 37 HTx recipients who presented with acute decline in left ventricular ejection fraction (LVEF) of &lt;50% and &gt;10% from baseline, with no biopsy evidence of rejection between 2007 and 2018. Coronary angiogram with IVUS was done to rule out allograft vasculopathy. Treatment of GD was per discretion of the treating clinician. Responders were defined as those with LVEF improvement &gt;10% at 180 days or greater post-presentation. LV and RV indices, the presence and pattern of late gadolinium enhancement (LGE) were determined by CMR. Results There were 34% females and mean age at transplant was 49±13 years. Median time from HTx to GD was 1.2 years. Presenting symptoms were heart failure (n=25), cardiogenic shock (n=1) and 11 patients were asymptomatic. Mean LVEF at presentation was 37±12% and donor specific antibodies were detected in 38% patients. Most patients were treated with steroid bolus (n=29), and/or plasmapheresis (n=23). There were no major changes made in immunosuppression in 6 patients. Delayed enhancement MRI was performed with standard inversion-recovery (IR) gradient echo sequences, between 5 and 20 minutes after institutional-standard protocol administration of IV gadolinium contrast. Biventricular LGE was present in 18/37 (49%) patients with GD and was more prevalent in responders (57%, 13 of 23) than non-responders (35%, 5 of 14), although not statistically significant (p=0.21). There were two patterns of LGE noted: 1) Diffuse epicardial (10 patients out which 9 were responders) and 2) Patchy pattern with non-specific distribution (8 patients out of which 4 were responders). Myocardial edema by triple IR sequencing was seen in 6 patients, all having diffuse epicardial pattern of enhancement matching the delayed enhancement pattern. When comparing different treatment groups, among those treated for GD (n=31), 12 of 21 (57%) responders had LGE and 4 of 10 (40%) non-responders had LGE (p=0.37), a pattern similar to the broader population. Among those not treated for GD (n=6), 1 of 2 responders had LGE and 1 of 4 non-responders had LGE (p=0.5). Conclusion CMR identified inflammation as a potential cause of GD in approximately 50% of HTx patients. There are 2 distinct patterns of LGE observed in GD, diffuse epicardial (56%) and patchy (44%). Although the presence of LGE in itself is not associated with myocardial recovery, 90% of patients with a diffuse epicardial pattern have recovery of GD. Funding Acknowledgement Type of funding source: None

INTRODUCTION: Using the National Cancer Database, we assessed the relationship between facility overall esophageal adenocarcinoma (EAC) case volume and survival. METHODS: We categorized facilities into volume quintiles based on annual EAC patient volume and performed a multivariable Cox proportional hazards regression between facility patient volume and survival. RESULTS: In a cohort of 116,675 patients, facilities with higher vs lower (≥25 vs 1–4 cases) annual EAC patient volume demonstrated improved survival (adjusted hazard ratio: 0.80. 95% confidence interval: 0.70–0.91). DISCUSSION: This robust volume-outcome effect calls for centralization of care for EAC patients at high annual case volume facilities.

Abstract Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers, such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity, two key risk factors in multiple myeloma disease prevalence, suggesting that BMAds may influence and be influenced by myeloma cells in the marrow. Here, we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAds play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from patients with multiple myeloma revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different preclinical murine models of multiple myeloma and in vitro using myeloma cell-adipocyte cocultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. In vivo, senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAds, in turn, provided resistance to dexamethasone-induced cell-cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug-resistant clone. Our findings reveal that bidirectional interactions between BMAds and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the BMAd or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma. Significance: This study changes the foundational understanding of how cancer cells hijack the bone marrow microenvironment and demonstrates that tumor cells induce senescence and metabolic changes in adipocytes, potentially driving new therapeutic directions.

Objective: To assess the efficacy and safety of closed-loop control (CLC) insulin delivery system in adolescents and young adults with type 1 diabetes. Research Design and Methods: Prespecified subanalysis of outcomes in adolescents and young adults aged 14–24 years old with type 1 diabetes in a previously published 6-month multicenter randomized trial. Participants were randomly assigned 2:1 to CLC (Tandem Control-IQ) or sensor augmented pump (SAP, various pumps+Dexcom G6 CGM) and followed for 6 months. Results: Mean age of the 63 participants was 17 years, median type 1 diabetes duration was 7 years, and mean baseline HbA1c was 8.1%. All 63 completed the trial. Time in range (TIR) increased by 13% with CLC versus decreasing by 1% with SAP (adjusted treatment group difference = +13% [+3.1 h/day]; 95% confidence interval [CI] 9–16, P < 0.001), which largely reflected a reduction in time >180 mg/dL (adjusted difference −12% [−2.9 h/day], P < 0.001). Time <70 mg/dL decreased by 1.6% with CLC versus 0.3% with SAP (adjusted difference −0.7% [−10 min/day], 95% CI −1.0% to −0.2%, P = 0.002). CLC use averaged 89% of the time for 6 months. The mean adjusted difference in HbA1c after 6 months was 0.30% in CLC versus SAP (95% CI −0.67 to +0.08, P = 0.13). There was one diabetic ketoacidosis episode in the CLC group. Conclusions: CLC use for 6 months was substantial and associated with improved TIR and reduced hypoglycemia in adolescents and young adults with type 1 diabetes. Thus, CLC has the potential to improve glycemic outcomes in this challenging age group. The clinical trial was registered with ClinicalTrials.gov (NCT03563313).

Background: Data are limited on the need for and benefits of pump setting optimization with automated insulin delivery. We examined clinical management of a closed-loop control (CLC) system and its relationship to glycemic outcomes. Materials and Methods: We analyzed personal parameter adjustments in 168 participants in a 6-month multicenter trial of CLC with Control-IQ versus sensor-augmented pump (SAP) therapy. Preset parameters (BR = basal rates, CF = correction factors, CR = carbohydrate ratios) were optimized at randomization, 2 and 13 weeks, for safety issues, participant concerns, or initiation by participants' usual diabetes care team. Time in range (TIR 70–180 mg/dL) was compared in the week before and after parameter changes. Results: In 607 encounters for parameter changes, there were fewer adjustments for CLC than SAP (3.4 vs. 4.1/participant). Adjustments involved BR (CLC 69%, SAP 80%), CR (CLC 68%, SAP 50%), CF (CLC 44%, SAP 41%), and overnight parameters (CLC 62%, SAP 75%). TIR before and after adjustments was 71.2% and 71.3% for CLC and 61.0% and 62.9% for SAP. The highest baseline HbA 1c CLC subgroup had the largest TIR improvement (51.2% vs. 57.7%). When a CR was made more aggressive in the CLC group, postprandial time >180 mg/dL was 43.1% before the change and 36.0% after the change. The median postprandial time <70 mg/dL before making CR less aggressive was 1.8%, and after the change was 0.7%. Conclusions: No difference in TIR was detected with parameter changes overall, but they may have an effect in higher HbA 1c subgroups or following user-directed boluses, suggesting that changes may matter more in suboptimal control or during discrete periods of the day. Clinical Trials Registration number: NCT03563313.

Introduction: While the COVID-19 pandemic has affected many aspects of clinical care, research, and medical training, its impact on hematology-oncology trainees and professional development has not been described. The American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO) sought to assess the impact of COVID-19 on fellows enrolled in hematology-oncology programs. Methods: In spring 2020, ASH and ASCO developed and administered a survey by e-mail to active hematology-oncology fellow members. Response formats used both a semi-Likert scale and open-ended text. Questions focused on fellow experiences and how changes in their programs have impacted their personal and professional lives across several domains. Multiple-choice responses were analyzed using descriptive statistics, and NVivo software was used for qualitative analysis of open-ended questions. Results: Respondent demographics are described in Table 1. Of 2,306 trainees, 620 (27%) responded to the survey. Most respondents continued patient care responsibilities during the pandemic (80%). Almost half of all trainees (47%) reported that they felt less productive than usual. Stress and/or anxiety about the current situation was the most cited factor affecting productivity in the overall cohort (Figure 1). One-third (33%) of respondents had volunteered or were assigned to clinical/non-clinical COVID-19-related efforts. Of the 90 visa holders in our cohort, 30% (N=27) reported experiencing issues with their visa/immigration status. Eight percent of respondents stated their career plans had changed due to COVID-19. Of those who said their plans had changed, 30 respondents were considering careers in academia pre-pandemic and 11 were considering private practice. However, only 14 respondents were considering academia post-pandemic while 19 were interested in private practice. Overall, most respondents had concerns about at least one of the following: salary reductions, availability of networking events, family well-being, mental health and obtaining a job (Figure 2). The prevalence of burnout increased from 22% (N=105) before the pandemic to 33% (N=161) during (p&lt;.001). Of the respondents who did not report burnout before COVID-19, 22% noted new-onset burnout during the pandemic. New-onset burnout prevalence varied based on the type of work respondents performed: no COVID-related work (17%), COVID-related non-clinical work (26%), and COVID-related clinical work (34%) (p&lt;0.01). The open-ended responses yielded several consistent themes. Clinical and educational constraints were enumerated: lost learning opportunities due to low patient volumes, unavailability of colleagues to discuss cases, and overall low perceived quality of virtual learning. Trainees also reported reduced motivation to complete work within a stipulated time frame due to lack of robust discussions in the virtual environment and technological challenges in navigating educational resources. Trainee research was also severely impacted as laboratories closed, experimental animal colonies were lost, and many research activities ceased. Respondents also expressed concern that cuts in research training initiatives and budgets would jeopardize faculty positions for graduating fellows and that funding for travel and conferences was suspended. Fellows' recommendations for ASH and ASCO included improved online education, virtual research training and networking opportunities, practical guidance on caring for immune-compromised patients during the pandemic, increased funding resources for trainees, mental health resources, and advocating on behalf of trainee visa holders. Conclusions: Hematology-oncology trainees reported their training experiences have been deeply impacted by the COVID-19 pandemic. A majority of trainees are concerned about the negative impact on career opportunities, research funding, financial well-being, and mental health. Burnout increased during COVID-19, especially in trainees who were assigned to specific COVID-related efforts. Training programs and professional societies can support trainees by increasing trainee research funding, online networking and learning opportunities, mental health resources and, support for international trainees. Disclosures Velazquez Manana: Corbus Pharmaceuticals: Other: Immediate family member stock ownership; Portola Pharmaceuticals: Other: Immediate family member stock ownership; Midatech: Other: Immediate family member stock ownership. Wun:Glycomimetics, Inc.: Consultancy.

AbstractBackgroundConsensus definitions for transfusion‐related acute lung injury (TRALI) and transfusion‐associated circulatory overload (TACO) have recently been revised; however, pulmonary transfusion reactions remain difficult to diagnose. We hypothesized that N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) levels could have utility in the identification and classification of pulmonary transfusion reactions.Study design and methodsWe performed a secondary analysis of a case‐control study of pulmonary transfusion reactions at four academic hospitals. We evaluated clinical data and measured NT‐proBNP levels prior to and following transfusion in patients with TACO (n = 160), transfused acute respiratory distress syndrome (ARDS) [n = 51], TRALI [n = 12], TACO/TRALI [n = 7], and controls [n = 335]. We used Wilcoxon Rank‐Sum tests to compare NT‐proBNP levels, and classification and regression tree (CART) algorithms to produce a ranking of covariates in order of relative importance for differentiating TACO from transfused controls.ResultsPre‐transfusion NT‐proBNP levels were elevated in cases of transfused ARDS and TACO (both P < .001) but not TRALI (P = .31) or TACO/TRALI (P = .23) compared to transfused controls. Pre‐transfusion NT‐proBNP levels were higher in cases of transfused ARDS or TRALI with a diagnosis of sepsis compared to those without (P < .05 for both). CART analyses resulted in similar differentiation of patients with TACO from transfused controls for models utilizing either NT‐proBNP levels (AUC 0.83) or echocardiogram results (AUC 0.80).ConclusionsNT‐proBNP levels may have utility in the classification of pulmonary transfusion reactions. Prospective studies are needed to test the predictive utility of pre‐transfusion NT‐proBNP in conjunction with other clinical factors in identifying patients at risk of pulmonary transfusion reactions.