Citations

Objectives: Pulmonary complications are common following hematopoietic stem cell transplantation. Numerous idiopathic post-transplantation pulmonary syndromes have been described. Patients at the severe end of this spectrum may present with hypoxemic respiratory failure and pulmonary infiltrates, meeting criteria for acute respiratory distress syndrome. The incidence and outcomes of acute respiratory distress syndrome in this setting are poorly characterized. Design: Retrospective cohort study. Setting: Mayo Clinic, Rochester, MN. Patients: Patients undergoing autologous and allogeneic hematopoietic stem cell transplantation between January 1, 2005, and December 31, 2012. Interventions: None. Measurements and Main Results: Patients were screened for acute respiratory distress syndrome development within 1 year of hematopoietic stem cell transplantation. Acute respiratory distress syndrome adjudication was performed in accordance with the 2012 Berlin criteria. In total, 133 cases of acute respiratory distress syndrome developed in 2,635 patients undergoing hematopoietic stem cell transplantation (5.0%). Acute respiratory distress syndrome developed in 75 patients (15.6%) undergoing allogeneic hematopoietic stem cell transplantation and 58 patients (2.7%) undergoing autologous hematopoietic stem cell transplantation. Median time to acute respiratory distress syndrome development was 55.4 days (interquartile range, 15.1–139 d) in allogeneic hematopoietic stem cell transplantation and 14.2 days (interquartile range, 10.5–124 d) in autologous hematopoietic stem cell transplantation. Twenty-eight-day mortality was 46.6%. At 12 months following hematopoietic stem cell transplantation, 89 patients (66.9%) who developed acute respiratory distress syndrome had died. Only 7 of 133 acute respiratory distress syndrome cases met criteria for engraftment syndrome and 15 for diffuse alveolar hemorrhage. Conclusions: Acute respiratory distress syndrome is a frequent complication following hematopoietic stem cell transplantation, dramatically influencing patient-important outcomes. Most cases of acute respiratory distress syndrome following hematopoietic stem cell transplantation do not meet criteria for a more specific post-transplantation pulmonary syndrome. These findings highlight the need to better understand the risk factors underlying acute respiratory distress syndrome in this population, thereby facilitating the development of effective prevention strategies.

Abstract 5-Fluorouracil (5-FU) is a cornerstone drug for the treatment of several aggressive tumors; however, adverse 5-FU toxicity contributes to approximately 1,300 deaths annually in the U.S. While three genetic variations in dihydropyrimidine dehydrogenase (DPD; DPYD gene) are well-established predictors of toxicity (i.e., *2A, I560S, D949V), the contributions of additional reported missense DPYD variants (>130) have not been adequately evaluated in clinical studies. Our lab has previously developed methods to study DPYD variants for potential clinical relevance to 5-FU toxicity using in vitro and cellular approaches (see Offer et al. Cancer Research 2013 & 2014). In the current study, we measured the in vitro enzyme activity of 47 uncharacterized missense variants that have been previously reported in dbSNP and NHLBI ESP databases. Additionally, we assessed the impact of these variants on 5-FU sensitivity in multiple transgenic human cellular models using real-time cellular analysis. Approximately one-third of the studied variants showed significantly reduced enzyme activity compared to wild type. Of the DPD-deficient variants identified in this study, 8 were profoundly deficient (<12.5% of “wildtype” activity), with enzyme activities similar to *2A. Two deficient variants showed modest reductions in enzyme activity (12.5-25% activity), similar to I560S. The remaining 5 deleterious variants exhibited mild deficiency (>25% activity, but significantly lower than “wildtype”), similar to D949V. Cellular sensitivity to 5-FU for cells expressing these variants paralleled the in vitro enzyme activity results, with deleterious variants showing reduced tolerance to 5-FU relative to cells transgenic for wildtype DPD. These trends were observed in multiple cell lines derived from various tissues and tumor types. Overall, our results add to the growing database of deleterious DPYD variations. Many of these variants have been observed primarily in non-Caucasian racial groups, consistent with our previous reports. These data suggest that the deleterious variants classified in this study may be important predictors of 5-FU toxicity, particularly in individuals of non-Caucasian ancestry. Additionally, these data suggest that genetic testing for rare variants may improve the success of predictive tests for 5-FU toxicity. Finally, this study suggests that in vitro and cellular models may be important pharmacogenomic methods to rapidly characterize variants of potential relevance in additional drug-gene pathways. Citation Format: Shikshya Shrestha, Steve Offer, Robert B. Diasio. Functional analysis of rare dihydropyrimidine dehydrogenase variants relevant to 5-fluorouracil toxicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5487. doi:10.1158/1538-7445.AM2015-5487

ObjectivesPrior analysis at our institution found that patients with hypertrophic cardiomyopathy (HCM) who experience postprandial symptoms (PPS) are more likely to have resting left ventricular outflow tract (LVOT) obstruction and reduced quality of life. Our objective was to determine whether PPS in patients with HCM vs healthy subjects occur as a result of measurable hemodynamic alterations in the postprandial hemodynamic response.MethodsWe conducted a prospective cross‐sectional study examining 45 patients with HCM and 10 controls who underwent fasting and postprandial 2‐dimensional Doppler echocardiography. Postprandial echocardiographic measurements were obtained at symptom onset or 30 minutes after consumption of a standardized meal, whichever occurred first.ResultsThe HCM population included 18 (40%) patients with PPS and 27 (60%) without PPS. Compared to controls, mean resting peak LVOT gradient was 23.4 ± 17.6 mmHg in HCM patients with PPS and 25.1 ± 33.1 mmHg in those without PPS (P = 0.10). The mean change in peak LVOT gradient after a meal was 0.7 ± 1.1 mmHg for controls, 5.0 ± 8.3 mmHg for HCM patients with PPS, and 1.5 ± 18.2 mmHg for HCM patients without PPS (P = 0.64).ConclusionAlthough the ability to provoke an increased LVOT gradient with a postprandial, upright exercise study protocol was recently reported, the current study suggests that a resting, supine, postprandial protocol does not elicit evidence of LVOT obstruction. Therefore, future investigations should consider whether simply performing an upright postprandial study in HCM patients with PPS will provide evidence of dynamic LVOT or if the addition of an exercise component is necessary.