Citations

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Abstract Introduction Right ventricular (RV) size informs about prognosis and need for pulmonary valve replacement in patients with repaired tetralogy of Fallot (rTOF). Cardiac magnetic resonance (CMR) is considered the reference standard for measurement of RV volumes. Despite known limitations for RV evaluation, 2D transthoracic echocardiography (TTE) remains the primary and most available imaging modality in the rTOF population. Purpose To determine which TTE RV size parameters best correlate with CMR-derived indexed RV end-diastolic (RVEDVi) and end-systolic (RVESVi) volumes in the rTOF population. We sought to determine the best TTE measurement thresholds to predict normal RV volume (RVEDVi ≤110 mL/m2) and significant RV dilatation by CMR (RVEDVi ≥150ml/m2). Method We retrospectively enrolled all rTOF patients followed at a single-center between 2010 and 2018 who had both TTE and CMR exams performed within a 12-month interval. All TTE exams were reviewed by an observer measuring RV areas, RV inlet and RV outlet at end-diastole and end-systole. Analyses of CMR studies were performed by 3 observers who measured RV area, RV inlet, RV outlet and RV volumes at end-diastole and end-systole. Correlations between TTE and CMR parameters were performed using Pearson correlation coefficients. Using the TTE RV parameters with the strongest correlation with CMR, we subsequently determined thresholds to predict a CMR RVEDVi ≤110ml/m2 and ≥150ml/m2 using ROC analysis. Results We enrolled 130 patients (59 women [45%], mean age 43±12.8 years). Median age at TOF repair was 4 [3–6] years; 18 patients (14%) had subsequent pulmonary valve replacement. Median interval between TTE and CMR exams was 114 [59–239] days. There were significant correlations between all TTE parameters and CMR RVEDVi. TTE indexed RV end-diastolic area (RVEDAi) most strongly correlated with CMR RVEDVi (r=0.73, p<0.0001). All TTE RV parameters significantly correlated with CMR RVESVi but indexed RV end-systolic area had the strongest correlation (r=0.77, p<0.0001). ROC analysis performed to predict RVEDVi of ≤110ml/m2 and ≥150ml/m2 using TTE RVEDAi revealed areas under the curve of 0.86±0.04 and 0.90±0.03, respectively. A TTE RVEDAi ≤17cm2/m2 predicted a normal CMR RV volume (≤110ml/m2) with a sensitivity of 90% and a specificity of 74%. A TTE RVEDAi ≥19cm2/m2 predicted a CMR RVEDVi ≥150 mL/m2 with a sensitivity of 93% and a specificity of 76%. Conclusion In rTOF patients, both diastolic and systolic TTE RV area best correlate with CMR-derived RV end-diastolic and end-systolic volumes. A cut-off value of TTE RVEDAi of 19cm2/m2 is 93% sensitive and 76% specific to predict a CMR RVEDVi ≥150ml/m2. Simple RV size measurement using TTE may help inform the need and frequency of CMR evaluations in rTOF patients.

Abstract Myelodysplastic syndromes (MDS) are a heterogeneous collection of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis, dysplasia, and risk of progression to secondary acute myeloid leukemia (AML). Despite the development of numerous prognostic scoring systems (MDS Comorbidity Index (MDS-CI),International Prognostic Scoring System (IPSS) and IPSS-R, updated WHO classifications, and WHO prognostic scoring system (WPSS)), little prospective data regarding the influence of these and other factors on patient outcomes is available. To better elucidate the features of early mortality in MDS we compare characteristics of patients dying within one year of MDS diagnosis with those surviving longer in our Adults in Minnesota with MDS (AIMMS) population based case-control study. The AIMMS study is a statewide prospective population-based case-control study (R01 CA142714) conducted by the University of Minnesota (UMN), Mayo Clinic, and the Minnesota Department of Health. Adults (age 20-85 years) with a new diagnosis of MDS between April 2010 and October 2014 were recruited through the Minnesota Cancer Surveillance System. Patients completed a comprehensive questionnaire to capture retrospective epidemiologic data. All cases went through central medical review including pathology review by two independent hematopathologists, cytogenetic analyses, and oncologist medical record review with assignment of IPSS, IPSS-R, WPSS 1.2 noting past medical history, exposures, and treatment history and response. Annual clinical review of all patient cases for four years after initial enrollment is ongoing in a batched, non-real time manner. Three hundred and ninety-nine patients with a confirmed diagnosis of MDS based on central review and one year of clinical follow-up review were included in the analysis. For the entire group, we observed early mortality in those with abnormal cytogenetics, three or greater cytogenetic abnormalities, treatment at a community medical center only (versus academic), and with 2-3 concurrent medical comorbidities (Table 1). Treatment with hypomethylating agents also correlated with early mortality but when adjusted for WPSS and IPSS-R, this association was no longer significant. To investigate varied impact of disease and patient characteristics within different groups of MDS patients, we did multivariable regression analysis within the following categories: High/Very High Risk IPSS-R; Very low/Low/Intermediate Risk IPSS-R; Treated Patients; Supportive Care Only Patients. In patients with high or very high risk IPSS-R, the presence of 3 or more cytogenetic abnormalities was the only significant predictor early mortality in a multivariable adjusted model (OR: 3.66, 95% CI: 1.57-8.53). Similarly, in those with very low, low, or intermediate IPSS-R, abnormal cytogenetics was the only significant predictor of early mortality in an adjusted model (OR: 3.71, 95% CI 1.49-9.26). In patients receiving supportive care only, early mortality was seen in those who had diabetes (OR: 3.06, 95% CI 1.11-8.42), had complex cytogenetics (OR for ≥ 3 abnormalities: 4.94, 95% CI 1.25-19.46), and had very high or high IPSS-R (OR: 4.20, 95% CI 1.43-12.34). Likewise, complex cytogenetics remained the sole significant predictor of early mortality in treated patients (OR: 4.84, 95% CI 1.43-16.37). Complex cytogenetics and prognostic risk category (either by WPSS or IPSS-R) have previously been associated with higher risk disease and early mortality without intervention. Our data confirm this association in a large prospectively followed MDS cohort and highlight the significance of cytogenetic abnormalities and complexity regardless of IPSS-R risk categorization or treatment. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Acute myeloid leukemia (AML) carries a poor prognosis in older adults. Limited clinical trial data exist to support the use of conventional cytarabine-based regimens in this population, and practice standards have been extrapolated from studies in younger patients. Intensive chemotherapy in older adults is associated with high rates of treatment-related mortality and poor overall survival. In 2010, Kantarjian and colleagues developed a risk model for 8-week mortality using adverse prognostic risk factors, including age ≥80 years, complex karyotype (≥3 abnormalities), poor performance status (ECOG score ≥2), and serum creatinine >1.3 mg/dL. This study validates the Kantarjian model for progression-free survival (PFS) and overall survival (OS) in older patients with AML treated with intensive chemotherapy. Methods: Adults aged ≥70 years with AML (≥20% blasts in bone marrow or peripheral blood) who received intensive chemotherapy at UPMC Hillman Cancer Center between 2000 and 2011 were evaluated. Patients were stratified into low, intermediate, and high-risk groups according to the Kantarjian (2010) model and analyzed for PFS and OS using the Kaplan-Meier method. Differences in PFS and OS between risk groups were assessed with the log-rank test. ECOG performance status was estimated using historical data at the time of diagnosis. Additional variables, including AML type (primary vs. secondary), percent blasts at diagnosis, percent CD34-positive blasts, hemoglobin, leukocytes, platelets, LDH, AST, ALT, total bilirubin, albumin, and Charlson comorbidity index (CCI) were tested for added prognostic value when incorporated into the model, using Cox proportional-hazards regression for PFS and OS. Results: Clinical data were collected for 68 patients. Of these, 26 patients, all of whom were diagnosed prior to 2003, were excluded from the final analysis due to insufficient electronic health records. The remaining 42 patients were used for the validation study. Median age at diagnosis was 73 years (range: 70-87). Twenty-seven patients (64%) had primary AML, whereas 10 (24%) had AML evolving from another hematologic disorder and 5 (12%) developed AML after radiation or chemotherapy for another malignancy. Eleven (26%) patients had ≥3 karyotypic abnormalities and the remaining 31 (74%) had fewer than 3. Thirty-three (79%) patients had an ECOG performance status of 0 or 1, and the remaining 9 (21%) did not have sufficient historical data to estimate ECOG score and were given a score of 0. In total, there were 23, 16, and 3 patients categorized into the low, intermediate, and high-risk groups, respectively. These groups had non-overlapping PFS and OS curves (p <0.001 for both endpoints). The low, intermediate, and high-risk groups had median PFS of 9.6, 5.1, and 2.1 months and median OS of 14.0, 6.3, and 2.1 months, respectively. None of the additional variables were found to add significant prognostic value to the existing model. Discussion: The Kantarjian (2010) model is a valid method of risk-stratifying older adults with respect to PFS and OS, and may be useful when weighing the risks and benefits of intensive chemotherapy in these patients. In this study, we did not identify other disease characteristics or measures of organ function that significantly improved the model, although our analysis is limited by small sample size. We note that all patients in our study had an ECOG score of 0 or 1, implying selection of healthier patients for induction chemotherapy at our institution. Our results suggest that patients in the intermediate and high-risk groups may not derive significant PFS and OS benefit from intensive chemotherapy when the risks of morbidity and mortality from treatment are considered. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Determining the optimal post-remission management for elderly patients with acute myeloid leukemia (AML) remains a challenge. AML is primarily a disease of the elderly with >60% of newly diagnosed patients aged 60 years and older. For younger AML patients, post-remission therapy in the form of high-dose cytarabine (HIDAC) consolidation or allogeneic hematopoietic stem cell transplant (HSCT) is critical in maintaining durable disease control and improving survival. However, post-remission HIDAC in elderly AML patients is associated with higher rates of neurotoxicity and decreased survival benefit compared to younger patients. The optimal post-remission therapy for elderly AML patients remains undefined. The objective of this study is to determine the outcomes of using varying doses (0.25-3 g/m2) of cytarabine as post-remission consolidation therapy in an elderly AML population. Methods: We conducted a single-center retrospective analysis of AML patients aged 60 years and older treated with cytarabine as consolidation therapy at UPMC Hillman Cancer Center between January 1, 2005 and December 31, 2014. Patients were excluded if they were not in complete morphologic remission prior to proceeding with cytarabine consolidation or if they proceeded directly to HSCT after consolidation therapy. Relapse-free survival (RFS) was measured from the time of post-induction bone marrow biopsy confirming remission to the date of relapse or death. Overall survival (OS) was defined as the duration from diagnostic bone marrow biopsy confirming AML diagnosis to the date of death. Kaplan-Meier analysis was used to estimate the survival distributions and log-rank test was used to compare survival functions from groups. Multivariate analysis was performed using Cox proportional hazard regression to determine the relationship of RFS and OS to patient's age, cytogenetic risk group, AML type (de novo vs secondary AML), transplant status, cytarabine dosage and number of cycles. All data was analyzed using SAS v9.4 (SAS Institute, Cary, NC, USA). Results: Out of 156 identified patients, 121 were eligible for analysis. Median age at diagnosis was 66 years (range 59-78) with 77 (64%) male patients. Thirty-six patients (30%) had secondary AML. Cytogenetic abnormalities were favorable in 7 (6%), intermediate in 86 (71%), unfavorable in 24 (20%), and unknown in 4 (3%) patients. Cytarabine was administered at a mean dose of 1.44 g/m2 (range 0.25-3.0, SD 0.84) and a median number of cycles of 4 (range 1-4). One patient (0.8%) developed reversible grade 3 neurotoxicity during cycle 2 at a dose of 2 g/m2 with ataxia, dysmetria, and tremors. For all patients, the median RFS was 12.5 months (95% CI 9.7-15.6). Median RFS was significantly different among the cytogenetic risk groups (p=0.0008 via log-rank test): favorable-risk RFS had not been reached because most subjects were in remission and alive at time of analysis, intermediate-risk RFS 13.6 months (95% CI 11.0-17.3), unfavorable-risk RFS 8.3 months (95% CI 3.5-8.9). In this study population, the median OS was 20.5 months (95% CI 16.4-27.1). Median OS was significantly different among the cytogenetic risk groups (p=0.003 via log-rank test): favorable-risk OS 131.3 months (95% CI 12.9-upper limit not reached), intermediate-risk OS 25.1 months (95% CI 18.9-39.4), and unfavorable-risk OS 10.8 months (95% CI 10.4-15.8). Average cytarabine dose did not significantly correlate with RFS or OS in the model. Multivariate analysis revealed a 27% decreased rate of relapse (HR 0.73, 95% CI 0.58-0.92, p=0.008), and 24% decreased mortality rate (HR 0.76, 95% CI 0.59-0.96, p=0.024) with each additional cytarabine cycle given. Conclusions: Our study supports the use of cytarabine as a tolerable and effective option for post-remission therapy in elderly AML patients, particularly those with favorable-risk cytogenetics. Each additional cycle administered was associated with improved RFS and OS rates in this study population. Disclosures No relevant conflicts of interest to declare.

Hyperoxia exposure in premature infants increases the risk of subsequent lung diseases, such as asthma and bronchopulmonary dysplasia. Fibroblasts help maintain bronchial and alveolar integrity. Thus, understanding mechanisms by which hyperoxia influences fibroblasts is critical. Cellular senescence is increasingly recognized as important to the pathophysiology of multiple diseases. We hypothesized that clinically relevant moderate hyperoxia (<50% O2) induces senescence in developing fibroblasts. Using primary human fetal lung fibroblasts, we investigated effects of 40% O2 on senescence, endoplasmic reticulum (ER) stress, and autophagy pathways. Fibroblasts were exposed to 21% or 40% O2 for 7 days with etoposide as a positive control to induce senescence, evaluated by morphological changes, β-galactosidase activity, and DNA damage markers. Senescence-associated secretory phenotype (SASP) profile of inflammatory and profibrotic markers was further assessed. Hyperoxia decreased proliferation but increased cell size. SA-β-gal activity and DNA damage response, cell cycle arrest in G2/M phase, and marked upregulation of phosphorylated p53 and p21 were noted. Reduced autophagy was noted with hyperoxia. mRNA expression of proinflammatory and profibrotic factors (TNF-α, IL-1, IL-8, MMP3) was elevated by hyperoxia or etoposide. Hyperoxia increased several SASP factors (PAI-1, IL1-α, IL1-β, IL-6, LAP, TNF-α). The secretome of senescent fibroblasts promoted extracellular matrix formation by naïve fibroblasts. Overall, we demonstrate that moderate hyperoxia enhances senescence in primary human fetal lung fibroblasts with reduced autophagy but not enhanced ER stress. The resulting SASP is profibrotic and may contribute to abnormal repair in the lung following hyperoxia.

Abstract Medical nutrition therapy for long‐chain fatty acid oxidation disorders (LC‐FAODs) currently emphasizes fasting avoidance, restricted dietary long‐chain fatty acid intake, supplementation with medium chain triglycerides, and increased carbohydrate intake. We hypothesize that increasing dietary protein intake relative to carbohydrate intake would preserve metabolic control yet induce physical benefits including reduced hepatic lipogenesis. Therefore, we compared two dietary approaches with similar fat intake but different carbohydrate to protein ratios in participants diagnosed with LC‐FAODs. Thirteen participants were enrolled and randomized into either a high‐protein (PRO) or a high‐carbohydrate (CHO) diet for 4 months. Baseline and 4‐month assessments included body composition, ectopic lipid deposition, and resting energy expenditure. End of study assessments also included total energy expenditure, metabolic responses to oral feedings, and whole‐body fatty acid oxidation capacity. At the end of the dietary intervention, both groups had similar energy expenditure, fat and glucose oxidation rates, and glucolipid responses to mixed meal and oral glucose loads. Neither dietary group experienced worsening symptoms related to their LC‐FAOD. Compared to the CHO group, the PRO group exhibited increased blood levels of short‐chain acylcarnitines, reduced intrahepatic lipid content, and maintained lean body mass while the CHO group lost lean mass. In patients with LC‐FAODs, increasing protein intake maintained metabolic control, reduced liver fat without risk of metabolic decompensation, and helped preserve lean body mass. We propose that a modest increase in dietary protein along with fasting avoidance and fat restriction may improve body composition and energy expenditure in patients with LC‐FAODs.

Objectives: Data are lacking regarding implementation of novel strategies such as follow-up clinics and peer support groups, to reduce the burden of postintensive care syndrome. We sought to discover enablers that helped hospital-based clinicians establish post-ICU clinics and peer support programs, and identify barriers that challenged them. Design: Qualitative inquiry. The Consolidated Framework for Implementation Research was used to organize and analyze data. Setting: Two learning collaboratives (ICU follow-up clinics and peer support groups), representing 21 sites, across three continents. Subjects: Clinicians from 21 sites. Measurement and Main Results: Ten enablers and nine barriers to implementation of “ICU follow-up clinics” were described. A key enabler to generate support for clinics was providing insight into the human experience of survivorship, to obtain interest from hospital administrators. Significant barriers included patient and family lack of access to clinics and clinic funding. Nine enablers and five barriers to the implementation of “peer support groups” were identified. Key enablers included developing infrastructure to support successful operationalization of this complex intervention, flexibility about when peer support should be offered, belonging to the international learning collaborative. Significant barriers related to limited attendance by patients and families due to challenges in creating awareness, and uncertainty about who might be appropriate to attend and target in advertising. Conclusions: Several enablers and barriers to implementing ICU follow-up clinics and peer support groups should be taken into account and leveraged to improve ICU recovery. Among the most important enablers are motivated clinician leaders who persist to find a path forward despite obstacles.