Faculty Bibliography

Background: Heart failure (HF) is an important contributor to the increased cardiovascular (CV) mortality incidence in ESKD. Therapies targeting HF's unique pathophysiology in ESKD are lacking. Hydralazine-isosorbide dinitrate (H-ISDN) targets reduced nitric oxide bioavailability and could improve CV mortality in ESKD Methods: Adult patients with HF on maintenance dialysis between January 2011 and December 31, 2016 were identified using the United States Renal Data System. There were 6306 patients with at least one prescription for H-ISDN and 75,851 non-users. The primary outcome was death from any cause. Secondary outcomes included cardiovascular death and sudden death. Treatment effects were estimated using stabilized inverse probability weights in Cox proportional hazards regression. Because H-ISDN has been shown to improve outcomes in Black HF patients, we investigated effect modification by race Results: Age was similar in H-ISDN users (66 +/- 13 years) and non-users (69 +/- 13 years) with 50% and 51% men, respectively. H-ISDN (51%) users were more likely to be of Black race than non-users (27%). Dialysis vintage was longer in H-ISDN (25 months) users compared with non-users (15 months). All characteristics were well balanced in weighted models. Risks of all-cause mortality, cardiovascular death, and sudden death were significantly reduced in H-ISDN users compared to non-users (Table). We did not identify significant effect modification by race (Figure)
Conclusion(s): To our knowledge, this is the first analysis of the impact of H-ISDN on mortality in ESKD. Our results suggest that combination H-ISDN improves survival in dialysis patients with HF

Introduction: Cytotoxic drugs are hampered by limited efficacy. Hence, a personalized treatment approach matching chemotherapy with appropriate patients remains an unmet need. Genomic heterogeneity creates an opportunity to discern key genomic aberrations and pathways that confer resistance and response to standard treatment options. We conducted a study using the Cellworks Computational Omics Biology Model (CBM) to identify novel genomic biomarkers associated with response among Non-Small Cell Lung Cancer (NSCLC) patients receiving platinum-based treatments.
Method(s): 104 NSCLC patients who received platinum-based chemotherapy were selected from TCGA: platinum-etoposide (N=18), platinum-gemcitabine (N=20), platinum-vinorelbine (N=31), platinum-paclitaxel (N=21), and platinum-docetaxel (N=14). Mutation and CNV from each case served as input for the CBM to generate a patient-specific protein network-map based on PubMed and other resources. Biomarkers unique to each patient were identified within protein network-maps. Drug impact on the disease network was biosimulated to determine efficacy score by measuring the effect of chemotherapy on the cell growth score, a composite of cell proliferation, viability, apoptosis, metastasis, DNA damage and other cancer hallmarks. Effectively, the mechanism of action of each drug was mapped to each patient's genome and biological consequences determined response.
Result(s): Among the 104 patients, 74 were responders (R) and 30 non-responders (NR), determined using compete and partial response based on RECIST criteria (Figure 1). The CBM predicted clinical response with 73% sensitivity and 77% specificity. Cellworks CBM identified novel biomarkers responsible for platinum-based combination therapy response as mentioned below. +Etoposide: 13q-del, RB1-del, MBD1-del, LIG4-del, ERCC5-del, ATP7B-del +Gemcitabine: AKT3-amp, MAPKAP2-amp, TAP1-del +Vinorelbine: TET2-del/LOF, TRIB3-amp, SLX4-del +Paclitaxel: KLF4-del, SNCG-del, RAC1-amp/GOF +Docetaxel: BCL2L1-amp, HMGA1-amp, NSD1-del, SLC22A7-amp, FSIP1-del These genes contributed to drug efficacy by impacting various pathways, including DNA repair, oxidative-stress, methylation machinery, spindle formation, and mitotic-catastrophe. The aberration frequency of these genes was high among the responders within each subgroup and was very low in non-responders. Additionally, a model of clinical outcome versus the linear and quadratic function of efficacy score, drug combination and the interaction of both showed that efficacy score provides predictive information above and beyond the choice of drug combination alone (likelihood ratio chi-sq = 35.56, df=13, p-value = 0.0007). [Formula presented]
Conclusion(s): This pilot study highlights how the Cellworks CBM biosimulation platform can help identify patients for therapy response prediction. By using novel biomarkers, a CBM-informed decision tree can be employed to identify the optimal drug combination for platinum-based therapy. We suggest that this approach be validated prospectively in a larger patient cohort. Keywords: Cancer Therapy Biosimulation, Multi-omics Therapy Biosimulation, Personalized Cancer Therapy
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Introduction: PD-L1 is an immune checkpoint protein that mediates immune evasion. In Non-Small Cell Lung Cancer (NSCLC), its expression is used to predict the outcome of treatment targeting PD-1/L1. However, clinical benefits do not occur uniformly, and new approaches are needed to assist in selecting patients for immunotherapy.
Method(s): 26 patients with known clinical response to pembrolizumab were selected from publicly available data (PMID:25765070) (Table 1). Mutation and copy number aberrations from individual cases served as input into the Cellworks Omics Biology Model (CBM) to generate a patient-specific protein network map from PubMed and other online resources. Disease-biomarkers unique to each patient were identified within protein network maps. Digital drug biosimulations were conducted by measuring the effect of pembrolizumab on a cell growth score comprised of a composite of cell proliferation, viability, apoptosis, metastasis, and other cancer hallmarks. Drug biosimulations were conducted to identify and evaluate therapeutic efficacy.
Result(s): Among 26 patients treated with pembrolizumab, 14 were clinical responders, defined as stable disease or partial response lasting longer than 6 months, and 12 non-responders. Notably, 9/12 non-responders were PD-L1 positive (Table 1). Cellworks biosimulation predicted response with 84.6% accuracy, 75% specificity, and 92.86% sensitivity. Positive predictive value was 81.25% and negative predictive value was 90%. CBM identified that response was influenced by pathways that impacted the tumor microenvironment (TME). Deletions of adenosine pathway genes were observed in responders, whereas CNVs for these genes were enriched in non-responders (Table 1). Loss of ENPP1, and INSIG1 and SENP2 CNV aberrations, all of which regulate the STING pathway, could play a significant role in governing immune checkpoint blockade (ICB) response. Although STK11 loss appears to be a biomarker for poor ICB response, it was equally enriched in responders (n=7) and non-responders (n=7) in this dataset. Notably, responders had STK11 mutations and chromosome 6 loss, whereas non-responders had STK11 loss with chromosome 6 wild type or gain. Finally, frameshift mutations (FSM) enhance neoepitope formation and were higher in responders (average FSM = 48) vs non-responders (average FSM = 19). [Formula presented]
Conclusion(s): Alterations of the adenosine and STING pathways play key roles in determining benefit from PD-1/L1 targeting and highlight therapeutic possibilities for improving outcome in specific patient subgroups based on PD-L1 expression. The Cellworks CBM captures a holistic picture of the TME using tumor omics and improves response prediction beyond PD-L1 testing. Keywords: Multi-omics Therapy Biosimulation, Personalized Cancer Therapy, Immunotherapy Biosimulation
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Background/Purpose: Axial gout involvement was first reported in 1950 (1). Over 100 cases have subsequently been published. Reported cases have presented as acute back pain, cord compression, and/or neurologic symptoms, with diagnosis made by invasive procedure (surgical excision or biopsy). However, the true extent of MSU deposition in the spine of gout patients, including asymptomatic patients or those with non-specific symptoms, is unknown and likely higher. We used DECT to determine the extent of MSU deposition in the lumbosacral spines of patients with gout, with and without tophi, compared to controls without gout.
Method(s): We recruited controls, nontophaceous, and tophaceous gout patients, age 45-80. Individuals with CPPD disease, RA, spondyloarthropathy, active spinal malignancy, or on urate lowering treatment (ULT) >= 6 months were excluded. Gout subjects met 2015 ACR gout classification criteria, with entry serum urate (sU) of >6.8 mg/dL ( >6.0 mg/dL if on ULT for < 6 months). Demographics, gout history, Aberdeen back pain scale, sU, ESR, and CRP were collected. Subjects underwent DECT of the lumbosacral spine (LS) to assess for MSU deposition.
Result(s): 75 subjects were enrolled, and 72 completed the study (1 nontophaceous gout patient lost to follow-up prior to DECT, 2 tophaceous excluded after sU at time of DECT found to be < 6.0mg/dL). All groups were similar in age in years (controls 61.8+/-3.8, nontophaceous 64.0+/-6.1, tophaceous 60.4+/-11.0, p=0.81) but differed in BMI (controls 28.3+/-6.5 kg/m², nontophaceous 34.1+/-7.2 kg/m², tophaceous 29.5+/-4.5 kg/m², p=0.03) and creatinine (controls 1.0+/-0.2 mg/dL, nontophaceous 1.4+/-0.7 mg/dL, tophaceous 1.4+/-0.6 mg/dL, p< 0.05). Mean sU and ESR were higher in gout subjects (sU-controls 5.3+/-1 mg/dL, nontophaceous 8.5+/-1.7 mg/dL, tophaceous 8.5+/-1.6 mg/dL, p< 0.05; ESR-controls 13.7+/-13.8 mm/h, nontophaceous 26.5+/-19.4 mm/h, tophaceous 25.1+/-15.7 mm/h, p< 0.05). Using standard DECT settings for MSU visualization, gout patients had larger MSU volumes than controls (controls 2.2+/-1.2 cm3, all gout 5.23+/-6.9 cm3; p =0.03). Tophaceous patients had numerically greater MSU deposition compared with nontophaceous (6.0+/-8.9 cm3, vs 4.4+/-4.3 cm3, ns). Reanalysis of a subset of scans using highly specific settings to eliminate artifact reduced the number of subjects with MSU signal but confirmed greater prevalence of deposition among gout patients (n=29; controls with deposition 0/9, nontophaceous with deposition 1/11, tophaceous with deposition 2/9). Back pain was also more common among gout patients. No subject had frank tophi on spinal DECT.
Conclusion(s): Gout patients have significantly greater intercritical inflammation and LS MSU deposition than controls, and trend toward greater deposition among patients with tophi. Preliminary results using the most stringent DECT threshold settings suggests MSU differences are not artifact. The complete data set is currently undergoing evaluation and the full results will be presented

Background/Purpose: Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common alleles contribute to the genetic high IFN trait. In this study, we examine whether these common gain-of-function alleles in the type I IFN pathway are associated with protection from mortality in acute COVID-19.
Method(s): We studied IFN pathway SLE risk genes in patients with acute COVID-19 admitted to NYU Langone hospitals (751 European-American and 398 African-American ancestry). The samples were genotyped using low depth sequencing and imputation, and we analyzed data from the following SNPs: IRF5 (rs2004640, rs3807306, rs10488631, rs2280714), IRF7/PHRF (rs1131665, rs4963128), IRF8 (rs17445836, rs12444486), and PRKG1 (rs7897633). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome.
Result(s): We observed specific IRF5 haplotypes that are protective against SLE risk were associated with increased risk of mortality in acute COVID-19 patients in European-American ancestry (OR=3.74, p=0.015). Alleles of PRKG1 were also associated with mortality from COVID-19 in the European-American ancestry cohort (OR=1.80, p=0.0057), and this risk factor was particularly strong in younger patients (OR=29.2, p=0.01 in ages 45-54). IRF8 genotype at rs1244486 was associated with protection from mortality in COVID-19 in African-American subjects aged 65 and older (OR=0.34, p=0.04).
Conclusion(s): We find that a number of type I IFN pathway genes associated with risk of SLE also modulate risk of death during acute COVID-19. Similar to their associations with SLE, these alleles are variably associated with COVID-19 mortality across ancestral backgrounds, suggesting ancestral differences in the genetic regulation of the IFN pathway. These data confirm the critical role of the IFN pathway in our defense against viral infections, and support the idea that some common SLE risk alleles exert protective effects in anti-viral immunity

OBJECTIVE:This study evaluated the safety and efficacy of orbital atherectomy (OA) for the treatment of severely calcified coronary artery bifurcation lesions. BACKGROUND:Percutaneous coronary intervention (PCI) of severely calcified coronary artery lesions is associated with lower procedural success and higher rates of target lesion failure compared to non-calcified lesions. OA is an effective treatment for calcified coronary artery lesions prior to stent implantation. However, there is little data regarding the safety and efficacy of OA in patients with coronary artery bifurcation lesions. METHODS:Data were obtained from analysis of patients with severe coronary artery calcification who underwent OA and coronary stent implantation at ten high-volume institutions. Data were pooled and analyzed to assess peri-procedural outcomes and 30-day major adverse cardiac events (MACE). RESULTS:A total of 1156 patients were treated with OA and PCI. 363 lesions were at a coronary artery bifurcation. There were no statistically significant differences in baseline characteristics between the bifurcation and non-bifurcation groups. In the bifurcation group, treatment involved the left anterior descending artery and its branches more frequently and right coronary artery less frequently. After propensity score matching, the 30-day freedom from MACE was not statistically significant between the two groups. CONCLUSION:In this multicenter cohort analysis, patients with severely calcified coronary bifurcation lesions had low rates of MACE and target vessel revascularization at 30 days at rates comparable to non-bifurcation lesions. This analysis demonstrates that OA is safe and effective for complex coronary lesions at both bifurcation and non-bifurcation locations.

BACKGROUND:Statins are the mainstay of treatment for low-density lipoprotein cholesterol (LDL-C) lowering, however, some patients cannot tolerate statins because of adverse effects. Ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are alternative treatment options. The purpose of this meta-analysis was to compare LDL-C reduction with ezetimibe vs PCSK9i in patients not on statins. METHODS:PubMed and EMBASE were searched until 14th March 2020 for randomized clinical trials (RCTs) assessing the efficacy of ezetimibe vs PCSK9i in patients not on statins. The primary outcome was a reduction in LDL-C levels. A subgroup analysis of statin intolerant patients was also performed. RESULTS:=0]. CONCLUSION:Among patients who are statin intolerant or not receiving statins, PCSK9i use is associated with significantly lower LDL-C levels than after treatment with ezetimibe. PCSK9i might be useful in the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) in this subset of patients.

BACKGROUND:There is limited understanding about why sarcopenia is happening in bladder cancer, and which modifiable and nonmodifiable patient-level factors affect its occurrence. OBJECTIVE:The objective is to determine the extent to which nonmodifiable risk factors, modifiable lifestyle risk factors, or cancer-related factors are determining body composition changes and sarcopenia in bladder cancer survivors. DESIGN, SETTING, AND PARTICIPANTS:Patients above 18 yr of age with a histologically confirmed diagnosis of bladder cancer and a history of receiving care at Duke University Medical Center between January 1, 1996 and June 30, 2017 were included in this study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Bladder cancer survivors from our institution were assessed for their dietary intake patterns utilizing the Diet History Questionnaire II (DHQ-II) and physical activity utilizing the International Physical Activity Questionnaire long form (IPAQ-L) tools. Healthy Eating Index 2010 (HEI2010) scores were calculated from DHQ-II results. Body composition was evaluated using Slice-O-Matic computed tomography scan image analysis at L3 level and the skeletal muscle index (SMI) calculated by three independent raters. RESULTS AND LIMITATIONS:A total of 285 patients were evaluated in the study, and the intraclass correlation for smooth muscle area was 0.97 (95% confidence interval: 0.94-0.98) between raters. The proportions of patients who met the definition of sarcopenia were 72% for men and 55% of women. Univariate linear regression analysis demonstrated that older age, male gender, and black race were highly significant predictors of SMI, whereas tumor stage and grade, chemotherapy, and surgical procedures were not predictors of SMI. Multivariate linear regression analysis demonstrated that modifiable lifestyle factors, including total physical activity (p=0.830), strenuousness (high, moderate, and low) of physical activity (p=0.874), individual nutritional components (daily calories, p=0.739; fat, p=0.259; carbohydrates, p=0.983; and protein, p=0.341), and HEI2010 diet quality (p=0.822) were not associated with SMI. CONCLUSIONS:Lifestyle factors including diet quality and physical activity are not associated with SMI and therefore appear to have limited impact on sarcopenia. Sarcopenia may largely be affected by nonmodifiable risk factors. PATIENT SUMMARY:In this report, we aim to determine whether lifestyle factors such as diet and physical activity were the primary drivers of body composition changes and sarcopenia in bladder cancer survivors. We found that lifestyle factors including dietary habits, individual nutritional components, and physical activity do not demonstrate an association with skeletal muscle mass, and therefore may have limited impact on sarcopenia.