Citations

Objective. To evaluate longitudinal cognitive/behavioral change over 12 months in participants enrolled in the ALS Multicenter Cohort Study of Oxidative Stress (ALS COSMOS). Methods. We analyzed data from 294 ALS participants, 134 of whom were studied serially. Change over time was evaluated controlling for age, sex, symptom duration, education, race, and ethnicity. Using multiple regression, we evaluated associations among decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores, forced vital capacity (FVC), and cognitive/behavioral changes. Change in cognitive/behavioral subgroups was assessed using one-way analyses of covariance. Results. Participants with follow-up data had fewer baseline behavior problems compared to patients without follow-up data. We found significant worsening of behavior (ALS Cognitive Behavioral Screen (ALS CBS) behavioral scale, p<0.001; Frontal Behavioral Inventory-ALS (FBI-ALS) disinhibition subscale, p=0.044). Item analysis suggested change in frustration tolerance, insight, mental rigidity, and interests (p<0.05). Changes in ALSFRS-R correlated with the ALS CBS. Worsening disinhibition (FBI-ALS) did not correlate with ALSFRS-R, FVC, or disease duration. Conclusion. We did not detect cognitive change. Behavioral change was detected, and increased disinhibition was found among patients with abnormal baseline behavioral scores. Disinhibition changes did not correlate with disease duration or progression. Baseline behavioral problems were associated with advanced, rapidly progressive disease and study attrition.

AbstractActive infection in the recipient is considered a relative contraindication for solid organ transplantation. However, heart transplantation (HT) can be curative in patients with ventricular assist device infections. For patients with infective endocarditis (IE), valve replacement is part of the management strategy based on emergent, acute, or elective indications. HT has been utilized as an uncommon and sporadic treatment option for carefully selected patients with refractory or recurrent IE after all other surgical treatment options have been exhausted or are not feasible. Herein, we review 19 published cases of IE in whom HT was undertaken in the setting of ongoing active infection with reported good outcomes. We attempt to propose general criteria for HT in the setting of IE and discuss challenges and hurdles that clinicians might encounter when considering HT for active IE in the absence of robust data or clearly defined criteria.

11559 Background: Paraneoplastic neurologic disease (PND) is an aberrant immune-mediated response against the nervous system triggered by occult malignancy. Given the rarity of this disease, a paucity of data exists describing breast cancer (BC)-related PND; thus, we sought to further examine this specific population of patients. Methods: Using an institution specific clinical search tool, we identified all patients at our institution from 1997-2016 with a diagnosis of BC-related PND, verified by an international expert. Retrospective review was used to record tumor and treatment factors associated with PND and BC. A descriptive analysis was performed of the characteristics associated with BC-related PND. Results: BC-related PND was diagnosed in 58 female patients. Average age at BC diagnosis was 54.0±10.3 years. Most had invasive cancer of Stage II or higher [Stage 0 (10.3%), I (10.3%), II (44.8%), III (13.8%), IV (6.9%), unknown (13.8%)]. Most patients were hormone receptor (HR)+ (63.8%), while 4 (6.9%) were HR-, and 17 (29.3%) were unknown. Of the 34 patients where Her2/neu (Her2) data was available, 7 (20.6%) were Her2+ and 27 (79.4%) were Her2-. The majority (62.1%) had neurological symptoms prior to BC, 5.2% were concurrent, and 32.7% developed PND after initial BC. The interquartile range for time from PND to BC diagnosis was -8.5 to 10.5 months. Of the 58 patients, 29 (50%) had autoantibodies detected: Purkinje Cell Cytoplasmic Autoantibody Type-1 (PCA-1[anti-Yo]) (10), amphiphysin-IgG (n = 9), Anti-Neuronal Nuclear Autoantibody Type-2 (ANNA-2[anti-Ri]) (n = 5), and other (n = 5). The most common syndromes were cerebellar ataxia (n = 14), myelopathy (n = 11), and myopathy (n = 11). Immunotherapy was used for PND in 53 of 58 (91.4%) patients; benefit from immunotherapy was assessed as complete 0 (0%), robust 11 (20.8%), mild to moderate 28 (52.8%), none 9 (17%), and indeterminate 5 (9.4%). Conclusions: BC-related PND is rare, with only 58 cases over 20 years at a large academic institution. Paraneoplastic symptoms often present prior to BC diagnosis and BC characteristics are typical of the general population. Over 75% of patients benefit from immunotherapy. These data may provide helpful information to providers treating this population of patients.

We report a unique case and presentation of a 77-year-old man with atrial fibrillation who presented with complex imaging features, including bifrontal cerebral hematomas that progressed to multifocal macro- and microhemorrhages, vasogenic edema, and cortical/meningeal enhancement. Cerebrospinal fluid analysis was only remarkable for a protein elevation of 65 mg/dL. Leptomeningeal vessel biopsy failed to demonstrate evidence of amyloid angiopathy but did show concentric obstructive intimal fibroplasia, suggestive of chronic venous congestion. Conventional cerebral angiography showed a Cognard type IV dural arteriovenous fistulae fed by bilateral ethmoidal arteries draining directly into ectatic cortical veins. A chronic occlusion of the anterior third of the superior sagittal sinus was also noted. The fistula was successfully surgically obliterated via an uncomplicated left frontal craniotomy approach. After rehabilitation therapy, he was discharged home with a modified Rankin Scale score of 3. Because effective treatment exists, this case underscores the importance of identifying this rare etiology of intracerebral hemorrhage and pursuing adequate workup.

Abstract Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. Hepatitis C virus (HCV) infection is a major risk factor for HCC in the US. HCV infection may cause cancer by suppressing host defense that controls the propagation of repetitive element (RE) sequences, including LINE-1 and Alu, the most representative REs in the human genome. DNA methylation of RE helps stabilize the genome, while reduced RE methylation, also referred as global hypomethylation, leads to genomic instability and is known as a hallmark of cancer. However, current available high-throughput technology for DNA methylation profiling only enables genomewide RE methylation study on a global scale. The role of individual RE methylation in cancer is largely understudied. In this study, using our recently developed and published machine learning algorithm to enhance the RE coverage of the Illumina methylation array platform, we examined the role of individual RE methylation in HCV-induced HCC across the entire genome. We conducted an epigenome-wide association study on 22 HCC, 20 cirrhotic, and 44 normal liver tissues. We included equal numbers of HCV-induced and alcohol-induced HCC/cirrhosis cases. The Illumina 450k array profiled 1939 REs and we computationally predicted 33184 REs; correlations between the overlapping 1541 profiled and predicted RE methylation were &gt; 0.91. Sex, tumor differentiation, and tumor stage were similarly distributed across the HCV and alcohol groups. We adjusted for batch effects and used Benjamini-Hochberg adjusted false discovery rate (FDR) to account for multiple testing. Relative to normal liver tissue, we observed over twice as many differentially methylated (FDR &lt; 0.05) REs in HCV-HCC compared to alcohol-HCC tissue (2911 vs 1304, 749 in common). We validated our results in The Cancer Genome Atlas (TCGA) (325 vs 129, 74 in common) with high correlation (r = 0.90). We also observed that 169 REs were significantly altered in HCV-cirrhosis tissue (compared to none in alcohol-cirrhosis tissue), of which, 17 REs in 13 genes, including PIK3CD, LY9, GCK, NLRC3, and PRKCZ, were consistently hypomethylated in both HCC and cirrhotic liver tissue induced by HCV (r = 0.87). Using TCGA RNA sequencing data, we found that these REs were located in gene body and their hypomethylation was associated with lower expression of their host genes (r &gt; 0.3, p &lt; 0.05). Gene Ontology Enrichment analysis showed that these genes were enriched in T-cell activation & differentiation and cytokine production (FDR &lt; 0.05). Our findings indicate that HCV infection has a more extensive impact on the DNA methylation landscape in RE than alcohol consumption, and that HCV infection may also induce similar hypomethylation in cirrhotic liver. Hypomethylated RE may alter local chromatin environment and disrupt expression of genes involved in immune and inflammatory responses, both of which may promote HCC development. RE hypomethylation in specific genomic locus may serve as early detection biomarker of HCC in patients with HCV-induced cirrhosis. Citation Format: Yinan Zheng, Jimmy Ren, Ryan A. Hlady, Keith D. Robertson, Robert L. Murphy, Lewis R. Roberts, Lifang Hou. DNA methylation of individual repetitive elements in HCV infection-induced HCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-235.