Citations

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 The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here we show that c-MYC itself is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic c-MYC activation include focally amplified distal enhancers or translocation of highly active enhancers from other genes to within topologically associating domains containing the c-MYC gene locus. The clinical outcome for patients with high levels of c-MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish c-MYC as a bona fide oncogene in a clinically significant group of high risk childhood neuroblastomas. Citation Format: Mark W. Zimmerman, Yu Liu, Shuning He, Adam D. Durbin, Brian J. Abraham, John Easton, Ying Shao, Xu Beisi, Shizhen Zhu, Xiaoling Zhang, Zhaodong Li, Nina Weichert-Leahey, Richard A. Young, Jinghui Zhang, A. Thomas Look. c-MYC drives a subset of high-risk pediatric neuroblastoma and is activated through mechanisms including enhancer hijacking and focal enhancer amplification [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 4135.

Abstract The liver is the most common site of metastasis in pancreatic ductal adenocarcinoma (PDAC). This metastatic tropism is dependent, at least in part, on the formation of a “pro-metastatic” niche that supports tumor cell seeding and colonization in the liver. However, mechanisms that direct the formation of this niche remain poorly understood. We show using the LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) model of PDAC that pancreatic tumor development enhances the susceptibility of the liver to metastatic seeding by inducing recruitment of F4/80+ and Ly6G+ myeloid cells and fibrosis within the liver. 3' mRNA sequencing (QuantSeq) on RNA isolated from the liver of KPC mice versus control PC mice revealed that the liver produces a specific set of myeloid chemoattractants, particularly serum amyloid A1 and A2 (SAA1/2), early during PDAC development. In addition, gene set enrichment analysis (GSEA) on genes upregulated in the liver of KPC mice demonstrated a significant enrichment of the interleukin 6 (IL-6)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway. Consistent with this finding, phosphorylation of STAT3 was detected in 20-30% of F4/80+ myeloid cells and 80-90% of hepatocytes. A requirement for IL-6/STAT3 signaling in the formation of a pro-metastatic niche was determined by comparing the metastatic potential of wild type mice, Il-6 knockout (Il-6-/-) mice, and mice treated with anti-IL-6 receptor (IL-6R) antibody after orthotopic implantation of KPC-derived PDAC cells. Compared to wild type mice, the liver of Il-6-/- mice and mice treated with anti-IL-6R antibody was less susceptible to metastatic seeding and showed significantly less accumulation of myeloid cells, fibrosis, and production of SAA1/2 in the liver. We obtained similar results with mice that lack Stat3 specifically in hepatocytes (Stat3flox/flox Alb-Cre), demonstrating that IL-6/STAT3 signaling in hepatocytes is necessary for the formation of a pro-metastatic niche in the liver. Further, using Saa1/2 double knockout (Saa-/-) mice, we found that SAA1/2 production by hepatocytes was required for formation of the pro-metastatic niche in the liver and increased susceptibility to metastatic seeding. Patients with a history of liver metastasis also showed higher levels of SAA1/2 in the plasma compared to normal donors, and SAA overexpression was detected in hepatocytes in liver biopsy samples collected from PDAC patients. Collectively, our study reveals a novel role for hepatocytes in directing the formation of a pro-metastatic niche in the liver during PDAC development and identifies IL-6/STAT3/SAA1/2 signaling as a promising therapeutic target for prevention of metastasis in PDAC. Citation Format: Jae W. Lee, Stacy K. Thomas, Chad A. Komar, Whitney L. Gladney, Xia Hua, Dong Xin, Abraham Shaked, Mitesh J. Borad, Ramesh K. Ramanathan, Ailing Ji, Nancy R. Webb, Maria C. de Beer, Frederick C. de Beer, Paige M. Porrett, Gregory L. Beatty. IL-6/STAT3 activation in hepatocytes drives pro-metastatic niche formation in the liver [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 1102.

Background. Control of cytomegalovirus (CMV) infection after solid organ transplantation (SOT) requires a functional immune system. We assessed the association between quantitation and function of CMV-specific CD8+ T cells and CMV infection in SOT recipients. Methods. During a 10-year period, selected kidney, heart, lung, pancreas, liver, and composite tissue recipients were tested for CMV-specific CD8+ T cells immune competence (CMV-CD8+), as measured by enumeration, interferon-gamma production, and CD107a/b degranulation. Quantitative and functional data were used to assemble T-cell immune competence (TIC) score. CMV infection was diagnosed by polymerase chain reaction in blood and other samples or histopathology. Results. Of 130 patients tested, 59 had CMV infection or disease. The median onset to CMV infection was 10.5 months (interquartile range [IQR], 5.5–18.7). Gastrointestinal disease (28.8%), pneumonia (20.3%), and CMV syndrome (17%) were most common presentation. An impaired nonspecific or CMV-CD8+ TIC score was associated with tissue-invasive disease (hazard risk, 2.84, 95% confidence interval, 1.03–11.81; P = 0.04). Patients with impaired CMV-CD8+ TIC score had longer viremia duration (42.4 days vs 18.8 d; P < 0.001). Patients with impaired nonspecific or CMV-CD8+ TIC score had higher risk of relapse (68.8% vs 27.9%; hazard risk, 2.56; 95% confidence interval, 1.09–5.89; P = 0.03). Patients with CMV infection or disease had lower median absolute lymphocyte count (380 [IQR, 240–540] vs 940 [IQR, 551–1210] cells/mm 3 ; P < 0.0001) and CD4+ T cell count (29 cells/mm 3 [IQR, 1.3–116.0] vs 325.5 cells/mm 3 [IQR, 151.5–589.8]; P < 0.0001). Conclusions. Nonspecific and CMV-specific CD8+ T-cell function correlated with the course of CMV after SOT, and measuring these has the potential to assist in its clinical management.

Key Points DNA ligase 4 deficiency is a defect causing lymphopenia (T-B-NK+) and a radiosensitive severe combined immunodeficiency phenotype. Flow cytometric analysis of phosphorylation/dephosphorylation states of histone H2AX allows for in-depth lineage-specific assessment.

ABSTRACT Purpose To determine whether quantitative methods could separate golfers with a possible dystonic cause of the “yips” from those that appear to be nondystonic. Methods Twenty-seven golfers completed 10 two-handed and 10 right hand–only putts. Surface EMG assessed forearm muscle co-contraction and motion detectors monitored wrist and putter movements. Based on a videotape review, golfers were grouped into those with yips of dystonic etiology, those with the yips nondystonic, and those with no yips. Results On video review of two-handed putting, five golfers had yips that appeared to be dystonic, nine had yips that did not appear to be dystonic, and 13 had no yips. During two-handed putting co-occurrence of a yipped putt and wrist flexor/extensor and/or pronator/supinator co-contraction was significantly more frequent in those with dystonic yips. The dystonic group had no increase in the number of yipped putts or yips with co-contraction when putting right hand only, whereas the nondystonic group had significantly more yipped putts and more yipped putts with co-contraction with right hand only. Conclusions Quantitative methods were identified that appear to identify golfers with a dystonic etiology for the yips. It is not just the frequency of yips nor just specific motion patterns alone, rather it is also a combination of yips with co-occurring co-contraction when putting with two hands, and then right hand only, that distinguished this possible etiology. Despite being a small study, identifying a dystonic pattern, even in a nonpressure indoor setting, may aid in assessment and possible monitoring of treatment.