A woman presenting with an unusual cause of fulminant liver failure and sepsis.

We present the case of a 61-year-old woman who presented with acutely worsening right upper quadrant pain and was found to be in acute liver failure with Klebsiella pneumoniae bacteremia. Despite aggressive intensive care management, the patient ultimately died of refractory shock attributed to sepsis and fulminant liver failure. On autopsy, she was found unexpectedly to have diffuse intrahepatic cholangiocarcinoma with metastases to regional lymph nodes and intravascular spread to the lungs. The case highlights a rare instance where intrahepatic cholangiocarcinoma presents with acute liver failure and discusses key intensive care management principles of this clinical syndrome.

F-18 FDG perfusion PET: intraprocedural assessment of the liver tumor ablation margin.

PURPOSE: To evaluate 18F-fluorodeoxyglucose (FDG) perfusion PET during FDG PET/CT-guided liver tumor microwave ablation procedures for assessing the ablation margin and correlating minimum margin measurements with local progression. METHODS: This IRB-approved, HIPAA-compliant study included 20 adult patients (11 M, 9 F; mean age 65) undergoing FDG PET/CT-guided liver microwave ablation to treat 31 FDG-avid tumors. Intraprocedural FDG perfusion PET was performed to assess the ablation margin. Intraprocedural decisions regarding overlapping ablations were recorded. Two readers retrospectively interpreted intraprocedural perfusion PET and postprocedural contrast-enhanced MRI. Assessability of the ablation margin and minimum margin measurements were recorded. Imaging follow-up for local progression ranged from 30 to 574 days (mean 310). Regression modeling of minimum margin measurements was performed. Hazard ratios were calculated to correlate an ablation margin threshold of 5 mm with outcomes. RESULTS: Intraprocedural perfusion PET prompted additional overlapping ablations of two tumors, neither of which progressed. Incomplete ablation or local progression occurred in 8/31 (26%) tumors. With repeat ablation, secondary efficacy was 26 (84%) of 31. Both study readers deemed ablation margins fully assessable more often using perfusion PET than MRI (OR 69.7; CI 6.0, 806.6; p = 0.001). Minimum ablation margins ≥ 5 mm on perfusion PET correlated with a low risk of incomplete ablation/local progression by both study readers (HR 0.08 and 0.02, p < 0.001). CONCLUSION: Intraprocedural FDG perfusion PET consistently enabled complete liver tumor microwave ablation margin assessments, and the perfusion PET minimum ablation margin measurements correlated well with local outcomes. Clinical trial registration clinicaltrials.gov (NCT02018107).

Structured reporting of CT enterography for inflammatory bowel disease: effect on key feature reporting, accuracy across training levels, and subjective assessment of disease by referring physicians.

PURPOSE: To compare the content and accuracy of structured reporting (SR) versus non-structured reporting (NSR) for computed tomographic enterography (CTE) of inflammatory bowel disease (IBD). MATERIALS AND METHODS: This IRB-approved, HIPAA-compliant, retrospective study included 30 adult subjects (15 male, 15 female; mean age 41.9 years) with IBD imaged with CTE. Nine radiologists (3 faculty, 3 abdominal imaging fellows, and 3 senior radiology residents) independently interpreted all examinations using both NSR and SR, separated by four weeks. Reports were assessed for documentation of 15 key reporting features and a subset of 5 features was assessed for accuracy. Thirty faculty reports (15 NSR [5 per reader] and 15 SR [5 per reader]) were randomly selected for review by three referring physicians, who independently rated quality metrics for each report. RESULTS: NSR documented the presence or absence of 8.2 ± 2.2 key features, while SR documented 14.6 ± 0.5 features (p < 0.001). SR resulted in increased documentation of 13 of 15 features including stricture (p < 0.001), fistula (p < 0.001), fluid collection (p = 0.003), and perianal disease (p < 0.001). Among a subset of five features, accuracy for diagnosing multifocal disease was minimally increased when using SR (76% NSR vs. 83% SR; p = 0.01), but accuracy for other features was not affected by report type. Referring physicians significantly preferred SR based on ease of information extraction (p < 0.01). CONCLUSION: Structured reporting of CTE for IBD improved documentation of key reporting features for trainees and faculty, though there was minimal impact on accuracy. Referring physicians subjectively preferred the structured reports.

T cell receptor/CARMA1/NF-κB signaling controls T-helper (Th) 17 differentiation.

IL-17-producing CD4 T cells play a key role in immune responses against extracellular bacteria and autoimmunity. Nuclear factor κB (NF-κB) is required for T-cell activation and selected effector functions, but its role in Th17 differentiation is controversial. Using genetic mouse models that impede T-cell-NF-κB signaling either downstream of the T-cell receptor (TCR) or of IκB kinase ß (IKKß), we demonstrate that NF-κB signaling controls not only survival and proliferation of activated T cells, but, if cell survival and cell-cycle progression are enabled, has an additional role in promoting completion of Th17 differentiation. CARD-containing MAGUK protein 1 (CARMA1), an adapter required for TCR/NF-κB signaling, was necessary for acquisition of IL-17A, IL-17F, IL-21, IL-22, IL-23R, and CCR6 expression in T cells cultured under Th17 conditions. In proliferating cells, lack of CARMA1 selectively prevented Th17, but not Th1 or Th2 differentiation, in a cell-intrinsic manner. Consistent with these data, CARMA1-KO mice were resistant to experimental autoimmune encephalomyelitis. Surprisingly, transcription factors essential for Th17 differentiation such as RORγt, AHR, and IRF4 were normally induced in CARMA1-KO T cells activated under Th17 conditions, suggesting that the Th17 differentiation program was initiated normally. Instead, chromatin loci of Th17 effector molecules failed to acquire an open conformation in CARMA1-KO T cells. Our results demonstrate that TCR/CARMA1/NF-κB controls completion of Th17 differentiation by enabling chromatin accessibility of Th17 effector molecule loci.

Competitive control of independent programs of tumor necrosis factor receptor-induced cell death by TRADD and RIP1.

Stimulation of tumor necrosis factor receptor 1 (TNFR1) can initiate several cellular responses, including apoptosis, which relies on caspases, necrotic cell death, which depends on receptor-interacting protein kinase 1 (RIP1), and NF-kappaB activation, which induces survival and inflammatory responses. The TNFR-associated death domain (TRADD) protein has been suggested to be a crucial signal adaptor that mediates all intracellular responses from TNFR1. However, cells with a genetic deficiency of TRADD are unavailable, precluding analysis with mature immune cell types. We circumvented this problem by silencing TRADD expression with small interfering RNA. We found that TRADD is required for TNFR1 to induce NF-kappaB activation and caspase-8-dependent apoptosis but is dispensable for TNFR1-initiated, RIP1-dependent necrosis. Our data also show that TRADD and RIP1 compete for recruitment to the TNFR1 signaling complex and the distinct programs of cell death. Thus, TNFR1-initiated intracellular signals diverge at a very proximal level by the independent association of two death domain-containing proteins, RIP1 and TRADD. These single transducers determine cell fate by triggering NF-kappaB activation, apoptosis, and nonapoptotic death signals through separate and competing signaling pathways.

Requirement for caspase-8 in NF-kappaB activation by antigen receptor.

Caspase-8, a proapoptotic protease, has an essential role in lymphocyte activation and protective immunity. We show that caspase-8 deficiency (CED) in humans and mice specifically abolishes activation of the transcription factor nuclear factor kappaB (NF-kappaB) after stimulation through antigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, and natural killer cells. Caspase-8 also causes the alphabeta complex of the inhibitor of NF-kappaB kinase (IKK) to associate with the upstream Bcl10-MALT1 (mucosa-associated lymphatic tissue) adapter complex. Recruitment of the IKKalpha, beta complex, its activation, and the nuclear translocation of NF-kappaB require enzyme activity of full-length caspase-8. These findings thus explain the paradoxical association of defective apoptosis and combined immunodeficiency in human CED.