Anti-N-methyl-D-aspartate receptor-associated encephalitis: A review of clinicopathologic hallmarks and multimodal imaging manifestations.

Anti-N-methyl-D-aspartate receptor-associated encephalitis (NMDARE) is a rare immune-mediated neuroinflammatory condition characterized by the rapid onset of neuropsychiatric symptoms and autonomic dysfunction. The mechanism of pathogenesis remains incompletely understood, but is thought to be related to antibodies targeting the GluN1 subunit of the NMDA receptor with resultant downstream dysregulation of dopaminergic pathways. Young adults are most frequently affected; the median age at diagnosis is 21 years. There is a strong female predilection with a female sex predominance of 4:1. NMDARE often develops as a paraneoplastic process and is most commonly associated with ovarian teratoma. However, NMDARE has also been described in patients with small cell lung cancer, clear cell renal carcinoma, and other benign and malignant neoplasms. Diagnosis is based on correlation of the clinical presentation, electroencephalography, laboratory studies, and imaging. Computed tomography, positron emission tomography, and magnetic resonance imaging are essential to identify an underlying tumor, exclude clinicopathologic mimics, and predict the likelihood of long-term functional impairment. Nuclear imaging may be of value for prognostication and to assess the response to therapy. Treatment may involve high-dose corticosteroids, intravenous immunoglobulin, and plasma exchange. Herein, we review the hallmark clinicopathologic features and imaging findings of this rare but potentially devastating condition and summarize diagnostic criteria, treatment regimens, and proposed pathogenetic mechanisms.

Imaging in Upper Tract Urothelial Carcinoma: A Review.

Medical imaging is a critical tool in the detection, staging, and treatment planning of upper urinary tract urothelial carcinoma (UTUC). This article reviews the strengths and weaknesses of the different imaging techniques and modalities available clinically. This includes multidetector computed tomography (CT), multiparametric magnetic resonance imaging (MRI), ultrasound (US), and positron emission tomography (PET) for the detection, staging, and management of UTUC. In addition, we review the imaging techniques that are being developed and are on the horizon but have not yet made it to clinical practice. Firstly, we review the imaging findings of primary UTUC and the techniques across multiple modalities. We then discuss imaging findings of metastatic disease. Lastly, we describe the role of imaging in the surveillance after resection of primary UTUC based upon current guidelines.

18F-Fluciclovine Uptake in Thymoma Demonstrated on PET/MRI.

ABSTRACT: A 68-year-old man with a history of prostate cancer post-primary treatment presented with rising prostate-specific antigen levels and was referred for 18F-fluciclovine PET/MRI to localize recurrent disease. PET/MRI revealed a solitary focus of uptake in a soft tissue nodule in the anterior mediastinum, which was resected and found to be a type B2 thymoma. 18F-fluciclovine uptake is mediated by amino acid transporters, primarily alanine-serine-cysteine transporter 2 and l-type amino acid transporter 1, previously demonstrated to be expressed on thymic carcinomas. This case highlights the possibility of overexpression of amino acid transporters in thymomas as well, rarely described before.

DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation.

The phenotype of germinal center (GC) B cells includes the unique ability to tolerate rapid proliferation and the mutagenic actions of activation induced cytosine deaminase (AICDA). Given the importance of epigenetic patterning in determining cellular phenotypes, we examined DNA methylation and the role of DNA methyltransferases in the formation of GCs. DNA methylation profiling revealed a marked shift in DNA methylation patterning in GC B cells versus resting/naive B cells. This shift included significant differential methylation of 235 genes, with concordant inverse changes in gene expression affecting most notably genes of the NFkB and MAP kinase signaling pathways. GC B cells were predominantly hypomethylated compared with naive B cells and AICDA binding sites were highly overrepresented among hypomethylated loci. GC B cells also exhibited greater DNA methylation heterogeneity than naive B cells. Among DNA methyltransferases (DNMTs), only DNMT1 was significantly up-regulated in GC B cells. Dnmt1 hypomorphic mice displayed deficient GC formation and treatment of mice with the DNA methyltransferase inhibitor decitabine resulted in failure to form GCs after immune stimulation. Notably, the GC B cells of Dnmt1 hypomorphic animals showed evidence of increased DNA damage, suggesting dual roles for DNMT1 in DNA methylation and double strand DNA break repair.

DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma.

Expression profiling has shown 2 main and clinically distinct subtypes of diffuse large B-cell lymphomas (DLBCLs): germinal-center B cell-like (GCB) and activated B cell-like (ABC) DLBCLs. Further work has shown that these subtypes are partially characterized by distinct genetic alterations and different survival. Here, we show with the use of an assay that measures DNA methylation levels of 50,000 CpG motifs distributed among more than 14,000 promoters that these 2 DLBCL subtypes are also characterized by distinct epigenetic profiles. DNA methylation and gene expression profiling were performed on a cohort of 69 patients with DLBCL. After assigning ABC or GCB labels with a Bayesian expression classifier trained on an independent dataset, a supervised analysis identified 311 differentially methylated probe sets (263 unique genes) between ABC and GCB DLBCLs. Integrated analysis of methylation and gene expression showed a core tumor necrosis factor-α signaling pathway as the principal differentially perturbed gene network. Sixteen genes overlapped between the core ABC/GCB methylation and expression signatures and encoded important proteins such as IKZF1. This reduced gene set was an accurate predictor of ABC and GCB subtypes. Collectively, the data suggest that epigenetic patterning contributes to the ABC and GCB DLBCL phenotypes and could serve as useful biomarker.

A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas.

We report that heat shock protein 90 (Hsp90) inhibitors selectively kill diffuse large B cell lymphomas (DLBCLs) that depend on the BCL-6 transcriptional repressor. We found that endogenous Hsp90 interacts with BCL-6 in DLBCL cells and can stabilize BCL-6 mRNA and protein. Hsp90 formed a complex with BCL-6 at its target promoters, and Hsp90 inhibitors derepressed BCL-6 target genes. A stable mutant of BCL-6 rescued DLBCL cells from Hsp90 inhibitor-induced apoptosis. BCL-6 and Hsp90 were almost invariantly coexpressed in the nuclei of primary DLBCL cells, suggesting that their interaction is relevant in this disease. We examined the pharmacokinetics, toxicity and efficacy of PU-H71, a recently developed purine-derived Hsp90 inhibitor. PU-H71 preferentially accumulated in lymphomas compared to normal tissues and selectively suppressed BCL-6-dependent DLBCLs in vivo, inducing reactivation of key BCL-6 target genes and apoptosis. PU-H71 also induced cell death in primary human DLBCL specimens.

Dissociable effects of cocaine-seeking behavior following D1 receptor activation and blockade within the caudal and rostral basolateral amygdala in rats.

Research with dopamine D(1) receptor antagonists or neuronal inactivating agents suggests that there is dissociable regulation of cocaine-seeking behavior by the rostral and caudal basolateral amygdala. In the present study, discrete infusions of the D(1) receptor agonist SKF 81297 (0.0-0.8 microg per side) were compared with those of the D(1) receptor antagonist SCH 23390 (0.0-2.0 microg per side) to demonstrate directly the importance of D(1) receptor mechanisms within the rostral and caudal basolateral amygdala for their functional heterogeneity in regulating cocaine-seeking behavior. Under a second-order schedule, cocaine-seeking behavior was studied during maintenance (cocaine and cocaine cues present) and reinstatement (only cocaine cues present). Food-maintained responding was used to examine the specificity of maximal behaviorally effective doses of SKF 81297 and SCH 23390. The results demonstrated that the D(1) agonist (0.4 or 0.8 microg) increased and the D(1) antagonist (1.0 microg) decreased cocaine-seeking behavior during maintenance when infused into the caudal but not the rostral basolateral amygdala. Cocaine intake was not affected by the agonist, and was decreased by the antagonist. During reinstatement, the D(1) agonist (0.4 microg) increased and the D(1) antagonist (1.0 microg) decreased cocaine-seeking behavior when infused into the rostral but not the caudal basolateral amygdala. In tests for behavioral specificity, the above effective doses of SKF 81297 and SCH 23390 used in self-administration experiments did not alter food-maintained responding. However, the 2.0-microg dose of SCH 23390 suppressed drug-maintained and food-maintained responding after infusion into both subregions. Collectively, these findings indicate dissociable sensitivity to D(1) receptor ligands within the caudal and rostral basolateral amygdala for altering cocaine-seeking behavior under different conditions that model phases of addiction.