Hatcherbekker2736

We report a retroviral positive patient who presented to us with recurrent skin lesions along with intermittent, colicky periumbilical abdominal pain associated with non-projectile, postprandial vomiting. Contrast-enhanced CT (CECT) of abdomen and pelvis was suggestive of proximal jejunal obstruction. Double balloon enteroscopy done which showed extensive deep ulceration with surrounding nodular surface and friable mucosa at 60 cm from pylorus with luminal narrowing. The biopsy from this region as well as the skin lesion on the forehead grew Talaromyces marneffei She was initially treated with liposomal amphotericin B for 2 weeks following which she received itraconazole for 3 weeks for disseminated talaromycosis infection. She had already been started on antiretroviral therapy (ART) 1 year back however her cluster of differentiation 4 (CD4) counts did not show any improvement. Proximal bowel obstruction leading to poor nutritional status compounded with ineffective ART therapy due to suboptimal absorption, dictated the staged management of her condition. Feeding jejunostomy was done with a plan to offer her resection and anastomosis of affected jejunal segment, should she require one, after optimising her nutritional and immunological status. © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.PURPOSE If routine diagnostics are inconclusive, neurological deterioration and death of brain cancer patients are attributed to tumor or therapy. Therefore, diagnosing symptoms of encephalopathy caused by human-cytomegalovirus-(HCMV)-reactivation remains uncommon. We investigated the role of HCMV-reactivation in neurological decline and clinical outcome after the start of radiochemotherapy. EXPERIMENTAL DESIGN HCMV-analyses and extended MRI-studies including additional independent retrospective neuroradiological evaluation were performed at predetermined intervals and in case of sudden neurological decline for 118 adult patients 63 histologically proven high-grade gliomas, 55 with brain metastases. Immunophenotyping from simultaneously taken whole blood samples was carried out to detect immune cells serving as prognostic marker for HCMV-associated complications. ENDPOINTS symptomatic viremia, overall survival (OS). RESULTS 24% (28/118) of all patients (12/44 glioblastoma, 3/13 anaplastic astrocytoma; 8/31 nor Cancer Research.Members of the scientific and clinical neuro-oncology community met in April 2019 to discuss the current challenges and opportunities associated with translating basic science discoveries in glioblastoma to improved survival for patients. A summary of key points of these discussions is presented in this report. Copyright ©2020, American Association for Cancer Research.PURPOSE The tumor microenvironment (TME) consists of a heterogenous cellular milieu that can influence cancer cell behavior. Its characteristics havean impact on treatments such as immunotherapy. These features can be revealed with single-cell RNA sequencing (scRNA-seq). We hypothesized that scRNA-seq analysis ofgastric cancer (GC) together with paired normal tissue and peripheral blood mononuclear cells (PBMCs) would identify critical elements of cellular deregulation not apparent with other approaches. EXPERIMENTAL DESIGN scRNA-seq was conducted on seven patients with GC and one patient with intestinal metaplasia. We sequenced 56,167 cells comprising GC (32,407 cells), paired normal tissue (18,657 cells) and PBMCs (5,103 cells). Protein expression was validated by multiplex immunofluorescence. RESULTS Tumor epithelium had copy number alterations, a distinct gene expression program from normal, with intra-tumor heterogeneity. GC TME was significantly enriched for stromal cells, macrophages, dendritic cells (DCs) and Tregs. TME-exclusive stromal cells expressed distinct extracellular matrix components than normal. Macrophages were transcriptionally heterogenous and did not conform to a binary M1/M2 paradigm. Tumor-DCs had a unique gene expression program compared to PBMC DCs. TME-specific cytotoxic T cells were exhausted with two heterogenous subsets. Helper, cytotoxic T, Treg and NK cells expressed multiple immune checkpoint or costimulatory molecules. Receptor-ligand analysis revealed TME-exclusive inter-cellular communication. CONCLUSIONS Single-cell gene expression studies revealed widespread reprogramming across multiple cellular elements in the GC TME. Cellular remodeling was delineated by changes in cell numbers, transcriptional states and inter-cellular interactions. This characterization facilitates understanding of tumor biology and enables identification of novel targets including for immunotherapy. Copyright ©2020, American Association for Cancer Research.PURPOSE Salivary gland carcinomas (SGCs) are rare, aggressive cancers with high rates of recurrence and distant metastasis. These factors, and a lack of active systemic therapies, contribute to poor clinical outcome. Response rates with immune checkpoint blockade have been low, although clinical data remain sparse. To improve the efficacy of therapies, a more comprehensive understanding of relevant molecular alterations and immunologic processes is needed. EXPERIMENTAL DESIGN To characterize the immune microenvironment and neoantigen landscape of SGCs, we performed RNA sequencing (RNAseq) in 76 tumors representing the 3 most lethal histologies adenoid cystic carcinoma (ACC), myoepithelial carcinoma (MECA), and salivary duct carcinoma (SDC). read more We analyzed transcriptomic profiles, tumor-infiltrating immune cell populations, and measures of T cell activation/dysfunction. In 37 cases also undergoing exome sequencing, we analyzed somatic mutations and neoantigens. RESULTS SDCs exhibited high levels of immune infiltration, with corresponding higher levels of T cell dysfunction, and higher mutational load. In contrast, ACCs were characterized by an immune-excluded microenvironment, the presence of M2-polarized macrophages and myeloid-derived suppressor cells, and very low mutational load. MECAs were more heterogeneous, with both immune-low and immune-high phenotypes represented. Across all SGCs, levels of immune infiltration were associated with mutation- and fusion-derived neoantigens, and with aggressive clinical behavior. CONCLUSIONS These findings provide new insights into the immune microenvironment and neoantigen landscape of SGCs, showing that mechanisms of immune escape appear to differ by histology. These data nominate potential immunologic vulnerabilities and may help guide the next steps of investigation in precision immunotherapy for these difficult-to-treat cancers. Copyright ©2020, American Association for Cancer Research.PURPOSE Our primary purpose is to explore safety and efficacy of high-dose icotinib in comparison with routine-dose icotinib in non-small cell lung cancer (NSCLC) patients harboring 21-L858R mutation. EXPERIMENTAL DESIGN Treatment-naïve, EGFR-mutant (21-L858R or exon 19 deletion at 21) NSCLC patients were enrolled. Patients with 21-L858R mutation were randomized to receive routine-dose icotinib (125mg, thrice daily; L858R-RD) or high-dose icotinib (250mg, thrice daily; L858R-HD) , whereas patients with exon 19 deletion received only routine-dose icotinib (19-Del-RD) until progression, death, or unacceptable toxicity. The primary endpoint was median progression-free survival (mPFS), assessed by an independent review committee (IRC). RESULTS From May, 2015 to November, 2017, 253 patients (86 in L858R-RD; 90 in L858R-HD; 77 in 19-Del-RD) were enrolled. The mPFS in L858R-HD group was similar to that in 19-Del-RD group (12.9 months and 12.5 months, respectively), and was significantly longer than that in L858R-RD group (12.9 months vs. 9.2 months, hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.53 to 1.05). A longer but statistically non-significant mPFS was observed between 19-Del-RD and L858R-RD groups (12.5 months vs. 9.2 months, HR 0.80; 95% CI 0.57 to 1.13). A higher objective response rate (ORR) was observed in L858R-HD group compared to L858R-RD group (73% vs. 48%), also between 19-Del-RD and L858R-RD groups (75% vs. 48%). Similar incidences of grade 3/4 toxicities were observed among the three treatment groups. CONCLUSIONS High-dose icotinib improved mPFS and ORR in NSCLC patients harboring 21-L858R mutation with acceptable tolerability, which could be a new therapeutic option for this patient population. Copyright ©2020, American Association for Cancer Research.PURPOSE Clear cell ovarian carcinoma (CCOC) is an aggressive disease that often demonstrates resistance to standard chemotherapies. Approximately 25% of CCOC show a strong APOBEC mutation signature. Here, we determine which APOBEC3 enzymes are expressed in CCOC, establish clinical correlates, and identify a new biomarker for detection and intervention. EXPERIMENTAL DESIGN APOBEC3 expression was analyzed by immunohistochemistry and RT-qPCR in a pilot set of CCOC specimens (n=9 tumors). The immunohistochemistry analysis of APOBEC3B was extended to a larger cohort to identify clinical correlates (n=48). Dose response experiments with platinum-based drugs in CCOC cell lines and carboplatin treatment of patient-derived xenografts (PDX) were done to address mechanistic linkages. RESULTS One DNA deaminase, APOBEC3B, is overexpressed in a formidable subset of CCOC tumors and is low or absent in normal ovarian and fallopian tube epithelial tissues. High APOBEC3B expression associates with improved progression-free survival (p=0.026) and moderately with overall survival (p=0.057). Cell-based studies link APOBEC3B activity and subsequent uracil processing to sensitivity to cisplatin and carboplatin. PDX studies extend this mechanistic relationship to CCOC tissues. CONCLUSIONS These studies demonstrate that APOBEC3B is overexpressed in a subset of CCOC and, contrary to initial expectations, associated with improved (not worse) clinical outcomes. A likely molecular explanation is that DNA damage caused APOBEC3B sensitizes cells to additional genotoxic stress by cisplatin. Thus, APOBEC3B is a molecular determinant and a candidate predictive biomarker of the therapeutic response to platinum-based chemotherapy. These findings may have broader translational relevance, as APOBEC3B is overexpressed in many different cancer types. Copyright ©2020, American Association for Cancer Research.Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome.