Citations

Context.— Plasmablastic lymphoma (PBL) is a rare aggressive lymphoma, usually positive for CD138 and frequently occurring in the oral cavity of human immunodeficiency virus (HIV) patients. Up to 10% of cases are negative for CD138 and diagnostically very challenging. Objective.— To investigate the appropriate approach to diagnose CD138− plasmablastic lymphoma and avoid misdiagnosis. Design.— We studied 21 cases of CD138− PBL from multiple large institutes in the United States and 21 cases from the literature. Results.— CD138− PBLs were positive for different B/plasma cell markers at various percentages: MUM1 (94.4%; 34 of 36), OCT2 (70.6%; 12 of 17), immunoglobulin light chains (68.8%; 22 of 32), CD38 (68.4%; 13 of 19), CD79a (34.2%; 13 of 38), and PAX5 (15.6%; 5 of 32), suggesting that MUM1, OCT2, immunoglobulin light chains, and CD38 are useful markers to help establish the lineage. A total of 83% of cases (30 of 36) were extraoral lesions. Extraoral lesions showed much lower Epstein-Barr virus (EBV) infection rates (16 of 30; 53.3%) and had worse prognosis. MYC was positive in 80% (8 of 10) of EBV+ cases and 40% (2 of 5) EBV− cases, indicating the importance of MYC in pathogenesis, especially in EBV+ cases. Conclusions.— Our study emphasizes that CD138− PBLs tend to be extraoral lesions, with much lower EBV infection rates, and diagnostically very challenging. Accurate diagnosis requires a thorough investigation and workup by using appropriate markers.

Background and Aims: This study aimed to investigate safety and efficacy of silmitasertib, an oral small molecule casein kinase 2 inhibitor, plus gemcitabine and cisplatin (G+C) versus G+C in locally advanced/metastatic cholangiocarcinoma. Approach and Results: This work is a Phase 1b/2 study (S4‐13‐001). In Phase 2, patients received silmitasertib 1000 mg twice daily for 10 days with G+C on Days 1 and 8 of a 21‐day cycle. Primary efficacy endpoint was progression‐free survival (PFS) in the modified intent‐to‐treat population (defined as patients who completed at least one cycle of silmitasertib without dose interruption/reduction) from both phases (silmitasertib/G+C n = 55, G+C n = 29). The response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. The median PFS was 11.2 months (95% confidence interval [CI], 7.6, 14.7) versus 5.8 months (95% CI, 3.1, not evaluable [NE]) ( p = 0.0496); 10‐month PFS was 56.1% (95% CI, 38.8%, 70.2%) versus 22.2% (95% CI, 1.8%, 56.7%); and median overall survival was 17.4 months (95% CI, 13.4, 25.7) versus 14.9 months (95% CI, 9.9, NE) with silmitasertib/G+C versus G+C. Overall response rate was 34.0% versus 30.8%; the disease control rate was 86.0% versus 88.5% with silmitasertib/G+C versus G+C. Almost all silmitasertib/G+C (99%) and G+C (93%) patients reported at least one treatment emergent adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib/G+C versus G+C were diarrhea (70% versus 13%), nausea (59% vs. 30%), fatigue (47% vs. 47%), vomiting (39% vs. 7%), and anemia (39% vs. 30%). Twelve patients (10%) discontinued treatment because of TEAEs during the study. Conclusions: Silmitasertib/G+C demonstrated promising preliminary evidence of efficacy for the first‐line treatment of patients with locally advanced/metastatic cholangiocarcinoma.

AbstractBackgroundMutation of the m. 8993 T > G ATP6 subunit of ATP synthase causes a maternally inherited Leigh Syndrome (LS), a rapidly fatal encephalomyelopathy in childhood called and related Neuropathy, Ataxia and Retinitis Pigmentosa (NARP) in adults. There is no cure, and relevant animal models are few. Here we describe a novel ATP6 mouse model of LS and preclinical efficacy of a gene therapy approach to neutralize the ATP6 mutation by competition with a mitochondrial targeted adeno‐associated virus serotype 9 (AAV9) vector containing wild‐type ATP6.MethodsLS transgenic mice with an ATP6 mutation were developed by microinjecting AAV2 modified by a COX8 mitochondrial targeting sequence (MTS) into mouse blastocysts to deliver the human ATP6 gene with a T > G mutation at position 8993 of the mitochondrial genome, responsible for clinical LS DNA, protein, and metabolic assays confirmed functional gene delivery and in depth physiological/clinical assessments supported germline transmission of an LS phenotype. Rescue of LS in this model was evaluated after intravenous injection of mito‐targeted AAV9 containing wild‐type ATP6 followed by reevaluation of phenotypes.ResultsLS transgenic mice expressed mutant ATP6 protein in multiple relevant tissues including brain, eye, liver. Mutant ATP6 incorporated into Complex V and conferred decreased ATP synthase efficiency. Mice exhibited hallmarks of the human disease with one or multiple systemic symptoms including early death, paralysis, hunching, vision loss and seizures over six generations. Necropsy revealed spongiform encephalopathy, retinal degeneration, and cardiomegaly. Rescue by mitochondrially directed AAV9 containing wild type ATP6 after disease onset conferred prolonged survival and reduced paralysis. When administered prior to disease onset all treated ATP6 mice survived with evidence of globally improved function.ConclusionsThe results are consistent with efficient delivery and expression of foreign genes in mitochondria by AAV vectors directed by MTS and support further development of such strategies via intravenous injection of mitochondrial targeted AAV9 to deliver corrective genes.

Abstract Objectives To develop and validate a standards-based phenotyping tool to author electronic health record (EHR)-based phenotype definitions and demonstrate execution of the definitions against heterogeneous clinical research data platforms. Materials and Methods We developed an open-source, standards-compliant phenotyping tool known as the PhEMA Workbench that enables a phenotype representation using the Fast Healthcare Interoperability Resources (FHIR) and Clinical Quality Language (CQL) standards. We then demonstrated how this tool can be used to conduct EHR-based phenotyping, including phenotype authoring, execution, and validation. We validated the performance of the tool by executing a thrombotic event phenotype definition at 3 sites, Mayo Clinic (MC), Northwestern Medicine (NM), and Weill Cornell Medicine (WCM), and used manual review to determine precision and recall. Results An initial version of the PhEMA Workbench has been released, which supports phenotype authoring, execution, and publishing to a shared phenotype definition repository. The resulting thrombotic event phenotype definition consisted of 11 CQL statements, and 24 value sets containing a total of 834 codes. Technical validation showed satisfactory performance (both NM and MC had 100% precision and recall and WCM had a precision of 95% and a recall of 84%). Conclusions We demonstrate that the PhEMA Workbench can facilitate EHR-driven phenotype definition, execution, and phenotype sharing in heterogeneous clinical research data environments. A phenotype definition that integrates with existing standards-compliant systems, and the use of a formal representation facilitates automation and can decrease potential for human error.

Background: Modular fluted tapered (MFT) stems have advanced treatment of Vancouver B 2 and B 3 periprosthetic femoral fractures, but series to date have been limited with respect to cohort size and follow-up duration. The purpose of this study was to determine implant survivorship, radiographic results, complications, and clinical outcomes of Vancouver B 2 and B 3 periprosthetic femoral fractures treated with MFT stems in a large series of patients. Methods: We identified 171 Vancouver B 2 (109) and B 3 (62) periprosthetic femoral fractures treated with an MFT stem between 2000 and 2018 using our institutional total joint registry. The mean age was 75 years, 50% were female, and the mean body mass index was 29 kg/m 2 . The median stem diameter was 18 mm and median stem length was 210 mm. The cumulative incidences of revision and reoperation with death as the competing risk were calculated, radiographs were reviewed, and clinical outcomes were evaluated using the Harris hip score (HHS). The mean follow-up was 5 years. Results: The 10-year cumulative incidence of any revision was 10%. There were 17 revisions, of which only 3 were for the distal fluted portion of the MFT stem. Revision indications included periprosthetic joint infection (PJI) (n = 6) and dislocation (n = 11). The 10-year cumulative incidence of any reoperation was 15%. In addition to the above 17 revisions, there were 7 reoperations for superficial wound complications (n = 4), Vancouver B 1 periprosthetic femoral fracture (n = 1), vascular occlusion (n = 1), and acetabular cartilage degeneration requiring an acetabular component (n = 1). Radiographically, there was 1 fracture nonunion. All unrevised MFT stems were radiographically well fixed. Subsidence of ≥5 mm occurred in 11%, but all implants were stable at the most recent follow-up. The mean HHS was 75 at 2 years (n = 71). Conclusions: In this large series of 171 Vancouver B 2 and B 3 periprosthetic femoral fractures treated with MFT stems, we found that such constructs were associated with a high rate of fracture healing and provided extremely reliable and durable implant fixation, with no revisions for aseptic loosening. Dislocation and PJI were the most common complications. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Heart disease has a higher fatality rate than any other disease. Increased Atrial fat on the left atrium has been discovered to cause Atrial Fibrillation (AF) in most patients. AF can put one’s life at risk and eventually lead to death. AF might worsen over time; therefore, it is crucial to have an early diagnosis and treatment. To evaluate the left atrium fat tissue pattern using Radon descriptor-based machine learning. This study developed a bridge between the Radon transform framework and machine learning to distinguish two distinct patterns. Motivated by a Radon descriptor-based machine learning approach, the patches of eight patients from CT images of the heart were used and categorized into “epicardial fat tissue” and “nonfat tissue” groups. The 10 feature vectors are extracted from each big patch using Radon descriptors and then fed into a traditional machine learning model. The results show that the proposed methodology discriminates between fat tissues and nonfat tissues clearly. KNN has shown the best performance with 96.77% specificity, 98.28% sensitivity, and 97.50% accuracy. To our knowledge, this study is the first attempt to provide a Radon transform-based machine learning method to distinguish between fat tissue and nonfat tissue on the left atrium. Our proposed research method could be potentially used in advanced interventions.

Abstract Importance: Pancreatic cancer presents as advanced disease in >80% of patients; yet, appropriate ages to consider prevention and early detection strategies are poorly defined. Objective: To investigate age-specific associations and attributable risks of pancreatic cancer for established modifiable and non-modifiable risk factors. Design, Setting, and Participants: We included 167,483 participants from 2 prospective U.S. cohort studies with 1190 incident cases of pancreatic cancer identified during >30 years of follow-up; 5107 pancreatic cancer cases and 8845 control participants of European ancestry from a completed multicenter genome-wide association study (GWAS); and 248,893 pancreatic cancer cases documented in the U.S. Surveillance, Epidemiology, and End Results (SEER) Program. Exposures: Across different age categories, we investigated cigarette smoking, obesity, diabetes, height, and non-O blood group in the prospective cohorts; weighted polygenic risk score of 22 previously identified single nucleotide polymorphisms in the GWAS; and male sex and Black race in the SEER program. Main outcomes and measures: Risk of developing pancreatic cancer by age evaluated by Cox, logistic, or Poisson regression, as determined by the study design. Results: In the prospective cohorts, all 5 risk factors were more strongly associated with pancreatic cancer risk among younger participants, with associations greatly attenuated among those over 70 years. The HRs comparing participants with 3-5 risk factors to those with no risk factors were 9.24 (95% CI, 4.11-20.77) among those aged ≤60 years, 3.00 (95% CI, 1.85-4.86) among those aged 61-70 years, and 1.46 (95% CI, 1.10-1.94) among those over 70 years (Pheterogeneity = 3×10-5). These factors together were related to 65.6%, 49.7%, and 17.2% of incident pancreatic cancers in these age groups, respectively. In the GWAS, the polygenic risk score was most strongly associated with pancreatic cancer risk among those aged ≤60 years, with lesser associations identified in older participants (Pheterogeneity = .01). In the SEER Program, male sex and Black race were also more strongly associated with pancreatic cancer risk among younger individuals (Pheterogeneity < 1×10-8). Conclusions and relevance: Inherited and lifestyle factors are more strongly associated with earlier-onset pancreatic cancer, emphasizing the importance of age at initiation for cancer prevention and control programs targeting this highly lethal malignancy. Citation Format: Chen Yuan, Jihye Kim, Qiao-Li Wang, Alice A. Lee, Ana Babic, PanScan/PanC4 I-III Consortium, Laufey T. Amundadottir, Alison P. Klein, Donghui Li, Marjorie L. McCullough, Gloria M. Petersen, Harvey A. Risch, Rachael Z. Stolzenberg-Solomon, Kimberly Perez, Kimmie Ng, Edward L. Giovannucci, Meir J. Stampfer, Peter Kraft, Brian M. Wolpin. The age-dependent association of risk factors with pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5891.