Citations

Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.

AbstractBackgroundProstate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression‐based subtyping model based on prostate‐specific biological processes was sought.MethodsUnsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, n = 68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts.ResultsClustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01–0.71; n = 855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n = 108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09–0.51).ConclusionsWith the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features.Plain language summary Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors—the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management.

Background The MIVI Q aspiration catheters have been shown to achieve significantly greater flow rates than other intracranial aspiration catheters in vitro. We describe our initial real-world experience with the MIVI Q catheter in emergent acute ischemic stroke (AIS) caused by distal and medium vessel occlusions (DMVO). Methods Data was collated from a prospectively maintained database which included patients from October 2019 to December 2022. Occlusion demographics, thrombectomy technique, reperfusion scoring, procedural complications and disposition were assessed. The primary outcome of interest was rate of successful reperfusion defined as thrombolysis in cerebral infarction (TICI) score 2b-3. Secondary outcomes included rate of first pass effect (FPE) and complications. Results We included 64 target occlusions in 51 patients. The Q catheter successfully reached the DMVO in all occlusions. Successful reperfusion was achieved in 49/64 (76.6%) occlusions, and TICI scores were similar for primary and secondary DMVOs (P value = 0.41). FPE was achieved in 39/64 (60.9%) occlusions and did not differ between primary and secondary DMVOs (P value = 0.13). Reperfusion hemorrhage occurred in 3/64 (4.7%) cases, small volume subarachnoid hemorrhage in 3/64 (4.7%) cases, and small hemorrhagic transformation in 1/64 (1.6%) cases; the rate of complications did not differ based on primary versus secondary DMVO (P value = 0.29). Conclusion The MIVI Q catheter is both safe and effective. Our real-world experience supports the superior flow rates demonstrated in vitro and translates into high rates of successful reperfusion in AIS caused by DMVO in clinical practice.

Abstract The comprehensive evaluation of somatic variants in cancer requires consensus interpretation of their potential clinical significance (diagnosis, prognosis, and treatment response) and oncogenicity. To aid precision medicine through public interpretations, a multifaceted collaborative effort is required to bring together a community, structured guidance, and a public platform. The over 200 multi-disciplinary experts in the Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG) provide a community that develops data curation guidelines and standards and curates evidence to determine the clinical significance and oncogenicity of somatic alterations in cancer. The Somatic CDWG established the Pediatric Cancer, Hematological Cancer, and Solid Tumor Taskforces to facilitate membership growth and targeted curation projects. Within these Taskforces, Somatic Cancer Variant Curation Expert Panels (SC-VCEPs) are developed through a 4-step approval process adapted from ClinGen germline VCEP procedures. Five SC-VCEPs (NTRK-fusions, FGFR variants, FLT3 variants, Histone H3 variants, and BCR::ABL1-like B-ALL alterations) are working through the approval process and one (Established Significance) is in the planning stage. SC-VCEPs tailor AMP/ASCO/CAP [PMID:27993330] and ClinGen/CGC/VICC Oncogenicity [PMID:35101336] guidelines, or create new classification guidance to aid granular assessment of their genomic alterations of interest. The Clinical Interpretations of Variants in Cancer (CIViC) knowledgebase provides the public platform for the Taskforces and SC-VCEPs to display their high-quality somatic cancer variant interpretations. These groups curate evidence from published literature and create Assertions summarizing evidence collected. These Assertions are further disseminated through other resources like ClinVar and the Variant Interpretation for Cancer Consortium (VICC) MetaKB. CIViC supports the application of AMP/ASCO/CAP tiering and levels for clinical significance Assertions. CIViC recently created Oncogenic Assertions, which supports the application of ClinGen/CGC/VICC codes. Three SC-VCEPs (FGFR, FLT3, and Histone H3) are tailoring the ClinGen/CGC/VICC Oncogenicity guidelines to their specific genes and CIViC will enable their ClinGen-approved, modified codes to be applied directly to their Oncogenic Assertions. Also, two SC-VCEPs (NTRK and BCR::ABL1-like) are developing fusion specific oncogenicity classification guidelines, which will be applied to their fusion specific CIViC Oncogenic Assertions. ClinGen Somatic groups have generated 695 CIViC Evidence Items and 33 Assertions from over 400 published papers. These numbers will continue to grow along with the development of more SC-VCEPs. ClinGen Somatic and CIViC foster collaboration, innovation, and most importantly the advancement of precision medicine. Citation Format: Jason Saliba, Arpad Danos, Kilannin Krysiak, Adam Coffman, Susanna Kiwala, Joshua McMichael, Cameron J. Grisdale, Ian King, Shamini Selvarajah, Xinjie Xu, Rashmi Kanagal-Shamanna, Laveniya Satgunaseelan, David Meredith, Mark Evans, Charles G. Mullighan, Yassmine Akkari, Gordana Raca, Angshumoy Roy, Alex H. Wagner, Ramaswamy Govindan, Obi L. Griffith, Malachi Griffith, on behalf of the ClinGen Somatic Clinical Domain Working Group. ClinGen Somatic and CIViC collaborate to comprehensively evaluate somatic variants in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6569.

Background: Risk for venous thromboembolism has a strong genetic component. Whole genome sequencing from the TOPMed program (Trans-Omics for Precision Medicine) allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods: The 3793 cases and 7834 controls (11.6% of cases were individuals of African, Hispanic/Latino, or Asian ancestry) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results: Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only PROC (odds ratio, 6.2 for carriers of rare variants; P =7.4×10 −14 ) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at PROC (odds ratio, 3.8; P =1.6×10 −14 ), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: PROS1 became significant (minimum P =1.8×10 −6 with the secondary filter), while SERPINC1 did not (minimum P =4.4×10 −5 with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, MS4A1 , became significant ( P =4.4×10 −7 using all missense variants with minor allele frequency <0.0005). Conclusions: Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel MS4A1 locus and to identify additional rare variation associated with venous thromboembolism.

BACKGROUND: The new sonolucent cranioplasty implant (clear polymethyl methacrylate, PMMA) adds functionality besides surgical reconstruction. One possible application uses the transcranioplasty ultrasound (TCUS) technique after PMMA cranioplasty to assess graft patency of extracranial-intracranial (EC-IC) bypass procedures. OBJECTIVE: To report our early multicenter experience. METHODS: This is a multicenter analysis of consecutive EC-IC bypass patients from 5 US centers (2019-2022) with closure postbypass using PMMA implant. RESULTS: Forty-four patients (median age 53 years, 68.2% females) were included. The most common indication for bypass was Moyamoya disease/syndrome (77.3%), and superficial temporal artery to middle cerebral artery bypass was the most common procedure (79.5%). Pretreatment modified Rankin Scales of 0 and 1 to 2 were noted in 11.4% and 59.1% of patients, respectively. Intraoperative imaging for bypass patency involved a combination of modalities; Doppler was the most used modality (90.9%) followed by indocyanine green and catheter angiography (86.4% and 61.4%, respectively). Qualitative TCUS assessment of graft patency was feasible in all cases. Postoperative inpatient TCUS confirmation of bypass patency was recorded in 56.8% of the cases, and outpatient TCUS surveillance was recorded in 47.7%. There were no cases of bypass failure necessitating retreatment. Similarly, no implant-related complications were encountered in the cohort. Major complications requiring additional surgery occurred in 2 patients (4.6%) including epidural hematoma requiring evacuation (2.3%) and postoperative surgical site infection (2.3%) that was believed to be unrelated to the implant. CONCLUSION: This multicenter study supports safety and feasibility of using sonolucent PMMA implant in EC-IC bypass surgery with the goal of monitoring bypass patency using TCUS.

Abstract Background Over the past decade, the use of technology‐enhanced simulation in emergency medicine (EM) education has grown, yet we still lack a clear understanding of its effectiveness. This systematic review aims to identify and synthesize studies evaluating the comparative effectiveness of technology‐enhanced simulation in EM. Methods We searched MEDLINE, EMBASE, PsycINFO, CINAHL, ERIC, Web of Science, and Scopus to identify EM simulation research that compares technology‐enhanced simulation with other instructional modalities. Two reviewers screened articles for inclusion and abstracted information on learners, clinical topics, instructional design features, outcomes, cost, and study quality. Standardized mean difference (SMD) effect sizes were pooled using random effects. Results We identified 60 studies, enrolling at least 5279 learners. Of these, 23 compared technology‐enhanced simulation with another instructional modality (e.g., living humans, lecture, small group), and 37 compared two forms of technology‐enhanced simulation. Compared to lecture or small groups, we found simulation to have nonsignificant differences for time skills (SMD 0.33, 95% confidence interval [CI] −0.23 to 0.89, n = 3), but a large, significant effect for non–time skills (SMD 0.82, 95% CI 0.18 to 1.46, n = 8). Comparison of alternative types of technology‐enhanced simulation found favorable associations with skills acquisition, of moderate magnitude, for computer‐assisted guidance (compared to no computer‐assisted guidance), for time skills (SMD 0.50, 95% CI −1.66 to 2.65, n = 2) and non–time skills (SMD 0.57, 95% CI 0.33 to 0.80, n = 6), and for more task repetitions (time skills SMD 1.01, 95% CI 0.16 to 1.86, n = 2) and active participation (compared to observation) for time skills (SMD 0.85, 95% CI 0.25 to 1.45, n = 2) and non–time skills (SMD 0.33 95% CI 0.08 to 0.58, n = 3). Conclusions Technology‐enhanced simulation is effective for EM learners for skills acquisition. Features such as computer‐assisted guidance, repetition, and active learning are associated with greater effectiveness.