Citations

Abstract Purpose: The identification of variants of uncertain significance (VUS) in the BRCA1 and BRCA2 genes by hereditary cancer testing poses great challenges for the clinical management of variant carriers. The ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) variant classification framework, which incorporates multiple sources of evidence, has the potential to establish the clinical relevance of many VUS. We sought to classify the clinical relevance of 133 single-nucleotide substitution variants encoding missense variants in the DNA-binding domain (DBD) of BRCA2 by incorporating results from a validated functional assay into an ACMG/AMP-variant classification model from a hereditary cancer–testing laboratory. Experimental Design: The 133 selected VUS were evaluated using a validated homology-directed double-strand DNA break repair (HDR) functional assay. Results were combined with clinical and genetic data from variant carriers in a rules-based variant classification model for BRCA2. Results: Of 133 missense variants, 44 were designated as non-functional and 89 were designated as functional in the HDR assay. When combined with genetic and clinical information from a single diagnostic laboratory in an ACMG/AMP-variant classification framework, 66 variants previously classified by the diagnostic laboratory were correctly classified, and 62 of 67 VUS (92.5%) were reclassified as likely pathogenic (n = 22) or likely benign (n = 40). In total, 44 variants were classified as pathogenic/likely pathogenic, 84 as benign/likely benign, and 5 remained as VUS. Conclusions: Incorporation of HDR functional analysis into an ACMG/AMP framework model substantially improves BRCA2 VUS re-classification and provides an important tool for determining the clinical relevance of individual BRCA2 VUS.

Precision oncology is expected to improve selection of targeted therapies, tailored to individual patients and ultimately improve cancer patients’ outcomes. Several cancer genetics knowledge databases have been successfully developed for such purposes, including CIViC and OncoKB, with active community-based curations and scoring of genetic-treatment evidences. Although many studies were conducted based on each knowledge base respectively, the integrative analysis across both knowledge bases remains largely unexplored. Thus, there exists an urgent need for a heterogeneous precision oncology knowledge resource with computational power to support drug repurposing discovery in a timely manner, especially for life-threatening cancer. In this pilot study, we built a heterogeneous precision oncology knowledge resource (POKR) by integrating CIViC and OncoKB, in order to incorporate unique information contained in each knowledge base and make associations amongst biomedical entities (e.g., gene, drug, disease) computable and measurable via training POKR graph embeddings. All the relevant codes, database dump files, and pre-trained POKR embeddings can be accessed through the following URL: https://github.com/shenfc/POKR.

AbstractSeizure is one of the manifestations of central nervous system inflammatory demyelinating diseases, which mainly include multiple sclerosis (MS), aquaporin 4 antibody‐positive neuromyelitis optica spectrum disorder (AQP4‐NMOSD), and myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD). Acute symptomatic seizures secondary to MS/AQP4‐NMOSD/MOGAD occur in the acute phase of the diseases, and are more frequent in MOGAD. In contrast, recurrent nonprovoked seizures, mainly attributed to autoimmune‐associated epilepsy, occur in the nonacute phase of the diseases. Seizures in MS/AQP4‐NMOSD/MOGAD mostly have a focal onset. MS patients with concomitant systemic infections, earlier onset, and greater disease activity are more likely to have seizures, whereas factors such as greater MS severity, the presence of status epilepticus, and cortical damage indicate a greater risk of developing epilepsy. In MOGAD, cerebral cortical encephalitis and acute disseminated encephalomyelitis (ADEM)‐like phenotypes (predominately ADEM and multiphasic disseminated encephalomyelitis) indicate a greater seizure risk. Multiple relapses with ADEM‐like phenotypes predict epilepsy in pediatrics with MOGAD. Pathophysiologically, acute symptomatic seizures in MS are associated with neuronal hyperexcitability secondary to inflammation and demyelination. Chronic epilepsy in MS is largely due to gliosis, neuronal dysfunction, and synaptic abnormalities. The mainstay of treatment for seizures secondary to MS/AQP4‐NMOSD/MOGAD consists of immunotherapy along with antiseizure medications. This critical review discusses the most‐updated evidence on epidemiology, clinical correlates, and inflammatory mechanisms underlying seizures and epilepsy in MS/AQP4‐NMOSD/MOGAD. Treatment cautions including drug‐drug interactions and the impact of treatments on the diseases are outlined. We also highlight pitfalls and challenges in managing such patients and future research perspectives to address unsolved questions.

Abstract Funding Acknowledgements Type of funding sources: None. Background The prevalence of Type-1 Brugada pattern in Caucasians and Asians have been estimated to be 20 and 180 per 100,000. However, the prevalence of Type-1 Brugada pattern in African Americans has never been studied. Purpose This study aims to identify the prevalence of Type-1 Brugada pattern in African Americans. Methods Medical records of African American patients ages 18 years old or older with at least one 12-lead electrocardiogram (ECG) performed at 16 hospitals from 5 states in a single healthcare system between January 1, 2011 to December 31, 2020 were included. The search engine software was used to identify patients with keywords (Brugada pattern, Brugada ECG, Brugada Type-1, or Brugada syndrome) documented in the electronic medical record. The 12-lead ECGs were retrospectively analyzed by 2 cardiologists. Any inconsistencies were reviewed by a third cardiac electrophysiologist. Type-1 Brugada pattern was diagnosed according to the recent Heart Rhythm Society Expert Consensus Statement. Results Among 43,116 African American patients, (46.9% males), 6 patients (mean age 44.8±13.9 years, 100% males) had Type-1 Brugada pattern documented on at least one 12-lead ECG. The prevalence of Type-1 Brugada pattern in this large patient population of African American was 13.9 per 100,000. None of the patients had major arrhythmic event at 6.7±4.7 years follow-up. Conclusions The prevalence of Type-1 Brugada pattern in African American is lower than Caucasian and Asian populations. The risk of major arrhythmic event of Type-1 Brugada pattern in African American appears to be low; however longer follow-up data is needed.

Objective To determine the harms of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors in people who need lipid-lowering therapy. Methods This systematic review included randomised controlled trials that compared PCSK9 inhibitors with placebo, standard care or active lipid-lowering comparators in people who need lipid-lowering therapy with the follow-up duration of at least 24 weeks. We summarised the relative effects for potential harms from PCSK9 inhibitors using random-effect pairwise meta-analyses and assessed the certainty of evidence using GRADE (Grading of Recommendation Assessment, Development and Evaluation) for each outcome. Results We included 32 trials with 65 861 participants (with the median follow-up duration of 40 weeks, ranging from 24 to 146 weeks). The meta-analysis showed an incidence of injection-site reaction leading to discontinuation (absolute incidence of 15 events (95% CI 11 to 20) per 1000 persons in a 5-year time frame, high certainty evidence). PCSK9 inhibitors do not increase the risk of new-onset diabetes mellitus, neurocognitive events, cataracts or gastrointestinal haemorrhage with high certainty evidence. PCSK9 inhibitors probably do not increase the risks of myalgia or muscular pain leading to discontinuation or any adverse events leading to discontinuation with moderate evidence certainty. Given very limited evidence, PCSK9 inhibitors might not increase influenza-like symptoms leading to discontinuation (risk ratio 1.5; 95% CI 0.06 to 36.58). We did not identify credible subgroup analyses results, including shorter versus longer follow-up duration of trials. Conclusions PCSK9 inhibitors slightly increase the risk of severe injection-site reaction but not cataracts, gastrointestinal haemorrhage, neurocognitive events, new-onset diabetes or severe myalgia or muscular pain.

Autophagy is a cellular digestion process that contributes to cellular homeostasis by the elimination of proteins and damaged organelles. Impaired autophagy has been implicated in aging‐related disorders and in neurodegenerative diseases, including motor neuron disorders. Therefore, upregulation of autophagy may serve as a promising therapeutic approach. Lanthionine ketenamine (LK), an amino acid metabolite found in mammalian brain tissue at low concentrations, activates autophagy in rat glioma and human neuroblastoma cells in vitro, as well as in hippocampus and cortex after in vivo administration. With the overall goal of using LK to induce autophagy flux to prevent age‐related motor neuron dysfunction, we recently tested the effects of two lanthionine ketenamine phosphonates (LK‐Ps) and one lanthionine ketenamine ethyl (ester) phosphonate (LKE‐P) on autophagy modulation in a mouse motor neuron‐like hybrid cell line (NSC‐34). For fluorescence visualization of autophagy flux, NSC‐34 cells were transfected with mCherry‐GFP‐LC3 plasmid. Motor neurons treated with LK analogs displayed increased autophagy flux measured by the ratio of mCherry area (lysosomes) over GFP area (autophagosomes that have not fused with lysosomes) compared to control cells. There results were corroborated by increased LC3‐II/LC3‐I ratio as measured by protein expression using Western blot; and presence of autophagic vacuoles identified using transmission electron microscopy. In conclusion, LK analogs constitute a promising tool to induce autophagy flux in motor neurons, which may serve to prevent age‐related motor axon withdrawal and muscle denervation.

Introduction: Multiple supervised machine learning (ML) models have been used to assess the outcomes in patients who underwent transcatheter aortic valve replacement (TAVR) procedure, however, supervised ML requires significant expert time for annotation and labeling. Unsupervised ML can provide insight into the dataset without this process. Hypothesis: We hypothesized that unsupervised k-means ML can identify distinct phenogroups in TAVR patients that can predict prognosis without a priori knowledge. Methods: A retrospective study of patients who underwent TAVR (Jan 2012-Dec 2017) at Mayo Clinic sites was performed. Baseline demographics, EKG, cardiac computed tomography, and echocardiographic data were abstracted. Variables with ≥ 20% missing data were excluded. Prior to the k-means clustering algorithm, principal component analysis was used for dimensionality reduction. Input variables were analyzed according to k-means determined clusters. Kaplan-Meier survival analysis was used to assess the survival of each cluster. Results: A total of 1071 consecutive patients were included in the final analysis. A total of 141 unique variables were used. The mean age was 80.7±8.6 years, 58.2% were male. Patients were divided into 2 distinct phenogroups. In the two phenogroups, cluster 0 (n=639) has significantly better survival than cluster 1 (n= 432) (log-rank p=0.0002) (Figure 1). Cluster 1 has features of low flow-low gradient (LFLG) hemodynamic profile, including lower systolic blood pressure, mean aortic valve gradient, peak aortic valve velocity, and worse LV ejection fraction. Conclusions: Unsupervised ML can identify distinct phenotype features with prognostic significance in TAVR patients. Our results suggest that patients with LFLG hemodynamic features are intrinsically different from other TAVR patients and require more attention to avoid adverse outcomes.

AbstractOraxol consists of an oral dosage form of the chemotherapeutic agent paclitaxel administered with a novel P‐glycoprotein inhibitor encequidar methanesulfonate monohydrate (formerly named HM30181A), which allows oral treatment of cancers that would otherwise be treated with intravenous paclitaxel. Here we describe the population pharmacokinetics (popPK) analyses for oral paclitaxel in patients with advanced/metastatic solid tumors to characterize pharmacokinetic (PK) profiles and quantify sources of PK variability. The best fit popPK model for oral paclitaxel, based on data from seven clinical studies (197 patients with advanced/metastatic solid tumors), involves a linear two‐compartment structural model containing first‐order absorption with a short lag time and first‐order elimination as well as a log additive error. In this popPK model, lower population estimates of central volume for Asian patients versus Caucasian patients did not translate into clinical meaningful differences in oral paclitaxel exposure. Age, sex, body weight or surface area, mild hepatic impairment, and mild to moderate renal impairment had no clinically meaningful effects on the systemic exposure of oral paclitaxel. Simulations were performed on clinical therapeutic dose (oral paclitaxel 205 mg/m2 once daily ×3 days per week) to predict exposure of oral paclitaxel and to support treatment benefits observed in a pivotal phase III trial.

AbstractBackgroundChemotherapy has been increasingly combined with surgery as multimodality treatment for resectable colorectal‐liver metastases (CLM). There is paucity of clinical data addressing optimal timing of chemotherapy relative to surgery. We examined outcomes of patients undergoing hepatectomy for resectable CLM.MethodsSeven hundred and eighteen patients treated with hepatectomy for CLM were analyzed from five hepatobiliary institutions between 2000 and 2018. Overall survival (OS) was measured from time of hepatectomy for patients receiving: surgery alone, neoadjuvant, adjuvant, and neoadjuvant‐plus‐adjuvant (perioperative) chemotherapy. Kaplan–Meier analysis was performed to detect differences in OS between treatment groups. Single‐ and multi‐variable analysis with Cox proportional hazards were run for OS between groups.ResultsOne hundred and thirty‐seven patients (19.08%) received surgery, 104 (14.48%) received neoadjuvant‐only, 214 (29.81%) received adjuvant‐only, and 263 (36.63%) received perioperative chemotherapy; with median OS of 48.20, 46.83, 56.27, and 49.93 months, respectively. No differences in median OS were seen between groups on Kaplan–Meier analysis. No significant difference in Charlson‐Deyo comorbidity status was seen between groups (p = 0.853), while significant difference was seen in maximum tumor size (p = 0.0023). On multivariate analysis, adjuvant (p = 0.010) and perioperative (p = 0.020) chemotherapy were independently associated with OS compared to surgery alone.DiscussionDespite group differences, chemotherapy after surgery was independently associated with improved OS in CLM.