Categorizing Monogenic Epilepsies by Genetic Mechanisms May Predict Efficacy of the Ketogenic Diet.

BACKGROUND: The ketogenic diet (KD) is an effective treatment for epilepsy. In recent years, studies have shown favorable efficacy of KD in epilepsy from genetic disorders. In this study, we propose an approach to KD in monogenic epilepsy: we evaluate the utility of categorizing genetic variants based on rational associations with the known mechanisms of KD. METHODS: Patients with monogenic epilepsy treated with KD were reviewed. The genetic etiologies were categorized into five groups: (1) conditions causing cellular energy impairment, (2) GABA-pathies, (3) mToR-pathies, (4) ion channelopathies, and (5) no known mechanisms associated with KD mechanisms. Treatment response was defined as a median reduction in seizure frequency of greater than 50%. RESULTS: Of 35 patients, 24 (69%) were responders at three months. Based on categories, Group 1 had the highest response rate with seven of seven (100%), followed by Group 2, six of seven (86%), and Group 3, two of three (67%). Patients in Groups 4 and 5 had poorer responses with three of seven (43%) and four of 11 (36%) response rates, respectively (P < 0.01). Median percentage of seizure reduction showed Group 1 with the highest reduction of 97.5%, Group 2 at 94%, and Groups 3, 4, and 5 at 62.5%, 30%, and 40%, respectively (P = 0.036). CONCLUSION: Our findings show a favorable response to KD in patients with monogenic epilepsy (69% at three months) with the highest response in patients with conditions involving cellular energy impairment and GABA-pathies. The KD, therefore, should be considered early in patients with monogenic epilepsy, especially those involving genes associated with cellular energy impairment or GABA-pathies.

Early dose reduction of dasatinib does not compromise clinical outcomes in patients with chronic myeloid leukemia: A comparative analysis of two prospective trials.

Dasatinib is a potent second-generation tyrosine kinase inhibitor (TKI) used as a first-line treatment option for patients with chronic myeloid leukemia (CML). Currently, dose modification due to adverse events (AEs) is common in patients treated with dasatinib. This study compared the outcomes of two sequential prospective trials that enrolled patients with newly diagnosed chronic phase of CML (CP-CML) and initiated dasatinib at a starting dose of 100 mg daily. In the PCR-DEPTH study, CP-CML patients who started dasatinib 100 mg daily were enrolled and followed up, while in the DAS-CHANGE study, when patients achieved early molecular response with any grade of AEs were enrolled and treated with dasatinib 80 mg once daily. A total of 102 patients (PCR-DEPTH) and 90 patients (DAS-CHANGE) were compared. Although the median value of the relative dose intensity (RDI) of dasatinib was significantly higher in PCR-DEPTH than in DAS-CHANGE (99.6 % vs. 80.1 %, p <0.001), the MMR rate at 12months showed a trend toward superiority in DAS-CHANGE compared to PCR-DEPTH (77.1 % vs 65.2 %, p = 0.084). The frequencies of MR4.0 at 24 and 36 months were higher in DAS-CHANGE than in PCR-DEPTH (44.4 % vs 28.8 %, p = 0.052 and 63.6 % vs 40.3 %, p= 0.013, respectively). RDIs were not different according to the MMR, MR4.0 or MR4.5 in analyses using a pooled population. Our results suggest that early dose reduction of dasatinib does not compromise efficacy in patients achieving EMR at 3 months and could be an interventional strategy for improving long term outcomes.

Case Report: Intellectual disability and borderline intellectual functioning in two sisters with a 12p11.22 loss.

Multiple genome sequencing studies have identified genetic abnormalities as major causes of severe intellectual disability (ID). However, many children affected by mild ID and borderline intellectual functioning (BIF) lack a genetic diagnosis because known causative ID genetic mutations have not been identified or the role of genetic variants in mild cases is less understood. Genetic variant testing in mild cases is necessary to provide information on prognosis and risk of occurrence. In this study, we report two sibling patients who were 5 years 9 months old and 3 years 3 months old and presented to the hospital due to developmental delay. Clinical assessment and chromosomal microarray analysis were performed. The patients were diagnosed with mild intellectual disability (ID) and borderline intellectual functioning (BIF). Genetic analysis identified a loss of 12p11.22, including the OVCH1-AS1, OVCH1, and TMTC1 genes, which was the only variant that occurred in both sisters. Identical variants were found in their father with probable BIF. Neither patient presented any brain structural abnormalities or dysmorphism, and no exogenous factors or parenting problems were reported. Thus, loss of 12p11.22 may be associated with our patients' cognitive impairment. The OVCH1, OVCH1-AS1 and TMTC1 variants identified in this study are the most likely disease-causing genes in the sisters. Our findings may expand as yet limited knowledge on mild ID and BIF causative variants, which would further support the diagnosis even if the severity is mild.

Atherosclerotic three-layer nanomatrix vascular sheets for high-throughput therapeutic evaluation.

In vitro atherosclerosis models are essential to evaluate therapeutics before in vivo and clinical studies, but significant limitations remain, such as the lack of three-layer vascular architecture and limited atherosclerotic features. Moreover, no scalable 3D atherosclerosis model is available for making high-throughput assays for therapeutic evaluation. Herein, we report an in vitro 3D three-layer nanomatrix vascular sheet with critical atherosclerosis multi-features (VSA), including endothelial dysfunction, monocyte recruitment, macrophages, extracellular matrix remodeling, smooth muscle cell phenotype transition, inflammatory cytokine secretion, foam cells, and calcification initiation. Notably, we present the creation of high-throughput functional assays with VSAs and the use of these assays for evaluating therapeutics for atherosclerosis treatment. The therapeutics include conventional drugs (statin and sirolimus), candidates for treating atherosclerosis (curcumin and colchicine), and potential gene therapy (miR-146a-loaded liposomes). The high efficiency and flexibility of the scalable VSA functional assays should facilitate drug discovery and development for atherosclerosis.

Geriatric risk model for older patients with diffuse large B-cell lymphoma (GERIAD): a prospective multicenter cohort study.

BACKGROUND/AIMS: Optimal risk stratification based on simplified geriatric assessment to predict treatment-related toxicity and survival needs to be clarified in older patients with diffuse large B-cell lymphoma (DLBCL). METHODS: This multicenter prospective cohort study enrolled newly diagnosed patients with DLBCL (≥ 65 yr) between September 2015 and April 2018. A simplified geriatric assessment was performed at baseline using Activities of Daily Living (ADL), Instrumental ADL (IADL), and Charlson's Comorbidity Index (CCI). The primary endpoint was event-free survival (EFS). RESULTS: The study included 249 patients, the median age was 74 years (range, 65-88), and 125 (50.2%) were female. In multivariable Cox analysis, ADL, IADL, CCI, and age were independent factors for EFS; an integrated geriatric score was derived and the patients stratified into three geriatric categories: fit (n = 162, 65.1%), intermediate-fit (n = 25, 10.0%), and frail (n = 62, 24.9%). The established geriatric model was significantly associated with EFS (fit vs. intermediate-fit, HR 2.61, p < 0.001; fit vs. frail, HR 4.61, p < 0.001) and outperformed each covariate alone or in combination. In 87 intermediate-fit or frail patients, the relative doxorubicin dose intensity (RDDI) ≥ 62.4% was significantly associated with worse EFS (HR, 2.15, 95% CI 1.30-3.53, p = 0.002). It was related with a higher incidence of grade ≥ 3 symptomatic non-hematologic toxicities (63.2% vs. 27.8%, p < 0.001) and earlier treatment discontinuation (34.5% vs. 8.0%, p < 0.001) in patients with RDDI ≥ 62.4% than in those with RDDI < 62.4%. CONCLUSION: This model integrating simplified geriatric assessment can risk-stratify older patients with DLBCL and identify those who are highly vulnerable to standard dose-intensity chemoimmunotherapy.