Guideline on the use of new anticancer drugs for the treatment of Hepatocellular Carcinoma 2010 update

The "Guideline on the Use of New Anticancer Drugs for the Treatment of Hepatocellular Carcinoma" was prepared by the Study Group on New Liver Cancer Therapies established by the "Research Project on Emergency Measures to Overcome Hepatitis" under the auspices of the Health and Labour Sciences Research Grant. The Guideline brings together data collected by the Study Group on the use and incidence of adverse events in 264 patients with advanced hepatocellular carcinoma (HCC) treated using sorafenib and in 535 patients with advanced HCC treated using miriplatin at 16 participating institutions up until 22 December 2010, as well as referring to the published studies, academic presentations, and reports from the private sector. The aim of this Guideline is to facilitate understanding and current thinking regarding the proper usage of new anticancer drugs towards actual use in therapy. In terms of the format, the Guideline presents "clinical questions" on issues pertaining to medical care, makes "recommendations" on diagnosis and treatment in response to each of these clinical questions, and provides a rationale for these recommendations in the form of "scientific statements". © 2012 The Japan Society of Hepatology

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Operator-Based Nonlinear Control for a Miniature Flexible Actuator Using the Funnel Control Method

Recently, the studies of soft actuators have been getting increased attention among various fields. Soft actuators are very safe for fragile objects and have an affinity to humans because they are composed of flexible materials. A miniature flexible actuator is a kind of pneumatically driven soft actuator. It has a bellowed shape and asymmetrical structure. This shape can generate a curling motion in two ways under positive and negative pressures with only one air tube. In the previous article, a control system using adaptive λ-tracking control was proposed. This control gain can become too large as time tends to infinity because the adaptive law exhibits a non-decreasing gain. To solve this problem, the funnel control method is proposed. The adaptive gain of this method not only increases but also decreases; however, the design scheme of the boundary function which is needed to decide on adaptive gain is not proposed here. In this article, an operator-based nonlinear control system’s design and the design scheme of the boundary function using an observer are proposed. Then, the effectiveness of the proposed method is verified by a simulation and an experiment

Practical therapeutic management of percutaneous atrial septal defect closure

Atrial septal defects (ASDs) are one of the most common congenital heart disorders encountered by cardiologists. Percutaneous ASD closure for secundum ASD is commonly performed not only for children but also for adults, given its non-inferiority to surgical repair. The choice of closure technique should be based on assessing a patient\u27s baseline comorbidities, including the presence of pulmonary hypertension, supraventricular tachycardias, and left ventricular diastolic dysfunction. Furthermore, anatomical features and defect types determined using echocardiography need to be considered when developing a management plan. Percutaneous closure is often the preferred method, given its comparable successful rate to surgical repair while also being far less invasive

Mid-Term Feasibility of Percutaneous Left Atrial Appendage Occlusion in Elderly Patients with Non-Valvular Atrial Fibrillation

Background: Percutaneous left atrial appendage occlusion (LAAO) therapy using the WATCHMAN system has been introduced to prevent thrombosis and minimize the use of anticoagulants in patients with non-valvular atrial fibrillation. Given the high risk of bleeding and stroke in elderly patients, these patients would be good candidates for this therapy. However, the efficacy and feasibility of LAAO therapy in elderly patients remains uncertain. Methods: Consecutive patients who underwent LAAO therapy using the WATCHMAN system in a large academic center between June 2020 and March 2023 were included. The safety and efficacy of LAAO therapy during the 1-year observation period in patients aged ≥85 years old were compared with those in the younger cohort. Results: A total of 188 patients (78.4 ± 6.9 years old, 133 male patients) were included. 34 patients were ≥85 years old, 96 were between 75 and 84 years old, and 58 were 2DS2-VASc score and were at greater risk of falling-related bleeding compared with the younger cohort. The device implantations were successful in all patients except for one. During the 1-year observation period, one patient had a peri-device leak >5 mm and there were 6 device-related cases of thrombosis, whose incidence was not significantly different between the groups (p = 0.98). The cumulative incidences of bleeding and thrombotic events in the elderly group were as low as in the younger cohort (p > 0.05 for both). Most anticoagulants were terminated regardless of age. Conclusion: The mid-term feasibility and efficacy of percutaneous LAAO therapy using the WATCHMAN system in elderly patients aged ≥85 years were as acceptable as in the younger cohort

Comparison in Short-Term Safety and Efficacy between New-Generation WATCHMAN FLX and Conventional WATCHMAN 2.5 for Percutaneous Left Atrial Appendage Closure

Background: Percutaneous left atrial appendage closure using the WATCHMAN system, to prevent thrombosis and minimize anti-coagulant use in patients with non-valvular atrial fibrillation, has recently been introduced. The safety and efficacy of new-generation WATCHMAN FLX, as compared to conventional WATCHMAN 2.5, remain unknown. Methods: Consecutive patients who received percutaneous left atrial appendage closure using the WATCHMAN system in our institute, between June 2020 and December 2021, were retrospectively analyzed. Safety and efficacy during the 45-day observational period were compared between the two devices. Results: A total of 93 patients (73.0 &plusmn; 7.3 years old, 63 men) who received WATCHMAN FLX (n = 44) or WATCHMAN 2.5 (n = 49) were included. The device implant success rate was 100% in the FLX device group and 98% in the 2.5 device group. There were no procedure-related complications in the FLX group, and one non-relevant pericardial effusion in the 2.5 device group. During the 45-day observational period, there were no procedure-related adverse events. No patients in the FLX group had a peri-device leak &gt;3 mm, whereas two patients in the 2.5 device group had a peri-device leak &gt;3 mm. Anti-coagulants could be terminated in most of the patients (85% versus 88%; p = 0.68). Conclusions: Percutaneous left atrial appendage closure using new-generation WATCHMAN FLX seemed to be as safe and effective as conventional WATCHMAN 2.5 during the short-term observational period