Loss of function,missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.     

经皮肺动脉瓣植入术在肺动脉瓣反流患者中的临床应用

经皮肺动脉瓣植入术(PPVI)在我国作为一种新兴的技术,开展相对较晚,但随着我国医疗水平的不断提高以及临床对于右心室流出道梗阻的先天性心脏病患者术后出现重度肺动脉瓣反流的不断重视,PPVI在我国得到了飞速发展。近十几年来,欧美国家已在临床成熟应用PPVI,相对于传统外科手术而言其具有微创、可重复性、术后疗效好等优点。现对PPVI在肺动脉瓣反流患者中的临床应用进行叙述。     

Current standards and future perspectives in adjuvant treatment for biliary tract cancers

Biliary tract cancer, including cholangiocarcinoma (CCA) and gallbladder cancer (GBC) are rare tumours with a rising incidence. Prognosis is poor, since most patients are diagnosed with advanced disease. Only ~20% of patients are diagnosed with early-stage disease, suitable for curative surgery. Despite surgery performed with potentially-curative intent, relapse rates are high, with around 60–70% of patients expected to have disease recurrence. Most relapses occur in the form of distant metastases, with a predominance of liver spread. In view of high tumour recurrence, adjuvant strategies have been explored for many years, in the form of radiotherapy, chemo-radiotherapy and chemotherapy. Historically, few randomised trials were available, which included a variety of additional tumours (e.g. pancreatic and ampullary tumours); most evidence relied on phase II and retrospective studies, with no high-quality evidence available to define the real benefit derived from adjuvant strategies.Since 2017, three randomised phase III clinical trials have been reported; all recruited patients with resected biliary tract cancer (CCA and GBC) who were randomised to observation alone, or chemotherapy in the form of gemcitabine (BCAT study; included patients diagnosed with extrahepatic CCA only), gemcitabine and oxaliplatin (PRODIGE-12/ACCORD-18; included patients diagnosed with CCA and GBC) or capecitabine (BILCAP; included patients diagnosed with CCA and GBC). While gemcitabine-based chemotherapy failed to show an impact on patient outcome (relapse-free survival (RFS) or overall survival (OS)), the BILCAP study showed a benefit from adjuvant capecitabine in terms of OS (pre-planned sensitivity analysis in the intention-to-treat population and in the per-protocol analysis), with confirmed benefit in terms of RFS. Based on the BILCAP trial, international guidelines recommend adjuvant capecitabine for a period of six months following potentially curative resection of CCA as the current standard of care for resected CCA and GBC. However, BILCAP failed to show OS benefit in the intention-to-treat (non-sensitivity analysis) population (primary end-point), and this finding, as well as some inconsistencies between studies has been criticised and has led to confusion in the biliary tract cancer medical community.This review summarises the adjuvant field in biliary tract cancer, with evidence before and after 2017, and comparison between the latest randomised phase III studies. Potential explanations are presented for differential findings, and future steps are explored.     

程序性死亡蛋白-1抗体治疗晚期胃癌的临床研究新进展

目前化疗仍为晚期胃癌的标准治疗手段,而多数患者诊断时已接近晚期。近年新兴的免疫治疗手段程序性死亡蛋白-1(PD-1,programmed death l)抗体,通过阻断肿瘤细胞逃避自身免疫机制,重新激活自身免疫对肿瘤的杀伤作用,从而达到肿瘤的治疗作用。针对晚期胃癌的PD-1抗体治疗的临床研究已在国内外开展,大部分均有较好效果。本文对近年免疫治疗中的PD-1抗体在晚期胃癌的重要临床研究进展进行介绍。     

王克穷教授参合腹诊应用大陷胸汤临证经验

《伤寒论》乃经方之祖,而其中关于腹诊论述的条文达1/4以上,是临床选方用药的重要依据,临床实践中对于经方的使用,更应该注重腹诊。大陷胸汤出自《伤寒论》,乃峻下之剂,然今之医者,恐其太过峻猛,鲜有人使用此方,近年来相关报道也较少,但若处方用药恰当,则可取得事半功倍的效果,为指导经方临床应用开阔了思路。     

钩虫病感染者免疫球蛋白水平、临床特点及胃肠镜下形态分析

目的分析钩虫病感染者血清免疫球蛋白(Ig)A、IgG、IgM和IgE水平,临床特点及胃肠镜下形态。方法分析16例钩虫病感染者的临床资料,观察患者的临床表现、Ig水平、血常规检查结果、胃肠镜检查结果及治疗结果。结果 16例患者的IgE水平明显高于正常参考上限值;IgA、IgG、IgM水平与正常参考上限值比较,差异不明显。经诊断患者的钩虫分布情况:十二指肠降部8例(50.00%),十二指肠球部5例(31.25%),回肠末端3例(18.75%),升结肠1例(6.25%),其中十二指肠及回肠末端均见钩虫者1例(6.25%)。所有患者均予阿苯达唑片驱虫治疗,治疗后1个月复查见贫血得到纠正,消化道症状得以缓解,复查胃肠镜未见虫体,均治愈。结论钩虫病感染者的IgE水平明显升高,胃肠镜检查是确诊钩虫病的重要手段,尤其是要加强对十二指肠降部的检查,并在确诊后及时给予正规治疗措施。