The Myelodepletive Phenotype in Myelofibrosis: Clinical Relevance and Therapeutic Implication

Myelofibrosis (MF) is a BCR-ABL1⁻ myeloproliferative neoplasm that arises from hematopoietic stem and progenitor cells frequently harboring a somatic driver mutation in 1 of 3 genes: JAK2, CALR, or MPL. The pathologic features of this hematologic malignancy include myeloproliferation, diffuse bone marrow fibrosis, and overactivation of the JAK-STAT pathway, resulting in enhanced inflammatory cytokine release. The common clinical manifestations of MF include systemic symptoms, abnormal peripheral blood count levels, and splenomegaly. However, it has become increasingly appreciated that significant clinical heterogeneity exists among patients with MF. Two distinct MF clinical phenotypes include the myeloproliferative and myelodepletive phenotype, with peripheral blood counts being the main discerning feature. Patients with the myeloproliferative phenotype will present with elevated peripheral blood counts and often experience significant constitutional symptoms and progressive splenomegaly. In contrast, patients with the myelodepletive phenotype will have low peripheral blood counts and will frequently require transfusion support. Current frontline therapies for MF, include ruxolitinib and fedratinib, which can exacerbate cytopenias and thereby pose an impediment to effective treatment of the myelodepletive patient. The present review discusses the clinical and prognostic implications of the myelodepletive phenotype and the therapeutic options and limitations for this subset of patients, representing an unmet clinical need.     

Management of upper gastrointestinal perforations

Perforation of the upper gastrointestinal (UGI) tract is a surgical emergency. Causes of oesophageal perforation include spontaneous (Boerhaave's), iatrogenic or foreign body ingestion. Perforation of the stomach and duodenum is most often caused by peptic ulcer disease. Management involves obtaining an accurate clinical diagnosis, through a combination of patient assessment, imaging and endoscopy. It is important to differentiate intramural from full thickness oesophageal perforations as this will guide the definitive surgical or endoscopic management. Perioperative care of these patients is as important as the definitive management step. This article will summarise an approach to managing perforation of the UGI tract; from initial assessment to postoperative care.     

基于“凡土脏取决于胆”议从胆论治阿尔茨海默病

阿尔茨海默病(Alzheimer’s Disease,AD)归属于中医"痴呆""呆病""健忘"等范畴,历代医家认为此病多以肾精失养,髓海空虚为主要病机,治疗多从脾、肾两脏着手,鲜有提及从胆论治。从中医学"凡土脏取决于胆"理论切入,以土脏与AD发病的关系为着眼点,并结合胆内藏精汁,助脾胃腐熟运化水谷;胆主升清降浊,疏利中土;胆内寄相火,参与腐熟水谷的生理功能和特性,阐述从胆论治AD的理论基础,以期为中医临床更加有效的防治阿尔茨海默病提供参考。     

Implementation of Recommendations for Long-Acting Contraception Among Women Aged 13 to 18 Years in Primary Care

ObjectiveClinical specialty societies recommend long-acting reversible contraceptives (LARCs) as first-line contraception for adolescent women. We evaluated whether a combined educational and process improvement intervention enhanced LARC placement in primary care within an integrated health care system.MethodsThe intervention included journal clubs, live continuing education, point-of-care guidelines, and new patient materials. We conducted a retrospective cohort study across 3 time periods: baseline (January 2013?September 2015), early implementation (October 2015–March 2016), and full implementation (April 2016–June 2017). The primary outcome was the proportion of LARCs placed by primary care clinicians among women aged 13 to 18 years compared with gynecology clinicians.ResultsKaiser Foundation Health Plan of Colorado cared for approximately 20,000 women aged 13 to 18 years in each calendar quarter between 2013 and 2017. Overall, LARC placement increased from 7.0 per 1000 members per quarter at baseline to 13.0 per 1000 during the full intervention. Primary care clinicians placed 6.2% of all LARCs in 2013, increasing to 32.1% by 2017 (P < .001), including 45.5% of contraceptive implants. Clinicians who attended educational sessions were more likely to adopt LARCs than those who did not (17.9% vs 6.4% respectively, P = .009). Neither overall LARC placement rates (relative risk, 1.9; 95% confidence interval, 0.7?5.6) nor contraceptive implant rates (relative risk, 3.0; 95% confidence interval, 0.9?9.8) increased significantly in clinicians who attended educational activities.ConclusionsThis multimodal intervention was associated with increased LARC placement for adolescent women in primary care. The combination of education and process improvement is a promising strategy to promote clinician behavior change.     

Brain impedance variation of directional leads implanted in subthalamic nuclei of Parkinsonian patients

ObjectiveConventional deep brain stimulation (DBS) systems with ring-shaped leads generate spherical electrical fields. In contrast, novel directional leads use segmented electrodes. Aim of this study was to quantify the impedance variations over time in subjects with the directional Cartesia-Boston® system.MethodsImpedance records, programming settings, and clinical data of 11 consecutive Parkinsonian patients implanted with DBS directional leads in two Italian centers (Udine and Vicenza) were retrospectively evaluated. Data were collected before starting stimulation (in the operating room and at days 5 and 40) and after switching stimulation on at the successive follow-up visits (1, 6 and 12 months).ResultsDirectional leads have significantly higher impedance than ring leads. Stimulated contacts had always lower impedance compared to non-stimulated contacts. Before DBS-on, all contacts had higher impedance in the operating room, with an initial decrease five days post-surgery and a subsequent increase at day 40, more evident for directional contacts. The impedance of directional leads increased post-implantation at 1 and 6 months with a plateau at 12 months.ConclusionsThere was a significant difference between the directional and ring leads at baseline (before activation of DBS) and during follow-up (chronic DBS).SignificanceOur study reveals new information about the impedance of segmented electrodes that is useful for patient management during the initial test period, as well as during long-term DBS follow-up.     

肝内胆管癌转化治疗

肝内胆管癌（ICC）可切除率低，进展期ICC的治疗有效率不高，预后很差。转化治疗在多种晚期肿瘤中有一定的疗效，是目前晚期肿瘤治疗的研究热点。随着对ICC基因组的深入了解和新的治疗药物的开发及组合，基于系统化疗的联合治疗策略，精准靶向治疗，免疫检查点抑制剂等显示出较好的疗效，使得部分进展期ICC病人能降期转化手术，获得长期生存。     

Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent in vitro and in vivo antitumor potency. Particularly, compound 30a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, p.o.) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.     

肾母细胞瘤MIB-1（Ki-67增殖指数）和p27kip1表达及与预后的关系

目的:探讨肾母细胞瘤MIB-1（Ki-67增殖指数）和细胞周期蛋白依赖性激酶抑制剂p27kip1的表达及与预后的关系。方法:经医院伦理委员会批准，连续纳入2008年1月至2013年8月在我院就诊的肾母细胞瘤患者样本作为研究对象，观察p27kip1和MIB-1阳性表达与患者临床特征的关系。结果:肿瘤组织中MIB-1阳性表达率高于正常肾组织，p27kip1阳性表达率低于正常肾组织，差异均有统计学意义（P＜0.05）。MIB-1和p27kip1表达与性别、年龄、病理分型、发病部位等均无相关性（P＞0.05），与临床分期存在相关性（P＜0.05）。MIB-1表达阳性患者中位生存时间低于阴性患者，而p27kip1表达阴性患者中位生存时间低于阳性患者（χ2=6.979、15.247，P=0.008、0.000）。结论:MIB-1表达增加和p27kip1表达降低与肾母细胞瘤的发生、发展、预后密切相关，临床应根据其表达情况进行针对性干预，以改善患者的预后。