Efficacy of late concurrent hypofractionated radiotherapy in advanced melanoma patients failing anti-PD-1 monotherapy

Advanced melanoma patients who failed anti-PD-1 therapy have limited options. We analyzed a cohort of 133 advanced melanoma patients receiving anti-PD-1 monotherapy in a referral center between April 2015 and December 2017, and included the 26 patients with confirmed progressive (PD) or stable disease who received additional radiotherapy with an unmodified anti-PD-1 mAb regimen. Tumor evaluations were done on radiated and nonradiated (RECIST 1.1) lesions, with abscopal effect defined as a partial (PR) or complete response (CR) outside radiated fields. Primary endpoint was the CR + PR rate in radiated + nonradiated lesions. Secondary endpoints were progression-free survival (PFS), melanoma-specific survival (MSS) and safety. First late radiotherapy, consisting of hypofractionated radiotherapy (3–5 sessions, 20–26 Gy), standard palliative radiotherapy or brain radiosurgery was begun after a median of 6.3 months of anti-PD-1 in 23, 2 and 1 patient(s), respectively. Best response was 8 (31%) CR, 2 (8%) profound PR allowing surgical resection of remaining metastases and 16 (62%) PD. Abscopal effect was seen in 35% of patients. Median PFS and MSS since anti-PD-1 initiation was 15.2 [95% CI: 8.0 not achieved (na)] and 35.3 [95% CI: 18.5 na] months, respectively. PFS curves seemed to achieve a plateau. We discontinued anti-PD-1 therapy in 9/10 of patients with no residual evaluable disease and observed one relapse after a median of 10 months off anti-PD1-therapy. No unusual adverse event was recorded. Limitations of the study include its retrospective nature and limited size. Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in patients who previously failed anti-PD-1 therapy. Controlled studies are needed.     

人脂肪干细胞复合脱细胞软骨基质支架在生物反应器中构建组织工程软骨

目的:观察人脂肪干细胞复合脱细胞软骨基质支架在生物反应器中初步构建组织工程软骨的可行性。方法:实验于2005-04/2006-05在解放军总医院骨科研究所完成。脂肪组织和关节软骨均来自膝关节置换术中切除的组织,并经患者知情同意。关节软骨冻干后经粉碎机粉碎,过筛,选取25～38μm大小的软骨微粒。在样品中先加入2.5g/L胰蛋白酶,37℃消化24h,再加入1%Triton X-100震荡72h。将软骨微粒和蒸馏水按1∶3的比例混合后滴加在模板中,置入冷冻干燥机冻干后行紫外线交联。紫外线照射8h完成。最后经25kGy 60Co辐照灭菌完成支架制备。取膝关节置换术中切除的髌下脂肪垫,酶消法获得脂肪干细胞,扩增后复合于脱细胞软骨基质制成圆柱状三维支架上(细胞密度5×1010L-1),置于生物反应器中进行诱导培养,同时设静态培养组作为对照,3周后观测大体形态和组织学形态变化,同时进行组织化学(包括番红花O,阿利新蓝染色)和Ⅱ型胶原免疫组织化学分析。结果:生物反应器组诱导培养3周苏木精-伊红染色显示支架结构消失,只有中心区域残存少量支架结构;静态培养组支架结构尚存在,有少量基质分泌。番红花O染色显示生物反应器组细胞外有大量蛋白聚糖沉积,阿利新蓝染色表明有软骨特异性蛋白多糖的聚集;而静态培养组只有部分区域染色且淡于生物反应器组。Ⅰ型胶原免疫组化的结果显示,在生物反应器组细胞能够合成大量软骨细胞特异性胶原成分,而静态培养组呈弱阳性。结论:生物反应器培养明显促进了脂肪干细胞的增殖与软骨分化,是体外构建组织工程软骨的良好方法。     

Aven‐mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma

Conventional high‐grade osteosarcoma is the most common primary bone sarcoma, with relatively high incidence in young people. In this study we found that expression of Aven correlates inversely with metastasis‐free survival in osteosarcoma patients and is increased in metastases compared to primary tumours. Aven is an adaptor protein that has been implicated in anti‐apoptotic signalling and serves as an oncoprotein in acute lymphoblastic leukaemia. In osteosarcoma cells, silencing Aven triggered G₂ cell‐cycle arrest; Chk1 protein levels were attenuated and ATR–Chk1 DNA damage response signalling in response to chemotherapy was abolished in Aven‐depleted osteosarcoma cells, while ATM, Chk2 and p53 activation remained intact. Osteosarcoma is notoriously difficult to treat with standard chemotherapy, and we examined whether pharmacological inhibition of the Aven‐controlled ATR–Chk1 response could sensitize osteosarcoma cells to genotoxic compounds. Indeed, pharmacological inhibitors targeting Chk1/Chk2 or those selective for Chk1 synergized with standard chemotherapy in 2D cultures. Likewise, in 3D extracellular matrix‐embedded cultures, Chk1 inhibition led to effective sensitization to chemotherapy. Together, these findings implicate Aven in ATR–Chk1 signalling and point towards Chk1 inhibition as a strategy to sensitize human osteosarcomas to chemotherapy. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Identification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequence

Fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. FADS can result from mutations in CHRNG, CHRNA1, CHRND, DOK7 and RAPSN; however, these genes only account for a minority of cases. Here we identify MUSK as a novel cause of lethal FADS. Fourteen affected fetuses from a Dutch genetic isolate were traced back to common ancestors 11 generations ago. Homozygosity mapping in two fetuses revealed MUSK as a candidate gene. All tested cases carried an identical homozygous variant c.1724T>C; p.(Ile575Thr) in the intracellular domain of MUSK. The carrier frequency in the genetic isolate was 8%, exclusively found in heterozygous carriers. Consistent with the established role of MUSK as a tyrosine kinase that orchestrates neuromuscular synaptogenesis, the fetal myopathy was accompanied by impaired acetylcholine receptor clustering and reduced tyrosine kinase activity at motor nerve endings. A functional assay in myocytes derived from human fetuses confirmed that the variant blocks MUSK-dependent motor endplate formation. Taken together, the results strongly support a causal role of this founder mutation in MUSK, further expanding the gene set associated with FADS and offering new opportunities for prenatal genetic testing.     

败血症病人死亡危险性预评估方法的探讨

目的:探索可早期预测严重败血症病人死亡的临床和实验室指标或系统模型。方法:对ICU连续收治的26例严重败血症病人行前瞻性观察28天,分析其死亡的相关临床和实验室指标。结果:共有14人(54％)死亡,多死于第1周内(74％)。根据循环中的细胞间粘附分子-1水平能早期预测其脏器衰竭和死亡。一些临床指标水平在死亡病人与生存病人之间差别较大,其中包括血总胆红素、pH值、红细胞压积、氧合指数、动静脉血氧差、四项SIRS指标和一些血流动力学指标等。结论:综合上述指标可以尝试建立起了一个能够早期评估病人死亡可能性的积分系统。     

耐一线药物及注射药物对耐多药结核病治疗效果的影响

背景和目的:最近的研究结果表明,对其他一线药物和注射类药物(如卡那霉素、卷曲霉素)等耐药是影响耐多药结核病(MDR-TB)患者治疗效果的独立危险因素.本研究旨在明确耐其他一线药物和注射类药物对韩国不合并人免疫缺陷病毒(HIV)感染的MDR-TB患者临床疗效的影响.方法:采用回顾性队列研究分析1996年1月至2005年12月首尔国家大学附属医院治疗的211例MDR-TB患者治疗效果,排除7例丢失和7例迁出,对197例患者进行了最终分析.