日本人の免疫性血栓性血小板減少性紫斑病患者における不十分な血漿交換は致死的な転帰と強く相関する

Plasma exchange (PEX) using fresh frozen plasma has considerably reduced the mortality rate in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP). However, some patients still do not survive even with treatment, but little information is available regarding which treatment these patients received. This study was conducted to obtain this information in 240 patients who met the current iTTP diagnostic criteria and completed at least 30 days of follow-up except for deceased cases. These patients were divided into three groups: survivors (n = 195), TTP-related deaths (n = 32), and other cause of death (n = 13). In the TTP-related death group, 26 of 32 patients experienced sudden death, mostly following radical hypotension and bradycardia. The median follow-up time after admission was 5.0 days, and the median number of PEX sessions was 2.5. Nine patients underwent autopsy and had cardiac microvascular thrombi in arterioles. Levels of lactate dehydrogenase, total bilirubin, serum creatinine, and D-dimer were significantly higher in the TTP-related death group than in the survivors group. Frequent PEX (> 20 sessions) was not associated with TTP-related death. In the acute phase of iTTP, patients with substantial organ damage caused by microthrombi have a greater mortality risk, even after just a few PEX sessions.博士（医学）・乙第1518号・令和3年12月21日© Japanese Society of Hematology 2021.The version of record of this article, first published in International journal of hematology, is available online at Publisher’s website: http://dx.doi.org/10.1007/s12185-021-03197-5.発行元が定める登録猶予期間終了の後、本文を登録予定（2022.10

Successful lung-protective ventilatory management during the VV-ECMO in a severe COVID-19 pneumonia patient with extensive pneumomediastinum and subcutaneous emphysema: a case report

BACKGROUND: Ventilatory management of respiratory failure with pneumomediastinum/subcutaneous emphysema is not established. Herein, we report a case of severe COVID-19 pneumonia with extensive pneumomediastinum/subcutaneous emphysema, rescued by thorough lung-protective ventilatory management after applying the VV-ECMO. CASE PRESENTATION: A 68-year-old male with no medical history was admitted to a local hospital and diagnosed with COVID-19 pneumonia. His pulmonary parameters worsened during invasive ventilation due to the development of pneumomediastinum/subcutaneous emphysema, and then he was transferred to our hospital. On arrival, we immediately decided to apply VV-ECMO and switch to ultraprotective ventilation. After maintaining the initial ventilation with a neuromuscular blocking agent for 2 days, we gradually increased PEEP while limiting PIP to 25 cmH2O. The patient was weaned off VV-ECMO on day 10; he was transferred to the medical ward after extubation. CONCLUSIONS: Lung-protective ventilatory management should be performed thoroughly during VV-ECMO in severe COVID-19 pneumonia with pneumomediastinum/subcutaneous emphysema

Efficacy and safety of nintedanib in Japanese patients with early-stage idiopathic pulmonary fibrosis: a study protocol for an observational study

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of unknown aetiology with a poor prognosis. Several clinical trials of nintedanib in patients with IPF have reported its inhibitory effect on reduced lung function, incidence of acute exacerbation of IPF and worsened health-related quality of life. Although nintedanib has a manageable safety and tolerability profile over long-term use, it was discontinued in over 20% of patients because of adverse events such as diarrhoea and liver dysfunction. This might explain why nintedanib use in patients with IPF is not widespread, especially among patients with early-stage IPF. In the present study, we aimed to clarify the efficacy, safety and tolerability of nintedanib in patients with stage I/II IPF, based on the Japanese IPF disease severity staging classification system.Methods and analysis: This is an ongoing, prospective, multicentre observational cohort study of patients with stage I/II IPF who will start receiving nintedanib. Totally, 215 patients at 35 sites in Kyushu and Okinawa, Japan will be enrolled and followed up for 3 years. Nintedanib therapy would be initiated at the discretion of the investigator. The primary endpoint, change in forced vital capacity (FVC) at 156 weeks, will be shown as the mean change in FVC from baseline to week 156 with 95% CIs estimated using the Wald method. The safety endpoint—occurrence of adverse events—will be assessed in each system organ class/preferred term.Ethics and dissemination: The study protocol and informed consent documents were approved by the Institutional Review Board at Nagasaki University Hospital (approval number 19102146) and each participating site. Written informed consent was obtained from all participants. Patient recruitment has begun. The results will be disseminated through scientific peer-reviewed publications and national and international conferences.Trial registration number: UMIN000038192

Long-term activation of anti-tumor immunity in pancreatic cancer by a p53-expressing telomerase-specific oncolytic adenovirus

Background: Pancreatic cancer is an aggressive, immunologically “cold” tumor. Oncolytic virotherapy is a promising treatment to overcome this problem. We developed a telomerase-specific oncolytic adenovirus armed with p53 gene (OBP-702). Methods: We investigated the efficacy of OBP-702 for pancreatic cancer, focusing on its long-term effects via long-lived memory CD8 + T cells including tissue-resident memory T cells (TRMs) and effector memory T cells (TEMs) differentiated from effector memory precursor cells (TEMps). Results: First, in vitro, OBP-702 significantly induced adenosine triphosphate (ATP), which is important for memory T cell establishment. Next, in vivo, OBP-702 local treatment to murine pancreatic PAN02 tumors increased TEMps via ATP induction from tumors and IL-15Rα induction from macrophages, leading to TRM and TEM induction. Activation of these memory T cells by OBP-702 was also maintained in combination with gemcitabine+nab-paclitaxel (GN) in a PAN02 bilateral tumor model, and GN + OBP-702 showed significant anti-tumor effects and increased TRMs in OBP-702-uninjected tumors. Finally, in a neoadjuvant model, in which PAN02 cells were re-inoculated after resection of treated-PAN02 tumors, GN + OBP-702 provided long-term anti-tumor effects even after tumor resection. Conclusion: OBP-702 can be a long-term immunostimulant with sustained anti-tumor effects on immunologically cold pancreatic cancer