Polymyositis and myocarditis after chemotherapy for advanced thymoma

AbstractPolymyositis and myocarditis very rarely develop during chemotherapy for thymoma. Most reported cases of myocarditis and polymyositis associated with thymoma were found at autopsy of patients who died of acute progression of myocarditis. We describe our experience with a 64-year-old man who had recurrent thymoma accompanied by polymyositis and myocarditis. Lower-extremity myalgia and palpitations developed on day 25 of chemotherapy with weekly paclitaxel. Steroid pulse therapy was effective for the management of polymyositis and myocarditis associated with thymoma. Polymyositis and myocarditis after paclitaxel monotherapy have not been documented previously. Whether paclitaxel induced polymyositis and myocarditis is unclear and these symptoms might have been a paraneoplastic phenomenon associated with thymoma. However, our experience suggested that patients with thymoma who received paclitaxel-based chemotherapy should be carefully observed for polymyositis and myocarditis. If such patients have high serum creatine phosphokinase and troponin levels, steroid pulse therapy should be considered without delay

Prevention of hypermelanosis by rearing Japanese flounder Paralichthys olivaceus in net-lined tanks

In artificially reared flatfish, especially the Japanese flounder Paralichthys olivaceus, pigmented skin (hypermelanosis) frequently appears on the fish’s blind side after normal metamorphosis. As no practical prevention method has yet been proposed, we examined the effectiveness of a loose net placed inside the rearing tank that covers the bottom and walls like a pouch. When juveniles (standard length [SL] 6 cm) were transferred to the net-lined tank (mesh size 4 mm) before the first appearance of hypermelanosis, the pigmented area after 2 months covered about 0.5% of the blind side; this is about 1/40th of the area covered by pigment in fish reared in an ordinary tank (20%). Although the initial appearance of pigmentation in the axilla area (the area covered by the pectoral fin) was not suppressed, utilization of a larger mesh size (12 mm) decreased the expansion of pigmentation in this area. Juveniles reared in the net-lined tank were about 5–15% smaller (SL) than those reared in the ordinary tank, but their body depth:SL ratio was closer to that of wild-caught juveniles. From the results of this study, we propose that net-lined rearing tanks with larger-sized mesh are a practical method of preventing hypermelanosis in Japanese flounder aquaculture systems

Analysis of Extrahepatic Multiple Primary Malignancies in Patients with Hepatocellular Carcinoma according to Viral Infection Status

Previous studies have investigated extrahepatic multiple primary malignancy (EHPM) associated with hepatocellular carcinoma (HCC). However, its correlation with viral infection, such as hepatitis B virus (HBV) or hepatitis C virus (HCV), has not been examined. The aim of this study is to investigate the association between EHPM and hepatitis infection in HCC patients. A total of 412 patients who underwent surgical resection for primary HCC were enrolled. Viral infection was evaluated by serum HBV surface antigen (HBs Ag) and HCV antibody (HCV Ab). Sixty-eight (16.5%) patients had one or more EHPM. The most frequent EHPM was gastric cancer (n = 32) in this cohort. No statistical significance was observed in the distribution of viral infection and incidence of entire EHPM. However, HCV Ab, HBs Ag, and negative status for both were correlated with the frequency of gastric (P = 0.0194), urinary tract (P = 0.0067), and breast cancer (P = 0.0036), respectively. Infection of Helicobacter pylori was investigated by immunohistochemistry in gastric EHPM and resulted that 20 out of 21 analyzed cases were negative for Helicobacter pylori. Although it should be verified by well-designed large cohort studies, the current results suggested correlation between HCV infection and gastric cancer, HBV infection and urinary tract cancer and viral hepatitis-free status and breast cancer in HCC patients

Comparison of proportions and prognostic impact of pathological complete response between evaluations of representative specimen and total specimen in primary breast cancer after neoadjuvant chemoradiotherapy: an ancillary study of JCOG0306

Background In JCOG0306 trial, a phase II study to examine the efficacy of neoadjuvant chemotherapy followed by radiation therapy (NAC-RT) to primary breast cancer, pathological complete response (pCR) was evaluated from specimens of the representative cross-section including the tumor center that had been accurately marked [representative specimen (RS) method]. In this ancillary study, we examined if the RS method was comparable to the conventional total specimen (TS) method, which is widely employed in Japan, to identify the pCR group showing excellent prognosis. Methods We obtained long-term follow-up data of 103 patients enrolled in JCOG0306 trial. As histological therapeutic effect, pCR (ypT0 and ypT0/is) and quasi-pCR [QpCR, ypT0/is plus Grade 2b (only a few remaining invasive cancer cells)] were evaluated with RS and TS methods. Concordance of pCR between these two methods and associations of the pCR with prognosis were examined. Results ypT0, ypT0/is, and QpCR were observed in 28 (27.2%), 39 (37.9%), and 45 (43.7%) patients with RS method, whereas these were 20 (19.4%), 25 (24.3%) and 40 (38.9%) with TS method, respectively. Between RS and TS methods, concordance proportions of ypT0 and ypTis were 92.2% and 86.4%, respectively. Risk of recurrence of ypT0/is group was lower than that of non-ypT0/is group (HR 0.408, 95% CI [0.175–0.946], P = 0.037) and risk of death of ypT0/is group was lower than that of non-ypT0/is group (HR 0.251, 95% CI [0.073–0.857], P = 0.027). The ypT0 and ypT0/is groups with RS method showed excellent prognosis similarly with those with TS method, and RS method was able to differentiate the OS and RFS between pCR and non-pCR than TS method significantly even if pCR was classified ypT0 or ypT0/is. With TS method, QpCR criteria stratified patients into the better and worse prognosis groupsmore clearly than pCR criteria of ypT0 or ypT0/is. Conclusions RS method was comparable to TS method for the evaluation of pCR in the patients who received NAC-RT to primary breast cancer provided the tumor center was accurately marked. As pCR criteria with RS method, ypT0/is appeared more appropriate than ypT0

Species identification, antifungal susceptibility, and clinical feature association of Aspergillus section Nigri isolates from the lower respiratory tract

Species of Aspergillus section Nigri are generally identified by molecular genetics approaches, whereas in clinical practice, they are classified as A. niger by their morphological characteristics. This study aimed to investigate whether the species of Aspergillus section Nigri isolated from the respiratory tract vary depending on clinical diagnosis. Forty-four Aspergillus section Nigri isolates isolated from the lower respiratory tracts of 43 patients were collected from February 2012 to January 2017 at the National Hospital Organization (NHO) Tokyo National Hospital. Species identification was carried out based on β-tubulin gene analysis. Drug susceptibility tests were performed according to the Clinical and Laboratory Standards Institute (CLSI) M38 3rd edition, and the clinical characteristics were retrospectively reviewed. A. welwitschiae was isolated most frequently, followed by A. tubingensis. More than half of the A. tubingensis isolates exhibited low susceptibility to azoles in contrast to only one A. welwitschiae isolate. Approximately three quarters of the patients from whom A. welwitschiae was isolated were diagnosed with colonization, whereas more than half the patients from whom A. tubingensis was isolated were diagnosed with chronic pulmonary aspergillosis (CPA). More attention needs to be given to the drug choice for patients with CPA with Aspergillus section Nigri infection because A. tubingensis, which was found to be frequently azole-resistant, was the most prevalent in these patients

Status of adult outpatients with congenital heart disease in Japan: The Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease Registry

BackgroundThe Japanese Network of Cardiovascular Departments for Adult Congenital Heart Disease (JNCVD-ACHD) was founded in 2011 for the lifelong care of adult patients with congenital heart disease (ACHD patients). This network maintains the first Japanese ACHD registry.Methods and resultsFrom 2011 to 2019, the JNCVD-ACHD registered 54 institutions providing specialized care for ACHD patients in 32 of the 47 prefectures in Japan. The registry collected data on the disease profile for 24,048 patients from 50 institutions and the patient characteristics for 9743 patients from 24 institutions. The most common ACHDs were atrial septal defect (20.5 %), ventricular septal defect (20.5 %), tetralogy of Fallot (12.9 %), and univentricular heart (UVH)/single ventricle (SV; 6.6 %). ACHD patients without biventricular repair accounted for 37.0 % of the population. Also examined were the serious anatomical and/or pathophysiological disorders such as pulmonary arterial hypertension (3.0 %) including Eisenmenger syndrome (1.2 %), systemic right ventricle under biventricular circulation (sRV-2VC; 2.8 %), and Fontan physiology (6.0 %). The sRV-2VC cases comprised congenitally corrected transposition of the great arteries without anatomical repair (61.9 %) and transposition of the great arteries with atrial switching surgery (38.1 %). The primary etiology (86.4 %) for Fontan physiology was UVH/SV. In addition, developmental/chromosomal/genetic disorders were heterotaxy syndromes (asplenia, 0.9 %; polysplenia, 0.7 %), trisomy 21 (4.0 %), 22q11.2 deletion (0.9 %), Turner syndrome (0.2 %), and Marfan syndrome (1.1 %).ConclusionsAlthough the specific management of ACHD has systematically progressed in Japan, this approach is still evolving. For ideal ACHD care, the prospective goals for the JNCVD-ACHD are to create local networks and provide a resource for multicenter clinical trials to support evidence-based practice

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

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

Spatial and temporal variation at major histocompatibility complex class IIB genes in the endangered Blakiston’s fish owl

Introduction Quantifying intraspecific genetic variation in functionally important genes, such as those of the major histocompatibility complex (MHC), is important in the establishment of conservation plans for endangered species. The MHC genes play a crucial role in the vertebrate immune system and generally show high levels of diversity, which is likely due to pathogen-driven balancing selection. The endangered Blakiston’s fish owl (Bubo blakistoni) has suffered marked population declines on Hokkaido Island, Japan, during the past several decades due to human-induced habitat loss and fragmentation. We investigated the spatial and temporal patterns of genetic diversity in MHC class IIβ genes in Blakiston’s fish owl, using massively parallel pyrosequencing. Results We found that the Blakiston’s fish owl genome contains at least eight MHC class IIβ loci, indicating recent gene duplications. An analysis of sequence polymorphism provided evidence that balancing selection acted in the past. The level of MHC variation, however, was low in the current fish owl populations in Hokkaido: only 19 alleles were identified from 174 individuals. We detected considerable spatial differences in MHC diversity among the geographically isolated populations. We also detected a decline of MHC diversity in some local populations during the past decades. Conclusions Our study demonstrated that the current spatial patterns of MHC variation in Blakiston’s fish owl populations have been shaped by loss of variation due to the decline and fragmentation of populations, and that the short-term effects of genetic drift have counteracted the long-term effects of balancing selection

Recent fragmentation of the endangered Blakiston’s fish owl (Bubo blakistoni) population on Hokkaido Island, Northern Japan, Revealed by Mitochondrial DNA and Microsatellite Analyses

Introduction Blakiston’s fish owl (Bubo blakistoni) was previously widespread on Hokkaido Island, Japan, but is now distributed only in limited forest areas. The population size on Hokkaido decreased during the 20th century due to reduction and fragmentation of the owl’s habitat. To elucidate temporal and spatial changes in population structure and genetic diversity, we analyzed 439 individuals collected over the last 100 years. Results We detected a population bottleneck and fragmentation event indicated by mitochondrial DNA (mtDNA) haplotype and microsatellite analyses. The lowest value for effective population size, which was estimated by moment and temporal methods from microsatellite data, occurred in the 1980s. Five haplotypes were found in the mtDNA control region; most haplotypes were previously widespread across Hokkaido, but have become fixed in separate areas after the bottleneck period. Genetic differentiation among local populations, as indicated by both mtDNA and microsatellite data, likely arose through population fragmentation. Conclusions The owl population may have been divided into limited areas due to loss of habitats via human activities, and have lost genetic variability within the local populations through inbreeding. Our mtDNA and microsatellite data show that genetic diversity decreased in local populations, indicating the importance of individuals moving between areas for conservation of this species on Hokkaido