Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tickborne infectious disease in China, Korea, and Japan caused by the SFTS virus (SFTSV). SFTS has a high mortality rate due to multiorgan failure. Recently, there are several reports on SFTS patients with mycosis. Here, we report a middle-aged Japanese SFTS patient with invasive pulmonary aspergillosis (IPA) revealed by an autopsy. A 61-year-old man with hypertension working in forestry was bitten by a tick and developed fever, diarrhea, and anorexia in 2 days. On day 4, consciousness disorder was appearing, and the patient was transferred to the University of Miyazaki Hospital. A blood test showed leukocytopenia, thrombocytopenia, as well as elevated levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatine kinase. The SFTSV gene was detected in serum using a reverse-transcription polymerase chain reaction. On day 5, respiratory failure appeared and progressed rapidly, and on day 7, the patient died. An autopsy was performed that revealed hemophagocytosis in the bone marrow and bleeding of several organs. IPA was observed in lung specimens. SFTSV infection may be a risk factor for developing IPA. Early diagnosis and treatment of IPA may be important in patients with SFTS.

BackgroundThe occurrence of a mediastinal germ cell tumor (GCT) and hematological malignancy in the same patient is very rare. Due to its rarity, there have been only two reports of the concurrent cases undergoing detailed genetic analysis with whole-exome sequencing (WES), and the possible clonal relationship between the both tumors remained not fully elucidated.MethodsWe performed whole-exome sequencing analysis of mediastinal GCT and acute myeloid leukemia (AML) samples obtained from one young Japanese male adult patient with concurrent both tumors, and investigated the possible clonal relationship between them.ResultsSixteen somatic mutations were detected in the mediastinal GCT sample and 18 somatic mutations in the AML sample. Mutations in nine genes, including TP53 and PTEN both known as tumor suppressor genes, were shared in both tumors.ConclusionsAll in our case and in the previous two cases with concurrent mediastinal GCT and AML undergoing with whole-exome sequencing analysis, TP53 and PTEN mutations were commonly shared in both tumors. These data not only suggest that these tumors share a common founding clone, but also indicate that associated mediastinal GCT and AML harboring TP53 and PTEN mutations represent a unique biological entity.

Hepatocyte growth factor activator inhibitor‐1 (HAI‐1), encoded by the SPINT1 gene, is a membrane‐bound protease inhibitor expressed on the surface of epithelial cells. Hepatocyte growth factor activator inhibitor‐1 regulates type II transmembrane serine proteases that activate protease‐activated receptor‐2 (PAR‐2). We previously reported that deletion of Spint1 in ApcMin/+ mice resulted in accelerated formation of intestinal tumors, possibly through enhanced nuclear factor‐κB signaling. In this study, we examined the role of PAR‐2 in accelerating tumor formation in the ApcMin/+ model in the presence or absence of Spint1. We observed that knockout of the F2rl1 gene, encoding PAR‐2, not only eliminated the enhanced formation of intestinal tumors caused by Spint1 deletion, but also reduced tumor formation in the presence of Spint1. Exacerbation of anemia and weight loss associated with HAI‐1 deficiency was also normalized by compound deficiency of PAR‐2. Mechanistically, signaling triggered by deregulated protease activities increased nuclear translocation of RelA/p65, vascular endothelial growth factor expression, and vascular density in ApcMin/+‐induced intestinal tumors. These results suggest that serine proteases promote intestinal carcinogenesis through activation of PAR‐2, and that HAI‐1 plays a critical tumor suppressor role as an inhibitor of matriptase, kallikreins, and other PAR‐2 activating proteases.

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Hepatocyte growth factor activator inhibitor-1 (HAI-1, also known as SPINT1) is an inhibitor of matriptase, a type-2 transmembrane protease widely expressed in epithelial cells. HAI-1 also functions as a chaperone to maintain the processing and localization of matriptase required for epithelial integrity. However, mechanisms underpinning the chaperone function remain to be elucidated. Here, we show that the first Kunitz domain (KD1) and the adjacent polycystic kidney disease (PKD) domain-like internal domain of HAI-1 are essential for the chaperone function. In HEK293T cells, which do not express endogenous HAI-1 or matriptase, forced matriptase overexpression was unsuccessful unless sufficient HAI-1 was co-expressed. Among mutant HAI-1 constructs, HAI-1 with inactivation mutation in KD1 (HAI-1mKD1) or HAI-1 lacking the PKD domain (HAI-1dPKD) was unable to support matriptase expression, and neither mutant formed a complex with activated matriptase. Matriptase did not localize to the cell surface when co-expressed with HAI-1dPKD. Moreover, HAI-1dPKD accumulated in the cytoplasm of HEK293T and HaCaT cells rather than localizing to the cell surface, presumably due to misfolding as judged by altered antibody recognition. On the other hand, activationlocked and activity-incompetent matriptase were stable and readily overexpressed and localized to the cell surface without HAI-1. Therefore, the observed matriptase instability was caused by its own catalytic activity in the absence of inhibitory HAI-1. The matriptase chaperone function of HAI-1 is thus mediated primarily by the inhibition of undesired intracellular matriptase activity, and the PKD domain is essential for the proper folding and trafficking of inhibitory HAI-1 and its chaperone function.

Colorectal cancer is one of the most important malignancies worldwide, with high incidence and mortality rates. Several studies have been conducted using two-dimensional cultured cell lines; however, these cells do not represent a study model of patient tumors very well. In recent years, advancements in three-dimensional culture methods have facilitated the establishment of patient-derived organoids, which have become indispensable for molecular biology-related studies of colorectal cancer. Patient-derived organoids are useful in both basic science and clinical practice; they can help predict the sensitivity of patients with cancer to chemotherapy and radiotherapy and provide the right treatment to the right patient. Regarding precision medicine, combining gene panel testing and organoid-based screening can increase the effectiveness of medical care. In this study, we review the development of three-dimensional culture methods and present the most recent information on the clinical application of patient-derived organoids. Moreover, we discuss the problems and future prospects of organoid-based personalized medicine.

Background: The occurrence of a mediastinal germ cell tumor (GCT) and hematological malignancy in the same patient is very rare. Due to its rarity, there have been only two reports of the concurrent cases undergoing detailed genetic analysis with whole-exome sequencing (WES), and the possible clonal relationship between the both tumors remained not fully elucidated. Methods: We performed whole-exome sequencing analysis of mediastinal GCT and acute myeloid leukemia (AML) samples obtained from one young male adult patient with concurrent both tumors, and investigated the possible clonal relationship between them. Results: 16 somatic mutations were detected in the mediastinal GCT sample and 18 somatic mutations in the AML sample. Mutations in nine genes, including TP53 and PTEN both known as tumor suppressor genes, were shared in both tumors. Conclusions: All in our case and in the previous two cases with concurrent mediastinal GCT and AML undergoing with whole-exome sequencing analysis, TP53 and PTEN mutations were commonly shared in both tumors. These data not only suggest that these tumors share a common founding clone, but also indicate that associated mediastinal GCT and AML harboring TP53 and PTEN mutations represent a unique biological entity.

Background Adult cases of retroperitoneal isolated enteric duplication cyst (IEDC) are rare, with only 17 case reports in the relevant literature. We herein present a case, which was characterized by changes in intra-cystic density on computed tomography (CT), which was safely resected by laparoscopic surgery. Case presentation The patient was a 60-year-old male who received abdominal CT to investigate the cause of increased serum CA19-9 levels. CT revealed a unilocular cystic mass located in the lower right retroperitoneum. The size increased from 5 to 10 cm in three and a half years and the CT value decreased from 101 Hounsfield Units (HU) to 20 HU. We performed laparoscopic surgical resection, because the possibility that the enlargement of the lesion represented malignant transformation could not be denied. The large cystic mass firmly adhered to the appendix and its mesentery via the retroperitoneum, the appendix was resected en bloc with the cystic lesion. Microscopically, it had no communication with the appendix, and had an intestinal wall structure of muscularis mucosae and muscularis propria. The final pathological diagnosis was IEDC in the retroperitoneal space. There was no histological evidence of malignancy. Conclusion When we encounter a retroperitoneal cystic lesion, we should consider the possibility of malignancy to determine the treatment strategy and perform a careful operation without breaking the cyst wall, irrespective of the preoperative diagnosis.