EBV関連胃癌の微小環境における樹状細胞 : 腫瘍細胞由来エクソソームとの関連を含めて

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 藤堂 具紀, 東京大学教授 川口 寧, 東京大学講師 紙谷 尚子, 東京大学准教授 伊佐山 浩通, 東京大学准教授 篠崎 大University of Tokyo(東京大学

Exosomes of Epstein-Barr Virus-Associated Gastric Carcinoma Suppress Dendritic Cell Maturation

The Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is characterized by the infiltration of lymphocytes and a unique tumor microenvironment. Exosomes from cancer cells are essential for intercellular communication. The aims of this study were to investigate the secretion of EBVaGC exosomes and their physiological effect on dendritic cell maturation in vitro and to characterize dendritic cells (DCs) in EBVaGC in vivo. Western blotting analysis of CD63 and CD81 of exosomes from EBV-infected gastric cancer cell lines indicated an increase in exosome secretion. The fraction of monocyte-derived DCs positive for the maturation marker CD86 was significantly suppressed when incubated with exosomes from EBV-infected gastric cancer cell lines. Immunohistochemical analysis of GC tissues expressing DC markers (S100, Langerin, CD1a, CD83, CD86, and BDCA-2) indicated that the density of DCs was generally higher in EBVaGC than in EBV-negative GC, although the numbers of CD83- and CD86-positive DCs were decreased in the group with high numbers of CD1a-positive DCs. A low number of CD83-positive DCs was marginally correlated with worse prognosis of EBVaGC in patients. EBVaGC is a tumor with abundant DCs, including immature and mature DCs. Moreover, the maturation of DCs is suppressed by exosomes from EBV-infected epithelial cells

A case of delayed exacerbation of interstitial lung disease after discontinuation of temsirolimus

Temsirolimus is an inhibitor of mammalian target of rapamycin and interstitial lung disease (ILD) is known to be one of the adverse events associated with temsirolimus, which usually improves rapidly after discontinuation of the drug and rarely worsens thereafter. Herein, we report a case of delayed exacerbation of ILD after discontinuation of temsirolimus for metastatic renal cell carcinoma in an 86-year-old male with chronic ILD. The patient developed gradually worsening dyspnea five weeks after an initiation of temsirolimus and was admitted to our facility. On his admission, although a pulmonary function test revealed a decreased diffusion capacity, there was no obvious progression of ILD on HRCT scan. His dyspnea once improved after discontinuation of temsirolimus, but it recurred and acute exacerbation of ILD was diagnosed 40 days after his last administration of temsirolimus. He received high-dose steroid therapy, however, he deteriorated and died. Histopathological examination of the lungs at autopsy revealed overlapping diffuse alveolar damage with chronic interstitial changes. In the present case, since there were no specific factors that could have caused acute exacerbation of ILD except for temsirolimus, it was considered to contribute to the exacerbation of underlying ILD. In conclusion, physicians should be aware of the possibility of temsirolimus-induced ILD not only while the medication is administered, but also even after it is discontinued. It is important to carefully interview the patient and to recognize the value of physiological tests, such as respiratory function tests and blood gas analysis, as well as imaging findings on HRCT

A case of intravascular lymphoma presenting with a lesion in the splenium of the corpus callosum

Intravascular lymphoma (IVL) is difficult to diagnose because its clinical presentation and laboratory and imaging findings are nonspecific. Herein, we report a case of IVL presenting as a lesion in the splenium of the corpus callosum. A 52-year-old man attended the emergency department with a 2-week history of progressively worsening abnormal behavior and gait disturbance. Magnetic resonance imaging on admission revealed an oval lesion in the splenium of the corpus callosum. The follow-up magnetic resonance imaging performed 2 months after disease onset revealed multiple high-signal areas in the bilateral cerebral white matter on T2-weighted images and diffusion-weighted images. The blood test results showed an elevated level of lactate dehydrogenase and serum-soluble interleukin-2 receptor. These findings were compatible with the diagnosis of IVL. IVL is often difficult to diagnose due to a wide variety of clinical presentations and imaging findings

High titers of infectious SARS-CoV-2 in corpses of patients with COVID-19

Objectives: The prolonged presence of infectious SARS-CoV-2 in deceased patients with COVID-19 has been reported. However, infectious virus titers have not been determined. Such information is important for public health, death investigation, and handling corpses. The aim of this study was to assess the level of SARS-CoV-2 infectivity in the corpses of patients with COVID-19. Methods: We collected 11 nasopharyngeal swabs and 19 lung tissue specimens from 11 autopsy cases with COVID-19 in 2021. We then investigated the viral genomic copy number by real-time reverse transcription-polymerase chain reaction and infectious titers by cell culture and virus isolation. Results: Infectious virus was present in six of 11 (55%) cases, four of 11 (36%) nasopharyngeal swabs, and nine of 19 (47%) lung specimens. The virus titers ranged from 6.00E + 01 plaque-forming units/ml to 2.09E + 06 plaque-forming units/g. In all cases in which an infectious virus was found, the time from death to discovery was within 1 day and the longest postmortem interval was 13 days. Conclusion: The corpses of patients with COVID-19 may have high titers of infectious virus after a long postmortem interval (up to 13 days). Therefore, appropriate infection control measures must be taken when handling corpses