KEIO JOURNAL OF MEDICINE最新文献

The uncontrolled growth of blood vessels is a major pathological factor in human eye diseases that can result in blindness. This effect is termed ocular neovascularization and is seen in diabetic retinopathy, age-related macular degeneration, glaucoma and retinopathy of prematurity. Current treatments for these diseases include laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents and vitreoretinal surgery. Although strategies to inhibit VEGF have proved to be dramatically successful in some clinical studies, there remains the possibility of significant adverse effects regarding the blockade of crucial physiological roles of VEGF and the invasive nature of the treatments. Moreover, it is evident that other pro-angiogenic factors also play important roles in the development of these diseases, as seen in cases in which anti-VEGF therapies have failed. Therefore, new types of effective treatments are required. In this review, we discuss a promising strategy for the treatment of ocular neovascular diseases, i.e., the inhibition of hypoxia-inducible factor (HIF), a master regulator of angiogenesis. We also summarize promising recently investigated HIF inhibitors as treatments for ocular diseases. This review will facilitate more comprehensive approaches to understanding the protective aspects of HIF inhibition in the prevention of ocular diseases.

Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in December 2019 as an outbreak of pneumonia of unknown origin. Previous studies have suggested the utility of chest computed tomography (CT) in the diagnosis of COVID-19 because of its high sensitivity (93%-97%), relatively simple procedure, and rapid test results. This study, performed in Japan early in the epidemic when COVID-19 prevalence was low, evaluated the diagnostic accuracy of chest CT in a population presenting with lung diseases having CT findings similar to those of COVID-19. We retrospectively included all consecutive patients (≥18 years old) presenting to the outpatient department of Keio University Hospital between March 1 and May 31, 2020, with fever and respiratory symptoms. We evaluated the performance of diagnostic CT for COVID-19 by using polymerase chain reaction (PCR) results as the reference standard. We determined the numbers of false-positive (FP) results and assessed the clinical utility using decision curve analysis. Of the 175 patients, 22 were PCR-positive. CT had a sensitivity of 68% and a specificity of 57%. Patients with FP results on CT diagnosis were mainly diagnosed with diseases mimicking COVID-19, e.g., interstitial lung disease. Decision curve analysis indicated that the clinical utility of CT imaging was limited. The diagnostic performance of CT for COVID-19 was inadequate in an area with low COVID-19 prevalence and a high prevalence of other lung diseases with chest CT findings similar to those of COVID-19. Considering this insufficient diagnostic performance, CT findings should be evaluated in the context of additional medical information to diagnose COVID-19.

Surgical treatments offer the chance for cure in primary or metastatic liver cancers. However, many patients experience disease progression after surgical interventions, or cannot undergo surgery as they present with unresectable disease at diagnosis. In such cases, available treatment options (local and systemic) have been limited in efficacy, which led to dismal survival rates in advanced hepatocellular carcinoma (HCC), intrahepatic colangiocarcinoma (ICC) or metastatic pancreatic ductal adenocarcinoma (PDAC). More recent developments in oncology have offered renewed hope for advanced liver cancer patients. Hypofractionated radiation has shown feasibility and promise in unresectable setting, and is now being tested in a randomized phase III trial in HCC (clinicaltrials.gov identifier NCT03186898). Antiangiogenic agents have strongly impacted the management of advanced HCC, with multiple drug options in first line setting (sorafenib, lenvatinib) and second line setting (regorafenib, cabozantinib, ramucirumab). Chemotherapy based regimens are standard of care in ICC and PDAC. Immunotherapy with anti-PD-1/PD-L1 or anti-CTLA4 antibodies has shown real potential to transform advanced HCC therapy, both in first line and second line settings. Finally, combinations of these new strategies are very attractive approaches, as they promise durable and profound responses in advanced HCC. But in order to achieve this promise more broadly, these concepts require greater understanding based on mechanistic preclinical studies and validation in correlative studies in clinical trials as a basis to establish optimal combinatorial strategies. The insights gained from this "bench to the bedside and back" approach raise the hope for a more efficient development of targeted agents in combination, and in earlier stages of the disease, with the goal of increasing survival in patients afflicted with this aggressive and deadly diseases. (Presented at the 2001st Meeting, July 4, 2022).

Messenger RNA was discovered in 1961 and it took 60 years until the first mRNA became FDA-approved product in the form of COVID-19 mRNA vaccine. During those years a lot of progress has been made by hundreds of scientists. It was 1978 when the first-time isolated mRNA delivered into mammalian cells produced the encoded protein. In vitro transcription introduced in 1984 made it possible to generate any desired mRNA from the encoding plasmid using phage RNA polymerases. In the early 90s mRNA was used for therapy as well as vaccine against infectious diseases and cancer. Inflammatory nature of the mRNAs limited their in vivo use. Replacing uridine with pseudouridine made the mRNA non-immunogenic, more stable and highly translatable. Delivery of the lipid nanoparticle-formulated nucleoside-modified mRNA encoding viral antigens became a platform for effective vaccine. Labile nature of the mRNA is ideal for transient production of the viral antigen, to generate effective antibody and cellular immune response. The mRNA platform is revolutionizing the delivery of effective and safe vaccines, therapeutics and gene therapies.

The skin is not merely a physical barrier but also an active immunological interface, exposed to various external stimuli including microbes. Over the recent years, our laboratory has defined hair follicles as control towers that regulates immune cells residing in the skin. Hair follicles produce chemokines and cytokines that are crucial for the localization and tissue-residency of immune cells including the Langerhans cells, resident memory T cells, and innate lymphoid cells. We also discovered that disruption of the ADAM17-EGF receptor axis and ADAM10-Notch signaling axis leads to dysbiosis on the skin surface and in the hair follicles, respectively. The former leads to microbiome predominance of Staphylococcus aureus and results in atopic skin inflammation, whereas the latter leads to Corynebacterium species predominance that trigger irreversible hair follicle destruction. These findings highlight the distinct mechanisms that regulate the microbiome in different compartments of the skin. In this talk, I will focus on the deeper layers of the skin-the hypodermis (a.k.a subcutaneous tissue), a common site for cellulitis, which we found to be enriched with macrophages. We enabled layer-specific depletion of macrophages, which had prominent effects on the organization of the extracellular matrix, counterintuitively rendering mice highly protected against S. aureus-mediated cellulitis. I will also introduce our ongoing efforts to understand the histology and pathophysiology of Degos disease, an extremely rare and highly fatal disease of unknown etiology.

Although the severity of acute cerebral infarction varies in patients receiving direct oral anticoagulants (DOACs), no practical method to predict the severity has been established. We analyzed retrospectively the relationship between cardioembolic cerebral infarction severity and coagulation indicators in patients treated with DOACs. We assessed the anticoagulation effect of DOACs using the activated partial thromboplastin time (APTT), prothrombin time (PT), and prothrombin time international standardized ratio (PT-INR) in 71 patients with cardioembolic cerebral infarction admitted to our hospital between January 2015 and December 2019. The participants were divided into a prolongation group (prolonged APTT for oral thrombin inhibitors or prolonged PT for oral factor Xa inhibitors, n =37) and a normal group (no prolongation of coagulation markers, n =34). Of the 71 patients, 21 (30%) and 50 (70%) were using oral thrombin and oral factor Xa inhibitors, respectively. PT, PT-INR, and APTT were significantly higher in the prolongation group (PT: 17.4 ± 5.1 vs. 12.8 ± 1.4 s, P < 0.001; PT-INR: 1.5 ± 0.5 vs. 1.1 ± 0.1, P < 0.001; APTT: 44.8 ± 26.4 vs. 30.4 ± 4.1 s, P = 0.003). The median National Institutes of Health Stroke Scale (NIHSS) score on admission and the prevalence of large vessel occlusion were significantly lower in the prolongation group (NIHSS: 2.0 vs. 9.5, P = 0.007; large vessel occlusion: 27% vs. 53%, P = 0.031). The prevalence of large vessel occlusion was low and stroke severity was mild in patients undergoing DOAC therapy with prolongation of coagulation assay markers upon onset of cardioembolic cerebral infarction.

Lymphedema occurs when interstitial fluid and fibroadipose tissues accumulate abnormally because of decreased drainage of lymphatic fluid as a result of injury, infection, or congenital abnormalities of the lymphatic system drainage pathway. An accurate anatomical map of the lymphatic vasculature is needed not only for understanding the pathophysiology of lymphedema but also for surgical planning. However, because of their limited spatial resolution, no imaging modalities are currently able to noninvasively provide a clear visualization of the lymphatic vessels. Photoacoustic imaging is an emerging medical imaging technique that provides unique scalability of optical resolution and acoustic depth of penetration. Moreover, light-absorbing biomolecules, including oxy- and deoxyhemoglobin, lipids, water, and melanin, can be imaged. Using exogenous contrast agents that are taken up by lymphatic vessels, e.g., indocyanine green, photoacoustic lymphangiography, which has a higher spatial resolution than previous imaging modalities, is possible. Using a new prototype of a photoacoustic imaging system with a wide field of view developed by a Japanese research group, high-resolution three-dimensional structural information of the vasculatures was successfully obtained over a large area in both healthy and lymphedematous extremities. Anatomical information on the lymphatic vessels and adjacent veins provided by photoacoustic lymphangiography is helpful for the management of lymphedema. In particular, such knowledge will facilitate the planning of microsurgical lymphaticovenular anastomoses to bypass the excess fluid component by joining with the circulatory system peripherally. Although challenges remain to establish its implementation in clinical practice, photoacoustic lymphangiography may contribute to improved treatments for lymphedema patients in the near future.