KEIO JOURNAL OF MEDICINE最新文献

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.

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.

Uterus transplantation (UTx) has seen increasing global adoption as an alternative for women with uterine factor infertility to achieve pregnancy. However, several medical, ethical, and social issues need to be addressed before UTx can be applied clinically. Since 2009, Japan has amassed a large database of basic research on UTx in non-human primates, but clinical application has not been realized because of conservative attitudes and prudent concerns. Nonetheless, UTx may be viable in Japan after comprehensive resolution of the concerns associated with this medical technology.

Heart failure is a life-threatening disease prevalent worldwide. Cardiac transplantation is the last resort for patients with severe heart failure, but donor shortages represent a critical issue. Cardiac regenerative therapy is beneficial, but it is currently unsuitable as a substitute for cardiac transplantation. Human induced pluripotent stem cells (hiPSCs) are excellent sources for the generation of terminally differentiated cells. The preparation of a large number of pure cardiomyocytes (CMs) is the major premise for translational studies. To control the quality of the generated CMs, an efficient differentiation method, purification strategy, and mass-scale culture must be developed. Metabolic purification and large-scale culture systems have been established, and pure hiPSC-derived CMs of clinical grade are now available for translational research. The most critical challenge in cell therapy is the engraftment of transplanted cells. To overcome the low engraftment ratio of single CMs, aggregations of CMs are developed as cardiac spheroids. A cardiac transplantation device with domed tips and lateral holes has been developed for the transplantation of cardiac spheroids. Large animal models are necessary as the next step in the process toward clinical application. The transplant device has successfully been used to inject cardiac spheroids uniformly into myocardial layers in swine, and this approach is progressing toward clinical use. Remaining issues include immunological rejection and arrhythmia, which will require further investigation to establish safe and effective transplantation. This review summarizes the present status and future challenges of cardiac regenerative therapies.

Pulmonary hypertension (PH) is a progressive disease characterized by increased pulmonary vascular resistance that leads to right ventricular (RV) failure, a condition that determines its prognosis. This review focuses on the clinical value of the evaluation of RV function in PH. First, the pathophysiology of PH, including hemodynamics, RV function, and their interaction (known as ventriculoarterial coupling), are summarized. Next, non-invasive imaging modalities and the parameters of RV function, mainly assessed by echocardiography, are reviewed. Finally, the clinical impacts of RV function in PH are described. This review will compare the techniques that yield comprehensive information on RV function and their roles in the assessment of PH.

SARS-CoV-2 whole-genome sequencing of samples from COVID-19 patients is useful for informing infection control. Datasets of these genomes assembled from multiple hospitals can give critical clues to regional or national trends in infection. Herein, we report a lineage summary based on data collected from hospitals located in the Tokyo metropolitan area. We performed SARS-CoV-2 whole-genome sequencing of specimens from 198 patients with COVID-19 at 13 collaborating hospitals located in the Kanto region. Phylogenetic analysis and fingerprinting of the nucleotide substitutions were performed to differentiate and classify the viral lineages. More than 90% of the identified strains belonged to Clade 20B, which has been prevalent in European countries since March 2020. Only two lineages (B.1.1.284 and B.1.1.214) were found to be predominant in Japan. However, one sample from a COVID-19 patient admitted to a hospital in the Kanto region in November 2020 belonged to the B.1.346 lineage of Clade 20C, which has been prevalent in the western United States since November 2020. The patient had no history of overseas travel or any known contact with anyone who had travelled abroad. Consequently, the Clade 20C strain belonging to the B.1.346 lineage appeared likely to have been imported from the western United States to Japan across the strict quarantine barrier. B.1.1.284 and B.1.1.214 lineages were found to be predominant in the Kanto region, but a single case of the B.1.346 lineage of clade 20C, probably imported from the western United States, was also identified. These results illustrate that a decentralized network of hospitals offers significant advantages as a highly responsive system for monitoring regional molecular epidemiologic trends.

In late March 2020, we faced a nosocomial outbreak of novel coronavirus disease 2019 (COVID-19) at Keio University Hospital, Tokyo, Japan. Presently, COVID-19 is an unprecedented worldwide biohazard, and a nosocomial outbreak can occur in any hospital at any time. Therefore, we reviewed the literature regarding hospital preparedness, the initial management of COVID-19, and the surveillance of healthcare workers (HCWs) to find information that would be generally useful for physicians when confronted with COVID-19. In terms of hospital preparedness, each hospital should develop an incident management system and establish a designated multidisciplinary medical team. To initiate case management, COVID-19 should be suspected based on patient symptoms and/or high-risk history and then should be confirmed by viral testing, such as reverse transcription polymerase chain reaction (RT-PCR) analysis. Although some patients will become critically ill, the guidelines for respiratory failure and septic shock for non-COVID-19 cases can be followed for supportive treatment. Antiviral medications should be carefully selected because the available information is confused by the large volume of preprint literature and unreliable data. HCWs who have come into contact with patients with COVID-19 can generate new in-hospital clusters of COVID-19 cases. Quarantine following contact tracking with risk stratification is effective in preventing transmission, and the essentials of medical surveillance include monitoring different types of symptoms, delegation of supervision, and continuation of surveillance regardless of the RT-PCR results. Preparation for COVID-19 is recommended before the first COVID-19 case is encountered.