Juntendo University Graduate School of Medicine has granted doctorates since 1963, and the total numbers of our two types doctorate holders (甲Kou and 乙Otsu) will reach 1,897 and 2,394, respectively, a total of 4,300, this year. In addition to graduates of Juntendo University School of Medicine, 835 of 230 other domestic universities/graduate schools and 311 of those in 26 countries other than Japan are included in these doctorate holders. To promote friendships among graduates of Juntendo University Graduate School characterized by such domestic and international diversity, as well as their development, Juntendo University Graduate School Alumni Association (English name: Club “Jin”) was founded in December 2015.

According to its constitutions, those who obtained doctorates at Juntendo University Graduate School of Medicine and Professors belonging to the graduate school committees are entitled to become its regular members. As for students, those taking doctoral courses at the school are qualified as its student members. Thus, the alumni association is a large group, consisting of about 4,400 regular and 550 student members, a total of approximately 5,000 members.

The board of trustees is made up of the following members: President: CEO Hideoki Ogawa; Vice-Presidents: Faculty of International Liberal Arts Dean Eiki Kominami, President of Juntendo University School of Medicine Alumni Association Kou Morichika, Professor Emeritus Kiyoshi Sato, and President Hajime Arai; Executive Trustee: Faculty of Medicine and Graduate School of Medicine Dean Hiroyuki Daida;and Secretariat General: Isao Nagaoka. In addition, 19 甲Kou and 24 乙Otsu doctorate holders have been appointed as trustees (listed below without honorifics).

The future activities and operations of Juntendo University Graduate School of Medicine Alumni Association will be determined mainly by members of the board of trustees while considering other members’ opinions.

Integrins are heterodimeric transmembrane receptors that mediate cell-matrix adhesion and are essential for multiple cellular functions in eukaryotes including development and cancer progression. Integrins interact with extracellular matrices through their extracellular domain and interact with intracellular proteins thought their cytoplamisc tails. Integrins transduce chemical and mechanical signals across the membrane to maintain the homeostasis. Among the integrin-interacting proteins inside the cell, a group of FERM domain-containing proteins play a pivotal role in mediating integrin functions, especially in cancer progression. Here, the integrin-interacting FERM domain-containing proteins in regulation of cancer progression will be discussed.

A disintegrin and metalloproteinase 28 (ADAM28) is overexpressed predominantly by carcinoma cells in more than 70% of the non-small cell lung carcinomas, showing positive correlations with carcinoma cell proliferation and metastasis. ADAM28 cleaves insulin-like growth factor binding protein-3 (IGFBP-3) in the IGF-I/IGFBP-3 complex, leading to stimulation of cell proliferation by intact IGF-I released from the complex. ADAM28 also degrades von Willebrand factor (VWF), which induces apoptosis in human carcinoma cell lines with negligible ADAM28 expression, and the VWF digestion by ADAM28-expressing carcinoma cells facilitates them to escape from VWF-induced apoptosis, resulting in promotion of metastasis. We have developed human antibodies against ADAM28 and shown that one of them significantly inhibits tumor growth and metastasis using lung adenocarcinoma cells. Our data suggest that ADAM28 may be a new molecular target for therapy of the patients with ADAM28-expressing non-small cell lung carcinoma.

Mutation or inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is an early event in the pathogenesis of clear cell renal cell carcinomas (RCCs) and is common in both hereditary and nonhereditary forms.

VHL disease is the most common hereditary renal cancer and is caused by the mutation of germline VHL gene. We summarized characteristics of Chinese VHL disease patients: There is a high proportion of novel mutation in Chinese VHL patients. The prevalence of novel mutations without family history was higher in this group of patients, presumably demonstrating the higher prevalence of de novo mutations in VHL gene in Chinese VHL disease patients. And genetic anticipation is existed in Chinese VHL patients.

In the research around VHL-Hypoxia-inducible factor (HIF)-Erythropoietin (EPO) pathway in RCC, we found HIF-2α is expressed more frequently than HIF-1α, and is more important in up-regulating the downstream molecules. Activation of EPO pathway is involved in cell growth, invasion, survival, and sensitivity to the targeted drug in RCCs, this is a potential therapeutic target for renal cancer.

The innovation of surgery centers on the trifecta; precision, low invasiveness and efficient training. Segmentation of the target organ based on the digital information of CT scan can provide the 3D imaging which enables surgical simulation and navigation. With the introduction of surgical robot, da Vinci, Precision Surgery will be implemented in all surgical procedures.

Breast cancer susceptibility genes, BRCA1/2, are associated with the development of breast cancer and have been studied extensively in Western societies. The role of BRCA1/2 genes in Chinese women with breast cancer has not been fully elucidated. We determined the prevalence and characteristics of BRCA1/2 germline mutations in a large cohort of 5,931 Chinese women with breast cancer. Further, we conducted a kin-cohort study to investigate the estimated cumulative risks in Chinese women who carry a deleterious BRCA1 or BRCA2 mutation. We also investigated the association between BRCA1 mutation carriers and response to neoadjuvant anthracycline-based chemotherapy among Chinese women with triple-negative breast cancer. Our findings provide guidelines for Chinese women with breast cancer who should undergo BRCA1/2 genetic testing. BRCA1 mutated triple-negative breast cancer patients are more likely respond to neoadjuavnt anthracycline-based regimens. In addition, BRCA1/2 mutation carriers may have a high risk to development of breast cancer in life-span, therefore, intensive surveillance and prophylactic surgery should be applied for these women.

Hereditary breast and ovarian cancer (HBOC) patients with BRCA1/2 mutation are estimated to be approximately 1,560,000 in Japan. But general doctors and medical staff do not fully recognize the significance of medical intervention for HBOC in Japan in spite of the large number of potential patients. Thus, investigation into the actual conditions of HBOC has not been established.

So, we have tried to establish a registration system to clarify the clinical and genetic characteristics of HBOC in Japan.

Risk reducing salpingo-oophorectomy (RRSO) has been performed as a clinical examination in our hospital. Average age at the time of RRSO was 49 years. And many of them have a family history of ovarian cancer, with a frequency of 63.3%. Pathological examination revealed a p53 signature in one case out of 30 cases, but no occult cancers were observed at my institute.

Genetic test for BRCA1/2 could also be used worldwide for companion diagnosis for the PARP2 inhibitor. Appropriate recognition for HBOC by general medical staff and cooperation with other departments will be required.

Increasing evidence has demonstrated that the high-frequency, low-penetrant genetic variations play important roles in the carcinogenesis of breast cancer. Although each genetic variant confers modest effect on breast cancer risk, the multiple genetic variants can cumulatively result in considerable effects on breast cancer over decades. This review summarizes the study strategies on the most common genetic polymorphisms, single nucleotide polymorphisms, mainly including candidate gene approach and genome-wide association study (GWAS). The authors briefly introduce their research works as well as some other studies performed among Chinese Han women. The future challenge of genetic polymorphism association study is to identify the causal variants and elucidate their molecular mechanisms.

The recent advance of precision medicine based on genetic information about a person’s disease would help us develop appropriate cancer diagnosis and treatment. However, the emergence of metastases and treatment failure, that accounts for cancer-related mortality in most cancer patients, is often conferred by tumor microenvironment presumably in a non-genetic fashion. Various non-neoplastic stromal cells orchestrating tumor microenvironment enable incipient carcinoma cells to acquire malignant phenotypes including invasion and metastatic traits and therapy-resistant propensity during the course of tumor progression.

Human carcinomas are not only composed of tumor cells but also comprised of non-neoplastic stroma cells, such as endothelial cells, leukocytes, macrophages, myofibroblasts, bone marrow-derived progenitors and abundant extracellular matrix (ECM). Fibroblast populations in tumor are termed carcinoma-associated fibroblasts (CAFs) that constitute a substantial proportion of the non-neoplastic mesenchymal cell compartment in various human tumors. To support the growth and progression of carcinoma cells, these fibroblasts are phenotypically converted from their progenitors to activated fibroblasts via interactions with nearby cancer cells during tumor progression. CAFs influence the hallmarks of carcinoma to promote tumor malignancy through the secretion of tumor-promoting growth factors, cytokines and exosomes, as well as through remodeling of the extracellular matrix. Recent studies have revealed the molecular mechanisms underlying CAF functions, especially in tumor invasion, metastasis and drug resistance. In this symposium, I introduce the impacts of recently identified biological roles of tumor- and metastasis-promoting CAFs for future therapeutic applications.

Objective: Nursing and healthcare-associated pneumonia (NHCAP) is similar to healthcare-associated pneumonia (HCAP) - a category of pneumonia proposed by the Japanese Respiratory Society (JRS). This study aims to determine the thus far unclear prognostic factors of NHCAP patients, and to clarify the relevance and effectiveness of the selection of antimicrobial agents in accordance with the NHCAP guidelines proposed by the JRS.

Materials: A retrospective observational study of NHCAP patients hospitalized at Juntendo University Shizuoka Hospital between January, 2010 and December, 2012 was undertaken.

Methods: Clinical data were obtained from clinical records, and subjects were assigned to a group which included survived patients at 30 days after admission, and a group which included patients who died within 30 days. The groups were compared regarding baseline characteristics, vital signs, laboratory data, performance status, determination of the severity of the pneumonia (such as with the A-DROP scoring system proposed by the JRS in cases of community-acquired pneumonia), microbiological examinations, and the antimicrobial agents used initially.

Results: 151 NHCAP patients in total were evaluated. A score of 3 or more in the A-DROP scoring system is a factor that has an independent influence on NHCAP patients’ prognoses. There were no statistically significant differences in the use of broad-spectrum antimicrobials between the two groups, even those where the use of broad-spectrum antimicrobials was recommended.

Conclusion: The results suggest that the severity of the pneumonia is an independent prognostic factor of NHCAP patients, for whom using broad-spectrum antimicrobials does not contribute to improving their prognoses.

Objective: The International Society of Nephrology-Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis (LN) was designed to provide beneficial pathologic information relevant to the renal outcome. We conducted a retrospective observational study to investigate the baseline characteristics and renal response to treatment for patients with LN, comparing the World Health Organization (WHO) and ISN/RPS classification systems.

Materials: A total of 39 Japanese patients (2 men; 37 women) with LN who underwent percutaneous needle renal biopsy between 1998 and 2012 were evaluated.

Methods: Renal biopsy samples were classified using the 1995 WHO and 2003 ISN/RPS criteria.

Results: Among WHO class IV patients, a higher number of patients reclassified into ISN/RPS class III achieved complete response to treatment compared to those reclassified into class IV at 6 months follow-up. Twenty patients in WHO class IVc were reclassified into ISN/RPS classes III, III+V, IV-S, IV-S+V, IV-G and IV-G+V. No patients developed end-stage renal failure requiring renal replacement therapy.

Conclusions: The results suggest that the ISN/RPS classification system is more advantageous in predicting renal outcome and guiding treatment, especially for those previously classified with WHO class IVc LN.

Objective: To clarify whether a lactating mother can give breast milk after vaccination for the mumps virus.

Material and Methods: A mother with a negative antibody titer for mumps virus had breastfed since before receiving a mumps viral vaccination and continued maternal feeding after inoculation. RT-LAMP and nested RT-PCR were used to examine breast milk samples 15, 22, 29, 42, and 49 days after the vaccination.

Results: RT-LAMP was only positive for mumps virus in the breast milk 29 days after vaccination. Samples measured using nested RT-PCR were positive 29 and 42 days after the vaccination.

Conclusions: The baby did not develop mumps, despite being fed with breast milk including the mumps viral vaccine strain. It will be necessary to determine whether babies can acquire immunity through exposure to a viral vaccine strain via breast milk.

Persistent atrial fibrillation (AF) is quite difficult to convert to sinus rhythm by spontaneous or pharmacological means. Although electrical conversion or catheter ablation may be an alternative therapy choice, some patients do not find these invasive treatments acceptable. If aiming for pharmacological sinus conversion, amiodarone has been mainly chosen despite its limited efficacy. In contrast, bepridil, which is only available as an anti-arrhythmic drug in Japan, is known to have a superior defibrillation effect against persistent AF. According to recent clinical reports, bepridil achieves more than approximately 60% of the sinus conversion rate for persistent AF. The high maintenance effect of sinus rhythm after pharmacological or electrical conversion has also been confirmed. In addition, bepridil helps prevent the recurrence of AF even after catheter ablation. A concern with bepridil is the adverse complication of QT prolongation and subsequent-occurrence of torsades de pointes due to strong potassium channel blocking effects. Although scrupulous attention is always required for follow-up, bepridil could be a unique choice of drug among those drugs on the current therapeutic scene for patients with persistent AF.

According to the literature, physical inactivity and lack of stimulating leisure activity are significantly important modifiable factors for cognitive aging. In this perspective article, we have summarized recent findings of non-pharmacological intervention effects on cognitive decline/dementia and have suggested that playing newly developed active video games, which can simultaneously increase both leisure-time physical activity and cognitively stimulating leisure activity, may be a good preventive measure against cognitive aging among the elderly. Public health interventions to promote lifelong leisure-time physical activity, using advanced active video games (e.g., safe, pleasant, free-to-play, and cognitively stimulating smartphone games which can promote not only leisure activity but also physical activity), could have the potential to decrease personal and social burdens associated with cognitive decline/dementia in old age.

Cancer in its early stages are approximately 1 cm. Actually, we can now detect cancers are as small as 0.5 cm, and it is safe to say that almost all cancers up to 1 cm can be completely and effectively treated. The weight of a 1-cm cancer is 1 gram. The size of a single cancer cell is about 20 microns. This means that it takes about 10⁹ cancer cells to make up a 1-cm cancer. In a time where a cancer with 10⁹ cells can be treated 100%, you can imagine how silly it is for a scientist to be desperately looking for a single cell of cancer. It is said to take about 20 years for a clinical cancer to develop. If someone discovers cancer at the age of 40, it means that cancer budded when the patient was 20 years old. In fact, only one in thousands of cancer buds fully blossoms. Not very many do, and the same could be said about humans.

Laparoscopic colectomy was first used for the treatment of colorectal cancer early in the 1990s, before spreading rapidly throughout the world. In comparison with open surgery, laparoscopic colectomy has the advantages of smaller incision, less pain, and faster recovery during the early postoperative period. Randomized controlled trials (RCTs) have compared it with open surgery, demonstrating similarities in terms of postoperative complications and long-term prognosis.

Endoscopic submucosal dissection (ESD) allows the dissection of relatively large tumors en bloc. Japanese national health insurance began to cover the procedure in 2012 for the treatment of intramucosal carcinoma (Tis) or carcinoma with slight submucosal invasion (T1a) in colorectal cancer. The clinical introduction of this procedure enabled radial treatment of early colorectal cancer (Tis/T1a). Furthermore, robotic surgery, the latest means of treatment for cancer, began to be covered by insurance in 2014 for the treatment of prostate cancer. At present, robotic surgery for colorectal cancer is not covered by insurance, and is carried out in the context of clinical trials with limited institutions. Robotic surgery enables precise surgery, and is likely to offer minimally invasive surgery for cases of rectal cancer in which it is especially important to preserve urinary and sexual function in the narrow pelvic space.

Over the past two decades, treatment of colorectal cancer has advanced rapidly. Endoscopic treatment, laparoscopic surgery, and robotic surgery now play an important role in minimally invasive treatment options for colorectal cancer and are expected to show further advances in the future.