Juntendo Medical Journal
Online ISSN : 2188-2126
Print ISSN : 2187-9737
ISSN-L : 2187-9737
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Special Reviews: 349th Triannual Meeting of the Juntendo Medical Society “Cancer Treatment Using Genome Information”
  • MASAMI ARAI
    2020 Volume 66 Issue 5 Pages 384-391
    Published: 2020
    Released: October 31, 2020
    JOURNALS OPEN ACCESS

     Hereditary breast and ovarian cancer (HBOC) syndrome is defined by pathogenic germline variants of BRCA1 or BRCA2 (BRCA1/2). Genetic testing for BRCA1/2 became prevalent in the last 10 years. Before then, clinical criteria were used to screen for familial breast cancer patients. In 2012, the Japanese HBOC Consortium established a nation-wide registration project for subjects who had undergone BRCA1/2 genetic testing. Approximately 4,000 subjects who underwent genetic testing for BRCA1/2 and over 700 carriers of the BRCA1/2 mutation were registered. The proband annual frequency for a pathological variant is approximately 20%. There are few hot-spots for BRCA1/2 pathogenic mutations in the Japanese population. The mutation with the highest frequency, p.Leu63Ter, was verified to be a Japanese founder mutation. Approximately 30% of carriers of the BRCA1/2 mutation underwent risk-reducing salpingo-oophorectomy. Testing with multi-gene hereditary cancer panels has been preferred to Sanger sequencing even for classical genetic counseling, and recently, apart from the diagnosis of HBOC, companion diagnostics or cancer panel testing and liquid biopsy have been used to predict responses to targeted molecular therapeutics. Thus, HBOC could be an incidental diagnosis received after searching for an effective drug. Considering this scenario, a new type of genetic counseling involving early introduction of anticipatory guidance in counseling for HBOC is required. Risk reduction surgeries and MRI in the follow-up for HBOC patients will be covered by medical insurance from April 2020. I am honored to have contributed to the trend by the establishment of a nation-wide registration system and the publication of a guidebook for HBOC.

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  • TAKUO HAYASHI, SHUNSUKE KATO
    2020 Volume 66 Issue 5 Pages 392-402
    Published: 2020
    Released: October 31, 2020
    JOURNALS OPEN ACCESS

     Application of next-generation DNA sequencing (NGS) has recently become increasingly common in the field of clinical oncology in several countries around the world. In Japan also, a system for applying NGS to routine clinical practice is gradually being established. During this process, we introduced in Japan the tumor-profiling MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) assay.

     We present here our initial experience with the use of MSK-IMPACT in 68 patients selected from two institutions in Japan between June 2016 and October 2017.

     MSK-IMPACT sequencing was successful and yielded results in specimens obtained from 64 of the 68 patients, representing an overall assay success rate of 94.1%. The top three cancer types tested were endometrial cancer (17.2%), pancreatic cancer (15.6%), and colorectal cancer (12.5%). Evaluation of the clinical actionability of the genetic alterations revealed that 25.0% of patients (n=16) harbored at least one actionable alteration. However, enrolling the patients in a genomically matched clinical trial was difficult, mainly because most clinical trials are limited to tumors arising from a specific organ/site.

     Although tumor profiling by NGS and administration of genomically matched therapy is a promising strategy, because of its high cost, we need to consider how we can fit it into the Japanese medical system. Towards this end, we believe that it is important to share our initial experience for furthering precision medicine in Japan.

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  • TAKEHITO SHUKUYA
    2020 Volume 66 Issue 5 Pages 403-409
    Published: 2020
    Released: October 31, 2020
    JOURNALS OPEN ACCESS

     Driver oncogenes are defined as oncogenes showing mutations that are responsible for the development and proliferation of malignant neoplasms. Driver mutations represent the Achilles heel of tumors, because tumor proliferation is dramatically suppressed once these gene products are inhibited using specific molecular targeted therapy. Non-small-cell lung cancer (NSCLC) was initially sub-classified into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma based on microscopic findings.

     However, new information on a driver oncogene called epidermal growth factor receptor (EGFR) mutation and its specific inhibitor changed the sub-classification of NSCLC. After the discovery of EGFR mutation and its specific inhibitor, several other driver oncogenes and their specific inhibitors were also discovered, adding to the sub-classification of NSCLC. Consequently, testing for driver oncogenes became essential for selecting the optimal treatment for advanced NSCLC. Earlier, these driver oncogenes were tested for individually, but next-generation sequencing technology - which enables multiplex driver oncogene testing - has recently been introduced into daily clinical practice. However, sample quality and quantity are essential in order to obtain complete results of genetic alterations.

     Treatment with inhibitors against driver oncogenes can shrink tumors dramatically, but tumors become resistant in 10-18 months. Mechanisms underlying resistance to specific inhibitors have been investigated, and novel drugs have been developed to overcome resistance. However, it remains challenging to cure advanced NSCLC with mutations in driver oncogenes. Therefore, immunotherapy should be introduced with the aim of inhibiting cancer progression long-term, and further investigation is warranted in this regard.

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Special Reviews: 351st Triannual Meeting of Juntendo Medical Society “Farewell Lectures of Retiring Professors” [2]
  • EIICHI INADA
    2020 Volume 66 Issue 5 Pages 410-415
    Published: 2020
    Released: October 31, 2020
    [Advance publication] Released: September 05, 2020
    JOURNALS OPEN ACCESS

     Anesthesia is one of the best medical discoveries. The first general anesthesia was given in Japan on October 13, 1804, but this achievement was not recognized in the world due to the closure of Japan. After the first demonstration of ether anesthesia in Boston, USA in 1846, anesthesia quickly spread to the world. The incidence of death-related anesthesia-related accidents was quite high in the early era of anesthesia. The incidence of death during anesthesia was as high as 1 in 1,000 anesthetics in 1890s. The incidence of anesthesia-related deaths was still high, i.e. about 1:1500 in the 1950s. There was no systematic approach to the anesthesia-related accidents. Global movement to improve the safety and quality of anesthesia care has started in the 1980s by collecting and analyzing big data. In addition to many guidelines on anesthesia safety, the development of monitors, anesthesia machines with many safety features, and easily controllable medications make anesthesia safer. Vigilance is the foundation of an anesthetic safety culture. Anesthesiologists will make every effort to make perioperative care including anesthetic treatment safer to aim zero mortality and less morbidity.

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  • HISAKI RINNO
    2020 Volume 66 Issue 5 Pages 416-423
    Published: 2020
    Released: October 31, 2020
    [Advance publication] Released: September 11, 2020
    JOURNALS OPEN ACCESS

     I joined Urayasu Hospital in 1987, just a few years after its establishment in May 1984. Since then, I have spent 33 years at the institution. The number of hospital beds has increased from 250 at its establishment to 785 at present. Initially, the Department of Internal Medicine was operated by around 10 staff members, and it was subsequently reorganized and subdivided by organ system in 2014.

     As of March 2020, the Department of Internal Medicine is operated by five staff members. In 2014, a blood purification center was established and I was appointed as the first head of the center. With the expansion of the hospital, I have gained experience by treating more patients. Over the past 30 years, there have been several major changes in the medical care of kidney diseases. These changes vary widely and include identification of chronic glomerulonephritis and diabetic nephropathy as the causative diseases of end-stage renal disease, approval of erythropoietin for the treatment of renal anemia, introduction of angiotensin II receptor blockers, establishment of the concept of chronic kidney disease (CKD), conceptualization of mineral and bone disorders in CKD, drug discovery for autosomal dominant polycystic kidney disease, and initiation of living-donor kidney transplants. I would like to describe the changes in clinical practice that I have experienced without discussing each disease in detail.

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Original Articles
  • HIROKO SHUKUZAWA, HAJIME BABA, HITOSHI MAESHIMA, TAKAHISA SHIMANO, MEG ...
    2020 Volume 66 Issue 5 Pages 424-430
    Published: 2020
    Released: October 31, 2020
    [Advance publication] Released: May 15, 2020
    JOURNALS OPEN ACCESS

     Levels of serum brain derived neurotrophic factor (BDNF) are lower in patients with major depressive disorder (MDD). The adrenal cortex secretes the corticosteroids cortisol and dehydroepiandrosterone (DHEA) under stress condition, and serum levels of DHEA are gender-dependent. Although BDNF expression is associated with these corticosteroids, the effect of gender on this association is not clear. To examine gender differences in the relationship between BDNF and corticosteroids in patients with MDD, we measured serum levels of cortisol, DHEA-sulfate (DHEA-S) and BDNF in men and women with depression. We recruited 189 inpatients with MDD (76 men and 113 women) from Juntendo Koshigaya Hospital. Serum cortisol, DHEA-S and BDNF levels were measured on the morning after admission. Multiple regression analyses were conducted to assess the effects of cortisol and DHEA-S on BDNF. After controlling for age, we found that serum BDNF levels were significantly influenced by the DHEA-S/cortisol ratio (p=0.010) in female participants. However, this association was absent in male participants. These results suggest gender differences exist in the effects of corticosteroids on BDNF. In female participants, the balance between neurotoxicity induced by cortisol and neuroprotection associated with DHEA-S may influence the pathology and symptoms of depression via BDNF.

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  • YUKO YAMAUCHI, YUKI UEHARA, SÉBASTIEN BOUTIN, NORIO YAMAMOTO, KYOKO KU ...
    2020 Volume 66 Issue 5 Pages 431-438
    Published: 2020
    Released: October 31, 2020
    [Advance publication] Released: June 03, 2020
    JOURNALS OPEN ACCESS

    Objective: The clinical significance of Arcobacter species has not been established due to a lack of suitable detection methods.

    Material and Methods: A total of 1,650 stool samples submitted to the Clinical Laboratory of Heidelberg University Hospital were inoculated onto agar plates selective for Campylobacter species isolation and incubated at 37℃.

    Results: Four (0.24%) of the samples were positive for Arcobacter butzleri isolates. Genus-specific primers for real-time PCR were designed to identify Arcobacter species. Of the 1,650 stool samples tested, twelve (0.73%), including the four culture-positive samples, were positive for Arcobacter species by real-time PCR. The sensitivity of real-time PCR was 10 4 CFU g -1 stool, 50 CFU reaction -1 using a stool sample.

    Conclusions: Although the sensitivity of real-time PCR was relatively low compared with other PCR methods, the present method detected a broad range of Arcobacter species. The combination of the stool culture using agar selective for Campylobacter species and real-time PCR for Arcobacter species may be clinically useful for the diagnosis and epidemiology of Arcobacter species infections.

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Case Reports
  • ARUNWAN CHANTARAT, YOKO TABE, KEIICHI SASAHARA, TAKASUKE OGAWA, JEERAP ...
    2020 Volume 66 Issue 5 Pages 439-442
    Published: 2020
    Released: October 31, 2020
    [Advance publication] Released: August 12, 2020
    JOURNALS OPEN ACCESS

     Bullous pemphigoid (BP) is an autoimmune blistering skin disease characterized by subepidermal bullae and circulating autoantibodies that bind to components of the hemidesmosome adhesion complex. The diagnosis of BP is based on clinical criteria and laboratory examinations, including direct and indirect immunofluorescence and the enzyme-linked immunosorbent assay (ELISA). Direct immunofluorescence and serological classic indirect immunofluorescence by using human salt-split skin sections and/or monkey esophagus sections have been mainly tested for BP. Antibodies targeting the structural hemidesmosomal proteins BP180 and BP230 have been shown to play a crucial role in the development of BP, and the detection of anti-BP180 antibodies by using an immunoassay ELISA or a chemiluminescent enzyme immunoassay (CLEIA) is routinely performed in Japan. We report on an 82-year-old man who was diagnosed with BP and followed up by testing anti-BP180 antibody. The patient responded well to the treatment, exhibiting a decreased anti-BP180 antibody that fluctuates in parallel with disease activity until a negative result, whereas the IIF test result was still positive. This discrepancy may be related to the fact that the IIF test detects the reaction of antibodies not only anti-BP180 but also anti-BP230. This study demonstrated that the enzyme immunoassay of anti-BP180 is useful as a part of routine examination for follow-up of disease activity and initial diagnosis of BP.

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