[THE RELATIONSHIP AMONG BRONCHIAL HYPERSENSITIVITY, BRONCHIAL HYPER REACTIVITY, AND BRONCHIAL HYPERRESPONSIVENESS IN ASTOGRAPH].

BACKGROUND: Bronchial hyperresponsiveness testing is useful for diagnosing and predicting the risk of bronchial asthma attacks. The Astograph is a tidal breathing method often used in as bronchial provocation testing in Japan. The minimum methachorine dose (Dmin) indicates bronchial sensitivity and is used mainly as an index of bronchial hyperresponsiveness. However, Dmin does not measured hyperresponsiveness, it cannot be compared directly with PC20 in standard methods using FEV1. METHODS: We investigated the relationship among sensitivity, reactivity, and hyperresponsiveness with the Astograph. We recruited 142 patients with confirmed or suspected bronchial asthma from outpatient clinic at St. Marianna University School of Medicine, Yokohama City Seibu Hospital. We calculated Dmin, SGrs/Grscont, PD35Grs, and PD15Grs compared them as bronchial hyperresponsiveness indices. RESULTS: Subjects had suspected asthma (n=103), or required assessment of asthma remission (n=39). There were significant relationships between logDmin and logPD35Grs (r=0.838, p<0.001), and between parameters and SGrs/Grscont (log PD35Grs r=-0.504, p<0.001, strong, logDmin: r=-0.191, p=0.023, weaker). Among subjects positive for hypersensitivity, (Dmin<10), 38 (36.5%) showed negative hyperresponsiveness (PD35Grs>25). PD15Grs was a strongly and significantly correlated with Dmin and PD35Grs. The ROC curve to detect PD35Grs<25, showed that the cutoff of PD15Grs was 10.7 (AUC 0.983, sensitivity 0.984, specificity 0.905). CONCLUSION: In Astograph, evaluation of bronchial hyperresponsiveness, we focused on relationship differences between sensitivity and reactivity, and hyperresponsiveness. We revealed the usefulness of the PD15Grs evaluation method.

[THE INFLUENCE OF SENSITIZATION TO ASPERGILLUS AND ALTERNARIA IN ADULT BRONCHIAL ASTHMATICS MANAGED VIA YOKOHAMA CITY SEIBU HOSPITAL'S COORDINATED-CARE SYSTEM].

BACKGROUND: The sensitizations to various fungal allergens influence to exacerbation of bronchial asthma. Aspergillus (Asp) and Alternaria (Alt) were one of important fungal allergens for asthma. AIM AND METHODS: To investigate the influence of sensitization to Asp or Alt in adult asthmatics managed via our asthma coordinated-care system, we recruited 119 patients (91 women) who were measured IgE for Asp (IgE-Asp) and IgE for Alt (IgE-Alt) at three times during two years,Results: In 119 patients, we detected positive IgE for Asp (IgE-Asp(+)) in 19 patients and positive IgE for Alt (IgE-Alt(+)) in 11 patients. 9 patients showed positive both of them. During two years, 7 patients became positive IgE-Asp and 3 cases became negative. And also, 3 cases became positive IgE-Alt and 3 cases became negative. At baseline, serum IgE, IgG4, and inhaled corticosteroid (ICS) dose of the group with IgE-Asp (+) or IgE-Alt (+), were significant higher than those of negative group. Among three groups, there was no significant change about other parameters at baseline, exacerbation frequency, or the change of parameters during two years. CONCLUSION: The sensitizations to Asp or Alt were present in 19 asthmatics (16%) managed via our coordinate-care system. During 2 years, there was not significant change at exacerbation frequency among three groups, but the levels of IgE, IgG4, or ICS dose were significantly higher at IgE-Asp (+) or IgE-Alt (+) group than negative group. In the asthma management, it was considered necessary to pay attention to the sensitization to Asp or Alt.

Case report: Electrocardiographic changes in pembrolizumab-induced fatal myocarditis.

Immune checkpoint inhibitor (ICI)-induced myocarditis is rare but fatal. Because of the rapid course of ICI-induced myocarditis, understanding of clinical course is only possible through information from case reports. We report a case of pembrolizumab-induced myocarditis in which we were able to document the course of electrocardiographic changes from onset to death. A 58-year-old woman with stage IV lung adenocarcinoma, who had completed her first cycle of pembrolizumab, carboplatin, and pemetrexed, was admitted with pericardial effusion. She underwent pericardiocentesis after admission. A second cycle of chemotherapy was administered 3 weeks after the first cycle. Twenty-two days after admission, she developed a mild sore throat and tested positive for SARS-CoV-2 antigen. She was diagnosed with mild coronavirus disease 2019 (COVID-19), isolated, and treated with sotrovimab. Thirty-two days after admission, an electrocardiogram showed monomorphic ventricular tachycardia (VT). Suspecting myocarditis caused by pembrolizumab, the patient was started on daily methylprednisolone after coronary angiography and endocardial biopsy. Eight days after the start of methylprednisolone administration, she was considered to have passed the acute stage. However, four days later, R-on-T phenomenon triggered polymorphic VT and she died. The impact of viral infections such as COVID-19 on patients be treated with immune checkpoint inhibitors is still unknown and we need to be careful with systemic management after viral infections.

RET fusion mutation detected by re-biopsy 7 years after initial cytotoxic chemotherapy: A case report.

Personalized medicine using molecular-targeted drugs to achieve better therapeutic response and long-term prognosis is common practice for lung cancer treatment. However, in cases before gene batch tests were available, medical treatment continued without the detection of rare mutations. We report a sixty-seven-old year man diagnosed with adenocarcinoma T1cN3M1a, stage IVA. Initial screening performed 7 years earlier using EGFR mutation and ALK immunohistochemical tests were negative. Although first-line cytotoxic combination chemotherapy was remarkably effective, a gradual regression of the primary lesion was noted. After a recent bronchoscopic re-biopsy, RET fusion was detected by gene panel test. In addition, we were able to confirm RET from FFPE specimens obtained from 7-year-old pleural effusion cell blocks. Subsequent administration of the molecular-targeted drug selpercatinib, was highly effective for the primary lesion and all metastatic lesions including brain metastases. We describe a case of RET fusion-positive lung cancer where molecular targeted therapy and cytotoxic drug showed a drastic response and long-term therapy was well maintained. Next generation sequencing was able to correctly diagnose RET fusion mutation using re-biopsy specimen after going undiagnosed for 7 years.

[A RESEARCH OF ADULT BRONCHIAL ASTHMATICS MANAGED UNDER YOKOHAMA CITY SEIBU HOSPITAL'S COORDINATED-CARE SYSTEM].

BACKGROUND: Our hospital in the western part of Yokohama City managed adult bronchial asthma patients via a coordinated care system with primary care clinics. The aim of the system is to provide effective daily and emergency medical care. METHODS: The study comprised 288 adult stable asthmatics (201 women) who were examined at Yokohama City Seibu Hospital between Jan 2009 and May 2018 and who were being managed under our coordinated care system at one of 80 primary clinics or hospitals. RESULTS: Of the 288 patients enrolled, 188 continued, 37 ended under management, and 63 dropped out from this system. The drop-out rate was highest at visit 1 (9%). The main reasons for end of cooperation under management were readjustment of asthma treatment and treatment for other diseases. The reasons for dropping out were low adherence, older age, and mild symptoms. There was a significant tendency in the frequency of patients who continued, ended under management, or dropped out (x2: 26.053, p=0.016), and the drop-out rate was significantly higher at visit 1. Comparing the characteristics of the patients who continued, ended under management, and dropped out within two visit, those who had dropped out were significantly younger (p=0.0067) and their duration of asthma was shorter (p=0.0009). The frequencies of emergency department visit and hospitalization were high until visit 2, but no significant trends were observed. CONCLUSION: Our coordinated care system managed 188 asthmatic patients (65.2%) properly. Patients with low adherence tended to drop out from the system at visit 1.

Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment.

The disruption of the tumor microenvironment (TME) is a promising anti-cancer strategy, but its effective targeting for solid tumors remains unknown. Here, we investigated the anti-cancer activity of the mitochondrial complex I inhibitor intervenolin (ITV), which modulates the TME independent of energy depletion. By modulating lactate metabolism, ITV induced the concomitant acidification of the intra- and extracellular environment, which synergistically suppressed S6K1 activity in cancer cells through protein phosphatase-2A-mediated dephosphorylation via G-protein-coupled receptor(s). Other complex I inhibitors including metformin and rotenone were also found to exert the same effect through an energy depletion-independent manner as ITV. In mouse and patient-derived xenograft models, ITV was found to suppress tumor growth and its mode of action was further confirmed. The TME is usually acidic owing to glycolytic cancer cell metabolism, and this condition is more susceptible to complex I inhibitors. Thus, we have demonstrated a potential treatment strategy for solid tumors.

Associations between neighborhood food environments and deficient protein intake among elderly people in a metropolitan suburb: A case study in Kisarazu city, Japan.

OBJECTIVES: Living in a poor food environment and its association with an increased risk of inadequate nutrient intake are increasingly important issues in Japan due to an increase in the elderly population. METHODS: The present study examined the relationships between neighborhood food environment and the protein and fat intakes of elderly Japanese individuals (n = 181) living in the metropolitan Tokyo suburb of Kisarazu. RESULTS: A logistic regression analysis adjusted for sociodemographic and shopping behavior variables revealed associations between subjectively evaluated poor neighborhood food environment and deficient protein intake. However, there was no significant association between excessive fat intake and neighborhood food environments. CONCLUSION: The findings demonstrate that living in a poor neighborhood food environment, which is becoming increasingly prevalent in Japan and other developed countries, has the potential to result in malnutrition, or at least in a low-quality diet, in elderly populations.