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The survival rate of adrenal Cushing syndrome patients has been greatly increased because of the availability of appropriate surgical and pharmacological treatments. Nevertheless, increased possibility of a heart attack induced by a cardiovascular event remains a major risk factor for the survival of affected patients. In experimental studies, hypercortisolemia has been found to cause cardiomyocyte hypertrophy via glucocorticoid receptor activation, including the possibility of cross talk among several hypertrophy signals related to cardiomyocytes and tissue-dependent regulation of 11β-hydroxysteroid dehydrogenase type 1. However, the factors are more complex in clinical cases, as both geometric and functional impairments leading to heart failure have been revealed, and their associations with a wide range of factors such as hypertension are crucial. In addition, knowledge regarding such alterations in autonomous cortisol secretion, which has a high risk of leading to heart attack as well as overt Cushing syndrome, is quite limited. When considering the effects of treatment, partial improvement of structural alterations is expected, while functional disorders are controversial. Therefore, whether the normalization of excess cortisol attenuates the risk related to cardiac hypertrophy has yet to be fully elucidated.

Although the negative effect of muscle loss during invasive treatment has been widely reported in patients with cancer, its value in patients with ovarian cancer is not clear. Therefore, this study was conducted to clarify whether muscle loss during cytoreductive surgery and chemotherapy affects prognosis in patients with ovarian cancer. We retrospectively recruited 58 patients with ovarian cancer who underwent site reductive surgery and chemotherapy at Shimane University Hospital from March 2006 to November 2013 and for whom pre- and postoperative computed tomography were available. Skeletal muscle changes and fat mass volume during primary debulking surgery and chemotherapy were subsequently investigated at the level of the third lumbar vertebra. Muscle and fat mass loss occurred independently in half of the patients. Muscle loss, but not fat loss, was associated with disease-free survival (p = 0.041 and p = 0.794, respectively) and poor overall survival (p = 0.033 and p = 0.61, respectively). Cancer therapy is invasive and causes compositional changes in the body, such as muscle and fat loss. During cancer therapy, muscle loss, but not fat loss, may be associated with worse prognosis in ovarian cancer.

Although white esophagus is an extremely rare disease, careful diagnosis and intensive treatment are required because of a relationship with black esophagus. Further case accumulation including duodenal and jejunum lesion is needed.

Title: Two cases of pembrolizumab-induced secondary adrenal insufficiency Background: Although few cases regarding pembrolizumab-induced secondary adrenal insufficiency were reported, it has recently been published that significantly higher prevalence of human leucocyte antigen (HLA)-DR15, B52, and Cw12 was revealed in 11 Japanese patients with immune checkpoint inhibitor-induced secondary adrenal insufficiency as compared with healthy controls and DR15 might be a predictive marker. This is based on the evidence that DR15 has associations with IL-17-mediated autoimmune disease such as Hashimoto’s thyroiditis, and that anti-programmed death 1 (PD-1) inhibitors activate the Th1 and Th17 pathways. We here introduce two Japanese patients with pembrolizumab-induced secondary adrenal insufficiency from a viewpoint of their HLA typing test results. Clinical Case: Case 1. A 52-year old male diagnosed with stage IV lung cancer (squamous non-small cell lung cancer) was treated with chemotherapy consisting of carboplatin, nab-paclitaxel, and pembrolizumab. Six days after the fourth cycle of pembrolizumab, he suffered from hypoglycemia and hyponatremia. Endocrinological examination findings showed ACTH and cortisol deficiency throughout the day, after which a diagnosis of secondary adrenal insufficiency was made based on no response shown in insulin tolerance, anterior pituitary function, and rapid ACTH stimulation tests. Pituitary cell antibody-1 was negative, and no evidence of a swollen/atrophied pituitary gland or space occupying lesion was observed in magnetic resonance imaging (MRI) results. Furthermore, Hashimoto’s thyroiditis was suspected based on anti-thyroid peroxidase antibody positivity. HLA typing test results highly corresponded with the reported results (A24, B52, Cw12, DR4, DR15). Case 2. A 70-year old male was treated with pembrolizumab for recurrence of lung squamous cell carcinoma (stage IV). Two weeks after completion of five cycles, severe diarrhea occurred, suspected to be a side effect of pembrolizumab, which was relieved with temporary use of prednisolone. However, diarrhea recured accompanied with a high fever, eosinophilia, and acute hyponatremia. Based on results showing deficiency of ACTH and cortisol, adrenal insufficiency was suspected. Anterior pituitary function and rapid ACTH stimulation test results supported that diagnosis, while pituitary cell antibody-1 was negative and MRI findings were not remarkable. Notably, completely different HLA typing test results were observed. Conclusion: Similar to the previous report, HLA-A24, B52, Cw12, DR4, and DR15 were found in case 1, whereas all subtypes including HLA-DR15 were lacking in case 2. We think that it should not be given low priority for cases lacking DR15 and the possibility of an association with IL-17 in such cases is required in feature study.

Objective : Health-care associated pneumonia (HCAP) is a new category of pneumonia. We investigated differences of epidemiology, pathogens, and outcomes be- tween HCAP patients in large hospitals and those in small hospitals. Methods : This was a retrospective observational study of patients hospitalized with HCAP from December 2009 to March 2010. HCAP was defined according to ATS/IDSA criteria. A large hospital was defined as 200 beds and a small hospital was 200 beds. Results : Of 117 patients, 61 patients were admitted to large hospitals and 56 patients were admitted to small hospitals. There was a significant difference of HCAP diagnostic criteria between the two groups. The A-DROP severity class was worse in the large hospital group than the small hospital group (P 0.05). Respiratory failure and disturbance of consciousness were more frequent in the large hospital group (P 0.05). The mortality rate was 8.2% n the large hospital group versus 1.8% in the small hospital group. Patients in the very severe A-DROP class had a high mortality rate of 33% in both groups. Conclusion : Patients with severe HCAP were more likely to be admitted to large hospitals. Patients in the very severe A-DROP class should receive intensive antibiotic therapy, but not all patients need broad-spectrum therapy. J. Med. Invest. 58 : 67-74, February, 2011

Objective: New effective therapy is desirable for patients with non-small cell lung cancer (NSCLC) who have failed previous treatments. Fractionated administration of paclitaxel may be less toxic and more active against NSCLC. The aim of this study was to evaluate the activity and toxicity of weekly paclitaxel therapy for NSCLC in a second-line setting. Methods: Patients with pathological or cytological diagnosis of NSCLC, measurable lesions, and one or more prior therapies were enrolled. We administered weekly infusions of 80 mg/m2 paclitaxel 3 times in a 4-week cycle. In the absence of progressive disease or intolerable toxicity, each patient was treated for a minimum of 4 cycles. Results: Of 39 patients enrolled, 1 patient achieved complete response and 11 patients achieved partial response (response rate, 31%: 95% confidence interval, 17–48%). The median survival time was 43 weeks (range, 7–128 weeks). Grade 3 or 4 leukopenia occurred in only 7 patients (18%). Neurotoxicity was the most frequent adverse effect (grades 1 and 2.26 and 5%, respectively). Although all patients recovered rapidly with corticosteroid treatment, drug-induced pneumonitis was observed in 3 patients (8%). Conclusion: Low-dose weekly paclitaxel is a promising therapy with high effectiveness for advanced NSCLC in patients with NSCLC who have failed previous treatments.

Previously, we reported that levels of chymase activity and its mRNA in cardiac tissues were significantly increased along with progression of cardiac fibrosis in cardiomyopathic hamsters, but the involvement of chymase in the progression of fibrosis has been unclear. In cultured human fibroblasts, the concentration of transforming growth factor-beta in the supernatant of medium was significantly increased after injection of human chymase. Furthermore, human chymase dose dependently increased cell proliferation, and this chymase-dependent proliferation was completely suppressed by a chymase inhibitor, Suc-Val-Pro-Phe(p)(OPh)(2) (10 micro M) or an anti-transforming growth factor-beta antibody (100 micro g/ml). In this study, we used Bio14.6 and F1B hamsters as cardiomyopathic and control hamsters, respectively. Cardiomyopathic hamsters were orally administered a novel chymase inhibitor, 4-[1-([bis-(4-methylphenyl)-methyl]-carbamoyl)-3-(2-ethoxy-benzyl)-4-oxo-azetidine-2-yloxy]-benzoic acid (BCEAB; 100 mg/kg per day), or placebo from 5- to 45-week-old. In the placebo-treated group, the cardiac chymase activity in cardiomyopathic hamsters 45 weeks old was significantly increased compared with that in control hamsters. BCEAB significantly reduced the cardiac chymase activity. The indexes (+dP/dt and -dP/dt) of cardiac function were significantly improved by treatment with BCEAB. The mRNA levels of collagen I and collagen III in the placebo-treated hamsters were significantly reduced to 69.6 and 76.5% by treatment with BCEAB, respectively. The fibrotic area in cardiac tissues in the BCEAB-treated hamsters was significantly suppressed to 50.7% compared with that in the placebo-treated treated hamsters. Therefore, the activation of transforming growth factor-beta by chymase may play an important role in the progression of cardiac fibrosis and cardiac dysfunction in cardiomyopathy.

The efficacy of the addition of inhaled oxitropium bromide in combination with inhaled corticosteroids in the treatment of elderly asthmatic patients whose asthma is not well controlled was evaluated. A randomized, open-label cross-over trial comparing 4-week treatment periods with and without regular inhalation of 200 μg of oxitropium bromide four times per day was performed. Twenty-four patients (mean age ± SD: 62 ± 7 years) completed the study. The dose of beclomethasone dipropionate in this patient group was 1300 ± 800 μg/day. Forced expiratory volume in 1 second (FEV1) was significantly improved after treatment with regular inhalation of oxitropium bromide when compared with FEV1 after treatment without oxitropium (1.73 ± 0.60 vs 1.63 ± 0.68). Both morning and evening peak expiratory flow rates were significantly greater during the treatment period with regular inhalation of oxitropium bromide. The score for dyspnea/chest tightness was also significantly improved during the oxitropium bromide period. There was no statistically significant improvement in forced vital capacity, scores for other symptoms or the frequency of rescue inhalation of fenoterol. The results of this study demonstrated that the addition of regular inhalation of oxitropium bromide is beneficial in elderly asthmatics whose asthma is not well controlled, even when treated with high-dose inhaled steroids.

To elucidate the actual condition of asthma treatment in emergency settings.A questionnaire survey on the situation of emergency care was conducted on 175 medical institutions providing either secondary or tertiary emergency care in Hyogo Prefecture during a 1-year period starting in April 2010. Data were investigated for each secondary medical region.Responses were obtained from 143 medical institutions (response rate, 81.7%). Steroid injection, aminophylline injection, and short-acting beta-agonists (SABA) were selected as drugs in emergency room treatment in many districts (in order, means of 86.7%, 79.5%, 72.3%). Concerning drugs prescribed on leaving hospital, transdermal β2 stimulator and SABA were selected in50% of districts. Prescriptions for long-term management varied among districts, as follows: inhaled corticosteroids (ICS), mean of 37.3% (0-66.7%); ICS/long-acting β-agonists (LABA), 27.9% (16.7-66.7%); and leukotriene receptor antagonist (LTRA), 20.5% (0-50.0%)These findings suggest that asthma treatment in emergency settings varies by facility and region.

To study the possibility that changes in high-sensitivity C-reactive protein (hs-CRP) may be a predictor of forced expiratory volume in 1 second (FEV1) decline over time in adult asthmatic subjects.Subjects with adult-onset asthma with no smoking history underwent complete medical evaluation at Yoka Public Hospital in both 2005 and in 2008 (n = 26). We analyzed the correlation between hs-CRP levels and FEV1 changes over time, in relation to whether or not they received inhaled corticosteroid (ICS) therapy. We also measured the cardio-ankle vascular index (CAVI), intima-media-thickness (IMT), and fraction of exhaled nitric oxide (FeNO) of hospital staff members who acted as non ICS asthmatic subjects (n = 11), and also performed multiple regression analysis.In the non-ICS asthmatic subjects group (n = 19), there was a significant correlation between log (hs-CRP) levels and FEV1 changes (R = -0.734, P0.001). After controlling for age, body mass index, CAVI, IMT, and FeNO, hs-CRP was found to be an independent risk factor.Hs-CRP levels are a predictor of FEV1 decline over time in adult-onset asthmatic patients with no smoking history, who are not receiving ICS therapy.

A series of new buta-1,3-diene derivatives possessing a (diethoxyphosphinoyl)difluoromethylene unit at the terminal carbon was prepared to examine the reactivity for Diels–Alder cycloaddition with various representative dienophiles.

A series of new buta-1,3-diene derivatives possessing a (diethoxyphosphinoyl)difluoromethylene unit at the terminal carbon was prepared to examine the reactivity for Diels–Alder cycloaddition with various representative dienophiles.

Purpose The combination of tegafur-uracil (UFT) with vinorelbine has provided synergistic activity against non-small cell lung cancer (NSCLC) in experimental models. The recommended dose of UFT in combination with vinorelbine in NSCLC was determined in a phase I study. The phase II study evaluated efficacy and tolerability of this combination in elderly patients. Methods Vinorelbine was infused on days 1 and 8, and UFT was administered twice daily on days 2 to 6 and days 9 to 13 of a 3-week cycle. UFT and vinorelbine were increased during the phase I study from 400 to 600 mg/d and 20 to 25 mg/m 2 , respectively, in 12 patients. In the phase II portion, previously untreated elderly patients were treated with 600 mg/d UFT and 20 mg/m 2 vinorelbine. Results At the dose level of 600 mg/d UFT and 25 mg/m 2 vinorelbine, dose-limiting toxicity of neutropenia or neutropenic fever was observed in two of three patients, determining the recommended dose of 600 mg/d UFT and 20 mg/m 2 vinorelbine. In 30 evaluable elderly patients of the phase II study, the response rate was 27% (8/30). The median survival and progression-free survival time was 11.8 (range 2.7–34.8) and 5.0 (range 0.5–32.5) months, respectively. Grade 3 or grade 4 neutropenia and grade 3 anemia occurred in 40% and 7% of phase II patients, respectively. Gastrointestinal toxicity was frequent but mild. As the most serious toxicity, pneumonitis was observed in three patients. Conclusion This combination of UFT and vinorelbine is both feasible and active in the treatment of elderly patients with advanced NSCLC.