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Meropenem is frequently employed as an empirical treatment for serious infections, but there has been no report on its population pharmacokinetic parameters for Japanese patients. Our aim is to undertake a population pharmacokinetic analysis of meropenem using non-linear mixed effects model (NONMEM). Data from 68 patients were analysed via NONMEM with the first-order method. The participants' covariates, including gender, age, actual body weight, serum creatinine, serum albumin, serum total protein and creatinine clearance, were analyzed by the forward inclusion and backward elimination method to identify their potential influence on meropenem pharmacokinetics. The adequacy of the constructed model was assessed by goodness-of-fit plots and the precision of the parameter estimated at each step of the model development. To assess the robustness of the estimated parameter, bootstrap analysis was performed. The data were best described by a one-compartment model. The serum creatinine values modified by the below normal limit in our hospital (mSCR) were an influential covariate for clearance (CL): CL (L/h) = 11·1 × (mSCR/0·7). The volume of distribution was estimated as 33·6 L. The coefficient of variation of the inter-individual variability of CL and the residual variability were 52·1% and 0·827% μg/mL, respectively. A comparison of the population pharmacokinetic parameters of meropenem in the final model estimated in NONMEM with original data, and 1000 bootstrap samples shows that both sets of estimates were comparable, thereby indicating the robustness of the proposed model. A population pharmacokinetic model that satisfactorily described the disposition and variability of meropenem in our Japanese population is described. NONMEM analysis showed that the clearance of meropenem depended on modified serum creatinine. The results of this study should help Japanese patients on meropenem by improving the prediction accuracy of dosing using the Bayesian method. [ABSTRACT FROM AUTHOR]

Background: Validating the expanded criteria for living donor liver transplantation for hepatocellular carcinoma using national data is highly significant. The aim of this study was to evaluate the validity of the new Japanese criteria for living donor liver transplantation for hepatocellular carcinoma patients and identify factors associated with a poor prognosis using the Japanese national data set., Methods: The study population comprised patients who underwent living donor liver transplantation for hepatocellular carcinoma at 37 centres in Japan between 2010 and 2018. In a nationwide survey, the overall survival and recurrence-free survival rates were evaluated based on the new Japanese criteria for applying the 5-5-500 rule when extending the indication beyond the Milan criteria. Prognostic factors within the Japanese criteria were determined using the Cox proportional hazards model., Results: Patients within (485 patients) and beyond (31 patients) the Japanese criteria exhibited 5-year overall survival rates of 81% and 58% and 5-year recurrence-free survival rates of 77% and 48% respectively. Patients who met the Milan criteria, but not the 5-5-500 rule, had poorer outcomes. Multivariate analysis for 474 patients identified a neutrophil-to-lymphocyte ratio greater than or equal to 5 and a history of hepatectomy as independent risk factors., Conclusion: This nationwide survey confirms the validity of the Japanese criteria. The poor prognostic factors within the Japanese criteria include a neutrophil-to-lymphocyte ratio greater than or equal to 5 and previous hepatectomy., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Background: Although osimertinib is a promising therapeutic agent for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the incidence of pneumonitis is particularly high among Japanese patients receiving the drug. Furthermore, the safety and efficacy of subsequent anticancer treatments, including EGFR-tyrosine kinase inhibitor (TKI) rechallenge, which are to be administered after pneumonitis recovery, remain unclear., Objective: This study investigated the safety of EGFR-TKI rechallenge in patients who experienced first-line osimertinib-induced pneumonitis, with a primary focus on recurrent pneumonitis., Patients and Methods: We retrospectively reviewed the data of patients with EGFR mutation-positive lung cancer who developed initial pneumonitis following first-line osimertinib treatment across 34 institutions in Japan between August 2018 and September 2020., Results: Among the 124 patients included, 68 (54.8%) patients underwent EGFR-TKI rechallenge. The recurrence rate of pneumonitis following EGFR-TKI rechallenge was 27% (95% confidence interval [CI] 17-39) at 12 months. The cumulative incidence of recurrent pneumonitis was significantly higher in the osimertinib group than in the first- and second-generation EGFR-TKI (conventional EGFR-TKI) groups (hazard ratio [HR] 3.1; 95% CI 1.3-7.5; p = 0.013). Multivariate analysis revealed a significant association between EGFR-TKI type (osimertinib or conventional EGFR-TKI) and pneumonitis recurrence, regardless of severity or status of initial pneumonitis (HR 3.29; 95% CI 1.12-9.68; p = 0.03)., Conclusions: Osimertinib rechallenge after initial pneumonitis was associated with significantly higher recurrence rates than conventional EGFR-TKI rechallenge., (© 2024. The Author(s).)

Background: Although anti-PD-1 antibody monotherapy (PD-1) is commonly used to treat advanced acral melanoma (AM), its efficacy is limited. Further, data on the efficacy of PD-1 plus anti-CTLA-4 antibody (PD-1+CTLA-4) for the treatment of AM are limited. Therefore, we compared the efficacy of PD-1+CTLA-4 and PD-1 in the treatment of Japanese patients with advanced AM., Methods: This retrospective study evaluated patients with advanced AM who were treated with PD-1 or PD-1+CTLA-4 as first-line immunotherapy in 24 Japanese institutions between 2014 and 2020. Treatment efficacy focussing on the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was compared between the two groups., Results: In total, 254 patients (palm and sole melanoma [PSM], n = 180; nail apparatus melanoma [NAM], n = 74) were included. Among the patients with PSM, the ORR (19% vs. 31%; P = 0.44), PFS (5.9 vs. 3.2 months; P = 0.74), and OS (23.1 vs. not reached; P = 0.55) did not differ significantly between the PD-1 and PD-1+CTLA-4 groups. Among the patients with NAM, the ORR (61% vs. 10%; P < 0.001) was significantly higher and PFS was longer (6.4 vs. 3.8 months; P = 0.10) in the PD-1+CTLA-4 group than in the PD-1 group. Cox multivariate analysis demonstrated that PD-1+CTLA-4 is an independent predictor of a favourable PFS in patients with NAM (P = 0.002)., Conclusions: The efficacy of PD-1+CTLA-4 is not superior to that of PD-1 for the treatment of advanced PSM. However, PD-1+CTLA-4 may be more efficacious than PD-1 for the treatment of advanced NAM., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yasuhiro Nakamura has served as a consultant and/or received honoraria from Merck Sharp & Dohme (MSD), Novartis, Bristol-Myers Squibb (BMS), Maruho, Ono Pharma, Taisho Toyama, and Taiho Pharma. Kenjiro Namikawa has served as a consultant and/or received honoraria from BMS, MSD, Novartis, and Ono Pharma. Yukiko Kiniwa has received honoraria from Novartis and Ono Pharma. Hiroshi Kato has received honoraria from Novartis and Ono Pharma. Osamu Yamasaki has received research funding and/or honoraria from Ono Pharma. Shusuke Yoshikawa has received honoraria from Novartis and Ono Pharma. Takeo Maekawa has received honoraria from BMS, MSD, Novartis, and Ono Pharma. Shigeto Matsushita has received honoraria from BMS, MSD, Novartis, and Ono Pharma. Tatsuya Takenouchi has received honoraria from BMS, MSD, Novartis, and Ono Pharma. Takashi Inozume has received honoraria from BMS, MSD, and Ono Pharma. Satoshi Fukushima has received research funding from Ono Pharma. Shintaro Saito has received honoraria from Ono Pharma. Atsushi Otsuka has served as a consultant and/or received honoraria from BMS, MSD, Novartis, and Ono Pharma, and has received research funding from Eisai. Noriki Fujimoto has received honoraria from Novartis and Ono Pharma. Taiki Isei has served as a consultant and/or received honoraria from Ono Pharma, Pfizer, BMS, and Novartis. Yoshiyasu Umeda has received honoraria from Ono Pharma and Novartis. Naoya Yamazaki has received research funding from Bristol-Myers Squibb, MSD, Novartis, Ono Pharma, and Takara Bio, and has served as a consultant and/or received honoraria from BMS, MSD, Novartis, and Ono Pharma. The other authors have no conflicts of interest to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Basal cell carcinoma is the most common type of skin cancer, and surgical excision with clear margins is the standard of care. Surgical margins are determined based on risk factors (high or low risk) for recurrence according to the National Comprehensive Cancer Network and Japanese basal cell carcinoma guidelines. The clarity of the clinical tumor border (well-defined or poorly defined) is considered a risk factor, and significant discrepancies in the judgment of clinical tumor borders among dermato-oncologists may occur. Therefore, we analyzed the dermato-oncologists' concordance in judging the clinical tumor border of basal cell carcinoma. Forty-seven dermato-oncologists (experts: 37; young trainees: 10) participated in this study. The datasets of clinical and dermoscopic photographs of 79 Japanese cases of head and neck basal cell carcinoma were used to determine the concordance in the judgment of clinical tumor border. The probability of the border that was selected more often was used to calculate the rater agreement rate for each dataset. Correct judgment was defined as a more frequently selected border, and the concordance rate of clarity of clinical tumor border for each dermato-oncologist was calculated based on the definition of the correct judgment. A median concordance rate of 85% or higher for all dermato-oncologists was predefined as an acceptable rate for clinical use. Of the 79 datasets, rater agreement rates were 80-100%, 60-79%, and 51-59% for 55, 19, and five datasets, respectively. The median concordance rate for all dermato-oncologists was 86% (interquartile range: 82-89%). There was no significant difference in the concordance rate between the experts and the trainees (median, 87% vs. 85.5%; p = 0.58). The concordance rates of dermato-oncologists for all datasets were relatively high and acceptable for clinical use., (© 2022 Japanese Dermatological Association.)

Purpose: The Endoscopic Surgical Skill Quantification System for qualified surgeons (QSs) was introduced in Japan to improve surgical outcomes. This study reviewed the surgical outcomes after initial experience performing laparoscopic distal gastrectomy (LDG) and evaluated the improvement in surgical outcomes following accreditation as a QS., Methods: Eighty-seven consecutive patients who underwent LDG for gastric cancer by a single surgeon were enrolled in this study. The cumulative sum method was used to analyze the learning curve for LDG. The surgical outcomes were evaluated according to the two phases of the learning curve (learning period vs. mastery period) and accreditation (non-QS period vs. QS period)., Results: The learning period for LDG was 48 cases. Accreditation was approved at the 67th case. The operation time and estimated blood loss were significantly reduced in the QS period compared to the non-QS period (230 vs. 270 min, p < 0.001; 20.5 vs. 59.8 ml, p = 0.024, respectively). Furthermore, the major complication rate was significantly lower in the QS period than in the non-QS period (0 vs. 10.6%, p = 0.044)., Conclusions: Experience performing approximately 50 cases is required to reach proficiency in LDG. After receiving accreditation as a QS, the surgical outcomes, including the complication rate, were improved., (© 2021. Springer Nature Singapore Pte Ltd.)

Background: Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients., Patients and Methods: We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4., Results: Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001)., Conclusions: First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events., Competing Interests: Disclosure YN receives institutional research funding from Kaken, Ono Pharma, Pola Pharma, and Torii, and has served as a consultant and/or has received honoraria from Bristol Myers Squibb (BMS), Maruho, Merck Sharp & Dohme (MSD), Novartis, Ono Pharma, Taisho Toyama, and Taiho Pharma. KN has served as a consultant and/or has received honoraria from BMS, MSD, Novartis, and Ono Pharma. SY has received honoraria from Novartis and Ono Pharma. YK has received honoraria from Novartis and Ono Pharma. TM has received honoraria from BMS, MSD, Novartis, and Ono Pharma. OY has received research funding and/or honoraria from Ono Pharma. TI has served as a consultant and/or has received honoraria from Ono Pharma, Pfizer, BMS, and Novartis Pharma. SM has received honoraria from Ono Pharma. SF has received research funding from Ono Pharma. SS has received honoraria from Ono Pharma. TT has received honoraria from BMS, MSD, Novartis, and Ono Pharma. HK has received honoraria from Novartis and Ono Pharma. AO has served as a consultant and/or has received honoraria from BMS, MSD, Novartis, and Ono Pharma and received research funding from Eisai. TI has received honoraria from BMS, MSD, and Ono Pharma. YU has received honoraria from Ono and Novartis Pharma. YT has received honoraria from BMS, Maruho, MSD, Novartis, and Ono Pharma. NY receives institutional research funding from BMS, MSD, Novartis, Ono, Takara Bio, Amgen, and Merck Biopharma, and has served as consultant and/or has received honoraria from BMS, MSD, Novartis, and Ono Pharma. The other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The International Space Station (ISS) is a closed facility that orbits the earth carrying not only its crew but also microorganisms. We have participated in microbiota analysis projects for the Japanese Experiment Module KIBO (ISS; operations nomenclature: Microbe-I, II, III, and IV) and were in charge of fungal screening. The interior of KIBO was sampled using swabs and microbe detection sheets (MDSs) for fungal detection. The dominant genera obtained by culture were Aspergillus and Penicillium. DNA analyses of the fungal biota using a clone library showed that KIBO was dominated by Malassezia, a fungal inhabitant of human skin. Three fungal species, Aspergillus sydowii, Penicillium palitans, and Rhodotorula mucilaginosa, which grew under microgravity in KIBO were observed under a field emission-scanning electron microscope on the ground. No novel phenotypic characteristics were noted. The results of antifungal susceptibility testing of all isolates did not differ significantly from previous reports of corresponding fungi. In Microbe-I (August 2009), MDSs were culture negative, while in the next stages the CFU of MDSs were 10 for Microbe-II (February 2011), 24 for Microbe-III (October 2012), and 151 for Microbe-IV (February 2015). These results indicated that fungi inside KIBO are increasing and expanding over time, and therefore continuous surveillance is crucial., (© 2021 The Societies and John Wiley & Sons Australia, Ltd.)

Background: Intrahepatic cholangiocarcinoma had been considered a contraindication for liver transplantation because of poorer outcomes. However, incidental intrahepatic cholangiocarcinoma in the explanted liver has been reported because of the difficulty of obtaining an accurate diagnosis in cirrhotic livers on preoperative imaging., Methods: We conducted a nationwide survey to analyze the incidence of incidental intrahepatic cholangiocarcinoma and outcomes after liver transplantation, in Japan., Results: Forty-five of 64 institutions (70%) responded to our initial investigation. Between January 2001 and December 2015, 6627 liver transplantations were performed in these 45 institutions, with 19 cases (0.3%) of incidental intrahepatic cholangiocarcinoma reported from 12 transplant centers. Six cases were diagnosed as hepatocellular carcinoma preoperatively. The 1-, 3-, and 5-year recurrence-free survival rates were 79%, 45%, and 45%, respectively. Tumor recurrence after liver transplantation was found in 10 patients (53%). The 1-, 3-, and 5-year overall survival rates were 79%, 63%, and 46%, respectively., Conclusions: Intrahepatic cholangiocarcinoma at liver transplantation is associated with a high risk of recurrence and poor prognosis, even these tumors are detected incidentally in the explanted liver., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Introduction: There is an insufficient number of infectious disease (ID) physicians in Japan. Hence, we considered a strategy to implement antimicrobial stewardship under these resource-limited settings., Methods: We compared carbapenem consumption, measured as days of therapy per 100 patient-days, between 24-month baseline and 12-month intervention periods. During the intervention period, an ID physician provided daily advises to prescribers against prolonged carbapenem use (≥14 days). Additionally, we sent all doctors a table containing the weekly point prevalence aggregate of carbapenem use of each department for 7-13 and ≥ 14 days via e-mail., Results: Among the 1241 carbapenem courses during the intervention period, the ID physician provided a total of 96 instances of feedback regarding carbapenem use for ≥14 days, with an acceptance rate of 76%. After the initiation of the intervention, the trend in monthly carbapenem consumption changed (coefficient: -0.62; 95% CI: -1.15 to -0.087, p = 0.024), and its consumption decreased (coefficient: -0.098; 95% CI: -0.16 to -0.039, p = 0.002) without an increase in the consumption of broad-spectrum antimicrobials or in-hospital mortality. Interestingly, the monthly number of carbapenem courses, but not the duration of carbapenem use, significantly decreased (coefficient: -3.02; 95% CI: -4.63 to -1.42, p = 0.001). The carbapenem-related annual estimated savings after the intervention was $83,745, with a 22% cost reduction., Conclusions: Our ID physician-led daily intervention with weekly feedback regarding long-term carbapenem use was effective in reducing antimicrobial consumption. Such feedback may be useful in changing the prescribing behavior and promoting appropriate antimicrobial usage even in resource-limited settings., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Growing evidence for the advantages of robotic pancreatoduodenectomy (RPD) has been demonstrated internationally. However, there has been no structured training program for RPD in Japan. Herein, we present the surgical training model of RPD and a standardized protocol for surgical technique., Methods: The surgical training model and surgical technique were standardized in order to implement RPD safely, based on the Dutch training system collaborated with the University of Pittsburgh Medical Center., Results: The surgical training model included various trainings such as basic robotic training, simulation training, biotissue training, and a surgical video review. Furthermore, a standardized protocol on the surgical technique was established to understand the tips, tricks, and pitfalls of RPD., Conclusions: Safe implementation of RPD can be achieved through the completion of a structured training program and learning surgical technique. A nationwide structured training system should be developed to implement the program safely in Japan.

Background: The prognosis of intrahepatic cholangiocarcinoma (ICC) has been poor, because of the high recurrence rate even after curative surgery. This study aimed to evaluate the prognostic impact of surgical resection of recurrent ICC., Patients and Methods: A total of 345 cases of ICC who underwent hepatectomy with curative intent in 17 institutions were retrospectively analyzed, focusing on recurrence patterns and treatment modalities for recurrent ICC., Results: Median survival time and overall 5-year recurrence-free survival rate were 17.8 months and 28.5%, respectively. Recurrences (n = 223) were classified as early (recurrence at ≤1 year, n = 131) or late (recurrence at >1 year, n = 92). Median survival time was poorer for early recurrence (16.3 months) than for late recurrence (47.7 months, p<0.0001). Treatment modalities for recurrence comprised surgical resection (n = 28), non-surgical treatment (n = 134), and best supportive care (BSC) (n = 61). Median and overall 1-/5-year survival rates after recurrence were 39.5 months and 84.6%/36.3% for surgical resection, 14.3 months and 62.5%/2.9% for non-surgical treatment, and 3 months and 4.8%/0% for BSC, respectively (p<0.0001). Multivariate analysis identified early recurrence, simultaneous intra- and extrahepatic recurrence, and surgical resection of recurrence as significant prognostic factors. In subgroup analyses, surgical resection may have positive prognostic impacts on intra- and extrahepatic recurrences, and even on early recurrence. However, simultaneous intra- and extrahepatic recurrence may not see any survival benefit from surgical management., Conclusion: Surgical resection of recurrent ICC could improve survival after recurrence, especially for patients with intra- or extrahepatic recurrence as resectable oligo-metastases., Competing Interests: The authors have declared that no competing interests exist.

Introduction: To investigate the efficacy and safety of trelagliptin 25 mg in patients with type 2 diabetes mellitus with severe renal impairment or end-stage renal disease., Materials and Methods: This multicenter, randomized, phase 3 study comprised a 12-week double-blind phase followed by a 40-week open-label phase. Patients had type 2 diabetes mellitus with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease (undergoing hemodialysis), and were receiving diet and/or exercise therapy with/without one antidiabetic drug., Results: Patients were randomized to trelagliptin (A/A, n = 55) or placebo (P/A, n = 52; double-blind phase). Both groups received trelagliptin in the open-label phase. The least square mean change (95% confidence interval [CI]) from baseline in hemoglobin A1c at the end of the double-blind phase was -0.71% (95% CI -0.885, -0.542) and 0.01% (95% CI -0.170, 0.183) in the A/A and P/A groups, respectively (intergroup least square means difference -0.72%, 95% CI -0.966, -0.473; P < 0.0001). Mean hemoglobin A1c decreased after trelagliptin treatment in the P/A group to similar levels observed in the A/A group and remained comparable in both groups versus baseline up to week 52. In the double-blind phase, the incidence of treatment-emergent adverse events (TEAEs) was 72.7% and 61.5% in the A/A and P/A group, respectively; most TEAEs were mild-to-moderate, except in one patient (P/A group), who experienced two severe TEAEs. The incidence of serious TEAEs was 7.3% and 3.8% in the A/A and P/A group, respectively., Conclusions: Once-weekly trelagliptin 25 mg was efficacious, with no major safety concerns, and represents a meaningful treatment option in this patient population., (© 2019 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Purpose: Pembrolizumab is an effective front-line treatment for advanced non-small cell lung cancer (NSCLC) in patients expressing high levels of programmed death-ligand 1 (PD-L1). However, it is unclear whether first-line pembrolizumab has similar efficacy among elderly (aged ≥ 75 years) and younger patients. This study aimed to investigate the safety and efficacy of front-line pembrolizumab monotherapy in older adults with NSCLC expressing high PD-L1., Methods: A total of 128 patients with advanced NSCLC expressing high PD-L1, including 47 older adults, received first-line pembrolizumab monotherapy at ten institutions in Japan, between February 2017 and February 2018. Data related to patient characteristics, efficacy of pembrolizumab therapy, and the type and severity of adverse events were recorded., Results: Overall, 47 patients [40 men and 7 women; median age 79 (range 75-88) years] were included in our analysis. In patients who received first-line pembrolizumab monotherapy, overall response, disease control rates, median progression-free survival (PFS), and median overall survival (OS) were 53.1%, 74.4%, 7.0 months, and not reached, respectively. Common adverse events included anorexia, fatigue, skin rash, and hypothyroidism. Two treatment-related deaths were noted, due to pneumonitis and infection. First-line pembrolizumab monotherapy was associated with improved PFS in patients with non-progressive disease (PD). In patients with non-PD and good performance status (PS), pembrolizumab monotherapy improved OS., Conclusions: Elderly patients with NSCLC expressing high PD-L1 tolerated front-line pembrolizumab monotherapy well. Their survival outcomes were equivalent to those of younger patients. In patients with non-PD, first-line pembrolizumab monotherapy may improve PFS; in conjunction with good PS, it additionally improves OS.

Aim: The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) is a common inflammatory disease that presents with periodic fever. We aimed to establish more specific diagnostic criteria for PFAPA based on the clinical characteristics of PFAPA patients in our directory., Method: The clinical, laboratory, genetic, and family history details of 257 Japanese PFAPA patients treated at our and other affiliated hospitals between April 2000 and April 2018 were analyzed along with quantitative measurements of the number of CD64 molecules on neutrophils, and the levels of serum inflammatory cytokines. The sensitivity and specificity of the criteria were calculated for several diseases., Results: Because recurrent fevers were crucial findings, they were defined as the required criterion. Tonsillitis/pharyngitis with white moss were important accompanying signs. Other symptoms associated with febrile episodes were cervical lymphadenitis with tenderness, aphthous stomatitis, sore throat, vomiting, and headache but not cough. A total of 159 (62%) patients had a family history of recurrent fevers, indicating autosomal dominant inheritance. C-reactive protein levels were extremely elevated during febrile attacks but normal in attack-free periods. Serum immunoglobulin D levels were high in 72 of the 199 tested patients. Oral glucocorticoid and cimetidine were extremely effective in all and 51.6% of the patients, respectively. We defined the above as supportive criteria. These criteria were sensitive and specific enough to distinguish PFAPA from other recurrent fever diseases. Raised serum interferon-γ levels and remarkable CD64 expression on neutrophils during flare-ups were recognized, indicating they contributed to diagnosis., Conclusion: Our new criteria are useful for diagnosing PFAPA., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Because of the advanced age of patients with cardiovascular disease (CVD), prevention of sleep disorder and dementia is a priority for cardiac rehabilitation (CR) during their long-term care. This study aimed to investigate the association of physical activity with sleep quality and cognitive function in elderly patients with CVD in the CR maintenance phase., Methods: We conducted a multicenter study through the Clinical Exercise Physiology Association Japan network, which included 102 elderly patients (mean age, 74±7.4 years) with CVD undergoing phase III CR at 6 institutions. Physical activity was assessed using a triaxial accelerometer for 7 consecutive days and was classified as locomotive and household activities. Physical fitness was assessed via 6-min walking distance (6MD), hand grip power, 10-m walking speed, one leg standing time with eyes open, and 10 times sit-to-stand tests. Sleep quality and cognitive function were evaluated using the Pittsburgh sleep quality index (PSQI) and mini-mental state examination (MMSE) scores, respectively., Results: The patients performed 5506.8±3743.6 steps/day and scored 5.8±3.5 points in the PSQI and 28.4±1.7 points in the MMSE. Sleep latency and MMSE scores correlated with locomotive activity, but not with household activity. Locomotive activity and 6MD were independent predictors of sleep latency and MMSE score, respectively. When patients with heart failure were excluded, the relationship between sleep latency and locomotive activity was preserved, but the relationship between exercise tolerance and cognitive function disappeared., Conclusion: Locomotive activity and exercise tolerance are associated with sleep latency and cognitive function in elderly patients with CVD continuing phase III CR. However, in this study, the relationship between exercise tolerance and cognitive function was offset by the presence of heart failure., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background and Objectives: Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria., Design, Setting, Participants, & Measurements: This was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing., Results: Changes in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), -16% (imarikiren 5 mg), -27% (imarikiren 20 mg), -38% (imarikiren 40 mg), -39% (imarikiren 80 mg), and -31% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo ( P <0.001 each) as well as for candesartan cilexetil 8 mg versus placebo ( P <0.001). Remission rates (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated., Conclusions: Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria., (Copyright © 2019 by the American Society of Nephrology.)

We aimed to explore the efficacy and safety of once-weekly trelagliptin 100 mg as an add-on therapy to insulin in Japanese patients with type 2 diabetes mellitus with inadequate glycaemic control. Patients with haemoglobin A1c (HbA1c) 7.5% to 10.0% who were receiving 8 to 40 units of insulin per day were randomized to receive, with insulin, trelagliptin 100 mg (A/A, n = 116) or placebo (P/A, n = 124) for a 12-week double-blind (DB) phase, after which all received trelagliptin for a 40-week open-label phase. Primary endpoints were HbA1c change from baseline to the end of the DB phase and adverse events (AEs). HbA1c significantly decreased in the A/A group vs the P/A group at the end of the DB phase (least square mean difference, -0.63% [95% CI, -0.83 to -0.44]: P < .0001). The frequency of treatment-emergent AEs during the DB phase was 44.0% in the A/A group and 47.6% in the P/A group. No patient experienced severe hypoglycaemia during trelagliptin treatment. Once-weekly trelagliptin 100 mg therapy with insulin demonstrated a significant reduction in HbA1c. Long-term treatment was well-tolerated, with no clinically significant hypoglycaemia, suggesting that trelagliptin with insulin is a meaningful treatment option in this patient population., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) is a rare disease characterized by predominant upper lobe pulmonary fibrosis of unknown etiology. However, the prognosis of IPPFE has not been discussed. We investigated the clinical characteristics and prognostic factors of IPPFE and idiopathic pulmonary fibrosis (IPF)., Methods: We performed a retrospective cohort study on 375 consecutive idiopathic interstitial pneumonia patients between April 2004 and December 2014. Among them, we diagnosed IPPFE and IPF patients using high-resolution computed tomography radiological criteria., Results: Twenty-nine IPPFE patients (9 males, 20 females) and 67 IPF patients (54 males, 13 females) were enrolled. IPPFE patients were significantly more likely to be females and nonsmokers and had lower body mass index, lower values of predicted percentage of forced vital capacity (%FVC), and a higher residual volume-to-total lung capacity ratio than IPF patients. Survival analysis revealed that they had significantly poorer prognosis than IPF patients in GAP (gender, age, and physiology) stages II + III. %FVC and GAP index independently predict mortality in patients with IPPFE., Conclusions: Patients with IPPFE showed poorer prognosis in the advanced stage than patients with IPF. %FVC and GAP index are independent predictors of survival in patients with IPPFE.

Metabolic acidosis has a negative impact on prognosis of dialysis patients. The aim of this study was to determine the prevalence of severe metabolic acidosis in dialysis patients treated with sevelamer hydrochloride. In 2004, a nationwide survey (101,516 dialysis patients) was conducted by the Japanese Society for Dialysis Therapy. We analyzed 32,686 dialysis patients whose bicarbonate levels were measured in the survey. Sevelamer hydrochloride was prescribed to 9231 dialysis patients while 23,455 dialysis patients were not prescribed sevelamer hydrochloride. In the present study, we defined severe acidosis as bicarbonate <15.8 mmol/L. The mean serum bicarbonate level correlated significantly and negatively with the daily dose of sevelamer hydrochloride (R(2) = 0.806, P < 0.0001). Logistic regression analysis indicated that the percentage of patients with severe acidosis increased significantly with increased dose of sevelamer hydrochloride (R(2) = 0.885, P < 0.00001). The estimated doses of sevelamer hydrochloride associated with severe acidosis in 10% and 15% of patients were 3.5 g/day (95% confidence interval [95%CI], 2.8-4.4) and 7.7 g/day (95%CI = 5.9-10.9), respectively. Severe acidosis was noted in 4.5% of patients who were not treated with sevelamer hydrochloride and in 16.1% of patients treated with sevelamer hydrochloride at ≥ 5.25 g/day (P < 0.0001). The results call for careful monitoring of serum bicarbonate level in hemodialysis patients treated with sevelamer hydrochloride., (© 2013 The Authors. Therapeutic Apheresis and Dialysis © 2013 International Society for Apheresis.)

Matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has been utilized for identification of various microorganisms. Malassezia species, including Malassezia restricta, which is associated with seborrheic dermatitis, has been difficult to identify by traditional means. This study was performed to develop a system for identification of Malassezia species with MALDI-TOF-MS and to investigate the incidence and variety of cutaneous Malassezia microbiota of 1-month-old infants using this technique. A Malassezia species-specific MALDI-TOF-MS database was developed from eight standard strains, and the availability of this system was assessed using 54 clinical strains isolated from the skin of 1-month-old infants. Clinical isolates were cultured initially on CHROMagar Malassezia growth medium, and the 28S ribosomal DNA (D1/D2) sequence was analyzed for confirmatory identification. Using this database, we detected and analyzed Malassezia species in 68% and 44% of infants with and without infantile seborrheic dermatitis, respectively. The results of MALDI-TOF-MS analysis were consistent with those of rDNA sequencing identification (100% accuracy rate). To our knowledge, this is the first report of a MALDI-TOF-MS database for major skin pathogenic Malassezia species. This system is an easy, rapid and reliable method for identification of Malassezia., (© 2014 Japanese Dermatological Association.)

A total of 515 yeast strains were isolated from the nasal smears of Queensland koalas and their breeding environments in Japanese zoological parks between 2005 and 2012. The most frequent species in the basidiomycetous yeast biota isolated from koala nasal passages was Cryptococcus neoformans, followed by Rhodotorula minuta. R. minuta was the most frequent species in the breeding environments, while C. neoformans was rare. Seven strains representing two novel yeast species were identified. Analyses of the 26S rDNA (LSU) D1/D2 domain and nuclear ribosomal DNA internal transcribed spacer region sequences indicated that these strains represent new species with close phylogenetic relationships to Cryptococcus and Rhodotorula. A sexual state was not found for either of these two novel yeasts. Key phenotypic characters confirmed that these strains could be placed in Cryptococcus and Rhodotorula. The names Cryptococcus lacticolor sp. nov. (type strain TIMM 10013(T) = JCM 15449(T) = CBS 10915(T) = DSM 21093(T), DDBJ/EMBL/Genbank Accession No.; AB375774 (ITS) and AB375775 (26S rDNA D1/D2 region), MycoBank ID; MB 802688, Fungal Barcoding Database ID; 3174), and Rhodotorula oligophaga sp. nov. (type strain TIMM 10017(T) = JCM 18398(T) = CBS 12623(T) = DSM 25814(T), DDBJ/EMBL/Genbank Accession No.; AB702967 (ITS) and AB702967 (26S rDNA D1/D2 region), MycoBank ID; MB 802689, Fungal Barcoding Database ID; 3175) are proposed for these new species.

Background: Surgical site infections (SSIs), particularly organ/space SSIs, remain a common cause of major morbidity after hepatectomy for hepatocellular carcinoma (HCC)., Methods: Risk factors for SSIs were analyzed in 359 patients who underwent hepatectomy for HCC between 2001 and 2010. The causative bacteria, management, outcome, and characteristics of organ/space SSIs were investigated., Results: Anatomic hepatectomy was performed for 296 patients (82.5%), and repeat hepatectomy was carried out for 59 patients (16.4%). SSIs developed in 52 patients (14.5%; incisional, 24 cases; organ/space, 31 cases [3 patients showed both incisional and organ/space SSIs]). No in-hospital mortality related to incisional or organ/space SSIs was encountered. Independent risk factors for SSIs were repeat hepatectomy and operative time ≥ 280 min. Independent risk factors for organ/space SSIs were repeat hepatectomy and bile leakage. Methicillin-resistant Staphylococcus aureus was detected more frequently in organ/space SSIs after repeat hepatectomy than after initial hepatectomy., Conclusions: Repeat hepatectomy and bile leakage represent independent risk factors for organ/space SSIs after hepatectomy for HCC. Establishing treatment strategies is important for preventing postoperative bile leakage and reducing the high rate of organ/space SSIs after repeat hepatectomy.

Accurate estimation of resting energy expenditure (REE) in children and adolescents is important to establish estimated energy requirements for the Japanese population. Our objectives were 1) to determine the REE of 6- to 17-y-old Japanese children and adolescents by indirect calorimetry in order to estimate energy expenditure for this group, 2) to compare measured REE with predicted REE to determine the accuracy of predictive equations of REE for Japanese children and adolescents, and 3) to derive new predictive equations for REE for Japanese children and adolescents based on measured REE. REE was measured in 221 Japanese children and adolescents, aged 6 to 17 y old (113 boys and 108 girls) using a ventilated indirect calorimeter. Anthropometric and body composition measurements were also performed. REE expressed as absolute values increased with age in both genders, and there was a significant difference between genders in the 12-17 y age group. REE was strongly correlated with body weight (BW) and fat-free mass (FFM). REE adjusted for BW or FFM decreased with age in both genders, and a gender difference was still observed in the 12-17 y age group after this adjustment. The highest accuracy of prediction was achieved using the Dietary Reference Intake for Japanese (1969) for boys and the Molnar equation for girls. Step-down multiple regression analysis was carried out using either a combination of age, gender, BW, and height, or a combination of age, gender, FFM, and fat mass (FM). The predictive equation accounted for 75% (R2) and 76% of the variance, respectively. In conclusion, absolute REE increased and REE adjusted for BW or FFM decreased with age. The major determinant of REE was FFM, but significant gender differences were observed in the 12-17 y range for both absolute REE and adjusted REE.

Introduction: Living donor hepatectomy is important because it determines donor safety and recipient outcome., Methods: We applied the counter-clockwise liver rotation method and the hanging maneuver from an early stage in two major types of living donor operations., Result: Twenty-eight living donors underwent these procedures with significant reduction in blood loss. Right hepatectomy was performed in 14 of the donors and extended left hepatectomy was performed in the other 14 donors., Conclusion: These techniques facilitate safe and bloodless living donor hepatectomy.

Background/aims: An omental flap covering the splanchnic vessels might reduce postoperative intraabdominal hemorrhage after pancreaticoduodenectomy. However, the efficiency of such a procedure remains to be verified. The purpose of this study was to determine the effect of omental flap placement in pancreaticoduodenectomy on the incidence of postoperative pseudoaneurysms., Methodology: Of 229 consecutive patients who underwent pancreaticoduodenectomy, the most recent 157 patients received the omental flap, while the initial 72 patients had no omental flap placement. Various preoperative factors were considered in the evaluation (age, gender, body mass index, primary disease and concurrent disease), as well as operative factors (operation time, blood loss, operative procedures, pancreatic texture, size of pancreatic duct and surgeon's experience)., Results: Eighty-one patients (35.4%) developed pancreatic fistula. Nine patients (3.9%) developed postoperative pseudoaneurysm. Among the patients with pancreatic fistula, those without omental flap developed pseudoaneurysms more frequently (21.7%) than those with omental flap placement (5.2%). Multivariate analysis identified pancreatic fistula, no use of omental flap and hypertension, in that order, as predisposing factors for a pseudoaneurysm. The omental flap significantly prevented pseudoaneurysms (p=0.021; OR=0.151; 95% CI, 0.030-0.751)., Conclusions: Omental flap placement over splanchnic vessels could be a feasible and efficient surgical procedure to prevent postoperative pseudoaneurysms following pancreaticoduodenectomy.

Between March 2005 and September 2009, 41,827 patients visited our emergency outpatient clinic, and 50 patients (0.12%) were admitted to our institution for chest trauma. Seventy percent of the chest traumas were caused by traffic accidents. Eighty-five percent of the traffic accidents were associated with car driving or motorcycle driving. Rib fracture, pneumothorax, hemothorax, and lung injury were seen in 56%, 40%, 22%, and 28% of the patients, respectively. Chest tube drainage was performed in 36% of the patients. Sixty-two percent of the patients with chest trauma underwent conservative follow-up. Only 1 patient underwent the ligation of the intercostal artery. One patient with chest trauma and fracture of the cervical vertebra and the pelvis died, who was in the state of cardio-pulmonary arrest on arrival. Forty-nine patients were discharged in 15.2 +/- 17.0 days. Twenty-two percent of the patients were hospitalized only 1 night.

Background/purpose: The purpose of this study was to identify risk factors for major morbidity after hepatectomies for hepatocellular carcinoma (HCC)., Methods: Univariate and multivariate analyses of risk factors for major morbidity were performed in 293 patients who underwent hepatectomy for HCC between 2001 and 2008., Results: Two hundred and forty-three patients (82.9%) underwent an anatomic hepatectomy, and a repeat hepatectomy was performed in 50 patients (17.1%). The prevalences of bile leakage and intraabdominal abscess were 12.9% and 9.2%, respectively. The risk factor for bile leakage was an operative time >or= 300 min and the risk factor for intraabdominal abscess was a repeat hepatectomy (odds ratios = 4.9 and 5.3, respectively). The main cause of bile leakage that made endoscopic therapy or percutaneous transhepatic biliary drainage necessary was a latent stricture of the biliary anatomy that had existed preoperatively, caused by previous treatments for HCC. Methicillin-resistant Staphylococcus aureus was the main causative bacteria of intraabdominal abscess after repeat hepatectomies., Conclusions: Our recent series revealed that prolonged operative time and repeat hepatectomy were independent risk factors for bile leakage and intraabdominal abscess, respectively, after hepatectomies for HCC. Preoperative assessment of the biliary anatomy should be considered for patients who have had previous multiple treatments for HCC, including hepatectomy, to reduce bile leakage that makes invasive treatment necessary.

Background: Morning blood pressure (BP) surge seems to be a risk factor for cardiovascular events. Although physical activity after arising significantly affects morning BP surge, it has remained unclear whether morning BP surge after controlling for physical activity (morning BP reactivity) is associated with target organ damage., Methods: We performed ambulatory BP monitoring with simultaneous actigraphy and echocardiography in 120 community-dwelling Japanese subjects. We determined the waking time by actigraphy, and defined morning BP surge (MBPS) as the average of systolic BP during the 2 h after awakening minus the average of systolic BPs during the 1 h that included the lowest sleep BP. The ratio of MBPS/(sum of the 2-h physical activity after the arising time)0.5 was calculated as the morning BP reactivity (MBPR)., Results: In all the subjects studied (n = 120), MBPR was positively associated with left ventricular (LV) mass index (r = 0.30, P = .001). The MBPR had a positive association with both 24-h BP variability (SD) (r = 0.373, P < .001) and awake BP variability (r = 0.20, P < .05). The MBP hyper-reactive group (the highest quartile [Q4] of MBPR: n = 30) had significantly higher LV mass index than the nonreactive group (the other quartiles [Q1 to 3]: n = 90) (140 v 113 g/m(2), P < .001). Even after controlling for age, body mass index, gender, and 24-h systolic BP, the MBP hyper-reactive status still remained a strong predictor for LV hypertrophy., Conclusions: Exaggerated MBPS, adjusted for physical activity, is associated with cardiac hypertrophy independent of ambulatory BP level in a community-dwelling population.

Background: Morning blood pressure (BP) surge in ambulatory BP monitoring was a risk factor for stroke in our previous study. We studied the determinants of the morning minus evening systolic BP difference (ME difference) in self-measured BP monitoring, as a possible risk factor for stroke in medicated hypertensive patients., Methods: Nine hundred sixty-nine hypertensive outpatients receiving stable antihypertensive drug treatment were studied using self-measured BP monitoring in the morning and evening., Results: The ME difference ranged from -37.3 to 53.3 mm Hg (mean 7.9 mm Hg). The highest quartile (Q4) of the ME difference group (>15.0 mm Hg) had older age (68.0+/-9.8 years v 66.2+/-10.3 years, P=.01) and higher prevalence of men (48.3% v 39.9%, P=.02), regular alcohol drinkers (34.7% v 26.0%, P=.01) and beta-blocker use (26.9% v 19.9%, P=.03) than the other quartile groups (Q1 to Q3), whereas there was no significant difference in the average of morning and evening (ME average) BP. In logistic regression analysis controlling for ME average and other confounding factors, independent risks for Q4 of ME difference were older age (10 years older: odds ratio [OR] 1.21, P=.01, 95% confidence interval (CI) 1.04-1.42), regular alcohol drinker (OR 1.51, P=.04, 95% CI 1.01-2.26), and beta-blocker use (OR 1.50, P=.02, 95% CI 1.06-2.12)., Conclusions: Older age, beta-blocker use, and regular alcohol drinking were significant determinants of the exaggerated ME difference in medicated hypertensive patients.

One hundred and seven patients with prostate cancer were treated at Mie University Hospital during the past 12 years between 1988 and 1999. They were between 53 and 83 years old, with an average age of 70.8 years old. The clinical stage was defined as A, B, C and D in 3 (2.8%), 19 (17.8%), 50 (46.7%) and 35 (32.7%) patients, respectively. At initial diagnosis, the tumor was well, moderately and poorly differentiated adenocarcinoma in 26 (24.3%), 47 (43.9%) and 34 (31.8%) patients, respectively. The median follow-up period was 52.3 months. The overall 1, 3 and 5-year survival rates were 98.0%, 86.8% and 75.2%, respectively. The 5-year survival rates for stage A, B, C and D were 100%, 93.8%, 82.1% and 56.9%, respectively. A significant difference (p = 0.017) in 5-year survival rate was noted between stage C and D. The 5-year survival rate was 100% for well differentiated, 78.0% for moderately differentiated, and 53.2% for poorly differentiated adenocarcinoma. A significant difference (p = 0.0016) in the 5-year survival rate was noted between well differentiated and poorly differentiated adenocarcinoma. According to the therapy, the 5-year survival rate in stage C was 86.2% for the radical prostatectomy group and 84.0% for the endocrine therapy group. There was no significant difference between these 2 treatment groups. Endocrine therapies, classified into maximum androgen blockade (MAB) and endocrine therapy other than MAB were performed for stage D as an initial therapy. Although the prognosis in the patients treated with MAB was better than that with other endocrine therapies, there was no significant difference between these 2 endocrine treatment groups.

There are inconsistent reports that the angiotensinogen (ATG) variant Met235-->Thr (T235) allele and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) variants are associated with hypertension and related target organ damage. Both high blood pressure (BP) and abnormal diurnal BP variation patterns are related to target organ damage, but it is not known whether the above genetic variants of the renin-angiotensin system are related to 24 h BP and the diurnal BP pattern in Japanese. We studied the association of the ATG T235 allele and ACE D allele with 24 h BP and diurnal BP variation in 235 of 262 consecutive untreated (or off medication) elderly Japanese hypertensives who underwent 24 h ambulatory BP monitoring. There was no significant association between the T235 or ACE D allele with office BP, but the T235 allele was significantly associated with 24 h BP and day BP, and the D allele was significantly associated with increased 24 h BP, day BP, and night BP. There were no effects of the T235 or D alleles on any BP parameters. Those with white-coat hypertension had a significantly lower T235 allele frequency (0.68) than those with sustained hypertension (0.79, p=0.010), but the difference in D allele frequency was marginal (0.30 vs. 0.38, p=0.057). In conclusion, in elderly Japanese hypertensive individuals, both the ATG T 235 and ACE D alleles are associated with increased 24 h BP and day BP, while only the ACE D allele is associated with increased night BP.

The authors investigated 5 Japanese cases of cerebrovascular accidents among users of oral contraceptives; 4 previously reported and 1 of their own. It is estimated that 200,000 women in this country use oral contraceptives, but, as of the present, only 5 cases of resultant cerebrovascular accidents have been reported. Of particular interest is the fact that 3 of the women had undergone multiple artificial abortions. The appearance of the side effects was dose independent and the symptoms were aggravated for 2 weeks after the cessation of medication.