Search

Stabilisation splint therapy has long been thought to be effective for the management of temporomandibular disorders (TMD). However, the superiority of stabilisation splint therapy compared to other TMD treatments remains controversial. The aim of this study was to determine the efficacy of stabilisation splint therapy combined with non-splint multimodal therapy for TMD. A total of 181 TMD participants were randomly allocated to a non-splint multimodal therapy (NS) group (n = 85) or a nonsplint multimodal therapy plus stabilisation splint (NS+S) group (n = 96). Non-splint multimodal therapy included self-exercise of the jaw, cognitive--behavioural therapy, self-management education and additional jaw manipulation. Three outcome measurements were used to assess treatment efficacy: mouth-opening limitation, oro-facial pain and temporomandibular joint sounds. A two-factor repeated-measures analysis of variance (ANOVA) was used to evaluate the efficacy of the two treatment modalities (NS vs. NS+S), and Scheffe's multiple comparison test was used to compare the treatment periods. Subgroup analyses were performed to disclose the splint effects for each TMD diagnostic group. All three parameters significantly decreased over time in both groups. However, there were no significant differences between the two treatment groups in the total comparison or subgroup analyses; an exception was the group with degenerative joint disease. No significant difference between the NS and NS+S treatment approaches was revealed in this study. Therefore, we conclude that the additional effects of stabilisation splint are not supported for patients with TMD during the application of multimodal therapy. [ABSTRACT FROM AUTHOR]

The efficacy of unrelated transplantation for patients with ALL who lack an HLA-matched sibling remains unclear. We performed a decision analysis to determine the efficacy of myeloablative transplantation from a genetically HLA-A, -B, -DRB1 allele-matched unrelated donor for patients with Ph chromosome-negative ALL aged 21-54 years. The transition probabilities were estimated from the Japan Adult Leukemia Study Group studies (ALL93; n=80, ALL97; n=82), and the Japan Marrow Donor Program database (transplantation in first CR (CR1): n=177). The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustment. Subgroup analyses were performed according to risk stratification based on the WBC count and cytogenetics, and according to age stratification. In all patients, unrelated transplantation in CR1 was shown to be superior in analyses both with and without QOL adjustment (40.8 vs 28.4% and 43.9 vs 29.0%, respectively). A similar tendency was observed in all subgroups. The decision model was sensitive to the probability of leukemia-free survival following chemotherapy and the probability of survival after transplantation in standard-risk and higher-aged patients. Unrelated transplantation in CR1 improves the long-term survival probability in patients who lack an HLA-matched sibling. However, recent improvements in treatment strategies may change this result. [ABSTRACT FROM AUTHOR]

Diabet. Med. 29, 980-985 (2012) Abstract Aim The aim of the study was to determine whether fasting serum non-esterified fatty acid (NEFA) could be associated with long-term progressive deterioration of insulin secretion in patients with Type 2 diabetes. Methods Seventy-seven Japanese patients with Type 2 diabetes (mean BMI 23.3 kg/m2) were followed for 10 years. We measured fasting C-peptide level every 1-2 years. By using the slope of regression line between fasting C-peptide level and duration, we calculated its individual annual decline as an index of insulin secretion. During the follow-up periods of C-peptide, the patients were evaluated for fasting serum non-esterified fatty acid, LDL cholesterol, HDL cholesterol and HbA1c levels for the last 8 years. We excluded patients who had renal dysfunction or anti-insulin antibodies from among the insulin-treated patients. Association between the individual annual decline of fasting C-peptide level and related factors were evaluated. Results The mean individual annual decline of fasting serum C-peptide level was −0.013 ± 0.027 nmol/l/year. Fasting serum non-esterified fatty acid level had no significant difference between the first and the last 2 years of the 8-year observation period of non-esterified fatty acid. Using multiple regression analysis, mean fasting serum non-esterified fatty acid level was associated with the individual annual decline of fasting serum C-peptide level (standardized regression coefficient −0.358, P = 0.0056), although other related factors, including HbA1c level, were not associated. Conclusions Mean fasting serum non-esterified fatty acid level during an 8-year observation was independently associated with long-term progressive deterioration of insulin secretion in Japanese patients with Type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Burns sustained in bathtubs are a social and medical problem in Japan, especially among the elderly. Between October 2003 and March 2009, 22 adult scald burn patients (men, 17; average age, 65.3±21.2 years) were transferred to Tokai University. In this study, we investigated the characteristics of these patients, and compared clinical parameters among patients with burns sustained in a bathtub (n =10) and those with burns sustained due to other causes (n =12). The average percentage total body surface area (%TBSA), dermal and deep burn area, and abbreviated burn severity index (ABSI) were 27.6±23.8, 19.9±20.5%, 7.8±13.1%, and 7.7±3.1, respectively. All patients in the bathtub burn group were elderly, 6 developed internal diseases, 3 had alcohol-related burns, and 4 died. Additionally, their %TBSA and ABSI were higher than those of the non-bathtub burn group patients. Burns sustained in bathtubs were more severe than those sustained due to other causes. The bathtub-related burn patients were elderly, and their burns were extensive and deep; hence, they were at a higher risk of developing internal diseases. Thus, introduction of safer bathing styles and bath systems will decrease incidences of bathtub-related burns. [Copyright &y& Elsevier]

Because forage rice (Oryza sativa L.) must be cost competitive with other forages, high dry matter (DM) and total digestible nutrient (TDN) yield are essential. To optimize forage rice production, it is important to maximize nutritional value in the leaf and stem rather than in the panicle because the hull restricts cattle's (Bos taurus) ability to digest rice grain. In particular, it is important to maximize TDN concentration and yield in the leaf sheath plus stem (stem) due to the high proportion of this component in the crop rather than in the leaf blade (leaf). The objective in this study was to evaluate the effects of timing of first harvest [95 or 116 days after transplanting (DAT) (booting or full heading stage, respectively)], N application rate (150 or 300 kg N ha-1), and N application method (100-ON method, applying N at 100 and 0% in the first and second crops, respectively; 67-33N method, applying N at 67 and 33%, respectively; 33-67N method, applying N at 33 and 67%, respectively) on TDN concentration and yield in double-harvest of forage rice systems in southwestern Japan. With the 100-ON method, stem TDN yield in the second crop was 39 g m-2 lower when the first crop was harvested at 116 DAT than at 95 DAT. However, with the 100-ON and 67-33N methods, stem TDN yield in the first crop was 152 and 163 g m-2 higher when the first crop was harvested at 116 DAT than at 95 DAT, respectively. When the first crop was harvested at 116 DAT, stem TDN yield in the first crop was 152 and 161 g m-2 higher with the 100-ON and 67-33N methods than with the 33-67N method, respectively. In contrast, stem TDN yield in the second crop was 115 and 142 g m-2 higher with the 67-33N and 33-67N methods than with the 100-ON method, respectively. To obtain high stem TDN yield in total of the first and second crops, harvesting the first crop at full heading and applying 300 kg N ha-1 at 67 and 33% in the first crop and second crops, respectively, is effective. Management practices that increase forage quality will help southwestern Japan to be more sufficient in forage production. [ABSTRACT FROM AUTHOR]

Rice (Oryza sativa L.) grain yields in western Japan have recently decreased as a result of higher temperatures during ripening. The improvement of rice cultivars for stable production is a pressing need because of climate change. In this study, the features of good ripening of the new rice cultivar Nikomaru were analyzed through a 3-yr field experiment. Nikomaru showed a yield increase of 7 to 8% compared with the leading cultivar in western Japan, Hinohikari, even though these cultivars have similar source size (available carbohydrate during ripening) and sink size (total spikelet number and rough grain size). The greater ripening index (percentage of ripened grains × 1000-grain weight) in Nikomaru, which determined the varietal yield differences in this study, was attributed to the translocated dry matter for ripening (AT) but not to the newly assimilated dry matter during ripening (ΔW). In addition, ΔT was positively correlated with the nonstructural carbohydrate content in the stem at full heading (NSCh). There was positive correlation between the NSCh and the percentage of ripened grains in the hotter years (2005 and 2007). It was suggested that a large NSCh as the main source of the ΔT contributes to the maintenance of a higher ripening rate especially under high temperatures. [ABSTRACT FROM AUTHOR]

Clinical studies using genetic randomization cannot accurately answer whether adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) who have a human leukocyte antigen (HLA)-matched sibling should undergo allogeneic hematopoietic stem cell transplantation (HSCT) or chemotherapy in first remission, as, in these studies, patients without a sibling donor undergo alternative donor transplantation or chemotherapy alone after a relapse. Therefore, we performed a decision analysis to identify the optimal strategy in this setting. Transition probabilities and utilities were estimated from prospective studies of the Japan Adult Leukemia Study Group, the database of the Japan Society for Hematopoietic Cell Transplantation and the literature. The primary outcome measure was the 10-year survival probability with or without quality of life (QOL) adjustments. Subgroup analyses were performed according to risk stratification on the basis of white blood cell count and cytogenetics, and according to age stratification. In analyses without QOL adjustments, allogeneic HSCT in first remission was superior in the whole population (48.3 vs 32.6%) and in all subgroups. With QOL adjustments, a similar tendency was conserved (44.9 vs 31.7% in the whole population). To improve the probability of long-term survival, allogeneic HSCT in first remission is recommended for patients who have an HLA-matched sibling. [ABSTRACT FROM AUTHOR]

The article discusses a study in Japan on the use of pylorus-preserving gastrectomy for treating early gastric cancer between 1995 and 2004. The study found that pylorus-preserving gastrectomy is a safe operation with a good prognosis in patients with early gastric cancer and is recommended as the standard procedure for early gastric cancer in the middle third of the stomach.

To determine whether the brown root rot disease caused by Phellinus noxius is present in the Amami islands, which are situated near Okinawa, we conducted six field surveys from 1999 to 2005. The brown root rot disease was found in 22 tree species in 17 plant families at 25 different sites in all the islands surveyed. Sixteen of these species were newly recorded as host plants of P. noxius. The disease was more common in the low elevation plains and on hills less than 100 m above sea level than in mountainous areas. This is the first report of the brown root rot disease caused by P. noxius in the Amami Islands, Japan, and Ohshima Island is currently the northern-most distribution point of the disease in the northern hemisphere. [ABSTRACT FROM AUTHOR]

To identify factors, associated with personal beliefs, involved in intentional non-adherence to prescribed medication of Japanese patients with chronic diseases.A cross-sectional study of Japanese subjects with chronic, primarily liver, gastrointestinal, or nervous system diseases who had been prescribed oral medicines for regular use, was performed. The subjects were admitted to a university hospital and were interviewed face-to-face on admission. Intentional non-adherence was defined as experience of deliberate adjustment of self-managed prescription medicines during the few months prior to hospital admission. Patients’ beliefs about taking medicines were assessed from the perspective of what the patient valued in order to take medicines without anxiety; whether the patient valued information about the medication such as its function and side-effects and/or mutual reliance on doctors. Using logistic multivariate regression analyses, factors associated with intentional non-adherence were identified.Among 154 subjects, 51 showed intentional non-adherence. Intentional non-adherence was associated with the following three factors: (a) the patients’ beliefs with respect to taking medicines without anxiety, especially putting no value on mutual reliance on the patient–doctor relationship (P < 0·001) and putting great value on knowing the drug's side-effects (P < 0·001), (b) poor comprehension of general aspects of medication (Pfor trend<0·001), and (c) being in the prime of life (40–59 years) (P = 0·011). Comprehension of the function of each medicine, experience of side-effects, anxiety about taking medicines, and the number of types of medicines taken, were not associated with non-adherence.Beliefs on which individual Japanese patients with chronic diseases attach value in order to take medicines without anxiety were potential factors for intentional non-adherence. This emphasizes the necessity of a patient-oriented approach to take account of patients’ personal beliefs about medicines to increase adherence rate in Japan. [ABSTRACT FROM AUTHOR]

Objective: To examine the physicians' preference between Web and fax-based remote data entry (RDE) system for an ongoing randomized controlled trial (RCT) in Japan.Methods: We conducted a survey among all the collaborating physicians (n = 512) of the CASE-J (Candesartan Antihypertensive Survival Evaluation in Japan) trial, who have been recruiting patients and sending follow-up data using the Web or a fax-based RDE system. The survey instrument assessed physicians' choice between Web and fax-based RDE systems, their practice pattern, and attitudes towards these two modalities.Results: A total of 448 (87.5%) responses were received. The proportions of physicians who used Web, fax, and the combination of these two were 45.9%, 33.3% and 20.8%, respectively. Multivariate logistic regression analyses revealed that physicians 55 years or younger [odds ratio (OR) = 1.9, 95% confidence interval (CI) = 1.1-3.3] and regular users of computers (OR = 4.2, 95% CI = 2.1-8.2) were more likely to use the Web-based RDE system.Conclusions: This information would be useful in designing an RCT with a Web-based RDE system in Japan and abroad. [ABSTRACT FROM AUTHOR]

Background Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data. Patients and methods Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan–Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model. Results OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883–1.775, P  = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312–0.673, P  <   0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively. Conclusion G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease. This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539. [ABSTRACT FROM AUTHOR]

A 20-year-old man was brought to the emergency room with chief complaints of dysarthria and vomiting after placing several drops of an inhalation liquid containing hexahydrocannabiphorol (HHCP) under his tongue. During ambulance transport, the patient had a post-vomiting convulsion that lasted approximately 1 minute. Upon arrival at the hospital, he was agitated, had dysarthria to the extent that he was in danger of falling from the stretcher, and was having visual hallucinations. Blood tests showed acidosis and a high lactic acid concentration. The patient was urgently admitted to the hospital with a diagnosis of acute poisoning and was started on supplemental intravenous fluids. The patient was able to communicate from the second day, started eating on the third day, finished receiving supplemental fluids on the fourth day, and was discharged from the hospital on the fifth day. HHCP was not illegal in Japan at the time and was distributed mainly through mail order. Clinical information on HHCP is lacking, but this case shows that the drug causes health problems. Although HHCP has been regulated by law in Japan since January 2024, clinicians and the general public should be aware that similar cases may occur in the future.

Objective: Acute sensorineural hearing loss represents a spectrum of conditions characterized by sudden onset hearing loss. The "Clinical Practice Guidelines for the Diagnosis and Management of Acute Sensorineural Hearing Loss" were issued as the first clinical practice guidelines in Japan outlining the standard diagnosis and treatment. The purpose of this article is to strengthen the guidelines by adding the scientific evidence including a systematic review of the latest publications, and to widely introduce the current treatment options based on the scientific evidence., Methods: The clinical practice guidelines were completed by 1) retrospective data analysis (using nationwide survey data), 2) systematic literature review, and 3) selected clinical questions (CQs). Additional systematic review of each disease was performed to strengthen the scientific evidence of the diagnosis and treatment in the guidelines., Results: Based on the nationwide survey results and the systematic literature review summary, the standard diagnosis flowchart and treatment options, including the CQs and recommendations, were determined., Conclusion: The guidelines present a summary of the standard approaches for the diagnosis and treatment of acute sensorineural hearing loss. We hope that these guidelines will be used in medical practice and that they will initiate further research., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest in this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

An increase in systemic blood pressure causes bleeding and ischemia owing to peripheral vascular breakdown, leading to various forms of organ damage. The brain, eyes, kidneys, and cardiovascular system are known target organs for hypertension. To our knowledge, no reports in Japan describe, in detail, the types of antihypertensive drugs used to treat hypertension in cats or its underlying causes. Therefore, we aimed to investigate the use of antihypertensive drugs in domestic cats with hypertension in Japan, the causes of hypertension, and the vital prognosis of these patients. In the present survey, we found that amlodipine was used alone (60/80 cats) or concomitantly (20/80 cats) in all cat patients with hypertension in Japan. We also determined that blood pressure measurements were not yet routinely performed on cats at veterinary clinics in Japan. Furthermore, we have new information suggesting that amlodipine administration in cats with hypertension, which lowers systolic arterial pressure levels to within the normal range (<140 mmHg), may have a negative impact on their survival. Routine blood pressure measurements for cats during their regular health checkups can help identify hypertension, and proper interpretation of blood pressure readings can facilitate suitable treatment measures.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant form of vascular dysplasia. Genetic diagnosis is made by identifying loss-of-function variants in genes, such as ENG and ACVRL1. However, the causal mechanisms of various variants of unknown significance remains unclear. In this study, we analyzed 12 Japanese patients from 11 families who were clinically diagnosed with HHT. Sequencing analysis identified 11 distinct variants in ACVRL1 and ENG. Three of the 11 were truncating variants, leading to a definitive diagnosis, whereas the remaining eight were splice-site and missense variants that required functional analyses. In silico splicing analyses demonstrated that three variants, c.526-3C > G and c.598C > G in ACVRL1, and c.690-1G > A in ENG, caused aberrant splicing, as confirmed by a minigene assay. The five remaining missense variants were p.Arg67Gln, p.Ile256Asn, p.Leu285Pro, and p.Pro424Leu in ACVRL and p.Pro165His in ENG. Nanoluciferase-based bioluminescence analyses demonstrated that these ACVRL1 variants impaired cell membrane trafficking, resulting in the loss of bone morphogenetic protein 9 (BMP9) signal transduction. In contrast, the ENG mutation impaired BMP9 signaling despite normal cell membrane expression. The updated functional analysis methods performed in this study will facilitate effective genetic testing and appropriate medical care for patients with HHT., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype. Partly due to its heterogeneity, it is currently challenging to stratify TNBC patients and predict treatment outcomes., Methods: In this study, we examined blood cytokine profiles of TNBC patients throughout treatments (pre-treatment, during chemotherapy, pre-surgery, and 1 year after the surgery in a total of 294 samples). We analyzed the obtained cytokine datasets using weighted correlation network analyses, protein-protein interaction analyses, and logistic regression analyses., Results: We identified five cytokines that correlate with good clinical outcomes: interleukin (IL)-1α, TNF-related apoptosis-inducing ligand (TRAIL), Stem Cell Factor (SCF), Chemokine ligand 5 (CCL5 also known as RANTES), and IL-16. The expression of these cytokines was decreased during chemotherapy and then restored after the treatment. Importantly, patients with good clinical outcomes had constitutively high expression of these cytokines during treatments. Protein-protein interaction analyses implicated that these five cytokines promote an immune response. Logistic regression analyses revealed that IL-1α and TRAIL expression levels at pre-treatment could predict treatment outcomes in our cohort., Conclusion: We concluded that time-series cytokine profiles in breast cancer patients may be useful for understanding immune cell activity during treatment and for predicting treatment outcomes, supporting precision medicine., Trial Registration: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with the unique trial number UMIN000023162. The association Japan Breast Cancer Research Group trial number is JBCRG-22. The clinical outcome of the JBCRG-22 study was published in Breast Cancer Research and Treatment on 25 March 2021. https://doi.org/10.1007/s10549-021-06184-w ., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We aimed to develop and test the reliability and validity of a foot care self-management assessment tool for older Japanese patients with diabetes. In this cross-sectional observational study, which was carried out according to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines, additional items were developed and selected to reflect older Japanese patients' needs a thorough investigation with experts in diabetes and geriatrics. A total of 200 older patients with diabetes in a foot care outpatient clinic were included in the study to finalize the scale items and verify the scale's reliability and validity. A factor analysis yielded a 4-factor, 9-item scale. Factors 1 to 4 were "skin condition" (3 items), "nail clipping" (2 items), "attention to wounds" (2 items), and "relationships with others" (2 items). The Cronbach's α coefficients for the 4 factors were .852, .900, .820, and .571, respectively. The overall scale was 0.797, indicating good internal consistency. Spearman's correlation coefficients for each of the 4 factors with the scale's total score showed good stability; all correlations were significant. In Japan's super-aged society, it is important to focus on foot care practices among older adults and to promote good foot care practices among early older adults so that they can practice self-care at home. Therefore, a scale for comprehensively evaluating foot care in elderly patients with diabetes is needed. The Foot Care Scale for Older Diabetics could be useful as a tool for assessing the ability to self-manage foot care in older Japanese patients with diabetes., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: We evaluated the clinical outcomes and costs of surgical aortic valve replacement (SAVR) and transfemoral transcatheter aortic valve implantation (TAVI) for aortic stenosis using the Japanese Diagnosis Procedure Combination (DPC) database., Methods: Using our extraction protocol, we retrospectively analyzed summary tables in the DPC database from 2016 to 2019, which were provided by the Ministry of Health, Labor and Welfare. A total of 27,278 patients were available (SAVR, n = 12,534; TAVI, n = 14,744)., Results: The TAVI group was older than the SAVR group (SAVR vs. TAVI: 74.6 vs. 84.5 years; P < 0.01), with a lower in-hospital mortality (1.0 vs. 0.6%; P < 0.01) and a shorter hospital stay (26.9 vs. 20.3 days; P < 0.01). TAVI conferred more total medical service reimbursement points than SAVR (493,944 vs. 605,241 points; P < 0.01), especially materials points (147,830 vs. 434,609 points; P < 0.01). Total insurance claims for TAVI were approximately 1 million yen higher than those for SAVR. Regarding the details of costs, only the operation cost was higher, while other costs were lower with TAVI than with SAVR., Conclusion: Our analysis revealed that both SAVR and TAVI showed acceptable clinical outcomes. TAVI was associated with higher total insurance claims than SAVR. If the material cost of TAVI operations can be reduced, greater cost-effectiveness can be expected., (© 2023. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

What limits the size of nature's most extreme structures? For weapons like beetle horns, one possibility is a tradeoff associated with mechanical levers: as the output arm of the lever system-the beetle horn-gets longer, it also gets weaker. This "paradox of the weakening combatant" could offset reproductive advantages of additional increases in weapon size. However, in contemporary populations of most heavily weaponed species, males with the longest weapons also tend to be the strongest, presumably because selection drove the evolution of compensatory changes to these lever systems that ameliorated the force reductions of increased weapon size. Therefore, we test for biomechanical limits by reconstructing the stages of weapon evolution, exploring whether initial increases in weapon length first led to reductions in weapon force generation that were later ameliorated through the evolution of mechanisms of mechanical compensation. We describe phylogeographic relationships among populations of a rhinoceros beetle and show that the "pitchfork" shaped head horn likely increased in length independently in the northern and southern radiations of beetles. Both increases in horn length were associated with dramatic reductions to horn lifting strength-compelling evidence for the paradox of the weakening combatant-and these initial reductions to horn strength were later ameliorated in some populations through reductions to horn length or through increases in head height (the input arm for the horn lever system). Our results reveal an exciting geographic mosaic of weapon size, weapon force, and mechanical compensation, shedding light on larger questions pertaining to the evolution of extreme structures., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) nomogram was developed to predict disease-free survival in patients with colorectal liver metastases (CRLM) undergoing upfront hepatectomy. However, the utility of the nomogram in patients with resected CRLM remains unknown in the current situation in which treatment strategies are changing with advances in drugs., Methods: Patients in the initial nomogram cohort (n = 727) and validation cohort (n = 2225) were divided into the upfront hepatectomy and preoperative chemotherapy groups. The nomogram was validated by measuring calibration and discrimination in the two cohorts. Calibration curves were plotted, and survival probabilities were compared. Finally, to quantify the discrimination power, we estimated the concordance index (C-index)., Results: In the upfront hepatectomy group, the C-index was 0.63, the suitable cutoff value of the Beppu score was 7, and adjuvant chemotherapy was significantly effective limited to high-risk patients (Beppu score ≥7). The C-index was 0.56 in the preoperative chemotherapy group., Conclusions: The JSHBPS nomogram remains beneficial for patients undergoing upfront hepatectomy in the recent era but is less effective for patients undergoing hepatectomy after chemotherapy. Patients with a Beppu score ≥7 showed high-risk recurrence, and adjuvant chemotherapy should be recommended for these patients., (© 2022 The Authors. Journal of Hepato-Biliary-Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

To improve treatment outcomes in patients with colorectal liver metastasis (CRLM), the Joint Committee for Nationwide Survey on CRLM was established by the Japanese Society for Cancer of the Colon and Rectum and the Japanese Society of Hepato-Biliary-Pancreatic Surgery. The aim of the study was to evaluate transition in the characteristics and treatment strategy in CRLM patients and analyze prognostic factors using large-scale data. The present study summarizes the data of patients newly diagnosed between 2015 and 2017 and presents prognostic data of patients newly diagnosed in 2013 and 2014. Survival curves were generated by the Kaplan-Meier method and compared by log-rank test. Multivariate analyses were carried out using Cox proportional hazard modeling. The data of 4502 patients newly diagnosed with CRLM between 2015 and 2017 and the prognostic data of 2427 patients diagnosed in 2013 and 2014 are included. Regarding the 2013 and 2014 prognostic data, the 5-year overall survival (OS) rates of patients who underwent hepatectomy alone was 59.8%. Multivariate analyses identified age at diagnosis of CRLM ≥70 years, concomitant extrahepatic metastasis at diagnosis of CRLM, tumor depth of primary lesion ≥subserosa/pericolic or perirectal tissue, mutant KRAS status, number of CRLM ≥5, maximum diameter of CRLM >5 cm, and surgical curability R1/R2 as independent predictors of OS. Analysis of the latest nationwide database of patients diagnosed with CRLM revealed changes in patients and oncological characteristics, a transition in treatment strategy, and different independent prognosticators to those reported previously., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Purpose: In the 5th edition of the World Health Organization classification, appendiceal goblet cell adenocarcinoma (GCA) is categorized separately from neuroendocrine tumors and other appendiceal adenocarcinomas. We clarified the clinicopathological characteristics of Japanese appendiceal GCA., Methods: We designed a retrospective multicenter cohort study and retrieved the data of patients with appendiceal neoplasms and histologically diagnosed appendiceal goblet cell carcinoid (GCC) treated from January 2000 to December 2017 in Japan. The available GCC slides were reviewed and diagnosed with a new grading system of GCA., Results: A total of 922 patients from 43 institutions were enrolled; of these, 32 cases were patients with GCC (3.5%), and 20 cases were ultimately analyzed. The 5-year survival rate was 61.4% (95% confidence interval: 27.4-83.2), and the median survival time was 93.1 months. For peritoneal metastasis, regional lymph node metastasis was a significant factor (p = 0.04), and Grade 3 was a potential factor (p = 0.07). No peritoneal metastasis was observed in either T1/2 patients (n = 2) or Grade 1 patients (n = 4). We were unable to detect any significant factors associated with regional lymph node metastasis., Conclusion: For peritoneal metastasis, regional lymph node metastasis was a significant factor, and Grade 3 was a potential factor., (© 2022. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: Numerous studies investigated patients with IPF; however, only a few examined patients with idiopathic interstitial pneumonias (IIPs)., Methods: The Japanese Idiopathic Interstitial Pneumonias (JIPS) Registry, which was initiated in December 2016, is a multicenter prospective observational study of patients newly diagnosed with IIPs from 86 facilities treating ILDs. The plan is to enroll more than 600 new patients during the 2-year enrolment period and to follow their progress for 3 years after the last case enrolment. If additional consent is obtained, the study will continue for another 2 years. Research questions mainly focus on identifying the frequency by IIP classification, patient background, and diagnostic methods during enrolment, survival, acute exacerbation rate, changes in high-resolution CT imaging, forced vital capacity, and interstitial pneumonia markers over time. Other research questions, including those regarding disease behavior in patients with progressive fibrosing-ILD and new biomarkers associated with genetic predispositions, will be investigated., Discussion: The JIPS Registry will provide a comprehensive description of the disease progression, prognosis, treatment status, new biomarkers, and validity of guidelines and central multidisciplinary decisions for IPF and similar diseases that can be differentiated from IPF among IIPs., Ethics and Dissemination: Ethical approval was obtained from the institutional review board of Kanagawa Cardiovascular and Respiratory Center (KCRC-16-0005), and that of Jichi Medical University approved the biobank part (I18-005). Results will be published in peer-reviewed journals and will be presented at national and international conferences., Trial Registration: ClinTrials.gov Registry (NCT03041623, first posted on February 3, 2017)., Competing Interests: Conflict of Interest R. Okuda has received lecture fees from Nippon Boehringer Ingelheim Gmb. T. Ogura has received advisory board fees from Nippon Boehringer Ingelheim Gmb, Taiho Pharmaceutical Co. Ltd., Shionogi & Co. Ltd., and Bristol Myers Squibb Co. T. Ogura also has received lecture fees from Nippon Boehringer Ingelheim Gmb., Shionogi & Co. Ltd., Astellas Co., AstraZeneca K.K., and Eizai Inc. S. Hisata has received lecture fees from Nippon Boehringer Ingelheim Gmb. T. Baba has received lecture fees from Nippon Boehringer Ingelheim Gmb. Y. Kondoh has received advisory board fees and personal fees from Nippon Boehringer Ingelheim Gmb., Asahi Kasei Pharma Corp., and Shionogi & Co. Ltd., advisory board fees from Janssen Pharmaceutical K.K., Healios K.K., Chugai Pharmaceutical Co., Ltd., and Taiho Pharmaceutical Co., Ltd., and personal fees from Astellas, AstraZeneca K.K., Eisai inc., KYORIN Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma, and Novartis Pharma K.K., outside the presentation work. T. Suda has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. T. Johkoh has received lecture fees from Nippon Boehringer Ingelheim Gmb. T. Iwasawa has received grants from Canon Medical systems and received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. H. Tomioka has received lecture fees from Nippon Boehringer Ingelheim Gmb. M. Bando has received lecture fees from Nippon Boehringer Ingelheim Gmb. A. Azuma has received a steering committee member fee, consultant fee, and lecture fee. Y. Inoue has received payments as lecture fees, participation on the steering committees, or advisor of Boehringer Ingelheim Gmb. T. Arai has received lecture fees from Boehringer Ingelheim Gmb, and Shionogi & Co. Ltd. R. Nakamura has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. A. Miyamoto has received a lecture fee from Nippon Boehringer Ingelheim Gmb. Y. Miyazaki has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. H Chiba has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. H. Ishii has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. N. Hamada received grants from Nippon Boehringer Ingelheim Gmb. S. Sato has received grants and lecture fees from Nippon Boehringer Ingelheim Gmb. T. Suzuki has received a lecture fee from Nippon Boehringer Ingelheim Gmb. Y. Nishioka has received grants or lecture fees from Nippon Boehringer Ingelheim Gmb. N. Hattori has received grants and lecture fees from Nippon Boehringer Ingelheim Gmb. N. Hashimoto received research grants and lecture fees from Boehringer Ingelheim Gmb. K. Hagiwara has received lecture fees from Nippon Boehringer Ingelheim Gmb. K. Kobayashi has received lecture fees from AstraZeneca K.K. and Takeda Pharmaceutical Co. Y. Terasaki, I. Kuwahira, S. Kato, S. Sakamoto, N. Ichihara, H. Miyata and T. Nukiwa have no competing interests., (Copyright © 2022 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic has had a severe impact on mental well-being. Vaccination may have played a pivotal role in enduring this mental health crisis. The present study aimed to longitudinally investigate the association between COVID-19 vaccination and mental health status among Japanese population in 2021. Longitudinal data of 17,089 individuals aged 15-79 years who participated in a nationwide online study were analyzed. Baseline and follow-up mental health statuses were assessed using the Kessler Psychological Distress Scale (K6). General linear and multivariable logistic regression models adjusted for baseline levels of mental distress were used to examine the association between vaccine receipt and follow-up levels of mental health. Mean K6 scores were lower in the vaccinated than in the non-vaccinated participants. Those who had received one or two doses of COVID-19 vaccines were associated with improved mental health at follow-up in subjects with psychological distress at baseline (odds ratio [OR] 1.31 and 1.35, respectively) and were inversely associated with deteriorated mental health status at follow-up in subjects without psychological distress at baseline (OR 0.66 and 0.70, respectively) compared with no vaccination groups, respectively. The present study would indicate that one or two doses of COVID-19 vaccinations contributed to mental well-being in Japan. This finding might provide evidence for promoting vaccination against COVID-19 and emerging infectious diseases in the future., (© 2022. The Author(s).)

Importance: Quality assurance of molecular tumor boards (MTBs) is crucial in cancer genome medicine., Objective: To evaluate the concordance of recommendations by MTBs and centrally developed consensus treatment recommendations at all 12 leading institutions for cancer genomic medicine in Japan using 50 simulated cases., Design, Setting, and Participants: This was a prospective quality improvement study of 50 simulated cancer cases. Molecular tumor boards from 12 core hospitals independently recommended treatment for 50 cases blinded to the centrally developed consensus treatment recommendations. The study's central committee consisted of representatives from all 12 core hospitals in Japan who selected the 50 simulated cases from The Cancer Genome Atlas database, including frequently observed genomic alterations. The central committee recommended centrally developed consensus treatment. The concordance rate for genomically matched treatments between MTBs and centrally developed consensus treatment recommendations was evaluated. Data analysis was conducted from January 22 to March 3, 2021., Exposures: Simulated cases of cancer., Main Outcomes and Measures: The primary outcome was concordance, defined as the proportion of recommendations by MTBs concordant with centrally developed consensus treatment recommendations. A mixed-effects logistic regression model, adjusted for institutes as a random intercept, was applied. High evidence levels were defined as established biomarkers for which the treatment was ready for routine use in clinical practice, and low evidence levels were defined as biomarkers for genomically matched treatment that were under investigation., Results: The Clinical Practice Guidance for Next-Generation Sequencing in Cancer Diagnosis and Treatment (edition 2.1) was used for evidence-level definition. The mean concordance between MTBs and centrally developed consensus treatment recommendations was 62% (95% CI, 57%-65%). Each MTB concordance varied from 48% to 86%. The concordance rate was higher in the subset of patients with colorectal cancer (100%; 95% CI, 94.0%-100%), ROS1 fusion (100%; 95% CI, 85.5%-100%), and high evidence level A/R (A: 88%; 95% CI, 81.8%-93.0%; R:100%; 95% CI, 92.6%-100%). Conversely, the concordance rate was lower in cases of cervical cancer (11%; 95% CI, 3.1%-26.1%), TP53 mutation (16%; 95% CI, 12.5%-19.9%), and low evidence level C/D/E (C: 30%; 95% CI, 24.7%-35.9%; D: 25%; 95% CI, 5.5%-57.2%; and E: 18%; 95% CI, 13.8%-23.0%). Multivariate analysis showed that evidence level (high [A/R] vs low [C/D/E]: odds ratio, 4.4; 95% CI, 1.8-10.8) and TP53 alteration (yes vs no: odds ratio, 0.06; 95% CI, 0.03-0.10) were significantly associated with concordance., Conclusions and Relevance: The findings of this study suggest that genomically matched treatment recommendations differ among MTBs, particularly in genomic alterations with low evidence levels wherein treatment is being investigated. Sharing information on matched therapy for low evidence levels may be needed to improve the quality of MTBs.

Understanding the structure of human sexual contact networks is vital in a broad range of disciplines, including sociology, biology, public health, and anthropology. However, sexual contact networks are yet to be understood because technical and privacy issues make it difficult to conduct accurate, large-scale surveys. In this study, we surveyed data openly available on one of the largest adult entertainment websites in Japan, where male clients (MCs) can write online customer reviews of female commercial sex workers (FCSWs). In particular, our investigation focused on a type of establishment called "soapland," the only type of sex industry in Japan where sexual intercourse is publicly permitted. Soaplands are scattered throughout Japan, and the study website covers approximately 66% of them. Using such a vast amount of data on a nationwide scale, we clarified the network structure of commercial sex, characterized by small-world, scale-free, and disassortative mating properties. To study geographical characteristics, we compared the resulting network with three different artificially generated networks via the random rewiring of links. Moreover, we considered a simple epidemic model on the resulting network, and investigated whether it would be more effective to provide infection control measures to FCSWs or MCs. We determined that active FCSWs constitute an important pathway of infection propagation in commercial sex networks, but MCs also play an essential role as weak ties., Competing Interests: The authors have declared that no competing interests exist.

In Japan, comprehensive genomic profiling (CGP) tests for refractory cancer patients have been approved since June 2019, under the requirement that all cases undergoing CGP tests are annotated by the molecular tumor board (MTB) at each government-designated hospital. To investigate improvement in precision oncology, we evaluated and compared the proportion of cases receiving matched treatments according to CGP results and those recommended to receive genetic counseling at all core hospitals between the first period (11 hospitals, June 2019 to January 2020) and second period (12 hospitals, February 2020 to January 2021). A total of 754 and 2294 cases underwent CGP tests at core hospitals in the first and second periods, respectively; 28 (3.7%) and 176 (7.7%) patients received matched treatments (p < 0.001). Additionally, 25 (3.3%) and 237 (10.3%) cases were recommended to receive genetic counseling in the first and second periods, respectively (p < 0.001). The proportion was associated with the type of CGP test: tumor-only (N = 2391) vs. tumor-normal paired (N = 657) analysis (10.0% vs. 3.5%). These results suggest that recommendations regarding available clinical trials in networked MTBs might contribute to increasing the numbers of matched treatments, and that tumor-normal paired rather than tumor-only tests can increase the efficiency of patient referrals for genetic counseling., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Introduction: LCL161 is a novel oral pan-inhibitor of apoptosis protein (IAP) antagonist. LCL161 enhances paclitaxel activity in cell lines and xenograft models. A phase I study of LCL161 combined with paclitaxel for the treatment of Japanese patients with advanced solid tumors was conducted., Methods: Each patient received oral LCL161 in a single weekly dose on days 1, 8, and 15 of a 21-day treatment cycle. In the second cycle, patients received a combination treatment with weekly paclitaxel (80 mg/m 2 ) whenever possible. A Bayesian logistic regression model by escalation with the overdose control principle was used., Results: Nine patients were treated with LCL161 at a dose of 600 mg (five patients) or 1200 mg (four patients). Seven patients were treated with LCL161 plus paclitaxel, and two patients received only LCL161 monotherapy. Because this study was terminated early due to a change in the LCL161 development strategy, the maximum tolerated dose (MTD) was not determined. One patient treated with LCL161 monotherapy at a dose of 1200 mg experienced dose limitind toxicity (grade 3 maculopapular rash). Another patient died on day 86 of bacterial pneumonia, which was suspected to be related to the study treatment. The most common serious adverse events were infections and infestations (n = 3)., Conclusion: The present study suggests that the risk of infection may increase when LCL161 is combined with paclitaxel, but other conclusions about the MTD, pharmacokinetic profile, and preliminary activity of the combination of LCL161 plus paclitaxel were not drawn., (© 2022 John Wiley & Sons Australia, Ltd.)

Background: We conducted a single-center cohort study of rheumatoid arthritis (RA) patients from 2011 to 2020 to understand their real world treatment and outcomes, especially changes in physical function and quality of life (QOL) in elderly patients, including those aged ≥ 80 years., Methods: For RA patients attending our outpatient clinic, we annually recorded tender and swollen joint counts, laboratory findings, therapeutic drugs, and scores from the Japanese Health Assessment Questionnaire and EuroQoL-5 Dimensions questionnaire. We examined changes in treatment and outcomes over time, by age group, in patients enrolled over a 10-year period, from 2011 to 2020., Results: One thousand eight hundred thirty RA patients were enrolled and data were recorded once a year, and a total of 9299 patient records were evaluated. The average age of patients increased by 3.7 years during the study period; the patients aged rapidly. Intensive pharmacological treatment was more frequent in younger patients. Disease activity, physical function, and QOL showed improvement in all age groups over the study period. Physical function and QOL showed greater changes with aging, compared with disease activity. This may be due to the effects of accumulated RA damage, disability due to aging, and depression., Conclusions: Intensive pharmacological treatment contributes to not only control of disease activity but also the improvement of physical activity and QOL, even in elderly patients. Relieving age-related physical impairment and depression may improve the QOL of very elderly RA patients., (© 2022. The Author(s).)

Background: Abnormalities in homologous recombination contribute to the aggressive nature of castration-resistant prostate cancer. Retinoblastoma transcriptional corepressor 1 (RB1) and breast cancer 2 (BRCA2) exist close to each other in the same chromosome, and the significance of their concurrent loss has become a hot topic in the field of cancer research., Case Presentation: A 61-year-old man presented with a chief complaint of a mass on his head and was diagnosed as multiple bone metastases from prostate cancer. He was treated with standard medication, but he died 2 years 6 months after being diagnosed with prostate cancer. Simultaneous biallelic loss of RB1 and BRCA2 as well as a truncating mutation of tumor protein p53 (TP53) were revealed by genomic analysis., Conclusion: To our knowledge, this is the first report of castration-resistant prostate cancer (CRPC) with BRCA2 and RB1 co-loss and TP53 mutation. To establish a treatment strategy for highly malignant cases with such multiple genetic features is important., (© 2022. The Author(s).)

The exaggerated horns of beetles are attractive models for studying the origin of novel traits and morphological evolution. Closely related species often differ profoundly in the size, number, and shape of their horns, and in the body region from which they extend. In addition, beetle horns exhibit exquisite nutrition-dependent phenotypic plasticity, leading to disproportionate growth of the horns in the largest, best-condition individuals and much smaller - even stunted - horn sizes in poor-condition individuals. These exciting phenomena in beetle horns have recently been revealed at the molecular level with the advent of next-generation sequencing. This section reviews the latest research on a horned beetle, the Japanese rhinoceros beetle Trypoxylus dichotomus, whose genome was recently sequenced., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Management of elderly patients with early gastric cancer is an important issue in an aging society such as Japan. While endoscopic resection is recommended as the standard treatment for early gastric cancers with extremely low risk of lymph node metastasis (<1%), gastrectomy with lymphadenectomy is recommended for the other early gastric cancers as the standard treatment even in elderly patients. Endoscopic submucosal dissection is the most recommended endoscopic resection procedure because of its high ability for 'en bloc' resection. Endoscopic submucosal dissection can reportedly provide favorable short-term outcomes in elderly patients. In terms of patient prognosis, the importance of considering patients' physical and nutritional conditions before endoscopic submucosal dissection has recently attracted attention. With respect to gastrectomy, the nationwide data in Japan have demonstrated relatively low 5-year overall survival and non-negligible post-operative 90-day mortality in men aged ≥75 years and women aged ≥80 years compared with those in younger patients. Among these elderly patients, 20% or more reportedly died within 5 years after gastrectomy mostly due to other diseases. These facts suggested the necessity of a less invasive management option for the elderly patients. Efforts are being made to provide a non-invasive follow-up option without gastrectomy following endoscopic resection in elderly patients. To avoid the increase in gastric cancer-related deaths, the selection of patients with relatively low lymph node metastasis risk is essential, and several tools to estimate the lymph node metastasis risk from early gastric cancers have been developed. To avoid overtreatment with gastrectomy in more elderly early gastric cancer patients, new endoscopic submucosal dissection indications for them are also warranted., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Triple-negative breast cancer (TNBC) is a biologically diverse disease, with characteristics such as homologous recombination deficiency (HRD), gene mutation, and immune reactions. Japan Breast Cancer Research Group 22 is a multicenter trial examining TNBC's response to neoadjuvant chemotherapy (NAC) according to the HRD status. This translational research investigated the clinical significance of the immune microenvironment of TNBC in association with HRD, tumor BRCA1/2 (tBRCA1/2) mutation, and response to NAC., Methods: Patients aged below 65 years with high HRD or germline BRCA1/2 (gBRCA1/2) mutation randomly received paclitaxel + carboplatin (group A1) or eribulin + carboplatin (A2), followed by anthracycline. Patients aged below 65 years with low HRD or those aged 65 years or older without gBRCA1/2 mutation randomly received eribulin + cyclophosphamide (B1) or eribulin + capecitabine (B2); nonresponders to the first four cycles of the therapy received anthracycline. A pathological complete response (pCR) was defined as the absence of residual cancer cells in the tissues. Pretreatment biopsy specimens were stained by multiplexed fluorescent immunohistochemistry using antibodies against CD3, CD4, CD8, Foxp3, CD204, and pan-cytokeratin. Immune cells with specific phenotypes were counted per mm 2 in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response., Results: This study analyzed 66 samples. T1 tumors had a significantly higher density of intratumoral CD8 + T cells than T2 or larger tumors. The tBRCA1/2 mutation or HRD status was not associated with the density of any immune cell. The density of intratumoral and stromal CD4 + T cells was higher in patients showing pCR than in those without pCR. In a multivariate analysis, intratumoral and stromal CD4 + T cell density significantly predicted pCR independent of age, chemotherapy dose, HRD status, and treatment groups (P = 0.009 and 0.0057, respectively). In a subgroup analysis, the predictive value of intratumoral and stromal CD4 + T cell density persisted in the platinum-containing chemotherapy group (A1+A2) but not in the non-platinum-containing group (B1+B2)., Conclusions: Intratumoral and stromal CD4 + T cell density was an independent predictor of pCR in patients with TNBC. A larger study is warranted to confirm the results., Trial Registration: UMIN000023162., (© 2022. The Author(s).)

Background: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors., Methods: We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm., Results: Overall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% [77.9%-83.4%]) than in NR-Group S (74.0% [69.3%-78.0%]) (hazard ratio, 0.64 [0.50-0.83]; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW., Conclusions: Adjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes., Trial Registration: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783 , date of registration: 18/04/2012)., (© 2022. The Author(s).)

The maximum limit on overtime working hours for physicians will be applied from 2024. To explore sociodemographic and work-related factors influencing overtime work among cardiovascular surgeons (CS) in Japan. This cross-sectional study included 607 CS who responded to an online survey. Working hours were categorized into ≤60 hours, 60-79 hours, and ≥80 hours per week according to Japan Ministry of Health, Labour and Welfare. Adjusted odds ratios (aOR) were calculated using a multinomial analysis with stepwise reduction after adjustment for potential confounders. Compared to ≤60 hours, significant factors related to 60-79 hours and ≥80 hours per week were age groups of 30s to 50s versus 60s (aOR: 7.48-3.22 and 23.64-4.87), management with cardiovascular drugs (aOR: 1.87 and 5.80), and postoperative wound management (aOR: 0.47 and 0.16), respectively. Significantly related informed consent for surgery (aOR: 3.29) was seen in 60-79 hours. Contrarily, CS who worked for ≥80 hours took on-duty 5 times or more per month (aOR: 3.89), performed night or holiday calls 20 times or more per month (aOR: 2.26), and attended the intensive care unit (aOR: 3.12). These findings suggest that younger, and some non-surgical work-related factors could influence long working hours among CS.

Background: Bevacizumab is a promising candidate for combination treatment with epidermal growth factor receptor tyrosine-kinase inhibitors (eg, erlotinib), which could improve outcomes for patients with metastatic EGFR-mutant non-small-cell lung cancer (NSCLC). We have previously shown in NEJ026, a phase 3 trial, that the combination of bevacizumab plus erlotinib significantly prolonged progression-free survival compared with erlotinib alone in these patients. In further analyses, we aimed to examine the effects of bevacizumab-erlotinib on overall survival, time from enrolment to progressive disease during second-line treatment or death, and quality of life., Methods: This open-label, randomised, multicentre, phase 3 trial (NEJ026) was done in 69 hospitals and medical, community-based centres across Japan. Eligible patients had stage IIIB, stage IV, or postoperative recurrent, EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg point mutation) NSCLC, had not previously received systemic chemotherapy, and were randomly assigned (1:1) by a computer-generated randomisation sequence and minimisation to receive either 150 mg oral erlotinib once daily plus 15 mg/kg intravenous bevacizumab once every 21 days, or 150 mg oral erlotinib once daily, until disease progression or intolerable toxicity. Randomisation was stratified according to sex, smoking status, EGFR mutation subtype, and clinical disease stage. All participants, investigators, and study personnel (including those assessing outcomes) were unmasked to treatment allocation. We report the secondary outcomes of overall survival and quality of life (the period from enrolment to confirmation of a minimally important difference on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ]-C30), and the exploratory outcome of time from enrolment to progressive disease during second-line treatment or death. Overall survival and the exploratory outcome were analysed in the modified intention-to-treat population, which comprised all randomly assigned patients who received at least one dose of the study drug and had response evaluations. Quality of life was analysed in patients in the modified intention-to-treat population who had completed the quality of life questionnaires. The trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, UMIN000017069, and the Japan Registry of Clinical Trials, jRCTs031180056, and is currently closed., Findings: Between June 3, 2015, and Aug 31, 2016, 228 patients were enrolled. 112 patients who received bevacizumab-erlotinib and 112 who received erlotinib only were included in the modified intention-to-treat population. At data cutoff (Nov 30, 2019) and a median follow-up of 39·2 months (IQR 23·9-43·5), the median overall survival was 50·7 months (95% CI 37·3-not estimable [NE]) in the bevacizumab-erlotinib group and 46·2 months (38·2-NE) in the erlotinib-only group (hazard ratio [HR] 1·007, 95% CI 0·681-1·490; p=0·97). In analysis of the exploratory outcome, after a median follow-up of 23·9 months (IQR 14·2-39·1), the median time from enrolment to progressive disease during second-line treatment or death was 28·6 months (95% CI 22·1-35·9) in the bevacizumab-erlotinib group and 24·3 months (20·4-29·1) in the erlotinib-only group (HR 0·773, 95% CI 0·562-1·065). The median time between enrolment and confirmation of a minimally important difference on the EORTC QLQ-C30 was 6·0 months (95% CI 5·2-11·3) in the bevacizumab-erlotinib group and 8·3 months (5·7-13·9) in the erlotinib-only group (p=0·47)., Interpretation: The addition of bevacizumab to erlotinib did not prolong survival in patients with metastatic EGFR-mutant NSCLC, but both treatment groups had relatively long survival durations. Why the addition of bevacizumab to erlotinib did not affect overall survival is unclear, but it is possible that the beneficial effects of combination therapy were not seen because overall survival was influenced by treatment regimens used after disease progression., Funding: Chugai Pharmaceutical., Competing Interests: Declaration of interests TF reports personal fees from Chugai Pharmaceutical, during the conduct of the study, and personal fees from AstraZeneca and Boehringer Ingelheim, outside the submitted work. HS reports grants from Chugai Pharmaceutical, AstraZeneca, and MSD, outside the submitted work, and personal fees from Ono Pharmaceutical, Nippon Boehringer Ingelheim, and Novartis Pharma, outside the submitted work. NF reports personal fees from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Bristol-Myers Squibb, Novartis, Taiho, Kyowa Kirin, MSD, and Pfizer, outside the submitted work. SS reports personal fees from Chugai Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, MSD, Bristol-Myers Squibb, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Eli Lilly, Novartis, Kyowa Hakko Kirin, and Yakult Honsha, outside the submitted work. SI reports grants from Ono Pharmaceutical, and personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, MSD, Bristol-Myers Squibb, Eli Lilly Japan, Taiho Pharmaceutical, and Daiichi Sankyo, outside the submitted work. OY reports personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, AstraZeneca, and Eli Lilly Japan, outside the submitted work. MO reports grants from Chugai Pharmaceutical, during the conduct of the study. MS reports grants and personal fees from Chugai Pharmaceutical, during the conduct of the study. KA reports personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, Astra Zeneca, MSD Oncology, and Bristol-Myers Squibb, outside the submitted work. YTsub reports personal fees from Chugai Pharmaceuticals, AstraZeneca, and Daiichi Sankyo, outside the submitted work. YF reports personal fees from Eli Lilly, Chugai Pharmaceutical, AstraZeneca, and Bristol-Myers Squibb, outside the submitted work. SW reports grants from AstraZeneca and Boehringer Ingelheim, and personal fees from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, MSD, Taiho Pharmaceutical, Pfizer, Novartis, and Daiichi Sankyo, outside the submitted work. KH reports grants from Taiho Pharmaceutical, Ono Pharma, and MSD, personal fees from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharma, Boehringer Ingelheim, Novartis, Kyorin Pharmaceutical, and Bristol-Myers Squibb, outside the submitted work, and has a patent EGFR mutation test licensed to LSI Medience. SM reports personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Pfizer Japan, Taiho Pharmaceutical, and Ono Pharmaceutical, outside the submitted work. KK reports personal fees from AstraZeneca, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Boehringer Ingelheim, and Taiho Pharmaceutical, outside the submitted work. MMa reports grants and personal fees from Chugai Pharmaceutical during the conduct of the study, and personal fees from Chugai Pharmaceutical, AstraZeneca, Boehringer Ingelheim, and Eli Lilly, outside the submitted work. All other authors declare no competing interests, (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The indicator amino acid oxidation method is a relatively new method for determining protein requirements. Our hypothesis was that the protein requirement of the casein-whey protein mixture (70% casein and 30% whey protein) was lower than the protein requirement of plain casein, because casein and whey proteins compensate for the lack of the first-limiting amino acids. The optimal mixing ratio was determined based on the amino acid scoring pattern which is used to calculate the digestible indispensable amino acid score. In this study, digestibility was not considered to determine the optimal mixing ratio because dairy protein is a good source of digestible protein. This study aimed to evaluate the protein requirements of Japanese young men by consuming casein and casein-whey protein mixture. Ten healthy young men (22±0.2 y old) participated in 12 experiments according to a graded protein intake (0.5, 0.7, 0.9, 1.0, 1.2, 1.4 g/kg/d) of casein and casein-whey protein mixture. The mean protein requirement was calculated as the breakpoint of breath 13 CO 2 enrichment using change-point regression models. The mean protein requirements of Japanese young men by consuming casein and casein-whey protein mixture were estimated to be 1.00 g/kg/d and 0.90 g/kg/d, respectively. These estimated requirements were consistent with the protein quality expected from the amount of the first-limiting amino acids. The indicator amino acid oxidation method may be useful to evaluate protein quality.

The prevalence of Shiga toxin-producing Escherichia coli O157 (STEC O157) strains in wild deer and boar in Japan was investigated. STEC O157 strains were isolated from 1.9% (9/474) of the wild deer and 0.7% (3/426) of the wild boar examined. Pulsed-field gel electrophoresis (PFGE) analysis classified the wild deer and boar strains into five and three PFGE patterns, respectively. The PFGE pattern of one wild boar strain was similar to that of a cattle strain that had been isolated from a farm in the same area the wild boar was caught, suggesting that a STEC O157 strain may have been transmitted between wild boar and cattle. Clade analysis indicated that, although most of the strains were classified in clade 12, two strains were classified in clade 7. Whole-genome sequence (WGS) analysis indicated that all the strains carried mdfA, a drug resistance gene for macrolide antibiotics, and also pathogenicity-related genes similar to those in the Sakai strain. In conclusion, our study emphasized the importance of food hygiene in processing meat from Japanese wild animals for human consumption.

Mitigating the environmental impact of nitrogen (N) derived from agricultural production is a significant issue in our progression towards a sustainable society. This study aims to estimate the N stock (i.e., as the accumulation of N input into farmland that is neither taken up by the crops nor discharged into the environment, but rather remains in the soil) related to rice production in Japan and to identify the relationship between the economic behaviour of rice farmers and N stock. The results indicate a persistent reduction in N stock since the early 1990s, caused mainly by the change in N input by a change in government policy away from production subsidies to more extensive use of market mechanisms. It seems clear that production subsidy policies provide little incentive for farmers to reduce their N input; however, even if the introduction of market mechanisms, farmers may not properly evaluate the contribution of N stock to agricultural production. Consequently, it may be difficult to achieve the optimal level of N stock from an environmental impact perspective. To achieve the optimal N stock, the relationship between farmer behaviour and N stock needs to be better understood., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The clinical utility of plasma cell-free DNA in precision cancer medicine has not been established. A pilot study was conducted to investigate the clinical utility of comprehensive genomic profiling by liquid biopsy in a Japanese population., Methods: In this PROFILE study, 102 patients with advanced solid tumors who showed progression with standard systemic therapy underwent liquid biopsy between August 2017 and February 2020. Liquid biopsy was performed using Guardant360., Results: Of the 102 patients, 56 were women, and the median age was 65 years. Regarding the types of cancer, 31 were hepatobiliary and pancreatic cancer, 17 were gastrointestinal cancer, and 13 were breast cancer. Frequently altered genes were TP53 (53.9%, 46/102), KRAS (25.5%, 26/102), PIK3CA (19.6%, 20/102), and EGFR (17.6%, 18/102). At least one genetic aberration was detected in 92 patients (90.2%). Actionable mutation was discovered in 88 patients (86.3%), and 67 patients (65.7%) were clinical trial candidates. Of the 102 patients, 22 (21.6%) were able to receive biomarker-matched therapy. Their best responses were as follows: 1 complete response, 3 partial responses, 7 stable diseases, and 11 progressive diseases. Additionally, the treated patients were divided on the basis of matching scores (≥ 50% vs. < 50%). The patients were divided into high and low groups. The high group had a higher disease control rate (DCR) of 75% compared with 20% in the low group (P = 0.010)., Conclusions: The results indicate that liquid biopsy is useful for identifying actionable mutations associated with the clinical response of selected patients., (© 2021. Society of Surgical Oncology.)

Background: The feasibility of laparoscopic surgery for primary appendiceal tumors compared to that of open surgery has not been demonstrated to date because primary appendiceal tumors are rare. This study aimed to compare the long-term outcomes between laparoscopic and open surgeries for primary appendiceal tumors., Methods: In this multicenter retrospective cohort study, the data of patients who had been histologically diagnosed with primary appendiceal tumors at 43 tertiary hospitals in Japan between 2000 and 2017 were analyzed. In total, 922 patients were assessed, and 679 cases were eligible for analysis. Using propensity scores, the baseline characteristics were matched for 114 open surgery cases and 114 laparoscopic surgery cases. The primary endpoints were recurrence-free survival (excluding patients with stage IV disease with distant metastasis) and overall survival., Results: The rate of conversion from laparoscopic to open surgery was 1.5%. The 5-year recurrence-free survival rates were 80.4% (95% confidence interval: 71.0-89.7) and 78.2% (95% confidence interval: 69.0-87.3) in the laparoscopic and open surgery groups, respectively, with no significant difference (p = 0.57). No significant difference was observed in the 5-year overall survival rates between the laparoscopic [83.5% (95% confidence interval: 74.4-92.7)] and open surgery [72.7% (95% confidence interval: 62.3-83.0); p = 0.09] groups. In multivariate analysis, laparoscopic surgery was not identified as an independent prognostic factor for overall survival [hazard ratio: 0.49 (95% confidence interval: 0.23-1.06), p = 0.0707]., Conclusions: Laparoscopic surgery is comparable to open surgery and can be considered a treatment option for primary appendiceal tumors., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Endocytoscope systems (ECS) can visualize cellular nuclei of the mucosa of the gastrointestinal tract and are predicted to provide real-time microscopic diagnosis. However, their practical diagnostic performance remains unclear. Therefore, we conducted a multicenter prospective study to evaluate the visualization of superficial esophageal neoplasm in vivo using an ECS, and its diagnostic capability., Methods: The study target was histologically confirmed squamous cell carcinoma (SCC) and high-grade intraepithelial neoplasia (HGIN). An integrated ECS was used to obtain ECS images. In each patient, three ECS images of cancerous and corresponding noncancerous regions were selected for evaluation. A pathological review board of five certified pathologists made the final diagnosis of the images. The primary endpoint was the sensitivity of ECS diagnosis by pathologists., Results: ECS images of 68 patients were assessed: 42 lesions were mucosal SCC, 13 were submucosal SCC, and 13 were HGIN. The rate of assessable images was 96% (95% CI 87.6-99.1). The sensitivity of ECS diagnosis by pathologists was 88% (95% CI 77.2-94.5)., Conclusions: ECS can provide high-quality images of cancerous lesions and a high diagnostic accuracy by pathologists, and could be useful for real-time endoscopic histological diagnosis of SCC and HGIN., Trial Registration: The UMIN Clinical Trials Registry Identification Number: 000004218., (© 2021. The Author(s).)

Purpose: To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients., Methods: Patients in group A (aged < 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline BRCA mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety., Results: The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%-81%) and 45% (27%-65%) in groups A1 and A2, respectively, and 19% (8%-35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively., Conclusions: In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen., Trial Registration: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.

Objective: In this study, we aimed to elucidate the relationship between the duration from diagnosis to femoral head collapse and the collapse rate among patients with pre-collapse osteonecrosis of the femoral head (ONFH)., Methods: In this retrospective, observational, multicenter study, we analyzed 268 patients diagnosed with ONFH and classified them using the Japanese Investigation Committee classification. The primary endpoint was duration from the time of diagnosis to femoral head collapse for each type of ONFH., Results: The 12-, 24-, and 36-month collapse rates among participants were 0%, 0%, and 0% for type A, respectively; 0%, 2.0%, and 10.8% for type B, respectively; 25.5%, 40.8%, and 48.5% for type C-1, respectively; and 57.4%, 70.3%, and 76.7% for type C-2 ONFH, respectively. A comparison of unilateral and bilateral ONFH, using Kaplan-Meier survival curves demonstrated similar collapse rates., Conclusions: The lowest collapse rate was observed for ONFH type A, followed by types B, C-1, and C-2. Additionally, a direct association was observed between the collapse rate and location of the osteonecrotic lesion on the weight-bearing surface.

Objectives: Natriuretic peptides are an important prognostic marker in patients with heart failure (HF). However, little is known regarding their prognostic significance in patients with atrial fibrillation (AF) without HF and natriuretic peptides levels are underused in these patients in daily practice., Methods: The Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. We investigated patients with AF without HF (defined as prior HF hospitalisation, New York Heart Association functional class≥2 or left ventricular ejection fraction<40%) using the data of B-type natriuretic peptide (BNP, n=388) or N-terminal pro-B-type natriuretic peptide (NT-proBNP, n=771) at enrolment. BNPs were converted to NT-proBNP using a conversion formula. We divided the patients according to quartiles of NT-proBNP levels and compared the backgrounds and outcomes., Results: Of 1159 patients (mean age: 72.1±10.2 years, median CHA 2 DS 2 -VASc score: 3 and oral anticoagulant (OAC) prescription: 671 (56%)), the median NT-proBNP level was 488 (IQR 169-1015) ng/L. Patients with high NT-proBNP levels were older, had higher CHA 2 DS 2 -VASc scores and had more OAC prescription (all p<0.001). Kaplan-Meier curves demonstrated that NT-proBNP levels were significantly associated with higher incidences of stroke/systemic embolism, all-cause death and HF hospitalisation during a median follow-up period of 5.0 years (log rank, all p<0.001). Multivariable Cox regression analyses revealed that NT-proBNP levels were an independent predictor of adverse outcomes even after adjustment by various confounders., Conclusion: NT-proBNP levels are a significant prognostic marker for adverse outcomes in patients with AF without HF and may have clinical value., Trial Registration Number: UMIN000005834., Competing Interests: Competing interests: MAk received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare and Daiichi-Sankyo., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The conventional H category-based classification for colorectal liver metastases (CRLM) was created by equal weighting of tumor number and tumor size; however, our previous nomogram to predict postoperative disease-free survival demonstrated that CRLM ≥5 as a parameter provided 4.5 times greater impact compared with a largest CRLM size >5 cm., Methods: A total of 3815 patients newly diagnosed with CRLM between 2005 and 2007, including 2220 resectable cases, were investigated. Six groups were created based on largest lesion size (≤ 5 vs >5 cm) and lesion number (1, 2-4, and ≥5)., Results: The novel (n) H1, nH2, and nH3 categories were defined as solitary lesions with a size ≤5 cm; lesions other than nH1 or nH3; and ≥5 lesions with any lesion size, respectively. In the resectable cohort, the 5-year cumulative overall survival rates were 64.0%, 53.5%, and 42.6% in the nH1, nH2, and nH3 groups, respectively (P < .001), and no significant differences were observed between the conventional H2 and H3 categories. In the overall cohort, the discrimination ability of the two classifications were comparable., Conclusion: The novel H category-based classification might be beneficial in predicting overall survival in patients with CRLM independent of their resectability., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Aim: We aimed to assess whether frailty and diabetes-related factors could predict the occurrence of adverse events in older patients with diabetes, who constitute a patient population prone to physical decline and reductions in skeletal muscle mass., Methods: This retrospective cohort study comprised 477 patients who were being managed by outpatient diabetes care, and the reductions in their muscle strength and walking speed were assessed. Patients were evaluated using the Kihon Checklist, Mini Nutritional Assessment and Mini Mental State Examination, and followed up for 1 year, during which adverse events were monitored and confirmed from past medical records and face-to-face interviews. Intergroup comparisons of participants with and without adverse events during the observation period were undertaken by the paired-sample t-, Mann-Whitney U- and chi-square tests. Multiple logistic regression analysis, adjusted for sex and age, was conducted to determine significant predictors of adverse event incidence., Results: Overall, 12.4% (n = 59; age 74.2 ± 6.2 years) of the patients experienced adverse events. We observed significant between-group differences in the Kihon Checklist total score, walking speed, hypoglycemia episodes, nephropathy, retinopathy, and neuropathy. Microvascular complications and frailty were significant predictors of adverse event incidence (respective odds ratio [95% confidence interval]: 1.403 [1.109-1.775] per additional complication; 2.419 [1.331-4.397] for frailty; both P < 0.05)., Conclusions: In this study, we found that frailty, which was assessed using the Kihon Checklist, and the number of microvascular complications predicted adverse events in older patients with diabetes and should to be assessed. Geriatr Gerontol Int 2021; 21: 359-363., (© 2021 Japan Geriatrics Society.)

Importance: Although treatment with first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically., Objective: To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation., Design, Setting, and Participants: Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio., Interventions: The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety., Results: From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%)., Conclusions and Relevance: In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation., Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000023761.