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Background: In patients undergoing transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS), data on the differences in subsequent cardiac structure and function among stratified groups with flow gradient patterns through the aortic valve are insufficient., Methods: In this large multicenter study, 4,523 patients undergoing TAVI for severe AS between 2013 and 2019 were divided into 3 groups according to the following criteria: (1) high-gradient AS (HG-AS) (mean pressure gradient [MPG] ≥40 mmHg), (2) classical low-flow low-gradient AS (cLFLG-AS) (MPG <40 mmHg, left ventricular [LV] ejection fraction [LVEF] <50%), and (3) paradoxical low-flow low-gradient AS (pLFLG-AS) (MPG <40 mmHg, LVEF ≥50% but stroke volume index [SVi] <35 mL/m2). Echocardiography was performed at baseline, post-procedure, and 1 year post-TAVI., Results: 3,697, 507, and 319 patients had HG-AS, cLFLG-AS, and pLFLG-AS, respectively. After adjusting for clinical factors, cLFLG-AS and pLFLG-AS had an approximately 1.5-fold higher 2-year all-cause mortality compared with HG-AS. During 1 year following TAVI, compared with HG-AS, cLFLG-AS showed greater reduction of LV systolic diameter (LVDs) and LV diastolic diameter (LVDd) and greater increase of LVEF (p<0.001 for all), and changes in LV mass index (LVMi) and SVi were comparable (p=0.915 and p=0.821, respectively). However, pLFLG-AS demonstrated less reduction of LVDs and LVDd (p=0.039 and p=0.001, respectively), less improvement of LVEF and LVMi (p=0.045 and p<0.001, respectively), and comparable change in SVi (p=0.364)., Conclusions: During 1 year post-TAVI, compared with HG-AS, cLFLG-AS achieves smaller LV diameters, greater increase in LVEF, and comparable regression of LVMi, whereas pLFLG-AS does not., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Aims: Neoatherosclerosis is a leading cause of late (>1 year) stent failure following drug-eluting stent implantation. The role of biodegradable (BP) versus durable polymer (DP) drug-eluting stents on long-term occurrence of neoatherosclerosis remains unclear. Superiority of biodegradable against durable polymer current generation thin-strut everolimus-eluting stent (EES) was tested by assessing the frequency of neoatherosclerosis 3 years after primary percutaneous coronary intervention (pPCI) among patients with ST-segment elevation myocardial infarction (STEMI)., Methods: The randomized controlled, multicentre (Japan and Switzerland) CONNECT trial (NCT03440801) randomly (1:1) assigned 239 STEMI patients to pPCI with BP-EES or DP-EES. The primary endpoint was the frequency of neoatherosclerosis assessed by optical coherence tomography (OCT) at 3 years. Neoatherosclerosis was defined as fibroatheroma or fibrocalcific plaque or macrophage accumulation within the neointima., Results: Among 239 STEMI patients randomized, 236 received pPCI with stent implantation (119 BP-EES; 117 DP-EES). A total of 178 patients (75%; 88 in the BP-EES group and 90 in the DP-EES group) underwent OCT assessment at 3 years. Neoatherosclerosis did not differ between the BP-EES (11.4%) and DP-EES (13.3%; odds ratio 0.83, 95% confidence interval 0.33-2.04, p=0.69). There were no differences in the frequency of fibroatheroma (BP-EES 9.1% vs DP-EES 11.1%, p=0.66) or macrophage accumulation (BP-EES 4.5% vs DP-EES 3.3%, p=0.68), and no fibrocalcific neoatherosclerosis was observed. Rates of target lesion failure did not differ between groups (BP-EES 5.9% vs DP-EES 6.0%, p=0.97)., Conclusions: Use of BP-EES for primary PCI in patients presenting with STEMI was not superior to DP-EES regarding frequency of neoatherosclerosis at 3 years., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: This study aimed to investigate the prevalence of social frailty and associated factors., Methods: A total of 655 consecutive patients who were able to complete the Kihon Checklist (KCL) and the Questionnaire on Social Frailty between June and August 2022 were enrolled. Social frailty was assessed using the Makizako Social Frailty Index. Patient characteristics were analyzed by analysis of variance. Factors associated with social frailty were analyzed using multivariate logistic analysis. Spearman's rank correlation coefficients were used to examine correlations between each KCL domain and social frailty., Results: Mean age was 68 years, and disease duration was 12 years; 73% of patients were female. Social frailty was present in 30.8% of patients, with 36.5% classified as social pre-frailty. Multivariate analysis revealed age and HAQ-DI to be independent factors associated with social frailty. The proportion of social frailty increased with increasing age and worsening HAQ-DI scores. The KCL domain "Isolation" was the most strongly associated with social frailty (r = 0.601, P < 0.001), with higher scores associated with a higher proportion of social frailty., Conclusions: Social frailty in RA patients is associated with age and physical impairment (HAQ-DI). Moreover, the KCL domain "Isolation" was strongly associated with social frailty., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: Metastatic nonclear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with poor prognosis. The clinical characteristics and prognostic factors of immuno-oncology (IO) combination therapy for nccRCC are not well known. This study analyzed patients with metastatic nccRCC treated with IO combination therapy., Methods: We retrospectively collected data from 447 patients with metastatic RCC treated with IO-based combination therapy as first-line treatment between September 2018 and July 2023 in a Japanese multicenter study. The primary endpoints were objective response rate, progression-free survival (PFS), and overall survival (OS), comparing groups treated with IO-IO and IO-tyrosine kinase inhibitor (TKI) therapies., Results: Seventy-five patients with metastatic nccRCC were eligible for analysis: 39 were classified into the IO-IO group and 36 into the IO-TKI group. Median PFS was 5.4 months (95% CI: 1.6-9.1) for the IO-IO group and 5.6 (95% CI: 3.4-12.0) for the IO + TKI group. Median OS was 24.2 months (95% CI: 7.5-NA) for the IO-IO group and 23.4 (95% CI: 18.8-NA) for the IO + TKI group, with no significant difference. In univariate analysis, International Metastatic Renal Cell Carcinoma Database Consortium scores, Karnofsky performance status, neutrophil-to-lymphocyte ratio, and the presence of liver metastases were significantly associated with OS, whereas in multivariate analysis, only the presence of liver metastases was significantly associated with OS (P = .035)., Conclusions: There was no significant difference in OS or PFS between IO-IO and IO-TKI combination therapy as first-line treatment for patients with nccRCC. Liver metastasis is a poor prognostic factor for such patients., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although Takotsubo syndrome (TTS) is generally considered a benign disease, recent reports showed the incidence of cardiogenic shock due to left ventricular outflow tract obstruction (LVOTO), mitral regurgitation (MR), and primary pump failure was estimated to be 6-20%., Case Summary: A 78-year-old woman presented with chest pain and cold sweats 2 days after surgery for lung cancer. Acute coronary syndrome was suspected based on her symptoms, electrocardiography, transthoracic echocardiography (TTE), and laboratory data; thus, emergency catheterization was performed. Normal coronaries were observed, with hyperkinesis at the base of the left ventricle and akinesis at its apex, leading to the diagnosis of the apical ballooning type of TTS. Pressure differences between the apex of the left ventricle (168/8/28 mmHg) and aorta (94/50/64 mmHg) indicated the presence of LVOTO. Two days after TTS onset, she developed cardiogenic shock (blood pressure was 54/38 mmHg). Transthoracic echocardiography showed acute MR due to systolic anterior motion of the mitral valve caused by LVOTO, which was further exacerbated by paroxysmal atrial fibrillation. Fluid resuscitation, intravenous β-blockers, and amiodarone were administered for reduction of the pressure gradient in the left ventricular outflow, rate control, and sinus rhythm maintenance. Her condition improved along with the MR, thereby improving LVOTO and maintaining sinus rhythm., Discussion: Takotsubo syndrome should be kept in mind as a potential cause of acute MR due to LVOTO. Catheterization and multiple follow-up TTE play a major role in early detection for this condition., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Alopecia associated with lupus erythematosus is broadly classified into reversible nonscarring alopecia seen in the acute phase, such as worsening of systemic lupus erythematosus (SLE) and cicatricial alopecia seen in chronic cutaneous lupus erythematosus represented by discoid lupus erythematosus (DLE). In DLE-induced alopecia, early therapeutic intervention before developing scarring alopecia is important, but the condition is often resistant to conventional treatment. Anifrolumab (ANI), a novel therapeutic agent for SLE that inhibits Type I interferon activity, has been shown to be effective against acute skin lesions, including alopecia, in patients with SLE. However, there are very few reports on the effect of ANI on alopecia due to DLE. We report on a 27-year-old Japanese woman with SLE whose alopecia due to chronic DLE was refractory to topical therapy and systemic therapy with oral glucocorticoid, multiple immunosuppressants, and belimumab for ∼8 years after onset and whose alopecia improved with ANI. ANI can be considered to be an effective treatment option in lupus patients presenting with alopecia due to DLE, even in the chronic refractory stage., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objectives: The present study aimed to examine discrepancies between assessments based on Routine Assessment of Patient Index Data 3 (RAPID3) and Simple Disease Activity Index (SDAI) in RA patients with controlled disease activity., Methods: Data from 464 RA patients in SDAI remission or low disease activity (REM/LDA) were analyzed. Patient-reported outcome (PRO) measures, including Health Assessment Questionnaire Disability Index (HAQ-DI), 25-question Geriatric Locomotive Function Scale (GLFS-25), and Kihon checklist (KCL), were assessed. Logistic regression models were used to identify factors associated with RAPID3 moderate or high disease activity (MDA/HDA). Cutoff values of RAPID3 MDA/HDA for each PRO evaluation item were determined using receiver operating characteristic curve analysis., Results: Among RA patients in SDAI REM/LDA, 84.9% were in RAPID3 REM/LDA. Multivariable analysis revealed that HAQ-DI, GLFS-25, and KCL were independently associated with RAPID3 MDA/HDA. Subdomain analysis of KCL revealed that activities of daily living, physical function, cognitive function, and depressive mood were significantly associated with RAPID3 MDA/HDA. Cutoff values for HAQ-DI and KCL were 0.38 and 8, respectively., Conclusions: In RA patients with controlled disease activity, discrepancies between RAPID3 and SDAI assessments were observed, with factors such as HAQ-DI, GLFS-25, and KCL being independently associated with RAPID3 MDA/HDA., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Context: Existing differences in persons with lower 30- or 60-minute plasma glucose (PG) levels during 75-g oral glucose tolerance test (OGTT) than fasting PG remain unclear., Objective: To clarify the characteristics of persons whose PG levels decrease after glucose administration during OGTT and their risk of incidence of diabetes in a Japanese general population., Methods: In this cohort study, a total of 3995 men and 3500 women (mean age 56.7 years) without diabetes were classified into 3 groups: (1) PG at both 30 and 60 minutes ≥ fasting PG; (2) PG at 30 minutes ≥ fasting PG and PG at 60 minutes < fasting PG; (3) PG at 30 minutes < fasting PG. The characteristics and the risk of diabetes onset were analyzed using ordered logistic regression and Cox proportional hazard regression, respectively., Results: Among 7495 participants, the numbers of individuals in the group 1, 2, and 3 were 6552, 769, and 174, respectively. The glucose response curve of the group 3 was boat shaped. Group 3 had the youngest age, lowest percentage of men, and best health condition, followed by groups 2 and 1. Among 3897 participants analyzed prospectively, 434 developed diabetes during the mean follow-up period of 5.8 years. The hazard ratio for diabetes onset in the group 2 was 0.30 with reference to the group 1. No-one in group 3 developed diabetes., Conclusion: People with lower 30-minute PG than fasting PG tended to be women, young, healthy, and at low risk of diabetes onset., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

A 65-year-old man presented with apparent bronchopneumonia. After treatment with antibiotics, he showed eosinophilia. Computed tomography (CT) imaging revealed bilateral consolidation, ground-glass opacities with nodular consolidations, and pleural effusion. Lung biopsy showed organising pneumonia with lymphoplasmacytic infiltration in the alveolar septa and in the thickened pleura and interlobular septa. All pulmonary abnormalities spontaneously went into remission within 12 months. At 73 years old, a follow-up CT scan revealed small nodules in both lungs and the review of the head CT scan showed thickening of the pituitary stalk in studying prolonged headache. Two years later, he visited the hospital complaining of severe oedema on the lower extremities with high serum immunoglobulin (Ig)G4 186 mg/dl. A whole-body CT scan showed retroperitoneal mass surrounding aortic bifurcation and compressing inferior vena cava, pituitary stalk thickening and gland swelling, and enlarged pulmonary nodules. Anterior pituitary stimulation tests showed central hypothyroidism, central hypogonadism, and adult growth hormone deficiency with partial primary hypoadrenocorticism. Retroperitoneal mass biopsy showed storiform fibrosis and obliterative phlebitis with marked lymphoplasmacytic infiltration with moderate IgG4-positivity. Immunostaining of the former lung specimen revealed dense interstitial infiltration of IgG4-positive cells. These findings indicated metachronous development of IgG4-related disease in lung, hypophysis, and retroperitoneum, according to the recent comprehensive diagnostic criteria of IgG4-related disease. Glucocorticoid therapy ameliorated oedema, on the other hand, unmasked partial diabetes insipidus at the initial dose of the treatment. Hypothyroidism and retroperitoneal mass regressed at 6 months of the treatment. This case warns us that long-term follow-up from prodromal to remission is necessary for the treatment of IgG4-related disease., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Zolpidem (ZOL) is a short-acting hypnotic that is sometimes used in drug-facilitated crimes such as sexual assaults, robbery and homicides. Therefore, it is important to understand the metabolism of ZOL. This study quantified ZOL and its metabolites, including two carboxylic acids (zolpidem phenyl-4-carboxylic acid [M1] and 6-carboxylic acid [M2]) and four hydroxyzolpidems (4-(hydroxymethyl)phenyl zolpidem [M3], 6-hydroxymethyl zolpidem [M4], 7-hydroxyzolpidem [7OH] and 8-hydroxyzolpidem [8OH]) in postmortem urine using liquid chromatography--triple quadrupole mass spectrometry. The concentration of M1 was highest in all cases, followed by total 7OH in five of six samples. The concentrations of M2 and total M4 were relatively high. Most of M4 and 8OH were excreted as conjugates, whereas up to 55% of 7OH was excreted in its free form. Peaks corresponding to zolpidem dihydrodiol (ZHDH), dihydro(hydroxy)zolpidem cysteine adduct (DHZCys) and zolpidem cysteine adduct (ZCys) were also detected in all the urine samples. ZDHD was excreted as conjugates, whereas almost all DHZCys and ZCys were in their free form., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Endoscopic duodenal stent placement is an alternative technique to gastrojejunostomy for gastric outlet obstruction due to pancreatic cancer. We compared the efficacy of endoscopic duodenal stent placement with that of gastrojejunostomy for treating patients with pancreatic cancer who are candidates for intensive combination chemotherapies as the first line of treatment., Methods: This retrospective observational study included 100 patients from 18 institutions in Japan. Inclusion criteria were as follows: (1) cytologically or histologically confirmed adenocarcinoma of the pancreas, (2) good performance status, (3) gastric outlet obstruction scoring system score of 0-1 and (4) no history of treatment for pancreatic cancer., Results: There was no significant difference in the background characteristics of patients in the endoscopic duodenal stent placement (n = 57) and gastrojejunostomy (n = 43) groups. The median overall survival in the endoscopic duodenal stent placement and gastrojejunostomy groups was 5.9 and 6.0 months, respectively. Clinical success was achieved in 93 cases; the median time to food intake resumption was significantly shorter in the endoscopic duodenal stent placement group (median: 3 days, n = 54) than in the gastrojejunostomy group (median: 5 days, n = 43). Chemotherapy was introduced in 63% of the patients in both groups after endoscopic duodenal stent placement or gastrojejunostomy. Chemotherapy was started earlier in the endoscopic duodenal stent placement group (median: 14 days) than in the gastrojejunostomy (median: 32 days) group., Conclusions: Endoscopic duodenal stent placement showed similar or better clinical outcomes than gastrojejunostomy. Thus, it might be a promising option in patients with good performance status., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Olanzapine is an inexpensive and durable agent for the treatment of chemotherapy-induced nausea and vomiting and is also superior to neurokinin-1 receptor antagonists in the control of nausea. This study aimed to investigate the efficacy and safety of a low dose of 5 mg olanzapine plus granisetron and dexamethasone for treatment of carboplatin (CBDCA)-induced nausea and vomiting in patients with thoracic malignancies., Materials and Methods: We conducted a prospective, open-label, single-arm, multicenter, phase II trial in four centers in Japan. Registered patients were scheduled to receive area under the curve (AUC) ≥5 mg/mL per minute of CBDCA and had never received moderately to highly emetogenic chemotherapy. Patients received olanzapine 5 mg/day orally after supper for 4 days, in combination with granisetron and dexamethasone. Primary endpoint was complete response (CR; no emesis and no use of rescue medication) rate during the overall phase (0-120 hours)., Results: Between February 2018 and June 2020, 51 patients were enrolled, and 50 patients were evaluated. The CR rates in the overall (0-120 hours), acute (0-24 hours), and delayed phases (24-120 hours) were 94.0%, 100%, and 94.0%, respectively. No grade 3 or higher adverse effects of olanzapine were observed., Conclusion: Prophylactic antiemetic therapy with a low dose of 5 mg olanzapine plus granisetron and dexamethasone showed durable efficacy with an acceptable safety profile. This three-drug combination appears to be a reasonable treatment approach in patients with thoracic malignancies receiving an AUC ≥5 mg/mL per minute of CBDCA-based regimen. Clinical trial identification number: UMIN000031267., Implications for Practice: The results of this phase II trial indicated that the prophylactic administration of low-dose of 5 mg olanzapine combined with granisetron and dexamethasone has promising activity with acceptable safety profile in patients with thoracic malignancy receiving high-dose carboplatin chemotherapy., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Lessons Learned: The 3-year disease-free survival rate of the twice-daily regimen was not inferior to that of the conventional three-times-daily regimen, and the twice-daily regimen did not lead to an increase in adverse events. The effectiveness of the twice-daily regimen highlights an increased number of treatment options for patients. This will facilitate personalized medicine, particularly for elderly or frail patients who may experience more severe side effects from the combination therapy., Background: Tegafur-uracil (UFT)/leucovorin calcium (LV) is an adjuvant chemotherapy treatment for colorectal cancer. We conducted a multicenter randomized trial to assess the noninferiority of a twice-daily compared with a three-times-daily UFT/LV regimen for stage II/III colorectal cancer in an adjuvant setting., Methods: Patients were randomly assigned to group A (three doses of UFT [300 mg/m 2 per day]/LV [75 mg per day]) or B (two doses of UFT [300 mg/m 2 per day]/LV [50 mg per day]). The primary endpoint was 3-year disease-free survival., Results: In total, 386 patients were enrolled between July 28, 2011, and September 27, 2013. The 3-year disease-free survival rates of group A (n = 194) and B (n = 192) were 79.4% and 81.4% (95% confidence interval, 72.6-84.4-74.5-85.9), respectively. The most common grade 3/4 adverse events in group A and B were diarrhea (3.9% vs. 7.3%), neutropenia (2.9% vs. 1.6%), increase in aspartate aminotransferase (4.0% vs. 3.9%), increase in alanine aminotransferase (6.2% vs. 6.8%), nausea (1.7% vs. 3.4%), and fatigue (1.1% vs. 2.3%)., Conclusion: Group B outcomes were not inferior to group A outcomes, and adverse events did not increase., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Objectives: With improvements in the outcome of treatment for non-small-cell lung cancer (NSCLC), other diseases may account for a high death rate after surgery in patients with stage I NSCLC. In the present study, we analysed the associations between the clinical factors and non-cancer death after surgery in these patients., Methods: The records of 514 patients with stage I NSCLC who underwent surgery were retrospectively reviewed; a proportional hazards model for the subdistribution of a competing risk was conducted to define the risk factors for non-cancer death., Results: The mean patient age was 67 years. A total of 367 patients (71%) underwent bilobectomy or lobectomy while 147 (29%) underwent sublobar resection. The pathological stage was IA in 386 (75%) and IB in 128 (25%) patients. Three patients (0.6%) died within 90 days after surgery, and 108 (21%) experienced postoperative complications. Until the time of writing this report, 83 patients had died during the follow-up. The cause of death was primary lung cancer in 38 (46%) patients and other diseases in 45 (54%) patients, including non-cancer causes in 29 patients, such as pneumonia, cardiac death and cerebral stroke. According to a multivariable competing risk analysis for non-cancer death age (≥70 years), sex (male), body mass index (BMI <18.5), postoperative complications and % forced expiratory volume in 1 s (<80) were identified as risk factors for postoperative non-cancer death., Conclusions: Advanced age (≥70 years), male sex, low BMI (<18.5), postoperative complications and low preoperative % forced expiratory volume in 1 s (<80) were found to be the risk factors for postoperative non-cancer death after surgery in patients with stage I NSCLC., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Context: Adrenal venous sampling (AVS) is the current criterion standard lateralization technique in primary aldosteronism (PA). Japanese registry data found that 30% of patients with unilateral PA did not undergo adrenalectomy, but the reasons for this and whether the same pattern is seen internationally are unknown., Objective: To assess the rate of AVS-guided adrenalectomy across an international cohort and identify factors that resulted in adrenalectomy not being performed in otherwise eligible patients., Design, Setting, and Participants: Retrospective, multinational, multicenter questionnaire-based survey of management of PA patients from 16 centers between 2006 and 2018., Main Outcome Measures: Rates of AVS implementation, AVS success rate, diagnosis of unilateral PA, adrenalectomy rate, and reasons why adrenalectomy was not undertaken in patients with unilateral PA., Results: Rates of AVS implementation, successful AVS, and unilateral disease were 66.3%, 89.3% and 36.9% respectively in 4818 patients with PA. Unilateral PA and adrenalectomy rate in unilateral PA were lower in Japanese than in European centers (24.0% vs 47.6% and 78.2% vs 91.4% respectively). The clinical reasoning for not performing adrenalectomy in unilateral PA were more likely to be physician-derived in Japan and patient-derived in Europe. Physician-derived factors included non-AVS factors, such as good blood pressure control, normokalemia, and the absence of adrenal lesions on imaging, which were present before AVS., Conclusion: Considering the various unfavorable aspects of AVS, stricter implementation and consideration of surgical candidacy prior to AVS will increase its diagnostic efficiency and utility., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Over the last two decades, extensive studies have been performed at the molecular level to understand the evolution of carnivorous plants. As fruits, the repertoire of protein components in the digestive fluids of several carnivorous plants have gradually become clear. However, the quantitative aspects of these proteins and the expression mechanisms of the genes that encode them are still poorly understood. In this study, using the Australian sundew Drosera adelae, we identified and quantified the digestive fluid proteins. We examined the expression and methylation status of the genes corresponding to major hydrolytic enzymes in various organs; these included thaumatin-like protein, S-like RNase, cysteine protease, class I chitinase, β-1, 3-glucanase, and hevein-like protein. The genes encoding these proteins were exclusively expressed in the glandular tentacles. Furthermore, the promoters of the β-1, 3-glucanase and cysteine protease genes were demethylated only in the glandular tentacles, similar to the previously reported case of the S-like RNase gene da-I. This phenomenon correlated with high expression of the DNA demethylase DEMETER in the glandular tentacles, strongly suggesting that it performs glandular tentacle-specific demethylation of the genes. The current study strengthens and generalizes the relevance of epigenetics to trap organ-specific gene expression in D. adelae. We also suggest similarities between the trap organs of carnivorous plants and the roots of non-carnivorous plants., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Background: The role of antithrombotic chemoprophylaxis in prevention of venous thromboembolism (VTE) in laparoscopic surgery for gastric and colorectal malignancies is unknown. This study compared the addition of enoxaparin following intermittent pneumatic compression (IPC) with IPC alone in patients undergoing laparoscopic surgery for gastrointestinal malignancy., Methods: In this multicentre RCT, eligible patients were older than 40 years and had a WHO performance status of 0 or 1. Exclusion criteria were prescription of antiplatelet or anticoagulant drugs and history of VTE. Patients were allocated to IPC or to ICP with enoxaparin in a 1 : 1 ratio. Stratification factors included sex, location of cancer, age 61 years and over, and institution. Enoxaparin was administered on days 1-7 after surgery. Primary outcome was VTE, evaluated by multidetector CT on day 7., Results: Of 448 patients randomized, 208 in the IPC group and 182 in the IPC with enoxaparin group were evaluated. VTE occurred in ten patients (4·8 per cent) in the IPC group and six (3·3 per cent) in the IPC with enoxaparin group (P = 0·453). Proximal deep vein thrombosis and/or pulmonary embolism occurred in seven patients (3·4 per cent) in the IPC group and one patient (0·5 per cent) in the IPC with enoxaparin group (P = 0·050). All VTE events were asymptomatic and non-fatal. Bleeding occurred in 11 of 202 patients in the IPC with enoxaparin group, and one patient needed a transfusion. All bleeding events were managed by discontinuation of the drug., Conclusion: IPC with enoxaparin after laparoscopic surgery for gastric and colorectal malignancies did not reduce the rate of VTE. Registration number: UMIN000011667 ( https://www.umin.ac.jp/)., (© 2020 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of British Journal of Surgery Society.)

Fungal pneumonia is a common disease in bottlenose dolphins (Tursiops truncatus), including pregnant and lactating ones. Voriconazole (VRCZ) is commonly used to treat respiratory fungal infections in this species; however, it is unknown whether VRCZ is transferred via the placenta and breastmilk and whether its usage is safe in pregnant and lactating dolphins. We measured VRCZ concentrations in breastmilk and dams', umbilical cord, and calves' plasma samples from four dam-calf dolphin pairs in the Port of Nagoya Public Aquarium, Japan, treated with or without VRCZ. Three pregnant and/or lactating dams were administered VRCZ (loading dose 1.5-2.3 mg/kg, for 3 days; maintenance dose 1.5-3.1 mg/kg, every 5-18 days), twice daily, orally, without side effects in dams or calves. VRCZ was detected in two dams' umbilical cord plasma (0.14 and 2.35 μg/ml) and in one calf's plasma (0.18 μg/ml), collected immediately after birth. Further, VRCZ was detected in breastmilk samples (maximum 13.45 μg/ml) from three VRCZ-administered dams and in plasma from three calves (maximum 7.54 μg/ml) given or nursed from VRCZ-administered dams' breastmilk. The calves' plasma VRCZ concentrations varied, depending on the amount of breastmilk and food consumed. VRCZ concentrations were higher in breastmilk samples than in dams' plasma. To our knowledge, this is the first report on placental and breastmilk VRCZ transfer to offspring in bottlenose dolphins. During VRCZ medication in pregnant and lactating bottlenose dolphins, it is crucial to monitor plasma VRCZ concentrations and any side effects in dams as well as in their calves., (© The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Aims: It is still unclear which enzymes contribute to the adaptive enhancement of alcohol metabolism by chronic alcohol consumption (CAC). ADH1 (Class I) has the lowest Km for ethanol and the highest sensitivity for 4-methylpyrazole (4MP) among ADH isozymes, while ADH3 (Class III) has the highest Km and the lowest sensitivity. We investigated how these two major ADHs relate to the adaptive enhancement of alcohol metabolism., Methods: Male mice with different ADH genotypes (WT, Adh1-/- and Adh3-/-) were subjected to CAC experiment using a 10% ethanol solution for 1 month. Alcohol elimination rate (AER) was measured after ethanol injection at a 4.0 g/kg dose. 4MP-sensitive and -insensitive AERs were measured by the simultaneous administration of 4MP at a dose of 0.5 mmol/kg in order to estimate ADH1 and non-ADH1 pathways., Results: AER was enhanced by CAC in all ADH genotypes, especially more than twofold in Adh1-/- mice, with increasing ADH1 and/or ADH3 liver contents, but not CYP2E1 content. 4MP-sensitive AER was also increased by CAC in WT and Adh3-/- strains, which was greater in Adh3-/- than in WT mice. The sensitive AER was increased even in Adh1-/- mice probably due to the increase in ADH3, which is semi-sensitive for 4MP. 4MP-insensitive AER was also increased in WT and Adh1-/- by CAC, but not in Adh3-/- mice., Conclusion: ADH1 contributes to the enhancement of alcohol metabolism by CAC, particularly in the absence of ADH3. ADH3 also contributes to the enhancement as a non-ADH1 pathway, especially in the absence of ADH1., (© The Author(s) 2019. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background: Relationships between blood glucose (BG) levels and insulin action, and incidence of hypertension have not been well known epidemiologically. This study aimed to investigate the association between indices of diabetes and the incidence of hypertension and compare the predictive powers of these indices in middle-aged Japanese., Methods: This 5-year cohort study included 2,210 Japanese aged 30-64 years without hypertension. Hazard ratios of high fasting blood glucose (FBG) levels, high post-loaded BG levels, high glycated hemoglobin (HbA1c) levels, insulin resistance (defined by homeostasis model assessment of insulin resistance [HOMA-IR]) and impaired insulin secretion at baseline for the incidence of hypertension were estimated using multivariable-adjusted Cox proportional hazard models. Hypertension was defined as blood pressure ≥ 140/90 mm Hg or receiving antihypertensive treatment., Results: During the follow-up, 456 participants developed hypertension. After adjustment for HbA1c and HOMA-IR, FBG was independently and significantly associated with hypertension. The hazard ratio of participants with FBG ≥ 7.0 mmol/l was 1.79 compared with those with FBG < 5.6 mmol/l. Even among those with HbA1c < 6.5%, HOMA-IR < 2.5, body mass index < 25 kg/m2, age < 55 years old, blood pressure < 130/80 mm Hg or non- and moderate drinking, the results were similar. High 120-minute BG level and impaired insulin secretion did not increase the risk for hypertension., Conclusions: FBG was a predictable index for future incidence of hypertension in middle-aged Japanese men and women. This is the first study comparing predictive powers of indices of diabetes for the incidence of hypertension., (© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: The objective of this study was to evaluate the validity of Eurolung risk models in a Japanese population and assess their utility as predictive indicators for the prognosis., Methods: Between 2007 and 2014, 612 anatomic lung resections were performed among 694 lung cancer patients in our institution. We analysed the cardiopulmonary morbidity and mortality and compared them with the predicted results. We also investigated the association between the Eurolung aggregate risk scores and the long-term outcomes using the Kaplan-Meier method and a multivariable analysis., Results: The percentage of cardiopulmonary complications was lower than that predicted by Eurolung 1 (22.4% vs 24.6%). The mortality rate was significantly lower than predicted by Eurolung 2 (0.7% vs 3.0%). The morbidity rate was stratified by Aggregate Eurolung 1. The stratification of the mortality rate by the Eurolung 2 aggregate score was also in line with the increase in score, although the observed number of deaths was quite small (4 cases). The 5-year overall survival was clearly separated according to the stratified Aggregate Eurolung 1 and 2 (P < 0.01 and P < 0.01, respectively). Besides pathological stage, both the Aggregate Eurolung 1 (score 0-7 vs 8-20) and 2 (score 0-8 vs 9-19) scores were shown to be independently associated with overall survival on multivariable., Conclusions: Eurolung risk models cannot be directly applied to the patients in our institution. However, Eurolung aggregate risk scores were helpful not only for stratifying morbidity and mortality after anatomic lung resection but also for predicting the long-term outcomes., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Context: Adrenal tumors (ATs), even those diagnosed as nonfunctioning, may cause metabolic disorders. Some primary aldosteronism (PA) patients with ATs are diagnosed with bilateral PA based on adrenal venous sampling (AVS), and their ATs are apparently nonfunctioning., Objective: To clarify the influence of apparently nonfunctioning ATs, we compared hormone levels and clinical complications between bilateral PA cases with and without ATs., Design, Setting, and Participants: After retrospectively assessing 2814 patients with PA in the multicenter Japan PA study, bilateral PA cases on AVS were divided into cases with and without ATs by computed tomography findings. Importantly, patients with cortisol levels >1.8 µg/dL after the 1-mg dexamethasone suppression test (DST) were excluded. Clinical characteristics and biochemical data were compared between them. The correlation between AT size and hormone levels was also analyzed., Main Outcome Measures: Analyzed were 196 bilateral PA patients with ATs and 331 those without ATs. Although basal cortisol and aldosterone levels were similar between them, cortisol levels after the 1-mg DST and the prevalences of diabetes mellitus and proteinuria were significantly higher and ACTH levels and plasma renin activity were significantly lower in cases with ATs than in those without. After adjusting for patients' backgrounds, cortisol levels after the 1-mg DST and plasma renin activity remained significantly different between them. Moreover, cortisol levels after the 1-mg DST and ACTH levels correlated with AT size., Conclusions: Apparently nonfunctioning ATs in bilateral PA cases may cause latent autonomous cortisol secretion, inducing diabetes and proteinuria., (Copyright © 2019 Endocrine Society.)

Objectives: The aim of this study was to identify risk factors to predict a biochemical recurrence (BCR) in patients treated with salvage radiation therapy (SRT) after radical prostatectomy (RP)., Methods: We retrospectively reviewed 122 Japanese patients who received SRT for BCR after RP. Using uni- and multivariate Cox proportional hazard models, we identified the predictive factors of BCR after SRT., Results: With a median follow-up of 61.3 months, 45.9% of the patients showed BCR after SRT, with 61.5 and 41.8% of non-BCR rates at the second and fifth years. Univariate proportional hazards analysis demonstrated that extraprostatic disease (P = 0.029), seminal vesicle invasion (P = 0.005), microvascular invasion (P = 0.001), postoperative Gleason score (P = 0.008) and pre-SRT prostate-specific antigen (PSA) (P = 0.005) were significantly associated with BCR after SRT. However, only the presence of microvascular invasion and a higher pre-SRT PSA were significant predictors in the multivariate analysis. The non-BCR rate in the second year after SRT for 15 patients with microvascular invasion and pre-SRT PSA > 1.2 ng/ml was only 21% compared to 72.5% of 72 patients with negative microvascular invasion and a pre-SRT PSA of <1.2 ng/ml (P = 0.000031)., Conclusions: While SRT is the most important secondary treatment option for patients with BCR after RP, the effectiveness of SRT may not be uniform. The combination of risk factors such as microvascular invasion in RP specimens and pre-SRT PSA may provide a better way to stratify the risk of BCR after SRT., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The aim of this study was to study the prognostic significance of tertiary Gleason grade (TGG) 5 in patients with clinically localized prostate cancer treated with robot-assisted radical prostatectomy (RARP)., Methods: A total of 600 Japanese patients who underwent RARP for clinical stage T1-3N0M0 prostate cancer were evaluated. TGG5 was evaluated according to the International Society of Urological Pathology criterion. Cox hazard regression was used to evaluate the prognostic significance of prostate-specific antigen and pathological features in RARP specimens., Results: Of the 600 RARP specimens, 92 (15%) had TGG5. TGG5 component was found in 30 (10%) of 287 cases with Gleason score (GS) 3 + 4, 55 (37%) of 149 cases with GS 4 + 3 and 7 (17%) of 40 cases with GS 4 + 4. There were no significant differences in pathological stage and surgical margin status between GS 3 + 4 with and without TGG5, as well as between GS 4 + 4 with and without TGG5. Of the 600 patients, 92 (15%) patients had biochemical recurrence (BCR) after surgery, with a median follow-up period of 42 (3-104) months. There were no differences in 5-year BCR-free survival rates between patients with GS 3 + 4 with and without TGG5 (92 vs. 100%, P = 0.16), as well as between patients with GS 4 + 3 with and without TGG5 (79 vs. 71%, P = 0.30). Similarly, there were no differences in 3-year BCRFS rates between patients with GS 4 + 4 with and without TGG5 (80 vs. 71%, P = 0.38)., Conclusions: In our population, the presence of TGG5 in RARP specimens had no strong impact on pathological and prognostic outcomes., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Receptor-regulated SMAD (R-SMAD: SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8) proteins are key transcription factors of the transforming growth factor-β (TGF-β) superfamily of cytokines. MAN1, an integral protein of the inner nuclear membrane, is a SMAD cofactor that terminates TGF-β superfamily signals. Heterozygous loss-of-function mutations in MAN1 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis. MAN1 interacts with MAD homology 2 (MH2) domains of R-SMAD proteins using its C-terminal U2AF homology motif (UHM) domain and UHM ligand motif (ULM) and facilitates R-SMAD dephosphorylation. Here, we report the structural basis for R-SMAD recognition by MAN1. The SMAD2-MAN1 and SMAD1-MAN1 complex structures show that an intramolecular UHM-ULM interaction of MAN1 forms a hydrophobic surface that interacts with a hydrophobic surface among the H2 helix, the strands β8 and β9, and the L3 loop of the MH2 domains of R-SMAD proteins. The complex structures also show the mechanism by which SMAD cofactors distinguish R-SMAD proteins that possess a highly conserved molecular surface.

Context: Recently, the relationship between primary aldosteronism (PA) and various metabolic disorders, including obesity, diabetes mellitus, and dyslipidemia, has been discussed. However, in PA, aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) have different etiologies., Objective: Our objectives were to clarify differences in obesity and metabolic disorders between APA and IHA and to gain insight in the pathogenesis of IHA., Design, Setting, and Participants: This is a retrospective cross-sectional study. We assessed the PA database established by the multicenter Japan Primary Aldosteronism Study. For comparative analysis, data were also collected from 274 patients with essential hypertension (EHT)., Main Outcome Measures: We compared prevalences of obesity and metabolic disorders between patients with APA and patients with IHA. Comparisons with sex-, age-, and blood pressure-matched patients with EHT were also performed. Correlations between metabolic parameters and plasma aldosterone concentrations (PACs) in each subtype were analyzed., Results: Analysis of 516 patients with APA and 1015 patients with IHA revealed PACs were significantly higher in patients with APA than patients with IHA. By contrast, after we adjusted for clinical backgrounds, the prevalence of obesity was significantly higher in patients with IHA than in patients with APA or EHT. Although the prevalences of diabetes mellitus and dyslipidemia did not significantly differ between patients with IHA and patients with APA, triglyceride and HbA1c were significantly higher in patients with IHA than in patients with APA. There was no significant correlation between metabolic parameters and PACs in either subtype., Conclusions: Patients with IHA tend to be obese despite lower PACs than in patients with APA. The present results suggest that obesity-related factors contribute to the pathogenesis of IHA.

Purpose: To investigate the impact of the time interval (TI) between prostate biopsy and robot-assisted radical prostatectomy (RARP) on the risk of biochemical recurrence (BCR)., Methods: We retrospectively reviewed the medical records of 793 consecutive patients who were treated with RARP at our institution. Patients were divided into three groups, according to TI, to compare BCR-free survival (BCRFS) rates: Group 1 (n = 196), TI < 3 months; Group 2 (n = 513), 3 ≤ TI < 6 months; Group 3 (n = 84), TI ≥ 6 months. Eighty-three patients with TI ≥ 6 months were matched with an equal number of patients with TI < 6 months based on propensity scores by using four preoperative factors: prostate-specific antigen (PSA), primary (pGS) and secondary (sGS) Gleason score and positive prostate biopsy., Results: The 5-year BCRFS rates for TI Groups 1, 2, and 3 were 76%, 80.7% and 82.6% (P = 0.99), respectively. The multivariate analysis revealed that PSA, pGS, sGS and a positive prostate biopsy were independent preoperative risk factors for BCR. The propensity adjusted 5-year BCRFS for patients with TI ≥ 6 months was 84.0%. This was not worse than that of patients with TI < 6 months (71.0%, P = 0.18)., Conclusions: In our cohorts, a delay in the time from biopsy to RARP did not significantly affect recurrence. Therefore, hasty treatment decisions are unnecessary for at least 6 months after diagnosis of early prostate cancer., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objective: To estimate cumulative incidence and mortality risk for gastric cancer by risk category., Methods: Risk was classified into four types according to the presence/absence of Helicobacter pylori infection and chronic atrophic gastritis: in order of lowest to highest risk, Group A: H. pylori(-) and atrophic gastritis(-); Group B: H. pylori(+) and atrophic gastritis(-); Group C:H. pylori(+) and atrophic gastritis(+); and, Group D: H. pylori(-) and atrophic gastritis(+). We used vital statistics for the crude all-cause and crude gastric cancer mortality rates in 2011 and data from population-based cancer registries (the Monitoring of Cancer Incidence in Japan) for gastric cancer incidence in 2011. For relative risk and prevalence, we used the results of a meta-analysis integrating previous studies and data from the Japan Public Health Center-based Prospective Study for the Next Generation, respectively (baseline survey 2011-16). We calculated the crude incidence and mortality rates and estimated the cumulative risk using a life-table method., Results: The estimated lifetime cumulative incidence risk was 11.4% for men and 5.7% for women. The estimated risk for Groups A, B, C and D was 2.4%, 10.8%, 26.7% and 35.5% for men, and 1.2%, 5.5%, 13.5% and 18.0% for women, respectively. Similarly, the estimated lifetime cumulative mortality risk was 3.9% for men and 1.8% for women. The estimated risk of mortality for Groups A, B, C and D was 0.8%, 3.6%, 9.0% and 12.0% for men, and 0.4%, 1.7%, 4.2% and 5.7% for women, respectively., Conclusions: Our results may be useful for designing individually tailored prevention programs., (© The Author 2017. Published by Oxford University Press.)

Background: In ST-elevation myocardial infarction (STEMI) patients with diffuse ectatic coronary artery, extensive thrombi inhibit achievement of final successful revascularization of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow after primary percutaneous coronary intervention. However, clinical and angiographic outcomes of such patients are uncertain. The present study examined clinical and angiographic outcomes in STEMI incorporating giant coronary artery with diffuse ectasia., Methods: Seven hundred and forty-four STEMI patients undergoing primary percutaneous coronary intervention were surveyed retrospectively. Culprit lesions in giant coronary artery with diffuse ectasia (Ectatic group, n=39) were investigated. Percutaneous coronary intervention success rate and angiographic or clinical outcomes at 360 days were compared with those of the Non-ectatic group ( n=705)., Results: Angiographic percutaneous coronary intervention success rate was significantly lower in the Ectatic group due to lower achievement of final TIMI grade 3 flow (53.8% vs. 92.9%, p<0.0001; 53.8% vs. 93.5%, p<0.0001, respectively). In follow-up angiography, 86% of the Ectatic group showed angiographic improvement from TIMI grade 2 or less immediately after percutaneous coronary intervention to TIMI grade 3 flow at follow-up. In contrast, angiographic improvement was observed in only 25% of cases in the Non-ectatic group. All-cause 360-day mortality was significantly lower in the ectatic group (2.6% vs. 14.5%, p=0.0361, respectively)., Conclusion: In patients with STEMI in giant coronary artery with diffuse ectasia, achievement of TIMI grade 3 flow was significantly reduced immediately after percutaneous coronary intervention. However, improvement of coronary flow up to TIMI grade 3 was not uncommon at follow-up angiogram. Patients had low mortality despite low TIMI grade 3 achievement immediately after primary percutaneous coronary intervention.

Background: There are few recent data on trends in childhood cancer incidence using population-based cancer registries in Japan., Methods: This study comprised 6110 reported cases of patients aged 0-14 years who were diagnosed as having primary cancer between 1993 and 2009. We chose cancer registries of seven prefectures, according to the international cancer registry standard of fewer than 10% death certificate only cases among cancer registries in Japan. We analyzed population-based cancer registration data in the seven prefectures between 1993 and 2009. We calculated childhood cancer incidence, age-specific incidence, crude incidence rate, age-adjusted incidence rate, confidence intervals and annual change for each prefecture and classified the data into 12 diagnostic groups, according to the International Classification of Childhood Cancer (ICCC)., Results: According to sex-specific incidence, males accounted for slightly more cases than females. Children 0-3 years old accounted for 41.1% of patients. Leukemia accounted for 36.0% of cancers, followed by central nervous system tumors with 15.0%, according to the ICCC. The crude incidence rate did not change substantially, remaining at an average 8-11 per 100 000 population. In addition, the age-adjusted incidence rate remained constant with an average 2 per 100 000 population., Conclusions: Using population-based cancer registry data, age-specific incidence and 12 diagnostic groups according to the ICCC showed characteristics of childhood cancers. The incidence rate of childhood cancers has been nearly stable in Japan over the past 15 years., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

A new randomized Phase III trial, the Japan Clinical Oncology Group (JCOG) 1408, which compares two dose fractionations (JCOG 0403 and JCOG 0702) for medically inoperable Stage IA NSCLC or small lung lesions clinically diagnosed as primary lung cancer, involves the introduction of a prescribed dose to the D 95% of the planning target volume (PTV) using a superposition/convolution algorithm. Therefore, we must determine the prescribed dose in the D 95% prescribing method to begin JCOG1408. JCOG 0702 uses density correction and the D 95% prescribing method. However, JCOG 0403 uses no density correction and isocenter- prescribing method. The purpose of this study was to evaluate the prescribed dose to the D 95% of the PTV equivalent to a dose of 48 Gy to the isocenter (JCOG 0403) using a superposition algorithm. The peripheral isodose line, which has the highest conformity index, and the D 95% of the PTV were analyzed by considering the weighting factor, i.e. the inverse of the difference between the doses obtained using the superposition and Clarkson algorithms. The average dose at the isodose line of the highest conformity index and the D 95% of the PTV were 41.5 ± 0.3 and 42.0 ± 0.3 Gy, respectively. The D 95% of the PTV had a small correlation with the target volume (r 2  = 0.0022) and with the distance between the scatterer and tumor volumes (r 2  = 0.19). Thus, the prescribed dose of 48 Gy using the Clarkson algorithm (JCOG0403) was found to be equivalent to the prescribed dose of 42 Gy to the D 95% of the PTV using the superposition algorithm., (© The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Aim: Whether high platelet reactivity (HPR) immediately after diagnostic angiography is associated with worse coronary reperfusion prior to and after primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) is unknown. This study aimed to assess the impact of P2Y12-mediated HPR on angiographic outcomes in patients with STEMI undergoing PPCI., Methods: STEMI patients undergoing PPCI and pretreated with a P2Y12 receptor antagonist underwent platelet function testing with the VerifyNow™ assay at the time of angiography. Light transmission aggregometry (LTA) was performed in a subgroup. HPR was defined according to expert consensus definitions. Pre-PCI coronary patency, thrombotic burden and indices of impaired post-PCI reperfusion were compared between HPR and non-HPR patients., Results: Among 164 patients, the prevalence of VerifyNow™-derived HPR was 71.3% at a median (interquartile range (IQR)) of 55 (40-75) minutes after a P2Y12 inhibitor loading dose. Compared with non-HPR patients, those with HPR had significantly lower rates of pre-PCI Thrombolysis in Myocardial Infarction (TIMI) flow grades 2 or 3 (51.1% vs. 32.5%, p = 0.04), higher rates of thrombus score (TS) grade 3/4 (29.8% vs. 52.1%, p = 0.015) and 4 (14.9% vs. 32.5%, p = 0.037) and lower median (IQR) corrected TIMI frame count (cTFC; 23.2 (15.8-32.5) vs. 26.0 (21.0-35.0), p = 0.02), respectively. These findings were consistent using LTA-based data. HPR and TS grade 4 were predictors of higher cTFC., Conclusions: In patients with STEMI undergoing PPCI pretreated with P2Y12 receptor inhibitors, pre-PPCI HPR was found to be associated with lower pre-PCI coronary patency, higher thrombotic burden and a worse index of post-PCI coronary reperfusion., (© The European Society of Cardiology 2016.)

The centromeres of many eukaryotic chromosomes are established epigenetically on potentially variable tandem repeats; hence, these chromosomes are at risk of being acentric. We reported previously that artificially created acentric chromosomes in the fission yeast Schizosaccharomyces pombe can be rescued by end-to-end fusion with functional chromosomes. Here, we show that most acentric/functional chromosome fusion events in S. pombe cells harbouring an acentric chromosome I differed from the non-homologous end-joining-mediated rearrangements that result in deleterious dicentric fusions in normal cells, and were elicited by a previously unidentified homologous recombination (HR) event between chromosome end-associated sequences. The subtelomere repeats associated with the non-fusogenic ends were also destabilized in the surviving cells, suggesting a causal link between general subtelomere destabilization and acentric/functional chromosome fusion. A mutational analysis indicated that a non-canonical HR pathway was involved in the rearrangement. These findings are indicative of a latent mechanism that conditionally induces general subtelomere instability, presumably in the face of accidental centromere loss events, resulting in rescue of the fatal acentric chromosomes by interchromosomal HR., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

We investigated the efficacy and safety of albumin-bound paclitaxel (nab-PTX) and carboplatin (CBDCA) with concurrent radiotherapy for unresectable locally advanced non-small-cell lung cancer (NSCLC). Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Concurrent chemoradiotherapy consisted of weekly administration of nab-PTX (40 mg/m(2)) plus CBDCA (area under the plasma concentration time curve (AUC) 2) and thoracic radiotherapy (60 Gy/30 fractions) for a total of 6 weeks. After concurrent chemoradiotherapy, patients received an additional two cycles of consolidation phase chemotherapy that consisted of 4-week cycles of nab-PTX (100 mg/m(2) on Days 1, 8 and 15)/CBDCA (AUC 5 mg/ml/min on Day 1). Response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival were estimated using the Kaplan-Meier method. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. A total of 10 patients were enrolled in this trial between September 2013 and January 2014 from three institutes. The overall response rate was 40.0% and the median progression-free survival was 6.7 months. Treatment-related death occurred in two patients. Grade 2 or worse severe radiation pneumonitis was observed in all three patients that had the volume of lung receiving at least 20 Gy (V20) >30%. The results of this study indicate that no further investigation is warranted into nab-PTX and CBDCA with concurrent thoracic radiation for Stage III NSCLC with V20 > 30% due to severe toxicity., (© The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Objective: The estimated glomerular filtration rate is significantly decreased after nephroureterectomy. Deteriorating renal function likely affects the eligibility for cisplatin-based chemotherapy in patients with upper tract urothelial carcinoma. The present study was undertaken to identify preoperative factors for the prediction of postoperative renal function and develop a prediction model., Methods: Between June 1996 and January 2014, 110 patients who underwent radical nephroureterectomy at our institution were analyzed in this study. The estimated glomerular filtration rate was calculated using the Modification of Diet in Renal Disease study equation. Univariate linear regression analyses were performed to investigate the correlation between postoperative estimated glomerular filtration rate and preoperative variables. A stepwise multivariate linear regression analysis was performed to identify independent predictors of postoperative estimated glomerular filtration rate., Results: Comparison of preoperative and postoperative estimated glomerular filtration rate for each patient showed a median difference of 13.1 ml/min/1.73 m(2). The postoperative estimated glomerular filtration rate was significantly lower than the preoperative estimated glomerular filtration rate (P < 0.001). On univariate analysis, age and preoperative estimated glomerular filtration rate were significantly correlated with postoperative estimated glomerular filtration rate. On multivariate analysis, age, preoperative estimated glomerular filtration rate and the presence of hydronephrosis were independent predictive factors of postoperative estimated glomerular filtration rate. The predicted postoperative estimated glomerular filtration rate, which was calculated using these independent factors, showed a significant correlation with the observed postoperative estimated glomerular filtration rate (correlation coefficient = 0.7533)., Conclusions: Age, preoperative estimated glomerular filtration rate and the presence of hydronephrosis were independent predictors of postoperative estimated glomerular filtration rate in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. The predicted postoperative estimated glomerular filtration rate based on these factors may be useful for choosing alternative management strategies such as neoadjuvant chemotherapy for patients with upper tract urothelial carcinoma., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The reduced diameter of skeletal myofibres is a hallmark of several congenital myopathies, yet the underlying cellular and molecular mechanisms remain elusive. In this study, we investigate the role of HACD1/PTPLA, which is involved in the elongation of the very long chain fatty acids, in muscle fibre formation. In humans and dogs, HACD1 deficiency leads to a congenital myopathy with fibre size disproportion associated with a generalized muscle weakness. Through analysis of HACD1-deficient Labradors, Hacd1-knockout mice, and Hacd1-deficient myoblasts, we provide evidence that HACD1 promotes myoblast fusion during muscle development and regeneration. We further demonstrate that in normal differentiating myoblasts, expression of the catalytically active HACD1 isoform, which is encoded by a muscle-enriched splice variant, yields decreased lysophosphatidylcholine content, a potent inhibitor of myoblast fusion, and increased concentrations of ≥ C18 and monounsaturated fatty acids of phospholipids. These lipid modifications correlate with a reduction in plasma membrane rigidity. In conclusion, we propose that fusion impairment constitutes a novel, non-exclusive pathological mechanism operating in congenital myopathies and reveal that HACD1 is a key regulator of a lipid-dependent muscle fibre growth mechanism., (© The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.)

Objective: Result of clinical trial for registration purpose is often difficult to generalize because of its limited population in number and inclusion criteria., Methods: To understand the efficacy of sorafenib under daily medical practice, we retrospectively investigated therapeutic outcomes of 175 Japanese patients with advanced renal cell carcinoma treated with sorafenib at 15 centers., Results: The objective response rate and disease control rate were 15.4 and 77.1%, respectively, being similar to those in the Phase II study in Japanese patients (19.4 and 73.6 months). Any tumor shrinkage was observed with 53% of patients, while tumor control without growth was in 61%. Lung lesions were more sensitive to sorafenib than other lesions, in terms of any tumor shrinkage (54%) and the extent of maximal shrinkage, while tumor control was better in lymph node metastases (77%) than in lung (69%). Liver was worse in any tumor shrinkage (35%), tumor control (55%) and the extent of tumor growth. Slightly, shorter median overall survival of 21.1 months compared with Phase II clinical trial (25.3 months) is likely to be attributable to different patient population, because median overall survival was improved to 26.4 months when the population was matched to that in Phase II trial. Univariate and multivariate analyses identified prognostic factors for worse overall survival, including intermediate and poor Memorial Sloan-Kettering Cancer Center risk, Eastern Cooperative Oncology Group performance status ≥1, the presence of non-clear cell component and the presence of liver metastasis., Conclusions: In conclusion, the present study confirmed the efficacy of sorafenib in the real-world setting on advanced renal cell carcinoma., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Toxicogenomics focuses on assessing the safety of compounds using gene expression profiles. Gene expression signatures from large toxicogenomics databases are expected to perform better than small databases in identifying biomarkers for the prediction and evaluation of drug safety based on a compound's toxicological mechanisms in animal target organs. Over the past 10 years, the Japanese Toxicogenomics Project consortium (TGP) has been developing a large-scale toxicogenomics database consisting of data from 170 compounds (mostly drugs) with the aim of improving and enhancing drug safety assessment. Most of the data generated by the project (e.g. gene expression, pathology, lot number) are freely available to the public via Open TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System). Here, we provide a comprehensive overview of the database, including both gene expression data and metadata, with a description of experimental conditions and procedures used to generate the database. Open TG-GATEs is available from http://toxico.nibio.go.jp/english/index.html., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Aim: The aim of this study was to evaluate the association of baseline tricuspid regurgitation (TR) on the outcomes after percutaneous mitral valve repair (PMVR) with the MitraClip system., Methods and Results: Data from 146 consecutive patients with functional mitral regurgitation (MR) were obtained. Two different groups, dichotomized according to the degree of pre-procedural TR (moderate/severe, n = 47 and none/mild, n = 99), had their clinical and echocardiographic outcomes through 12-month compared. At 30-day, the primary safety endpoint was significantly higher in moderate/severe TR compared with none/mild TR (10.6 vs. 2.0%, P = 0.035). Marked reduction in MR grades observed post-procedure were maintained through 12 months. Although NYHA functional class significantly improved in both groups compared with baseline, it was impaired in moderate/severe TR compared with the none/mild TR group (NYHA > II at 30 day: 33.3 vs. 9.2%, P < 0.001; at 1 year: 38.5 vs. 12.3%, respectively, P = 0.006). Left ventricle reverse remodelling and ejection fraction improvement were revealed in both groups. The primary efficacy endpoint at 12-month determined by freedom from death, surgery for mitral valve dysfunction, or grade ≥ 3+ MR was comparable between groups, but combined death and re-hospitalization for heart failure rates were higher in the moderate/severe TR group. Multivariable Cox regression analysis demonstrated that baseline moderate/severe TR and chronic kidney disease were independent predictors of this combined endpoint., Conclusions: Although PMVR with MitraClip led to improvement in MR, TR, and NYHA functional class in patients with baseline moderate/severe TR, the primary safety endpoint at 30-day was impaired, while moderate/severe TR independently predicted death and re-hospitalization for heart failure at 12-month., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Adipose tissue stromal vascular fraction contains mesenchymal stem cells, which show protective effects when administered to damaged tissues, mainly through secreted trophic factors. We examined the protective effects of adipose-derived stem cells (ASCs) and ASC-conditioned medium (ASC-CM) against retinal damage and identified the neuroprotective factors in ASC-CM. ASCs and mature adipocytes were isolated from mouse subcutaneous tissue. ASCs were injected intravitreally in a mouse model of light-induced retinal damage, and ASC injection recovered retinal function as measured by electroretinogram and inhibited outer nuclear layer, thinning, without engraftment of ASCs. ASC-CM and mature adipocyte-conditioned medium were collected after 72 hours of culture. In vitro, H2O2- and light-induced cell death was reduced in a photoreceptor cell line with ASC-CM but not with mature adipocyte-conditioned medium. In vivo, light-induced photoreceptor damage was evaluated by measurement of outer nuclear layer thickness at 5 days after light exposure and by electroretinogram recording. ASC-CM significantly inhibited photoreceptor degeneration and retinal dysfunction after light exposure. Progranulin was identified as a major secreted protein of ASCs that showed protective effects against retinal damage in vitro and in vivo. Furthermore, progranulin phosphorylated extracellular signal-regulated kinase, cAMP response element binding protein, and hepatocyte growth factor receptor, and protein kinase C signaling pathways were involved in the protective effects of progranulin. These findings suggest that ASC-CM and progranulin have neuroprotective effects in the light-induced retinal-damage model. Progranulin may be a potential target for the treatment of the degenerative diseases of the retina.

Objectives: The purpose of this study was to compare the efficacy of 320-detector row computed tomography (CT) with that of 64-detector row CT for three-dimensional assessment of pulmonary vasculature of candidates for pulmonary segmentectomy., Methods: We included 32 patients who underwent both 320- and 64-detector CT before pulmonary segmentectomy, which was performed by cutting the pulmonary artery and bronchi of the affected segment followed by dissection of the intersegmental plane along the intersegmental vein. Before the operation, three-dimensional pulmonary vasculature images were obtained for each patient, and the arteries and intersegmental veins of the affected segments were identified. Two thoracic surgeons independently assessed the vessels with visual scoring systems, and kappa analysis was used to determine interobserver agreement. The Wilcoxon signed-rank test was used to compare the visual scores for the assessment of the visualization capabilities of the two methods. In addition, the final determination of pulmonary vasculature at a given site was made by consensus from thoracic surgeons during operation, and receiver operating characteristic analysis was performed to compare their efficacy of pulmonary vasculature assessment. Sensitivity, specificity and accuracy of either method were also compared by means of McNemar's test., Results: Of the 32 cases, there were no operative complications, but 1 patient died of postoperative idiopathic interstitial pneumonia. Visualization scores for the pulmonary vessels were significantly higher for 320- than those for 64-detector CT (P < 0.0001 for the affected arteries and P < 0.0001 for the intersegmental veins). As for pulmonary vasculature assessment, the areas under the curve showed no statistically significant differences in between the two methods, while the specificity and accuracy of intersegemental vein assessment were significantly better for 320- than those for 64-detector row CT (P < 0.05). Interobserver agreement for the assessment yielded by either method was almost perfect for all cases., Conclusions: Three hundred and twenty-detector row CT is more useful than conventional 64-detector row CT for preoperative three-dimensional assessment of pulmonary vasculature, especially when we identify the intersegmental veins, in candidates for pulmonary segmentectomy.

Objective: Preoperative nomograms can accurately predict the rate of biochemical recurrence after radical prostatectomy. Although these nomograms were shown to be valid in several external validation cohorts of Caucasian patients, they have not been validated in non-Caucasian patients from Asian countries. We therefore validated these preoperative nomograms in a Japanese cohort, using different cutoff values of prostate-specific antigen concentrations for biochemical recurrence., Methods: We analyzed 637 patients who underwent radical prostatectomy for clinically localized prostate cancer at the Tokyo Medical University Hospital between February 2000 and January 2011. We evaluated two prostate-specific antigen cutoff values for biochemical recurrence, 0.2 and 0.4 ng/ml. Using c-index and calibration plots, we validated the previously developed Kattan and Stephenson nomograms., Results: Overall, the mean 5-year non-biochemical recurrence rate was 72 ± 4%. Using a prostate-specific antigen cutoff values of 0.2 and 0.4 ng/ml, the c-indices for the Kattan nomogram were 0.714 and 0.733. Similarly, using a prostate-specific antigen cutoff values of 0.2 and 0.4 ng/ml, the c-indices for the Stephenson nomograms were 0.717 and 0.671. The calibration plots showed that the predictive value of the Stephenson nomogram at a prostate-specific antigen cutoff of 0.2 ng/ml was close to the actual outcomes compared with other combinations of nomograms and prostate-specific antigen cutoff levels., Conclusions: Because the c-indices of both nomograms were generally high, these nomograms can be applied to our cohort. The addition of biopsy information did not markedly improve the c-index but resulted in good calibration, indicating that the Stephenson nomogram may be a better fit for our patient cohort.

Human chromosome 7 open reading frame 24 (C7orf24)/γ-glutamyl cyclotransferase has been suggested to be a potential diagnostic marker for several cancers, including carcinomas in the bladder urothelium, breast and endometrial epithelium. We here investigated the epigenetic regulation of the human C7orf24 promoter in normal diploid ARPE-19 and IMR-90 cells and in the MCF-7 and HeLa cancer cell lines to understand the transcriptional basis for the malignant-associated high expression of C7orf24. Chromatin immunoprecipitation analysis revealed that histone modifications associated with active chromatin were enriched in the proximal region but not in the distal region of the C7orf24 promoter in HeLa and MCF-7 cells. In contrast, elevated levels of histone modifications leading to transcriptional repression and accumulation of heterochromatin proteins in the C7orf24 promoter were observed in the ARPE-19 and IMR-90 cells, compared to the levels in HeLa and MCF-7 cancer cells. In parallel, the CpG island of the C7orf24 promoter was methylated to a greater extent in the normal cells than in the cancer cells. These results suggest that the transcriptional silencing of the C7orf24 gene in the non-malignant cells is elicited through heterochromatin formation in its promoter region; aberrant expression of C7orf24 associated with malignant alterations results from changes in chromatin dynamics.