Search

Aims: Left ventricular (LV) diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF) are common cardiac complications of patients with systemic sclerosis (SSc). Exercise stress echocardiography is often used in symptomatic patients with SSc to detect abnormal increases in pulmonary pressures during exercise, but the pathophysiologic and prognostic significance of exercise stress echocardiography to assess the presence of HFpEF in these patients is unclear., Methods and Results: Patients with SSc (n=140) underwent ergometry exercise stress echocardiography with simultaneous expired gas analysis. The HFA-PEFF score ≥ 5 points was used to diagnose HFpEF. Thirty-five patients met the HFpEF criteria (prevalence 25%). Compared to patients with SSc-non-HFpEF, those with SSc-HFpEF were older and had a higher prevalence of coronary artery disease, more severe LV diastolic dysfunction (by definition), depressed right ventricular systolic function, reduced exercise capacity (lower peak oxygen consumption), and poorer ventilatory efficiency. Exercise right heart catheterization (RHC) was performed in 25 patients and it confirmed elevated pulmonary capillary wedge pressure during peak exercise in patients with SSc-HFpEF. Participants were followed up to assess the primary composite endpoint: all-cause mortality, HF hospitalization, unplanned hospital visits requiring intravenous diuretics, or oral diuretic intensification. Compared to SSc-non-HFpEF, SSc-HFpEF had a 5.3-fold increased risk of the composite outcomes (hazard ratio 5.29, confidence intervals 2.06-13.5, p=0.0005)., Conclusion: In addition to pulmonary hemodynamics, exercise stress echocardiography may be useful to identify the HFpEF phenotype that has different pathophysiology and clinical outcomes in patients with SSc., (© The Author(s) 2025. 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.)

Objective: The objective of this study was to provide a convenient preoperative prediction of the risk of early postoperative mortality., Materials and Methods: This retrospective study included patients who underwent surgery for spinal metastasis at our hospital between 2009 and 2021. Preoperative blood test data of all patients were collected, and the survival time was calculated by dividing the blood data. A multivariate analysis was conducted using a Cox proportional hazards model to identify prognostic factors., Results: The study population included 83 patients (average: 64.5 years), 22 of whom died within 3 months. The most common lesion was the thoracic spine, and incomplete paralysis was observed in 57 patients. The surgical methods included posterior implant fixation (n = 17), posterior decompression (n = 31), and posterior decompression with fixation (n = 35). In the univariate analysis, the presence of abnormal values was significantly associated with postoperative survival in six preoperative blood collection items (hemoglobin, C-reactive protein, albumin, white blood cell, gamma-glutamyl transpeptidase, and lactate dehydrogenase). In a multivariate analysis, four test items (hemoglobin, C-reactive protein, white blood cell, and lactate dehydrogenase) were identified as independent prognostic factors.Comparing cases with ≥3 abnormal values among the above four items (high-risk group; n = 23) and those with ≤2 (low-risk group; n = 60), there was a significant difference in survival time. In addition, it was possible to predict cases of early death within 3 months after surgery with 73% sensitivity and 89% specificity., Conclusions: The study showed that four preoperative blood test abnormalities (hemoglobin, C-reactive protein white blood cell, and lactate dehydrogenase) indicated the possibility of early death within 3 months after surgery., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder primarily observed in Asian populations, particularly in Japan. Although pulse methylprednisolone therapy is an effective treatment for AIGA, predictors of therapeutic response remain poorly defined., Objectives: To identify factors that predict the efficacy of pulse methylprednisolone therapy in patients with AIGA., Methods: Data obtained from 32 patients with AIGA were assessed based on clinical, histopathological and serological examinations. Statistical analyses were conducted to explore predictors of response to pulse methylprednisolone therapy., Results: The average age of participants was 32.1 years (SD 12.3); 66% were male and 34% female. The response to pulse methylprednisolone therapy was closely associated with the time from the onset to start of therapy (Wilcoxson's rank sum test, P = 0.02, n = 27), with earlier intervention resulting in a better outcome. Notably, male patients and patients presenting with severe symptoms at diagnosis responded better to treatment. High serum carcinoembryonic antigen (CEA) levels and histological evidence of inflammation around sweat glands also correlated with a positive therapeutic response., Conclusions: Earlier intervention, elevated serum CEA levels and inflammation around sweat glands are potential indicators of a successful response to pulse methylprednisolone therapy in patients with AIGA., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. 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: Enfortumab vedotin (EV) was approved for patients with metastatic urothelial carcinoma (mUC) who progressed after anticancer therapy on September 2021 in Japan. The association between the occurrence of EV-related side effects and clinical outcome remains to be elucidated., Methods: We identified 97 mUC patients treated with EV therapy at our five institutions from the date of approval to March 2023. The median follow-up period was 7.0 months. We retrospectively analyzed the efficacy and safety of EV., Results: The median age of the patients was 71 years old, 39% had PS of 1 or more, and 56.7% had primary tumor in upper urinary tract. Overall response rate (ORR) to EV therapy, median progression-free survival (PFS), and overall survival (OS) were 43.3%, 7.52 months, and 12.78 months, respectively. Any grade of treatment-related skin disorder, dysgeusia, peripheral neuropathy, gastrointestinal disorder, and hyperglycemia occurred in 61 (62.9%), 36 (37.1%), 34 (35.1%), 29 (29.9%), and 18 (18.6%) patients, respectively. The patients with EV-associated peripheral neuropathy had significantly higher ORR (58.8% vs. 34.9%, P = .032) and longer median PFS (8.05 vs. 6.31 months, P = .017) and OS (not reached vs. 11.57 months, P = .008, respectively) than those without. The occurrence of peripheral neuropathy after EV treatment and the presence of peritoneal dissemination were factors independently associated with PFS (hazard ratio = 0.46, P = .008 and hazard raito = 3.83, P = .004, respectively) and OS (hazard ratio = 0.30, P = .005 and hazard raito = 4.53, P = .002, respectively)., Conclusions: The occurrence of EV-related peripheral neuropathy might be associated with the efficacy of EV therapy in mUC patients., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: We aimed to evaluate the effects of age on clinical characteristics and outcomes in biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD)-naïve patients with rheumatoid arthritis (RA)., Methods: We analysed the cases of 234 Japanese b/tsDMARD-naïve RA patients who underwent b/tsDMARD treatment in a multicentre ultrasound prospective observational cohort. We compared the clinical characteristics at baseline and outcomes at 12 months between those aged ≥60 years and those <60 years., Results: Compared to the <60-year-old group (n = 78), the ≥60-year-old group (n = 156) had higher inflammatory marker values and ultrasound combined scores, especially wrist joints, at baseline. Age at baseline positively correlated significantly with the ultrasound scores at baseline; however, age was not a significant variable by the multiple regression analysis. The patients treated with different MOAs in the ≥60-year-old group had comparable outcomes and multiple regression analysis revealed that mechanism of action (MOA) was not a significant contributor to the Clinical Disease Activity Index at 12 months., Conclusions: RA patients with advanced age demonstrated distinctive clinical characteristics. The MOAs were not associated with clinical outcomes and ultrasound outcomes in RA patients with advanced age., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Background: Fosnetupitant, a neurokinin-1 receptor antagonist, is used to prevent chemotherapy-induced nausea and vomiting (CINV) in patients undergoing highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). Previous phase III trials demonstrated the non-inferiority of its 30-minute infusion to fosaprepitant in efficacy and a favorable safety profile., Methods: This was a single-arm, phase II study to investigate the safety of a 15-minute infusion of fosnetupitant in patients with gastrointestinal and breast cancer. Patients who had received their dose of fosnetupitant in a 30-minute infusion without developing an allergic reaction were eligible and received their next fosnetupitant dose for 15 minutes. The primary endpoint was the incidence of an allergic reaction during the first 15-minutes infusion, and the secondary endpoints were the incidence of injection site reaction (ISR), the incidence of a grade ≥ 3 treatment-related adverse event (TRAE) with fosnetupitant, and complete response (CR) rate., Results: The study period was from February 17, 2023 to June 20, 2023. In an exploratory analysis, medical records from the end of the study period to December 31, 2023 were retrospectively evaluated to assess the time-saving effect and safety of the short-term infusion of fosnetupitant. Fifty-six patients with gastrointestinal and 14 patients with breast cancer were enrolled, one of whom with breast cancer did not receive study treatment at her own request. No allergic reactions occurred during the 15-minutes infusion. Furthermore, there were no allergic reactions across all 280 short-term injections (Table 1). Additionally, no ISR or grade 3 or higher TRAE were reported. The CR rate was 87.0%., Conclusion: Short-term infusion of fosnetupitant, administered over 15 minutes, was demonstrated to be safe and effective for patients receiving HEC or MEC (Japan Registry of Clinical Trials Trial ID: jRCT1041220144)., (© The Author(s) 2024. Published by Oxford University Press.)

Hepatocellular carcinoma (HCC) in the caudate lobe presents surgical challenges due to the lack of distinct anatomical landmarks. This case report introduces a novel surgical approach combining Takasaki's classification and indocyanine green negative counterstaining for precise anatomical caudate lobectomy. A 78-year-old patient with hepatocellular carcinoma in the caudate lobe underwent surgery following preoperative volumetric assessment. The method involved a glissonian approach for both left and right pedicles, coupled with meticulous dissection of hepatic pedicles of the caudate lobe guided by taping of left and right glissonian pedicles, followed by indocyanine green administration for improved visualization of caudate lobe boundaries. The procedure enabled complete tumor resection with minimal blood loss. At 50 months postsurgery, the patient maintains favorable liver function and performance status. This innovative approach offers a promising solution for precise resection of caudate lobe hepatocellular carcinoma, potentially improving surgical outcomes and long-term prognosis., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Stage IVA cervical cancer is a tumor that invades the mucosa of the bladder or rectum without distant metastasis and is difficult to treat, and concurrent chemoradiotherapy is recommended. Although radical surgery following neoadjuvant chemotherapy is a treatment option for stage IVA cervical cancer, the evidence is limited. A 51-year-old woman with bulky cervical cancer and rectal invasion was referred to our hospital. Paclitaxel and cisplatin were administered as neoadjuvant chemotherapies. After two cycles of chemotherapy, the tumor size decreased markedly. Total pelvic exenteration was performed, and a complete resection was achieved. Four cycles of paclitaxel and cisplatin were administered postoperatively. Thirty-three months after the completion of adjuvant chemotherapy, the patient was alive and free of disease. Radical surgery after neoadjuvant chemotherapy may be a treatment option for stage IVA cervical cancer with bulky tumors., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Background: Transabdominal ultrasonography and transperineal ultrasonography (TPUS) appear correspond to colonoscopy (CS) for evaluating ulcerative colitis (UC) activity, but their utility in UC diagnosis remains unclear. This research compared the accuracy of TPUS and CS for assessing rectal activity and differentiating noninflammatory bowel disease proctitis from UC in pediatric cases., Methods: The study is a blinded, prospective, and controlled trial. Prospectively, values of fecal calprotectin (FCP) and findings of the TPUS and CS were compared between child cases of UC and non-IBD proctitis. Findings of rectal wall thickening (RWT), rectal wall flow (RWF) on power Doppler, and microvascular signal at wall circumference (MSWC) on monochrome superb microvascular imaging assessed using TPUS were compared with the CS., Results: Thirty patients with Mayo endoscopic subscore (MES) 0 to 1 UC, 57 with MES 2 to 3 UC, and 44 with proctitis were registered. Fecal calprotectin, RWF, and MSWC indicated significant differences among the groups (P < .05). Rectal wall thickening showed no significant difference between MES 0-1 and proctitis (P = .76). Rectal wall thickening and MSWC were independent predictors of endoscopic activity of UC, resulting in a sensitivity and specificity of 100% for RWT ≥4.5 mm and positive MSWC. Fecal calprotectin and RWF were independent predictors for differentiating MES 0 to 1 and proctitis, and FCP and RWT were independent predictors for differentiating MES 2 to 3 and proctitis. Sensitivity and specificity were 77.2% and 80.9%, respectively, for FCP >242.5 μg/g and RWF negative; and they were both 100% for RWT >4.1 mm and MSWC positive., Conclusions: Transperineal ultrasonography with mSMI may enable the evaluation of rectal activity and differentiation of UC from non-IBD proctitis with accuracy comparable to endoscopy., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. 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.)

We report a case of reactive lymphoid hyperplasia (RLH) mimicking colorectal liver metastases (CRLM) on preoperative workup that was clinically indistinguishable. A 78-year-old woman was found to have locally-advanced sigmoid cancer (T4), and then treated with radical sigmoidectomy. One year after the surgery, plain computed tomography (CT) revealed a low-density area in the right hepatic lobe. Metastatic liver tumors could not be ruled out with CT/ magnetic resonant imaging (MRI) and positron emission tomography-CT . Based on these findings, the patient was diagnosed with CRLM at S7 of the liver. The patient underwent right posterior sectionectomy. The tumor was adjacent to the right hepatic vein; however, no invasion was observed. The patient was pathologically diagnosed as having RLH. The patient showed no signs of recurrence 16 months after initial surgery. RLH is clinically indistinguishable from CRLM. Further evaluation is required to elucidate the effective strategies of detecting and treating hepatic RLH., Competing Interests: None declared., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Objectives: We evaluated the real-world safety/effectiveness of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), in patients with RA in Japan registered in a post-marketing surveillance study., Methods: This interim analysis included data from July 2013 to December 2018. Adverse events (AEs), serious AEs (SAEs), Simplified Disease Activity Index (SDAI)/Clinical Disease Activity Index (CDAI)/Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] scores, and rates of SDAI/CDAI/DAS28-4(ESR)-defined remission and low disease activity were analysed using 6 months of data. Risk factors for serious infections were assessed by multivariable analyses., Results: Safety and disease activity were evaluated in 6866 and 6649 patients, respectively. Overall, 32.73%/7.37% of patients reported AEs/SAEs. Clinically important AEs with tofacitinib included serious infections/infestations [3.13% of patients; incidence rate (IR; patients with events) 6.91/100 patient-years (PY)], herpes zoster (3.63%; IR 8.02/100 PY), and malignancies (0.68%; IR 1.45/100 PY). SDAI/CDAI/DAS28-4(ESR) scores and remission/low disease activity rates improved over 6 months. Male sex, older age, Steinbrocker's stage IV, history of infection, and diabetes mellitus at baseline were independent risk factors for serious infection., Conclusions: In patients with RA receiving tofacitinib in Japan, safety was consistent with the reported profile, and disease activity improved over 6 months., Study Identifier: NCT01932372., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

We previously demonstrated that dietary supplementation with Dunaliella tertiolecta (DT) increases uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT) and improves diet-induced obesity (DIO) in C57BL/6 J mice at thermoneutrality (30 °C). Here, we investigated whether DT improves DIO in a thermoneutral UCP1-deficient (KO) animal. KO mice were fed a high-fat diet supplemented with DT for 12 weeks. Compared to control group without DT, body weight was significantly reduced in DT group with no difference in food intake. Dunaliella tertiolecta-supplemented mice exhibited lower adiposity and well-maintained multilocular morphology in BAT, in which a significant increase in gene expression of PR domain containing 16 was detected in DT group compared to control group. Moreover, increase in UCP2 level and/or decrease in ribosomal protein S6 phosphorylation were detected in adipose tissues of DT group relative to control group. These results suggest that DT supplementation improves DIO by stimulating UCP1-independent energy dissipation at thermoneutrality., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Behavioral persistency reflects internal brain states, which are the foundations of multiple brain functions. However, experimental paradigms enabling genetic analyses of behavioral persistency and its associated brain functions have been limited. Here, we report novel persistent behavioral responses caused by electric stimuli in the nematode Caenorhabditis elegans. When the animals on bacterial food are stimulated by alternating current, their movement speed suddenly increases 2- to 3-fold, persisting for more than 1 minute even after a 5-second stimulation. Genetic analyses reveal that voltage-gated channels in the neurons are required for the response, possibly as the sensors, and neuropeptide signaling regulates the duration of the persistent response. Additional behavioral analyses implicate that the animal's response to electric shock is scalable and has a negative valence. These properties, along with persistence, have been recently regarded as essential features of emotion, suggesting that C. elegans response to electric shock may reflect a form of emotion, akin to fear., Competing Interests: Conflicts of interest The author(s) declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Objectives: To investigate the appropriate timing, useful findings and combination of magnetic resonance imaging (MRI) and ultrasound (US) for predicting the radiographic progression in early rheumatoid arthritis (RA)., Methods: Forty-four active RA patients, who examined by both of MRI and US in the symptomatic wrist and finger joints, were recruited in Nagasaki University Hospital from 2010 to 2017 and treated by the treat-to-target therapeutic strategy for 1 year. MRI was evaluated by RA MRI scoring and US by Outcomes Measures in Rheumatology Clinical Trial, respectively. Plain radiographs were assessed by the Genant-modified Sharp score for the symptomatic side in the same manner as MRI and US. Radiographic progression was defined as an annual increase ≥0.75 at 1 year. Factors associated with radiographic progression were analysed. Also, the optimal combination of MRI and US at each timepoint was considered., Results: Logistic regression model revealed that MRI-proven bone marrow oedema at baseline and 6 months and joint counts of power-Doppler grade ≥2 articular synovitis at 3 or 6 months were significantly associated with radiographic progression at 1 year., Conclusion: This study may suggest the favourable timing and combination of MRI and US at each point to predict radiographic progression in patients with early-stage RA., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA., Methods: Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4+ T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4+ and CD14+ cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively., Results: CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4flox/floxLck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4+ cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14+ cells in patients with RA was significantly decreased with CaMK4 inhibitors., Conclusion: Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Functionally distinct CD4+ helper T (Th) cell subsets, including Th1, Th2, Th17, and regulatory T cells (Treg), play a pivotal role in the regulation of acquired immunity. Although the key proteins involved in the regulation of Th cell differentiation have already been identified how the proteogenomic landscape changes during the Th cell activation remains unclear. To address this issue, we characterized proteogenomic signatures of differentiation to each Th cell subsets by RNA sequencing and liquid chromatography-assisted mass spectrometry, which enabled us to simultaneously quantify more than 10,000 protein-coding transcripts and 8,000 proteins in a single-shot. The results indicated that T cell receptor activation affected almost half of the transcript and protein levels in a low correlative and gene-specific manner, and specific cytokine treatments modified the transcript and protein profiles in a manner specific to each Th cell subsets: Th17 and Tregs particularly exhibited unique proteogenomic signatures compared to other Th cell subsets. Interestingly, the in-depth proteome data revealed that mRNA profiles alone were not enough to delineate functional changes during Th cell activation, suggesting that the proteogenomic dataset obtained in this study serves as a unique and indispensable data resource for understanding the comprehensive molecular mechanisms underlying effector Th cell differentiation., (© The Author(s) 2022. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.)

Drug-induced liver injury (DILI) is a major factor influencing new drug withdrawal; therefore, an appropriate toxicity assessment at the preclinical stage is required. Previous in silico models have been established using compound information listed in large data sources, thereby limiting the DILI risk prediction for new drugs. Herein, we first constructed a model to predict DILI risk based on a molecular initiating event (MIE) predicted by quantitative structure-activity relationships, admetSAR parameters (e.g. cytochrome P450 reactivity, plasma protein binding, and water-solubility), and clinical information (maximum daily dose [MDD] and reactive metabolite [RM]) for 186 compounds. The accuracy of the models using MIE, MDD, RM, and admetSAR alone were 43.2%, 47.3%, 77.0%, and 68.9%, while the "predicted MIE + admetSAR + MDD + RM" model's accuracy was 75.7%. The contribution of MIE to the overall prediction accuracy was little effect or rather worsening it. However, it was considered that MIE was a valuable parameter and that it contributed to detect high DILI risk compounds in the early development stage. We next examined the effect of stepwise changes in MDD on altering the DILI risk and estimating the maximum safety dose (MSD) for clinical use based on structural information, admetSAR, and MIE parameters because it is important to estimate the dose that could prevent the DILI onset in clinical conditions. Low-MSD compounds might increase the DILI risk, as these compounds were classified as "most-DILI concern" at low doses. In conclusion, MIE parameters were especially useful to check the DILI concern compounds and to prevent the underestimation of DILI risk in the early stage of drug development., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: To evaluate the efficacy of water-cooled clothing that continuously cools restricted body areas to suppress body temperature increase as an anti-heatstroke measure for workers in hot environments that exceed body temperature., Methods: Ten healthy men were placed in Room A (air temperature: 25°C, relative humidity: 50%) for 15 min. They were then transferred to Room B (air temperature: 40°C, relative humidity: 50%), where they rested for 10 min, then put on cooling clothing, and again rested for 15 min (the control group rested for 25 min). They then performed intense ergometer exercise for 40 min at 40% maximal oxygen consumption after which they rested for 10 min. The three trial conditions were CON (long-sleeved summer work clothes), VEST (cooling vest), and P-VEST (partial cooling vest). In VEST and P-VEST, water-cooled clothing continuously recirculated with 10°C water was used to cool the upper body. In P-VEST, only the neck, axillae, and heart areas were in contact with the cooled clothing. The measured indices were the rectal, esophageal, and external auditory canal temperatures; heart rate; estimated sweat volume; and subjective evaluations., Results: Compared with the CON condition, the rectal, esophageal, and external auditory canal temperatures and the heart rate were significantly lower and the subjective indices were decreased in the VEST and P-VEST conditions., Conclusions: Partial cooling showed a body cooling effect similar to that of whole upper body cooling. Partial body cooling promoted the heat dissipation, suggesting that partial cooling is efficient for maintaining body cooling in hot environments., (© 2023 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

Objectives: To evaluate the efficacy and safety of canakinumab in Japanese patients with colchicine-resistant or colchicine-intolerant familial Mediterranean fever (FMF) in a real-world clinical setting., Methods: We reviewed 13 Japanese FMF patients to whom canakinumab was introduced during the period of October 2017 to December 2020. All patients were diagnosed as FMF according to Tel-Hashomer criteria. We performed genetic analyses for Mediterranean fever or MEFV by targeted next-generation sequencing. Efficacy was assessed by attack frequency and the percentage of patients who achieved attack improvement at 24 weeks. Safety was assessed by adverse events observed during canakinumab treatment., Results: The median duration and follow-up of canakinumab treatment were 13 and 16 months, respectively. The median attack frequency was 0.50 [0.30-1.00] at 24 weeks, which was a significant decrease from 2.00 [0.85-2.88] at the time of induction (p = .019). There were three patients (23%) with complete resolution of attacks at 24 weeks. No serious adverse events were observed. However, one patient had small intestinal ulceration which led to the discontinuation of canakinumab., Conclusions: Although the number of cases is small, this study suggests that canakinumab is efficacious and safe for use in Japanese patients with colchicine-resistant or colchicine-intolerant FMF in a real-world clinical setting in Japan., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Brown and beige adipocytes, which express thermogenic uncoupling protein-1 (UCP1), stimulate glucose and lipid metabolism, improving obesity and metabolic diseases such as type 2 diabetes and hyperlipidemia. Overexpression of cellular repressor of E1A-stimulated genes 1 (CREG1) promotes adipose tissue browning and inhibits diet-induced obesity (DIO) in mice. In this study, we investigated the effects of CREG1 administration on DIO inhibition and adipose browning. Subcutaneous administration of recombinant CREG1 protein to C57BL/6 mice stimulated UCP1 expression in interscapular brown adipose tissue (IBAT) and improved DIO, glucose tolerance and fatty liver compared with those in phosphate-buffered saline-treated mice. Injection of Creg1-expressing adenovirus into inguinal white adipose tissue (IWAT) significantly increased browning and mRNA expression of beige adipocyte marker genes compared with that in mice injected with control virus. The effect of Creg1 induction on beige adipocyte differentiation was supported in primary culture using preadipocytes isolated from IWAT of Creg1-transgenic mice compared with that of wild-type mice. Our results indicate a therapeutic effect of CREG1 on obesity and its associated pathology and a potential of CREG1 to stimulate brown/beige adipocyte formation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Autonomic disorders are common in patients with systemic lupus erythematosus (SLE), but the therapeutic strategy and methods for evaluating the effects of therapy have not been established. We describe the three cases of SLE patients who developed severe autonomic disorders as demonstrated by the head-up tilt table test (HUT). All three patients were treated by intensive immunosuppressive treatments including intravenous cyclophosphamide (IVCY); their HUT results all became negative. Our cases suggest that IVCY treatment can be a good therapeutic option for severe autonomic disorders in SLE patients. The HUT is a useful objective method for the diagnosis of and the evaluation of longitudinal therapeutic effects on autonomic disorders in SLE patients with orthostatic intolerance., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Four cases of idiopathic multi-centric Castleman disease (iMCD) reportedly have variants in hereditary autoinflammatory disease-related genes; however, the frequency and role of these variants in iMCD is still unknown. We therefore investigated such gene variants among patients with iMCD and aimed to reveal the relationship between iMCD and autoinflammatory disease-related genes. We reviewed 14 Japanese iMCD patients who were recruited between January 2015 and September 2019. All patients met both the Japanese tentative diagnostic criteria for Castleman disease and the international consensus diagnostic criteria for iMCD. We performed genetic analyses for 31 autoinflammatory disease-related genes by targeted next-generation sequencing. The MEFV gene variants were observed in 10 of 14 patients with iMCD. Although iMCD had a high percentage of exons 2 or 3 variants of MEFV, comparison of data from healthy Japanese subjects indicated that there was no significant difference in the percentage between healthy Japanese subjects and patients with iMCD. Variants of uncertain significance (VUS) in the TNFRSF1A and CECR1 genes were observed in two of the patients, respectively. We divided patients into two groups-those with MEFV variants (excluding E148Q variants) and those without MEFV variants-and compared the clinical characteristics between these two groups. Patients with MEFV variants, excluding E148Q variants, exhibited a significantly higher likelihood of fever and significantly lower levels of hemoglobin than those lacking MEFV variants. Our results indicated that patients with iMCD tended to have a high frequency of MEFV gene variants and the presence of such variants can affect iMCD clinical phenotypes., (© 2021 British Society for Immunology.)

Previous studies of the brown bear (Ursus arctos) on Hokkaido Island, Japan, have detected three geographically distinct subpopulations representing different mitochondrial lineages and shown that gene flow between subpopulations has occurred due to male-biased dispersal. In this study, we determined whole-genomic sequences for six Hokkaido brown bears and analyzed these data along with previously published genomic sequences of 17 brown bears from other parts of the world. We found that the Hokkaido population is genetically distinct from the other populations, keeping genetic diversity higher than the endangered populations in western Europe but lower than most populations on the continents. A reconstruction of historical demography showed no increase in population size for the Hokkaido population during the Eemian interglacial period (130,000-114,000 years ago). In a phylogenetic analysis of the autosomal data, the Hokkaido population formed a clade distinct from North American and European populations, showing that it has maintained genetic diversity independently from continental populations following geographical isolation on the island. This autosomal genetic similarity contrasts with the geographically separate mitochondrial lineages on Hokkaido and indicates the occurrence of male-driven gene flow between subpopulations., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Among the bisphosphonates (BPs), nitrogen-containing BPs (N-BPs) have much stronger anti-bone-resorptive actions than non-N-BPs. However, N-BPs have various side effects such as acute influenza-like reactions after their initial administration and osteonecrosis of the jawbones after repeated administration. The mechanisms underlying such effects remain unclear. To overcome these problems, it is important to profile the inflammatory nature of N-BPs. Here, we analyzed the inflammatory reactions induced in mouse ear pinnae by the N-BPs alendronate (Ale) and zoledronate (Zol). We found the following: (i) Ale and Zol each induced two phases of inflammation (early weak and late strong ear swelling); (ii) both phases were augmented by lipopolysaccharides (LPSs; cell-surface constituent of gram-negative bacteria, including oral bacteria), but prevented by inhibitors of the phosphate transporters of solute carrier 20/34 (SLC20/SLC34); (iii) macrophages and neutrophils were involved in both phases of Ale+LPS-induced ear-swelling; (iv) Ale increased or tended to increase various cytokines, and LPS augmented these effects, especially that on interleukin 1β (IL-1β); (v) adenosine triphosphate (ATP) was involved in both phases, and Ale alone or Ale+LPS increased ATP in ear pinnae; (vi) the augmented late-phase swelling induced by Ale+LPS depended on both IL-1 and neutrophil extracellular traps (NETs; neutrophil-derived net-like complexes); (vii) neutrophils, together with macrophages and dendritic cells, also functioned as IL-1β-producing cells, and upon stimulation with IL-1β, neutrophils produced NETs; (viii) stimulation of the purinergic 2X7 (P2X7) receptors by ATP induced IL-1β in ear pinnae; (ix) NET formation by Ale+LPS was confirmed in gingiva, too. These results suggest that (i) N-BPs induce both early-phase and late-phase inflammation via ATP-production and P2X7 receptor stimulation; (ii) N-BPs and LPS induce mutually augmenting responses both early and late phases via ATP-mediated IL-1β production by neutrophils, macrophages, and/or dendritic cells; and (iii) NET production by IL-1β-stimulated neutrophils may mediate the late phase, leading to prolonged inflammation. These results are discussed in relation to the side effects seen in patients treated with N-BPs. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Objectives: Our previous study showed that the effectiveness of tumor necrosis factor (TNF) inhibitors was attenuated in anti-human T-cell leukemia virus type 1 (HTLV-1) antibody-positive patients with rheumatoid arthritis (RA). We aimed to evaluate the effectiveness and safety of non-TNF inhibitors in anti-HTLV-1 antibody-positive patients with RA., Methods: We reviewed patients with RA who received abatacept or tocilizumab as the first biologic agent. We used the data of patients treated with TNF inhibitors from our previous study to compare the effectiveness between the anti-HTLV-1 antibody-positive patients treated with TNF inhibitors and non-TNF inhibitors using the inverse probability of treatment weights (IPTW) method., Results: A total of 359 patients were divided into anti-HTLV-1 antibody-negative and -positive patients of 332 and 27, respectively. No statistically significant difference was observed in the change in the clinical disease activity index between the anti-HTLV-1 antibody-positive and -negative patients. The results using the IPTW method showed a significant association between the non-TNF inhibitors treatment and a better response. None of the patients developed adult T-cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis during the 24 weeks., Conclusion: Our results indicate that non-TNF inhibitors treatment is safety, and the effectiveness is not attenuated also in anti-HTLV-1 antibody-positive patients.

Background: Neoplastic seeding (NS) can occur after tissue biopsy, which is a clinical issue especially in mastectomy with immediate reconstruction. This is because postoperative radiation is not usually given and local recurrence of preserved skin flap may increase. The purpose of this study is to investigate the importance of preoperative evaluation of NS and the validity of biopsy scar excision., Patients and Methods: We retrospectively analysed 174 cases of mastectomy with immediate breast reconstruction. The primary endpoint is the frequency of clinical and pathological NS and the secondary endpoint is the problem of excision of needle biopsy site., Results: Three cases (1.7%) had preoperative clinical findings of NS. Pathological examination revealed NS in all three cases. Biopsy scars could be excised in 115 cases among 171 cases without clinical NS. Pathological NS was found in 1 of 66 (1.5%) cases of which pathological examination was performed. Biopsy scars could not be excised in the remaining 56 cases: the biopsy scar could not be identified in 41 cases, and there was concern about a decrease in flap blood flow after excision in 15 cases. In 12 of these 15 cases, the scars were close to the skin incision; excision of these scars might have triggered skin necrosis between the incision and the biopsy scar excision site. No postoperative complications were observed., Conclusions: It is important to preoperatively evaluate clinical NS, and biopsy scars should be excised in clinical NS cases. Even in cases without clinical NS, biopsy scar excision should be considered. It is also important to perform a biopsy in consideration of the incision design for reconstructive surgery., (© The Author(s) 2021. Published by Oxford University Press.)

Objectives: To clarify venous phase contrast-enhanced CT findings in early pancreatic adenocarcinomas by retrospectively evaluating CT images of pancreatic adenocarcinomas that developed during follow-up after treatment for non-pancreatic cancers., Methods: The study cohort comprised six patients who developed pancreatic adenocarcinomas between April 2005 and April 2020 during follow-up after treatment for non-pancreatic primary cancers. Two radiologists retrospectively evaluated CT images and reached consensus on previously reported CT findings that were suggestive of small pancreatic adenocarcinomas; namely pancreatic duct interruption and dilatation, pancreatic parenchymal atrophy, focal hypoattenuated areas, and appearance of cystic lesions. Time intervals between the first CT with these suggestive findings and the latest pre-operative CT were recorded. Doubling times were calculated in patients with hypoattenuated areas on initial CT scans., Results: Small (<10 mm) focal hypoattenuated areas with ( n = 2) or without rim enhancement ( n = 1) were identified on initial CT images of three patients. Pancreatic duct interruption and dilatation, pancreatic parenchymal atrophy, and cystic lesion were identified in two, one and one patient, respectively. Time intervals between initial and latest preoperative CT examination were 6-19 months (median, 14.5 months). Tumor doubling time according to CT findings was calculated as 46-407 days (median 106 days)., Conclusion: Venous phase contrast-enhanced CT can provide findings that are suggestive of early pancreatic adenocarcinoma. Pancreatic phase contrast-enhanced CT should therefore be performed in patients with such findings with the aim of early detection of pancreatic adenocarcinoma., Advances in Knowledge: Pancreatic adenocarcinoma can develop subsequently in patients with non-pancreatic malignancies. Patients with non-pancreatic cancers are often followed up with monophasic contrast-enhanced CT in venous phase timing. Venous phase contrast-enhanced CT can provide some findings suggestive of early pancreatic adenocarcinoma. Knowledge of these findings is important for early detection of pancreatic adenocarcinoma., (© 2021 The Authors. Published by the British Institute of Radiology.)

We have previously indicated that a single injection of alendronate, one of the nitrogen-containing bisphosphonates (NBPs), affects murine hematopoietic processes, such as the shift of erythropoiesis from bone marrow (BM) to spleen, disappearance of BM-resident macrophages, the increase of granulopoiesis in BM and an increase in the number of osteoclasts. NBPs induce apoptosis and the formation of giant osteoclasts in vitro and/or in patients undergoing long-term NBP treatment. Therefore, the time-kinetic effect of NBPs on osteoclasts needs to be clarified. In this study, we examined the effect of alendronate on mouse osteoclasts and osteoclastogenesis. One day after the treatment, osteoclasts lost the clear zone and ruffled borders, and the cell size decreased. After 2 days, the cytoplasm of osteoclasts became electron dense and the nuclei became pyknotic. Some of the cells had fragmented nuclei. After 4 days, osteoclasts had euchromatic nuclei attached to the bone surface. Osteoclasts had no clear zones or ruffled borders. After 7 days, osteoclasts formed giant osteoclasts via the fusion of multinuclear and mononuclear osteoclasts. These results indicate that NBPs affect osteoclasts and osteoclastogenesis via two different mechanisms., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Japanese Society of Microscopy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Regulation of hyaluronan (HA) is important for the maintenance of epidermal homeostasis. Here, we examined the mechanism by which 1-ethyl-β-N-acetylglucosaminide (β-NAG2), a newly developed N-acetylglucosamine (NAG) derivative, increases HA production in cultured human epidermal keratinocytes. When keratinocytes were treated with β-NAG2, mRNA expression of HA synthase 3, which is responsible for HA production in human keratinocytes, was not influenced, but the intracellular level of UDP-NAG, a substrate used for HA synthesis, was increased. By using a synthetic substrate for β-N-acetylglucosaminidase (β-NAGase), keratinocytes were found to possess β-NAGase activity, and treatment of o-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino N-phenyl carbamate (PUGNAc), an inhibitor of β-NAGase, abolished the release of NAG from β-NAG2 in keratinocytes. Furthermore, PUGNAc attenuated the β-NAG2-induced intracellular UDP-NAG and HA production in keratinocytes. These results suggest that β-NAG2 is converted to NAG by endogenous β-NAGase in keratinocytes, and the resulting NAG is further metabolized to UDP-NAG and utilized for HA production., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

In order to improve the safety of novel therapeutic drugs, better understanding of the mechanisms of action is important. Ado-trastuzumab emtansine (also known as T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive breast cancer. While the treatment with T-DM1 results in significant efficacy in the selected patient population, nonetheless, there are concerns with side effects such as thrombocytopenia and hepatotoxicity. While current understanding of the mechanism of T-DM1-mediated side effects is still incomplete, there have been several reports of HER2-dependent and/or -independent mechanisms that could be associated with the T-DM1-induced adverse events. This review highlights the importance of HER2-independent mechanism of T-DM1 to induce hepatotoxicity, which offers a new insight into a role for CKAP5 in the overall maytansinoid-based ADC (DM1 and DM4)-mediated cytotoxicity. This discovery provides a molecular basis for T-DM1-induced off-target toxicity and opens a new avenue for developing the next generation of ADCs., (Published by Oxford University Press on behalf of Antibody Therapeutics 2021.)

Objectives: To determine whether specific parameters contribute to clinical outcomes at 1 year post-diagnosis in early rheumatoid arthritis (RA) patients under the 'treat-to-target' strategy in clinical practice., Methods: We retrospectively analyzed 125 RA patients selected according to the following criteria; the patients' symptom duration was ≤6 months, and none had experience with DMARDs. We evaluated the patients' clinical disease activity at baseline and 1 year of treatment and the musculoskeletal ultrasound (MSUS)-detected synovitis activity at baseline. We performed an analysis to identify parameters that contribute to SDAI remission and the use of biologic/targeted synthetic (b/ts) DMARDs at 1 year post-diagnosis., Results: Forty-seven patients received b/tsDMARDs therapy, and 58 patients achieved SDAI remission at 1 year post-diagnosis. Rheumatoid factor positivity, low patient's/evaluator's global assessment at baseline, and methotrexate use at 1 year post-diagnosis were associated with SDAI remission. The baseline clinical disease activity and MSUS scores were not associated with SDAI remission. Anti-cyclic citrullinated peptide antibody positivity/high titer and high swollen joint counts or the presence of severe synovial hypertrophy at baseline were associated with the use of b/tsDMARDs therapy., Conclusion: The value of the expected poor-prognosis factors may be diminished by intensive therapy within the 'windows of opportunity'.

Objectives: Our newly developed brief collaborative care intervention program has been suggested to be effective in reducing breast cancer patients' unmet needs and psychological distress; however, there has been no controlled trial to investigate its effectiveness. The purpose of this study was to examine the effectiveness of the program in relation to patients' perceived needs and other relevant outcomes for patients including quality of life, psychological distress and fear of recurrence (Clinical trial register; UMIN-CTR, Clinical registration number; R5172)., Methods: Fifty-nine highly distressed breast cancer patients receiving adjuvant chemotherapy and/or hormonal therapy were randomly assigned either to a treatment as usual group or to a collaborative care intervention, consisting of four sessions that mainly included assessment of the patients' perceived needs, learning skills of problem-solving treatment for coping with unmet needs and psycho-education provided by trained nurses supervised by a psycho-oncologist., Results: Although >80% of the eligible patients agreed to participate, and >90% of participants completed the intervention, there were no significant differences with regard to patients' needs, quality of life, psychological distress and fear of recurrence, both at 1 and 3 months after intervention., Conclusion: Newly developed brief collaborative care intervention program was found to be feasible and acceptable. The trial, however, failed to show the effectiveness of the program on patients' relevant subjective outcomes. Further intervention program having both brevity and sufficient intensity should be developed in future studies., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: While the aetiology of idiopathic multicentric Castleman disease (iMCD) remains unclear, the involvement of autoinflammatory mechanisms has been suggested. Herein we report a Japanese patient with iMCD with a novel heterozygous Ile729Met mutation in exon 10 of the Mediterranean fever (MEFV) gene., Methods: We performed genetic analysis via targeted next-generation sequencing analysis and Sanger sequencing and conducted molecular dynamics simulations to investigate the hydrophobic interactions around the 729th amino acid in human pyrin., Results: In February 2011, a 59-year-old man was diagnosed with IgG4-related disease at our department based on the findings of cervical and hilar lymphadenopathies, typical lung lesions and cervical lymph node biopsy. The patient was followed up without treatment, as he was asymptomatic. However, he had been experiencing prolonged fatigue and fever with high levels of CRP since June 2017. Axillary lymph node biopsy findings led to the diagnosis of iMCD. He was successfully treated with an IL-6 inhibitor and has been in remission for 12 months. Genetic analyses for hereditary autoinflammatory disease-related genes were performed, revealing a novel heterozygous Ile729Met mutation in exon 10 of the MEFV gene. We identified that this novel mutation significantly altered the local interaction of the human pyrin B30.2 domain by molecular dynamics simulation analysis and experimentally had the potential for inflammasome activation with increased inflammatory cytokines., Conclusion: The abnormal function of pyrin due to a mutation in the MEFV gene in this patient may have contributed to the development of MCD by inducing IL-6 production via inflammasome signalling., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Hypothermic ex-situ machine perfusion (MP) has been shown to be a promising alternative to static cold storage (SCS) for preservation of solid organs for transplantation and vascularized composite allotransplantation. Perfusion with blood-based perfusion solutions in austere environments is problematic due to their need for appropriate storage and short shelf life, making it impractical for military and emergency use. Acellular perfusion has been shown to be effective, but the ideal perfusate solution for MP of amputated limbs is yet to be determined. The purpose of this study is to evaluate the efficacy of alternative perfusate solutions, such as dextran-enriched Phoxilium, Steen, and Phoxilium in ex-vivo hypothermic MP of amputated limbs in a porcine model., Materials and Methods: Amputated forelimbs from Yorkshire pigs (n = 8) were preserved either in SCS (n = 2) at 4°C for 12 hours or machine-perfused at 10°C for 12 hours with oxygenated perfusion solutions (n = 6) at a constant flow rate. The perfusates used include modified Steen-solution, Phoxilium (PHOX), or Phoxilium enriched with dextran-40 (PHODEX). The perfusate was exchanged after 1 and 6 hours of perfusion. Machine data were recorded continuously. Perfusate samples for clinical chemistry, blood gas analysis, and muscle biopsies were procured at specific timepoints and subsequently analyzed. In this semi in-vivo study, limb replantation has not been performed., Results: After amputation, every limb was successfully transferred and connected to our perfusion device. The mean total ischemia time was 77.5 ± 5.24 minutes. The temperature of the perfusion solution was maintained at 10.18 ± 2.01°C, and perfusion pressure at 24.48 ± 10.72 mmHg. Limb weight increased by 3% in the SCS group, 36% in the PHODEX group, 25% in the Steen group, and 58% in the PHOX group after 12 hours. This increase was significant in the PHOX group compared with the SCS group. All perfusion groups showed a pressure increase of 10.99 mmHg over time due to edema. The levels of HIF-1a decreased over time in all groups except the Steen and the PHODEX group. The biomarkers of muscle injury in the perfusate samples, such as creatine kinase and lactate-dehydrogenase, showed a significant difference between groups, with highest values in the PHODEX group. No significant differences were found in the results of the blood gas analysis., Conclusion: With the exception of significantly higher levels of creatine kinase and lactate dehydrogenase, MP with dextran-enriched Phoxilium provides similar results as that of the commercially available perfusates such as Steen, without the need for cold storage, and at circa 5% of the cost of the Steen solution. Further large-scale replantation studies are necessary to evaluate the efficacy of dextran-enriched Phoxilium as an alternate perfusate solution., (© Association of Military Surgeons of the United States 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Current guidelines do not recommend that sentinel lymph node biopsy is routinely performed for ductal carcinoma in situ; thus, indications for sentinel lymph node biopsy in patients with ductal carcinoma in situ remain controversial. In this study, we investigated whether sentinel lymph node biopsy can be safely omitted when ductal carcinoma in situ has been diagnosed by preoperative biopsy., Methods: We retrospectively analysed sentinel lymph node metastasis rates and upstaging to invasive cancer in surgical specimens, performed receiver operating characteristic analysis for ductal carcinoma in situ lesion size and assessed correlations with preoperative clinicopathological factors of 277 patients with ductal carcinoma in situ diagnosed by preoperative biopsy at our institution., Results: Among 277 patients with sentinel lymph node biopsy, six (2.2%) had sentinel lymph node metastasis. All six were upstaged to invasive cancer by pathological examination of surgical specimens. In total, 69 patients (24.9%) were upstaged to invasive cancer. The mean size of ductal carcinoma in situ lesions on preoperative imaging was significantly larger for the 69 upstaged patients (50.0 mm) than for the non-upstaged patients (34.4 mm; P < 0.0001). Of the 277 patients with sentinel lymph node biopsy, 117 (42.2%) had preoperative ductal carcinoma in situ lesions <31.8 mm, which was identified as the optimal cut-off size by receiver operating characteristic analysis. Of these 117 patients, 96 (82.1%, 95% confidence interval: 73.9-88.5%) could be safely omitted from sentinel lymph node biopsy because all of them remained as ductal carcinoma in situ and had negative sentinel lymph nodes at surgery., Conclusions: Size of ductal carcinoma in situ lesions on preoperative diagnostic imaging is a predictor of diagnosis of invasive cancer on pathological examination of surgical specimens. Sentinel lymph node biopsy may be unnecessary in ductal carcinoma in situ diagnosed by preoperative biopsy in patients with small lesions., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: We investigated the diagnostic efficacy of power Doppler ultrasound (PDUS) to detect enthesitis in Japanese patients with peripheral spondyloarthritis (SpA). Methods: This was a single-center cohort study of patients with peripheral symptoms suggestive of SpA. Articular synovia, tendons, and entheses were assessed by PDUS at baseline. Clinical, laboratory, and radiologic findings and classification criteria for SpA were also evaluated. Results: 136 patients were consecutively evaluated. A definite diagnosis was obtained in 111 patients, including 72 with SpA and 39 non-SpA. Among the patients with SpA, PDUS demonstrated articular synovitis in 40 of the 72 patients (56%), tenosynovitis or peritendinitis in 48 (67%), and enthesitis in 63 (88%). Considering PDUS alone, enthesitis in at least one site was the most useful means of differentiating SpA from non-SpA (sensitivity 87.5%; specificity 82.1%; accuracy 85.6%; positive likelihood ratio 4.88). Combining that finding along with fulfillment of Amor, European Spondyloarthropathy Study Group, or Assessment of SpondyloArthritis international Society criteria for peripheral SpA increased the specificity of the diagnosis (92.5%, 92.3%, and 97.4%, respectively). Conclusion: PDUS enthesitis is useful for the diagnosis of SpA with peripheral symptoms. Combining PDUS enthesitis with established SpA classification criteria is beneficial in diagnosing peripheral SpA.

Mammalian pluripotent stem cells (PSCs) have distinct molecular and biological characteristics among species, but to date we lack a comprehensive understanding of regulatory network evolution in mammals. Here, we carried out a comparative genetic analysis of 134 genes constituting the pluripotency gene regulatory network across 48 mammalian species covering all the major taxonomic groups. We report that mammalian genes in the pluripotency regulatory network show a remarkably high degree of evolutionary stasis, suggesting the conservation of fundamental biological process of mammalian PSCs across species. Nevertheless, despite the overall conservation of the regulatory network, we discovered rapid evolution of the downstream targets of the core regulatory elements and specific amino acid residues that have undergone positive selection. Our data indicate development of lineage-specific pluripotency regulating networks that may explain observed variations in some characteristics of mammalian PSCs. We further revealed that positively selected genes could be associated with species' unique adaptive characteristics that were not dedicated to regulation of PSCs. These results provide important insight into the evolution of the pluripotency gene regulatory network underlying variations in characteristics of mammalian PSCs., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Objective: A prospective, observational, post-marketing surveillance was conducted to assess the safety and effectiveness of temsirolimus in patients with renal cell carcinoma in Japan., Methods: Patients prescribed temsirolimus for advanced renal cell carcinoma were registered and received temsirolimus (25 mg weekly, intravenous infusion for 30-60 minutes) in routine clinical settings (observation period: 96 weeks)., Results: Among 1001 patients included in the safety analysis data set (median age, 65.0 years; men, 74.8%; Eastern Cooperative Oncology Group performance status 0 or 1, 69.6%), 778 (77.7%) reported adverse drug reactions. The most common (≥10%) all-grade adverse drug reactions were stomatitis (26.7%), interstitial lung disease (17.3%) and platelet count decreased (11.1%). The incidence rate of grade ≥3 interstitial lung disease was 4.5%. The onset of interstitial lung disease was more frequent after 4-8 weeks of treatment or in patients with lower Eastern Cooperative Oncology Group performance status (21.6% for score 0 vs 8.3% for score 4, P < 0.001). Among 654 patients in the effectiveness analysis data set, the response and clinical benefit rates were 6.7% (95% confidence interval 4.9-8.9) and 53.2% (95% confidence interval 49.3-57.1), respectively. The median progression-free survival was 18.3 weeks (95% confidence interval 16.9-21.1)., Conclusions: The safety and effectiveness profile of temsirolimus observed in this study was similar to that observed in the multinational phase 3 study. The results are generalizable to the real-world scenario at the time of this research, and safety and effectiveness of temsirolimus as a subsequent anticancer therapy for renal cell carcinoma warrants further investigation. (ClinicalTrials.gov identifier NCT01210482, NCT01420601)., (© The Author(s) 2020. Published by Oxford University Press.)

Objectives: The aim of this study was to develop and validate a simple and reliable gas chromatography-mass spectrometry (GC-MS) method to simultaneously determine urinary 1-naphthol (1-NAP) and 2-naphthol (2-NAP) for biological monitoring of occupational exposure to naphthalene., Methods: NAPs were derivatized in situ with acetic anhydride after enzymatic hydrolysis, extracted with n-hexane, and analyzed using GC-MS. Validation of the proposed method was conducted in accordance with US Food and Drug Administration guidance. A final validation was performed by analyzing a ClinChek ® -Control for phenolic compounds., Results: The linearity of calibration curves was indicated by a high correlation coefficient (>0.999) in the concentration range 1-100 μg/L for each NAP. The limits of detection and quantification for each NAP were 0.30 and 1.00 μg/L, respectively. The recovery was 90.8%-98.1%. The intraday and interday accuracies, expressed as the deviation from the nominal value, were 92.2%-99.9% and 93.4%-99.9%, respectively. The intraday and interday precision, expressed as the relative standard deviation, was 0.3%-3.9% and 0.4%-4.1%, respectively. The ClinChek ® values obtained using our method were sufficiently accurate., Conclusions: The proposed method is simple, reliable, and appropriate for routine analyses, and is useful for biological monitoring of naphthalene exposure in occupational health practice., (© 2020 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

Objectives: To evaluate the real-world safety and effectiveness of etanercept (ETN) in Japanese patients with rheumatoid arthritis. Methods: This postmarketing surveillance study (NCT00503139) assessed the safety and effectiveness of ETN treatment over 3 and 2 years (from June 2007 to September 2011), respectively. Safety was evaluated by occurrence and seriousness of adverse drug reactions (ADRs), and of adverse events (AEs) for malignancies. Effectiveness was assessed using the Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate (ESR) with four variables (swollen and tender joint counts, ESR, and patient global assessment; DAS28-4/ESR). Treatment was considered effective if patients had a good/moderate response by the European League Against Rheumatism response criteria. Results: ADRs occurred in 256/675 (37.9%) patients, the most common being injection site reactions (4.4%) and nasopharyngitis (3.3%). Serious ADRs occurred in 60/675 (8.9%) patients, the most frequent being pneumonia (1.2%). The incident rate of malignancies (AEs) was 1.06 per 100 patient-years. Mean baseline DAS28-4/ESR for the 581 patients included in effectiveness analysis was 5.42, which decreased to 3.32 at 2 years. Eighty-two percent of patients achieved a moderate/good response at 2 years. Conclusion: Long-term ETN treatment safety and effectiveness were sustained over 3 and 2 years, respectively.

Objective: Post-marketing surveillance (PMS) was performed in Japan to obtain information on the safety and efficacy of crizotinib., Methods: Target patients included almost all patients with anaplastic lymphoma kinase-positive non-small cell lung cancer who were administered crizotinib. The observation period was 52 weeks. In the present study, we focused on the treatment status and safety of crizotinib therapy and analyzed the real-world data obtained by this PMS (ClinicalTrials.gov: NCT01597258)., Results: The safety analysis set included 2028 Japanese patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of adverse drug reactions (ADRs) was 91.6%, and common ADRs (incidence ≥15%) were nausea (32.2%), diarrhea (24.3%), photopsia (18.9%), vomiting (17.5%) and dysgeusia (16.8%). Many patients (623 patients) discontinued treatment of crizotinib because of adverse events within 12 weeks after therapy initiation, which tended to frequently occur in the following cases: (1) elderly, (2) body weight <40 kg, (3) body surface area <1.2 m2 (4) ECOG PS 2-4, (5) higher Brinkman index and (6) history of occupational/environmental exposure such as asbestos/pneumoconiosis. The proportions of patients remaining on crizotinib therapy were 68.2% for 3 months, 55.2% for 6 months and 36.1% for 12 months, with a median duration of 7.9 months. Multivariate analysis with a Cox proportional hazard model identified 10 statistically significant patient background factors influencing the duration of crizotinib therapy., Conclusions: No new safety concerns were observed in this PMS study. Our results provide useful information regarding the status of crizotinib therapy in the clinical setting., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Pneumocystis pneumonia (PCP) is a serious complication in patients with rheumatic diseases who are receiving immunosuppressive therapy. These patients have a higher mortality from PCP than those with human immunodeficiency virus. We examined factors associated with poor prognosis in patients with rheumatic diseases and evaluated PCP treatment in this population. Methods: This retrospective, single-center, observational cohort study included 31 patients with rheumatic diseases who were admitted to Juntendo University Hospital for PCP treatment from June 2006 to December 2017. The primary outcome was non-disease-specific mortality at discharge. Results: The median age at PCP diagnosis was 64 years. The survival rate was 61.3% (19/31). Twelve patients died, in all cases due to respiratory failure due to PCP. Among variables at PCP diagnosis and those related to PCP treatment, the presence of coexisting pulmonary diseases and greater glucocorticoid dose at PCP diagnosis were associated with higher mortality. The mortality related to biological agents for PCP was low. Rapid tapering of glucocorticoids improved survivability. Conclusion: In the treatment of PCP in patients with rheumatic diseases, rapid tapering of glucocorticoids was associated with a higher survival rate than the use of conventional therapy.

Acetoaceto-o-toluidide (AAOT) is made from ortho-toluidine (OTD) and is used for the synthesis of pigments. A report of occupational urinary bladder carcinomas in Japanese workers chronically exposed to OTD and AAOT has recently been published. OTD is a well-known human urinary bladder carcinogen; however, little is known about the toxicity and the carcinogenicity of AAOT. The aim of the present study is to evaluate the toxic effects of AAOT on urinary bladder epithelium. In vitro, the cytotoxicities of AAOT and OTD were evaluated in rat (MYP3) and human (1T1) urothelial cells. The LC50 of AAOT was higher than that of OTD in both MYP cells and 1T1 cells. In vivo, 6-week-old male and female F344 rats were fed diets supplemented with 0%, 1.5%, or 3% AAOT for 4 weeks. Incidences of simple hyperplasia, cell proliferative activity, and γ-H2AX expression, which is a novel marker for the prediction of carcinogenicity, were significantly increased in a dose-dependent manner in the bladder urothelium of male and female rats administered AAOT. Furthermore, in male and female rats administered AAOT, the major urine metabolite of AAOT was OTD. These results demonstrate that AAOT has proliferation-enhancing activity and suggest that OTD metabolized from AAOT may play a pivotal role in the deleterious effects of AAOT in rats. The results of the present study also indicate that AAOT, like other carcinogenic aromatic amines, is likely to be a human bladder carcinogen., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Tumor protein 53-induced nuclear protein 1 (TP53INP1) is a key stress protein with tumor suppressor function. Several studies have demonstrated TP53INP1 downregulation in many cancers. In this study, we investigated the correlations of TP53INP1 mRNA expression in breast cancer tissues with prognosis and the correlations of microRNAs that regulate TP53INP1 expression in breast cancer patients with long follow-up., Methods: A total of 453 invasive breast cancer tissues were analyzed for TP53INP1 mRNA expression. We examined correlations of clinicopathological factors and expression levels of TP53INP1 mRNA in these samples. The expressions of miR-155, miR-569 and markers associated with tumor-initiating capacity were also analyzed. The median follow-up period was 9.0 years., Results: We found positive correlations between low expression of TP53INP1 mRNA and shorter disease-free survival and overall survival in breast cancer patients (P = 0.0002 and P < 0.0001, respectively), as well as in estrogen receptor α (ERα)-positive patients receiving adjuvant endocrine therapy (P = 0.01 and P = 0.0008, respectively). No correlations were found in ERα-negative patients. Low TP53INP1 mRNA levels positively correlated with higher grade and ERα-negativity. Multivariate analysis indicated that TP53INP1 mRNA level was an independent risk factor for overall survival both in overall breast cancer patients (hazard ratio, 2.13; 95% confidence interval, 1.17-3.92) and ERα-positive patients (hazard ratio, 2.34; 95% confidence interval, 1.18-4.64)., Conclusions: We show that low expression of TP53INP1 is an independent factor of poor prognosis in breast cancer patients, especially ERα-positive patients. TP53INP1 might be a promising candidate biomarker and therapeutic target in ERα-positive breast cancer patients., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)