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Background: This study aimed to evaluate the safety and efficacy of first-line nivolumab plus chemotherapy for real-world patients with human epidermal growth factor receptor 2 (HER2)-negative advanced gastric cancer (AGC). Materials and methods: This single-institutional retrospective study enrolled patients with HER2-negative AGC who were treated with nivolumab plus chemotherapy between September 2021 and January 2024. Early tumor shrinkage (ETS) and depth of response (DpR) were assessed. Results: There were 136 patients with a median age of 65 years (range 27-83 years); 57% were men, the rate of programmed cell death ligand 1 combined positive score of

Background: Trifluridine (FTD)/tipiracil (TPI) is a standard salvage treatment for advanced gastric cancer (AGC). This study aimed to assess the efficacy and safety of FTD/TPI in heavily pretreated patients with AGC in clinical practice. Materials and methods: This retrospective cohort study conducted at a single Japanese institute between November 2019 and May 2022 included patients with inoperable advanced or recurrent gastric cancer (GC) who received FTD/TPI with or without ramucirumab (RAM) in the third-line or later setting. Univariate and multivariate analyses were carried out to examine the clinical factors associated with disease progression and survival. Results: A total of 98 consecutive patients, including 2 patients treated with RAM, were enrolled. Eighty-five patients had prior immune checkpoint inhibitor administration before FTD/TPI and 86 patients were treated with FTD/FPI as the fourth or later line of treatment. Objective response rate was 2.3% (2/87), and disease control rate was 40.2% (35/87). Nausea, anorexia, and diarrhea were the observed adverse events (AEs) in 45, 24, and 19 patients, respectively. The most common grade 3 or 4 AE was neutropenia. Multivariate analysis revealed that performance status (PS) ≥1, elevated serum carcinoembryonic antigen (CEA) and/or carbohydrate antigen 19-9 (CA19-9) levels, and primary tumor location were independently associated with shorter progression-free survival. In terms of overall survival, PS ≥1, elevated serum CEA and/or CA19-9, and the presence of moderate to severe ascites demonstrated statistically significant associations with poorer survival. Conclusions: FTD/TPI could be a therapeutic option for AGC patients previously treated with nivolumab in clinical practice. AEs associated with FTD/TPI were manageable in heavily pretreated patients with AGC.

Small-cell neuroendocrine carcinoma (SCNEC) of the cervix is a rare disease characterized by a high incidence of mixed tumors with other types of cancer. The mechanism underlying this mixed phenotype is not well understood. This study established a panel of organoid lines from patients with SCNEC of the cervix and ultimately focused on one line, which retained a mixed tumor phenotype, both in vitro and in vivo. Histologically, both organoids and xenograft tumors showed distinct differentiation into either SCNEC or adenocarcinoma in some regions and ambiguous differentiation in others. Tracking single cells indicated the existence of cells with bipotential differentiation toward SCNEC and adenocarcinomas. Single-cell transcriptional analysis identified three distinct clusters: SCNEC-like, adenocarcinoma-like, and a cluster lacking specific differentiation markers. The expression of neuroendocrine markers was enriched in the SCNEC-like cluster but not exclusively. Human papillomavirus 18 E6 was enriched in the SCNEC-like cluster, which showed higher proliferation and lower levels of the p53 pathway. After treatment with anticancer drugs, the expression of adenocarcinoma markers increased, whereas that of SCNEC decreased. Using a reporter system for keratin 19 expression, changes in the differentiation of each cell were shown to be associated with the shift in differentiation induced by drug treatment. These data suggest that mixed SCNEC/cervical tumors have a clonal origin and are characterized by an ambiguous and flexible differentiation state., Competing Interests: Disclosure Statement J.K., K.O., and M.I. are members of the Department of Clinical Bio-resource Research and Development at Kyoto University, which is sponsored by KBBM, Inc. H.U. is an employee of KBBM, Inc., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Although findings from both animal and clinical research indicate that the blood-brain barrier (BBB) contributes to the pathogenesis of various psychiatric disorders (including depression), the underlying mechanisms are unknown. We investigated the levels of the tight-junction proteins claudin-5 and aquaporin-4 (AQP-4) in astrocytes of learned helplessness (LH) rats (an animal model of depression) and non-LH rats (a model of resilience)., Methods: We administered inescapable mild electric shock to rats and then identified the LH and non-LH rats by a post-shock test. The expressions of claudin-5 and AQP-4 in several brain regions of the LH and non-LH rats were then evaluated by a western blot analysis., Results: The levels of both claudin-5 and AQP-4 in the CA-1 and CA-3 hippocampal areas of the LH group were significantly lower than those of the control group, whereas those of the non-LH rats were not significantly different from those of the control and LH rats., Conclusions: These results suggest that LH rats but not non-LH rats experienced down-regulations of claudin-5 and AQP-4 in the CA-1 and CA-3. It is possible that a region-specific modulation of claudin-5 and AQP-4 is involved in the mechanisms of vulnerability but not resilience in depression., Competing Interests: Declaration of competing interest On behalf of all the authors, the corresponding author states that there is no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Efficacy of anti-PD-1 antibody monotherapy (PD1) or anti-PD-1 plus anti-CTLA-4 combination therapy (PD1 +CTLA4) for melanoma is affected by its clinical subtype. The amount of tumor mutation burden (TMB) caused by cumulative sun damage (CSD) is occasionally used to explain this; however, their relationship in Japanese nonacral cutaneous melanoma (NACM) is still unclear., Objective: To analyze the ICI efficacy and its relationship with CSD of the primary lesion in Japanese patients with NACM., Methods: Japanese patients with advanced BRAF wild-type NACM who received first-line ICIs were recruited. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), and the degree of solar elastosis (SE) were evaluated., Results: A total of 146 patients (PD1 group 113 and PD1 +CTLA4 group 33) were included. No significant differences in ORR were observed between the PD1 and PD1 +CTLA4 groups (35 % vs. 36 %; P = 0.67) or PFS and OS (median PFS 6.1 months vs. 8.5 months; P = 0.46, median OS 28.1 months vs. not reached; P = 0.59). Multivariate survival analysis revealed that PD1 +CTLA4 did not prolong the PFS and OS. The SE score had no effect on either PFS or OS., Conclusions: ICI efficacy was not as high as those reported in Western countries, and PD1 +CTLA4 did not present better clinical efficacy compared to PD1. Indicators of CSD did not serve as a predictor for clinical advantage. These findings may partially support the theory that ICI efficacy is affected by CSD; however, other unrecognized factors may also exist., Competing Interests: Conflict of interest Takashi Inozume has received honoraria from Bristol-Myers Squibb (BMS), Ono Pharma, and MSD. Kenjiro Namikawa has served as a consultant or/and has received honoraria from BMS, MSD, Novartis, and Ono Pharma. Hiroshi Kato has received honoraria from Novartis and Ono Pharma. Shusuke Yoshikawa has received honoraria from Novartis and Ono Pharma. Yukiko Kiniwa has received honoraria from Novartis and Ono Pharma. Tatsuya Takenouchi has received honoraria BMS, MSD, Novartis, and Ono Pharma. Shigeto Matsushita has received honoraria from BMS, MSD, Novartis, and Ono Pharma. Yasuhiro Fujisawa received honoraria from BMS, MSD, Novartis, Ono Pharma, and Eizai. Takeo Maekawa has received honoraria from BMS, MSD, Novartis, and Ono Pharma. Taiki Isei has served as a consultant or/and has received honoraria from Ono, Pfizer, BMS, and Novartis Pharma. Masahito Yasuda received honoraria from Novartis. Naoya Yamazaki receives institutional research funding from BMS, MSD, Novartis, Ono, and Takara Bio, and has served as consultant or/and has received honoraria from BMS, MSD, Novartis, and Ono Pharma. Hisashi Uhara received honoraria from BMS, MSD, Novartis, Ono Pharma, Taiho, Sun Pharma, Mitsubishi Tanabe Pharma, Janssen Pharma, Kyowa Hakko Kirin, and Merck Biopharma Co. Yasuhiro Nakamura has served as a consultant or/and has received honoraria from MSD, Novartis, BMS, Maruho, Ono Pharma, Taisho Toyama, and Taiho Pharma. The other authors have no conflicts of interest to disclose., (Copyright © 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: The aim of this research was to investigate the factors associated with postponing dental attendance amongst Japanese workers during the coronavirus disease 2019 (COVID-19) pandemic., Methods: We conducted an internet-based survey in Japan from November 24 to 29, 2021. The participants were selected from people registered with an online research company. The inclusion criteria for this study were full-time or part-time workers aged 20 to 69 years. Participants filled out a questionnaire about their oral health, behaviour, and working conditions., Results: A total of 1840 participants were included in the analysis. Three hundred ninety-eight participants (21.5%) answered that they postponed dental attendance due to COVID-19. Multiple logistic regression showed that women were more likely to postpone dental attendance (odds ratio [OR], 1.74; 95% confidence interval, 1.33-2.26). Moreover, employment status, household income, changes in income, working at home, interdental cleaning device use, regular dental attendance, awareness of untreated teeth, and dental pain were also associated with postponing dental attendance. The results of decision tree analysis showed that regular dental attenders with dental pain were the most likely to postpone dental attendance., Conclusions: The characteristics of postponed dental visits for Japanese workers differ depending on whether one is a regular dental attender or not. Amongst regular dental attenders, worsening oral health due to interruptions in dental attendance is concerning. Meanwhile, untreated teeth might be neglected amongst nonregular dental attenders. Preventing patients from refraining from dental attendance, regardless of whether or not they are regular dental attenders, is important during the COVID-19 pandemic., Competing Interests: Conflict of interest None disclosed., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The Testicular Workup for Ischemia and Suspected Torsion (TWIST) score was created to help physicians in the clinical evaluation of acute scrotum in which testicular torsion (TT) is suspected. There have been only a few reports on validation of the TWIST score since the original study was published., Objectives: To validate the TWIST score as a scoring system., Patients and Methods: We reviewed the records of 106 patients with acute scrotum in our prospectively maintained database. The patients were divided into two groups by the final diagnosis: testicular torsion (group TT) or non-testicular torsion (group NTT). We retrospectively calculated the TWIST score of the patients. Patients were divided into low (0-2), intermediate (3-4), or high (5-7) risk groups according to the total score., Results: Fifteen patients (14%) had TT. The median age at presentation was 13.3 years (range 1.6-16.2) in group TT and 10.4 years (range 0.25-18.9) in group NTT, respectively. The sensitivity of clinical and Color Doppler ultrasonography (CDUS) findings to diagnose TT was 100%, whereas the specificity was 93.4%. Positive predictive value (PPV) and negative predictive value (NPV) were 71.4% and 100%, respectively. According to the calculated TWIST score, 65, 23, and 18 patients belonged to low, intermediate, and high risk groups, respectively. TT was found in 1(1.3%), 3(13%), and 11 (61%) patients of low, intermediate, and high risk groups, respectively. The NPV of the TWIST score for the low risk group was 98.5%, whereas the PPV of the TWIST score for the high risk group was 61.1%. Among the four patients with TT in low risk and intermediate risk groups, three patients presented to our institutions within 6 h after the onset. The torsion was 180° in two of the three patients., Conclusion: The TWIST score can be useful for clinical diagnosis of testicular torsion, but is inferior to clinical findings along with CDUS. We should consider the possibility that a TWIST score could be underestimated when patients present with acute scrotum immediately after onset or the affected testis is mildly twisted., (Copyright © 2022 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: The excessive blockade of dopamine D2 receptors (DRD2s) with long-term antipsychotic treatment is known to induce a dopamine supersensitivity state (DSS). The mechanism of DSS is speculated to be a compensatory up-regulation of DRD2s, but an excess blockade of DRD2s can also cause glutamatergic neuronal damage. Herein, we investigated whether antipsychotic-induced neuronal damage plays a role in the development of DSS., Methods: Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSS rats and non-DSS rats based on their voluntary locomotion data. We then determined the tissue levels of glutamate transporter-1 (GLT-1)/glutamine synthetase (GS) and heat shock protein-70 (HSP-70) in the rats' brain regions., Results: The levels of HSP-70 in the striatum and CA-3 region of the DSS rats were significantly higher than those of the control and non-DSS rats, whereas the dentate gyrus HSP-70 levels in both the DSS and non-DSS rats were increased versus the controls. The levels of GLT-1/GS in the CA-3 and nucleus accumbens were increased in the DSS rats., Conclusions: These results suggest that the DSS rats experienced striatal neuronal damage and indicate that a HAL-induced upregulation of HSP-70 and the GLT-1/GS system in the CA3 may be involved in the development of DSS. It remains unknown why the non-DSS rats did not suffer neuronal damage. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, dopamine supersensitivity psychosis, and tardive dyskinesia, further investigations of our findings are warranted., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The aim of this systematic review is to evaluate the current evidence in the context of clinical prediction model for post-hepatectomy liver failure (PHLF)., Methods: A systematic search of the English literature for a period from December 2005 to September 2020 was conducted. Primary outcome was defined using the three common PHLF criteria (50-50 criteria, peak bilirubin>7 mg/dl criteria, and ≥ grade B PHLF criteria by the International Study Group of Liver Surgery). Studies that reported the value of area under receiver operative characteristic curve (AUC) for the occurrence of PHLF were included., Results: Twenty eight of 1327 screened articles were eligible for inclusion. Eighteen studies developed the prediction models. The median AUC was found to be 0.79 (0.65-0.933). The parameters related to the amount of future liver remnant volume were most commonly identified as significant predictors for PHLF in statistical analysis (24 studies) and were most frequently incorporated in the prediction models (18 studies). The parameters associated with portal hypertension were significant for predicting PHLF in 16 studies and were adopted in the prediction models in 14 studies., Conclusion: Parameters related to future liver remnant volume and portal hypertension seem to be facilitating in predicting PHLF., (Copyright © 2021 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Clinical and animal studies have suggested a possible beneficial effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH). Although SGLT2 inhibitors have been shown to reduce hepatic fat deposition in association with loss of body weight, the mechanism of this action has remained unknown. We here show that the SGLT2 inhibitor canagliflozin ameliorated fatty liver and hyperglycemia without affecting body weight or epididymal fat weight in obese diabetic KKAy mice. Lipidomics analysis based on liquid chromatography and tandem mass spectrometry revealed that canagliflozin treatment increased the amounts of prostaglandin E 2 (PGE 2 ) and resolvin E3 in the liver of these mice. We also found that PGE 2 attenuated fat deposition in mouse primary hepatocytes exposed to palmitic acid. Our results thus suggest that PGE 2 may play an important role in the amelioration of hepatic fat deposition by canagliflozin, with elucidation of its mechanism of action potentially providing a basis for the development of new therapeutics for NAFLD-NASH., Competing Interests: Declaration of competing interest T.H. is a member of the Joint Research Course (Division of Development of Advanced Therapy for Metabolic Disease) established with funds from Boehringer Ingelheim. W.O. has received research grants from Mitsubishi Tanabe Pharma Corp., Kowa Pharmaceutical Co., Novo Nordisk Pharma, Astellas Pharma Inc., Dainippon Sumitomo Pharma Co., Ono Pharmaceutical Co., Takeda Pharmaceutical Co., Abbott, Novartis Pharmaceuticals, Daiichi Sankyo, Eli Lilly, and Boehringer Ingelheim as well as lecture fees from Mitsubishi Tanabe Pharma Corp., Dainippon Sumitomo Pharma Co., Novartis Pharmaceuticals, Boehringer Ingelheim, Takeda Pharmaceutical Co., and Abbott Japan., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Although the learning curve in various surgical procedures is increasingly discussed, there have been only a few reports about the learning curve especially in proximal hypospadias repair., Objectives: To evaluate the learning curve in one-stage hypospadias repair for proximal hypospadias., Materials and Methods: We retrospectively reviewed 73 cases of primary hypospadias repair by a single pediatric urologist using one-stage urethroplasty with a preputial skin graft between 2007 and 2018. The overall complication rate included fistula, glans dehiscence, and meatal stenosis. To analyze the impact of the surgeon's experience on the complication rate, we compared the complication rates among different groups of 20 consecutive cases each. In addition, we graphed the actual data of the operative time and cumulative complication rate to evaluate the learning curve. The cumulative complication rate was defined as the surgeon's complication rate (the number of complications accumulated at a time/number of cases at that time)., Results: The median age at surgery was 18 months (range: 7-87). The median follow-up was 40 months (range: 3-114). In total, 13 (18%) children had complications: 9 fistulae, 3 glans dehiscence, and 2 metal stenoses. The analysis of each 20 cases revealed that the complication rate declined over time as the surgeon became more experienced. It was mainly attributed to a decline of the fistula rate. The diagram of the operative time showed a reduction with the increasing surgical experience. Additionally, the diagram of the cumulative complication rate demonstrated a plateau after 50 cases., Conclusion: Our study showed the positive impact of surgeon experience on the outcome of one-stage repair for proximal hypospadias. In addition, the learning curve in proximal hypospadias repair stabilized after about 50 cases although the supervision of experienced surgeons is required during the early phase of learning curve., Competing Interests: Conflict of interest None declared., (Copyright © 2021 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: Uterine leiomyosarcoma is a rare and aggressive gynecologic malignancy originating in the myometrium of the uterine corpus that tends to recur even after complete surgical excision. Current therapeutic agents have only modest effects on uterine leiomyosarcoma. Although antibodies and antibody-drug conjugates have been recognized as useful targeted therapies for other cancers, no study has yet evaluated the effects of this approach on uterine leiomyosarcoma., Objective: This study aimed to examine the activity of tumoral CD70 in uterine leiomyosarcoma and assess the antitumor activity of CD70-antibody-drug conjugate treatment in uterine leiomyosarcoma., Study Design: Target membrane proteins were screened by profiling and comparing membrane protein expression in 3 uterine leiomyosarcoma cell lines (SK-UT-1, SK-LMS-1, and SKN) and normal uterine myometrium cells using the isobaric tags for relative and absolute quantitation labeling method. Western blotting, fluorescence-activated cell sorting analyses, and immunohistochemistry were used to examine CD70 expression in the membrane proteins in uterine leiomyosarcoma cell lines and clinical samples. We developed an antibody-drug conjugate with a monoclonal antibody of the target membrane protein linked to monomethyl auristatin F and investigated its antitumor effects against uterine leiomyosarcoma (in vitro, in vivo, and in patient-derived xenograft models)., Results: CD70 was identified as a specific antigen highly expressed in uterine leiomyosarcoma cell lines. Of the 3 uterine leiomyosarcoma cell lines, CD70 expression was confirmed in SK-LMS-1 cells by western blotting and fluorescence-activated cell sorting analysis. CD70 overexpression was observed in 19 of 21 (90.5%) tumor specimens from women with uterine leiomyosarcoma. To generate CD70-antibody-drug conjugate, anti-CD70 monoclonal antibody was conjugated with a novel derivative of monomethyl auristatin F. CD70-antibody-drug conjugate showed significant antitumor effects on SK-LMS-1 cells (half maximal inhibitory concentration, 0.120 nM) and no antitumor effects on CD70-negative uterine leiomyosarcoma cells. CD70-antibody-drug conjugate significantly inhibited tumor growth in the SK-LMS-1 xenograft mouse model (tumor volume, 129.8 vs 285.5 mm 3 ; relative reduction, 54.5%; P<.001) and patient-derived xenograft mouse model (tumor volume, 128.1 vs 837.7 mm 3 ; relative reduction, 84.7%; P<.001)., Conclusion: Uterine leiomyosarcoma tumors highly express CD70 and targeted therapy with CD70-antibody-drug conjugate may have a potential therapeutic implication in the treatment of uterine leiomyosarcoma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM., Patients and Methods: We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan-Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies., Results: In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group [6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026]. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03)., Conclusions: Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors., Competing Interests: Disclosure YN has served as an advisor/consultant to MSD and Novartis and has received honoraria from Bristol-Myers Squibb, Maruho, MSD, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, and Taisho Toyama Pharma. KN has served as an advisor/consultant to Bristol-Myers Squibb, MSD, Novartis, and Ono Pharmaceutical, and has received honoraria from Bristol-Myers Squibb, Eisai, MSD, Novartis, Ono Pharmaceutical, Pharma International, Takara Bio, and Toray Industries. KY has served as an advisor/consultant to Brystol-Myers-Squibb, Novartis, and Ono Pharmaceutical, and has received honoraria from Bristol-Myers Squibb, Novartis, and Ono Pharmaceutical. SY has served as an advisor/consultant to Novartis and has received honoraria from Bristol-Myers Squibb, MSD, Novartis, and Ono Pharmaceutical. HU has received honoraria from Bristol-Myers Squibb, Novartis, and Ono Pharmaceutical. YN has received honoraria from Ono Pharmaceutical. SF receives institutional research funding from Brystol-Myers-Squibb, MSD, and Ono Pharmaceutical, and has received honoraria from MSD and Ono Pharmaceutical. TT has received honoraria from Bristol-Myers Squibb, MSD, Novartis, and Ono Pharmaceutical. HU receives institutional research funding from Abbvie, Daiichi Synkyo, Eisai, Kaken Pharmaceutical, Kyowa Hakko Kirin, Maruho, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co. Ltd., Nihonkayaku, Ono Pharmaceutical, Pola Pharma, Taiho Pharmaceutical, Torii Pharmaceutical, and Tsumura & Co, has served as an advisor/consultant to Bristol-Myers Squibb, Chugai Pharma, Kyowa Hakko Kirin, MSD, Novartis, and Ono Pharmaceutical, and has received honoraria from Bristol-Myers Squibb, Chugai Pharma, Maruho, MSD, Novartis, Ono Pharmaceutical, Pola Pharma, Janssen China R&D, Kyowa Hakko Kirin, and Mitsubishi Tanabe Pharma. TF receives institutional research funding from MSD, Ono Pharmaceutical, and Zenyaku Kogyo, and has received honoraria from Bristol-Myers Squibb, Minophagen Pharmaceuticals, MSD, Novartis, and Ono Pharmaceutical. YT has received honoraria from Bristol-Myers Squibb, Maruho, and Ono Pharmaceutical. AO receives institutional research funding from Bristol-Myers Squibb and Ono Pharmaceutical and has received honoraria from Bristol-Myers Squibb and Ono Pharmaceutical. SM has received honoraria from Bristol-Myers Squibb, Kyowa Hakko Kirin, MSD, and Ono Pharmaceutical. TI has received honoraria from Bristol-Myers Squibb, MSD, Novartis, and Ono Pharmaceutical. NY receives institutional research funding from Bristol-Myers Squibb, MSD, Novartis, Ono Pharmaceutical, and Takara Bio, and has received honoraria from Bristol-Myers Squibb, MSD, Novartis, and Ono Pharmaceutical. None of these entities had any role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript. All remaining authors have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Neuroendocrine carcinoma of small cell type (SCNEC) is a rare pathological subtype in cervical cancer, which has a worse prognosis than other histological cell types. Due to its low incidence and the lack of experimental platforms, the molecular characteristics of SCNEC in the cervix remain largely unknown. Using the cancer tissue-originated spheroid (CTOS) method-an ex vivo 3D culture system that preserves the differentiation status of the original tumors-we established a panel of CTOS lines of SCNEC. We demonstrated that xenograft tumors and CTOSs, respectively, exhibited substantial intra-tumor and intra-CTOS variation in the expression levels of chromogranin A (CHGA), a neuroendocrine tumor marker. Since hypoxia affects differentiation in various tumors and in stem cells, we also investigated how hypoxia affected neuroendocrine differentiation of SCNEC of the uterine cervix. In the CTOS line cerv21, hypoxia suppressed expression of the neuroendocrine markers CHGA and synaptophysin (SYP). Flow cytometry analysis using CD99 (a membrane protein marker of SCNEC) revealed decreased CD99 expression in a subset of cells under hypoxic conditions. These expression changes were attenuated by HIF-1α knockdown, and by a Notch inhibitor, suggesting that these molecules played a role in the regulation of neuroendocrine differentiation. The examined SCNEC markers were suppressed under hypoxia in multiple CTOS lines. Overall, our present results indicated that neuroendocrine differentiation in SCNEC of the uterus is a variable phenotype, and that hypoxia may be one of the factors regulating the differentiation status., Competing Interests: Declaration of competing interest J.K. and M.I. belong to the Department of Clinical Bio-resource Research and Development in at Kyoto University, which is sponsored by KBBM, Inc., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To investigate factors associated with the development of root caries in dentition without root caries experience and interactive relationships between risk factors., Methods: We conducted surveys, consisting of an oral examination (oral hygiene, assessment of the number of teeth, coronal and root caries) and a self-reported questionnaire, among employees of a company in Tokyo, Japan in 2016 and 2018. Questionnaires collected data on smoking status, oral hygiene habits, sugar intake, and frequency of dental visits. Multiple logistic regression and decision tree analyses were used to determine factors associated with the development of root caries., Results: A total of 299 participants aged 25-63 years were included in the analysis. Males, older adults, smokers/past smokers had a significantly greater risk of developing root caries. The risk of developing root caries was significantly associated with the number of teeth with gingival recession at baseline (6-9 teeth, odds ratio [OR]: 7.69, 95 % confidence interval [CI]: 2.31-25.56; 10+ teeth, OR: 9.19, 95 % CI: 2.73-30.95, relative to ≤5 teeth); and with the number of coronal decayed and filled (DF) teeth (11-13 teeth, OR: 3.21, 95 % CI: 1.12-9.24; and ≥14 teeth, OR: 3.60, 95 % CI: 1.27-10.20, relative to ≤10 teeth). Other factors associated with root caries development differed according to the number of teeth with gingival recession and included drinking sugar-sweetened beverages, and the amount of toothpaste used., Conclusions: Gingival recession and number of coronal DF teeth were associated with the development of root caries., Clinical Significance: Multiple factors are associated with root caries development. The effect of risk factors such as drinking sweetened beverages and less toothpaste use is greater in individuals with greater gingival recession and more coronal decayed and filled teeth. Dental practitioners should focus on modifiable risk factors to prevent root caries., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This study aimed to evaluate postoperative long-term liver restoration and splenic enlargement and their clinical significance in living donor liver transplantation. One hundred and sixteen donors who had donated livers more than 5 years previously accepted the invitation to participate in this study. The liver restoration rate and the splenic enlargement rate were calculated as the rate with respect to the original volume. The mean liver restoration rate was 0.99 ± 0.12 and older age was associated with a higher incidence for liver restoration rate <0.95 (P = .005), whereas type of donor operation was not. The donors with liver restoration rate <0.95 showed lower serum albumin levels than those with liver restoration rate ≥0.95. The mean splenic enlargement rate was 1.10 ± 0.16. Right lobe donors demonstrated higher splenic enlargement rate (1.14 ± 0.18) than left lobe/lateral segment donors (1.06 ± 0.13). In the donors with splenic enlargement rate ≥1.10, platelet count was not fully restored to the preoperative level. In conclusion, older age increases the risk for incomplete postoperative liver restoration, which may be associated with a decrease in albumin more than 5 years after donation. Right lobe donation poses a risk of splenic enlargement, which is associated with incomplete restoration of platelet count., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Multidrug resistance is a major concern in uterine leiomyosarcoma treatment. Development of effective chemotherapies and management of drug resistance in patients is necessary. The copper efflux transporter adenosine triphosphatase copper transporting beta is a member of the P-type adenosine triphosphatase family and is also known as a strong platinum efflux transporter. Various reports have shown the association between adenosine triphosphatase copper transporting beta and platinum resistance; however, suitable inhibitors or methods for inhibiting platinum efflux via adenosine triphosphatase copper transporting beta are not developed., Objective: Our study focused on platinum resistance in uterine leiomyosarcoma. The role of adenosine triphosphatase copper transporting beta in uterine leiomyosarcoma resistance to platinum drugs was investigated both in vitro and in vivo., Study Design: Adenosine triphosphatase copper transporting beta expression was investigated by Western blotting and the efficacy of copper sulfate pretreatment and cisplatin administration in adenosine triphosphatase copper transporting beta-expressing cells was investigated both in vitro and in vivo., Results: Western blot analysis of SK-LMS-1 cells (uterine leiomyosarcoma cell line) revealed strong adenosine triphosphatase copper transporting beta expression. A permanent SK-LMS-ATPase copper transporting beta-suppressed cell line (SK-LMS-7B cells) was generated, and cisplatin exhibited a significant antitumor effect in SK-LMS-7B cells, both in vitro (SK-LMS-1 cells, half-maximal inhibitory concentration, 17.2 μM; SK-LMS-7B cells, half-maximal inhibitory concentration, 4.2 μM, P < .01) and in xenografts compared with that in SK-LMS-1 cells (5.8% vs 62.8%, P < .01). Copper sulfate was identified as a preferential inhibitor of platinum efflux via adenosine triphosphatase copper transporting beta. In SK-LMS-1 cells pretreated with 15 μM copper sulfate for 3 hours, the cisplatin half-maximal inhibitory concentration decreased significantly compared with that in untreated cells and resulted in significantly increased intracellular platinum accumulation (1.9 pg/cell vs 8.6 pg/cell, P < .01). The combination of copper sulfate pretreatment with cisplatin administration was also effective in vivo and caused cisplatin to exhibit significantly increased antitumor effects in mice with SK-LMS-1 xenografts (3.1% vs 62.7%, P < .01)., Conclusion: Our study demonstrates that adenosine triphosphatase copper transporting beta is overexpressed in uterine leiomyosarcoma cells and that copper sulfate, which acts as an inhibitor of platinum efflux via adenosine triphosphatase copper transporting beta, may be a therapeutic agent in the treatment of uterine leiomyosarcoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In vitro testing can facilitate the rapid assessment of next generation nicotine delivery products (NGPs) with comparisons to combustible tobacco products. In vitro assays for cytotoxicity and oxidative stress were employed at BAT (UK) and JT (Japan) to test total particulate matter (TPM) of a scientific reference cigarette and aerosol collected mass (ACM) of a commercially available E-cigarette and two tobacco heating products (THP). 3R4F TPMs were generated using the Health Canada intense (HCI) regimen, a modified regime (mHCI) for the THP ACMs and the CORESTA recommended method no. 81 for the E-cigarette ACM. Human lung cells were exposed to the test product TPM/ACMs at concentrations between 0-200 μg/ml followed by the employment of commercially available assays for endpoint analysis that included reactive oxygen species (ROS) generation, the glutathione ratio (GSH:GSSG), activation of the antioxidant response elements (ARE) and cellular viability. TPM/ACM nicotine concentrations were quantified using a UPLC-PDA technique. At both laboratories the 3R4F TPM induced significant and dose-dependent responses in all in vitro assays, whereas no significant responses could be measured for the NGP ACMs. In conclusion, both laboratories obtained comparable results across all endpoints therefore demonstrating the utility of the in vitro techniques combined with standardised test products to support the assessment of NGPs., (Copyright © 2019. Published by Elsevier B.V.)

Background: Accurate evaluation of the postoperative position of total knee arthroplasty (TKA) components is crucial in the analysis of the association of alignments with clinical outcomes. The aim of this study was to investigate the reliability of measurements of component positions after TKA using three-dimensional computed tomography (3D-CT) reconstruction., Methods: Two independent orthopedic surgeons (an attending surgeon and a fellow) examined 30 knees after primary TKA. The coronal, sagittal, and rotational positions of the femoral and tibial components were measured twice at an interval of six weeks on 3D-CT images reconstructed using ZedKnee software. Mean intra- and interobserver differences of measured angles were calculated, and the intra- and interobserver reliability was determined using intraclass correlation coefficients (ICCs), with agreement assessed by Bland-Altman analysis., Results: The mean intraobserver difference between alignment measurements for femoral and tibial components was <2° (range 0.23-1.17°) and the mean interobserver difference was <1° (range 0.22-0.97°). The intra- and interobserver ICCs were >0.8 for all component positions. The only systematic bias found in the intra- and interobserver agreements occurred for the sagittal position of the femoral component., Conclusion: Three-dimensional-CT measurements of component positions after TKA showed good intra- and interobserver reliability for the femoral and tibial components in coronal, sagittal and rotational positions. The intra- and interobserver agreements were favorable for all but the sagittal position of the femur. These results suggest that 3D-CT can be used to evaluate the alignment of all TKA components except for the sagittal position of the femur., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Acute ischemic stroke caused by cervical internal carotid artery stenosis (ICS) with altered consciousness and progressive paralysis leads to a poor neurologic prognosis. When such a patient is brought to the hospital in the hyperacute phase, intravenous tissue plasminogen activator is first administered. However, when an indwelling carotid artery stent is required after administration, physicians often hesitate to use antithrombotic drugs. In this report, we propose performing staged angioplasty (SAP) for such cases., Methods: Four patients were retrospectively investigated. In all 4 patients, we immediately performed only percutaneous transluminal angioplasty (PTA) without antiplatelet drugs. If both cerebral perfusion on angiography and neurologic findings improved, no additional treatment was provided; otherwise, emergency carotid artery stenting (eCAS) was performed. In PTA-successful cases, eCAS or carotid endarterectomy (CEA) was performed with single or dual antiplatelet drugs at a later date., Results: The success rate of PTA was 50% (2 of 4), and the overall treatment success rate was 100% (4 of 4). Three patients had favorable outcomes (modified Rankin Scale [mRS] score 0-2), but unfortunately, 1 patient had severe disability (mRS score >3) on discharge. The PTA-successful patients had no perioperative complications. On the other hand, 1 of the 2 patients who underwent eCAS experienced embolic complications, including distal embolization., Conclusions: In this investigation, both eCAS and SAP could be performed safety. However, performing SAP first without antiplatelet drugs to avoid hemorrhagic complications and cerebral hyperperfusion syndrome appears to have considerable validity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The spontaneous expansion of tea cultivation has led to the degradation of forest ecosystem services in the Wuyishan national nature reserve (WNNR). In 2008, the local government put forward the policy of "returning tea to forests" (RTTF) to protect the forest ecosystem. However, in order to measure its effects over the past ten years, it is necessary to accurately quantify the economic benefits of this ecological policy. This study tracked the land use changes in WNNR during the last 17 years and estimated the ecosystem service value caused by the RTTF policy. We used virtual market methods to convert different types of public feedback into a unified monetary value, and estimated the economic benefits of RTTF by combining the land use changes. Results showed that the added value of forest ecosystem services not only compensated for the loss of tea profits, but also brought about remarkable economic benefits (approximately US$140 million). Through the combination of ecological changes and economic benefits, we proposed a future direction of the RTTF policy adjustment. More broadly, we provided a method to quantify economic effects (or economic losses) from the perspective of public feedback on the basis of ecological changes. This attempt has contributed to the solving of econometric problems related to ecological policy by combining bioinformatics with ecological economics., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Due to resistance and immune-related adverse events (irAE) some melanoma patients require ipilimumab after nivolumab therapy. However, little is known about the result of this switching., Objective: Investigate the outcome of ipilimumab switching in Japanese patients., Methods: We retrospectively collected 60 patients who were treated with ipilimumab after nivolumab from 9 institutes in Japan. Information of the primary tumor, treatment, response, irAE), and survival was collected., Results: In our cohort, acral lentiginous and mucosal melanoma accounted for 53% of the cases. The most common reason for initiating ipilimumab was disease progression (93%). Median interval from the last nivolumab administration to first ipilimumab administration was 29days. Only 38% of patients completed 4 injections of ipilimumab. The best overall response was 3.6%. IrAE occurred in 78% of patients and 70% of those were of grade 3/4 (G3/4) and 31% of patients experienced 2 or more irAEs. An within interval of 28days or less between the last nivolumab administration and ipilimumab administration was correlated with the development of G3/4 pyrexia and 3 or more irAEs, but irAE occurrence did not affect survival. Multivariate analysis showed that endocrine irAE (relative risk=0.22, P=0.015) and skin irAE (relative risk=2.78, P=0.048) were significant factors associated with survival., Conclusion: In our study, the response ratio to ipilimumab after nivolumab was unsatisfactory and associated with a high frequency of severe irAEs. As there are few second-line treatment options for patients with BRAF wild-type advanced melanoma after nivolumab failure, patients should be closely monitored if ipilimumab is initiated., (Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Pyrrocorphin is an air-sensitive porphyrinoid with a highly reduced hexahydroporphyrin core. In contrast, pyrrolidine-fused pyrrocorphin (Pyr) obtained by successive 1,3-dipolar cycloaddition reactions of azomethine ylide to 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin is less air-sensitive. In order to reveal the effect of highly reduced porphyrin rings on the physicochemical properties of their metal complexes, we have prepared diamagnetic (S=0) Ni(II) complex Ni(II)(Pyr). The addition of excess pyridine (Py) to the toluene solution of Ni(II)(Pyr) yielded five-coordinate Ni(II)(Pyr)(Py), which was then completely converted to six-coordinate paramagnetic (S=1) Ni(II)(Pyr)(Py) 2 . The latter was characterized by UV-Vis, 1 H NMR, CV, SQUID, and X-ray crystallography as well as DFT calculations. As compared with analogous complexes of porphyrin (Por), chlorin (Chl), and isobacteriochlorin (Iso) reported by Herges and co-workers (R. Herges et al., Inorg. Chem. 2015), Ni(II)(Pyr)(Py) 2 has longer equatorial NiN and shorter axial NiN bonds. The CV study has shown a large decrease in HOMO-LUMO gap as the reduction of porphyrin ring proceeds, which has further been confirmed by UV-Vis and DFT calculation. Titration studies using 1 H NMR and UV-Vis have shown that the first binding constant of pyridine toward Ni(II)(Pyr) is ca. 4 times as large as that of Ni(II)(Iso) and ca 230 times as large as that of Ni(II)(Por). Thus, we have concluded that the binding constant of pyridine to Ni(II) porphyrinoid increases by the following order: Por

The common marmoset has recently gained a great deal of attention as an experimental primate model for biological science and medical research. To use the common marmoset for development of novel treatments and rehabilitation for locomotor disorders, it is crucial to understand fundamental baseline characteristics of locomotion in this species. Therefore, in the present study we performed kinematic and kinetic analyses of quadrupedal locomotion in this animal. A total of 14 common marmosets walking quadrupedally along a walkway were analyzed using synchronized high-speed cameras, with two force platforms set in the walkway. Our results demonstrated that the marmoset uses a lateral sequence walking pattern, in contrast to the macaque and other primates, which usually adopt a diagonal sequence pattern. Furthermore, peak vertical ground reaction force on the forelimb was larger than that on the hindlimb. The rate of energy recovery for quadrupedal walking in the common marmoset was much smaller than that in the macaque, indicating that the marmoset generally utilizes bouncing mechanics in locomotion, even though the duty factor is >0.5. This description of locomotor characteristics of intact marmosets may serve as a basis for comparative analyses of changes in gait due to rehabilitation and regenerative treatments., (Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.)

Background: Although nivolumab significantly prolongs survival of metastatic melanoma, about 10% of patients experience severe, even fatal immune-related adverse events (irAEs). Biomarkers to predict irAEs are, therefore, of great interest., Objective: We aimed to correlate changes in routine blood count parameters to the occurrence of serious irAEs (grade 3/4 [G3/4] or lung/gastrointestinal [lung/GI] irAEs) in patients with melanoma who were treated with nivolumab., Methods: We retrospectively analyzed data from 101 patient with melanoma treated with nivolumab from 8 institutes in Japan. We used logistic regression analyses to investigate associations between severe irAEs and fluctuations in routine blood count parameters (total white blood cell [WBC] count, relative neutrophil, monocyte, lymphocyte, and eosinophil count) during the treatment. Receiver-operating characteristic curve was used to determine a cutoff value for the blood count parameters and area under the curve (AUC)., Results: Univariate analysis revealed that G3/4 irAEs were associated with increased total WBC count (P=0.034, cutoff value=+27%, AUC=0.68, odds ratio [OR]=1.58) and decreased relative lymphocyte count (RLC, P=0.042, cutoff value=-23%, AUC=0.65, OR=1.65). However, multivariate analysis showed that the same factors, increased WBC count (P=0.014, cutoff value=+59.1%, AUC=0.79, OR=6.04) and decreased RLC (P=0.012, cutoff value=-32.3%, AUC=0.81, OR=5.01) were independent factors associated with lung/GI irAEs., Conclusions: Our results suggest that increased WBC count and decreased RLC are associated with G3/4 and lung/GI irAEs. Our analysis was based on the data point at which irAE occurrence was noticed and, therefore, these factors are not predictive, however, they could be a "signal" of severe irAE occurrence in patients with melanoma treated with nivolumab., (Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Congenital left ventricular diverticulum (CLVD) is a rare congenital anomaly and may be associated with fatal adverse events. A previously healthy 20-year-old man collapsed as a result of sudden ventricular fibrillation (VF). Despite intractable VF, he had return of spontaneous circulation with cardiopulmonary resuscitation and subsequent introduction of venoarterial extracorporeal membrane oxygenation (ECMO). After ECMO was discontinued, cardiac magnetic resonance imaging revealed CLVD at the posterolateral wall of the left ventricle. Given the risk of recurrent VF and left ventricular rupture, he underwent surgical repair for CLVD and implantation of a subcutaneous implantable cardioverter defibrillator., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The effects of sterilization methods on the storage stability of erythropoietin (EPO) in polymer-based syringes were assessed by quantifying protein oxidation, aggregation, and particle formation. Micro-particle counting and size exclusion chromatography coupled with a multi-angle light scattering detector demonstrated much lower levels of protein particles and aggregates for EPO stored for 12 weeks in steam-sterilized than in radiation (Rad)-sterilized syringes. Intermediate levels of damage were observed for EPO stored in ethylene oxide-sterilized syringes. HPLC analysis documented that the Rad-sterilized syringes caused increased oxidation of the protein during storage. In contrast, in the steam- and ethylene oxide-sterilized syringes EPO oxidation did not change. Analysis with electron spin resonance revealed that only Rad-sterilized syringes formed radicals in the syringe body, which persisted over the 12-week storage period. These results demonstrated that Rad-sterilization generated radicals in the syringes which in turn caused increased EPO oxidation, particle formation, and protein aggregation. Therefore, steam sterilization was shown to be a preferable sterilization method for the polymer-based syringe system when using biopharmaceutical drugs highly sensitive to oxidation, and particle formation and aggregation., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The knee flexion angle after a total knee arthroplasty is an important indicator of clinical outcome. However, there is little appropriate information about the correlation between the ligament balancing and knee flexion angle after total knee arthroplasty. The purpose of this study was to investigate the effect of the ligamentous balance in extension and flexion on knee flexion angle one year after posterior cruciate ligament sacrificing rotating platform total knee arthroplasty., Methods: Eighty-five total knee arthroplasties in 71 patients were investigated in this study. The postoperative knee flexion angle and the percentage of improvement in the balanced group in which the difference between varus and valgus was less than 2° and the unbalanced group in extension and the rectangular group in which the asymmetry of the flexion gap was within 2° and the trapezoidal group in flexion were compared. The factors affecting postoperative knee flexion angle were also investigated in a forced entry multiple regression analysis., Results: The mean flexion angle improved significantly from 116.2° to 122.5° in the rectangular group. By contrast, in the trapezoidal group, no significant improvement was seen (from 115.5° to 117.4°). The statistically significant difference was found between the rectangular and trapezoidal group in flexion in terms of the improvement of the knee flexion angle while there was no difference between the balanced and unbalanced group in extension. The multiple regression analysis showed that the asymmetry of the flexion gap was a predictor of the postoperative knee flexion angle., Conclusions: Asymmetric flexion gap affected negatively the postoperative knee flexion angle after posterior cruciate ligament sacrificing rotating platform total knee arthroplasty. A gap balancing technique is recommended for this type of implant., (Copyright © 2016 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Extracranial vertebral artery aneurysm related to neurofibromatosis type 1 (NF1) is rare. Aneurysmal rupture typically induces such symptoms as cervical hematoma, hemothorax, and hypotension. Here we report a case of ruptured extracranial vertebral artery aneurysm in a patient with NF1 who, rather than cervical hematoma, hemothorax, or hypotension, developed a vertebral arteriovenous fistula (AVF) after aneurysm rupture., Case Description: A 35-year-old woman with a family history of NF1 presented with sudden-onset right neck and shoulder pain. Computed tomography angiography showed a right extracranial vertebral artery aneurysm. She had neither a cervical hematoma nor hypotension; however, angiography showed an AVF secondary to aneurysmal rupture. The patient was treated with endovascular coil embolization to prevent re-rupture. Postoperatively, her right neck and shoulder pain improved, and she was discharged without further neurologic deficits., Conclusions: This patient's clinical course suggests that if there is minimal bleeding from an NF1-associated ruptured extracranial vertebral artery aneurysm, then typical symptoms, such as cervical hematoma, hemothorax, and hypotension, may be absent. Thus, ruptured extracranial vertebral artery aneurysm should be considered in the differential diagnosis of patients with NF1 with sudden-onset radiculopathy, even in the absence of typical symptoms. The detection of a vertebral AVF provides a useful clue to the diagnosis of aneurysm rupture in such cases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Although extramammary Paget disease (EMPD) usually appears as carcinoma in situ, it sometimes becomes invasive (iEMPD) and fatal. However, a TNM staging system for iEMPD has yet to be established., Objective: The aim of this study was to establish a TNM staging system for iEMPD., Methods: We retrospectively collected iEMPD patients treated at 12 institutes in Japan. Factors reported to be associated with survival such as distant metastasis, lymph node (LN) metastasis, and primary tumor status were evaluated using the log-rank test., Results: We enrolled 301 iEMPD patients, of whom 114 had remote metastases (49 had both distant and LN metastasis; 2, distant metastasis only; and 63, LN metastasis only) and the remaining 187 patients had no remote metastasis. Distant metastasis (M1) showed worse survival (P<0.00001). In the analysis of the 250 patients without distant metastasis, LN metastasis also showed worse survival (P<0.00001). Among the patients with LN metastasis, 2 or more LN metastases (N2) showed worse survival than did single LN metastasis (N1, P=0.02). Lastly, in the analysis of the 187 patients without metastasis, tumor thickness of over 4mm or lymphovascular invasion showed worse survival (T2, P<0.05 and P<0.001, respectively). Patients with neither of these features were defined as T1. From these results, we propose this TNM staging system: stage I, T1N0M0; stage II, T2N0M0; stage IIIa, anyTN1M0; stage IIIb, anyTN2M0; stage IV, anyTanyNM1. Other than stages II and IIIa, each stage had a statistically distinct survival curve., Conclusion: We propose a TNM staging system for EMPD using simple factors for classification that could provide important prognostic information in managing EMPD. However, accumulation of more patient data and further revision of the system are required., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: To examine the effect of the histology of carcinoma and sarcoma components on survival outcome of uterine carcinosarcoma., Patients and Methods: A multicenter retrospective study was conducted to examine uterine carcinosarcoma cases that underwent primary surgical staging. Archived slides were examined and histologic patterns were grouped based on carcinoma (low-grade versus high-grade) and sarcoma (homologous versus heterologous) components, correlating to clinico-pathological demographics and outcomes., Results: Among 1192 cases identified, 906 cases were evaluated for histologic patterns (carcinoma/sarcoma) with high-grade/homologous (40.8%) being the most common type followed by high-grade/heterologous (30.9%), low-grade/homologous (18.0%), and low-grade/heterologous (10.3%). On multivariate analysis, high-grade/heterologous (5-year rate, 34.0%, P = 0.024) and high-grade/homologous (45.8%, P = 0.017) but not low-grade/heterologous (50.6%, P = 0.089) were independently associated with decreased progression-free survival (PFS) compared with low-grade/homologous (60.3%). In addition, older age, residual disease at surgery, large tumor, sarcoma dominance, deep myometrial invasion, lymphovascular space invasion, and advanced-stage disease were independently associated with decreased PFS (all, P < 0.01). Both postoperative chemotherapy (5-year rates, 48.6% versus 39.0%, P < 0.001) and radiotherapy (50.1% versus 44.1%, P = 0.007) were significantly associated with improved PFS in univariate analysis. However, on multivariate analysis, only postoperative chemotherapy remained an independent predictor for improved PFS [hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.27-0.43, P < 0.001]. On univariate analysis, significant treatment benefits for PFS were seen with ifosfamide for low-grade carcinoma (82.0% versus 49.8%, P = 0.001), platinum for high-grade carcinoma (46.9% versus 32.4%, P = 0.034) and homologous sarcoma (53.1% versus 38.2%, P = 0.017), and anthracycline for heterologous sarcoma (66.2% versus 39.3%, P = 0.005). Conversely, platinum, taxane, and anthracycline for low-grade carcinoma, and anthracycline for homologous sarcoma had no effect on PFS compared with non-chemotherapy group (all, P > 0.05). On multivariate analysis, ifosfamide for low-grade/homologous (HR 0.21, 95% CI 0.07-0.63, P = 0.005), platinum for high-grade/homologous (HR 0.36, 95% CI 0.22-0.60, P < 0.001), and anthracycline for high-grade/heterologous (HR 0.30, 95% CI 0.14-0.62, P = 0.001) remained independent predictors for improved PFS. Analyses of 1096 metastatic sites showed that carcinoma components tended to spread lymphatically, while sarcoma components tended to spread loco-regionally (P < 0.001)., Conclusion: Characterization of histologic pattern provides valuable information in the management of uterine carcinosarcoma., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Mature cystic teratoma is a germ cell tumor of the ovaries and is often observed in clinical practice. However, extragonadal teratomas are rare tumors and have been reported outside the ovaries, (e.g., in the greater omentum). The mechanism underlying the development of extragonadal teratomas remains unknown. We encountered a case of extragonadal teratoma in the pouch of Douglas that appeared to be a parasitic dermoid cyst. From our experience and the literature review, we discuss the potential mechanism leading to the development of extragonadal teratomas. A 41-year-old nonpregnant woman was referred to our department due to myoma and anemia. A 4-cm asymptomatic mass in the pouch of Douglas was observed, and the patient was diagnosed with ovarian mature cystic teratoma. She underwent laparoscopic surgery, and intraoperative findings revealed that the fallopian tube was injured and torn, and a residual small ovary was observed in the left side of the ovary. A tumor measuring approximately 4 cm observed in the pouch of Douglas was extracted without rupturing. The tumor was diagnosed as a parasitic dermoid cyst by macroscopic and histopathological findings. Auto-amputation could be the underlying mechanism that leads to an isolated parasitic dermoid cyst in the pouch of Douglas., (Copyright © 2015 AAGL. Published by Elsevier Inc. All rights reserved.)

Using histological and electrophysiological methods, we identified the neuroanatomical properties of the common marmoset corticospinal tract (CST), which underlies hand/arm motor control. Biotinylated dextran amine (BDA) was injected into the primary motor cortex to anterogradely label CST axons in the cervical segments, revealing that most CST axons descend in the contralateral dorsolateral funiculus (DLF; 85.0%), and some in the ipsilateral DLF (10.7%). Terminal buttons were mainly found in the contralateral lamina VII of the gray matter, but projection to lamina IX, where forelimb motoneurons are located, was rare. Bilateral projections were more abundant than found in the rat CST, resembling the CST organization of other primates. Intracellular recordings were made from 57 forelimb motoneurons on the contralateral side to stimulation, which revealed no monosynaptic excitatory postsynaptic potentials (EPSPs), but di- or polysynaptic EPSPs and inhibitory synaptic potentials were commonly found. Local field potentials showed monosynaptic excitation mainly in laminae VII, where abundant BDA-labeled CST terminals were observed. These results suggest that direct corticomotoneuronal projection is absent in common marmosets but di- or oligosynaptic effects would be mediated by spinal interneurons., (Copyright © 2015 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Background: Although extramammary Paget's disease (EMPD) mostly presents as intraepithelial carcinoma, we sometimes encounter patients with invasive EMPD (iEMPD) who have lymph node metastasis and may develop distant metastasis. Although sentinel lymph node biopsy (SLNB) is widely accepted for various cancers, there is no large study that has assessed its role in iEMPD., Objective: The main objective of this study is to assess the role of SLNB in patients with iEMPD., Materials and Methods: We retrospectively collected data on 151 iEMPD patients treated from 1998 to 2012 in 11 institutes in Japan. All 151 patients received curative surgery for their primary tumor and none of them had distant metastasis. SLNB was performed on the 107 patients without lymphadenopathy to determine their LN status. The 44 other patients with lymphadenopathy underwent one of the following procedures to determine their LN status: SLNB in 22 cases, immediate LN dissection in 21, and LN biopsy in 1., Results: Compared to those without lymphadenopathy, patients with lymphadenopathy had advanced primary tumors (nodule in the primary tumor, thicker tumor, deeper invasion level, and lymphovascular invasion). The rate of LN metastasis in patients with lymphadenopathy was 80%, compared to 15% in patients without lymphadenopathy who underwent SLNB. Compared to those with negative SLN, patients with positive SLN had advanced primary tumors (nodule in the primary tumor, deeper invasion level, and lymphovascular invasion). Multivariate analysis revealed that dermal invasion (odds ratio 5.8, p=0.04) and lymphovascular invasion (odds ratio 18.0, p=0.0023) were independent factors associated with SLN positivity. Notably, there was no difference in survival between patients with or without SLN metastasis (p=0.71). On the other hand, patients with lymphadenopathy showed worse survival than those with positive SLN (p=0.045)., Conclusion: Clinical lymphadenopathy was strongly correlated with pathological LN metastasis and also associated with worse survival than absence of lymphadenopathy. The rate of occult LN metastasis detected by SLNB was 15%. Survival was not affected by SLN status even when an advanced primary tumor was present in patients with positive SLN. Our results raise the possibility that SLNB and subsequent LN dissection improved the survival of patients with early stage lymphatic spread. Our study indicates that SLNB should be considered for iEMPD if lymphadenopathy is not apparent., (Copyright © 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Growing teratoma syndrome (GTS) is rare clinical phenomenon occurring as a sequelae of a malignant germ cell tumor. We present the case of a 20-year-old woman who developed GTS after undergoing fertility-sparing surgery and chemotherapy for an immature teratoma. She underwent left salpingo-oophorectomy, right ovarian cystectomy, and disseminated tumor reduction during her primary surgery. The postsurgical histology report identified the tumor as an immature teratoma, grade 3, International Federation of Gynecology and Obstetrics (FIGO) stage IIIb. She subsequently received 3 cycles of chemotherapy consisting of bleomycin, etoposide, and cisplatin. At 17 months after the chemotherapy, follow-up computed tomography (CT) scan revealed an enlarged mass in her right paracolic gutter and a small peritoneal lesion in the pouch of Douglas. Her serum alpha-fetoprotein level was not elevated. These findings were compatible with GTS, but it was difficult to rule out a recurrent immature teratoma. Diagnostic exploratory laparoscopic surgery revealed the enlarged tumors that had been detected by the CT scan. Although there were multiple tumors in the pouch of Douglas, we were able to resect all of them laparoscopically. Histological diagnosis of the surgically resected specimens was of a mature teratoma, and so we concluded that this tumor was a GTS. Our experience suggests that laparoscopic surgery is an effective alternative diagnostic and therapeutic approach in cases suspicious of GTS where the disease is disseminated to the peritoneum., (Copyright © 2015 AAGL. Published by Elsevier Inc. All rights reserved.)

Uterine adenomyoma is often overlooked, and cervical adenomyoma is extremely rare. Previous reports suggest that a uterine adenomyoma usually occurs in the uterine corpus but rarely in the uterine cervix. Approximately 20 reports of cervical adenomyoma have been published to date. However, cervical adenomyoma has been rarely investigated using magnetic resonance imaging. We encountered a large multicystic tumor in the uterine cervix of a 26-year-old woman that was difficult to diagnose preoperatively. On the basis of cytology, biopsy, and imaging findings, the cervical multicystic tumor measured approximately 13.0 cm. The patient underwent vaginal adenomyomectomy, and the tumor was completely resected. A histologic diagnosis of cervical adenomyoma was made because of proliferation of endocervical glands and the presence of rounded smooth muscle stroma. Awareness of this tumor in the uterine cervix is important for accurate diagnosis and treatment. Herein we present a rare case of a large cervical adenomyoma, with imaging studies, an image of the operation, histologic findings, and a literature review., (Copyright © 2014 AAGL. Published by Elsevier Inc. All rights reserved.)

Background: The current study sought to assess the role of initial neck dissection (ND) for patients with node-positive oropharyngeal squamous cell carcinomas (OPSCC)., Methods: The data for 202 patients with previously untreated node-positive OPSCC were gathered from 12 institutions belonging to the Head and Neck Cancer Study Group in the Japan Clinical Oncology Group. These patients were categorized into two groups, consisting of the initial ND group and the wait-and-see group, according to treatment policy., Results: Regional recurrence was observed in 17 of 93 patients undergoing initial ND, whereas, recurrent or persistent diseases were observed in 40 of 109 patients who did not undergo initial ND. The 4-year overall survival rates (OS) for the wait-and-see group and initial ND groups were 74.0% and 78.7%, respectively, and the 4-year regional control rates (RC) for each group were 77.6% and 84.9%. There were no significant differences in either OS or RC (p=0.3440 and p=0.2382, respectively). However, for patients with N3 disease, the 4-year OS of the initial ND group (100%) was favorable. For patients with N2a disease, the 4-year RC of the initial ND group was higher than that of the wait-and-see group statistically (100% vs 62.5%, p=0.0156)., Conclusions: The role of initial ND was limited in patients with node-positive OPSCC. The treatment strategy not involving initial ND is considered feasible and acceptable when nodal evaluation after definitive radiotherapy or chemoradiotherapy is applied adequately. However, it is possible that initial ND improves outcomes in patients with resectable large-volume nodal disease., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The functionality of a newly developed silicone oil-free (SOF) syringe system, of which the plunger stopper is coated by a novel coating technology (i-coating™), was assessed. By scanning electron microscopy observations and other analysis, it was confirmed that the plunger stopper surface was uniformly covered with the designed chemical composition. A microflow imaging analysis showed that the SOF system drastically reduced both silicone oil (SO) doplets and oil-induced aggregations in a model protein formulation, whereas a large number of subvisible particles and protein aggregations were formed when a SO system was used. Satisfactory container closure integrity (CCI) was confirmed by means of dye and microorganism penetration studies. Furthermore, no significant difference between the break loose and gliding forces was observed in the former, and stability studies revealed that the SOF system could perfectly show the aging independence in break loose force observed in the SO system. The results suggest that the introduced novel SOF system has a great potential and represents an alternative that can achieve very low subvisible particles, secure CCI, and the absence of a break loose force. In particular, no risk of SO-induced aggregation can bring additional value in the highly sensitive biotech drug market., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Cell surface receptors ubiquitylated after ligand stimulation are internalized and delivered to the lysosomal pathway for degradation. Ubiquitylated receptors are captured by ESCRT protein complexes that sort them to the lysosomal pathway. Hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) is a component of endosomal sorting complexes required for transport (ESCRT)-0 that recognizes ubiquitin attached to receptors, indicating that it functions as a key molecule for ubiquitin-dependent endosomal sorting. In a previous study on interleukin (IL)-2 receptor β (IL-2Rβ) and IL-4 receptor α (IL-4Rα), which are constitutively internalized without ligand stimulation, we revealed that Hrs bound to IL-2Rβ and IL-4Rα in a ubiquitin-independent manner, and identified a hydrophobic amino acid cluster in the cytoplasmic region of IL-2Rβ and IL-4Rα as the Hrs-interacting domain. However, a chimeric receptor containing the hydrophobic amino acid cluster inserted into the C-terminal of IL-2Rα was not delivered to late endosomes, but recycled back to the plasma membrane. In the present study, we explored the functional domain related to endosomal sorting in IL-2Rβ together with the hydrophobic amino acid cluster, and discovered the importance of an approximately 30-amino acid stretch following the C-terminus of the hydrophobic amino acid cluster in IL-2Rβ. Even though the amino acid stretch following the hydrophobic amino acid cluster was composed of arbitrary amino acids, such a stretch was also permissive for the sorting ability, suggesting that the hydrophobic amino acid cluster functions as an endosomal sorting signal. These findings clarify part of the molecular mechanism underlying the ubiquitin-independent endosomal sorting of cytokine receptors that are constitutively internalized without ligand stimulation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: We evaluated association of prognosis of endometrial carcinoma patients and treatment-free intervals (TFIs)., Study Design: We compared the effectiveness of second-line chemotherapy performed for patients with TFIs of 6-12 months and 12 or more months following a first-line chemotherapy based on taxane (paclitaxel) and carboplatin, with or without the anthracycline (TC)., Results: Progression-free and overall survivals were significantly shorter in patients with TFIs of 6-12 months than those with TFIs of 12 or more months. Among the patients who received similar second-line chemotherapy, response rates of 15 patients with TFIs of 12 or more months and 7 patients with TFIs of 6-12 months were 67% and 43%, respectively. Progression-free survival was significantly worse in those with TFIs of 6-12 months (median, 7 months) than those with TFIs of 12 or more months (median, 12 months)., Conclusion: Our small retrospective analysis suggests that recurrent endometrial carcinomas with TFIs of 6-12 months can be regarded as being partially sensitive to TC-based chemotherapy., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Identification of reliable markers of radiosensitivity and the key molecules that enhance the susceptibility of esophageal cancer cells to anticancer treatments would be highly desirable. To identify molecules that confer radiosensitivity to esophageal squamous carcinoma cells, we assessed the radiosensitivities of the TE-5, TE-9 and TE-12 cloneA1 cell lines. TE-12 cloneA1 cells showed significantly greater susceptibility to radiotherapy at 5 and 10Gy than either TE-5 or TE-9 cells. Consistent with that finding, 24h after irradiation (5Gy), TE-12 cloneA1 cells showed higher levels of caspase 3/7 activity than TE-5 or TE-9 cells. When we used DNA microarrays to compare the gene expression profiles of TE-5 and TE-12 cloneA1 cells, we found that the mRNA and protein expression of insulin-like growth factor binding protein 3 (IGFBP3) and Bcl-2-associated athanogene 1 (BAG1) was five or more times higher in TE-12 cloneA1 cells than TE-5 cells. Conversely, knocking down expression of IGFBP3 and BAG1 mRNA in TE-12 cloneA1 cells using small interfering RNA (siRNA) significantly reduced radiosensitivity. These data suggest that IGFBP3 and BAG1 may be key markers of radiosensitivity that enhance the susceptibility of squamous cell esophageal cancer to radiotherapy. IGFBP3 and BAG1 may thus be useful targets for improved and more individualized treatments for patients with esophageal squamous cell carcinoma., (Copyright © 2010 Elsevier Inc. All rights reserved.)

In the macaque cerebral cortex, the SPP1 (secreted phosphoprotein 1) gene is mainly expressed in corticospinal neurons. In this study, we found that SPP1 was principally expressed in motor neurons in lamina IX of the macaque spinal cord. The expression level varied among different spinal segments and correlated positively with neuron size. The expression was weak in Errγ-positive neurons, presumably gamma motor neurons, and in neurons in sacral Onuf's nucleus. These results suggest that SPP1 is a molecular characteristic of spinal motor neurons and is preferentially expressed in neurons with high conduction velocities., (Copyright © 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.)

Arginine (Arg)-specific ADP-ribosylation is one of the posttranslational modifications of proteins and is thought to play an important role in reversibly regulating functions of the target proteins in eukaryotes. However, the physiological target protein has not been established. We examined the fragmentation pattern of both ADP-ribosyl-Arg (ADP-R-Arg) and Arg-ADP-ribosylated peptides by quadrupole tandem mass spectrometry and found a specific cleavage of ADP-R-Arg into N-(ADP-ribosyl)-carbodiimide (ADP-R-carbodiimide) and ornithine. Based on this specific fragmentation pattern, we successfully identified the modification site and sequence of Arg-ADP-ribosylated peptide using a two-step collision and showed that ADP-R-carbodiimide is an excellent marker ion for precursor ion scanning of Arg-ADP-ribosylated peptide. We propose that a combination of the precursor ion scanning with ADP-R-carbodiimide as a marker ion and two-step collision is useful in searching for physiological target proteins of Arg-ADP-ribosylation.