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Abstract The compact neutron emission spectrometer (CNES) having a tangential sightline was installed to observe a significant Doppler shift of the neutron energy due to the high-energy tangential neutral beam (NB) injections in the Large Helical Device (LHD) for understanding of the energy distribution of fast-ion. The CNES is based on a 1-inch diameter and 1-inch height EJ301 liquid scintillator coupled with a conventional 1-inch photomultiplier tube. The histogram of the integrated pulse signal (Q total) during different NBs heating phases measured by the CNES shows that the edge of Q total changes depending on NB directions. Using the simple derivative unfolding technique, the neutron energy spectra were unfolded from the measured Q total histogram. Peaks of the neutron energy shift to 2.0 MeV, 2.42 MeV, and 3.0 MeV according to the injection direction of NBs. The obtained neutron energy is almost consistent with the virgin deuterium-deuterium neutron energy evaluated by the simple two-body kinematics considering the sightline of CNES, NB injection angle, and NB injection energy.

CD74 is a transmembrane protein that functions as a specialized chaperone of HLA class II and CD74 in tumor cells was suggested to be involved in cell proliferation in several kinds of malignant tumors. CD74 is also known to be expressed in macrophages, therefore, we investigated the CD74 expression in clear cell renal cell carcinoma (ccRCC). Immunohistochemistry of CD74 indicated that CD74 was expressed not only in cancer cells but also macrophages. CD74 was detected in surface membrane and cytoplasm of cancer cells in 92 of 94 cases (98%) and of 87 of 94 cases (93%). CD74 was expressed both in cancer cells and TAMs in 86 of 94 cases (91%). In vitro studies using cancer cell lines and monocyte-derived macrophages stimulated by anti-CD74 antibodies showed that CD74 signal accelerated cancer cell proliferation and macrophage activation. However, macrophage activation via CD74 signal did not influence macrophage-mediated cancer cell growth. RNA-sequence of macrophages stimulated by anti-CD74 antibodies indicated that CD74 signal was associated to inflammatory responses in macrophages. In conclusion, we examined the expression and functional significance of CD74 in ccRCC using tissue specimens and cell culture studies. The function of CD74 was suggested to be different in cancer cells and in macrophages, and further studies are necessary to clarify the functional significance of CD74 in ccRCC., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

TK-ALCL1, a novel anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK + ALCL) cell line, was established from the primary tumor site of a 59-year-old Japanese male patient. The immune profile of TK-ALCL1 corresponds to that seen typically in primary ALCL cells, i.e., positive for ALK, CD30, EMA, and CD4, but negative for CD2, CD3, CD5, CD8a, and EBV-related antigens. The rearrangement of the T cell receptor-gamma locus shows that TK-ALCL1 is clonally derived from T-lineage lymphoid cells. FISH and RT-PCR analysis revealed that TK-ALCL1 has the nucleophosmin (NPM)-ALK fusion transcript, which is typical for ALK + ALCL cell lines. When TK-ALCL1 was subcutaneously inoculated into 6-week-old BALB/c Rag2 -/- /Jak3 -/- (BRJ) mice, it formed tumor masses within 4-6 weeks. Morphological, immunohistochemical, and molecular genetic investigations confirmed that the xenograft and the original ALCL tumor were identical. The ALK inhibitors Alectinib and Lorlatinib suppressed proliferation in a dose-dependent manner. Thus, TK-ALCL1 provides a useful in vitro and in vivo model for investigation of the biology of ALK + ALCL and of novel therapeutic approaches targeting ALK., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Background: Maintaining higher-level functional capacity is important for independent living in older age. The aging trajectory of the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC) has three patterns; however, the subscale patterns are unclear., Aims: This study aimed to clarify the aging trajectory patterns of the TMIG-IC subscales among community-dwelling older Japanese., Methods: Participants were 3,169 community-dwelling older Japanese who participated in the 2012-2022 mail survey of the Otassha study. The aging trajectory patterns of the TMIG-IC total and subscale scores for those aged 65-90 years were identified using group-based trajectory modeling. Further, the combination frequency of the subscale trajectory patterns was determined., Results: Three patterns were identified: early-onset decreasing, late-onset decreasing, and high-stable., Discussion: The instrumental activities of daily living (IADL) trajectory was maintained until approximately 80 years of age; however, chronic disease prevailed the most in the early-onset decreasing pattern. The early-onset decreasing pattern of intellectual activity (IA) was present in 25% of participants, showing impaired IA from 65 years of age. The late-onset decreasing pattern of social roles (SR) was present in 30% of participants, showing a sharp decline compared to other subscales. For many people, the patterns of decrease in SR and IA overlapped., Conclusions: To maintain higher-level functional capacity, interventions that include disease management and prevention of decline in IADL and increase the awareness of the social support provided throughout old age and interventions for people with an early decline in IA should be implemented., (© 2024. The Author(s).)

Interleukin 32 (IL-32) is a proinflammatory cytokine secreted from several kinds of cancer cells. In the present study, we investigated the significance of IL-32 in lung adenocarcinoma by immunohistochemistry and bioinformatics analysis. IL-32 was positive in cancer cells of 21 cases (9.2%) of total 228 cases. Increased IL-32 gene expression was linked to worse clinical course in TCGA analysis, however, IL-32 expression in immunohistochemistry was not associated to clinical course in our cohort. It was also found that high IL-32 expression was seen in cases with increased lymphocyte infiltration. In vitro studies indicated that IFN-γ induced gene expression of IL-32 and PD1-ligands in lung adenocarcinoma cell lines. IL-32, especially IL-32β, also induced overexpression of PD1-ligands in human monocyte-derived macrophages. Additionally, Cancer-cell-derived IL-32 was elevated by stimulation with anticancer agents. In conclusion, IL-32 potentially induced by inflammatory conditions and anticancer therapy and contribute to immune escape of cancer cells via development the immunosuppressive microenvironment. IL-32 might be a target molecule for anti-cancer therapy., (© 2024. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Background: Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the nonrandomized, open-label, phase 1 KEYNOTE-434 study (NCT02862457). We report results from part B, which evaluated epacadostat plus pembrolizumab and chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC)., Methods: Eligible patients aged ≥ 20 years had histologically or cytologically confirmed stage IIIB or IV NSCLC with no prior systemic therapy, and ECOG performance status of 0 or 1. Patients received epacadostat 100 mg orally twice-daily, pembrolizumab 200 mg intravenously every-3-weeks for ≤ 35 cycles, and 4 cycles of chemotherapy (cohort 1: cisplatin plus pemetrexed, non-squamous; cohort 2: carboplatin plus pemetrexed, non-squamous; cohort 3: carboplatin plus paclitaxel, squamous or non-squamous). Primary endpoint was incidence of dose-limiting toxicities (DLTs). Following unfavorable results from other studies, a protocol amendment removed epacadostat from the treatment combination., Results: Of 19 patients, 7 were enrolled in cohort 1, and 6 each in cohorts 2 and 3. Median follow-up was 13.7 (range, 4.2-27.8) months. Five of 17 (29%) DLT-evaluable patients experienced ≥ 1 DLT (cohort 1, n = 1; cohorts 2 and 3, n = 2 each); most commonly maculopapular rash (grade 3, n = 3) and increased alanine aminotransferase (grade 2, n = 1; grade 3, n = 2). All patients experienced treatment-related adverse events (AEs); 58% experienced grade 3 or 4 treatment-related AEs. Objective response rate was 47%., Conclusion: The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC., Trial Registration: ClinicalTrials.gov , NCT02862457., (© 2023. Merck & Co., Inc., Rahway, NJ, USA and its affiliates.)

Serpinb9 is an inhibitor of granzyme B and is potentially involved in the immune escape of tumor cells. In the present study, bioinformatics analysis using open databases suggested that SerpinB9 is overexpressed in testicular embryonal carcinoma. Immunohistological analysis was performed on 28 cases of testicular germ cell tumors to investigate the relationship between SerpinB9 expression in testicular germ cell tumors and the tumor immune environment. SerpinB9 was significantly upregulated in the non-seminoma group and inversely correlated with the number of tumor-infiltrating CD8-positive cells. In addition, yolk sac tumors were characterized by the loss of human leukocyte antigen-class I expression. These findings suggest that SerpinB9 contributes to the immune escape of testicular germ cell tumors. Targeting therapy for SerpinB9 might therefore be useful in immunotherapy for testicular germ cell tumors resistant to immune checkpoint inhibitors., (© 2023. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Immunotherapies that target programmed cell death protein 1 (PD-1) signals are standard therapies for advanced-stage lung cancer, and the expression of programmed death-ligand 1 (PD-L1) in cancer tissue predicts immunotherapy efficacy. Although programmed death-ligand 2 (PD-L2) is expressed in cancer cells and macrophages, similar to PD-L1, its significance in lung cancer is unclear. Double immunohistochemistry analyses using anti-PD-L2 and anti-PU.1 antibodies were carried out on tissue array sections from 231 cases of lung adenocarcinoma, and PD-L2 expression in macrophages was evaluated. High PD-L2 expression in macrophages was associated with longer progression-free survival (PFS) and cancer-specific survival (CSS) and observed more often in females, non-heavy smokers, and patients with epidermal growth factor receptor (EGFR) mutations and those at a lower disease stage. Significant correlations were found more frequently in patients with EGFR mutations. Cell culture studies revealed that cancer cell-derived soluble factors induced PD-L2 overexpression in macrophages, suggesting the involvement of the JAK-STAT signaling pathway. The present findings suggest that PD-L2 expression in macrophages predicts PFS and CSS in lung adenocarcinoma without immunotherapy., (© 2023. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Background: Superficial pharyngeal cancer can be treated with curative intent while preserving function using minimally invasive peroral endoscopic resection techniques such as endoscopic submucosal dissection (ESD). However, severe adverse events occasionally occur, such as laryngeal edema requiring temporary tracheotomy and fistula formation. Therefore, we investigated the risk factors for adverse events associated with ESD for superficial pharyngeal cancer., Methods: This retrospective observational study was conducted at a single institution, and 63 patients who underwent ESD were enrolled. The primary outcome was the risk factors for adverse events associated with ESD. The secondary outcomes were adverse events associated with ESD and their frequency., Results: The overall adverse event rate was 15.9% (10/63). The incidence of laryngeal edema requiring prophylactic temporary tracheotomy was 11.1%, while laryngeal edema requiring emergency temporary tracheotomy, postoperative bleeding, aspiration pneumonia, fistula, abscess, and stricture formation occurred in 1.6% of patients, respectively. Logistic regression analyses showed that a history of radiotherapy for head and neck cancer was a risk factor for adverse events (odds ratio [OR], 16.67; 95% confidence interval [CI], 3.04-91.34; p = 0.001). After adjusting the model for differences in the baseline risk factors using the inverse probability of treatment weighting method, the adverse events were found to increase in association with a history of radiotherapy for head and neck cancer (OR, 39.66; 95% CI,5.85-268.72; p < 0.001)., Conclusion: History of radiotherapy for head and neck cancer is an independent risk factor for adverse events associated with ESD for superficial pharyngeal cancer. Among adverse events, laryngeal edema requiring prophylactic temporary tracheotomy was particularly high., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Ferroptosis suppressor protein 1 and glutathione peroxidase 4 have been identified as key molecules in two independent pathways associated with ferroptosis inhibition. This study investigated the prognostic significance and clinical associations of FSP1 and GPX4 expression in esophageal squamous cell carcinoma (ESCC) and assessed the therapeutic potential of regulating these molecules in ESCC cells., Methods: Immunohistochemical analysis was performed on surgical specimens of 97 patients with ESCC for FSP1 and GPX4 expression. To identify the change in ESCC cell viability, FSP1 and GPX4 inhibitors were administered to three cell lines. In addition, ferroptosis as the cause of reduced cell viability by FSP1 and GPX4 inhibition was confirmed., Results: Prognosis was significantly worse for patients in the group positive for both FSP1 and GPX4 compared with the other groups (p < 0.001). In multivariate analysis, positivity for both FSP1 and GPX4 was an independent poor prognostic factor (p = 0.002). The combination of FSP1 and GPX4 inhibitors induced cell death more potently than each inhibitor did alone. Furthermore, the ferroptosis inhibitor markedly canceled this cell death., Conclusions: Overexpression of FSP1 and GPX4 is a poor prognostic factor for patients with ESCC. Simultaneous suppression of both FSP1 and GPX4 caused potent cell death, which was markedly abrogated by ferroptosis inhibitors. These findings indicate that simultaneous regulation of FSP1 and GPX4 may be a new therapeutic target in ESCC., (© 2022. The Author(s).)

Tumor-associated macrophage (TAM)-derived IL-6 is involved in small-cell lung cancer (SCLC) progression and chemoresistance via the activation of signal transducer and activator of transcription 3 (STAT3) in the tumor microenvironment. This study aimed to identify natural compounds that suppress cell-cell interactions between TAMs and SCLC cells by inhibiting STAT3 activation. We used a library of natural compounds to identify candidate agents possessing anti-SCLC effects by inhibiting macrophage-induced tumor proliferation. SBC-3 and SBC-5, human SCLC cell lines, were used for in vitro experiments. Furthermore, we assessed the efficacy of these candidate agents in a murine xenograft model of human SCLC. Among the natural compounds examined, onionin A (ONA) inhibited IL-6-induced STAT3 activation and SCLC cell proliferation. ONA also reduced the secretion of IL-6 from macrophages and interfered with the direct effect of cell-cell interactions between macrophages and SCLC cells. Furthermore, ONA administration suppressed tumor progression in a tumor-bearing mouse model. ONA was identified as the most useful candidate for targeting cell-cell interactions between cancer cells and TAMs for anti-SCLC therapy., (© 2023. The Author(s).)

Background: Eosinophilic esophagitis (EoE) is a type 2 helper T-cell (Th2)-mediated allergic disease that involves mast cells. This study aimed to clarify the relationship between perception of symptoms and mast cell levels in patients with EoE., Methods: We enrolled patients with asymptomatic esophageal eosinophilia (aEE) and those with symptomatic EoE. Immunofluorescence staining was performed on esophageal biopsy specimens to quantify mast cell-related molecules, such as tryptase, proteinase-activated receptor (PAR)-2, and vasoactive intestinal peptide receptor (VPAC)-1., Results: We evaluated 28 and 58 patients with aEE and EoE, respectively. There were no significant differences in clinical and endoscopic features and peak eosinophil counts between both groups. Mast cell tryptase-positive areas were significantly higher in EoE than in aEE (4.9 [3.5-6.2] vs. 2.0 [1.2-3.4] %, p < 0.01). The number of PAR-2-positive cells was significantly higher in EoE than in aEE (14 [8.8-20.0] vs. 4 [2.8-8.0] cells/high-power field [HPF], p < 0.01). The number of VPAC-1-positive cells was significantly higher in the EoE group than in the aEE group (13 [8.8-16.0] vs. 6 [3.0-9.3] cells/HPF, p < 0.01). A positive correlation was observed between the numbers of PAR-2-positive cells and VPAC-1-positive cells (r = 0.851, p < 0.01). Moreover, mast cell tryptase-positive areas positively correlated with the number of PAR-2- and VPAC-1-positive cells (r = 0.352, p < 0.01; r = 0.355, p < 0.01, respectively)., Conclusions: Esophageal mast cells and their receptors, PAR-2 and VPAC-1, may contribute to the perception of symptoms in patients with EoE., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Background: Preoperative inflammatory or nutritional biomarkers and clinicopathological features may be survival predictors in resectable esophageal squamous cell carcinoma., Methods: We included 118 patients with resectable squamous esophageal carcinoma (stages I-IV), assessing preoperative CRP- and albumin-based modified Glasgow prognostic score, the modified controlling nutritional status score, C-reactive protein, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, pathologic stage, and tumor location(s), looking for correlation with overall survival and relapse-free survival. Using univariate and Cox analysis, we selected the most reliable prognostic factors., Results: Five-year overall survival and recurrence-free survival were 54.9% and 48.5%, respectively. C-reactive protein values correlated negatively with hypoalbuminemia (P = 0.0036). On univariate analysis, tumor stage, invasion depth, location, nodal involvement, albumin, and modified Glasgow prognostic score were significant prognostic factors for overall and recurrence-free survival. Preoperative C-reactive protein was prognostic factor for overall survival, but not for relapse-free survival (P = 0.017, 0.063, respectively). The Cox proportional hazards model showed the modified Glasgow prognostic score to be an independent prognostic factor for relapse-free survival and overall survival after using the stepwise variable selection procedure. Cox analysis including clinicopathological factors and modified Glasgow prognostic scores showed that only tumor location(s) and pathologic stage were independent prognostic factors for overall survival and recurrence-free survival., Conclusion: Although the modified Glasgow prognostic score is not superior to pathologic stage and tumor location as a biomarker of preoperative nutrition/inflammation and clinicopathological factors, it remains an important prognostic marker in resectable esophageal cancers. Preoperative decreased inflammatory response and improved nutritional status may contribute to prognosis in patients with esophageal cancer., (© 2022. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Mood and anxiety disorders are frequent in the elderly and increase the risk of frailty. This study aimed to identify novel biomarkers of major depressive disorder (MDD) and anxiety in the elderly. We examined 639 participants in the community-dwelling Otassha Study (518 individuals considered healthy control, 77 with depression, anxiety, etc.), mean age 75 years, 58.4% of female. After exclusion criteria, we analyzed VOCs from 18 individuals (9 healthy control, 9 of MDD/agoraphobia case). Urinary volatile and semi-volatile organic compounds (VOCs) were profiled using solid-phase microextraction and gas chromatography-mass spectrometry. Six urinary VOCs differed in the absolute area of the base peak between participants with MDD and/or agoraphobia and controls. High area under the receiver-operating characteristic curve (AUC) values were found for phenethyl isothiocyanate (AUC: 0.86, p = 0.009), hexanoic acid (AUC: 0.85, p = 0.012), texanol (AUC: 0.99, p = 0.0005), and texanol isomer (AUC: 0.89, p = 0.005). The combined indices of dimethyl sulfone, phenethyl isothiocyanate, and hexanoic acid, and texanol and texanol isomer showed AUCs of 0.91 (p = 0.003) and 0.99 (p = 0.0005) and correlated with the GRID-HAMD and the Kihon Checklist (CL score), respectively. These VOCs may be valuable biomarkers for evaluating MDD and/or agoraphobia in the elderly., (© 2022. The Author(s).)

Tumor-associated macrophages (TAMs) have protumor functions in various cancers. However, their significance in hepatoblastoma, the most common liver tumor in children, remains unclear. The aim of this study was to explore the potential roles of TAMs in hepatoblastoma. Immunohistochemical analysis revealed that the density of CD204-positive TAMs was significantly higher in the embryonal component than in other histological subtypes of hepatoblastoma. An in vitro co-culture study with Huh6 cells and human monocyte-derived macrophages (HMDMs) showed that macrophage-colony-stimulating factor receptor (M-CSFR) was strongly up-regulated in the Huh6 cells that were directly co-cultured with HMDMs. The expressions of M-CSFR ligands (interleukin-34 and M-CSF) were also increased by co-culture with HMDMs. The proliferation of HepG2 cells (another hepatoblastoma cell line expressing M-CSFR) was inhibited by an M-CSFR inhibitor. M-CSFR was found to be highly expressed in the embryonal component and in recurrent lesions. The number of CD204-positive macrophages was also higher in the M-CSFR-positive areas than in the M-CSFR-negative areas. Thus, M-CSFR expression appeared to be induced by cell-cell contact with macrophages in hepatoblastoma cells, and M-CSFR inhibitor is potentially effective against M-CSFR-positive hepatoblastoma, especially recurrent cases., (© 2022. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Background: The benefits of robotic gastrectomy (RG) over laparoscopic gastrectomy (LG) remain controversial. This single-center, propensity score-matched study aimed to compare the outcomes of RG with those of LG for treating gastric cancer., Methods: We searched the prospective gastric cancer database of our institute for patients with gastric cancer who underwent RG or LG between January 2014 and December 2019, excluding patients with remnant stomach cancer and those who underwent concurrent surgery for comorbid malignancies. One-to-one propensity score matching was performed to reduce bias from confounding patient-related variables, and short- and long-term outcomes were compared between the groups., Results: We identified 1189 patients who underwent LG (n = 979) or RG (n = 210). After propensity score matching, we selected 210 pairs of patients who underwent LG (distal gastrectomy, 138; total or proximal gastrectomy, 72) or RG (distal gastrectomy, 143; total or proximal gastrectomy, 67). RG was associated with a significantly shorter operative time (RG = 201 min vs. LG = 231 min, p = 0.0051), less blood loss (RG = 13 mL vs. LG = 42 mL, p < 0.0001), lower postoperative morbidity (RG = 1.0% vs. LG = 4.8%, p = 0.0066), and a shorter postoperative hospital stay (p = 0.0002) than LG. Drain amylase levels on postoperative Days 1 and 3 in the RG group were significantly lower than those in the LG group (p < 0.0001)., Conclusions: RG is a safe and feasible treatment for gastric cancer, with a shorter operative time, less blood loss, and lower postoperative morbidity than LG. The application of robotics in minimally invasive gastric cancer surgery may offer an alternative to conventional surgery. Multicenter, prospective, randomized controlled trials comparing RG with conventional LG are needed to establish the feasibility and efficacy of minimally invasive gastric cancer surgery., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Jackhammer esophagus (JE) is a hypercontractile esophageal motility disorder diagnosed using high-resolution manometry (HRM). We sought to determine the clinical presentation and therapeutic data of patients with JE in Japan., Methods: The study included patients with JE, diagnosed through HRM performed for suspicious esophageal motility disorders. Demographics, esophagogastroduodenoscopy, radiology, and therapy data were collected from patient charts., Results: Among the 4,412 HRM tests performed, 89 patients (61.6 ± 13.4 years; 64 males, 25 females) were diagnosed with JE (2.0%). Dysphagia was the most frequent symptom (80%), followed by chest pain (40%) and heartburn (25%). Esophagogastroduodenoscopy showed abnormal findings in 32% of patients: corkscrew/rosary beads appearance in 26%, narrowing in 11%. Eosinophilic infiltration (> 15 eosinophils/high power field) was diagnosed in 21%. Esophagography showed abnormal findings in 9% of the patients. For the initial therapy, 47 patients received medical treatment followed by peroral endoscopic myotomy (21 patients) and laparoscopic myotomy (two patients). Thirteen patients did not receive any treatment and 10 of those (77%) reported spontaneous resolution of symptoms. Patients who required invasive treatment experienced severe disability in their quality of life and greater maximal distal contractile integral than those who did not., Conclusions: HRM showed that the prevalence of JE was very low (2%). Esophagogastroduodenoscopy revealed some characteristic features of JE in patients. Some patients showed improvement of symptoms without invasive treatments. Follow-up with/without medical treatment should be considered before performing invasive treatment in patients whose distal contractile integral is relatively low and the quality of life is not impaired., (© 2022. The Author(s).)

Background: Endoscopic submucosal dissection (ESD) is becoming widely popular as a less invasive treatment option for superficial esophageal squamous cell carcinoma. However, data on long-term survival after esophageal ESD in patients with severe comorbidities are limited. This study aimed to evaluate long-term survival after ESD in such patients., Methods: Altogether, 584 consecutive patients underwent esophageal ESD at our institution from May 2004 to September 2016. Based on the American Society of Anesthesiologists Physical Status (ASA-PS) classification system, patients were grouped according to severe (ASA-PS ≥ 3) or non-severe comorbidities (ASA-PS 1/2). The overall survival (OS), disease-specific survival (DSS), and risk factors for mortality were compared between the groups using a propensity score matching analysis., Results: In a matched cohort of 69 pairs, the 5-year OS rate was poorer in ASA-PS 3 patients than in ASA-PS 1/2 patients (63.9% vs. 92.5%, P < 0.01), while the 5-year DSS rate was similar between the groups (100% vs. 100%). The mortality rate was significantly higher in ASA-PS 3 patients than in ASA-PS 1/2 patients (hazard ratio 3.47; 95% confidence interval 1.79-6.74; P < 0.01). Death due to exacerbation of comorbidities was significantly more frequent in ASA-PS 3 patients than in ASA-PS 1/2 patients (42.4% vs. 8.3%, P < 0.04)., Conclusion: Because of the exacerbation of comorbidities, patients with severe comorbidities had poorer long-term outcomes after esophageal ESD than those with non-severe comorbidities. Further studies will be necessary to evaluate esophageal ESD in patients with severe comorbidities., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To determine the optimal treatment for spontaneous spinal epidural hematoma (SSEH). The aim of this study was to identify factors associated with SSEH., Methods: In 62 patients with SSEH, several patient-related parameters were analyzed as candidate factors associated with Frankel grade before treatment or at the last follow-up. These parameters were compared between patients with and without surgery. In addition, multivariate ordinal logistic regression analysis was used to identify factors significantly associated with Frankel's grade before treatment or at the last follow-up., Results: There were significant differences in age, location of the hematoma, and Frankel grade before treatment and at the last follow-up between surgical and nonsurgical cases in all patients, but there were no significant differences in any of these parameters when comparing patients with pre-treatment Frankel grade C. The location of the hematoma was significantly associated with the severity of paralysis before treatment. In surgical cases, the time from onset to surgery and the location of the hematoma was significantly associated with the prognosis. When the time from onset to surgery was evaluated using the criteria of 12, 24, and 48 h, 24 and 48 h had a significant impact on the prognosis. In the analysis of nonsurgical cases, only the vertical size of the hematoma was significantly associated with prognosis., Conclusion: The time from onset to surgery and the location of the hematoma were prognostic factors in surgical cases, while the vertical size of the hematoma was a prognostic factor in nonsurgical cases., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Platinum-doublet chemotherapy has been conventionally used for patients with advanced gastroenteropancreatic (GEP) neuroendocrine carcinoma (NEC) but evidence of chemotherapy is based on studies with small sample sizes and remains scarce. Thus, we conducted a systematic review and meta-analysis to elucidate the efficacy of platinum-doublet chemotherapy for advanced GEP-NEC., Methods: We performed a database search in PubMed/MEDLINE and EMBASE. Eligible studies were prospective and retrospective studies documenting the efficacy of platinum plus etoposide (EP) and platinum plus irinotecan (IP) for advanced GEP-NEC. Overall response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were pooled and weighted using generic inverse variance in a random-effects meta-analysis model., Results: Nineteen studies including 1157 patients were identified. The ORR of the platinum-doublet regimen, EP, and IP was 49.1% (95% confidence interval [CI], 41.8-56.5), 44.4% (95% CI: 35.9-53.0), and 59.4% (95% CI: 48.0-70.8). The pooled median OS of the platinum-doublet regimen, EP, and IP was 12.9 months (95% CI:10.9-15.3), 12.9 months (95% CI: 10.8-15.4), and 12.9 months (95% CI: 6.0-27.8), and the pooled median PFS of the platinum-doublet regimen, EP, and IP was 5.4 months (95% CI: 4.5-6.4), 5.4 months (95% CI 4.5-6.5), and 4.0 months (95% CI: 1.4-11.7), respectively., Conclusion: Considerable response rate and survival time of the platinum-doublet regimen for advanced GEP-NEC were observed. IP and EP regimens can be reasonably applicable and these results provide a reference for oncologists in deciding the suitable regimen for patients with advanced GEP-NEC., (© 2022. The Author(s).)

Purpose: Aprepitant is used with dexamethasone and 5-HT 3 receptor antagonists as an antiemetic treatment for chemotherapy, including cisplatin. Aprepitant is a substrate of cytochrome P450 (CYP) 3A4 and is known to cause its inhibition and induction. In addition, dexamethasone is a CYP3A4 substrate that induces CYP3A4 and CYP3A5 expression. In this study, we aimed to quantitatively evaluate the profile of CYP3A activity using its endogenous markers in non-small cell lung cancer patients receiving a standard cisplatin regimen with antiemetics, including aprepitant., Methods: Urinary 11β-hydroxytestosterone (11β-OHT)/testosterone concentration ratio and plasma 4β-hydroxycholesterol (4β-OHC) concentrations were measured before and after cisplatin treatment (days 1, 4, and 8). CYP3A5 was genotyped, and plasma aprepitant concentrations were measured on day 4 to examine its influence on CYP3A endogenous markers., Results: The urinary 11β-OHT/testosterone concentration ratio in the 35 patients included in this study increased by 2.65-fold and 1.21-fold on days 4 and 8 compared with day 1, respectively. Their plasma 4β-OHC concentration increased by 1.46-fold and 1.66-fold, respectively. The mean plasma aprepitant concentration on day 4 was 1,451 ng/mL, which is far lower than its inhibitory constant. The allele frequencies of CYP3A5*1 and CYP3A5*3 were 0.229 and 0.771, respectively. In patients with the CYP3A5*1 allele, the plasma 4β-OHC concentration was significantly lower at baseline but more potently increased with chemotherapy., Conclusion: CYP3A activity was significantly induced from day 4 to day 8 in patients receiving cisplatin and three antiemetic drugs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Glioblastoma is a glioma characterized by highly malignant features. Numerous studies conducted on the relationship between glioblastoma and the microenvironment have indicated the significance of tumor-associated macrophages/microglia (TAMs) in glioblastoma progression. Since interleukin (IL)-1β secreted by TAMs has been suggested to promote glioblastoma growth, we attempted to elucidate the detailed mechanisms of IL-1β in glioblastoma growth in this study. A phospho-receptor tyrosine kinase array and RNA-sequencing studies indicated that IL-1β induced the activation of signal transducer and activator of transcription-3 and nuclear factor-kappa B signaling. Glioblastoma cells stimulated by IL-1β induced the production of IL-6 and CXCL8, which synergistically promoted glioblastoma growth via signal transducer and activator of transcription-3 and nuclear factor-kappa B signaling. By immunohistochemistry, IL-1β expression was seen on TAMs, especially in perinecrotic areas. These results suggest that IL-1β might be a useful target molecule for anti-glioblastoma therapy., (© 2021. Japan Human Cell Society.)

Background: The superiority of outcomes associated with anatomical resection (AR) versus those associated with non-anatomical resection (NAR) remains controversial in patients with hepatocellular carcinoma (HCC). The aim of this study was to evaluate the significance of AR on therapeutic outcomes of patients with small HCCs (≤ 5 cm), using propensity score-matched (PSM) analysis., Methods: A total of 195 patients who had undergone elective hepatic resection for small HCCs (≤ 5 cm) were included in this study. We conducted PSM analysis for baseline characteristics (age, sex, hepatitis virus status, retention rate of indocyanine green at 15 min, and Child-Pugh grade), preoperative serum α-fetoprotein, and tumor characteristics (tumor size, tumor number, portal vein invasion, and surgical margin status) to eliminate potential selection bias. The prognostic significance of AR on the disease-free and overall survival was analyzed in patients selected by PSM analysis., Results: Applying PSM analysis, the patients were divided into PSM-AR (N = 66) and PSM-NAR (N = 66) groups. Disease-free survival was significantly better in the PSM-AR group than that of the PSM-NAR group (P = 0.018), while there was no significant difference in the overall survival between the PSM-AR and PSM-NAR groups (P = 0.292). The univariate HRs of the PSM-AR group were 0.55 (95% CI, 0.33-0.90) for disease-free survival and 0.61 (95% CI, 0.24-1.53) for overall survival, respectively. Remnant liver recurrence was significantly lower in the AR group (P = 0.014)., Conclusions: AR may improve the disease-free survival in HCC patients with tumors of ≤5 cm diameter., (© 2021. The Society for Surgery of the Alimentary Tract.)

Purpose: This study aimed to investigate the correlation between mindful eating and nutritional intake, food consumption, and healthful and unhealthful plant-based dietary patterns in young Japanese women., Methods: The sample comprised 215 female undergraduates who responded to a two-questionnaire anonymous survey conducted in Tokyo, Japan in 2018 and 2019 from November to December. We measured mindful eating status using the Expanded Mindful Eating Scale (EMES) and used Japanese plant-based dietary indices to determine plant-based dietary patterns. Partial correlation analyses were conducted to determine the correlation of mindful eating with energy and nutrient intake, food consumption, and plant-based dietary patterns, after adjusting for demographics and body mass index., Results: Participants with higher sub-scores in "health of the planet" and "awareness and appreciation for food" ate higher quantities of several micronutrients and plant-based foods and were more likely to have a healthful plant-based dietary pattern. They were also less likely to have an unhealthful plant-based dietary pattern. In contrast, participants with higher scores in "non-judgmental awareness" ate less protein, whole grains, and vegetables, and were likely to have an unhealthful plant-based dietary pattern., Conclusion: This study is the first to show that young Japanese women with normal or lean body weight were more likely to consume healthful plant-based foods when they ate mindfully., Level V: Opinions of respected authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG part of Springer Nature.)

Background: Lugol chromoendoscopy has been conventionally used for the detection and delineation of esophageal squamous cell carcinoma (SCC). However, the boundaries of some lesions are unclear even with Lugol chromoendoscopy, and there is a risk of residual lesions or over-excision. This study aimed to evaluate the utility of narrow-band imaging (NBI) for the delineation of esophageal SCC in endoscopic resection., Methods: Among 367 esophageal SCCs endoscopically resected between January and December 2019 at our institute, this retrospective study included consecutive lesions, which were first marked with NBI, followed by Lugol chromoendoscopy. The proportion of residual cancer, which was defined as histologically proven cancer confirmed adjacent to the scar within 1 year after endoscopic resection, was evaluated. To evaluate whether the marks added by Lugol chromoendoscopy after NBI marking were more reliable, we evaluated the presence of cancer in the iodine-unstained area outside the NBI-determined marks, i.e., the cancerous area missed by NBI. The presence of cancer in the iodine-stained areas inside the NBI-determined marks, i.e., the cancerous area missed by Lugol, was also evaluated. These were compared to assess the risk of residual cancer in endoscopic resection with NBI and Lugol chromoendoscopy., Results: Among 304 lesions, 2 (0.7%) residual cancers were detected. The cancerous area missed by NBI and the cancerous area missed by Lugol were identified in 18 (6%) and 43 (14%) lesions, respectively (P = 0.001)., Conclusions: NBI might be acceptable for delineating the extent of esophageal SCCs that are difficult to delineate with Lugol chromoendoscopy., (© 2021. The Japan Esophageal Society.)

In this paper, we review our work in the last 10 years wherein we examined the sulfides in the acetone extracts of garlic (Allium sativum), onion (A. cepa), and Welsh onion (A. fistulosum), obtained and characterized the structures of new sulfides, three 3,4-dimethylthiolane-type sulfides from onion and Welsh onion, respectively, and four acyclic-type, nine 3,4-dimethyl- thiolane-type, four 2-methylthiolane (and thiane)-type, two 1,2-dithiolane-type, and two 2-oxothiolane-type sulfides, together with (E)-ajoene and one kujounin-type sulfide from garlic. During this process, structural corrections were made in onionin A group, garlicnin A, and garlicnin B group in some 3,4-dimethylthiolane-type sulfides. Next, hypothetical pathways for the production of the aforementioned sulfides were proposed. Furthermore, it was revealed that a typical 3,4-dimethylthiolane-type sulfide, onionin A 1 obtained from onion, having the isomeric structure of garlicnin B 1 obtained from garlic, decreased tumor proliferation and controlled tumor metastasis. These results showed that onionin A 1 is an effective agent for controlling tumors, and that the antitumor effects observed in vivo are likely caused by reversing the antitumor immune system. Activation of the antitumor immune system by onionin A 1 might be an effective adjuvant therapy for patients with osteosarcoma, ovarian cancer and other malignant tumors., (© 2021. The Author(s).)

Background: Due to its tumor-specific metabolic pathway characteristics, 5-aminolevulinic acid (5-ALA) is a natural amino acid widely used in cancer treatment. The current study, demonstrated that 5-ALA induced ferroptosis via glutathione peroxidase 4 (GPX4) and heme oxygenase 1 (HMOX1) and had an antitumor effect in esophageal squamous cell carcinoma (ESCC)., Methods: Expression of GPX4 and HMOX1 in pathologic specimens of 97 ESCC patients was examined, and prognostic analyses were performed. Real-time polymerase chain reaction (RT-PCR), RNA microarray, and Western blotting analyses were used to evaluate the role of 5-ALA in ferroptosis in vitro. In addition, this study used ferrostatin-1, a ferroptosis inhibitor, and a lipid peroxidation reagent against cell lines treated with 5-ALA. Finally, the role of 5-ALA was confirmed by its effect on an ESCC subcutaneous xenograft mouse model., Results: The study showed that upregulation of GPX4 and downregulation of HMOX1 were poor prognostic factors in ESCC. In an RNA microarray analysis of KYSE30, ferroptosis was one of the most frequently induced pathways, with GPX4 suppressed and HMOX1 overexpressed by 5-ALA treatment. These findings were verified by RT-PCR and Western blotting. Furthermore, 5-ALA led to an increase in lipid peroxidation and exerted an antitumor effect in various cancer cell lines, which was inhibited by ferrostatin-1. In vivo, 5-ALA suppressed GPX4 and overexpressed HMOX1 in tumor tissues and led to a reduction in tumor size., Conclusions: Modulation of GPX4 and HMOX1 by 5-ALA induced ferroptosis in ESCC. Thus, 5-ALA could be a promising new therapeutic agent for ESCC.

Background: Endoscopic submucosal dissection (ESD) is accepted as the standard treatment for early-stage esophageal neoplasia. However, esophageal perforation may occur, leading to mediastinitis and pneumothorax, which occasionally require emergency surgery. Moreover, failure of en bloc resection causes local recurrence. However, studies on the predictors of such difficulties during ESD are limited. Hence, we evaluated the predictors associated with the difficulty of ESD for esophageal neoplasia including failure of en bloc resection or perforation., Methods: Data of 549 consecutive patients who were treated with ESD between May 2004 and March 2016 at a single institution were retrospectively studied. Exclusion criteria were the presence of metachronous esophageal neoplasia or missing data. The primary outcome was determining the predictors associated with the difficulty of ESD for esophageal neoplasia including failure of en bloc resection or perforation., Results: Altogether, 543 patients with 736 lesions were evaluated. Failure of en bloc resection occurred in 6 patients (1.1%) with 6 lesions, and perforation occurred in 11 patients (2.0%) with 11 lesions (1.5%). Multivariate logistic regression analysis showed that large lesion diameter (odds ratio [OR] 1.49; 95% confidence interval [CI] 1.21-1.84; p < 0.001) and previous chemoradiotherapy (OR 5.24; 95% CI 1.52-18.06; p = 0.009) were independent predictive factors., Conclusions: Larger lesions and previous chemoradiotherapy for esophageal cancer increased the risk for failure of en bloc resection or perforation in patients who underwent esophageal ESD.

Endometriosis is a chronic inflammatory disease. Endometriotic cysts contain hemoglobin (Hb) and infiltrated macrophages, indicating that the metabolism of Hb by macrophages may play an important role in the inflammation of endometriotic cysts. In this study, we investigated the distribution of immune cells and CD163 (Hb receptor)-positive cells in the endometriotic cyst wall using immunohistochemistry. We also examined the role of macrophage activation by Hb on the pathogenesis of endometriotic cysts by measuring the cytokine concentration in the cystic fluids and macrophage-culture supernatant using ELISA. Macrophages were the most prominent immune cells observed in the endometriotic cysts and were differentially distributed in the different histological areas of the cyst wall. The localization of CD163-positive macrophages was restricted to the hemorrhagic and outer areas in the cyst wall. High concentrations of IL-6 and CCL2 were found in the cystic fluids, and inflammatory cytokines (IL-6, TNF-α, and CCL2) were secreted from macrophages on stimulation by Hb. IL-6 is a promotional factor for endometriotic stromal cells and ovarian clear cell carcinoma, the most common histological subtype of endometriosis-related ovarian cancer, hence, the continuous activation of macrophages by Hb could be a potential mechanism underlying endometriosis development and carcinogenesis.

Background: Eosinophilic esophagitis (EoE) is a chronic allergic disease with esophageal symptoms and intraepithelial eosinophil infiltration. Effects of potassium-competitive acid blockers (P-CABs) on EoE have not been elucidated. We aimed to examine and compare the effects of P-CABs and PPIs on symptomatic, endoscopic, and histological responses of patients with EoE., Methods: We analyzed 118 EoE patients who received PPI or P-CAB therapy with rabeprazole 10 mg (RPZ10, N = 22), rabeprazole 20 mg (RPZ20, N = 34), esomeprazole 20 mg (EPZ20, N = 25), or vonoprazan 20 mg (VPZ20, N = 33). We evaluated symptomatic responses by classifying the patients into three groups: complete relief, partial relief, and no change. Endoscopic responses were evaluated using the endoscopic reference score (EREFS) following PPI or P-CAB therapy. Histological responses were evaluated by determining eosinophil counts in esophageal biopsy samples and classifying the patients into two groups: complete remission [0/1 eosinophil/high-power field (eos/HPF)] and remission (< 15 eos/HPF)., Results: There were no differences among the therapy groups in terms of clinical characteristics, endoscopic findings, and histological findings of the patients before treatment. The rate of complete relief in clinical symptoms was 54.5% in the RPZ10 group, 64.7% in the RPZ20 group, 72.0% in the EPZ20 group, and 75.7% in the VPZ20 group. There were no significant differences in the therapeutic effect among the therapy groups. Similarly, endoscopic and histological complete remission rates were not significantly different among the therapy groups., Conclusions: Vonoprazan showed similar efficacy to PPIs in EoE.

Purpose: Part A of the open-label, phase I KEYNOTE-434 study evaluated the safety and tolerability of epacadostat, an indoleamine 2,3-dioxygenase-1 inhibitor, alone and in combination with pembrolizumab in Japanese patients with advanced solid tumors., Methods: Japanese patients with refractory/recurrent metastatic or locally advanced tumors were enrolled. Cohort 1 received oral epacadostat 25 mg or 100 mg twice daily (BID) and subsequently received epacadostat in combination with intravenous pembrolizumab 200 mg every 3 weeks. Cohort 2 received epacadostat 25 mg or 100 mg BID with pembrolizumab 200 mg every 3 weeks. The primary objective was evaluation of safety and tolerability using a modified toxicity probability interval method. Secondary objectives were pharmacokinetic (PK) and pharmacodynamic profiles of epacadostat alone and in combination with pembrolizumab., Results: Six patients were enrolled in cohort 1 (epacadostat 25 mg, n = 3; epacadostat 100 mg, n = 3); none experienced dose-limiting toxicities (DLTs). Nine patients were enrolled in cohort 2 (epacadostat 25 mg and pembrolizumab, n = 3; epacadostat 100 mg and pembrolizumab, n = 6); one patient receiving epacadostat 100 mg and pembrolizumab experienced grade 4 rhabdomyolysis-a DLT. Grade 3 or 4 treatment-related adverse events occurred in two patients (13.3%). There were no treatment-related deaths. Pembrolizumab had no impact on epacadostat PK and vice versa. The PK profile of pembrolizumab in the current study was comparable with historical pembrolizumab PK data., Conclusion: Epacadostat in combination with pembrolizumab was generally safe and well tolerated among Japanese patients with advanced solid tumors. Clinical trial registration NCT02862457.

Background: Influence of cognitive intervention programs on brain activity has not been enough explored., Aims: The aims of the present study were to clarify changes in brain activity from a cognitive intervention program utilizing the board game "Go" and to examine the relationship between brain activity and the acquisition of Go skills., Methods: Eighteen community-dwelling older adults were randomly assigned either to an intervention group (IG), in which members attended 12 Go lessons either in groups or individually using tablet computers, or a control group (CG), in which members attended health education lectures unrelated to Go. Fluorine-18 fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET), cognitive assessments, and Go tests were performed before and after the intervention., Results: The results showed different patterns of regional FDG uptake in both groups: regional cerebral glucose metabolism was significantly increased in the left middle temporal gyrus (MTG) and bilateral putamen (p < 0.01; cluster level) in the IG, and in the left superior frontal gyrus in the CG, (p < 0.01; cluster level). Furthermore, Go test scores were significantly improved in the IG (p < 0.05), and a significant association was observed between changes in Go test scores and glucose metabolism in the left MTG (p < 0.05)., Conclusions and Discussion: This study indicates that a cognitive intervention program using Go may enhance brain activity. Further studies with larger populations and longer observation periods are needed to clarify the neural mechanisms underlying our Go intervention program.

Background: The delta-shaped anastomotic technique (Delta-SA) has been accepted as a standard reconstruction method in totally laparoscopic distal gastrectomy with Billroth I reconstruction (TLDG B-I). However, some anastomosis-related surgical complications have been reported. We evaluated the safety and feasibility of modified Delta-SA, called intracorporeal triangular anastomotic technique (INTACT), in this study., Methods: From January 2010 to May 2018, we identified patients who underwent TLDG B-I with INTACT (n = 289) and Delta-SA (n = 221). Using one-to-one propensity score matching, surgical outcomes and gastrointestinal function were compared between the two groups., Results: After one-to-one propensity score matching, 177 pairs of INTACT and Delta-SA patients were selected. Patient background was closely balanced between the two groups. Operative time (186 [159, 213] min vs. 237 [213, 264] min; P < 0.001), estimated blood loss (0 [0, 10] g vs. 20 [0, 50] g; P < 0.001), and postoperative hospital stay (7 [7, 9] days vs. 10 [9, 13] days; P < 0.001) were significantly lower in the INTACT group than in Delta-SA group. There were no patients with postoperative leakage in the INTACT group and three patients in the Delta group (0.0% vs. 1.7%; P = 0.041). Endoscopic food residue grade ≥ 3 based on the Residue, Gastritis, Bile classification system at 1 year after surgery was observed in 14 patients in the INTACT group and 30 patients in the Delta group (9.6% vs. 17.0%; P = 0.052)., Conclusion: INTACT in TLDG B-I is safe and feasible for gastric cancer. Given its acceptable surgical outcomes, this alternative reconstruction method can be an option with TLDG B-I.

Objective: To optimize the delays alternating with nutation for tailored excitation (DANTE) pulse as a vascular crushing gradient to eliminate macro-and micro-vascular signals and to generate a macrovascular space-related map by applying DANTE with multiple conditions., Materials and Methods: Numerical simulation was performed to estimate the optimal flip angle (FA) of the DANTE. A phantom study was conducted to evaluate the impact of the FA and gradient area (GA) of the DANTE with three flow velocities and various parameters of the DANTE. Finally, an in vivo study was performed to assess the optimal DANTE parameters and to map the estimated macrovascular signal of the arterial spin labeling (ASL) signal., Results: Numerical simulation revealed that the decrease of magnetization plateaued at 12.5° of FA. The phantom study showed that the setting of larger FA or GA decreased the ASL signals. The decrease of the ASL signal depended on the flow velocity, and the dependence increased with decreasing GA. The in vivo study revealed that larger FA and GA decreased the perfusion signal., Discussion: An optimized DANTE makes it possible to efficiently suppress the macro-and-micro vascular signals depending on the flow velocity. Moreover, macrovascular signal mapping may be useful to assess altered hemodynamic states.

Background: High red cell distribution width (RDW) is reportedly provoked by chronic inflammation and poor nutritional status; high pre-operative RDW is related to poor prognosis in some cancers. However, the prognostic significance of post-operative RDW in gastric cancer (GC) patients is unclear., Methods: We enrolled 221 patients who had undergone curative surgery for histopathologically diagnosed gastric adenocarcinoma., Results: Optimal cutoff values were determined by ROC analysis to be 14.85 (pre-operative) and 14.05 (post-operative). We accordingly divided patients into the high (pre-RDW High ; ≥ 14.85) and low (pre-RDW Low ; < 14.85) pre-operative RDW groups, and the high (post-RDW High ; ≥ 14.05) and low (post-RDW Low ; < 14.05) post-operative RDW subgroups. Five-year overall survival (OS) rates differed significantly in pre-RDW High group (52.4%) and pre-RDW Low group (78.0%; P < 0.0001). Five-year OS rates also differed significantly in post-RDW High (52.7%) and post-RDW Low subgroups (88.3%; P < 0.0001). Multivariate analysis showed post-operative RDW, but not pre-operative RDW, to be an independent prognostic indicator for OS., Conclusions: Post-operative RDW may be a useful prognostic indicator in GC patients.

Background: No study has reported trajectories of kidney function in later life. This long-term prospective study attempted to classify trajectories of estimated glomerular filtration rate (eGFR) and identify factors associated with these trajectories., Methods: We collected data from annual geriatric health checkups conducted during 2002-2017 in Kusatsu Town, Gunma Prefecture, Japan. The participants were 1990 adults aged 65-90 years (mean [SD] age, 71.0 [5.7] years; 57.0% women), and the total number of observations was 9291. Data were analyzed with a group-based semiparametric mixture model and age-adjusted univariable cumulative logit models., Results: Trajectory of kidney function, as determined by eGFR, was classified as low, middle, and high (4.8%, 38.9%, and 56.3% of men, respectively, and 5.2%, 31.5%, and 63.3% of women). Among men and women in the low trajectory group, chronic kidney disease (CKD) stage worsened from stage G3a (51.8 ml/min/1.73 m 2 in men and 53.6 in women) at age 65 years to stage G4 (28.0 ml/min/1.73 m 2 in men and 28.5 in women) by age 85 years. A history of hypertension (men and women) and heart disease (men) were more likely in the low trajectory group than in the middle and high trajectory groups., Conclusions: About 5% of community-dwelling older adults had an eGFR < 30 later in life. Our findings suggest that those with stage G3a CKD at age 65 years should be managed intensively, to control risk factors for CKD progression.

Navoximod (GDC-0919) is a small molecule inhibitor of indoleamine-2,3-dioxygenase 1. This study investigated the safety, tolerability and pharmacokinetics of navoximod alone and in combination with atezolizumab in Japanese patients with advanced solid tumours. This was a phase I, open-label, dose-escalation study. Patients received monotherapy with navoximod 400 mg, 600 mg or 1000 mg orally twice daily (BID) in Stage 1 and navoximod 200 mg, 400 mg, 600 mg or 1000 mg orally BID plus atezolizumab 1200 mg intravenously every 21 days in Stage 2. Objectives included safety, tolerability, efficacy and pharmacokinetic outcomes.Overall, 20 patients were enrolled (Stage 1: n = 10; Stage 2: n = 10). No dose-limiting toxicities were observed. In Stage 1, treatment-related adverse events (TRAEs) of any grade that occurred in ≥20% of patients were chromaturia (50%) and maculopapular rash (20%). Grade ≥ 3 TRAEs were reported in two patients (20%; maculopapular rash and lipase increased). In Stage 2, TRAEs that occurred in ≥30% of patients were chromaturia (60%) and, decreased appetite (40%). Grade ≥ 3 TRAEs were reported in three patients (30%; hyponatraemia, aspartate aminotransferase increased, alanine aminotransferase increased, lymphopaenia and neutropaenia). Stable disease was observed in five patients (50%) in Stage 1 and eight patients (80%) in Stage 2. Navoximod showed linear pharmacokinetics. The recommended dose of navoximod monotherapy was determined as 1000 mg orally BID, and could be considered 1000 mg orally BID in combination with atezolizumab. Navoximod as monotherapy and in combination with atezolizumab was well tolerated in Japanese patients with advanced solid tumours.

Aims: The benefit of preoperative biliary drainage for patients with operable periampullary cancers is controversial because biliary drainage would activate inflammatory response such as cholangitis. The aim of this study was to identify a novel prognostic score in patients with operable periampullary cancers including pancreatic cancer and extrahepatic distal bile duct cancer with a typical reference to preoperative biliary drainage and inflammatory status., Methods: Between 2000 and 2015, 246 patients were enrolled in this retrospective study. The patients were divided into four groups of the following three factors; the presence of preoperative biliary drainage, decreased serum albumin value (< 3.5 g dl -1 ), and increased CR P value (> 1.0 mg dl -1 ). The relationship between clinicopathological variables and disease-free survival (DFS) as well as over-all survival (OS) was investigated by univariate and multivariate analyses. To compare the sensitivity and specificity among the types of cancer, the area under the receiver operating characteristics curve (AUC) was evaluated in patients with pancreatic cancer and extrahepatic distal bile duct cancer., Results: In multivariate analysis of DFS and OS, the novel prognostic factor combining preoperative biliary drainage and inflammatory status was an independent risk factor of tumor recurrence and prognosis as well as differentiation of the tumor and resected margin., Conclusion: The novel prognostic score combining preoperative biliary drainage and inflammatory status may be an independent predictor of tumor recurrence and prognosis in patients with periampullary cancers.

Adrenal insufficiency (AI) is an immune-related adverse event of immune checkpoint inhibitors and on occasion could be serious. There have been few reports of clinical information regarding AI associated with anti-programmed cell death protein-1 (anti-PD-1) antibody in non-small-cell lung cancer (NSCLC) patients. Patients with advanced NSCLC treated with anti-PD-1 antibodies between December 2015 and October 2017 were identified from the medical records of our institution. We investigated the frequency, symptoms, test results, and treatment outcomes of AI, and prognosis of patients who developed AI. In total, 282 NSCLC patients were treated with anti-PD-1 antibodies, and 4 patients (1.4%) were diagnosed as AI and 6 patients (2.1%) as suspicious of AI according to the laboratory data or clinical findings. The median follow-up period was 13.6 months. All patients with AI and suspicious of AI were treated with corticosteroid replacement, and performance status (PS) was improved in 50% of patients. Two of 10 patients were thought to have central AI. Six patients of 10 patients continued to receive anti-PD-1 antibodies with corticosteroid hormone replacement after diagnosis. The median progression-free survival and overall survival were 10.2 and 15.4 months, respectively. In conclusion, the incidence of AI among NSCLC patients treated with anti-PD-1 antibodies was similar to previous studies. Corticosteroid replacement improved PS, symptoms, and laboratory data of patients with AI and suspicious of AI. Corticosteroid replacement may contribute to continuation of anti-PD-1 antibodies and survival outcome was preferable in patients with AI and suspicious of AI receiving corticosteroid treatment.

This study aimed to assess the clinical value of C-reactive protein-albumin ratio (CAR) at the initiation of first-line treatment for castration-resistant prostate cancer (CRPC). We identified 221 CRPC patients treated with either androgen-signaling inhibitors (ASIs: abiraterone and enzalutamide) or docetaxel as the first-line treatment. The value of CAR was evaluated at the initiation of first-line treatment. The optimal cutoff value of CAR for the prediction of lethality was defined by the receiver operating characteristic curve and the Youden Index. The primary endpoints of the study included overall survival (OS) and cancer-specific survival (CSS). The median age was 74 years. The optimal cutoff value of CAR in newly diagnosed CRPC patients was 0.5 (CAR > 0.5: n = 77 and CAR ≤ 0.5: n = 144). The 3-year OS and CSS rate in patients with CAR > 0.5 were significantly lower than those with CAR ≤ 0.5 (OS: 30.9% vs 55.5%, p < 0.001) (CSS: 42.5% vs 65.4%, p < 0.001). A multivariate analysis consistently demonstrated that CAR was an independent predictor for both OS and CSS. When stratified by the first-line treatments, patients with CAR > 0.5 has significantly shorter CSS than those with CAR ≤ 0.5 in abiraterone (median of 23 vs 49 months, p < 0.001) and enzalutamide (median of 23 vs 41 months, p = 0.0016), whereas no difference was observed in patients treated with docetaxel as the first-line treatment (median of 34 and 37 months, p = 0.7708). Despite the limited cohort size and retrospective design, increased CAR seemed to serve as an independent predictor of OS and CSS for patients newly diagnosed with CRPC.

A gastrointestinal-airway fistula (GAF) after esophagectomy is a very serious postoperative complication that can cause severe respiratory complications due to digestive juice inflow. Generally, GAF is managed by invasive surgical treatment; less-invasive treatment has yet to be established. We performed esophageal stent placement (ESP) in three cases of GAF after esophagectomy. We assessed the usefulness of ESP through our clinical experience. All GAFs were successfully managed by ESP procedures. After the procedure, the stent positioning and expansion were appropriately evaluated by radiological assessments over time. The stent was removed after endoscopic confirmation of fistula closure on days 8, 23, and 71. Only one patient with a long-term indwelling stent developed a manageable secondary gastrobronchial fistula as a procedure-related complication. In conclusion, ESP was shown to be a less-invasive and effective therapeutic modality for the treatment of GAF.

Background: Esophageal eosinophilia (EE) is a basal condition of eosinophilic esophageal disorders including eosinophilic esophagitis (EoE) and asymptomatic EE. EoE is considered as an allergic disorder, while it is unclear whether other non-allergic conditions are involved in the pathophysiology of EE. The aim of this study is to investigate the non-allergic risk factors for EE., Methods: This cross-sectional study included subjects who underwent esophagogastroduodenoscopy on a medical health check-up. We compared clinical characteristics between subjects with EE (n = 27) and those without EE (n = 5937)., Results: The detection rate of EE was 0.45% (27/5964 persons). Of 27 subjects with EE, 20 subjects were symptomatic and 7 were asymptomatic. On univariate analysis, subjects with EE significantly had higher body mass index (BMI) compared to those without EE; 23.4 (4.4) vs 22.3 (4.5) kg/m 2 , median (interquartile range), p = 0.005. Endoscopic findings revealed that subjects with EE had significantly higher proportion of hiatal hernia (29.6% vs 14.7%; p = 0.049). Subjects with EE were significantly younger and had higher proportion of bronchial asthma; 45 (11.5) vs 51 (18) years, p = 0.013; 25.9% vs 5.2%, p < 0.001, respectively. Multivariate analysis showed that subjects with EE were positively associated with BMI [odds ratio (OR) 1.11; 95% confidence interval (CI) 1.03-1.20; p = 0.010) and hiatal hernia (OR 2.63; 95% CI 1.12-6.18; p = 0.026) compared to those without EE. On trend test, advanced BMI classification had significant trend for increased prevalence of EE (p = 0.002)., Conclusions: Obesity and hiatal hernia may be non-allergic risk factors for EE in Japanese adults.

Background: We have sometimes experienced technical difficulty performing thoracoscopic esophagectomy because of the position of the descending aorta or width of the mediastinal space. In this study, we retrospectively investigated predictive preoperative factors that influence the procedure of thoracoscopic esophagectomy with a focus on the position of the descending aorta and width of the mediastinal space., Methods: Ninety-five patients who underwent thoracoscopic esophagectomy for esophageal cancer by two specialists were included in this study. Thirty patients in whom both the operation time and blood loss in the thoracic region exceeded the median were categorized to the difficult group. The remaining 65 patients were categorized into the common group. During the evaluation of the position of the descending aorta, we measured the aorta-vertebra angle at the level of the left inferior pulmonary vein. During the evaluation of the width of the mediastinal space, we measured the sternum-vertebra distance at the level of the tracheal bifurcation., Results: A forward stepwise logistic regression analysis revealed the following independent predictive factors of the technical difficulty of thoracoscopic esophagectomy: aorta-vertebra angle (≥ 30°), sternum-vertebra distance (< 100 mm), and clinical T stage (T3)., Conclusions: The position of the descending aorta, width of the mediastinal space, and clinical T stage are predictive factors of the technical difficulty of thoracoscopic esophagectomy. These factors might become supporting indices for the indication for thoracoscopic esophagectomy among trainees or the surgeons who introduce this procedure.

Background: Single-port laparoscopic surgery maximizes the advantages of laparoscopic surgery by reducing damage of the abdominal wall. However, no comparative studies have addressed its application to gastrectomy for advanced gastric cancer (AGC). We therefore aimed to demonstrate the safety and feasibility of single-port laparoscopic gastrectomy (SLG) for the treatment of AGC by comparing it with conventional multi-port laparoscopic gastrectomy (MLG)., Methods: We searched the prospective gastric cancer database of our institute for patients with AGC who underwent SLG or MLG between October 2007 and December 2013. Cases of R2 resection with distant metastasis or concurrent surgery for comorbid malignant lesions were excluded. One-to-one propensity score matching was performed to reduce bias from confounding patient-related variables, and the short- and long-term outcomes were compared between the two groups., Results: We identified 216 patients who underwent SLG (n = 100) or MLG (n = 116). After propensity score matching, we selected 73 pairs of patients who underwent SLG (distal gastrectomy, 49; total gastrectomy, 24) or MLG (distal gastrectomy, 45; total gastrectomy, 28). While the mean operative times were comparable between the groups, the SLG group had less blood loss, a lower postoperative morbidity, and shorter postoperative hospital stays. The 5-year survival rates were 74.2% in the SLG group and 60.2% in the MLG group (P = 0.081 by log-rank test)., Conclusions: SLG is shown to be safe and feasible for the treatment of AGC, with better short-term results and acceptable oncologic outcomes and may be applicable for AGC treatment.

Background: Retracting the lateral liver segment during laparoscopic distal gastrectomy is important for achieving an optimal surgical field. However, excessive force may injure the liver, causing temporary abnormalities of liver function tests after laparoscopic surgery. We developed a new liver retraction method and assessed its safety and utility., Patients and Methods: We retrospectively analyzed records in our surgical database of consecutive surgical patients who underwent laparoscopic distal gastrectomy for early gastric cancer. We divided the 229 patients into two groups based on the liver retraction method used, either flexible liver retraction with clipping and suturing (FLICS) or the Nathanson retractor (NR). One-to-one propensity score matching was performed to match patients, resulting in the records of 53 pairs of cases extracted from the database. Operative and postoperative outcomes were assessed, including following the values of serum liver enzymes, total bilirubin, and C-reactive protein until postoperative day 30., Results: There were no significant differences in patient characteristics or preoperative data in the two groups. The retraction method was not changed intraoperatively for any patients. The operative time was significantly shorter in the FLICS group, but the amount of bleeding did not differ. Liver injury was not observed as a result of liver retraction during surgery. In both groups, serum liver enzymes temporarily increased after surgery but improved rapidly thereafter. The postoperative increases in aspartate transaminase, alanine transaminase, and C-reactive protein levels were significantly lower in the FLICS than in the NR group. No serious complications associated with liver retraction were observed in either group., Conclusions: Our new liver retraction technique provided an optimal surgical field without inducing liver dysfunction. It is a simple, safe, and effective liver retraction technique.

Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/PNET) is an aggressive bone tumor. Bone marrow aspiration and biopsy (BMAB) has been recognized as the gold standard for assessing bone marrow status. While the latest guideline suggests the need to omit bone marrow aspiration in patients with no findings on 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) based on one retrospective report, there is no study using 18 F-FDG PET/computed tomography (CT). We retrospectively reviewed 26 consecutive, previously untreated, ES/PNET patients. We compare the results of bone marrow aspiration and biopsy (BMAB) and those of 18 F-FDG PET/CT in ES/PNET patients. All of the 21 patients without metastases on 18 F-FDG PET/CT had negative BMAB. The sensitivity of bone marrow involvement in bone metastases positive patients on 18 F-FDG PET/CT was 75% (3/4), and the specificity was 100% (22/22). In addition to the metastatic findings on 18 F-FDG PET/CT, tumor diameter, lactate dehydrogenase level at diagnosis, and the presence or absence of bone metastasis were factors related to bone marrow involvement. It may be a reasonable option to omit BMAB in ES/PNET patients with no distant metastasis based on 18 F-FDG PET/CT findings.

Zinc bacteriochlorophyll-d analogs possessing a methylene group at the 132-position were prepared by chemical modification of naturally occurring chlorophyll-a. The synthetic 31-epimers were successfully separated by reverse phase HPLC to give diastereomerically pure samples. The stereochemistry of the chiral C31-center in the separated bacteriochlorophyll-d analogs was determined by HPLC analysis of the authentic stereoisomers prepared stereospecifically. Both the epimers were monomeric in tetrahydrofuran to give sharp absorption bands, while they self-aggregated to form chlorosomal oligomers with red-shifted bands in an aqueous Triton X-100 micelle solution. The resulting large oligomers deaggregated by addition of Triton X-100 to give monomeric species. Their aggregation and deaggregation were dependent on the 31-stereochemistry, indicating that each epimer produced self-aggregates that were supramolecularly different. The substitution with the 132-methylene group enhanced their self-aggregation abilities and the stability of their resulting self-aggregates.

In non-small cell lung cancer (NSCLC) patients, the expression of tumor programmed death ligand 1 (PD-L1) is an important parameter for deciding the timing of the use of anti-programmed cell death 1 (PD-1) antibody. There has been increasing concern over the benefit of anti-PD-1 antibody in high-risk patients, such as those with preexisting interstitial lung disease (ILD). However, the status and value of PD-L1 as a predictive biomarker and the efficacy of anti-PD-1 antibody in NSCLC patients with preexisting ILD remains uncertain. We retrospectively reviewed the medical records of advanced/recurrent NSCLC patients who had undergone analysis of the tumor PD-L1 expression. We identified 358 patients with advanced/recurrent NSCLC who had undergone analysis of tumor PD-LI expression. Of these, 210 received anti-PD-1 antibody. Tumor-cell PD-L1 expression was similar between the groups with and without preexisting ILD (median, 35%; interquartile range, 0-70%; vs. median, 10%; interquartile range, 1-68%; p = 0.66). Of the 210 patients who received anti-PD-1 antibody, 14 patients had preexisting ILD. The progression-free survival (PFS) showed no significant difference between the patients receiving anti-PD-1 antibody with and without preexisting ILD (median PFS, 4.3 vs. 5.3 months; HR, 0.97; p = 0.84). Within the patients with preexisting ILD, the PFS was tended to be longer in the patients with tumor PD-L1 expression ≥ 50% than in those with tumor PD-L1 expression < 50% (median PFS, 12.5 vs. 2.5 months; HR, 0.47; p = 0.14). The value of PD-L1 expression as a biomarker may be comparable between patients with and without preexisting ILD.