Publications by authors named "Sho Sato"

89 Publications

Translational CNS Steady-State Drug Disposition Model in Rats, Monkeys, and Humans for Quantitative Prediction of Brain-to-Plasma and Cerebrospinal Fluid-to-Plasma Unbound Concentration Ratios.

AAPS J 2021 Jun 3;23(4):81. Epub 2021 Jun 3.

Global DMPK, Preclinical and Translational Sciences, Research, Takeda Pharmaceutical Company Limited, Shonan Health Innovation Park (iPark), 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.

Capturing unbound drug exposure in the brain is crucial to evaluate pharmacological effects for drugs acting on the central nervous system. However, to date, there are no reports of validated prediction models to determine the brain-to-plasma unbound concentration ratio (K) as well as the cerebrospinal fluid (CSF)-to-plasma unbound concentration ratio (K) between humans and other species. Here, we developed a translational CNS steady-state drug disposition model to predict K and K across rats, monkeys, and humans by estimating the relative activity factors (RAF) for MDR1 and BCRP in addition to scaling factors (γ and σ) using the molecular weight, logD, CSF bulk flow, and in vitro transport activities of these transporters. In this study, 68, 26, and 28 compounds were tested in the rat, monkey, and human models, respectively. Both the predicted K and K values were within the 3-fold range of the observed values (71, 73, and 79%; 79, 88, and 78% of the compounds, respectively), indicating successful prediction of K and K in the three species. The overall predictivity of the RAF approach is consistent with that of the relative expression factor (REF) approach. As the established model can predict K and K using only in vitro and physicochemical data, this model would help avoid ethical issues related to animal use and improve CNS drug discovery workflow.
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http://dx.doi.org/10.1208/s12248-021-00609-6DOI Listing
June 2021

Direct Comparison of the Prediction of the Unbound Brain-to-Plasma Partitioning Utilizing Machine Learning Approach and Mechanistic Neuropharmacokinetic Model.

AAPS J 2021 May 18;23(4):72. Epub 2021 May 18.

Global DMPK, Takeda California Inc., San Diego, California, 92121, USA.

The mechanistic neuropharmacokinetic (neuroPK) model was established to predict unbound brain-to-plasma partitioning (K) by considering in vitro efflux activities of multiple drug resistance 1 (MDR1) and breast cancer resistance protein (BCRP). Herein, we directly compare this model to a computational machine learning approach utilizing physicochemical descriptors and efflux ratios of MDR1 and BCRP-expressing cells for predicting K in rats. Two different types of machine learning techniques, Gaussian processes (GP) and random forest regression (RF), were assessed by the time and cluster-split validation methods using 640 internal compounds. The predictivity of machine learning models based on only molecular descriptors in the time-split dataset performed worse than the cluster-split dataset, whereas the models incorporating MDR1 and BCRP efflux ratios showed similar predictivity between time and cluster-split datasets. The GP incorporating MDR1 and BCRP in the time-split dataset achieved the highest correlation (R = 0.602). These results suggested that incorporation of MDR1 and BCRP in machine learning is beneficial for robust and accurate prediction. K prediction utilizing the neuroPK model was significantly worse compared to machine learning approaches for the same dataset. We also investigated the predictivity of K using an external independent test set of 34 marketed drugs. Compared to machine learning models, the neuroPK model showed better predictive performance with R of 0.577. This work demonstrates that the machine learning model for K achieves maximum predictive performance within the chemical applicability domain, whereas the neuroPK model is applicable more widely beyond the chemical space covered in the training dataset.
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http://dx.doi.org/10.1208/s12248-021-00604-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131289PMC
May 2021

Hepatitis B Surface Antigen Decline During Sofosbuvir and Ribavirin Therapy in Hepatitis B Inactive Carriers Who were co-infected with Hepatitis C.

Intern Med 2021 May 14. Epub 2021 May 14.

Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Japan.

Direct-acting antiviral (DAA) therapy carries a potential risk of inducing hepatitis B virus (HBV) reactivation. However, the HBV kinetics during and after DAA therapy in patients co-infected with hepatitis C virus (HCV) and HBV remain unknown. We retrospectively evaluated the HBV kinetics during and after sofosbuvir/ribavirin therapy in four HBV inactive carriers co-infected with HCV. HCV was eradicated in all patients. Changes in HBV-DNA levels during treatment differed among patients. The hepatitis B surface antigen (HBsAg) levels uniformly decreased (mean -0.530 logIU/mL) by the end of treatment and returned to near the baseline in all patients. Sofosbuvir/ribavirin therapy thus demonstrated a suppressive effect on HBsAg.
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http://dx.doi.org/10.2169/internalmedicine.7337-21DOI Listing
May 2021

Elevated serum tyrosine concentration is associated with a poor prognosis among patients with liver cirrhosis.

Hepatol Res 2021 May 8. Epub 2021 May 8.

Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan.

Aim: Chronic liver insufficiency is often associated with changes in amino acid metabolism. We evaluated whether change in serum amino acid concentrations had prognostic value among patients with liver cirrhosis.

Methods: This retrospective study evaluated 158 patients who had been hospitalized with cirrhosis. Baseline serum concentrations of branched-chain amino acids (BCAAs) and tyrosine, as well as the BCAA-to-tyrosine ratio, were evaluated. Cox proportional hazards analysis was used to calculate the hazard ratios for factors that were associated with mortality or liver transplantation.

Results: Among the 158 patients, baseline measurements showed decreased serum BCAA concentrations for 59 patients (37.3%), elevated serum tyrosine concentrations for 80 patients (50.6%), and a decreased BCAA-to-tyrosine ratio for 114 patients (72.2%). During a median follow-up period of 3.0 years, death or liver transplantation occurred at a rate of 0.136 cases/1 person-year. Multivariable analysis showed that transplant-free survival was independently predicted by older age, male sex, comorbid hepatocellular carcinoma, Child-Turcotte-Pugh score, and serum tyrosine concentration. Receiver operating characteristic curve analysis showed that a serum tyrosine concentration of >110 µmol/L was the optimal cut-off value for predicting transplant-free survival (adjusted hazard ratio 1.89, 95% confidence interval 1.15-3.11, p = 0.012). Kaplan-Meier analysis showed a significant difference in the 5-year transplant-free survival probability between patients with high and low serum tyrosine concentrations (42.1% vs. 60.7%, p < 0.001).

Conclusions: Elevated serum tyrosine concentration, but not changes in serum BCAA concentration or the BCAA-to-tyrosine ratio, may indicate a high risk of death or liver transplantation for patients with liver cirrhosis.
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http://dx.doi.org/10.1111/hepr.13651DOI Listing
May 2021

Prognostic impact of dimensional factors in pT1 gastric cancer.

Surg Oncol 2021 Apr 22;38:101584. Epub 2021 Apr 22.

Department of Gastroenterological Surgery, Yokohama City University, School of Medicine. Japan.

Background: The significance of the dimensional factors (tumor diameter, area and volume) as the prognostic factor has not been precisely evaluated in pT1 gastric cancer.

Objectives: This study aimed to identify the clinical impact and to confirm the clinical feasibility of the dimensional factors as prognostic factors in pT1 gastric cancer.

Methods: We analyzed prognostic factors for disease-specific survival (DSS), overall survival (OS) using clinicopathological factors by univariate and multivariate analyses and the pattern of recurrence in 2011 pT1 gastric cancer (mucosal and submucosal cancers) undergoing R0 gastrectomy. The cut-off values of each dimensional factor was decided by the ROC curve.

Results: Cox proportional hazard regression model showed that older age (≥75) and more advanced pN stage were adverse independent prognostic factors for DSS, and revealed that older age (≥75), greater preoperative co-morbid diseases, proximal and total gastrectomy, operative method and Clavien-Dindo classification (≥grade III) were independent adverse factors for OS. Any dimensional factors were not independent prognostic factors for any survival.

Conclusions: The dimensional factors do not influence both OS and DSS in pT1 gastric cancer patients and so it is difficult to apply these dimensional factors for conducting therapeutic strategies.
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http://dx.doi.org/10.1016/j.suronc.2021.101584DOI Listing
April 2021

Real-World Therapeutic Outcomes of S-1 Adjuvant Chemotherapy for pStage II/III Gastric Cancer in the Elderly.

Eur Surg Res 2021 1;62(1):40-52. Epub 2021 Apr 1.

Department of Gastroenterological Surgery, Yokohama City University, School of Medicine, Yokohama, Japan.

Background: The predictive factors for discontinuation of S-1 administration and prognostic factors in elderly patients with pStage II/III gastric cancer receiving S-1 adjuvant chemotherapy remain unclear.

Methods: Between January 2004 and December 2016, 80 elderly gastric cancer patients (≥70 years) undergoing curative D2 gastrectomy were enrolled in this study. Predictive factors for completion of S-1 administration over 1 year, adverse events due to S-1 administration, and prognostic factors for overall survival (OS) and relapse-free survival (RFS) were evaluated.

Results: Twenty-eight patients (35%) completed 8 courses of S-1. The median relative dose intensity was 82.1% (IQR 31.1-100%). The incidence rates of hematological and nonhematological adverse events were acceptable. Distal gastrectomy was an independent predictive factor for completion of S-1 administration (odds ratio [OR] 0.364; 95% confidence interval [CI] 0.141-0.939; p = 0.037). Higher postoperative neutrophil count/lymphocyte count (N/L) ratio and more advanced stage adversely influenced OS. Multivariate analysis revealed that a higher postoperative N/L ratio and more advanced stage adversely affected RFS.

Conclusion: To complete adjuvant S-1 administration to elderly patients with pStage II/III gastric cancer, total gastrectomy should be avoided if possible. A new regimen for elderly gastric cancer patients with higher postoperative N/L ratios and more advanced stage should be established.
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http://dx.doi.org/10.1159/000515175DOI Listing
April 2021

Psoas muscle depletion during preoperative chemotherapy for advanced gastric cancer has a negative impact on long-term outcomes after gastrectomy.

Asia Pac J Clin Oncol 2021 Feb 28. Epub 2021 Feb 28.

Department of Gastroenterological Surgery, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.

Aim: The significance of sarcopenia in cancers has been widely recognized. However, few studies have focused on chronological changes in sarcopenia in cancer patients. This study aimed to clarify the clinical significance of changes in the psoas muscle area before and after preoperative chemotherapy.

Methods: This study included 39 patients who underwent gastrectomy followed by preoperative chemotherapy for advanced gastric cancer between January 2010 and December 2016 in our hospital. The psoas muscle area was measured at the umbilical level before and after chemotherapy, and the relationship between its chronological changes and the long-term prognosis was examined.

Results: Patients were classified into two groups according to changes in the psoas muscle area before and after preoperative chemotherapy: remarkable muscle depletion and normal groups. No significant differences were observed in clinicopathological factors. Notably, the remarkable muscle depletion group included significantly more male patients (P = .018) and showed a high weight loss rate (P < .001). Although no significant difference was observed in the recurrence-free survival between the two groups (P = .484), overall survival was significantly worse in the remarkable muscle depletion group (P < .001). Multivariate analysis for prognosis revealed that pathological stage III or higher (P = .022) and decreased psoas muscle area (P = .038) were independent prognostic factors.

Conclusions: The present findings suggest that psoas muscle depletion during preoperative chemotherapy is a prognostic factor for poor long-term outcomes in patients who underwent gastrectomy followed by preoperative chemotherapy for advanced gastric cancer.
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http://dx.doi.org/10.1111/ajco.13514DOI Listing
February 2021

Comparison of Converse Ω Anastomosis and Extracorporeal Anastomosis After Laparoscopic Distal Gastrectomy for Gastric Cancer.

Surg Laparosc Endosc Percutan Tech 2021 Feb 3. Epub 2021 Feb 3.

Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center Departments of Gastroenterological Surgery Biostatistics, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa Prefecture, Japan.

Background: Converse Ω anastomosis is a recently developed technique of delta-shaped anastomosis for intracorporeal gastroduodenostomy to simplify the anastomotic procedures and reduce their potential risks. This study aimed to evaluate the safety and effectiveness of converse Ω anastomosis, comparing it with conventional extracorporeal Billroth-I anastomosis after laparoscopic distal gastrectomy (LDG) for gastric cancer.

Patients And Methods: Among 169 gastric cancer patients who underwent LDG with Billroth-I anastomosis anastomosis between April 2013 and March 2018, we selected 100 patients by propensity score matching (50 in the converse Ω anastomosis group and 50 in the extracorporeal anastomosis group). Patients' characteristics, intraoperative outcomes, postoperative complications, and survival time were compared between the 2 groups.

Results: Median anastomosis time was significantly longer in the converse Ω group than in the extracorporeal group (40.0 vs. 30.5 min, P=0.005). However, the total procedure time did not differ significantly between the groups. Intraoperative blood loss volume was significantly lower in the converse Ω group than in the extracorporeal anastomosis group (40 vs. 120 mL, P<0.001). There were no significant differences in the number of dissected lymph nodes, postoperative morbidity, mortality, or length of hospital stay. The postoperative body mass index and the prognostic nutritional index did not differ between the groups 1 year after surgery. There were no significant differences in overall survival and relapse-free survival between the 2 groups.

Conclusions: Converse Ω anastomosis is feasible and safe. This novel technique can be adopted as a treatment option for reconstruction after LDG in patients with early-stage gastric cancer. Therefore, the risks and benefits of converse Ω anastomosis after LDG should be confirmed in larger cohorts.
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http://dx.doi.org/10.1097/SLE.0000000000000906DOI Listing
February 2021

Synthetic mRNA-based differentiation method enables early detection of Parkinson's phenotypes in neurons derived from Gaucher disease-induced pluripotent stem cells.

Stem Cells Transl Med 2021 Apr 20;10(4):572-581. Epub 2020 Dec 20.

Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.

Gaucher disease, the most prevalent metabolic storage disorder, is caused by mutations in the glucocerebrosidase gene GBA1, which lead to the accumulation of glucosylceramide (GlcCer) in affected cells. Gaucher disease type 1 (GD1), although defined as a nonneuronopathic subtype, is accompanied by an increased risk of Parkinson's disease. To gain insights into the association of progressive accumulation of GlcCer and the Parkinson's disease phenotypes, we generated dopaminergic (DA) neurons from induced pluripotent stem cells (iPSCs) derived from a GD1 patient and a healthy donor control, and measured GlcCer accumulation by liquid chromatography-mass spectrometry. We tested two DA neuron differentiation methods: a well-established method that mimics a step-wise developmental process from iPSCs to neural progenitor cells, and to DA neurons; and a synthetic mRNA-based method that overexpresses a transcription factor in iPSCs. GD1-specific accumulation of GlcCer was detected after 60 days of differentiation by the former method, whereas it was detected after only 10 days by the latter method. With this synthetic mRNA-based rapid differentiation method, we found that the metabolic defect in GD1 patient cells can be rescued by the overexpression of wild-type GBA1 or the treatment with an inhibitor for GlcCer synthesis. Furthermore, we detected the increased phosphorylation of α-synuclein, a biomarker for Parkinson's disease, in DA neurons derived from a GD1 patient, which was significantly decreased by the overexpression of wild-type GBA1. These results suggest that synthetic mRNA-based method accelerates the analyses of the pathological mechanisms of Parkinson's disease in GD1 patients and possibly facilitates drug discovery processes.
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http://dx.doi.org/10.1002/sctm.20-0302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980209PMC
April 2021

Systemic Review and Meta-analysis of Impact of Splenectomy for Advanced Gastric Cancer.

In Vivo 2020 Nov-Dec;34(6):3115-3125

Department of Biostatistics, School of Medicine, Yokohama City University, Yokohama, Japan.

Background/aim: Prophylactic splenectomy has shown no inferiority for tumors not invading the greater curvature side. Despite this, the clinical impact of prophylactic splenectomy for proximal advanced gastric cancer is not clear. This review aimed to clarify the impact of splenectomy for advanced gastric cancer in the upper third of the stomach.

Materials And Methods: A systematic review and meta-analysis were conducted based on PubMed and EMBASE databases. The following search terms were used: "gastric cancer" OR "splenectomy" OR upper third of the stomach" OR preservation of the spleen.

Results: Out of 765 articles, 18 studies (combined n=6,341) were included in the analysis. Four randomized controlled trials (RCT) and eight retrospective studies suggested the benefits of spleen-preserving gastrectomy. Six retrospective studies showed no significant benefit of spleen-preserving gastrectomy. Prophylactic splenectomy showed a close association with a higher incidence of postoperative morbidity (pancreatic fistula and anastomotic leakage) with no concomitant improvement in overall survival. Prophylactic splenectomy should not be routinely performed and RCTs are necessary to confirm the impact of splenectomy for cN(+) at the splenic hilum tumors and tumors invading the greater curvature.
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http://dx.doi.org/10.21873/invivo.12145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811676PMC
September 2020

High expression of maternal embryonic leucine-zipper kinase (MELK) impacts clinical outcomes in patients with ovarian cancer and its inhibition suppresses ovarian cancer cells growth ex vivo.

J Gynecol Oncol 2020 Nov;31(6):e93

Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Japan.

Objective: Maternal embryonic leucine zipper kinase (MELK) is receiving an attention as a therapeutic target in various types of cancers. In this study, we aimed to evaluate the prognostic significance of expression in ovarian cancer using clinical samples, and assessed the efficacy of a small molecule MELK inhibitor, OTS167, using patient-derived ovarian cancer cells as well as cell lines.

Methods: Expression levels of MELK in 11 ovarian cancer cell lines were confirmed by western blotting. Inhibitory concentration of OTS167 was determined by colorimetric assay. messenger RNA (mRNA) expression was evaluated in 228 ovarian cancer patients by quantitative polymerase chain reaction. Growth inhibition of OTS167 was also evaluated using freshly-isolated primary ovarian cancer cells including spheroid formation condition.

Results: mRNA expression was significantly higher in ovarian cancer than in normal ovaries (p<0.001), and high mRNA expression was observed in patients with advanced stage, positive ascites cytology and residual tumor size. Patients with high mRNA expression showed shorter progression-free survival (p=0.001). Expression of MELK was also confirmed in 10 of 11 ovarian cancer cell lines tested, and the half maximal inhibitory concentration of MELK inhibitor, OTS167, ranged from 9.3 to 60 nM. Additionally, OTS167 showed significant growth inhibitory effect against patient-derived ovarian cancer cells, regardless of their tumor locations, histologic subtypes and stages.

Conclusions: We demonstrated MELK as both a prognostic marker and a therapeutic target for ovarian cancer using clinical ovarian cancer samples. MELK inhibition by OTS167 may be an effective approach to treat ovarian cancer patients.
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http://dx.doi.org/10.3802/jgo.2020.31.e93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593222PMC
November 2020

Mucinous Cystadenocarcinoma of the Pancreas with Cyst Infection in a Male Patient.

Intern Med 2020 1;59(19):2383-2389. Epub 2020 Oct 1.

Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Japan.

Follow-up computed tomography revealed a 40-mm pancreatic tail cyst in a 59-year-old man with type 1 diabetes mellitus. An intraductal papillary mucinous neoplasm was suspected; mucinous cystic neoplasm (MCN) was not considered because the patient was a man. During follow-up, cyst infection occurred but was improved by conservative treatment. At the 24-month follow up examination, cyst nodules had developed, corresponding to an increase in the carbohydrate antigen 19-9 level. Mucinous cystadenocarcinoma (MCC) was diagnosed pathologically based on distal pancreatectomy. A diagnosis of male MCN/MCC is often delayed, which may lead to a poor prognosis. MCN infection is also rare and poorly recognized. We observed an atypical male case of MCN/MCC.
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http://dx.doi.org/10.2169/internalmedicine.4937-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644490PMC
November 2020

Mechanistic Multilayer Quantitative Model for Nonlinear Pharmacokinetics, Target Occupancy and Pharmacodynamics (PK/TO/PD) Relationship of D-Amino Acid Oxidase Inhibitor, TAK-831 in Mice.

Pharm Res 2020 Aug 5;37(8):164. Epub 2020 Aug 5.

Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.

Purpose: TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) currently under clinical development for schizophrenia. In this study, a mechanistic multilayer quantitative model that parsimoniously connects pharmacokinetics (PK), target occupancy (TO) and D-serine concentrations as a pharmacodynamic (PD) readout was established in mice.

Methods: PK, TO and PD time-profiles were obtained in mice and analyzed by mechanistic binding kinetics model connected with an indirect response model in a step wise fashion. Brain distribution was investigated to elucidate a possible mechanism driving the hysteresis between PK and TO.

Results: The observed nonlinear PK/TO/PD relationship was well captured by mechanistic modeling framework within a wide dose range of TAK-831 in mice. Remarkably different brain distribution was observed between target and reference regions, suggesting that the target-mediated slow binding kinetics rather than slow penetration through the blood brain barrier caused the observed distinct kinetics between PK and TO.

Conclusion: A quantitative mechanistic model for concentration- and time-dependent nonlinear PK/TO/PD relationship was established for TAK-831 in mice with accounting for possible rate-determining process. The established mechanistic modeling framework will provide a quantitative means for multilayer biomarker-assisted clinical development in multiple central nervous system indications.
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http://dx.doi.org/10.1007/s11095-020-02893-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478952PMC
August 2020

Laparoscopic Total Gastrectomy for Gastric Cancer in Elderly Patients.

In Vivo 2020 Sep-Oct;34(5):2933-2939

Department of Surgery, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.

Background/aim: The purpose of this study was to evaluate the safety and efficacy of laparoscopic total gastrectomy (LTG) for elderly patients.

Patients And Methods: We retrospectively analyzed 136 patients who underwent LTG. We divided the patients into elderly patients (>75 years of age) and non-elderly patients (≤75 years of age).

Results: The American Society of Anesthesiologists score, Charlson comorbidity index, Glasgow Prognostic Score and rate of comorbidities were higher in the elderly group; the rates of other clinicopathological characteristics did not differ between the two groups. Regarding the nutritional status, the body weight loss rate in the elderly group was higher in comparison to the non-elderly group (81% vs. 84%, p=0.004). The disease-specific survival (DSS) did not differ between two groups to a statistically significant extent (3-year DSS rates: 83.7 vs. 94.5%; p=0.152).

Conclusions: LTG was acceptable for elderly patients as the elderly and non-elderly groups showed comparable short-term and long-term outcomes.
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http://dx.doi.org/10.21873/invivo.12123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652532PMC
June 2020

Eosinophilic Gastroenteritis in an Ulcerative Colitis Patient During Treatment with Tumor Necrosis Factor-alpha Antagonist.

Intern Med 2020 15;59(16):1977-1981. Epub 2020 Aug 15.

Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Japan.

A 45-year-old man with steroid-dependent ulcerative pancolitis was hospitalized with frequent diarrhea, abdominal pain and distension 3 months after induction of golimumab, a tumor necrosis factor-alpha antagonist. Computed tomography showed wall thickening from the stomach to the colon and massive ascites. Peripheral blood test revealed eosinophilia. A large number of eosinophils were observed in the ascites fluid. Although esophagogastroduodenoscopy showed no abnormal findings and colonoscopy showed ulcerative colitis with a Mayo endoscopic subscore of 1, eosinophil infiltration was histologically observed. Based on these findings, we diagnosed him with eosinophilic gastroenteritis and started prednisolone. Consequently, his eosinophil counts and abdominal symptoms dramatically improved.
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http://dx.doi.org/10.2169/internalmedicine.4554-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492116PMC
January 2021

Tumor-related mutations in cell-free DNA in pre-operative plasma as a prognostic indicator of recurrence in endometrial cancer.

Int J Gynecol Cancer 2020 09 21;30(9):1340-1346. Epub 2020 Jul 21.

Gynecologic Oncology, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan

Objectives: Circulating tumor DNA (ctDNA) has potential as a basis for understanding the molecular features of a tumor non-invasively and for use as a diagnostic, prognostic, and disease-monitoring marker. The aim of this study was to evaluate the clinical roles of ctDNA in patients with endometrial cancer.

Methods: Since and are among the most common mutated genes in endometrial cancer, somatic mutations of these genes were investigated in tumor specimens and plasma collected before surgery, using droplet digital polymerase chain reaction (ddPCR). ctDNA was defined as positive when the corresponding mutation between somatic and plasma was also detected in plasma cell-free DNA (cfDNA). Relationships of the presence of ctDNA with clinicopathological features were examined.

Results: Somatic and/or mutations were found in 68 (34%) of 199 patients with endometrial cancer. Ten (14.7%) of 68 patients had similar mutations in cfDNA. ctDNA detected in pre-operative plasma was correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage (p=0.008), histology (p=0.028), and lymphovascular space invasion (p=0.002), and with shorter recurrence-free and overall survival (p=0.004 and p=0.010, respectively, by log-rank test).

Conclusion: Tumor-related ctDNA detected in plasma before surgery was associated with poorer oncologic outcome on univariate analysis in patients with endometrial cancer harboring or mutations.
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http://dx.doi.org/10.1136/ijgc-2019-001053DOI Listing
September 2020

A two-stage reconstruction for aortoesophageal fistula after replacement of thoracic aorta for Stanford Type B dissecting aortic aneurysm: esophagectomy and a double-tract reconstruction using the pedicled jejunum: a case report and literature review.

Clin J Gastroenterol 2020 Oct 26;13(5):722-727. Epub 2020 Jun 26.

Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

An aortoesophageal fistula (AEF) is a rare, potentially fatal condition, and esophagectomy is usually performed simultaneously with aortic surgery. However, esophageal reconstruction method has not been established. This case report describes a two-stage operation for AEF after replacement of thoracic aorta for Stanford Type B dissecting aortic aneurysm. A 61-year-old man who had underwent total arch replacement with frozen elephant trunk for Stanford Type B dissecting aortic aneurysm 3 years ago admitted to the hospital with high fever. Based on the computed tomography and endoscopic findings, he was diagnosed with having aortoesophageal fistula (AEF). After administration of antibiotics with fasting foods and drinks for a month, he underwent the second aortic replacement, thoracic esophagectomy, cervical esophagostomy, gastrostomy and omental wrapping. After 3 months, he underwent double-tract reconstruction using the pedicled jejunal transfer with supercharge and superdrainage via the subcutaneous route. After reconstruction surgery, the patient was doing well. Two-stage reconstruction was a safe procedure for AEF case who underwent aortic replacement, esophagectomy and omental wrapping. The pedicled jejunum reconstruction via subcutaneous route is an optional procedure for second reconstruction surgery.
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http://dx.doi.org/10.1007/s12328-020-01158-9DOI Listing
October 2020

Current and future strategies for treatment of ovarian clear cell carcinoma.

J Obstet Gynaecol Res 2020 Sep 23;46(9):1678-1689. Epub 2020 Jun 23.

Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan.

Ovarian clear cell carcinoma (OCCC) is one of the five histological types of epithelial ovarian cancer (EOC). OCCC comprises 23% of all EOC cases in Japan, whereas the rate of OCCC in North America and Europe is much lower. OCCC is generally categorized as a rare gynecologic malignancy, and there is limited evidence for specific treatment. The clinical basis for treatment of OCCC is mostly based on retrospective studies, many of which were performed in Japan. Until recently, most randomized clinical trials for EOC have included OCCC; therefore, current treatment for OCCC is basically the same as that for other histologic types of EOC. However, the clinical characteristics of OCCC differ from those of high-grade serous carcinoma, particularly for chemosensitivity, and there is a need to develop new treatment for OCCC. The molecular background of OCCC has unique features: tumors are usually negative for p53 mutations and positive for ARID1A and/or PIK3CA mutations, whereas p53 mutations are common in high-grade serous or endometrioid carcinomas. These features may help in development of new treatment for OCCC. In this review, we described the current evidence for treatment of OCCC, including surgery, radiotherapy, chemotherapy, molecular targeted therapy and immunotherapy, and we discuss ongoing clinical trials and preclinical studies of new treatment approaches for OCCC.
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http://dx.doi.org/10.1111/jog.14350DOI Listing
September 2020

Successful Management of Hemosuccus Pancreaticus due to Pancreatic Adenocarcinoma by Chemoradiotherapy.

Intern Med 2020 Sep 2;59(17):2135-2141. Epub 2020 Jun 2.

Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Japan.

Management of hemosuccus pancreaticus (HP) due to pancreatic adenocarcinoma is problematic. This is the first report of the successful management of HP caused by pancreatic adenocarcinoma by chemoradiotherapy, which is a treatment option for cases with a high surgical risk that are not suitable for interventional radiology. In the present case, bloody pancreatic juice was detected in the main pancreatic duct, and anemia worsened without repeated blood transfusions. The patient ultimately underwent chemoradiotherapy comprising radiation of 3 Gy in 15 fractions concomitant with systemic chemotherapy of S-1. After the treatments, the anemia improved, and the patient was discharged on day 45.
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http://dx.doi.org/10.2169/internalmedicine.4372-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516308PMC
September 2020

Neoantigen load and HLA-class I expression identify a subgroup of tumors with a T-cell-inflamed phenotype and favorable prognosis in homologous recombination-proficient high-grade serous ovarian carcinoma.

J Immunother Cancer 2020 05;8(1)

Department of Immunotherapeutics, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan.

Background: There is increasing evidence for the benefit of poly ADP ribose polymerase (PARP) inhibitors in a subset of high-grade serous ovarian carcinoma (HGSC) patients, especially those with homologous recombination (HR)-deficient tumors. However, new treatment strategies, such as immune checkpoint inhibition, are required for patients with HR-proficient tumors.

Methods: A total of 80 cases of HGSC were analyzed in this study. Whole exome and RNA sequencing was performed for these tumors. Methylation arrays were also carried out to examine and promoter methylation status. Mutations, neoantigen load, antigen presentation machinery, and local immune profile were investigated, and the relationships of these factors with clinical outcome were also analyzed.

Results: As expected, the numbers of predicted neoAgs were lower in HR-proficient (n=46) than HR-deficient tumors (n=34). However, 40% of the patients with HR-proficient tumors still had higher than median numbers of neoAgs and better survival than patients with lower numbers of neoAgs. Incorporation of human leukocyte antigen (HLA)-class I expression status into the survival analysis revealed that patients with both high neoAg numbers and high HLA-class I expression (neoAgHLA) had the best progression-free survival (PFS) in HR-proficient HGSC (p=0.0087). Gene set enrichment analysis demonstrated that the genes for effector memory CD8 T cells, TH1 T cells, the interferon-γ response, and other immune-related genes, were enriched in these patients. Interestingly, this subset of patients also had better PFS (p=0.0015) and a more T-cell-inflamed tumor phenotype than patients with the same phenotype (neoAgHLA) in HR-deficient HGSC.

Conclusions: Our results suggest that immune checkpoint inhibitors might be an alternative to explore in HR-proficient cases which currently do not benefit from PARP inhibition.
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http://dx.doi.org/10.1136/jitc-2019-000375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254153PMC
May 2020

[Effectiveness of L-Carnitine in the Treatment of Fatigue Associated with Chemotherapy in Patients with Gastric Cancer].

Gan To Kagaku Ryoho 2020 Mar;47(3):490-492

Dept. of Surgery, Gastroenterological Center, Yokohama City University Medical Center.

Aim: Low serum carnitine levels have been reported in patients with cancer receiving chemotherapy and are considered one of the factors causing fatigue associated with chemotherapy. We evaluated the effectiveness of L-carnitine in the treatment of fatigue associated with chemotherapy in patients with gastric cancer(GC).

Materials And Methods: We performed a randomized controlled trial between December 2013 and December 2018. Untreated patients with advanced GC were included in the study; 1 patient developed an allergy after receiving the first chemotherapy and was excluded from the study. The primary endpoint was brief fatigue inventory(BFI). Patients were categorized into 2 groups: those who received L-carnitine oral supplements(group C)and those who did not receive L-carnitine oral supplements(group N).

Results: The serum carnitine levels were improved significantly in group C compared with group N. BFIwas more aggravated in group N than group C; however, the difference was not significant.

Conclusion: We could not demonstrate the effectiveness of L-carnitine in the treatment of fatigue associated with chemotherapy in patients with GC.
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March 2020

On-treatment Serum Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) Level and Risk of Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis B during Nucleot(s)ide Analogue Therapy.

Int J Mol Sci 2020 Mar 17;21(6). Epub 2020 Mar 17.

Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka 410-2295, Japan.

We aimed to analyze the serum level of a novel fibrosis marker, Mac-2-binding protein glycosylation isomer (M2BPGi), and its predictive value for hepatocellular carcinoma (HCC) development in chronic hepatitis B (CHB) under nucleot(s)ide analogue (NA) therapy. Serum M2BPGi levels were quantified in 147 CHB patients at baseline, 48 weeks after starting NA therapy, and at the patients' last visit. The serum M2BPGi level serially decreased at each time point. During the median follow-up time of 6.6 years, 14 of 147 patients developed HCC. Multivariate Cox proportional hazard analysis demonstrated that high serum M2BPGi at 48 weeks was an independent risk factor for HCC development. A cutoff value of M2BPGi at 48 weeks > 1.5 showed an adjusted hazard ratio = 34.9 (95% confidence interval, 4.3-284.9). The 3- and 5-year cumulative incidence of HCC in patients with low M2BPGi were 0.9% and 4.2%, respectively, whereas those in patients with high M2BPGi were 10.1% and 25.6%, respectively ( < 0.001). In conclusion, Serum M2BPGi level at 48 weeks is a useful predictor for HCC development in patients with CHB who receive NA therapy.
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http://dx.doi.org/10.3390/ijms21062051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139452PMC
March 2020

Efficacy of Video-assisted Thoracoscopic Esophagectomy for Stage II/III Esophageal Cancer: Analysis Using the Propensity Scoring System.

Anticancer Res 2020 Mar;40(3):1587-1595

Department of Clinical Statistics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

Background/aim: The purpose of this study was to evaluate the usefulness of minimally invasive esophagectomy (MIE) for stage II/III esophageal cancer (EC).

Patients And Methods: We compared surgical outcomes between MIE and open esohagectomy in EC patients with pStage II/III using the propensity scoring system.

Results: Fifty-seven patients were classified into the MIE group and 57 patients into the open esophagectomy (OE) group. The incidence of major complications was similar between the two groups. The 5-year OS was significantly better in the MIE group (69.0% vs. 35.5%; p=0.004) and no significant difference was observed in the 5-year recurrence-free survival (RFS, 52.2% vs. 29.2%; p=0.064). Multivariate analysis showed MIE was a prognostic factor of OS (p<0.001) and RFS (p=0.032).

Conclusion: MIE was as safe and feasible as OE, and an independent prognostic factor for OS and RFS in patients with stage II/III EC.
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http://dx.doi.org/10.21873/anticanres.14106DOI Listing
March 2020

Low Incidence of High-Grade Pancreatic Intraepithelial Neoplasia Lesions in a Crmp4 Gene-Deficient Mouse Model of Pancreatic Cancer.

Transl Oncol 2020 Mar 24;13(3):100746. Epub 2020 Feb 24.

Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Pancreatic intraepithelial neoplasia (PanIN), the most common premalignant lesion of the pancreas, is a histologically well-defined precursor to invasive pancreatic ductal adenocarcinoma (PDAC). However, the molecular mechanisms underlying the progression of PanINs have not been fully elucidated. Previously, we demonstrated that the expression of collapsin response mediator protein 4 (CRMP4) in PDAC was associated with poor prognosis. The expression of CRMP4 was also augmented in a pancreatitis mouse model. However, the role of CRMP4 in the progression of PanIN lesions remains uncertain. In the present study, we examined the relationship between CRMP4 expression and progression of PanIN lesions using genetically engineered mouse models. PanIN lesions were induced by peritoneal injection of the cholecystokinin analog caerulein in LSL-KRAS; Pdx1-Cre (KC-Crmp4 wild-type, WT) mice and LSL-KRAS; Pdx1-Cre; Crmp4 (KC-Crmp4 knockout, KO) mice. We analyzed pancreatic tissue sections from these mice and evaluated PanIN grade by hematoxylin and eosin staining. CRMP4 expression was examined and the cellular components assessed by immunohistochemistry using antibodies against CRMP4, CD3, and α-smooth muscle actin (SMA). The incidence of high-grade PanIN in KC-Crmp4 WT mice was higher than that in KC-Crmp4 KO animals. CRMP4 was expressed not only in epithelial cells but also in αSMA-positive cells in stromal areas of PanIN lesions. The CRMP4 expression in stromal areas correlated with PanIN grade in WT mice. These results suggested that the expression of CRMP4 in stromal cells may underlie the incidence or progression of PanIN.
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http://dx.doi.org/10.1016/j.tranon.2020.100746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044544PMC
March 2020

Elevated serum procalcitonin levels and their association with the prognosis of patients with liver cirrhosis.

Eur J Gastroenterol Hepatol 2020 09;32(9):1222-1228

Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital.

Objectives: Bacterial infection is a major complication in patients with liver cirrhosis. Procalcitonin is an early diagnostic marker of bacterial infection. This study aimed to investigate the association between the serum procalcitonin levels and the prognosis of patients with liver cirrhosis.

Methods: We retrospectively analyzed the serum procalcitonin levels in 236 hospitalized patients with liver cirrhosis. The impact of the serum procalcitonin level on their prognoses was evaluated using multivariate Cox proportional hazards analyses and the Kaplan-Meier method.

Results: The serum procalcitonin level was higher (≥0.05 ng/mL) in 151 (64%) patients, and it was significantly higher in the patients with Child-Turcotte-Pugh class C than in those with Child-Turcotte-Pugh classes A/B. Patients with refractory ascites, hepatic encephalopathy, gastrointestinal bleeding, and bacterial infections had elevated serum procalcitonin levels. The multivariate analyses showed a serum procalcitonin level ≥0.05 ng/mL was an independent prognostic factor for liver cirrhosis (hazard ratio = 1.64; 95% confidence interval = 1.07-2.53; P = 0.024). During a median follow-up interval of 2.1 years, the three-year cumulative survival rates for the patients with normal and elevated serum procalcitonin levels were 72.9 and 56.0%, respectively (P < 0.001). The subgroup analyses that stratified the patients according to age, the Child-Turcotte-Pugh classification, and the presence of liver cancer showed the serum procalcitonin level was significantly associated with their prognoses.

Conclusions: The patients with liver cirrhosis had higher serum procalcitonin levels, regardless of local bacterial infections, and higher procalcitonin levels were associated with poor prognoses.
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http://dx.doi.org/10.1097/MEG.0000000000001644DOI Listing
September 2020

Identification of novel mutations of ovarian cancer-related genes from RNA-sequencing data for Japanese epithelial ovarian cancer patients.

Endocr J 2020 Feb 19;67(2):219-229. Epub 2019 Nov 19.

Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka, 350-1241 Saitama, Japan.

Ovarian cancer has the highest mortality rate among gynecological cancers. Gene mutations are involved in the carcinogenesis, metastasis, and therapeutic response in ovarian cancer. However, the variety and proportion of gene mutation is not fully analyzed in Japanese ovarian cancer patients, especially, in those with recurrent tumors. In the present study, RNA-sequencing was performed for 32 clinical ovarian specimens obtained from 24 Japanese patients (24 primary cancer specimens and 8 recurrent specimens paired with corresponding primary cancer specimens). Mutations in 24 primary specimens were analyzed by comparing the sequence data mapped on RefSeq genes with those in the public online databases BRCA Exchange, COSMIC, ClinVar, and cBioportal. Mutations were observed in TP53 in 16 specimens (67%), BRCA1 in 9 (38%), BRCA2 in 13 (54%), ARID1A in 3 (13%), PIK3CA in 2 (8%), KRAS in 1 (4%), PTEN in 1 (4%), and CTNNB1 in 1 (4%), excluding synonymous mutations. Among those identified muations, 13 of 14 mutations in TP53, 10 of 11 mutations of BRCA1, 10 of 23 mutation positions of BRCA2, none of 7 mutations of ARID1A, 1 mutation of PIK3CA, and 1 mutation of CTNNB1 were consistent with those reported in the public online databases; however, the other mutations identified were novel. Comparison between matched-paired specimens of primary and recurrent tumors revealed the changes of mutational status in expressed RNAs. RNA-sequencing-based mutation analysis will be useful to reveal ethnic differences of gene mutations in ovarian cancer and to understand the contribution of gene mutations to recurrence.
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http://dx.doi.org/10.1507/endocrj.EJ19-0283DOI Listing
February 2020

Investigation of MDR1-overexpressing cell lines to derive a quantitative prediction approach for brain disposition using in vitro efflux activities.

Eur J Pharm Sci 2020 Jan 1;142:105119. Epub 2019 Nov 1.

Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, Japan.

MDR1-overexpressing Lilly Laboratories cell porcine kidney 1 cells (LLC-PK1-MDR1) and Madin-Darby canine kidney cells (MDCK-MDR1) are widely used in drug discovery to evaluate the in vivo relevance of MDR1-mediated efflux. However, as the in vitro efflux ratio (ER) of these cell lines are variable among research facilities, the in vitro ER of these cell lines that would affect quantitative predictivity of brain disposition has not been fully clarified. The aim of this study was to examine the effect of ER on the quantitative predictivity of brain disposition toward compounds with MDR1 and/or breast cancer resistant protein (BCRP) liabilities. Test compounds including internal molecules and five typical substrates of MDR1 and/or BCRP were assessed via an in vitro transporter assay to determine the corrected flux ratio (CFR) and an in vivo animal study using wild-type (WT) and Mdr1a (-/-)/Bcrp(-/-) (dual KO) rats. To assess the in vivo ER for MDR1, the two cell lines LLC-PK1-MDR1 and MDCK-MDR1 were used. After intravenously administering 29 test compounds to rats, the K ratio (ratio of K to K), which is considered to be the unbound plasma-to-brain ratio (K) that does not require correction for protein binding in both plasma and brain, was determined by measuring their concentrations in the plasma and brain. The K ratio of these compounds was predicted by fitting scaling factor that was extrapolated from the in vitro to in vivo ER for MDR1 and BCRP, defined as α and β, respectively. K ratio values of 83% and 68% of compounds were predicted by using MDCK-MDR1 and LLC-PK1-MDR1, respectively, within a 2-fold range of the actual corresponding values. The α predicted from CFRs of MDCK-MDR1 was 47-fold smaller than that of LLC-PK1-MDR1; however, a dramatic change in β was not observed. This result appears to be consistent with the data of in vitro transport activity of MDR1, which was estimated to be ~28-fold higher in MDCK-MDR1 than in LLC-PK1-MDR1 by correlation analysis with CFR. Through this study, we revealed that 1) brain disposition in rats was well-predicted by considering the in vitro efflux activities for both MDR1 and BCRP, and 2) MDCK-MDR1 was the superior cell line for the quantitative prediction of brain disposition.
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http://dx.doi.org/10.1016/j.ejps.2019.105119DOI Listing
January 2020

[Endoscopic Treatment of a Symptomatic Pineal Cyst].

No Shinkei Geka 2019 Oct;47(10):1101-1105

Department of Neurosurgery, Toho University Ohashi Medical Center.

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http://dx.doi.org/10.11477/mf.1436204080DOI Listing
October 2019

Prognostic significance of serum tyrosine concentration in patients with primary biliary cholangitis under ursodeoxycholic acid therapy.

Hepatol Res 2020 Feb 5;50(2):214-223. Epub 2020 Jan 5.

Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan.

Aim: Chronic liver insufficiency is often associated with alteration in amino acid metabolism. We evaluated the prognostic value of changes in serum amino acid concentrations in patients with primary biliary cholangitis.

Methods: A total of 75 primary biliary cholangitis patients who started urusodeoxycholic acid therapy were retrospectively enrolled. Baseline serum concentrations of branched-chain amino acids and tyrosine, and branched-chain amino acid-to-tyrosine ratio were determined. The hazard ratios of factors associated with liver-related events were analyzed by Cox proportional hazard analysis.

Results: Of the 75 patients enrolled, 12 showed a decrease in serum branched-chain amino acid levels, and 15 showed an increase in serum tyrosine levels. The branched-chain amino acid-to-tyrosine ratio decreased in 16 patients. During a median 5.6-year follow up, liver-related events occurred in 11 patients. Multivariate analysis showed that high serum tyrosine levels at baseline and high alkaline phosphatase levels 48 weeks after starting urusodeoxycholic acid therapy were independent risk factors for event occurrence. From the receiver operator characteristics curve analysis, serum tyrosine concentration >110 μmol/L was identified as a cut-off value with an adjusted hazard ratio of 20.9 (95% confidence interval 4.3-101.5, P < 0.001). Kaplan-Meier analysis showed that the 5-year cumulative incidences of event occurrence in patients with high and low serum tyrosine concentration were 56.5% and 5.5%, respectively (P < 0.001). The 10-year survival probabilities also showed significant differences between patients with high and low serum tyrosine concentration (44.9% vs. 92.0%, P < 0.001).

Conclusion: Elevation of serum tyrosine concentration indicates a high risk of liver-related events in primary biliary cholangitis patients receiving urusodeoxycholic acid therapy.
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http://dx.doi.org/10.1111/hepr.13434DOI Listing
February 2020

Genetic and Lineage Classification of Glioma-Initiating Cells Identifies a Clinically Relevant Glioblastoma Model.

Cancers (Basel) 2019 Oct 15;11(10). Epub 2019 Oct 15.

Department of Neurosurgery, Toho University Ohashi Medical Center, Tokyo 153-8515, Japan.

The Cancer Genome Atlas (TCGA) project described a robust gene expression-based molecular classification of glioblastoma (GBM), but the functional and biological significance of the subclasses has not been determined. The present comprehensive analysis of 25 glioma-initiating cell (GIC) lines classifies GIC lines into four subtypes (classical, mesenchymal, proneural, and neural) that are closely related to the TCGA GBM subclasses and display distinct lineage characteristics and differentiation behavior that recapitulate neural development. More importantly, the GIC subtypes exhibit distinct biological phenotypes in relation to self-renewal capacity, proliferation, invasiveness, and angiogenic potential in vitro and in vivo. In addition, the GIC subtypes exhibit divergent patterns of signaling pathway activation and deactivation of the Wnt, Notch, and TGF-β pathways. These results will improve drug discovery targeting certain genetic mutation in glioblastoma and improve the development of precision medicine.
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http://dx.doi.org/10.3390/cancers11101564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826962PMC
October 2019