Publications by authors named "Yoichi Tanaka"

146 Publications

Increased DNA-incorporated thiopurine metabolite as a possible mechanism for leukocytopenia through cell apoptosis in inflammatory bowel disease patients with NUDT15 mutation.

J Gastroenterol 2021 Sep 4. Epub 2021 Sep 4.

Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8642, Japan.

Background And Aims: Polymorphisms in the nucleotide diphosphate-linked moiety X-type motif 15 (NUDT15) gene are associated with thiopurine-induced leukopenia in patients with inflammatory bowel disease (IBD). NUDT15-associated subcellular thiopurine metabolism has not been investigated in primary lymphocytes. We hypothesized that NUDT15 mutation increases DNA-incorporated deoxythioguanosine (dTG) and induces apoptosis in lymphocytes.

Methods: DNA-incorporated dTG in peripheral blood mononuclear cells (PBMCs) and 6-thioguanine nucleotides (6-TGN) in red blood cells were measured in patients with IBD undergoing thiopurine treatment. The association of a single nucleotide polymorphism for NUDT15 (rs116855232) with dTG was examined. The pro-apoptotic effect of DNA-incorporated dTG was examined ex vivo in association with NUDT15 genotypes by co-culturing patient-derived peripheral CD4 T lymphocytes with 6-thioguanine (6-TG).

Results: dTG was significantly higher in NUDT15 variants than in non-variants. dTG, but not 6-TGN, negatively correlated with peripheral lymphocyte counts (r =  - 0.31 and  - 0.12, p = 0.012 and 0.173, respectively). DNA-incorporated dTG significantly accumulated to a greater extent in lymphocytes from NUDT15 variants when co-cultured with 6-TG ex vivo than in those from non-variants and was associated with decreased proliferation and increased apoptosis.

Conclusion: Increased DNA-incorporated dTG may be responsible for thiopurine-induced leukocytopenia through cell apoptosis in IBD patients with NUDT15 mutation.
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http://dx.doi.org/10.1007/s00535-021-01820-0DOI Listing
September 2021

Importance of Polymorphisms in Thiopurine Treatments.

J Pers Med 2021 Aug 10;11(8). Epub 2021 Aug 10.

Division of Medicinal Safety Science, National Institute of Health Sciences, Kawasaki City 210-9501, Kanagawa, Japan.

Thiopurines, mercaptopurine, and azathioprine are used as immunosuppressants in the treatments of inflammatory bowel disease, rheumatoid arthritis, and organ transplantation and as chemotherapeutic drugs for the treatment of acute leukemia and chronic myeloid leukemia. This drug class sometimes causes severe adverse reactions, including bone marrow suppression and hair loss. Genetic polymorphisms of the metabolizing enzyme thiopurine S-methyltransferase have been used for predicting these reactions in Caucasians, but these allele frequencies are less frequently observed in Asian populations. Recently, nudix hydrolase 15 () polymorphisms have been shown to play an important role in thiopurine-induced adverse reactions in Asians. In this review, we summarize the studies, mainly in Asian countries, and their implementation in several countries.
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http://dx.doi.org/10.3390/jpm11080778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399029PMC
August 2021

Classification of circadian pain rhythms and pain characteristics in chronic pain patients: An observational study.

Medicine (Baltimore) 2021 Jun;100(25):e26500

Graduate School of Health Sciences, Kio University.

Abstract: This study aimed to perform cluster analysis in patients with chronic pain to extract groups with similar circadian rhythms and compare neuropathic pain and psychological factors among these groups to identify differences in pain-related outcomes. A total of 63 community-dwellers with pain lasting at least 3 months and Numerical Rating Scale scores of ≥2 were recruited from 3 medical institutions. Their pain circadian rhythms were evaluated over 7 days by measuring pain intensity at 6-time points per day using a 10-cm visual analog scale. Cluster analysis was performed using 6 variables with standardized visual analog scale values at 6-time points for individual participants to extract groups with similar pain circadian rhythms. The results of the Neuropathic Pain Symptom Inventory and psychological evaluations in each group were compared using the Kruskal-Wallis test. The results revealed 3 clusters with different circadian rhythms of pain. The total and evoked pain subscale Neuropathic Pain Symptom Inventory scores differed among the 3 clusters. The results suggest that a thorough understanding of circadian pain rhythms in chronic pain patients may facilitate the performance of activities of daily living and physical exercise from the perspective of pain management.
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http://dx.doi.org/10.1097/MD.0000000000026500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238338PMC
June 2021

Effectiveness of patient education focusing on circadian pain rhythms: A case report and review of literature.

World J Clin Cases 2021 Jun;9(17):4441-4452

Graduate School of Health Sciences, Kio University, Kitakatsuragi-gun 635-0832, Nara, Japan.

Background: Neuropathic pain management should aim at improving quality of life and daily living activities of patients; therefore, emphasis should be placed on pain management including understanding the pain patterns during daily activity. Therefore, lifestyle guidance should be based on a detailed understanding of pain; however, previous studies commonly evaluated pain intensity at a single point in time. We report a case on patient education intervention based on the relationship between pain circadian rhythms and detailed physical activity during the day.

Case Summary: A man in his 60s, who suffered a brachial plexus injury in a traffic accident, presented with neuropathic pain. Early assessment of the importance of daily living activities to the patient, pain rhythmicity, and physical activity, was performed. The early assessments showed that the pain intensity was lower on days when more light-intensity physical activity (LIPA) was performed, than on days when less LIPA was performed. Consequently, patient education focused on methods to decrease the pain intensity that tended to worsen in the afternoon, and encouraged behavioral changes by suggesting the patient to take walks," which could be used to maintain LIPA in the afternoon. On reassessment, the afternoon LIPA, which had been the focus of attention, had increased and a change was noted in the circadian rhythm of pain.

Conclusion: Patient education based on a composite assessment elicited positive results in relation to the pain circadian rhythm and physical activity.
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http://dx.doi.org/10.12998/wjcc.v9.i17.4441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173436PMC
June 2021

Pill Counting in the Determination of Factors Affecting Medication Adherence in Patients with Type 2 Diabetes: A Retrospective Observational Study.

Diabetes Ther 2021 Jul 13;12(7):1993-2005. Epub 2021 Jun 13.

Department of Clinical Pharmacy, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.

Introduction: For medication adherence, pill counting has higher accuracy in objective assessment. However, previous reports have shown that factors such as psychological bias and other people's involvement in managing and helping patients take their medications may influence the outcomes. In Japan, all prescription medicines of patients are checked by medical reconciliation, and a pill count is performed during hospitalization. This study investigated factors affecting the medication adherence of patients with type 2 diabetes mellitus (T2DM), including patient- and medication-related factors, by pill counting using medical reconciliation in a situation where the patient's psychological bias is low.

Methods: This study included 103 patients with T2DM who had been treated with oral hypoglycemic agents (OHAs) for at least 24 weeks. Patients whose OHAs were managed by another person were excluded. We calculated medication adherence values (MAVs) according to the following formula: MAV = (total prescription days - prescription days of OHAs brought when admitted)/(days from the start of OHAs to hospitalization). The relationship between MAVs and patient- and medication-related factors was analyzed.

Results: On multiple linear regression analysis of patient-related factors with P < 0.10 in the univariate analysis as explanatory variables, a lower number of chronic diseases (β = 0.017; P < 0.001) and higher number of OHAs (β = - 0.021; P = 0.04) were independent factors for lower MAV. Medication-related factors were not found to be independent factors.

Conclusions: Our findings suggest that poor adherence was independently associated with lower number of chronic diseases and higher number of OHAs in patients with T2DM.
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http://dx.doi.org/10.1007/s13300-021-01091-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266921PMC
July 2021

Implementation of Pharmacogenomic Information on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Front Med (Lausanne) 2021 24;8:644154. Epub 2021 Mar 24.

Division of Medicinal Safety Science, National Institute of Health Sciences, Kawasaki, Japan.

Drug-related Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare but severe adverse drug reactions, termed as idiosyncratic reactions; however, predicting their onset remains challenging. Pharmacogenomic information associated with SJS/TEN has accumulated on several drugs in the last 15 years, with clinically useful information now included on drug labels in several countries/regions or guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC) for implementation. However, label information might be different among countries. This mini-review summarizes pharmacogenomic information on drug labels of five drugs in six countries and compared descriptions of drug labels and CPIC guidelines. Finally, we discuss future perspectives of this issue. Pharmacogenomic information on drug labels is not well-harmonized across countries/regions, but CPIC guidelines are a scientifically sound goal for future pharmacogenomic implementation.
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http://dx.doi.org/10.3389/fmed.2021.644154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024462PMC
March 2021

An international retrospective study for tolerability of 6-mercaptopurine on NUDT15 bi-allelic variants in children with acute lymphoblastic leukemia.

Haematologica 2021 07 1;106(7):2026-2029. Epub 2021 Jul 1.

Department of Transplantation and Cell Therapy, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan; Department of Pediatric Hematology and Oncology Research, National Center for Child Health and Development, Tokyo, Japan; Department of Pediatrics, the University of Tokyo, Tokyo.

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http://dx.doi.org/10.3324/haematol.2020.266320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8252943PMC
July 2021

Differential effects of mesalazine formulations on thiopurine metabolism through thiopurine S-methyltransferase inhibition.

J Gastroenterol Hepatol 2021 Aug 29;36(8):2116-2124. Epub 2021 Jan 29.

Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan.

Background And Aim: Thiopurines are often used in combination with mesalazine for the treatment of ulcerative colitis (UC). Mesalazine formulations are delivered to the digestive tract by various delivery systems and absorbed as 5-aminosalicylic acid (5-ASA). 5-ASA is known to inhibit thiopurine S-methyltransferase (TPMT) activity and to affect thiopurine metabolism. There have been no studies comparing TPMT inhibition by multimatrix mesalazine (MMX) with other formulations. We investigated the difference in TPMT inhibition by different mesalazine formulations and prospectively confirmed the clinical relevance.

Methods: Plasma concentrations of 5-ASA, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), and TPMT activities were measured in UC patients receiving various mesalazine formulations (time-dependent or pH-dependent mesalazine or MMX) as monotherapy. Patients already on both time-dependent or pH-dependent mesalazine and thiopurines switched their mesalazine to MMX, examining 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) 0 and 8 weeks after switching. Clinical relapse after switching was also monitored for 24 weeks.

Results: Plasma 5-ASA and N-Ac-5-ASA levels were significantly higher in patients receiving time-dependent mesalazine (n = 12) compared with pH-dependent mesalazine (n = 12) and MMX (n = 15), accompanied by greater TPMT inhibition. Prospective switching from time-dependent mesalazine to MMX decreased 6-TGN levels, increased those of 6-MMP, and increased 6-MMP/6-TGN ratios. Furthermore, this resulted in significantly more relapses than switching from pH-dependent mesalazine to MMX.

Conclusions: Time-dependent mesalazine has higher plasma 5-ASA and N-Ac-5-ASA levels and greater TPMT inhibition than MMX. Therefore, switching from time-dependent mesalazine to MMX may lead to an increase of 6-MMP/6-TGN, which may reduce the clinical effectiveness of thiopurines, warranting close monitoring after switch.
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http://dx.doi.org/10.1111/jgh.15411DOI Listing
August 2021

Central Sensitivity Is Associated with Poor Recovery of Pain: Prediction, Cluster, and Decision Tree Analyses.

Pain Res Manag 2020 30;2020:8844219. Epub 2020 Oct 30.

Department of Neurorehabilitation, Graduate School of Health Sciences, Kio University, Nara, Japan.

The process of pain recovery varies and can include the recovery, maintenance, or worsening of symptoms. Many cases of patients with pain show a tendency of recovering as predicted; however, some do not. The characteristics of cases that do not fit the prediction of pain recovery remain unclear. We performed cluster and decision tree analyses to reveal the characteristics in cases that do not fit the prediction of pain recovery. A total of 43 patients with musculoskeletal pain (nonoperative: 22 patients, operative: 13 patients) and central pain (brain disease: 5 patients, spinal cord disease: 3 patients) were included in this longitudinal study. Central sensitivity syndrome (CSS) outcome measures (Central Sensitisation Inventory), pain intensity-related outcome measures (Short-Form McGill Pain Questionnaire-2 (SFMPQ-2)), and cognitive-emotional outcome measures (Hospital Anxiety and Depression Scale and Pain Catastrophising Scale-4) of all patients were assessed at baseline and after 1-2 months. Regression analysis was used to calculate pain recovery prediction values. A hierarchical cluster analysis based on the predicted change of SFMPQ-2 and the observed change of SFMPQ-2 was used to extract subgroups that fit and those that do not fit pain recovery prediction. To extract the characteristics of subgroups that do not fit the prediction of pain recovery, a decision tree analysis was performed. The level of significance was set at 5%. In the results of cluster analysis, patients were classified into three subgroups. Cluster 1 was characterised by worse pain intensity from baseline, cluster 2 by pain, having recovered less and mildly than the predicted value, and Cluster 3 by a marked recovery of pain. In the results of the decision tree analysis, the CSI change was extracted as an indicator related to the classification of all clusters. Our findings suggest that the poor improvement of CSS is characteristic in cases that do not fit the prediction of pain recovery.
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http://dx.doi.org/10.1155/2020/8844219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647749PMC
March 2021

Determining whether the effect of liraglutide on non-alcoholic fatty liver disease depends on reductions in the body mass index.

JGH Open 2020 Oct 30;4(5):995-1001. Epub 2020 Jun 30.

Department of Clinical Pharmacy, School of Pharmacy Kitasato University Minato-ku Japan.

Background And Aim: Non-alcoholic fatty liver disease (NAFLD) initially presents as steatosis, which can progress to non-alcoholic steatohepatitis (NASH), and often presents clinically alongside metabolic syndromes. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are regularly utilized to treat type 2 diabetes mellitus. The GLP-1 RA-liraglutide-ameliorates liver enzymes, histological features, and liver fat content of patients with NASH. However, few studies have examined whether the effect of GLP-1 RAs depends on changes in the patient's body mass index (BMI). Therefore, this retrospective study aimed to investigate whether the efficacy of liraglutide depended on the baseline BMI or a reduction in BMI.

Methods: Fifty-five Japanese patients with type 2 diabetes mellitus and NAFLD who received liraglutide treatment for 24 weeks were assessed. The association between BMI and liver function or fibrosis was evaluated based on the aspartate aminotransferase, alanine aminotransferase, and fibrosis-4 indices.

Results: We found that 24 weeks of liraglutide treatment improved liver function and fibrosis in patients with type 2 diabetes mellitus and NAFLD, regardless of BMI changes or obesity status.

Conclusions: Our findings provide important insight into the impact of BMI on liver function and fibrosis in patients with type 2 diabetes mellitus and NAFLD who are treated with liraglutide.
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http://dx.doi.org/10.1002/jgh3.12384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578289PMC
October 2020

Heterochronous Suture Line Recurrences in the Jejunal Pouch following Total Gastrectomy for Stage II Gastric Cancer: A Case Report and Literature Review.

Case Rep Oncol 2020 Jan-Apr;13(1):225-232. Epub 2020 Mar 19.

Department of Surgery, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Japan.

We report the case of a 65-year-old male who developed heterochronous local recurrences of gastric cancer in the jejunal pouch (J-pouch) four times after total gastrectomy. He underwent total gastrectomy, J-pouch, and Roux-en-Y reconstruction for stage II gastric cancer in 2005. Four local recurrences appeared on the esophago-jejunal anastomosis, the suture line within the pouch, the esophago-jejunal anastomosis, and the anastomosis between the jejunum and Y-loop, which were resected by partial excision or endoscopic submucosal dissection. Suture line recurrence of gastric cancer is rare. The common features for each recurrence included the surgically negative resection margins, observation of the same histopathological subtype, absence of remote metastasis or peritoneal seeding, and the recurrence on the anastomotic suture line, suggesting that the cause of recurrence was the implantation of exfoliated cancer cells probably in the suture line. However, there is no established procedure for preventing implantation recurrence currently, the effectiveness of lumen lavage is suggested.
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http://dx.doi.org/10.1159/000505392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154264PMC
March 2020

Anomalies of the right vertebral vein increasing the difficulty of lymph-node dissection along the right recurrent laryngeal nerve: a single-institution, retrospective study.

Esophagus 2020 07 22;17(3):257-263. Epub 2020 Feb 22.

Department of Gastroenterological Surgery, Saitama Cancer Center Hospital, 780 Komuro Inamachi, Kitaadachi-gun, Saitama, 362-0806, Japan.

Background: Radical lymph-node dissection along the recurrent laryngeal nerves (RLN) improves the prognosis of patients with esophageal cancer. The RLN is a landmark for achieving adequate lymph-node dissection. However, the right RLN is sometimes covered by the right vertebral veins (VVs), making it undetectable. We investigated the relationship between this anomaly of the right VVs and the challenges of performing lymphadenectomy along the right RLN.

Methods: Patients with esophageal cancer, who underwent thoracoscopic esophagectomy with radical lymph-node dissection, were registered. The patterns of the right VVs were evaluated by preoperative computed tomography. The time required for identifying the right RLN or completing the lymphadenectomy was determined by reviewing surgical videos.

Results: In total, 178 patients were enrolled. Eighty patients (45%) had right VVs passing dorsal to the right subclavian artery (Dorsal group). More time was required to detect the right RLN in these cases (11 vs 9.5 min for the other cases, p = 0.034). In the Dorsal group, there were 15 patients who had specific VV patterns: The right VV converged on the lower portion of the right brachiocephalic vein (BCV), or passed through to the more medial side of the mediastinum. These patients required more time for detecting the right RLN (25 vs 9 min, p < 0.0001) and for completing the lymphadenectomy (41 vs 32 min, p = 0.048) than the other cases.

Conclusion: The right VVs behind the subclavian artery, joining the lower part of the BCV or passing through the medial side, made it difficult to identify the right RLN and complete the lymphadenectomy.
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http://dx.doi.org/10.1007/s10388-020-00723-yDOI Listing
July 2020

Successful combination of endoscopic and laparoscopic removal of multiple ingested needles: A case report.

Medicine (Baltimore) 2020 Feb;99(8):e19343

Department of Internal Medicine, Digestive and Liver Disease Center, Tokai University Tokyo Hospital, Tokyo.

Rationale: Foreign body (FB) ingestion is a relatively common clinical situation in the emergency department. However, multiple sharply pointed foreign bodies located in different organs are rare conditions and no definite treatment guidelines has been established.

Patient Concerns: A 31-year-old amateur magician visited the outpatient clinic with a chief complaint of epigastric discomfort. He might have accidentally swallowed some needles while practicing a magic trick 2 days before.

Diagnosis: Imaging tests revealed 1 needle was stuck in the left liver lobe through the stomach wall, 1 was in the third portion of the duodenum, 3 were in the ascending colon, and 2 were in the transverse colon.

Interventions: A needle in the duodenum and 5 in the colon were removed by endoscopy. The needle stuck in the liver from the stomach was not visible inside the stomach and was successfully removed by laparoscopy a few days later.

Outcomes: The patient was able to tolerate an oral diet and was discharged on postoperative day 4 without any complications.

Lessons: Developing a treatment plan in cases of multiple sharp FB may be difficult. A multidisciplinary team of endoscopists and surgeons is needed to determine the best possible treatment plan. This experience illustrates the importance of the planning of the sequence and method of removal of multiple foreign bodies from the gastrointestinal tract.
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http://dx.doi.org/10.1097/MD.0000000000019343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034740PMC
February 2020

The Mediating Effect of Central Sensitization on the Relation between Pain Intensity and Psychological Factors: A Cross-Sectional Study with Mediation Analysis.

Pain Res Manag 2019 8;2019:3916135. Epub 2019 Apr 8.

Department of Neurorehabilitation, Graduate School of Health Sciences, Kio University, Nara, Japan.

Background: Central sensitization (CS) and psychological factors are associated with pain intensity; however, the mediating role of CS on the relation between psychological factors and pain intensity remains unclear.

Objectives: We performed mediation analysis to investigate how CS mediates relation between psychological factors and pain intensity.

Methods: Twenty patients with musculoskeletal pain were included in this cross-sectional study. Central sensitization inventory (CSI), one pain intensity-related outcome measure (Short-Form McGill Pain Questionnaire 2 (SFMPQ2)), and three psychological outcome measures (Hospital Anxiety and Depression Scale (HADS), Pain Catastrophizing Scale-4 (PCS), and Tampa Scale for Kinesiophobia-11 (TSK)) of all participants were assessed. The mediation analysis with a bootstrap sampling procedure was used to assess the indirect effects. The level of significance was set at 5%.

Results: Mediation analysis showed that the HADS-anxiety, HADS-depression, and PCS had significant indirect effects on the pain ratings of CSI. Additionally, the direct effect was significant only for PCS.

Conclusions: The relationship among anxiety symptoms, depression symptoms, and pain intensity was completely mediated by CS. Furthermore, the relationship between catastrophic thinking and pain intensity was partially mediated by CS. Our findings suggest that CS mediates relation between psychological factors and pain intensity, and CS-focused intervention may be important.
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http://dx.doi.org/10.1155/2019/3916135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476126PMC
December 2019

Tolerability of Erythrocyte Ribavirin Triphosphate Concentrations Depends on the ITPA Genotype.

Ther Drug Monit 2019 08;41(4):497-502

Department of Clinical Pharmacy, Center for Clinical Pharmacy and Sciences, School of Pharmacy, Kitasato University.

Background: Ribavirin (RBV) is an antiviral drug that is part of the current standard therapy for chronic hepatitis C (CHC). It is enzymatically converted to ribavirin triphosphate (RTP) that inhibits the activity of viral RNA polymerase, thereby preventing viral replication. However, one of its adverse effects includes hemolytic anemia that limits its application. The variant of ITPA (inosine triphosphatase), which dephosphorylates inosine triphosphate to inosine monophosphate, is a protective factor for RBV-induced anemia. RTP is an important metabolite required for ribavirin action. This study evaluated the time-dependent association of RTP concentrations in erythrocytes, RBV-induced toxicity, and virological response to RBV treatment for hepatitis C.

Methods: A total of 28 Japanese patients with CHC were treated with RBV/peg-interferon/simeprevir or RBV/sofosbuvir and were genotyped for ITPA variants (rs1127354 and rs7270101). We measured RTP concentrations in erythrocytes in a total of 76 samples collected at 4, 8, and 12 weeks from the initiation of treatment.

Results: The ITPA rs1127354 variant was found in 7 patients. This was associated with significantly higher RTP concentrations in erythrocytes than in the wild-type patients (P < 0.001). Moreover, a significant correlation was observed between RTP concentrations and decline in hemoglobin (Hb) levels from baseline values in ITPA wild type and rs1127354 variant 12 weeks after treatment initiation (P < 0.01; r = -0.618 and -0.967, respectively). Multiple regression analysis revealed that ITPA genotype and erythrocyte RTP concentrations were major factors associated with reduced Hb levels in RBV therapy for CHC. However, we did not find any association between erythrocyte concentrations and virological response.

Conclusions: The increased tolerability to RTP concentrations in erythrocytes in the ITPA variant rs1127354 plays a role in preventing RBV-induced severe anemia in this ITPA variant.
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http://dx.doi.org/10.1097/FTD.0000000000000626DOI Listing
August 2019

Detection of KK-LC-1 Protein, a Cancer/Testis Antigen, in Patients with Breast Cancer.

Anticancer Res 2018 Oct;38(10):5923-5928

Department of Surgery, School of Medicine, Kitasato University, Sagamihara, Japan.

Background: Kita-Kyushu lung cancer antigen-1 (KK-LC-1) is a cancer/testis antigen and predominant target for cancer immunotherapy. Its detection is only established based on gene expression. In this study, we established a monoclonal antibody against KK-LC-1 to detect its protein expression in formalin-fixed samples.

Materials And Methods: The monoclonal antibody against KK-LC-1 was evaluated and the detection of KK-LC-1 between gene expression and protein expression was compared in patients with breast cancer. The monoclonal antibody clone 34B3, which we established, stained testicular germ cells positively.

Results: The rates of detection of KK-LC-1 gene and protein expression were 11.8% and 52.9%, respectively. Protein expression was detected in all triple-negative breast cancer cases studied (n=8). Furthermore, KK-LC-1 was detected in all tumours without oestrogen receptor expression.

Conclusion: This study indicated that KK-LC-1 expression was detected in breast cancer, especially in oestrogen receptor-negative subtypes.
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http://dx.doi.org/10.21873/anticanres.12937DOI Listing
October 2018

Phase II feasibility study of preoperative concurrent chemoradiotherapy with cisplatin plus 5-fluorouracil and elective lymph node irradiation for clinical stage II/III esophageal squamous cell carcinoma.

Int J Clin Oncol 2019 Jan 14;24(1):60-67. Epub 2018 Aug 14.

Esophageal Surgery Division, National Cancer Center Hospital, Tokyo, Japan.

Background: Preoperative chemoradiotherapy (CRT) is a standard treatment for stage II/III esophageal cancer. Preoperative chemotherapy is also considered a standard treatment for stage II/III esophageal squamous cell carcinoma (ESCC) in patients who undergo radical lymph node dissection. We conducted a feasibility study of preoperative CRT with cisplatin plus 5-fluorouracil (CF) and elective lymph node irradiation followed by esophagectomy with radical lymph node dissection in patients with stage II/III ESCC.

Methods: Patients with clinical stage II/III, excluding T4, ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy comprised two courses of CF infusion repeated after 4-weeks. Radiation therapy was concurrently administered to the primary tumor, metastatic lymph nodes, and regional lymph nodes at a dose of 41.4 Gy. After the completion of CRT, transthoracic esophagectomy with 2-3 fields lymphadenectomy was performed. The primary endpoint was the completion rate of protocol treatment with R0 resection.

Results: Thirty-one eligible patients were enrolled. During CRT, the most common grade 3 or 4 toxicities were leukopenia (65%), neutropenia (65%), anemia (13%), thrombocytopenia (13%), febrile neutropenia (13%), anorexia (16%), esophagitis (16%) and hyponatremia (16%). Thirty patients (96.8%) underwent surgery. One patient received palliative chemotherapy because of appearance of lung metastasis during CRT. The completion rate of protocol treatment was 93.5% (29/31). There was one treatment-related death after surgery. Pathological complete response was achieved in 42% (13/30).

Conclusion: Preoperative CRT with CF and elective lymph node irradiation showed an acceptable toxicity and promising activity especially in ESCC.
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http://dx.doi.org/10.1007/s10147-018-1336-xDOI Listing
January 2019

Clinical factors associated with the occurrence of nausea and vomiting in type 2 diabetes patients treated with glucagon-like peptide-1 receptor agonists.

J Diabetes Investig 2019 Mar 22;10(2):408-417. Epub 2018 Aug 22.

Department of Clinical Pharmacy, School of Pharmacy, Kitasato University, Tokyo, Japan.

Aims/introduction: Research has proved a correlation between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and gastrointestinal adverse events. Predominantly, nausea and vomiting are frequent gastrointestinal adverse events that lead to the discontinuation of GLP-1 RAs treatment. The present study aims to investigate clinical factors related to nausea and vomiting, considering diabetic complications and agents affecting the gastrointestinal tract, such as proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs), in patients with type 2 diabetes treated with GLP-1 RAs.

Materials And Methods: This retrospective study included Japanese patients with type 2 diabetes who started receiving GLP-1 RAs therapy. We assessed nausea and vomiting up to 48 weeks after treatment with GLP-1 RAs and used Fine-Gray's proportional hazards model to investigate clinical factors related to nausea and vomiting.

Results: A total of 130 patients were included in this study. Patients with PPIs or H2RAs showed a higher incidence of nausea and vomiting at 48 weeks than those without PPIs or H2RAs. The multivariate analysis revealed that female sex, retinopathy and treatment with PPIs or H2RAs were statistically significant risk factors for nausea and vomiting. Analysis of patients without PPIs or H2RAs showed that female sex and retinopathy were also statistically significant risk factors.

Conclusions: The present study showed a significant correlation of PPIs or H2RAs, female sex, and diabetic retinopathy with nausea and vomiting in patients with type 2 diabetes treated with GLP-1 RAs. Hence, the occurrence of nausea and vomiting in patients with these factors warrants attention.
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http://dx.doi.org/10.1111/jdi.12900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400150PMC
March 2019

Clinical Pharmacy Education in Japan: Using Simulated Patients in Laboratory-Based Communication-Skills Training before Clinical Practice.

Pharmacy (Basel) 2018 Jun 1;6(2). Epub 2018 Jun 1.

Research and Education Center for Clinical Pharmacy, School of Pharmacy, Kitasato University 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.

The Japanese pharmaceutical curriculum was extended from four to six years in 2006. Students now receive practical communication-skills training in their fourth year, before progressing to train in hospital and community pharmacies in their fifth year. Kitasato University School of Pharmacy, Tokyo, had established a program to meet these aims before the 2006 guidance. In the present study, we discuss and evaluate the features of this communication-skills training program. This study enrolled 242 fourth-year pharmacy students at Kitasato University. Students filled out a questionnaire survey after completing the laboratory element of their undergraduate education. As part of training, students were asked to obtain patient data from a model medical chart, before performing simulated patient interviews covering hospital admission and patient counseling. These simulations were repeated in a small group, and feedback was provided to students by both the simulated patient and the faculty after each presentation. It was found that students were able to develop their communication skills through this approach. Thus, an effective system of gradual and continuous training has been developed, which allows students to acquire clinical and practical communication skills.
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http://dx.doi.org/10.3390/pharmacy6020049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025166PMC
June 2018

Induction of inosine triphosphatase activity during ribavirin treatment for chronic hepatitis C.

Clin Chim Acta 2018 Jul 23;482:16-20. Epub 2018 Mar 23.

Department of Clinical Pharmacy, School of Pharmacy, Kitasato University, Japan.

Background: Ribavirin (RBV) is an antiviral agent and the primary component for chronic hepatitis C (CHC) therapy. Hemolytic anemia is limitation for RBV treatment. Inosine triphosphatase (ITPA) activity has been associated with severity of RBV-induced anemia. However, changes in ITPA activity during CHC therapy are unknown. The aim of this study was to measure the time-dependent change in ITPA activity over the RBV treatment.

Methods: Forty-two patients with CHC were evaluated for ITPA activity over the course of RBV treatment.

Results: The median value of ITPA activity at start of RBV treatment was 134.2 μmol/h/g hemoglobin (Hb; range, 26.3-251.0 μmol/h/g Hb). The ITPA activity values at 4, 8, and 12 weeks during RBV treatment were 143.2, 202.2, and 225.7 μmol/h/g Hb, respectively, and these ITPA values were significantly elevated compared with the start of treatment (p < 0.001). In patients with ITPA variants, patients with anemia (Hb < 10 g/dL) had greater elevated ITPA activities compared with patients without anemia at 12 weeks.

Conclusion: Our findings indicate that ITPA activities are elevated with RBV therapy, and this elevation may be a risk of anemia in late therapeutic phase in patients that began with low ITPA activity.
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http://dx.doi.org/10.1016/j.cca.2018.03.018DOI Listing
July 2018

Clofarabine exerts antileukemic activity against cytarabine-resistant B-cell precursor acute lymphoblastic leukemia with low deoxycytidine kinase expression.

Cancer Med 2018 04 23;7(4):1297-1316. Epub 2018 Feb 23.

Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan.

Cytosine arabinoside (Ara-C) is one of the key drugs for the treatment of acute myeloid leukemia. It is also used for consolidation therapy of acute lymphoblastic leukemia (ALL). Ara-C is a deoxyadenosine analog and is phosphorylated to form cytosine arabinoside triphosphate (Ara-CTP) as an active form. In the first step of the metabolic pathway, Ara-C is phosphorylated to Ara-CMP by deoxycytidine kinase (DCK). However, the current cumulative evidence in the association of the Ara-C sensitivity in ALL appears inconclusive. We analyzed various cell lines for the possible involvement of DCK in the sensitivities of B-cell precursor ALL (BCP-ALL) to Ara-C. Higher DCK expression was associated with higher Ara-C sensitivity. DCK knockout by genome editing with a CRISPR-Cas9 system in an Ara-C-sensitive-ALL cell line induced marked resistance to Ara-C, but not to vincristine and daunorubicin, indicating the involvement of DCK expression in the Ara-C sensitivity of BCP-ALL. DCK gene silencing due to the hypermethylation of a CpG island and reduced DCK activity due to a nonsynonymous variant allele were not associated with Ara-C sensitivity. Clofarabine is a second-generation deoxyadenosine analog rationally synthesized to improve stability and reduce toxicity. The IC50 of clofarabine in 79 BCP-ALL cell lines was approximately 20 times lower than that of Ara-C. In contrast to Ara-C, although the knockout of DCK induced marked resistance to clofarabine, sensitivity to clofarabine was only marginally associated with DCK gene expression level, suggesting a possible efficacy of clofarabine for BCP-ALL that shows relative Ara-C resistance due to low DCK expression.
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http://dx.doi.org/10.1002/cam4.1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911575PMC
April 2018

Regional evaluation of childhood acute lymphoblastic leukemia genetic susceptibility loci among Japanese.

Sci Rep 2018 01 15;8(1):789. Epub 2018 Jan 15.

Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.

Genome-wide association studies (GWAS) performed mostly in populations of European and Hispanic ancestry have confirmed an inherited genetic basis for childhood acute lymphoblastic leukemia (ALL), but these associations are less clear in other races/ethnicities. DNA samples from ALL patients (aged 0-19 years) previously enrolled onto a Tokyo Children's Cancer Study Group trial were collected during 2013-2015, and underwent single nucleotide polymorphism (SNP) microarray genotyping resulting in 527 B-cell ALL for analysis. Cases and control data for 3,882 samples from the Nagahama Study Group and Aichi Cancer Center Study were combined, and association analyses across 10 previous GWAS-identified regions were performed after targeted SNP imputation. Linkage disequilibrium (LD) patterns in Japanese and other populations were evaluated using the varLD score based on 1000 Genomes data. Risk associations for ARID5B (rs10821936, OR = 1.84, P = 6 × 10) and PIP4K2A (rs7088318, OR = 0.76, P = 2 × 10) directly transferred to Japanese, and the IKZF1 association was detected by an alternate SNP (rs1451367, OR = 1.52, P = 2 × 10). Marked regional LD differences between Japanese and Europeans was observed for most of the remaining loci for which associations did not transfer, including CEBPE, CDKN2A, CDKN2B, and ELK3. This study represents a first step towards characterizing the role of genetic susceptibility in childhood ALL risk in Japanese.
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http://dx.doi.org/10.1038/s41598-017-19127-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768812PMC
January 2018

Uncovering the influence of social skills and psychosociological factors on pain sensitivity using structural equation modeling.

J Pain Res 2017 11;10:2223-2231. Epub 2017 Sep 11.

Department of Neurorehabilitation, Graduate School of Health Sciences, Kio University.

Pain is a subjective emotional experience that is influenced by psychosociological factors such as social skills, which are defined as problem-solving abilities in social interactions. This study aimed to reveal the relationships among pain, social skills, and other psychosociological factors by using structural equation modeling. A total of 101 healthy volunteers (41 men and 60 women; mean age: 36.6±12.7 years) participated in this study. To evoke participants' sense of inner pain, we showed them images of painful scenes on a PC screen and asked them to evaluate the pain intensity by using the visual analog scale (VAS). We examined the correlation between social skills and VAS, constructed a hypothetical model based on results from previous studies and the current correlational analysis results, and verified the model's fit using structural equation modeling. We found significant positive correlations between VAS and total social skills values, as well as between VAS and the "start of relationships" subscales. Structural equation modeling revealed that the values for "start of relationships" had a direct effect on VAS values (path coefficient =0.32, <0.01). In addition, the "start of relationships" had both a direct and an indirect effect on psychological factors via social support. The results indicated that extroverted people are more sensitive to inner pain and tend to get more social support and maintain a better psychological condition.
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http://dx.doi.org/10.2147/JPR.S143342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602447PMC
September 2017

Susceptibility to 6-mercaptopurine toxicity related with NUDT15 and ABCC4 variants in Japanese childhood acute lymphoblastic leukemia.

Authors:
Yoichi Tanaka

Rinsho Ketsueki 2017 ;58(8):950-956

Department of Clinical Pharmacy, School of Pharmacy, Kitasato University.

6-Mercaptopurine (6-MP) is one of the main components for the treatment of childhood acute lymphoblastic leukemia (ALL). However, many patients require a dose reduction of 6-MP due to its severe toxicities. NUDT15 variants are one of the factors that cause 6-MP intolerability in Asians. In each patient with heterozygous variants of NUDT15, 6-MP intolerability differs. Therefore, we hypothesized that the combination of NUDT15 genotype with ABCC4 genotype, which is associated with 6-MP efflux, might enable to accurately predict 6-MP intolerability. We analyzed the association between 6-MP-related events and the genotypes of NUDT15 and ABCC4. All patients with both NUDT15 rs116855232 heterozygous variants and ABCC4 rs3765534 variants suffered from severe leukopenia and required 6-MP dose reduction to less than 35 mg/m/day. In conclusion, genotyping NUDT15 and ABCC4 facilitates the prediction of 6-MP intolerability. The results of this study will improve personalized medicines in Japanese patients with childhood ALL.
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http://dx.doi.org/10.11406/rinketsu.58.950DOI Listing
December 2017

State dependence of climatic instability over the past 720,000 years from Antarctic ice cores and climate modeling.

Sci Adv 2017 Feb 8;3(2):e1600446. Epub 2017 Feb 8.

Institute of Low Temperature Science, Hokkaido University, Kita-19, Nishi-8, Kita-ku, Sapporo 060-0819, Japan.

Climatic variabilities on millennial and longer time scales with a bipolar seesaw pattern have been documented in paleoclimatic records, but their frequencies, relationships with mean climatic state, and mechanisms remain unclear. Understanding the processes and sensitivities that underlie these changes will underpin better understanding of the climate system and projections of its future change. We investigate the long-term characteristics of climatic variability using a new ice-core record from Dome Fuji, East Antarctica, combined with an existing long record from the Dome C ice core. Antarctic warming events over the past 720,000 years are most frequent when the Antarctic temperature is slightly below average on orbital time scales, equivalent to an intermediate climate during glacial periods, whereas interglacial and fully glaciated climates are unfavourable for a millennial-scale bipolar seesaw. Numerical experiments using a fully coupled atmosphere-ocean general circulation model with freshwater hosing in the northern North Atlantic showed that climate becomes most unstable in intermediate glacial conditions associated with large changes in sea ice and the Atlantic Meridional Overturning Circulation. Model sensitivity experiments suggest that the prerequisite for the most frequent climate instability with bipolar seesaw pattern during the late Pleistocene era is associated with reduced atmospheric CO concentration via global cooling and sea ice formation in the North Atlantic, in addition to extended Northern Hemisphere ice sheets.
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http://dx.doi.org/10.1126/sciadv.1600446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5298857PMC
February 2017

Association of Epithelial Atypia With Recurrence After Surgical Excision in Conjunctival Papilloma.

Eye Contact Lens 2018 Sep;44 Suppl 1:S77-S81

Departments of Ophthalmology (H.Y., M.D., T.Y., S.D., Y.S., J.S.), and Pathology and Laboratory Medicine (J.M., Y.T.), Ichikawa General Hospital, Tokyo Dental College, Chiba, Japan; and Department of Ophthalmology (H.Y., M.D., K.T.), Keio University School of Medicine, Tokyo, Japan.

Purpose: To investigate the association between recurrence of conjunctival papillomas and presence of atypical epithelial changes in patients undergoing surgical excision for conjunctival papilloma.

Methods: We retrospectively reviewed 1,195 ophthalmic pathology specimens from 2004 to 2014 at Ichikawa General Hospital. Pathologic specimens of 5 patients with a final diagnosis of "conjunctival papilloma" were stained with hematoxylin-eosin, Ki 67, p53, human papillomavirus (HPV) 16 and 18 antibodies.

Results: Of 1,195 patients, 5 patients (4 men, 1 woman; age range: 27∼57 years, mean age: 38.4 years) had a diagnosis of conjunctival papilloma, which constituted to 0.42% of the pathologic diagnosis made for the ophthalmology specimens. All specimens displayed multiple fronds of thickened conjunctival epithelium that enclosed cores of vascularized connective tissues. Three patients with recurrence after surgical excision demonstrated moderate to severe epithelial atypia, who also showed higher staining with Ki67 and p53 compared with patients with no recurrence. HPV16 and 18 antibodies staining did not appear to relate to recurrences.

Conclusions: Conjunctival papillomas with higher positive staining for Ki67 and p53 seem to have a higher risk of recurrence even after complete surgical excision and necessitate careful follow-up.
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http://dx.doi.org/10.1097/ICL.0000000000000330DOI Listing
September 2018

SOX2 and Rb1 in esophageal small-cell carcinoma: their possible involvement in pathogenesis.

Mod Pathol 2017 05 20;30(5):660-671. Epub 2017 Jan 20.

Department of Pathology, Tohoku University Graduate School of Medicine, Miyagi, Japan.

Clinicopathological features and pathogenesis of esophageal small-cell carcinoma remain unclear. We hypothesized common cellular origin and pathogenesis in small-cell carcinoma of esophagus and lung associated with SOX2 overexpression and loss of Rb1. Expression of squamous-basal markers (CK5/6 and p40), glandular markers (CK18 and CEA), SOX2, and Rb1 were evaluated in 15 esophageal small-cell carcinomas, 46 poorly differentiated squamous cell carcinomas, and 88 small-cell lung carcinoma, as well as 16 embryonic esophagus. Esophageal small-cell carcinoma expressed higher levels of glandular markers and lower levels of squamous-basal markers than poorly differentiated squamous cell carcinoma. No significant differences were observed in immunohistochemistry profiles between small-cell carcinoma of the esophagus and the lung. SOX2 expression was high in esophageal small-cell carcinoma (70%±33% of nuclei), small-cell lung carcinoma (70%±26%), and the embryonic esophagus (75%±4%), and it was significantly lower in poorly differentiated squamous cell carcinoma (29%±28%). Rb1 expression was significantly lower in esophageal small-cell carcinoma (0.3%±1%), small-cell lung carcinoma (2%±6%), and the embryonic esophagus (7%±5%), and it was significantly higher in poorly differentiated squamous cell carcinoma (51%±24%). The immunohistochemistry profiles of small-cell carcinoma of the esophagus and the lung are highly similar. The loss of Rb1 function is a key contributor to the pathogenesis of both neoplasms. In addition, SOX2 overexpression observed in esophageal and lung small-cell carcinoma as well as in the embryonic esophagus indicated that esophageal small-cell carcinoma may arise from embryonic-like stem cells in the esophageal epithelium. The two distinct differentiation patterns (neuroendocrine and glandular) of esophageal small-cell carcinoma further support the fact that SOX2 has a pivotal role in the differentiation of pluripotent stem cells into esophageal small-cell carcinoma cells.
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http://dx.doi.org/10.1038/modpathol.2016.222DOI Listing
May 2017

Expression of Cytokeratin 13, 14, 17, and 19 in 4-nitroquinoline-1-oxide-induced Oral Carcinogenesis in Rat.

Bull Tokyo Dent Coll 2016 ;57(4):241-251

Department of Oral Medicine, Oral and Maxillofacial Surgery, Tokyo Dental College.

The management of epithelial dysplastic spread around an oral squamous cell carci-noma is very important, particularly intraoperatively. Both cytokeratin (CK) 14 and CK19 are believed to be involved in the development of precancerous lesions, and their expression profiles are quite specific in these and early cancer lesions. Here, expression of CK13, 14, 17, and 19 was investigated in a rat model of 4-nitroquinoline-1-oxide-induced tongue cancer during a series of carcinogenetic processes to determine their value in assessing the features of epithelial dysplastic spread around a cancer. Based on tissue conditions, the results showed that expression levels of CK13 and 14 decreased in the order of no change, dysplasia, and cancer, whereas those of CK17 and 19 increased in the same order. Expression of CK13 showed a significant difference among no change, dysplasia, and cancer. This indicates that comparing the immunohistochemical staining profiles of CKs, especially CK13, could help in assessing the characteristics of epithelial dysplastic spread around a cancer.
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http://dx.doi.org/10.2209/tdcpublication.2010-0029DOI Listing
January 2018

Caruncular and Pericaruncular Sebaceous Gland Hyperplasia: A Report of 2 Cases and Literature Review.

Eye Contact Lens 2018 Sep;44 Suppl 1:S316-S319

Department of Ophthalmology (M.O., M.S., M.D., J.S.), Tokyo Dental College Ichikawa General Hospital, Chiba, Japan; Department of Ophthalmology (M.O., M.D., K.T.), Keio University School of Medicine, Tokyo, Japan; Department of Ophthalmology (M.S.), Fukushima University School of Medicine, Fukushima, Japan; Department of Pathology and Laboratory Medicine (J.M., Y.T.), Tokyo Dental College Ichikawa General Hospital, Chiba, Japan; and Department of Ophthalmology (H.O.), Jichi Medical University, Saitama, Japan.

Purpose: To report the clinical and histopathological features of two patients with caruncular and pericaruncular sebaceous gland hyperplasia (SGH) with a literature review.

Methods: We performed a retrospective pathology database search of 1195 ophthalmic specimens receiving the clinical diagnosis of SGH for caruncular/pericaruncular lesions during 2004 to 2014 at Tokyo Dental College, Ichikawa General Hospital. Paraffin sections were stained with hematoxylin and eosin. A retrospective patient record and literature review was also performed.

Results: Database search disclosed 2 male patients with SGH of 1195 specimens (0.15%). Pathological specimens revealed neither any cellular/nuclear atypia nor any mitotic figures and invasive features. No recurrences were observed in these 2 cases 12 to 18 months after excision.

Conclusions: Caruncle and pericaruncular SGH is an uncommon lesion which needs careful histopathological evaluation for differentiation especially from caruncular neoplasias.
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http://dx.doi.org/10.1097/ICL.0000000000000278DOI Listing
September 2018
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