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Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse reaction in cancer patients treated with several cytotoxic anticancer agents including paclitaxel. Duloxetine, an antidepressant known as a serotonin-noradrenalin reuptake inhibitor, is the only agent that has moderate evidence for the use to treat painful CIPN. The present retrospective cohort study aimed to analyze risk factors for paclitaxel-induced peripheral neuropathy (PIPN), and investigate ongoing prescription drug use for PIPN in Japan. Female breast and gynecologic cancer patients who underwent paclitaxel-based chemotherapy at a single center in Japan between January 2016 and December 2019 were enrolled in this study. Patients' information obtained from electronic medical records were statistically analyzed to test possible risk factors on PIPN diagnosis. Patients' age, total paclitaxel dose, the history of female hormone-related diseases, hypertension and body mass index (BMI), but not additional platinum agents, were significantly associated with increased PIPN diagnosis. Drugs prescribed for PIPN included duloxetine, pregabalin, mecobalamin and Goshajinkigan, a polyherbal medicine, regardless of poor evidence for their effectiveness against CIPN, and were greatly different between breast and gynecologic cancer patients diagnosed with PIPN at the departments of Surgery and Gynecology, respectively. Thus, older age, greater total paclitaxel dose, the history of estrogen-related diseases, hypertension and BMI are considered risk factors for PIPN in paclitaxel-based chemotherapy of female cancer patients. It appears an urgent need to establish a guideline of evidence-based pharmacotherapy for PIPN., Competing Interests: The authors have declared that no competing interests exist.

FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab is the preferred first-line treatment for right-sided metastatic colorectal cancer with RAS mutation. However, severe adverse events are common in Japanese patients. We report the successful management of multiple stage IV colorectal cancers in a patient who received multidisciplinary treatment, including chemotherapy and Japanese Kampo medicine. A 68-year-old man presented with epigastralgia and appetite loss and was diagnosed with multiple stage IV colorectal cancers. Colonoscopy identified type II tumors in the ascending colon, sigmoid colon, and upper rectum. Histopathological examination of a biopsy specimen revealed well- to moderately differentiated tubular adenocarcinoma. Enhanced computed tomography of the thorax and abdomen showed multiple pulmonary nodules and para-aortic lymph node swelling. Laparoscopic loop-ileostomy was performed to avoid bowel obstruction due to severe stenosis of ascending colon cancer. Intraoperative observation revealed two white nodules suggestive of metastasis in the lateral area of the liver. Therefore, we diagnosed multiple stage IV colorectal cancers with multiple metastases (lung, liver, and distant lymph nodes). His postoperative course was uneventful, and chemotherapy was started. Since the cancer cells harbored a RAS mutation, he received FOLFOXIRI plus bevacizumab. Japanese Kampo medicine consisting of Hangeshashinto and Juzen-taiho-to, to prevent diarrhea and fatigue, was administered daily. After 12 courses of chemotherapy, though circumferential stenosis still existed in the ascending colon, the tumors in the sigmoid colon and upper rectum were unclear. Enhanced computed tomography showed shrinkage of the pulmonary nodules and para-aortic lymph node; therefore, laparoscopic-assisted ileocecal resection was performed. The postoperative histopathological examination revealed moderately differentiated adenocarcinoma. The patient recovered uneventfully, and Kampo medicine consisting of Ninjin'yoeito was administered for postoperative weakness. Administration of adjuvant chemotherapy in this patient led to a near complete response that has been maintained without recurrence for 2 years and 8 months without reduced quality of life., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Although the clinical outcome of esophageal cancer has recently improved, the relapse rate remains high for all disease stages. At present, there is no diagnostic method to predict the long-term outcome for esophageal cancer. In this study, we evaluated serum preoperative proinflammatory cytokine levels and investigated the correlation between preoperative interleukin-6 (IL-6) and IL-8 levels and survival of patients with esophageal cancer., Methods: Between 2008 and 2015, we evaluated preoperative serum cytokine levels in 122 patients who underwent esophagectomy for esophageal cancer. Serum IL-6 and IL-8 levels were measured by enzyme-linked immunosorbent assays. We investigated the relationship between serum cytokine levels and the response to chemotherapy and survival., Results: The preoperative IL-6 levels were significantly associated with shorter recurrence-free survival (RFS, p = 0.001) and overall survival (OS, p = 0.001) after esophagectomy. Higher IL-8 levels were significantly associated with RFS (p = 0.018). In the multivariate analysis, age, preoperative chemotherapy, lymph node metastasis, serum C-reactive protein (CRP) levels and serum IL-6 levels (hazard ratio (HR), 2.888; p = 0.049) were significantly independent prognostic factors of RFS. Additionally, age, pathological stage, and serum IL-6 levels (HR, 3.247; p = 0.027) were shown to be significantly independent prognostic factors of OS. Serum IL-6 levels were significantly higher in the non-responder group (pathological response pGrade0 and pGrade1) after neoadjuvant therapy., Conclusions: High preoperative serum IL-6 levels are associated with a poor response to chemotherapy or chemoradiotherapy and poor prognosis after esophagectomy. Preoperative serum IL-6 levels may be a useful independent prognostic marker for esophageal cancer patients.

Background: Esophageal spindle cell carcinoma (ESpCC) is a malignant tumor composed of sarcomatous components. ESpCC is treated as a squamous cell carcinoma. However, because ESpCC is a rare tumor, little is known regarding its prognosis. This study aimed to analyze patients with ESpCC who were surgically treated at our hospital, determine the validity of surgery, and identify factors that indicate a prognosis., Methods: Treatment characteristics, overall survival (OS), and recurrence-free survival (RFS) of 28 patients with ESpCC who underwent surgery at our hospital between 1990 and 2016 were assessed. Furthermore, factors associated with OS and RFS were analyzed., Results: Subtotal esophagectomy with 3-field lymph node dissection and lower esophagectomy with 2-field lymph node dissection were performed in 25 and 3 patients, respectively. Chemotherapy was administered as preoperative therapy to two patients. Postoperative therapy, comprising radiotherapy and chemotherapy, was administered to three and nine patients, respectively. The 3- and 5-year RFS were 66.4% and 61.6% and the 3- and 5-year OS were 73% and 61.9%, respectively. Macroscopic type was identified as a prognostic factor. In terms of OS, prognosis was significantly worse in ulcerative-type ESpCC than in the polypoid type., Conclusion: The 5-year OS of ESpCC mainly treated with surgical therapy was 61.9%. However, prognosis was poor in some patients with ulcerative-type ESpCC according to macroscopic type. In the future, it will be necessary to accumulate more cases and investigate therapeutic strategies added to surgery to improve prognosis.

Background: This study aimed to analyze the determinants of patients' choice between palliative chemotherapy and best supportive care (BSC) and to investigate how this choice affects overall survival (OS) and length of hospitalization according to Eastern Cooperative Oncology Group (ECOG) performance status (PS)., Methods: An oncologist explained the palliative chemotherapy and BSC options to 129 patients with incurable cancer during their first consultation. Data on the ECOG PS, treatment decision, OS, and the length of hospitalization were retrospectively collected over 4 years., Results: Patients with an ECOG PS of 0-2 chose palliative chemotherapy more often than those with an ECOG PS of 3-4 (P < 0.01). Patients with ≤70 years chose palliative chemotherapy more often than those with > 70 (P < 0.05). And patients with gastric cancer and colon cancer chose palliative chemotherapy more often than those with CUP (carcinoma of unknown primary) (P < 0.05, P < 0.05 respectively). Factors associated with a significantly poorer OS in an adjusted analysis included the ECOG PS and treatment decision (hazard ratios: 0.18 and 0.43; P < 0.001, P < 0.01 respectively). In patients with an ECOG PS of 0-2, palliative chemotherapy was not associated with a longer OS compared with BSC (median OS: 14.5 vs. 6.8 months, respectively; P = 0.144). In patients with an ECOG PS of 3-4, palliative chemotherapy resulted in a significant survival gain compared to with BSC (median OS: 3.8 vs. 1.4 months, respectively; P < 0.05). Strong positive correlations between OS and the length of hospitalization were observed in patients with an ECOG PS of 3-4 who underwent palliative chemotherapy (r 2  = 0.683) and the length of hospitalization was approximately one-third of their OS., Conclusions: The determinants for treatment choice were age, ECOG PS and type of cancer, not sex difference. Oncologists should explain to patients that OS and the length of hospitalization vary according to the ECOG PS when selecting between palliative chemotherapy and BSC.

Objective: We aimed to clarify the current status of pharmacotherapy for tic disorders and comorbidities in Japan. We used a systematic survey to collate the consensus of Japanese experts and compare it with the recent international evidence., Methods: We devised a questionnaire on pharmacotherapy for tics and comorbidities and sent it to Japanese experts on tic disorders. Based on the response to the first survey, we revised the questionnaire and conducted a second survey to determine the consensus among the experts on a 4-point Likert scale by the Delphi method., Results: The first survey revealed variability in preferred medications and dosages among the experts in Japan. However, we were able to build a general consensus on pharmacotherapy for tic disorders and comorbidities based on the second survey. Aripiprazole and risperidone were the first- and second-line medication for tic disorders, respectively. Agonists of α- 2 adrenergic receptors were seldom prescribed. Fluvoxamine was the first-line medication for comorbid obsessive-compulsive disorder, and atomoxetine for comorbid attention deficit/hyperactivity disorder., Conclusions: This study will help Japanese physicians choose medications for tic disorders more judiciously and will improve the quality of tic pharmacotherapy in Japan., (Copyright © 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Objective: The objective was to assess the burden of chemotherapy for castration-resistant prostate cancer (CRPC) in Japan., Methods: Utilizing a large administrative hospital database we compared a set of outcome measures 12 months before and after initiation of chemotherapy, namely total medical costs, number of outpatient visits, number of hospital admissions and number of days spent in hospital., Results: A total of 598 CRPC patients were identified in the database. Total healthcare costs increased from 143,578 Japanese Yen (JPY) per patient per month (PPPM), before chemotherapy, to 333,628 JPY after start of chemotherapy. The number of hospital admissions increased by 280%, and the number of days spent in hospital by 380%., Conclusions: The overall costs of chemotherapy for patients diagnosed with castration-resistant prostate cancer in Japan are high. Our findings can serve as a basis for health economic evaluations.

Treatment of severe periodontitis with non-surgical therapy remains challenging in dentistry. The present study aimed to evaluate the clinical efficacy of hydrogen peroxide (H 2 O 2 ) photolysis-based antimicrobial chemotherapy adjunctively performed with root debridement (RD) for moderate to severe periodontitis. A randomized controlled trial was conducted that included 53 patients with 142 test teeth. The test teeth were randomly assigned to one of three treatment groups: Group 1, RD + H 2 O 2 photolysis; Group 2, RD followed by administration of a local drug delivery system (minocycline chloride gel); or Group 3, RD alone. Clinical and microbiological examination were performed for up to 12 weeks following treatment. Probing pocket depth (PPD) and bleeding on probing (BoP) were improved after each treatment session. At 12 weeks, Group 1 had achieved significantly lower PPDs than the other groups, though there were no significant differences in BoP between Group 1 and the other groups. Counts of Porphyromonas gingivalis, a known periodontal pathogen, in Group 1 were significantly lower than those in Group 3, and were comparable to those in Group 2. Therefore, it is suggested that H 2 O 2 photolysis treatment can be used as a novel adjunctive antimicrobial chemotherapy for non-surgical periodontal treatment.

Background: Hikikomori, a form of social withdrawal first reported in Japan, may exist globally but cross-national studies of cases of hikikomori are lacking., Aims: To identify individuals with hikikomori in multiple countries and describe features of the condition., Method: Participants were recruited from sites in India, Japan, Korea and the United States. Hikikomori was defined as a 6-month or longer period of spending almost all time at home and avoiding social situations and social relationships, associated with significant distress/impairment. Additional measures included the University of California, Los Angeles (UCLA) Loneliness Scale, Lubben Social Network Scale (LSNS-6), Sheehan Disability Scale (SDS) and modified Cornell Treatment Preferences Index., Results: A total of 36 participants with hikikomori were identified, with cases detected in all four countries. These individuals had high levels of loneliness (UCLA Loneliness Scale M = 55.4, SD = 10.5), limited social networks (LSNS-6 M = 9.7, SD = 5.5) and moderate functional impairment (SDS M = 16.5, SD = 7.9). Of them 28 (78%) desired treatment for their social withdrawal, with a significantly higher preference for psychotherapy over pharmacotherapy, in-person over telepsychiatry treatment and mental health specialists over primary care providers. Across countries, participants with hikikomori had similar generally treatment preferences and psychosocial features., Conclusion: Hikikomori exists cross-nationally and can be assessed with a standardized assessment tool. Individuals with hikikomori have substantial psychosocial impairment and disability, and some may desire treatment., (© The Author(s) 2014.)

Background: Eradication of Helicobacter pylori (H. pylori) at a younger age is considered to be effective in preventing gastric cancer. This study assessed the characteristics of eradication therapy in young patients., Materials and Methods: We enrolled 1073 patients with H. pylori infection between 2000 and 2013. The subjects were divided into three groups according to age into the young (≤30 years), middle-aged (31-50 years), and elder (≥51 years) groups. We also examined 472 cases to investigate clinical eradication characteristics., Results: The rate of clarithromycin (CAM) resistance was 57.9%, 34.5%, and 35.2% in the young, middle-aged, and elder group, respectively, in 2012-2013 and was significantly higher in the young group than in the elder group (p = .01). Metronidazole (MNZ) resistance was similar among the three groups at each time point. While CAM resistance rose over the study period, MNZ resistance was noted to have decreased of late. The overall initial eradication success rate was 91.9% (95% CI, 89.1-94.1) in our cohort. Eradication efficiency was comparable in the young, middle-aged, and elder group at 94.3% (95% CI, 87.4-97.5), 90.2% (95% CI, 82.9-94.6), and 91.8% (95% CI, 88.1-94.5) respectively. Side effects such as skin rash were observed in 14.8%, 3.9%, and 3.5% of the respective groups. There were significant differences in the incidence of side effects between the young group and other groups (p < .05, respectively)., Conclusion: Since CAM resistance and the incidence of side effects are higher in young individuals, it is especially important to select eradication regimens based on testing for antimicrobial susceptibility., (© 2014 John Wiley & Sons Ltd.)

Since 2002, we have conducted a series of intervention programs in Sado Island, Japan, to increase awareness of the appropriate use of antimicrobials among public and health-care staff. The objective of our study was to determine the antimicrobial susceptibility of Staphylococcus aureus among children in a semi-closed geographic region with controlled antimicrobial use. The average hospital visit-based rate for antimicrobial drug prescription drastically decreased from 535 per 1,000 clinic visits before the intervention programs to 45-75 per 1,000 clinic visits after the intervention programs (P < 0.0001). We obtained 1,260 clinical isolates of S. aureus from 957 pediatric outpatients aged 0-15 years between 2002 and 2010 at Sado General Hospital. The prevalence of methicillin-resistant S. aureus (MRSA) in the final year of the study (2010, 7.9%) was significantly lower than that in the early period of the study (2003, 23.6%; P < 0.001). All tested S. aureus isolates were susceptible to trimethoprim/sulfamethoxazole, teicoplanin, linezolid, and vancomycin. The prevalence of gentamicin-resistant S. aureus in isolates from skin lesions was significantly higher than in isolates from other lesions (41.3% versus 28.5%; P < 0.05). In conclusion, prevalence of MRSA in children in our study population could be decreased by eliminating unnecessary antimicrobial drug prescriptions.

The mainstays of the harmonized final document about ethnic factors in the acceptability of foreign clinical data include a complete clinical data package and a bridging study (for efficacy and/or for safety). A clinical data package that meets all of the regional regulatory requirements is defined as a complete clinical data package for submission and potential approval, irrespective of its geographic origin. The acceptability of the foreign clinical data component of the complete data package depends upon whether it can be extrapolated or employed as a bridge to the population of the new region. Ethnic factors can be defined as the intrinsic characteristics of recipients of a medicine, and extrinsic characteristics associated with the environment and culture in which the subjects reside. Based on retrospective studies, inter-ethnic differences in ADME seem to be not greater than intra-ethnic variations for most medicines, and extrinsic factors appear to be more important than intrinsic factors for the assessment of efficacy and safety of the drug across ethnicity. Medical practice may represent one of the biggest differences and may perhaps prove to be very difficult to provide a harmonization for these extrinsic factors. The bridging study concept has primarily been brought up to overcome the difficulties inherent to extrinsic factors caused by different ethnicity. In Japan, the clinical trials advice division of the organization for pharmaceutical safety and research (OPSR) has been dealing with consultations about bridging studies since February 1998. The contents of consultations can be classified into 5 types. The most common type involves the desire by industries to bridge or extrapolate the results of foreign, phase III, clinical studies by conducting the dose-response studies domestically in the form of bridging studies. Until we have more information and have collected experiences in the variations caused by the regional differences as a result of extrinsic as well as intrinsic ethnic factors, we hope and believe that this document will serve to help provide great advancements in the acceptance of foreign clinical data.