Publications by authors named "Kentaro Sakamaki"

115 Publications

QOL assessment after palliative surgery for malignant bowel obstruction caused by peritoneal dissemination of gastric cancer: a prospective multicenter observational study.

Gastric Cancer 2021 Mar 31. Epub 2021 Mar 31.

Department of Surgery, Kobe City Medical Center General Hospital, Kobe, Japan.

Background: Patients with peritoneal dissemination of gastric cancer have poor oral intake caused by malignant bowel obstruction (MBO). Palliative surgery has often been undertaken to improve quality of life (QOL), but few prospective studies on palliative surgery in this patient population have been published.

Patients And Methods: We prospectively investigated the significance of palliative surgery using patient-reported QOL measures. Patients underwent palliative surgery by small intestine/colon resection or small intestine/colon bypass or ileostomy/colostomy for MBO. The primary endpoint was change in QOL assessed at baseline, 14 days, 1 month, and 3 months following palliative surgery using the Euro QoL Five Dimensions (EQ-5D™) questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire gastric cancer module (QLQ-STO22). Secondary endpoints were postoperative improvement in oral intake and surgical complications.

Results: Between April 2013 and March 2018, 63 patients were enrolled from 14 institutions. The mean EQ-5D™ utility index baseline score of 0.6 remained consistent. Gastric-specific symptoms mostly showed statistically significant improvement from baseline. Forty-two patients (67%) were able to eat solid food 2 weeks after palliative surgery and 36 patients (57%) tolerated it for 3 months. The rate of overall morbidity of ≥ grade III according to the Clavien-Dindo classification was 16% (10 patients) and the 30-day postoperative mortality rate was 3.2% (2 patients).

Conclusions: In patients with MBO caused by peritoneal dissemination of gastric cancer, palliative surgery did not improve QOL while improving solid food intake, with an acceptable postoperative morbidity and mortality rate.
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http://dx.doi.org/10.1007/s10120-021-01179-4DOI Listing
March 2021

Sofosbuvir-based therapies associated with regression of liver fibrosis in patients with hepatitis C virus infection: A prospective observational study.

Medicine (Baltimore) 2021 Mar;100(12):e25110

Department of Gastroenterology, Yokohama City University Graduate School of Medicine.

Abstract: Oral direct-acting antiviral (DAA) treatment leads to >95% sustained virological response (SVR) and could be clinically useful in regression of liver fibrosis in chronic hepatitis C virus (HCV) infection. We evaluated if ledipasvir/sofosbuvir or sofosbuvir + ribavirin is associated with regression of fibrosis in HCV patients who achieved SVR.In this prospective cohort study performed at 3 sites in Japan, patients with genotype 1 and genotype 2 were given standard treatment of ledipasvir 90 mg/sofosbuvir 400 mg and sofosbuvir 400 mg + 200-1000 mg/day ribavirin, respectively, for 12 weeks. Liver fibrosis was assessed using Mac-2-binding protein glycosylation isomer (M2BPGi) and other fibrosis markers (platelet count, Fib-4 index, liver stiffness measurement [LSM]) in patients who achieved SVR.A total of 98.1% of (n = 101/103) patients in genotype 1 cohort and 100% (n = 16/16) in the genotype 2 cohort achieved SVR12. Based on per-protocol analysis, M2BPGi levels showed a significant decrease (-2.2  cut-off index [COI], P < .0001) at week 48 after treatment initiation. Forty-three patients showed a significant decrease in Fib-4 index (-1.2, P < .0001), and 44 patients showed improvement in LSM (-5.9 kPa, P < .0001).Achievement of SVR after antiviral therapy was associated with fibrosis regression. M2BPGi correlated well with LSM at week 48 after treatment initiation, supporting the sustainable benefit of HCV therapy.
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http://dx.doi.org/10.1097/MD.0000000000025110DOI Listing
March 2021

Prospective cohort study of febrile neutropenia in breast cancer patients administered with neoadjuvant and adjuvant chemotherapies: CSPOR-BC FN study.

Breast 2021 Apr 16;56:70-77. Epub 2021 Feb 16.

Division of Oncology/Hematology, National Cancer Center Hospital East, Chiba, Japan.

Background: As Asians are more vulnerable to febrile neutropenia (FN) than Caucasians, evaluations of FN incidence and risk factors in Asians are important for the appropriate use of primary pegfilgrastim (PEG-G).

Patients And Methods: Japanese breast cancer patients receiving standard adjuvant chemotherapies were prospectively enrolled in multicenter institutions from August 2015 to July 2017. FN was evaluated from 2 treatment policies: true FN (T-FN): ≥37.5 °C, grade 4 neutropenia, mandatory hospital visit (visiting); surrogate FN (S-FN): ≥37.5 °C, oral antibiotic, no mandatory visit (non-visiting). PEG-G was used at the physicians' discretion. The primary endpoint was FN incidence during all cycles. Multivariate logistic regression analysis was performed to identify T-FN risk factors.

Results: Of 1005 enrolled patients, 980 women treated with FEC, E(A)C, and TC were analyzed. The FN incidence proportions in all patients were 22.5%, 27.5%, and 33.9% for FEC, E(A)C, and TC, respectively. Those of T-FN were 27.7%, 22.4%, and 36.6%; those of S-FN were 17.3%, 32.4%, and 31.5% with more frequent primary PEG-G usage. The relative dose intensity (RDI) of the 3 regimens was ≥0.85 in both groups. In the analysis of risk factors, TC (odds ratio = 2.67), age ≥ 65 years (2.24), and pretreatment absolute neutrophil count (ANC)/1000 μl (0.8) remained significant.

Conclusions: FN incidences were above 20% in the 3 regimens, with TC showing the highest. RDI was maintained at a high level in both visiting and non-visiting groups. Patient-related risk factors were age and pretreatment ANC.
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http://dx.doi.org/10.1016/j.breast.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907535PMC
April 2021

Challenges on Multiple Endpoints in Clinical Trials: An Industry Survey in Japan.

Ther Innov Regul Sci 2020 05 6;54(3):528-533. Epub 2020 Jan 6.

Data Science Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan.

Background: Two issues on clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, relationship between rare events and endpoints, and differences in multiplicity adjustment between regions; and (2) the current practice on multiplicity adjustment and sample size calculation. This article provides a summary of the results of a survey on the first issue.

Methods: The survey was conducted among 63 members of the Japan Pharmaceutical Manufacturers Association from October to November 2017.

Results: Thirty-five companies based in Japan and 12 companies based in other countries, 47 companies in total, responded to the survey. The terms co-primary endpoints, secondary endpoint, and composite endpoint were used in a variety of ways. An endpoint for a clinically most important event that is expected to occur rarely differed between regions. Although the Pharmaceuticals and Medical Devices Agency did not demand multiplicity adjustment, it was considered in clinical trials with multiple endpoints for approval in Japan.

Conclusions: The use of terminology differed from the definition in the Food and Drug Administration guidance and the European Medicines Agency guideline. There remain challenges on a clinically most important event that is expected to occur rarely and multiplicity adjustment in clinical trials with multiple endpoints.
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http://dx.doi.org/10.1007/s43441-019-00084-4DOI Listing
May 2020

Multicentre randomised phase II study of the perioperative administration of flurbiprofen axetil in patients with non-small cell lung cancer: study protocol of the FLAX Study.

BMJ Open 2020 11 30;10(11):e040969. Epub 2020 Nov 30.

Surgery, Yokohama City University, Yokohama, Japan.

Introduction: In patients with non-small cell lung cancer, surgical treatment with postoperative adjuvant chemotherapy is performed. However, the improvement of overall survival achieved by postoperative adjuvant chemotherapy may be insufficient in consideration of the deterioration of quality of life (QOL). Considering the relationships among surgical treatments, inflammation and carcinogenesis, non-steroidal anti-inflammatory drugs (NSAIDs) are a candidate postoperative treatment for preventing recurrence and maintaining QOL. In this study, we investigate the effects of the perioperative administration of flurbiprofen axetil on postoperative recurrence in patients with non-small cell lung cancer.

Methods And Analysis: This study is a multicentre, parallel group, open label, randomised controlled trial. Patients clinically suspected of non-small cell lung cancer are randomly assigned to the flurbiprofen axetil group or the no-NSAIDs group. A total of 420 patients (210 per group) will be registered. The primary analysis will evaluate the treatment effect of flurbiprofen axetil on postoperative recurrence.

Ethics And Dissemination: The study protocol was approved by the Clinical Research Review Board of Saitama Medical University in September 2019 (No. 192002) and will be approved by each institutional review board of all participating institutions before patient enrolment. This study complies with the latest version of the Declaration of Helsinki, Clinical Trial Act and related notifications. Results will be published in a peer-reviewed journal.

Trial Registration Number: Japan Registry of Clinical Trials (jRCTs031190167; Pre-results) (https://jrct.niph.go.jp/).
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http://dx.doi.org/10.1136/bmjopen-2020-040969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705564PMC
November 2020

Reply to authors.

Clin Infect Dis 2020 Oct 26. Epub 2020 Oct 26.

International Medical Department, Hokkaido University Hospital, Sapporo, Japan.

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http://dx.doi.org/10.1093/cid/ciaa1658DOI Listing
October 2020

Drain Placement After Uncomplicated Hepatic Resection Increases Severe Postoperative Complication Rate: A Japanese Multi-institutional Randomized Controlled Trial (ND-trial).

Ann Surg 2021 02;273(2):224-231

Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.

Objective: To assess the clinical impact of a no-drain policy after hepatic resection.

Summary Of Background Data: Previous randomized controlled trials addressing no-drain policy after hepatic resection seem inconclusive because they did not adopt appropriate study design to validate its true clinical impact.

Methods: This unblinded, randomized controlled trial was done at 7 Japanese institutions. Patients undergoing hepatic resection without biliary reconstruction were randomized to either D group or ND group. When the risk of postoperative bile leakage or hemorrhage were considered high, the patients were excluded during the operation. Primary endpoint was the postoperative complication of C-D grade 3 or higher within 90 postoperative days. A noninferiority of ND group to D group was assessed, and if it was confirmed, a superiority was assessed.

Results: Between May 2015 and July 2017, a total of 400 patients were finally included in the per-protocol set analysis: 199 patients in D group and 201 patients in ND group. Intraoperatively, 37 patients were excluded from the final enrollment because of high risk of bile leakage or hemorrhage. Postoperative complication rate of C-D grade 3 or higher was 8.0% (16/199) in the D group and 2.5% (5/201) in the ND group. The risk difference was -5.5% (95% confidence interval: -9.9% to -1.2%) and fulfilled the prescribed noninferiority margin of 4%. No postoperative mortality was experienced in both groups. Bile leakage was diagnosed in 8.0% (16/199) of the D group and none in the ND group (P < 0.001). In none of the subgroups classified based on 8 potentially relevant factors, drain placement was favored in terms of C-D grade 3 or higher complication.

Conclusions: Drains should not be placed after uncomplicated hepatic resections.
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http://dx.doi.org/10.1097/SLA.0000000000004051DOI Listing
February 2021

Primary results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 and docetaxel/cisplatin/S-1 as neoadjuvant chemotherapy for advanced gastric cancer.

Ann Gastroenterol Surg 2020 Sep 16;4(5):540-548. Epub 2020 Jul 16.

Hiroshima City Asa Hospital Hiroshima Japan.

Aim: Neoadjuvant chemotherapy (NAC) is promising to improve the survival of resectable gastric cancer. However, suitable regimen and treatment duration for NAC have not yet been established.

Methods: We conducted a randomized phase II trial to compare two and four courses of neoadjuvant S-1/cisplatin (SC) and S-1/cisplatin/docetaxel(DCS) using a two-by-two factorial design for locally resectable advanced gastric cancer. Patients with M0 and either T4 or T3 in case of junctional cancer or scirrhous-type cancer received two or four courses of SC or DCS. Then, patients underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was 3-year overall survival. The planned sample size was 120 eligible patients.

Results: Between October 2011 and September 2014, 132 patients were assigned to CS (n = 66; 33 in 2-courses and 33 in 4-courses) and DCS (n = 66; 33 in 2-courses and 33 in 4-courses). The 3-year OS was 58.1% in CS and 60.0% in DCS with hazard ratio of 0.80 (95% CI, 0.48-1.34), while it was 53.1% in the two courses and 65.0% in the four courses with hazard ratio of 0.72 (95% CI, 0.43-1.22). In the survival analysis by duration in each regimen, the 3-year OS was 58.1% for both two and four courses in CS, while it was 48.5% for two courses of DCS and 71.9% for four courses of DCS.

Conclusions: Considering high 3-year OS, four courses DCS has a value to be tested in a future phase III study to confirm superiority of neoadjuvant chemotherapy for locally advanced gastric cancer.
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http://dx.doi.org/10.1002/ags3.12352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511564PMC
September 2020

Mass screening of asymptomatic persons for SARS-CoV-2 using saliva.

Clin Infect Dis 2020 Sep 25. Epub 2020 Sep 25.

International Medical Department, Hokkaido University Hospital, Sapporo, Japan.

Background: COVID-19 has rapidly evolved to become a global pandemic due largely to the transmission of its causative virus through asymptomatic carriers. Detection of SARS-CoV-2 in asymptomatic people is an urgent priority for the prevention and containment of disease outbreaks in communities. However, few data are available in asymptomatic persons regarding the accuracy of PCR testing. Additionally, although self-collected saliva has significant logistical advantages in mass screening, its utility as an alternative specimen in asymptomatic persons is yet to be determined.

Methods: We conducted a mass-screening study to compare the utility of nucleic acid amplification, such as reverse transcriptase polymerase chain reaction (RT-PCR) testing, using nasopharyngeal swabs (NPS) and saliva samples from each individual in two cohorts of asymptomatic persons: the contact tracing cohort and the airport quarantine cohort.

Results: In this mass-screening study including 1,924 individuals, the sensitivity of nucleic acid amplification testing with nasopharyngeal and saliva specimens were 86% (90%CI:77-93%) and 92% (90%CI:83-97%), respectively, with specificities greater than 99.9%. The true concordance probability between the nasopharyngeal and saliva tests was estimated at 0.998 (90%CI:0.996-0.999) on the estimated airport prevalence at 0.3%. In positive individuals, viral load was highly correlated between NPS and saliva.

Conclusion: Both nasopharyngeal and saliva specimens had high sensitivity and specificity. Self-collected saliva is a valuable specimen to detect SARS-CoV-2 in mass screening of asymptomatic persons.
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http://dx.doi.org/10.1093/cid/ciaa1388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543374PMC
September 2020

Reply by Authors.

J Urol 2020 11 4;204(5):1011. Epub 2020 Sep 4.

Bristol Urological Institute, North Bristol NHS Trust, Southmead Hospital, Bristol, United Kingdom.

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http://dx.doi.org/10.1097/JU.0000000000001149.02DOI Listing
November 2020

Survival analysis of a prospective multicenter observational study on surgical palliation among patients receiving treatment for malignant gastric outlet obstruction caused by incurable advanced gastric cancer.

Gastric Cancer 2021 Jan 13;24(1):224-231. Epub 2020 Aug 13.

Department of Surgical Oncology, School of Medicine, Graduate School of Medicine, Gifu University, Gifu, Japan.

Background: We had previously reported that surgical palliation could maintain quality of life (QOL) while improving solid food intake among patients with malignant gastric outlet obstruction (GOO) caused by advanced gastric cancer. The present study aimed to perform a survival analysis according to the patients' QOL to elucidate its impact on survival.

Methods: Patients with GOO who underwent either palliative gastrectomy or gastrojejunostomy were included in this study. A validated QOL instrument (EQ-5D) was used to assess QOL at baseline and 2 weeks, 1 month, and 3 months following surgical palliation. Postoperative improvement in oral intake was also evaluated using the GOO scoring system (GOOSS). Thereafter, univariate and multivariate survival analyses were performed to determine independent prognostic factors.

Results: The median survival time of the 104 patients included herein was 11.30 months. Patients who received postoperative chemotherapy, PS 0/1, baseline EQ-5D ≥ 0.75, improved or stable EQ-5D, and improved oral intake expressed as GOOSS = 3 had significantly better survival. Multivariate analysis identified postoperative chemotherapy, a better baseline PS, a better baseline EQ5D, improved or stable EQ5D scores, and improved oral intake 3 months after surgical palliation as independent prognostic factors.

Conclusion: Apart from preoperative PS and postoperative chemotherapy, the present study identified better baseline QOL, improvement in postoperative QOL, and improvement in oral intake as prognostic factors among patients who underwent palliative surgery for advanced gastric cancer with GOO.
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http://dx.doi.org/10.1007/s10120-020-01114-zDOI Listing
January 2021

The Role of Multiparametric US of the Liver for the Evaluation of Nonalcoholic Steatohepatitis.

Radiology 2020 09 23;296(3):532-540. Epub 2020 Jun 23.

From the Department of Gastroenterology and Hepatology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan (K. Sugimoto, H.T., M.A., Y.Y., Y.K., T.I.); Department of Pathology, Jichi Medical University, Tochigi, Japan (H.O.); Center for Data Science, Yokohama City University, Kanagawa, Japan (K. Sakamaki); Department of Gastroenterology and Hepatology, International University of Health and Welfare, Sanno Hospital, Tokyo, Japan (F.M.); and Department of Electrical, Electronic and Computer Engineering, Faculty of Engineering, Gifu University, Gifu, Japan (T.H.).

Background Nonalcoholic steatohepatitis (NASH) is diagnosed with histopathologic testing, but noninvasive surrogate markers are desirable for screening patients who are at high risk of NASH. Purpose To investigate the diagnostic performance of dispersion slope, attenuation coefficient, and shear-wave speed measurements obtained using two-dimensional (2D) shear-wave elastography (SWE) in assessing inflammation, steatosis, and fibrosis and in the noninvasive diagnosis of NASH in patients suspected of having nonalcoholic fatty liver disease (NAFLD). Materials and Methods This prospective study collected data from 120 consecutive adults who underwent liver biopsy for suspected NAFLD and were enrolled between April 2017 and March 2019. Three US parameters (dispersion slope [(m/sec)/kHz], attenuation coefficient [dB/cm/MHz], and shear-wave speed [in meters per second]) were measured using a 2D SWE system immediately before biopsy. The biopsy specimens were scored by one expert pathologist according to the Nonalcoholic Steatohepatitis Clinical Research Network criteria (119 participants underwent a histologic examination). Diagnostic performance was assessed using the area under the receiver operating characteristic curve (AUC) for the categories of inflammation, steatosis, and fibrosis. Results One hundred eleven adults (mean age, 53 years ± 18 [standard deviation]; 57 men) underwent a US examination. Dispersion slope enabled the identification of lobular inflammation, with an AUC of 0.95 (95% confidence interval [CI]: 0.91, 0.10) for an inflammation grade greater than or equal to A1 (mild), 0.81 (95% CI: 0.72, 0.89) for an inflammation grade greater than or equal to A2 (moderate), and 0.85 (95% CI: 0.74, 0.97) for an inflammation grade equal to A3 (marked). Attenuation coefficient enabled the identification of steatosis, with an AUC of 0.88 (95% CI: 0.80, 0.97) for steatosis grade greater than or equal to S1 (mild), 0.86 (95% CI: 0.79, 0.93) for steatosis grade greater than or equal to S2 (moderate), and 0.79 (95% CI: 0.68, 0.89) for steatosis grade equal to S3 (severe). Shear-wave speed enabled the identification of fibrosis, with an AUC of 0.79 (95% CI: 0.69, 0.88) for fibrosis stage greater than or equal to F1 (portal fibrosis), 0.88 (95% CI: 0.82, 0.94) for fibrosis stage greater than or equal to F2 (periportal fibrosis), 0.90 (95% CI: 0.84, 0.96) for fibrosis stage greater than or equal to F3 (septal fibrosis), and 0.95 (95% CI: 0.91, 0.99) for fibrosis stage equal to F4 (cirrhosis). The combination of dispersion slope, attenuation coefficient, and shear-wave speed showed an AUC of 0.81 (95% CI: 0.71, 0.91) for the diagnosis of NASH. Conclusion Dispersion slope, attenuation coefficient, and shear-wave speed were found to be useful for assessing lobular inflammation, steatosis, and fibrosis, respectively, in participants with biopsy-proven nonalcoholic fatty liver disease. © RSNA, 2020 .
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http://dx.doi.org/10.1148/radiol.2020192665DOI Listing
September 2020

Grading Severity and Bother Using the International Prostate Symptom Score and International Consultation on Incontinence Questionnaire Male Lower Urinary Tract Symptoms Score in Men Seeking Lower Urinary Tract Symptoms Therapy.

J Urol 2020 Nov 29;204(5):1003-1011. Epub 2020 May 29.

Bristol Urological Institute, North Bristol NHS Trust, Southmead Hospital, Bristol, United Kingdom.

Purpose: We established severity banding ranges, bother assessment and key item content in principal patient reported outcomes measures in men seeking therapy for lower urinary tract symptoms.

Materials And Methods: Data for International Prostate Symptom Score (I-PSS) and International Consultation on Incontinence Questionnaire Male Lower Urinary Tract Symptoms (ICIQ-MLUTS) were derived from a study evaluating 820 men at 26 United Kingdom hospitals. ROC curves were used to establish severity bandings.

Results: Classification tree showed that thresholds between mild-moderate and moderate-severe severity bands were 15 and 27 for I-PSS, 16 and 26 for ICIQ-MLUTS/severity, and 22 and 81 for ICIQ-MLUTS/bother, respectively. Highest area under the ROC curve and lowest Akaike's information criteria of univariate logistic regression indicated that ICIQ-MLUTS/bother was more related to global quality of life than were I-PSS and ICIQ-MLUTS/severity. The symptoms affecting I-PSS-quality of life (QoL) were only fully identified by ICIQ-MLUTS, because 2 key symptoms (urinary incontinence and post-micturition dribble) are not measured by I-PSS. ICIQ-MLUTS demonstrated that bother of some lower urinary tract symptoms is disproportionate to severity, and that persisting high bother levels following surgery are more likely due to storage (18% to 25%) and post-voiding (18% to 28%) lower urinary tract symptoms than voiding lower urinary tract symptoms (5% to 13%). Symptom improvement after surgery was uncertain if baseline I-PSS-QoL score was less than 3.

Conclusions: The severity threshold scores were measured for the 2 key lower urinary tract symptoms patient reported outcomes measures, and the results indicate suitable categories of symptom severity for use in men referred for urological care. The ICIQ-MLUTS measures all the lower urinary tract symptoms affecting quality of life and includes individual symptom bother scores.
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http://dx.doi.org/10.1097/JU.0000000000001149DOI Listing
November 2020

The efficacy of sequential second-line endocrine therapies (ETs) in postmenopausal estrogen receptor-positive and HER2-negative metastatic breast cancer patients with lower sensitivity to initial ETs.

Breast Cancer 2020 Sep 11;27(5):973-981. Epub 2020 May 11.

Department of Breast and Endocrine Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.

Purpose: Second-line endocrine therapy (ET) for estrogen receptor (ER)-positive and human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC) is offered based on the response to first-line ET. However, no clinical trials have evaluated the efficacy and safety of secondary ETs in patients with poor responses to initial ET. This study evaluated the efficacy of second-line ET in ER-positive and HER2-negative postmenopausal MBC patients with low or very low sensitivity to initial ET.

Methods: This multicenter prospective observational cohort study evaluated the response of 49 patients to second-line ETs in postmenopausal MBC patients with low or very low sensitivity to initial ET. The primary endpoint was the clinical benefit rate (CBR) for 24 weeks.

Results: Of the 49 patients assessed, 40 (82%) received fulvestrant in the second line, 5 (10%) received selective estrogen receptor modulators, 3 (6%) received aromatase inhibitors (AIs) alone, and 1 received everolimus with a steroidal AI. The overall CBR was 44.9% [90% confidence interval (CI): 34.6-57.6, p = 0.009]; CBR demonstrated similar significance across the progesterone receptor-positive (n = 39, 51.3%, 90% CI: 39.6-65.2, p = 0.002), very low sensitivity (n = 17, 58.8%, 90% CI: 42.0-78.8, p = 0.003), and non-visceral metastases (n = 25, 48.0%, 90% CI: 34.1-65.9, p = 0.018) groups. The median progression-free survival was 7.1 months (95% CI: 5.6-10.6).

Conclusion: Second-line ET might be a viable treatment option for postmenopausal patients with MBC with low and very low sensitivity to initial ET. Future studies based on larger and independent cohorts are needed to validate these findings.
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http://dx.doi.org/10.1007/s12282-020-01095-yDOI Listing
September 2020

Impact of the micropapillary component on the timing of recurrence in patients with resected lung adenocarcinoma.

Eur J Cardiothorac Surg 2020 11;58(5):1010-1018

Department of Surgery, Yokohama City University, Yokohama, Japan.

Objectives: A micropapillary (MIP) component is reported to be associated with a poor prognosis in patients with completely resected lung adenocarcinoma. The purpose of this study was to investigate the impact of an MIP component on the timing of postoperative recurrence using hazard curves.

Methods: A total of 1289 patients with lung adenocarcinoma who underwent complete pulmonary resection from 2008 to 2015 were studied. Hazard curves representing the changes in hazard over time were evaluated.

Results: The hazard curve displayed an initial wide, high peak within 1 year after surgery in patients with an MIP component, whereas some gentle peaks around the second year were noted in patients without an MIP component. The presence of an MIP component was associated with a worse recurrence-free survival and an early recurrence in stage I patients but not in advanced-stage patients. In multivariable Cox regression, the presence of an MIP component and lymph node metastasis, pleural invasion and gender were associated with a poor prognosis.

Conclusions: Patients with an MIP component retained a high risk of early recurrence after surgery, and the risk for recurrence persisted over the long term. Even after complete resection in stage I lung adenocarcinoma patients, an MIP component remains correlated with a poor prognosis.
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http://dx.doi.org/10.1093/ejcts/ezaa138DOI Listing
November 2020

Multiplicity Adjustment and Sample Size Calculation in Clinical Trials with Multiple Endpoints: An Industry Survey of Current Practices in Japan.

Ther Innov Regul Sci 2020 09 6;54(5):1097-1105. Epub 2020 Feb 6.

Data Science Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan.

Background: Two issues in clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, the relationship between rare events and endpoints, and the differences in multiplicity adjustment between regions, and (2) the current practice on multiplicity adjustment and sample size calculation. This article summarizes the results of the survey on the second issue.

Methods: Eligible trials for this survey fulfilled the following conditions: (1) confirmatory phase 3 trial; (2) use of multiple primary endpoints, co-primary endpoints, key secondary endpoint(s) or composite endpoint(s); (3) inclusion of Japanese participants; and (4) protocols created in 2010 or later. The survey was conducted at member companies of the Japan Pharmaceutical Manufacturers Association from October 2017 to November 2017.

Results: Useable responses were obtained from 78 trials in 13 companies based in Japan and 9 companies based in other countries. The Bonferroni procedure was mostly used in clinical trials with multiple primary endpoints, while multiple testing procedures that consider a hierarchy of endpoints or a structure of hypotheses were used in clinical trials with key secondary endpoint(s). In sample size calculation, we can consider the probability of study success, such as the probability of statistical significance in at least one comparison of primary endpoints; however, other probabilities were also considered. This survey reveals that multiplicity adjustment and the correlation of endpoints were not always considered in sample size calculation.

Conclusions: In clinical trials with multiple endpoints, clinical importance was considered when determining multiple testing procedures. Challenges remain with the definition of power, the consideration of multiple testing procedures and the correlation between endpoints in sample size calculation.
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http://dx.doi.org/10.1007/s43441-020-00126-2DOI Listing
September 2020

Randomized phase II study of chemoradiotherapy with cisplatin + S-1 versus cisplatin + pemetrexed for locally advanced non-squamous non-small cell lung cancer: SPECTRA study.

Lung Cancer 2020 03 10;141:64-71. Epub 2020 Jan 10.

Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.

Objectives: SPECTRA is a multicenter, randomized phase II study of chemotherapy with cisplatin (CDDP) plus S-1 versus CDDP plus pemetrexed (PEM) in combination with thoracic radiotherapy (TRT) for locally advanced non-squamous non-small cell lung cancer, in order to determine which of these two regimens might be preferable for comparison with standard therapies in a future phase III study.

Materials And Methods: Patients were randomly assigned to receive CDDP + S-1 (CDDP 60 mg/m on day 1 and S-1 80 mg/m2 on days 1-14, every 4 weeks, up to 4 cycles) or CDDP + PEM (CDDP 75 mg/m + PEM 500 mg/m on day 1, every 3 weeks, up to 4 cycles) combined with TRT (60 Gy in 30 fractions). The primary endpoint was the 2-year progression-free survival (PFS) rate. The sample size had been set at 100 patients.

Results: A total of 102 patients were randomized to receive CDDP + S-1 or CDDP + PEM (CDDP + S-1, n = 52; CDDP + PEM, n = 50) between January 2013 and October 2016. The results in the CDDP + S1 group and CDDP + PEM group were as follows: completion rates of TRT (60 Gy)/chemotherapy (4 cycles) was 92 %/73 % and 98 %/86 %, respectively; the response rates were 60 % and 64 %, respectively; median PFS after a median follow-up of 32.1 months, 12.7/13.8 months (hazard ratio [HR] = 1.16; 95 % confidence interval [CI], 0.73-1.84); 2-year PFS rate, 36.5 % (95 % CI, 23.5-49.6)/32.1 % (95 %CI, 18.9-45.4); median OS, 48.3/59.1 months (HR = 1.05; 95 %CI, 0.58-1.90); 2-year OS rate, 69.2 % (95 %CI, 56.7-81.8)/66.4 % (95 %CI, 53.0-79.9); Grade 3 toxicities: febrile neutropenia (12 %/2 %), anorexia (8 %/16 %), diarrhea (8 %/0 %), esophagitis (6 %/8 %), and neutropenia (35 %/50 %); Grade 2 or worse radiation pneumonitis, 15 % (8 patients)/4 % (2 patients).

Conclusion: The 2-year PFS rate in the CDDP + S-1 arm was higher than that in the CDDP + PEM arm. Both treatments were safe, with manageable toxicities.
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http://dx.doi.org/10.1016/j.lungcan.2020.01.008DOI Listing
March 2020

Impact of the Gene Expression on Outcomes in Stage II/III Gastric Cancer Patients Who Received Adjuvant S-1 Chemotherapy.

In Vivo 2020 Jan-Feb;34(1):461-467

Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan

Background/aim: Endothelial cell-specific molecule-1 (ESM-1) is a soluble proteoglycan which has important role in various biological events. We investigated the impact of the ESM-1 expression in cancer tissues on outcomes in stage II/III gastric cancer patients who received adjuvant S-1 chemotherapy.

Patients And Methods: The ESM-1 mRNA expression in cancerous tissues and adjacent normal mucosa from 253 patients was measured. The associations between the ESM-1 gene expression and the survival and clinicopathological features were investigated.

Results: A significant association was observed between high ESM-1 expression and undifferentiated adenocarcinoma. The overall survival curve was significantly lower in patients with high ESM-1 expression than in those with low expression (p=0.005). High ESM-1 expression was a significant independent prognosticator (HR=2.291, p=0.007).

Conclusion: ESM-1 gene expression in cancerous tissues is an important prognosticator in stage II/III gastric cancer patients who received adjuvant S-1 chemotherapy.
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http://dx.doi.org/10.21873/invivo.11796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984110PMC
June 2020

High gamma-glutamyl hydrolase and low folylpolyglutamate synthetase expression as prognostic biomarkers in patients with locally advanced gastric cancer who were administrated postoperative adjuvant chemotherapy with S-1.

J Cancer Res Clin Oncol 2020 Jan 21;146(1):75-86. Epub 2019 Nov 21.

Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Kanagawa, 241-8515, Japan.

Purpose: The enzymes gamma-glutamyl hydrolase (GGH) and folylpolyglutamate synthetase (FPGS) regulate intracellular folate concentrations needed for cell proliferation, DNA synthesis, and repair. High GGH expression affects 5-FU thymidylate synthase (TS) inhibition and is a risk factor for various malignancies. Here, the clinical significance of GGH and FPGS expression was investigated in Stage II/III gastric cancer patients undergoing postoperative adjuvant chemotherapy with S-1.

Methods: Surgical specimens of cancer tissue and adjacent normal mucosa, obtained from 253 patients with previously untreated gastric cancer, were examined. GGH and FPGS mRNA expression was measured by qPCR to evaluate their clinicopathological significance in gastric cancer patients after curative resection.

Results: While FPGS expression showed no significant differences between the cancerous and normal samples, GGH expression was higher in cancer tissue than in adjacent normal mucosa. High GGH expression was correlated with age, histological type, and vascular invasion. Overall survival (OS) of patients with high GGH mRNA expression was significantly poorer than of patients with low GGH expression. Multivariate analysis showed that high GGH expression was an independent prognostic factor of OS (HR: 2.58, 95% CI 1.29-5.16). Patients who received S-1 adjuvant treatment showed a significantly poor OS between high GGH/low FPGS and low GGH/high FPGS. Patients without adjuvant treatment showed no significant difference.

Conclusion: GGH expression was significantly higher in gastric cancer tissue than in adjacent normal mucosa. High GGH and low FPGS expression is a useful independent predictor of poor outcomes in stage II/III gastric cancer patients undergoing postoperative adjuvant chemotherapy with S-1.
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http://dx.doi.org/10.1007/s00432-019-03087-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942012PMC
January 2020

Correlation between the macroscopic severity of Crohn's disease in resected intestine and bowel wall thickness evaluated by water-immersion ultrasonography.

Scand J Gastroenterol 2019 Nov 26;54(11):1331-1338. Epub 2019 Oct 26.

Inflammatory Bowel Disease Center, Yokohama City University Medical Center, Yokohama, Japan.

Transabdominal ultrasonography is a common and accurate tool for managing Crohn's disease (CD); however, the significance of the resulting data is poorly understood. This study was performed to determine the association between bowel wall thickness evaluated by water-immersion ultrasonography and macroscopic severity, namely, refractory inflammation and subsequent fibrosis in CD surgical specimens. We retrospectively evaluated 100 segments of colon and small intestine from 27 patients with CD. The resected specimens were placed in saline postoperatively, and bowel wall thickness was measured by water-immersion ultrasonography and compared with macroscopic findings. Correlations between bowel wall thickness and macroscopic findings were assessed using analysis of variance and receiver operating characteristic curves. According to the progression of macroscopic severity, the mean bowel wall thickness was increased as follows: macroscopically intact: 4.1 mm, longitudinal ulcer scars: 5.4 mm, longitudinal open ulcers: 6.0 mm, large ulcers: 6.4 mm, cobblestone-like lesions: 7.1 mm, and fibrotic strictures: 7.4 mm. For all lesions except longitudinal ulcer scars, the bowel wall thickness was significantly thicker than that of macroscopically-intact areas ( < .001). According to receiver operating characteristic curves, bowel wall thickness >4.5 mm was associated with CD lesions, and thickness >5.5 mm was associated with more severe lesions. The bowel wall thickness of CD lesions was evaluated by water-immersion ultrasonography correlated with macroscopic disease severity.
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http://dx.doi.org/10.1080/00365521.2019.1683224DOI Listing
November 2019

Atypical femoral fracture in patients with bone metastasis receiving denosumab therapy: a retrospective study and systematic review.

BMC Cancer 2019 Oct 22;19(1):980. Epub 2019 Oct 22.

Department of Medical Oncology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan.

Background: While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy.

Methods: To analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions.

Results: The study population consisted of 277 patients who had received a median of 10 doses (range, 1-79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77-4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF.

Conclusions: We found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.
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http://dx.doi.org/10.1186/s12885-019-6236-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805596PMC
October 2019

Sphenoid sinus development in patients with acquired middle ear cholesteatoma.

Auris Nasus Larynx 2020 Jun 17;47(3):391-400. Epub 2019 Oct 17.

Department of Otorhinolaryngology, Head and Neck Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.

Objective: In this study, we examine the relationship between developmental insufficiency of mastoid air cells and abnormal morphology of the paranasal sinuses in patients with chronic otitis media (COM) and acquired middle ear cholesteatoma (AMEC) using precise image assessment, in order to evaluate whether the anatomical features of paranasal sinuses has any impact on the pathogenesis in COM and AMEC.

Methods: A total of 127 patients, including 45 COM patients and 82 AMEC patients, were enrolled for this study. The existence of nasal septal deviation, the existence of paranasal sinus opacification, the modified Lund-Mackay score, the diameters of the paranasal sinuses, the Vidic classification, mastoid development, and cranial size were assessed by CT examination. A further 76 adult patients who underwent high-resolution CT imaging of their skull bone for other diseases were enrolled as the control.

Results: The AMEC group showed a significantly shorter sphenoid length (P < 0.01) and lower Vidic classification score (P < 0.01) compared to the control group in this study. In addition, we observed that patients with AMEC had less pneumatization of the mastoid air cells compared to the control individuals, and that the sphenoid length of the poor MC score group was significantly shorter than that of the good MC score group.

Conclusion: Our results suggested that the developmental deficiency in sphenoid length caused by long-standing pediatric rhinosinusitis might indicate the potential of chronic middle ear inflammation in childhood and impact the pneumatization of mastoid air cells. Therefore, chronic rhinosinusitis during the childhood and adolescence might play a role in the pathophysiology of AMEC.
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http://dx.doi.org/10.1016/j.anl.2019.09.008DOI Listing
June 2020

Comprehensive biomarker analyses identifies RNA expression and thymidylate synthase 5'UTR SNP as predictors of benefit from S-1 adjuvant chemotherapy in Japanese patients with stage II/III gastric cancer.

J Cancer 2019 28;10(21):5130-5138. Epub 2019 Aug 28.

Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.

: A comprehensive molecular analysis was conducted to identify prognostic and predictive markers for adjuvant S-1 chemotherapy in stage II/III Japanese gastric cancer (GC) patients and to evaluate their potential suitability for alternative cytotoxic or targeted drugs. : We investigated genetic polymorphisms of enzymes potentially involved in 5-fluoruracil (5-FU) metabolism as well as platinum resistance, previously identified genomic subtypes potentially predicting 5-FU benefit, and mRNA expression levels of receptor tyrosine kinases and as potential treatment targets in a single institution cohort of 252 stage II/III GC patients treated with or without S-1 after D2 gastrectomy. : 88% and 62% GC had a potentially 5-FU sensitive phenotype by SNP analyses of 3'UTR, and 5'UTR, respectively. 24%, 46%, 40%, 5%, and 44% GC had a potentially platinum sensitive phenotype by SNP analyses of rs11615, rs3212986, , and , respectively. High , or mRNA expression was observed in 49%, 66%, 72%, and 54% GC, respectively. High expression was the only significant prognosticator (HR=3.912, 95%CI: 1.706-8.973, p=0.0005). High (p=0.031), low (p=0.124), high (p=0.165) RNA expression, and 5'UTR subtype 2R/2R, 2R/3C, or 3C (p=0.058) were significant independent predictors for S-1 resistance. : The present study suggests that platinum-based or RTK targeted agents could be alternative treatment options for a substantial subgroup of Japanese GC patients currently treated with S-1. , and 5'UTR SNP appear to be promising predictive markers for S-1 resistance warranting validation in an independent GC series.
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http://dx.doi.org/10.7150/jca.34741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775596PMC
August 2019

Clinical Significance of Gene Expression in Cancerous Tissue in Patients With Gastric Cancer.

Anticancer Res 2019 Oct;39(10):5715-5720

Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan

Background/aim: The PRKCI gene encodes Protein kinase C iota. The overexpression of protein kinase C iota is associated with poor outcomes in patients with gastric and other cancers, but the role of the PRKCI gene in gastric cancer is not fully understood. Thus, we evaluated the clinical significance of PRKCI gene expression in gastric cancer.

Materials And Methods: PRKCI mRNA expression levels in cancerous tissues and adjacent normal mucosa from 398 patients with gastric cancer were measured. Relationships between PRKCI gene expression and clinicopathological characteristics and outcomes were examined.

Results: Overall survival was lower in patients with a high expression of PRKCI than in those with low expression (p=0.016). No other relationships were observed. A high PRKCI expression was found to be an independent prognostic factor (p=0.036, HR=1.44, 95%CI=1.02-2.02).

Conclusion: PRKCI gene expression in cancerous tissue might be a useful prognostic factor in patients with gastric cancer after gastrectomy.
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http://dx.doi.org/10.21873/anticanres.13771DOI Listing
October 2019

Incidence of cancer-associated thromboembolism in Japanese gastric and colorectal cancer patients receiving chemotherapy: a single-institutional retrospective cohort analysis (Sapporo CAT study).

BMJ Open 2019 08 21;9(8):e028563. Epub 2019 Aug 21.

Department of Gastroenterology and Hepatology, Hokkaido University, Sapporo, Japan.

Objective: Few data regarding the incidence of cancer-associated thromboembolism (TE) are available for Asian populations. We investigated the incidence of TE (TEi) and its risk factors among gastric and colorectal cancer (GCC) patients received chemotherapy in a daily practice setting.

Design: A retrospective cohort study.

Setting: A single-institutional study that used data from Sapporo City General Hospital, Japan, on patients treated between January 2008 and May 2015.

Participants: Five hundred Japanese GCC patients who started chemotherapy from January 2008 to May 2015.

Primary And Secondary Outcome Measures: TE was diagnosed by reviewing all the reports of contrast-enhanced CT performed during the follow-up period. All types of thrombosis detected by CT or additional imaging tests, such as venous TE, arterial TE and cerebral infarction, were defined as TE. Medical records of all identified patients were reviewed and potential risk factors for TE, including clinicopathological backgrounds, were collected. We defined the following patients as 'active cancer'; patients with unresectable advanced GCC, cancer recurrence during or after completing adjuvant chemotherapy and/or presence of other malignant tumours.

Results: Of the 500 patients, 70 patients (14.0%) developed TE during the follow-up period. TEi was 9.2% and 17.3% in GCC patients, 18.1% and 3.5% in active and non-active cancer patients, and 24.0% and 12.9% in multiple and single primary, respectively. Multivariate logistic regression analysis showed that colorectal cancer (CRC) (OR 2.371; 95% CI 1.328 to 4.233), active cancer (OR 7.593; 95% CI 2.950 to 19.543) and multiple primary (OR 2.527; 95% CI 1.189 to 5.370) were independently associated with TEi.

Conclusion: TEi was 14.0% among Japanese GCC patients received chemotherapy, and was significantly higher among patients with CRC, active cancer and multiple primary than among those with gastric cancer, non-active cancer and single primary, respectively.

Trial Registration Number: UMIN000018912.
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http://dx.doi.org/10.1136/bmjopen-2018-028563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707673PMC
August 2019

Challenges on Multiple Endpoints in Clinical Trials: An Industry Survey in Japan.

Ther Innov Regul Sci 2019 Jun 18:2168479019855994. Epub 2019 Jun 18.

3 Data Science Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan.

Background: Two issues on clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, relationship between rare events and endpoints, and differences in multiplicity adjustment between regions; and (2) the current practice on multiplicity adjustment and sample size calculation. This article provides a summary of the results of a survey on the first issue.

Methods: The survey was conducted among 63 members of the Japan Pharmaceutical Manufacturers Association from October to November 2017.

Results: Thirty-five companies based in Japan and 12 companies based in other countries, 47 companies in total, responded to the survey. The terms , , and were used in a variety of ways. An endpoint for a clinically most important event that is expected to occur rarely differed between regions. Although the Pharmaceuticals and Medical Devices Agency did not demand multiplicity adjustment, it was considered in clinical trials with multiple endpoints for approval in Japan.

Conclusions: The use of terminology differed from the definition in the Food and Drug Administration guidance and the European Medicines Agency guideline. There remain challenges on a clinically most important event that is expected to occur rarely and multiplicity adjustment in clinical trials with multiple endpoints.
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http://dx.doi.org/10.1177/2168479019855994DOI Listing
June 2019

Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer.

Int J Clin Oncol 2020 Jan 15;25(1):1-42. Epub 2019 Jun 15.

Tokyo Medical and Dental University, Tokyo, Japan.

The number of deaths from colorectal cancer in Japan continues to increase. Colorectal cancer deaths exceeded 50,000 in 2016. In the 2019 edition, revision of all aspects of treatments was performed, with corrections and additions made based on knowledge acquired since the 2016 version (drug therapy) and the 2014 version (other treatments). The Japanese Society for Cancer of the Colon and Rectum guidelines 2019 for the treatment of colorectal cancer (JSCCR guidelines 2019) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment and to deepen mutual understanding between healthcare professionals and patients by making these guidelines available to the general public. These guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. Controversial issues were selected as clinical questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSCCR guidelines 2019.
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http://dx.doi.org/10.1007/s10147-019-01485-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946738PMC
January 2020

Irreversible Electroporation versus Radiofrequency Ablation: Comparison of Systemic Immune Responses in Patients with Hepatocellular Carcinoma.

J Vasc Interv Radiol 2019 Jun;30(6):845-853.e6

Department of Gastroenterology and Hepatology, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan.

Purpose: Irreversible electroporation (IRE) differs from thermal radiofrequency (RF) ablation, especially in terms of the reparative process in the ablation zone induced. To elucidate this, the systemic immune responses after 2 mechanistically different types of ablation (IRE and RF ablation) were evaluated in patients with hepatocellular carcinoma (HCC).

Materials And Methods: Twenty-one patients with HCC who underwent either RF ablation (n = 11) or IRE (n = 10) were studied. Peripheral blood samples were collected from all patients at 4 timepoints: before ablation, within 1 hour after ablation, 1 day after ablation, and 4 days after ablation. The phenotypes and functions of immune cells in peripheral blood and serum levels of cytokines and chemokines were monitored and analyzed using the mixed-effects model. Follow-up radiological images were also obtained to assess temporal changes in the ablation zone.

Results: The most significant difference was seen in the levels of macrophage migration inhibitory factor (MIF) in the IRE group compared to the RF ablation group (P = .0011): the serum levels of MIF in the IRE group significantly increased immediately after IRE and then rapidly decreased to the pre-ablation range 1 day after IRE, but, in contrast, no consistent trend was observed in the RF ablation group. The axial diameter (P = .0009) and area (P = .0192) of the ablation zone of IRE were significantly smaller than those of RF ablation 1 year after ablation.

Conclusions: IRE was found to be associated with a significant early increase in MIF levels, which may facilitate the early reparative process and result in significant shrinkage of the ablation zone.
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http://dx.doi.org/10.1016/j.jvir.2019.03.002DOI Listing
June 2019

Effects of perioperative Eicosapentaenoic acid-enriched oral nutritional supplement on lean body mass after total gastrectomy for gastric cancer.

J Cancer 2019 29;10(5):1070-1076. Epub 2019 Jan 29.

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

: In previous our phase III study to compare perioperative standard diet with or without Eicosapentaenoic acid (EPA)-enriched oral nutritional supplement (EPA-ON), additional EPA-ON did not contribute to prevent body weight loss after total gastrectomy. This report clarified whether EPA-ON could prevent loss of lean body mass (LBM) after total gastrectomy, a key secondary endpoint, in our phase III trial. : This phase III study was designed as multicenter, open-label, superiority, randomized trial to confirm the preventive effect of EPA-ON body weight loss after total gastrectomy for gastric cancer. Eligible patients were randomized to either Standard-diet group or EPA-ON group by a centralized dynamic method. Standard-diet group was given no additional nutritional supplementation perioperatively (standard diet), while EPA-ON group was given an EPA-enriched supplement (ProSure, Abbott Japan, Tokyo, Japan) in addition to their standard diet. This supplement included 600 kcal with 2.2 g/day of EPA. For both groups, patients underwent total gastrectomy with Roux-en Y reconstruction. : A total of 123 patients (Group A: 60, Group B: 63) were analyzed in the study. All background factors were well balanced between the both groups. Median loss of LBM was 6.74% (range -3.91% to 20.27%) in the Standard-diet group and 6.89% (range -5.11% to 20.04%) in the EPA-ON group at 1 month after surgery and was 8.59% (range -4.40% to 20.27%) in the Standard-diet group and 7.77% (range -5.57% to 23.35%) in the EPA-ON group at 3 months after surgery, which was not significantly different at the both (p=0.794 and p=0.393, respectively). : The perioperative EPA-ON could not be recommended to prevent loss of LBM after total gastrectomy.
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http://dx.doi.org/10.7150/jca.29632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400678PMC
January 2019

Comparison of anti-inflammatory effects of rivaroxaban vs. dabigatran in patients with non-valvular atrial fibrillation (RIVAL-AF study): multicenter randomized study.

Heart Vessels 2019 Jun 1;34(6):1002-1013. Epub 2019 Jan 1.

Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Some experimental studies have shown that direct oral anticoagulants (DOACs) have anti-inflammatory effects. However, the interval changes in inflammatory markers in patients with non-valvular atrial fibrillation (AF) who receive DOACs remain unknown. Between July 2013 and April 2014, a total of 187 AF patients randomly assigned to receive rivaroxaban (n = 91) or dabigatran (n = 96) were assessed for eligibility. The levels of the following inflammatory markers were serially evaluated: high-sensitivity C-reactive protein, pentraxin-3, interleukin (IL)-1β, IL-6, IL-18, tumor necrosis factor-α, monocyte chemotactic protein-1, growth and differentiation factor-15, and soluble thrombomodulin (sTM). The aim in this study was to evaluate the anti-inflammatory effects of rivaroxaban and dabigatran in patients with AF, in addition to the impact of markers on bleeding events. Finally, 117 patients (rivaroxaban: n = 55, dabigatran: n = 62) were included in the analysis at 12 months. Although the interval changes in sTM levels tended to be greater in the dabigatran group [0.3 (0-0.7) vs. 0.5 (0-1.0) FU/ml, p = 0.061], there were no significant differences in the interval changes in any inflammatory marker between 2 groups. There were no significant differences in bleeding events between 2 groups. The interval changes in sTM levels were significantly greater in patients with bleeding compared with those without [0.8 (0.5-1.3) vs. 0.4 (- 0.1-0.8) FU/ml, p = 0.017]. There were no significant differences in the interval changes in any inflammatory marker between rivaroxaban and dabigatran treatments in patients with AF. The increased levels of sTM after DOACs treatment might be related to bleeding events.
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http://dx.doi.org/10.1007/s00380-018-01324-7DOI Listing
June 2019