Publications by authors named "Koji Oba"

199 Publications

Increased Red Blood Cell Distribution Width in the First Year after Diagnosis Predicts Worsening of Systemic Sclerosis-Associated Interstitial Lung Disease at 5 Years: A Pilot Study.

Diagnostics (Basel) 2021 Dec 4;11(12). Epub 2021 Dec 4.

Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) varies among individuals. Red blood cell distribution width (RDW) has been reported to be a predictor of idiopathic pulmonary fibrosis. However, there are no studies on the relationship between RDW and SSc-ILD. We conducted a retrospective study of 28 patients who were diagnosed with SSc-ILD on their first visit to our hospital and were followed-up for 5 years. The correlation between the changes in RDW, KL-6, and SP-D (ΔRDW, ΔKL-6, ΔSP-D) and the changes in percent-predicted forced lung volume and % carbon monoxide diffusion (Δ%FVC, Δ%DLco) was investigated. ΔRDW at 1 year after diagnosis was significantly inversely correlated with Δ%FVC at 5 years after diagnosis (r = -0.51, < 0.001) and Δ%DLco at 5 years after diagnosis (r = -0.47, < 0.001), whereas ΔKL-6 and ΔSP-D at 1 year were not correlated with Δ%FVC or Δ%DLco at 5 years. In the group of SSc-ILD patients with RDW increase in the first year after diagnosis, %FVC and %DLco were significantly lower than baseline at 3-, 4-, and 5-year assessments. In the group of patients without RDW increase in the first year, %FVC and %DLco did not decrease during the follow-up period. In conclusion, the changes in RDW in the first year after diagnosis may be useful surrogate markers to predict the long-term course of SSc-ILD.
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http://dx.doi.org/10.3390/diagnostics11122274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700407PMC
December 2021

Intraperitoneal Chemotherapy as Adjuvant or Perioperative Chemotherapy for Patients with Type 4 Scirrhous Gastric Cancer: PHOENIX-GC2 Trial.

J Clin Med 2021 Nov 30;10(23). Epub 2021 Nov 30.

Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

The prognosis of patients with type 4 scirrhous gastric cancer remains poor due to a high risk of peritoneal metastasis. We have previously developed combined chemotherapy regimens of intraperitoneal (IP) paclitaxel (PTX) and systemic chemotherapy, and promising clinical efficacy was reported in gastric cancer with peritoneal metastasis. Herein, a randomized, phase III study is proposed to verify the efficacy of IP PTX to prevent peritoneal recurrence. Gastric cancer patients with type 4 tumors and without apparent distant metastasis, including peritoneal metastasis, will be randomized for standard systemic chemotherapy or combined IP and systemic chemotherapy based on peritoneal lavage cytology findings. Those with negative peritoneal cytology will receive radical gastrectomy and adjuvant chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). Those with positive peritoneal cytology will receive three courses of S-1 plus oxaliplatin (control arm), or S-1 plus oxaliplatin and IP PTX (experimental arm). Subsequently, they undergo gastrectomy and receive postoperative chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). The primary endpoint is disease free survival after a 3-year follow-up period. Secondary endpoints are overall survival, survival without peritoneal metastasis, safety, completion rate, curative resection rate, and histological response of preoperative chemotherapy. A total of 300 patients are to be enrolled.
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http://dx.doi.org/10.3390/jcm10235666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8658657PMC
November 2021

Misleading Reporting (Spin) in Noninferiority Randomized Clinical Trials in Oncology With Statistically Not Significant Results: A Systematic Review.

JAMA Netw Open 2021 12 1;4(12):e2135765. Epub 2021 Dec 1.

Interfaculty Initiative in Information Studies, The University of Tokyo, Tokyo, Japan.

Importance: Spin, the inaccurate reporting of randomized clinical trials (RCTs) with results that are not statistically significant for the primary end point, distorts interpretation of results and leads to misinterpretation. However, the prevalence of spin and related factors in noninferiority cancer RCTs remains unclear.

Objective: To examine misleading reporting, or spin, and the associated factors in noninferiority cancer RCTs through a systematic review.

Data Sources: A systematic search of the PubMed database was performed for articles published between January 1, 2010, and December 31, 2019, using the Cochrane Highly Sensitive Search Strategy.

Study Selection: Two investigators independently selected studies using the inclusion criteria of noninferiority parallel-group RCTs aiming to confirm effects to cancer treatments published between January 1, 2010, and December 31, 2019, reporting results that were not statistically significant for the primary end points.

Data Extraction And Synthesis: Standardized data abstraction was used to extract information concerning the trial characteristics and spin based on a prespecified definition. The main investigator extracted the trial characteristics while both readers independently evaluated the spin. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed.

Main Outcomes And Measures: The main outcome was spin prevalence in any section of the report. Spin was defined as use of specific reporting strategies, from whatever motive, to highlight that the experimental treatment is beneficial, despite no statistically significant difference for the primary outcome, or to distract the reader from results that are not statistically significant. The associations (prevalence difference and odds ratios [ORs]) between spin and trial characteristics were also evaluated.

Results: The analysis included 52 of 2752 reports identified in the PubMed search. Spin was identified in 39 reports (75.0%; 95% CI, 61.6%-84.9%), including the abstract (34 reports [65.4%; 95% CI, 51.1%-76.9%]) and the main text (38 reports [73.1%; 95% CI, 59.7%-83.3%]). Univariate analysis found that the spin prevalence was higher in reports with data managers (prevalence difference, 27%; 95% CI, 1.1%-50.3%), reports without funding from for-profit sources (prevalence difference, 31.2%; 95% CI, 4.8%-53.8%), and reports of novel experimental treatments (prevalence difference, 37.5%; 95% CI, 5.8%-64.7%). Multivariable analysis found that novel experimental treatment (OR, 4.64; 95% CI, 0.98-22.02) and funding only from nonprofit sources only (OR, 5.20; 95% CI, 1.21-22.29) were associated with spin.

Conclusions And Relevance: In this systematic review, most noninferiority RCTs reporting results that were not statistically significant for the primary end points showed distorted interpretation and inaccurate reporting. The novelty of an experimental treatment and funding only from nonprofit sources were associated with spin.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.35765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8652604PMC
December 2021

DENEB: Development of new criteria for curability after local excision of pathological T1 colorectal cancer using liquid biopsy.

Cancer Sci 2021 Nov 27. Epub 2021 Nov 27.

Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

According to the current international guidelines, high risk patients diagnosed with pathological T1 (pT1) colorectal cancer (CRC) who underwent complete local resection but may have risk of developing lymph node metastasis (LNM) are recommended additional intestinal resection with lymph node dissection. However, around 90% of the patients without LNM are exposed to the risk of being overtreated due to the insufficient pathological criteria for risk stratification of LNM. Circulating tumor DNA (ctDNA) is a non-invasive biomarker for molecular residual disease and relapse detection after treatments including surgical and endoscopic resection of solid tumors. The CIRCULATE-Japan project includes a large-scale patient-screening registry of the GALAXY study to track ctDNA status of patients with stage II to IV or recurrent CRC that can be completely resected. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective study, within the GALAXY study for patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk-stratification criteria for LNM. The aim of this study is to explore the ability of predicting LNM using ctDNA analysis compared to the standard pathological criteria. The ctDNA assay will build new evidence to establish a non-invasive personalized diagnosis in patients that will facilitate tailored/optimal treatment strategies for CRC patients.
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http://dx.doi.org/10.1111/cas.15226DOI Listing
November 2021

Association between hospital treatment volume and survival of women with gynecologic malignancy in Japan: a JSOG tumor registry-based data extraction study.

J Gynecol Oncol 2022 01 1;33(1):e3. Epub 2021 Nov 1.

Department of Obstetrics and Gynecology, Tokai University School of Medicine, Kanagawa, Japan.

Objective: Associations between hospital treatment volume and survival outcomes for women with 3 types of gynecologic malignancies, and the trends and contributing factors for high-volume centers were examined.

Methods: The Japan Society of Obstetrics and Gynecology tumor registry databased retrospective study examined 206,845 women with 80,741, 73,647, and 52,457 of endometrial, cervical, and ovarian tumor, respectively, who underwent primary treatment in Japan between 2004 and 2015. Associations between the annual treatment volume and overall survival (OS) for each tumor type were examined using a multivariable Cox proportional hazards model with restricted cubic splines. Institutions were categorized into 3 groups (low-, moderate-, and high-volume centers) based on hazard risks.

Results: Hazard ratio (HR) for OS each the 3 tumors decreased with hospital treatment volume. The cut-off points of treatment volume were defined for high- (≥50, ≥51, and ≥27), moderate- (20-49, 20-50, and 17-26), and low-volume centers (≤19, ≤19, and ≤16) by cases/year for endometrial, cervical, and ovarian tumors, respectively. Multivariate analysis revealed younger age, rare tumor histology, and initial surgical management as contributing factors for women at high-volume centers (all, p<0.001). The proportion of high-volume center treatments decreased, whereas low-volume center treatments increased (all p<0.001). Treatment at high-volume centers improved OS than that at other centers (adjusted HR [aHR]=0.83, 95% confidence interval [CI]=0.78-0.88; aHR=0.78, 95% CI=0.75-0.83; and aHR=0.90, 95% CI=0.86-0.95 for endometrial, cervical, and ovarian tumors).

Conclusion: Hospital treatment volume impacted survival outcomes. Treatments at high-volume centers conferred survival benefits for women with gynecologic malignancies. The proportion of treatments at high-volume centers have been decreasing recently.
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http://dx.doi.org/10.3802/jgo.2022.33.e3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728670PMC
January 2022

Improvement in Surgical Outcomes Using 3D Printed Models for Lateral Pelvic Lymph Node Dissection in Rectal Cancer.

Dis Colon Rectum 2021 Oct 29. Epub 2021 Oct 29.

Department of Surgical Oncology, Faculty of Medicine, The University of Tokyo Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo.

Background: Lateral pelvic lymph node dissection for rectal cancer is challenging due to the complexity of the pelvic wall anatomy, and incomplete lateral pelvic lymph node dissection may result in local recurrence in the lateral pelvis. Although three-dimensional printed organ models are useful for understanding spatial anatomy, it currently remains unclear whether they improve surgical outcomes.

Objective: We aimed to assess whether the surgical effectiveness of lateral pelvic lymph node dissection is increased by the use of individualized three-dimensional printed pelvic models.

Design: This was a retrospective study using a propensity matching analysis.

Settings: This study was conducted at a university hospital in Japan.

Patients: In total, 115 patients comprising 184 pelvic sides (right, 85 sides; left, 99 sides) who underwent lateral pelvic lymph node dissection for colorectal adenocarcinoma between January 2012 and December 2019 were enrolled.

Interventions: We compared surgical outcomes using three-dimensional printed pelvic models with control outcomes.

Main Outcome Measures: The primary outcome was the number of harvested lateral pelvic lymph nodes on one pelvic side after the propensity matching analysis.

Results: After matching, 35 pelvic sides each were allocated to the three-dimensional model and control groups, and no significant differences were observed in patient characteristics between the two groups. The number of harvested lateral pelvic lymph nodes was significantly higher in the three-dimensional model group (median, 9; range 3-16) than in the control group (median, 6; range, 0-22) (p=0.047).

Limitations: This was a retrospective study using propensity score matching. However, historical backgrounds were not matched and the majority of lateral pelvic lymph node dissection procedures in the three-dimensional model group were recently performed. This limitation may have influenced surgical outcomes.

Conclusion: The present study demonstrated that by referring to individualized three-dimensional printed pelvic models, colorectal surgeons harvested a larger number of lateral pelvic lymph nodes during lateral pelvic lymph node dissection. This result suggests that three-dimensional printed models help surgeons to complete more detailed procedures. See Video Abstract at http://links.lww.com/DCR/B776.
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http://dx.doi.org/10.1097/DCR.0000000000002327DOI Listing
October 2021

Preoperative sarcopenia is a poor prognostic factor in lower rectal cancer patients undergoing neoadjuvant chemoradiotherapy: a retrospective study.

Int J Clin Oncol 2022 Jan 6;27(1):141-153. Epub 2021 Nov 6.

Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.

Background: This study aimed to investigate the effect of sarcopenia on the prognosis of advanced lower rectal cancer patients receiving neoadjuvant chemoradiotherapy (CRT). Sarcopenia has been recognized as an adverse factor for surgical outcomes in several malignancies. However, the impact of preoperative sarcopenia on rectal cancer patients receiving CRT is still unknown.

Methods: This retrospective study included cT3-T4 anyN M0 lower rectal cancer patients who underwent CRT followed by R0 resection at our institution between October 2003 and December 2016. CRT consisted of 5-fluorouracil-based oral chemotherapy and long course radiation (50.4 Gy/28 fr). The psoas muscle area at the third lumbar vertebra level was evaluated by computed tomography before and after CRT, and was adjusted by the square of the height to obtain the psoas muscle mass index (PMI). Sarcopenia was defined as the sex-specific lowest quartile of the PMI. We assessed the association between pre- and post-CRT sarcopenia and postoperative prognosis.

Results: Among 234 patients, 55 and 179 patients were categorized as sarcopenia and non-sarcopenia patients, respectively. Although post-CRT sarcopenia correlated with residual tumor size, it had no association with other pathological features. The median follow-up period was 72.9 months, and the 5-year DFS and OS were 67.0% and 85.8%, respectively. Multivariate analysis showed that post-CRT sarcopenia was independently associated with poor DFS (HR: 1.76; P = 0.036), OS (HR: 2.01; P = 0.049), and recurrence in the liver (HR: 3.01; P = 0.025).

Conclusions: Sarcopenia is a poor prognostic indicator in lower advanced rectal cancer patients treated with CRT.
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http://dx.doi.org/10.1007/s10147-021-02062-zDOI Listing
January 2022

Percentage of residual B cells after 2 weeks of rituximab treatment predicts the improvement of systemic sclerosis-associated interstitial lung disease.

J Dermatol 2022 Jan 18;49(1):179-183. Epub 2021 Oct 18.

Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

The benefit of rituximab (RTX) for systemic sclerosis-associated interstitial lung disease (SSc-ILD) has been shown in previous clinical trials. However, predictors of RTX efficacy have not been clarified. We investigated whether B-cell responsiveness to RTX is related to therapeutic effect. Ten SSc-ILD patients treated with RTX in an independent clinical trial (Japan Registry of Clinical Trials, jRCTs031180373) were included in this analysis. Peripheral B-cell counts were examined retrospectively before RTX administration (baseline) and at 2, 4, 12, and 24 weeks after the first RTX administration, along with percent-predicted forced vital capacity (%FVC) before and 24 weeks after RTX treatment. Relative to baseline, the percentage of residual peripheral blood B cells at 2 weeks after RTX was negatively correlated with the %FVC improvement at the 24-week assessment (r = -0.41, p = 0.04). In the subgroup with less than 5% B-cell persistence at week 2, %FVC at the 24-week assessment was significantly improved compared to baseline (p = 0.02). In another subgroup with more than 5% residual B cells, %FVC was not significantly different after 24 weeks compared to baseline (p = 0.41). In conclusion, the removal rate of B cells after 2 weeks of RTX treatment may be a useful surrogate marker of subsequent SSc-ILD improvement.
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http://dx.doi.org/10.1111/1346-8138.16206DOI Listing
January 2022

Association between working overtime and psychological stress reactions in elementary and junior high school teachers in Japan: a large-scale cross-sectional study.

Ind Health 2021 Oct 12. Epub 2021 Oct 12.

Tokai Central Hospital, Japan.

This study aimed to investigate the relationship between working overtime and psychological stress reactions among school teachers. It also evaluated the interaction of overtime work types (on weekdays, on holidays, and bringing work home) and task content (educational, peripheral and both). This cross-sectional study was conducted on Japanese elementary and junior high school teachers. Primary outcome was psychological stress reactions measured with the Brief Job Stress Questionnaire. Participants were asked how long they work overtime on weekdays, holidays, and at home. Participants were also asked whether they engaged in educational tasks and/or peripheral tasks during that overtime work. Multiple linear regression analyses were applied and 6,135 participants were included in the analyses after imputing missing data. Working hours of all three types were significantly correlated with higher psychological stress reactions. Moreover, engaging in both educational and peripheral tasks showed higher psychological stress reactions than in only educational tasks when working overtime on weekdays and holidays. In conclusion, reducing overtime work regardless of work types is crucial for mitigating psychological stress reactions for teachers. It might also be possible to manage the psychological stress reactions by splitting the role of task contents, when working overtime on weekdays and holidays at school.
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http://dx.doi.org/10.2486/indhealth.2021-0069DOI Listing
October 2021

Focused Assessment with Sonography for Trauma (FAST) training for first-year resident physicians at a university hospital in Japan: A longitudinal, observational study.

SAGE Open Med 2021 3;9:20503121211044367. Epub 2021 Sep 3.

Department of Emergency Medicine, Osaka Medical College, Osaka, Japan.

Background: Ultrasound training is an essential part of residency programs during emergency medicine rotations for first-year trainees (postgraduate year 1). The Focused Assessment with Sonography for Trauma examination used to assess for internal bleeding in trauma patients is one of the essential skills postgraduate year 1 residents must acquire during the emergency medicine rotation.

Method: A prospective, longitudinal, observational study of postgraduate year 1 residents during a 2-month long emergency medicine rotation conducted from 1 April 2019 to 31 May 2021. The primary outcome was the mean difference between the hands-on Focused Assessment with Sonography for Trauma examination scores of the first week of the emergency medicine rotation and the same hands-on Focused Assessment with Sonography for Trauma examination scores of the last week of the emergency medicine rotation. All postgraduate year 1 residents had open access to the ultrasound machine to practice examining on other postgraduate year 1 residents or could use it on real patients under supervision of emergency medicine physicians.

Result: A total of 91 postgraduate year 1 residents (65 male and 26 female) were recruited and submitted to the hands-on Focused Assessment with Sonography for Trauma test in both the first and last weeks of the rotation. The mean test score for the postgraduate year 1 residents in the first week was 7.81 (standard deviation = 2.11). The mean test score in the last week was 16.17 (standard deviation = 2.60). The primary outcome of this study was the score difference between the first and last weeks (mean = 8.35, 95% confidence interval = 7.73 to 8.94,  < 0.001, paired -test).

Conclusion: Hands-on practical Focused Assessment with Sonography for Trauma training for postgraduate year 1 residents during emergency medicine rotations significantly improved their Focused Assessment with Sonography for Trauma test scores.
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http://dx.doi.org/10.1177/20503121211044367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422809PMC
September 2021

Clinical TNM staging for esophageal, gastric, and colorectal cancers in the era of neoadjuvant therapy: A systematic review of the literature.

Ann Gastroenterol Surg 2021 Jul 18;5(4):404-418. Epub 2021 Feb 18.

Department of Biostatistics School of Public Health Graduate School of Medicine The University of Tokyo Tokyo Japan.

Aim: Clinical staging is vital for selecting appropriate candidates and designing neoadjuvant treatment strategies for advanced tumors. The aim of this review was to evaluate diagnostic abilities of clinical TNM staging for gastrointestinal, gastrointestinal cancers.

Methods: We conducted a systematic review of recent publications to evaluate the accuracy of diagnostic modalities on gastrointestinal cancers. A systematic literature search was performed in PubMed/MEDLINE using the keywords "TNM staging," "T4 staging," "distant metastases," "esophageal cancer," "gastric cancer," and "colorectal cancer," and the search terms used in Cochrane Reviews between January 2005 to July 2020. Articles focusing on preoperative diagnosis of: (a) depth of invasion; (b) lymph node metastases; and (c) distant metastases were selected.

Results: After a full-text search, a final set of 55 studies (17 esophageal cancer studies, 26 gastric cancer studies, and 12 colorectal cancer studies) were used to evaluate the accuracy of clinical TNM staging. Positron emission tomography-computed tomography (PET-CT) and/or magnetic resonance imaging (MRI) were the best modalities to assess distant metastases. Fat and fiber mode of CT may be useful for T4 staging of esophageal cancer, CT was a partially reliable modality for lymph node staging in gastric cancer, and CT combined with MRI was the most reliable modality for liver metastases from colorectal cancer.

Conclusion: The most reliable diagnostic modality differed among gastrointestinal cancers depending on the type of cancer. Therefore, we propose diagnostic algorithms for clinical staging for each type of cancer.
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http://dx.doi.org/10.1002/ags3.12444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316742PMC
July 2021

Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis.

J Neurol 2022 Feb 30;269(2):885-896. Epub 2021 Jun 30.

Central Coordinating Unit, Clinical Research Support Center, The University of Tokyo Hospital, Tokyo, Japan.

Objective: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS).

Methods: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment.

Results: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483).

Conclusions: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.
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http://dx.doi.org/10.1007/s00415-021-10670-yDOI Listing
February 2022

Impact of Body Weight Gain on the Incidence of Nonalcoholic Fatty Liver Disease in Nonobese Japanese Individuals.

Am J Gastroenterol 2021 04;116(4):733-740

1Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; 2Center for Preventive Medicine, St. Luke's International University, Tokyo, Japan.

Introduction: We aimed to investigate the effect of recent short-term weight gain on the incidence of nonalcoholic fatty liver disease (NAFLD) in nonobese (body mass index < 25 kg/m) participants.

Methods: This retrospective cohort study included nonobese individuals who participated in an annual health checkup between 2008 and 2018 in Tokyo, Japan. We estimated the multivariable adjusted hazard ratio for the development of NAFLD diagnosed via ultrasound after a 3-kg unit gain in weight measured at a 2-year landmark time point postbaseline. Multivariable adjustments included weight change from the age of 20 and other relevant confounding factors. Sensitivity analyses using additional landmark time points at 1, 3, 4, and 5 years postbaseline and time-dependent Cox proportional hazards regressions were performed.

Results: Among the 27,064 nonobese participants (142,699 person years of follow-up), 2,895 were diagnosed with NAFLD. Approximately 90% of the patients with NAFLD maintained their nonobese status before disease diagnosis. The adjusted hazard ratio for the development of NAFLD (for a 3-kg unit of weight gain) at the 2-year landmark time point postbaseline was 1.60 (95% confidence interval, 1.46-1.76) in nonobese men and 1.66 (95% confidence interval, 1.51-1.83) in nonobese women. This association was maintained in the sensitivity analyses.

Discussion: Recent short-term weight gain is an independent risk factor for NAFLD development in nonobese men and women. Clinicians should be mindful of the association between weight gain and NAFLD onset, even in the nonobese population.
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http://dx.doi.org/10.14309/ajg.0000000000001030DOI Listing
April 2021

Safety and efficacy of panitumumab in combination with trifluridine/tipiracil for pre-treated patients with unresectable, metastatic colorectal cancer with wild-type RAS: The phase 1/2 APOLLON study.

Int J Clin Oncol 2021 Jul 29;26(7):1238-1247. Epub 2021 Apr 29.

Gastroenterological Chemotherapy Department, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3 Chome-8-31, Ariake, Koto, Tokyo, 135-8550, Japan.

Background: We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy.

Methods: APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety.

Results: Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m twice daily; days 1-5 and 8-12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8-45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5-6.5), 14.1 months (95% CI 12.2-19.3), 37.0% (95% CI 24.3-51.3), 81.5% (95% CI 68.6-90.8), and 5.8 months (95% CI 4.29-6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred.

Conclusion: Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.
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http://dx.doi.org/10.1007/s10147-021-01902-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213662PMC
July 2021

Impact of follow-up on generalized pairwise comparisons for estimating the irinotecan benefit in advanced/metastatic gastric cancer.

Contemp Clin Trials 2021 06 15;105:106400. Epub 2021 Apr 15.

Université de Versailles-St Quentin, France; Institut Curie & INSERM U900, Biostatistics for Precision Medicine (STAMPM), Saint-Cloud, France; Université Paris Saclay, France. Electronic address:

Background And Objectives: The net treatment effect (∆) is a new method to assess the treatment benefit that combines multiple time-to-event, binary and continuous endpoints according to a pre-specified sequence. It represents the net probability for a random patient treated in the experimental arm to have a better overall outcome than a random patient from the control arm does. We aimed at characterizing the impact of follow-up on ∆ estimated from both time-to-event and binary toxicity endpoints, in randomized controlled trials (RCTs) of irinotecan-based regimen in advanced/metastatic gastric cancer (AGC).

Study Design: Three RCTs are reanalysed. The net treatment effect using from one to three outcomes (i.e. overall survival, time to progression and toxicity in this order) and the hazard ratio (HR) were estimated after various cut-off dates and compared to the values obtained after complete follow-up were reported.

Results: In all three RCTs (897 patients), the irinotecan-based regimen was superior to the non-irinotecan containing regimen in terms of HR and ∆. This superiority was lower when the net treatment effect also accounted for toxicity. The HR was slightly less influenced by an incomplete follow-up than ∆ was, but correction proposed by Péron to account for censored observations showed quite robust results.

Conclusions: The net treatment effect using Péron's correction can be used in case of interim analyses or high censoring rates. In addition to relative measures such as the hazard ratio, it provides a simple mean to evaluate the net treatment effect with and without toxicity outcomes.
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http://dx.doi.org/10.1016/j.cct.2021.106400DOI Listing
June 2021

Sites of blood collection and topical antiseptics associated with contaminated cultures: prospective observational study.

Sci Rep 2021 03 18;11(1):6211. Epub 2021 Mar 18.

Department of Emergency Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka, 596-8686, Japan.

We aimed to determine whether puncture sites for blood sampling and topical disinfectants are associated with rates of contaminated blood cultures in the emergency department (ED) of a single institution. This single-center, prospective observational study of 249 consecutive patients aged ≥ 20 years proceeded in the ED of a university hospital in Japan during 6 months. Pairs of blood samples were collected for aerobic and anaerobic culture from all patients in the ED. Physicians selected puncture sites and topical disinfectants according to their personal preference. We found 50 (20.1%) patients with potentially contaminated blood cultures. Fifty-six (22.5%) patients were true bacteremia and 143 (57.4%) patients were true negatives. Multivariate analysis associated more frequent contamination when puncture sites were disinfected with povidone-iodine than with alcohol/chlorhexidine (adjusted risk difference, 12.9%; 95% confidence interval [CI] 8.8-16.9; P < 0.001). Sites of blood collection were also associated with contamination. Femoral and central venous with other sites were associated with contamination more frequently than venous sites (adjusted risk difference), 13.1% (95% CI 8.2-17.9; P < 0.001]) vs. 17.3% (95% CI 3.6-31.0; P = 0.013). Rates of contaminated blood cultures were significantly higher when blood was collected from femoral sites and when povidone-iodine was the topical antiseptic.
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http://dx.doi.org/10.1038/s41598-021-85614-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973780PMC
March 2021

Serum TARC Levels in Patients with Systemic Sclerosis: Clinical Association with Interstitial Lung Disease.

J Clin Med 2021 Feb 9;10(4). Epub 2021 Feb 9.

Department of Dermatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Systemic sclerosis (SSc) is a multisystem fibrotic disorder with autoimmune background. Accumulating evidence has highlighted the importance of T helper (Th) 2 cells in the pathogenesis of SSc and its complications. Because thymus and activation-regulated chemokine (TARC) is a potent chemoattractant for Th2 cells, we measured serum TARC levels in SSc patients and analyzed their correlation with interstitial lung disease (ILD), a major complication of SSc. Serum TARC levels were significantly elevated in patients with SSc, especially in those with the diffuse subtype, compared with healthy controls. In particular, dcSSc patients with SSc-associated ILD (SSc-ILD) showed higher TARC levels than those without SSc-ILD. However, there was no significant correlation between serum TARC levels and pulmonary function in SSc patients. Serum TARC levels did not correlate with serum levels of interleukin-13, an important Th2 cytokine, either. Furthermore, in the longitudinal study, serum TARC levels did not predict the onset or progression of SSc-ILD in patients with SSc. These results were in contrast with those of KL-6 and surfactant protein D, which correlated well with the onset, severity, and progression of SSc-ILD. Overall, these results suggest that serum TARC levels are not suitable for monitoring the disease activity of SSc-ILD.
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http://dx.doi.org/10.3390/jcm10040660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915627PMC
February 2021

Phase II study of an oxaliplatin-based regimen for relapsed colon cancer patients treated with oxaliplatin-based adjuvant chemotherapy (INSPIRE study).

Cancer Chemother Pharmacol 2021 05 8;87(5):665-672. Epub 2021 Feb 8.

Cancer Center, Aichi Medical University, Nagakute, Japan.

Background: The aim of this study was to evaluate the efficacy and safety of first-line chemotherapy with re-introduction of oxaliplatin (OX) more than 6 months after adjuvant chemotherapy including OX.

Methods: Stage II/III colon cancer patients with neuropathies of grade ≤ 1 who relapsed more than 6 months after adjuvant chemotherapy including OX were considered eligible. Eligible patients were treated with 5-fluorouracil, l-leucovorin and OX plus molecularly targeted agents or capecitabine and OX plus bevacizumab (BV) or S-1 and OX plus BV. The primary endpoint was the progression-free survival (PFS), and the secondary endpoints were the overall survival (OS), response rate (RR) and toxicity.

Results: A total of 50 patients were enrolled between September 2013 and May 2019. Twelve patients received 5-fluorouracil, l-leucovorin and OX (FOLFOX) plus BV, 21 patients received capecitabine and OX plus BV, 10 patients received S-1 and OX plus BV and 7 patients received FOLFOX plus cetuximab or panitumumab. The median PFS was 11.5 months (95% confidence interval [CI] 8.3-16.0), the median OS was 45.4 months (95% CI 37.4-NA), and the RR was 56.0% (95% CI 42.3-68.8). Adverse events of grade ≥ 3 that occurred in ≥ 5% of cases were neutropenia in 6 patients (12%), peripheral sensory neuropathy in 5 patients (10%), diarrhea in 4 patients (8%), hypertension in 4 patients (8%), anorexia in 3 patients (6%) and allergic reactions in 3 patients (6%).

Conclusions: First-line chemotherapy with re-introduction of OX more than 6 months after adjuvant chemotherapy including OX can be used safely with expected efficacy for relapsed colon cancer patients.
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http://dx.doi.org/10.1007/s00280-021-04232-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026470PMC
May 2021

Serum Calponin 3 Levels in Patients with Systemic Sclerosis: Possible Association with Skin Sclerosis and Arthralgia.

J Clin Med 2021 Jan 14;10(2). Epub 2021 Jan 14.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan.

Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis and vasculopathy in various organs with a background of inflammation initiated by autoimmune abnormalities. Calponin 3 plays a role in the cell motility and contractibility of fibroblasts during wound healing in the skin. We aimed to evaluate serum calponin 3 levels in SSc patients and their association with clinical manifestations of SSc. Serum samples were collected from 68 patients with SSc and 20 healthy controls. Serum calponin 3 levels were examined using enzyme-linked immunosorbent assay kits, and their association with clinical features of SSc was statistically analyzed. The upper limit of the 95% confidence interval of serum calponin 3 levels in healthy controls was utilized as the cut-off value when dividing SSc patients into the elevated and normal groups. Serum calponin 3 levels were significantly higher in SSc patients than in healthy controls (mean (95% confidence interval), 15.38 (14.66-16.11) vs. 13.56 (12.75-14.38) ng/mL, < 0.05). The modified Rodnan total skin thickness score was significantly higher in the elevated serum calponin 3 level group than in the normal level group (median (25-75th percentiles), 10.0 (2.0-16.0) vs. 6.5 (3.25-8.75), < 0.05). Moreover, SSc patients with increased serum calponin 3 levels also had a higher frequency of arthralgia (40% vs. 9%, < 0.05). Elevated serum calponin 3 levels were associated with skin sclerosis and arthralgia in SSc patients. Serum calponin 3 levels might be a biomarker that reflects the severity of skin sclerosis and joint involvement in SSc.
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http://dx.doi.org/10.3390/jcm10020280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828654PMC
January 2021

COVID-19 pandemic highlighted the importance of telemedicine in the collagen disease of systemic sclerosis.

Clin Exp Rheumatol 2021 Jul-Aug;39 Suppl 131(4):160. Epub 2020 Nov 5.

Department of Dermatology, The University of Tokyo Graduate School of Medicine, and Systemic Sclerosis Center, The University of Tokyo Hospital, Tokyo, Japan.

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August 2021

Outlier detection and influence diagnostics in network meta-analysis.

Res Synth Methods 2020 Nov 1;11(6):891-902. Epub 2020 Oct 1.

Departments of Health Promotion and Human Behavior, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan.

Network meta-analysis has been gaining prominence as an evidence synthesis method that enables the comprehensive synthesis and simultaneous comparison of multiple treatments. In many network meta-analyses, some of the constituent studies may have markedly different characteristics from the others, and may be influential enough to change the overall results. The inclusion of these "outlying" studies might lead to biases, yielding misleading results. In this article, we propose effective methods for detecting outlying and influential studies in a frequentist framework. In particular, we propose suitable influence measures for network meta-analysis models that involve missing outcomes and adjust the degree of freedoms appropriately. We propose three influential measures by a leave-one-trial-out cross-validation scheme: (1) comparison-specific studentized residual, (2) relative change measure for covariance matrix of the comparative effectiveness parameters, (3) relative change measure for heterogeneity covariance matrix. We also propose (4) a model-based approach using a likelihood ratio statistic by a mean-shifted outlier detection model. We illustrate the effectiveness of the proposed methods via applications to a network meta-analysis of antihypertensive drugs. Using the four proposed methods, we could detect three potential influential trials involving an obvious outlier that was retracted because of data falsifications. We also demonstrate that the overall results of comparative efficacy estimates and the ranking of drugs were altered by omitting these three influential studies.
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http://dx.doi.org/10.1002/jrsm.1455DOI Listing
November 2020

Oxidized albumin in blood reflects the severity of multiple vascular complications in diabetes mellitus.

Metabol Open 2020 Jun 14;6:100032. Epub 2020 Mar 14.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Albumin has an oxidized form, known as non-mercaptalbumin (HNA), which reflects systemic oxidative stress. The association between serum HNA levels and diabetic complications are yet to be reported. In this cross-sectional study, we investigated 164 diabetic subjects to assess the correlation between HNA% (the proportion in the total albumin) and various clinical parameters. HNA% was significantly associated with the severity of multiple complications including neuropathy (23.3 ± 4.1% vs 26.2 ± 5.1%) and nephropathy (24.1 ± 3.9%, 24.6 ± 4.2%, 28.5 ± 6.1%, 31.3 ± 5.7%, 37.8 ± 2.9%, stage 1/2/3/4/5, respectively). These findings highlight the universal importance of oxidative stress, indicating HNA% potential as a versatile marker of the severity of diabetic complications.
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http://dx.doi.org/10.1016/j.metop.2020.100032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7424782PMC
June 2020

Efficacy of bezafibrate for preventing myopathic attacks in patients with very long-chain acyl-CoA dehydrogenase deficiency.

Brain Dev 2021 Feb 11;43(2):214-219. Epub 2020 Aug 11.

Hokkaido University Hospital Clinical Research and Medical Innovation Center, Research and Development Division, Japan.

Background: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks.

Patients And Methods: We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions.

Results: The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients' ability to conduct everyday activities was also improved by the treatment.

Conclusion: Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.
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http://dx.doi.org/10.1016/j.braindev.2020.07.019DOI Listing
February 2021

Radiomics Approach Outperforms Diameter Criteria for Predicting Pathological Lateral Lymph Node Metastasis After Neoadjuvant (Chemo)Radiotherapy in Advanced Low Rectal Cancer.

Ann Surg Oncol 2020 Oct 7;27(11):4273-4283. Epub 2020 Aug 7.

Department of Colorectal Surgery, Toranomon Hospital, Tokyo, Japan.

Background: Advanced low rectal cancer has a non-negligible risk of lateral pelvic lymph node (LPLN) metastasis (LPLNM) and lateral local recurrence (LR) after neoadjuvant (chemo)radiotherapy and total mesorectal excision. LPLN dissection (LPLND) reduces LR but increases postoperative complications and sexual/urinary dysfunction.

Objective: The aim of this study was to develop a new radiomics-based prediction model for LPLNM in patients with rectal cancer.

Methods: A total of 247 patients with rectal cancer and enlarged LPLNs treated by (chemo)radiotherapy and LPLND were enrolled in this retrospective, multicenter study. LPLN radiomic features were extracted from pretreatment portal venous-phase computed tomography images. A radiomics score of LPLN was constructed based on the least absolute shrinkage and selection operator regression in a primary cohort of 175 patients. Model performance was assessed in terms of discrimination, calibration, and decision curve analysis, and was externally validated in 72 patients.

Results: The radiomics score showed significantly better discrimination compared with pretreatment short-axis diameter measurements in both the primary (area under the curve [AUC] 0.91 vs. 0.83, p = 0.0015) and validation (AUC 0.90 vs. 0.80, p = 0.0298) cohorts. Decision curve analysis also indicated the superiority of the radiomics score. In a subanalysis of patients with a short-axis diameter ≥ 7 mm, the radiomics nomogram, incorporating the radiomics score and LPLN shrinkage to ≤ 4 mm, had better discrimination compared with a model incorporating only LPLN shrinkage in both cohorts.

Conclusions: Radiomics-based prediction modeling provides individualized risk estimation of LPLNM in rectal cancer patients treated with (chemo)radiotherapy, and outperforms measurements of pretreatment LPLN diameter.
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http://dx.doi.org/10.1245/s10434-020-08974-wDOI Listing
October 2020

Risk factors for outlet obstruction after laparoscopic surgery and diverting ileostomy for rectal cancer.

Surg Today 2021 Mar 4;51(3):366-373. Epub 2020 Aug 4.

Omiya Ichonaika Clinic, 2-24-2 Nakacho, Omiya-ku, Saitama city, Saitama Prefecture, 330-0845, Japan.

Purpose: Outlet obstruction is defined as bowel obstruction at the stoma opening. The aim of this study was to evaluate the risk factors for outlet obstruction in patients with rectal cancer who underwent laparoscopic surgery and diverting ileostomy.

Methods: Among consecutive patients who underwent laparoscopic curative resection for primary rectal cancer between 2013 and 2015, 261 patients with diverting ileostomy were included in the analysis. The thickness of the abdominal wall, including the thickness of the rectus abdominis muscle, was measured using preoperative computed tomography. The clinicopathological factors were compared between the patients with and without outlet obstruction.

Results: Fourteen (5.4%) patients were diagnosed with outlet obstruction, but reoperation was not required. The rectus abdominis muscle was significantly thicker in male patients with outlet obstruction compared to those without outlet obstruction, but not in females. In a multivariate analysis, a rectus abdominis muscle thickness of 10 mm or more was determined to be an independent risk factor for outlet obstruction (odds ratio, 7.0482; p = 0.0061).

Conclusions: The thickness of the rectus abdominis muscle may be used to predict the occurrence of outlet obstruction in male patients with rectal cancer who undergo laparoscopic surgery and diverting ileostomy.
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http://dx.doi.org/10.1007/s00595-020-02096-2DOI Listing
March 2021

Protocol of the QUATTRO-II study: a multicenter randomized phase II study comparing CAPOXIRI plus bevacizumab with FOLFOXIRI plus bevacizumab as a first-line treatment in patients with metastatic colorectal cancer.

BMC Cancer 2020 Jul 23;20(1):687. Epub 2020 Jul 23.

Department of Medical Oncology, Kagawa University Hospital, Kagawa, Japan.

Background: First-line treatment with FOLFOXIRI plus bevacizumab (BEV) is highly effective and regarded as one of the standards-of-care for patients with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea as side effects. AXEPT, an Asian phase III study, showed that modified CAPIRI+BEV [capecitabine (CAP: 1600 mg/m), irinotecan (IRI: 200 mg/m), and BEV (7.5 mg/m)] was non-inferior to FOLFIRI+BEV as a second-line therapy for mCRC patients and was associated with a lower incidence of hematologic toxicities. Thus, a reduced dose of the CAP and IRI regimen in combination with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) may be more feasible than FOLFOXIRI+BEV, without compromising efficacy.

Methods: QUATTRO-II is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses of OX and IRI will be investigated as a safety lead-in. In Step 2, patients will be randomized to the recommended dose of either CAPOXIRI+BEV or FOLFOXIRI+BEV. Induction triplet chemotherapy plus BEV treatments will be administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The primary endpoint is progression-free survival (PFS). The similarity in PFS between the two arms will be evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls between 0.80 and 1.25. Ensuring a 70% probability that the observed HR will be "0.8 < HR < 1.25" under the assumption of the true HR of 1.0, and 100 patients will be evaluated during the 3-year study period. Secondary endpoints include overall survival, overall response rate, safety, and patient reported outcome (PRO) (FACT/GOG-Ntx4).

Discussion: Considering the lower incidence of hematologic toxicities with modified CAPIRI+BEV than with FOLFIRI+BEV, CAPOXIRI+BEV may be a promising treatment option if sufficient efficacy and lower hematologic toxicities are indicated in this study. Additionally, a lower incidence of peripheral sensory neuropathy (PSN) reported following CAPEOX treatment compared to that after FOLFOX in ACHIEVE, an adjuvant phase III trial, suggest that CAPOXIRI+BEV can mitigate OX-induced PSN.

Trial Registration: Clinicaltrials.gov NCT04097444 . Registered September 20, 2019, https://clinicaltrials.gov/ct2/show/study/NCT04097444 / Japan Registry of Clinical Trials jRCTs041190072. Registered October 9, 2019.
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http://dx.doi.org/10.1186/s12885-020-07186-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376863PMC
July 2020

Interleukin (IL)-17F and IL-17E are related to fibrosis and vasculopathy in systemic sclerosis.

J Dermatol 2020 Nov 19;47(11):1287-1292. Epub 2020 Jul 19.

Departments of, Department of Dermatology, School of Public Health, The University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Systemic sclerosis (SSc) is an autoimmune disease that causes fibrosis and vasculopathy of the skin and internal organs against a background of autoimmune abnormalities. In recent years, the importance of the interleukin (IL)-17 family for inflammatory diseases has received much attention, but autoimmune diseases have not yet been fully explored. As for SSc, there is also no unified perspective on the involvement of the IL-17 family in its development, and few studies have been conducted linking IL-17F and IL-17E particularly to the disease severity. In the present study, we examined the correlation between serum IL-17F and IL-17E levels and disease severity in SSc patients. Moreover, the expression of the receptors for these cytokines, IL-17RB and IL-17RC, in skin tissues obtained by skin biopsy was examined by immunohistochemistry. Both cytokines were significantly elevated in the sera of patients with diffuse cutaneous SSc patients compared with healthy controls. Serum IL-17F levels correlated with modified Rodnan total skin thickness score, a semiquantitative measure of skin sclerosis, percent predicted forced vital capacity, percent predicted carbon monoxide lung diffusion capacity and serum levels of Krebs von den Lungen-6 and surfactant protein-D, serological markers of interstitial lung disease. Serum IL-17E levels were significantly correlated with percent predicted forced vital capacity and serum Krebs von den Lungen-6 levels. Serum levels of IL-17F and IL-17E also correlated with the prevalence of digital ulcers, and serum IL-17F levels were associated with elevated right ventricle systolic pressure values. In addition, IL-17RC and IL-17RB expression was increased in the skin tissues of diffuse cutaneous SSc patients. These results suggested that IL-17F and IL-17E could be involved in fibrosis and vasculopathy in SSc through their respective receptors in the affected organ tissues.
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http://dx.doi.org/10.1111/1346-8138.15508DOI Listing
November 2020

Phase Ib/II Study of Biweekly TAS-102 in Combination with Bevacizumab for Patients with Metastatic Colorectal Cancer Refractory to Standard Therapies (BiTS Study).

Oncologist 2020 12 3;25(12):e1855-e1863. Epub 2020 Aug 3.

Tokai Central Hospital, Kakamigahara, Japan.

Lessons Learned: A biweekly TAS-102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS-102 plus BEV combination. Biweekly TAS-102 plus BEV combination could reduce unnecessary dose reduction of TAS-102, maintain higher doses, and possibly be effective even in cases without chemotherapy-induced neutropenia (CIN). The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS-102 plus BEV.

Background: TAS-102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS-102 (70 mg/m /day on days 1-5 and 8-12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS-102 plus BEV combination.

Methods: Patients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS-102 (twice daily on days 1-5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression-free survival rate at 16 weeks (16-w PFS rate).

Results: From October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS-102 (70 mg/m /day). Of the 44 eligible patients, the 16-w PFS rate was 40.9% (95% confidence interval, 26.3%-56.8%), and the null hypothesis was rejected (p < .0001). Median progression-free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%).

Conclusion: Biweekly TAS-102 plus BEV showed promising antitumor activity with safety.
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http://dx.doi.org/10.1634/theoncologist.2020-0643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108052PMC
December 2020

Associations between visceral obesity and renal impairment in health checkup participants: a retrospective cohort study.

Clin Exp Nephrol 2020 Oct 1;24(10):935-945. Epub 2020 Jul 1.

Takeda Hospital Medical Examination Center, Kyoto, 6008216, Japan.

Background: Obesity is a risk factor for chronic kidney disease. Although body mass index (BMI) or waist circumference is indicators of obesity, actual measurements of visceral fat area (VFA) more accurately reflect the amount of visceral fat. We aimed to determine the most sensitive obesity indicator for predicting renal impairment among VFA, BMI, waist circumference, waist-to-height ratio, and visceral-to-subcutaneous fat ratio (VSR).

Methods: Subjects who underwent VFA measurements during health checkups in 2012 were included. Obesity was defined using a separate baseline value for each indicator [VFA (100 cm), BMI (25 kg/m), waist circumference (85 cm for men and 90 cm for women), waist-to-height ratio (0.5), VSR (0.4)]. Changes in estimated glomerular filtration rate (eGFR) and time to new-onset proteinuria were measured. The relationships between obesity indicators and eGFR were evaluated using a linear mixed-effects model. The relationships between obesity indicators and new-onset proteinuria were evaluated using Poisson regression analysis.

Results: Analysis was performed on 2753 subjects (mean age 50.3 years). The VFA ≥ 100 cm group exhibited a larger annual difference in eGFR compared to the < 100 cm group (- 0.24 mL/min/1.73 m, P = 0.03). There was a statistically significant difference in the proteinuria incidence rate ratio, which was 1.54 times (95% confidence interval 1.01-2.35) in the VFA ≥ 100 cm group. Statistically significant correlations were not observed with any of the other obesity indicators.

Conclusion: VFA is suggested to be the most sensitive obesity indicator for decline in kidney function and new-onset proteinuria.
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http://dx.doi.org/10.1007/s10157-020-01921-9DOI Listing
October 2020

Rationale and design of the EMPYREAN study.

ESC Heart Fail 2020 10 23;7(5):3134-3141. Epub 2020 Jun 23.

Department of Cardiovascular Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.

Aims: A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA-REG OUTCOME trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus.

Methods And Results: This ongoing study is a prospective, randomized, open-label, multicentre investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are conducted using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non-linear least squares method for square analysis. The primary endpoint is the change in the low-frequency (0.04-0.15 Hz)/high-frequency (0.15-0.4 Hz) ratio from baseline to 24 weeks.

Conclusions: This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes.
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http://dx.doi.org/10.1002/ehf2.12825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524086PMC
October 2020
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