Publications by authors named "Kenichi Yoshimura"

162 Publications

A phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected non-small-cell lung cancer with mutation (West Japan Oncology Group 11719L/ADJUST study).

Ther Adv Med Oncol 2021 21;13:1758835920987647. Epub 2021 Jan 21.

Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka, Japan.

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is a standard treatment in mutated advanced non-small-cell lung cancer (NSCLC); however, previous data have suggested that EGFR-TKI has limited potential as adjuvant therapy. On the contrary, based on subset analysis with the immune checkpoint inhibitor (ICI) plus platinum-doublet chemotherapy in advanced NSCLC with mutation, we hypothesized that this combination was worth testing as adjuvant therapy in patients with mutated NSCLC.

Methods: Herein, we introduce our phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected NSCLC with mutation. Accrued patients will be pathological stage II-IIIA with completely resected NSCLC and whose tumors have mutation. Treatment comprises four cycles of cisplatin plus vinorelbine combined with atezolizumab followed by maintenance with atezolizumab. The primary endpoint is the disease-free survival (DFS) rate at 2 years. Secondary endpoints are DFS, overall survival, and safety. In total, 18 patients will be enrolled in this study.

Discussion: Ongoing phase III trials of adjuvant ICI allow the inclusion of patients with mutation, but our current trial will provide the earliest clinical data on the efficacy of platinum-doublet chemotherapy with atezolizumab.
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http://dx.doi.org/10.1177/1758835920987647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841658PMC
January 2021

Serum laminin γ2 monomer as a novel diagnostic and predictive biomarker for hepatocellular carcinoma.

Hepatology 2021 Feb 20. Epub 2021 Feb 20.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, 920-8641, Japan.

Backgrounds And Aims: Structural dynamics of basement membrane components remained to be elucidated in the process of hepatocarcinogenesis. We evaluated the characteristics of hepatocellular carcinoma (HCC) expressing laminin γ2 monomer (LG2m), a previously unrecognized basement membrane component not detected in normal tissues, for HCC diagnosis. We further determined if elevated serum LG2m is a risk factor for HCC development in patients with chronic hepatitis C (CHC).

Approach And Results: In HCC cell lines, LG2m was expressed in alpha-fetoprotein-negative cluster of differentiation 90-positive cells characterized by highly metastatic natures. Using 14 cell lines and 258 HCC microarray data, we identified that LG2m gene signature was associated with Hoshida's S1/Boyault's G3 molecular subclasses with poor prognosis, which could not be recognized by alpha-fetoprotein. Serum LG2m was assessed in 24 healthy donors, 133 chronic liver disease and 142 HCC patients, and sensitivity and specificity of LG2m testing for HCC diagnosis were 62.9% and 70.5%, respectively (cutoff: 30pg/ml). We evaluated the consequence of LG2m elevation in two independent HCC cohorts (n = 47 and n = 81), and LG2m-high HCC showed poor prognosis with later development of distant organ metastasis (cutoff: 60pg/ml). LG2m was slightly elevated in a subset of CHC patients, and Kaplan-Meier analysis indicated a high incidence of HCC (n = 70). For validation, we enrolled 399 CHC patients with sustained virological response (SVR) as a multicenter prospective study, and serum LG2m elevation correlated with a high incidence of HCC in the CHC patients with SVR (P < 0.0001).

Conclusions: LG2m is a novel predictive biomarker for the development of metastatic HCC. Elevated serum LG2m is a HCC risk in CHC patients who have achieved SVR.
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http://dx.doi.org/10.1002/hep.31758DOI Listing
February 2021

Phase 1/2 study of alectinib in RET-rearranged previously-treated non-small cell lung cancer (ALL-RET).

Transl Lung Cancer Res 2021 Jan;10(1):314-325

Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.

Background: Rearranged during transfection () rearrangements occur in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib administered at doses of 300 mg and 600 mg twice daily (BID) is approved for.

Alk: rearranged NSCLC in Japan and other countries, respectively. Since alectinib has activity against RET, we conducted a phase (P) 1/2 study of alectinib to determine its activity in Japanese patients with.

Ret: rearranged NSCLC.

Methods: This study was a single-arm, open-label, multi-institutional P1/2 trial. Previously treated patients with -rearranged NSCLC, screened by nation-wide network (LC-SCRUM-Japan), were recruited. In P1, alectinib (600 or 450 mg BID) was administered following a 3+3 design and its safety was assessed. During P2, alectinib was administered at the recommended dose (RD) determined in P1. The primary endpoint was the objective response rate (ORR) in RET inhibitor-naïve patients treated with the RD of alectinib.

Results: Thirty-four patients were administered alectinib. In cohort 1 (600 mg BID) of P1, we observed 5 dose-limiting toxicities (DLTs), including grade 3 rash and thromboembolic event, in 3 of 6 patients. In cohort 2 (450 mg BID), we observed no DLTs in 3 patients. Pharmacokinetic analysis revealed that AUC to 600 mg BID was higher than that previously reported in global trials. We determined 450 mg BID as the RD for P2. In 25 RET inhibitor-naïve patients, one achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%). The median progression-free survival (PFS) was 3.4 months (95% CI, 2.0-5.4), while the median overall survival was 19.0 months (5.4-NE). We observed grade 3 adverse events (AEs) (4%) including pneumonitis in P2.

Conclusions: Alectinib exerts limited activity against -rearranged NSCLC. Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients.
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http://dx.doi.org/10.21037/tlcr-20-549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867784PMC
January 2021

Salvage surgery for non-small cell lung cancer after tyrosine kinase inhibitor treatment.

Lung Cancer 2021 Mar 10;153:108-116. Epub 2021 Jan 10.

Department of General Thoracic Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan.

Objectives: The prognostic impact of surgical intervention for recurrent or residual non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement after tyrosine-kinase inhibitor (TKI) treatment remains unclear. We aimed to describe the characteristics and outcomes of patients undergoing salvage surgery in this setting.

Methods: We retrospectively collected and analyzed nationwide Japanese data on perioperative and postoperative outcomes of patients who underwent salvage surgery after EGFR or ALK-TKI during 2010-2015. The primary endpoint was a 3-year overall survival (OS) rate and secondary endpoints were the rate of adverse events, perioperative mortality rate, 3-year recurrence-free survival (RFS) rate, and median survival time after salvage lung resection. Univariate and multivariate analyses were performed to identify independent prognostic factors of OS and RFS.

Results: Thirty-six patients were included (EGFR-TKI: 33, ALK-TKI: 3). The 3-year OS and RFS after the surgery were 75.1 % (95 % confidence interval [CI] 55.9-86.9 %) and 22.2 % (95 % CI 8.6-39.7 %), respectively. Of clinicopathological factors, the progression of disease while on TKI and preoperative carcinoembryonic antigen (CEA) levels (≥5 ng/mL) were shown to be worse independent prognosticators of OS (hazard ratio [HR] 9.38, 95 % CI 1.57-55.88, P = .014; HR 4.84, 95 % CI 1.62-14.46, P = .005, respectively). Older age at initial treatment (≥70 years) and advanced pathological T stage (T2-T4) were the worse prognosticators for RFS (HR 12.58, 95 % CI 2.51-62.97, P = .002; HR 3.06, 95 % CI 1.04-9.03, P = .043, respectively). Grade 3 adverse events occurred in 5.6 % (2/36) patients, but no deaths were reported within 90 days after surgery.

Conclusion: Our study showed that salvage surgery after TKI treatment was safe and feasible and may contribute to prolonged OS time by reducing the local tumor burden.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.037DOI Listing
March 2021

Suggestion for Research Design: Noninferiority Design in Elderly Patients With Soft-Tissue Sarcoma.

J Clin Oncol 2021 Mar 13;39(7):862-863. Epub 2021 Jan 13.

Masaki Uchihara, MD, Department of Breast and Medical Oncology, Department of Diabetes, Endocrinology, and Metabolism, National Center for Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan; Kenichi Yoshimura, PhD, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Kasumi, Minami-ku, Hiroshima, Japan, and Akihiko Shimomura, MD, PhD, Yukino Kawamura, MD, and Chikako Shimizu, MD, PhD, Department of Breast and Medical Oncology, National Center for Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan.

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http://dx.doi.org/10.1200/JCO.20.02907DOI Listing
March 2021

A study protocol for expanding the screening interval of endoscopic screening for gastric cancer based on individual risks: prospective cohort study of gastric cancer screening.

Ann Transl Med 2020 Dec;8(23):1604

Miyagi Cancer Association, Sendai, Japan.

Background: The Japanese government has recommended a 2-year endoscopic screening interval for gastric cancer. However, insufficient resources have constrained participation in endoscopic screening for gastric cancer. One way to avoid endoscopic screening harms and provide equal access is to define the appropriate screening interval.

Methods: To expand screening interval from more than 2 years for low-risk group, a single-arm cohort of endoscopic screening started. At the baseline screening, the participants underwent endoscopic screening for gastric cancer, () antibody test, and serum pepsinogen test (first year), and followed after 2 and 4 years (within the first 5 years). We also assessed infection and atrophy status on images of upper gastrointestinal endoscopy at the baseline. A new screening model will be developed by dividing the participants into high-risk and low-risk groups based on demographics, history of eradication, serological testing, and endoscopic diagnosis. The cumulative gastric cancer incidence after negative results at baseline are compared between the low-risk group on the 3rd screening round after 4 years from baseline and the total screening group on the 2nd screening round after 2 years. If the cumulative gastric cancer incidence in the low-risk group on the 3rd screening round is lower than that in the total screening group on the 2nd screening round, the screening interval can be expanded to 4 years in the low-risk group.

Discussion: To reduce mortality from gastric cancer, a high participation rate of the target population is required. The screening interval of endoscopic screening can be changed if the individual risks for infection are clarified. Our goal in this study is to obtain relevant data that can be used to improve the efficient use of endoscopic screening for gastric cancer by referring to individual risks in Japan.

Trial Registration: UMIN000025839 (University Hospital Medical Information Network, Japan).
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http://dx.doi.org/10.21037/atm-20-5949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791261PMC
December 2020

The impact of peritoneal lavage cytology in biliary tract cancer (KHBO1701): Kansai Hepato-Biliary Oncology Group.

Cancer Rep (Hoboken) 2020 Dec 6:e1323. Epub 2020 Dec 6.

Kansai Hepato-Biliary Oncology Group, Osaka, Japan.

Background: Only few studies in literature have analyzed the clinical effects of peritoneal lavage status in biliary tract cancers.

Aim: We aimed to assess the effect of cytology-positive peritoneal lavage on survival for patients with biliary tract cancer who underwent curative resection.

Methods: The KHBO1701 study was a multi-institutional retrospective study that assessed the clinical effects of peritoneal lavage cytology in biliary tract cancers. Using clinicopathological data from 11 Japanese institutions, we compared long-term outcomes between patients with cytology-positive and cytology-negative peritoneal lavage.

Results: Of 169 patients who underwent curative resection, 164 were cytology-negative, and five were cytology-positive. The incidence of portal invasion and preoperative carbohydrate antigen 19-9 levels were higher in the cytology-positive group than in the cytology-negative group. The incidence of peritoneal metastatic recurrence was also higher, and overall survival tended to be worse in the cytology-positive group. In contrast, recurrence-free survival was similar between the cytology-negative and cytology-positive groups.

Conclusions: The positive status of peritoneal lavage cytology could moderately affect the survival of patients with biliary tract cancers. Given that surgical resection is the only curative treatment option, it may be acceptable to resect biliary tract cancers without other non-curative factors, regardless of peritoneal lavage cytology status.
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http://dx.doi.org/10.1002/cnr2.1323DOI Listing
December 2020

Salvage surgery for non-small-cell lung cancer after definitive radiotherapy.

Ann Thorac Surg 2020 Nov 26. Epub 2020 Nov 26.

Department of General Thoracic Surgery, Dokkyo Medical University, Mibu, Tochigi, Japan.

Background: The aim of this study is to describe the characteristics and outcomes of patients with non-small-cell lung cancer undergoing salvage surgery after chemoradiotherapy, conventional external beam, stereotactic body radiotherapy (SBRT), and ion beam radiotherapy.

Methods: We retrospectively evaluated patients who underwent salvage surgery between 2010 and 2016. Data on perioperative morbidity and mortality and patient outcomes were analyzed.

Results: In total, 156 patients were included; of them, 110 and 46 were categorized into Category 1: chemoradiotherapy or conventional external beam and Category 2: SBRT or ion beam radiotherapy, respectively. The 3-year overall survival (OS) and recurrence free survival (RFS) rates in Category 1 was 67.3% and 49.8%, respectively. In Category 1, pathological nodal stage was an independent prognosticator of both OS (hazard ratio [HR]: 3.53, 95% CI: 1.05-11.83) and RFS (HR: 4.32, 95% CI: 1.32-14.14). In Category 2, the 3-year OS and RFS rates were 57.7% and 46.4%, respectively. Age ≥70 years at initial treatment was the only independent prognosticator of OS (HR: 5.61, 95% CI: 1.44-21.87), while age at initial treatment (HR: 6.13, 95% CI 1.38-27.12) and pathological nodal metastasis (HR: 3.84, 95% CI: 1.40-10.57) were independent prognosticators for RFS. The overall 30- and 90-day mortality rates were 0% and 0.9% in Category 1 and 0% and 4.3% in Category 2, respectively.

Conclusions: Patients who undergo salvage surgery can have reasonable outcomes, and salvage surgery can be considered in selected patients.
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http://dx.doi.org/10.1016/j.athoracsur.2020.10.035DOI Listing
November 2020

Comparison of cancer control between segmentectomy and wedge resection in patients with clinical stage IA non-small cell lung cancer.

J Thorac Cardiovasc Surg 2020 Oct 22. Epub 2020 Oct 22.

Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan. Electronic address:

Objective: The study objective was to compare cancer control between segmentectomy and wedge resection in patients with clinical stage IA non-small cell lung cancer.

Methods: Between 2010 and 2015, 457 patients with clinical stage IA (8th edition) non-small cell lung cancer undergoing wedge resection or segmentectomy were identified at 3 institutions. Propensity scores were calculated on the basis of the extent of resection (wedge resection or segmentectomy) and included adjustment for confounding variables, such as age, sex, smoking status, pulmonary functions, laterality, tumor size, maximum standardized uptake value on F-fluorodeoxyglucose positron emission tomography, presence of ground-glass opacity on high-resolution computed tomography, histology, and visceral pleural invasion for multivariable analysis and matching. The primary end point was cumulative incidence of recurrence.

Results: In all cohorts, postoperative recurrence occurred in 36 of 195 patients (18.5%) undergoing wedge resection and 14 of 262 patients (5.3%) undergoing segmentectomy. Cumulative incidence of recurrence was significantly lower in patients undergoing segmentectomy (5-year cumulative incidence of recurrence, 5.3%) than in those undergoing wedge resection (5-year cumulative incidence of recurrence, 19.1%; P < .001). In propensity score-adjusted multivariable analysis, segmentectomy was identified as an independent favorable prognostic factor for cumulative incidence of recurrence (hazard ratio, 0.47; 95% confidence interval, 0.24-0.90; P = .022). In propensity score matching of 163 pairs, cumulative incidence of recurrence was significantly lower in patients undergoing segmentectomy (5-year cumulative incidence of recurrence, 6.6%) than in those undergoing wedge resection (5-year cumulative incidence of recurrence, 13.2%; P = .041).

Conclusions: Cancer control was better in segmentectomy than in wedge resection. Segmentectomy is the preferred oncologic procedure as sublobar resection to treat clinical stage IA non-small cell lung cancer.
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http://dx.doi.org/10.1016/j.jtcvs.2020.10.024DOI Listing
October 2020

Hypothesis generative head-to-head study comparing efficacy of afatinib and osimertinib based on immunological biomarkers in Japanese NSCLC patients with EGFR mutations (Heat on Beat study).

Ther Adv Med Oncol 2020 31;12:1758835920967254. Epub 2020 Oct 31.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8606, Japan.

Background: In the FLAURA trial, superiority of osimertinib over the standard of care (SOC) was not demonstrated in Asian patients; SOC seemed favorable among Japanese patients (hazard ratio 1.39, 95% confidence interval 0.82-2.33). Three reasons are suggested: since rechallenge with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is covered by health insurance in Japan, EGFR-TKI rechallenge rate was higher in SOC than in the osimertinib group, which resulted in a long-term sequential administration of EGFR-TKIs; treatment discontinuation rate was high in the osimertinib group due to adverse events such as interstitial pneumonia among Japanese patients. EGFR-TKIs enhance tumor antigen-specific cytotoxicity of T cells, especially first- and second-generation EGFR-TKIs, which are more active against various cells with wild-type EGFR, including regulatory T cells. Consequently, subsequent immune checkpoint inhibitor therapy seemed more promising in the SOC group. Therefore, optimal first-line EGFR-TKI for EGFR-mutant advanced lung cancer may not have been identified in Japanese patients.

Methods: The Heat on Beat study is a randomized, open-label, multicenter, phase II study to compare OS between initial treatment with afatinib and osimertinib in treatment-naïve patients with advanced or recurrent EGFR-mutant NSCLC. Exploration of immunomonitoring through peripheral blood mononuclear cells will also be performed, before, during, and after treatment. Treatment-naïve EGFR mutation-positive non-small cell lung cancer (NSCLC) patients ( = 100) will be randomized to two groups in a 1:1 ratio. The co-primary endpoints are 3-year survival rate and characterization of immune environment associated with response to afatinib, osimertinib, or immune checkpoint inhibitors. Enrollment will start in May 2020 at 28 sites in Japan and continue for 1 year, with 3-year follow-up.

Discussion: Because there is no clinical trial comparing second- with third-generation EGFR-TKI for advanced EGFR-mutant NSCLC, our study would provide a major impact on clinical practice. Japan Registry of Clinical Trials, jRCTs031190221, registered date: 25 February 2020, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190221.
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http://dx.doi.org/10.1177/1758835920967254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607717PMC
October 2020

A concern regarding estimated sensitivities and specificities of nasopharyngeal and saliva specimens for SARS-CoV-2 infection.

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

Future Medical Center, Hiroshima University, Hiroshima, Japan.

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http://dx.doi.org/10.1093/cid/ciaa1655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665413PMC
October 2020

A phase II study of daily carboplatin plus irradiation followed by durvalumab for stage III non-small cell lung cancer patients with PS 2 up to 74 years old and patients with PS 0 or 1 from 75 years: NEJ039A (trial in progress).

BMC Cancer 2020 Oct 6;20(1):961. Epub 2020 Oct 6.

Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka-City, Saitama, 350-1298, Japan.

Background: Durvalumab is a standard drug used during maintenance therapy after chemoradiotherapy in patients with locally advanced non-small cell lung cancer (LA-NSCLC). However, little is known about the clinical benefits of durvalumab after chemoradiotherapy in patients with LA-NSCLC with a performance status (PS) of 2 and/or aged > 75 years. As daily carboplatin plus concurrent thoracic radiotherapy is recommended for elderly patients according to guideline, the current phase II study aims to investigate the effect of daily carboplatin plus radiotherapy followed by durvalumab for patients with stage III NSCLC who have a PS of 2 and/or are older.

Methods: Daily carboplatin plus radiotherapy followed by durvalumab is performed for the patients with stage III NSCLC who have a PS of 2 and/or are older. This is a trial in progress manuscript.

Study Treatment: Daily, intravenous, low-dose carboplatin (30 mg/m in a 30-min infusion) is administered to patients 1 h before radiotherapy for the first 20 fractions. Radiotherapy for all patients consisted of 60 Gy administered as 30 fractions over 6 weeks. Durvalumab at a dose of 10 mg/kg/body is intravenously administered every 2 weeks for up to 12 months after chemoradiotherapy.

Exploratory Assessment: In the future, an exploratory investigation will be performed to determine whether the combined assessment of T-cell markers, PD-L1 expression, and tumor mutation burden could predict the outcomes of the regimen.

Discussion: The results of our study will exhibit the efficacy and tolerability of durvalumab as maintenance therapy after daily carboplatin plus radiotherapy.

Trial Registration: During the first registration (before induction chemoradiotherapy), 70 patients will be included; then, we include 58 patients during the second registration (before durvalumab treatment after chemoradiotherapy). https://jcrb.niph.go.jp/ .

Primary Endpoint: The primary endpoint of the current study is the 12-month progression-free survival (PFS) rate after the initiation of durvalumab.

Secondary Endpoints: The secondary endpoints are the feasibility, objective response, PFS, overall survival, and adverse events.
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http://dx.doi.org/10.1186/s12885-020-07406-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542352PMC
October 2020

Near-focus magnification and second-generation narrow-band imaging for early gastric cancer in a randomized trial.

J Gastroenterol 2020 Dec 6;55(12):1127-1137. Epub 2020 Oct 6.

Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Magnifying endoscopy with narrow-band imaging (NBI) is effective for the diagnosis of early gastric cancer (EGC). However, magnifying endoscopy is not yet popular globally because of the required level of skill and lack of availability. To overcome these problems, dual-focus endoscopy (standard- and near-focus (NF) modes) has been developed. In this study, we evaluated the diagnostic performance of NF with second-generation (2G)-NBI (NF-NBI) for the diagnosis of EGC.

Methods: This was a secondary analysis of a multicenter randomized controlled trial of 4523 high-risk patients who underwent gastroscopies at 13 institutions in Japan. Patients were randomly assigned to white-light imaging (WLI) followed by 2G-NBI or to 2G-NBI followed by WLI. Lesions suspicious for EGC, newly detected by non-magnifying WLI or 2G-NBI, were subsequently observed with NF-NBI. All detected lesions were biopsied or resected. The diagnostic performance of NF-NBI was compared with the final histology.

Results: A total of 870 detected lesions (145 EGC, 725 non-EGC) were analyzed. Overall diagnostic performance for EGC using NF-NBI was accuracy 87.7%, sensitivity 60.7%, specificity 93.1%, positive predictive value 63.8%, and negative predictive value 92.2%. There were no significant differences in diagnostic performance between lesions detected by WLI or 2G-NBI. For lesions diagnosed with high (333 lesions) and low (537 lesions) confidences, accuracy was 92.2% and 84.9%, sensitivity was 64.7% and 58.5%, and specificity was 90.5% and 88.8%, respectively.

Conclusion: The diagnostic performance of NF-NBI is good and acceptable for diagnosis of EGC in combination with either WLI or 2G-NBI.
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http://dx.doi.org/10.1007/s00535-020-01734-3DOI Listing
December 2020

Effects of LDL apheresis on proteinuria in patients with diabetes mellitus, severe proteinuria, and dyslipidemia.

Clin Exp Nephrol 2021 Jan 28;25(1):1-8. Epub 2020 Aug 28.

Department of Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan.

Background: Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria.

Methods: This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation.

Results: LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls.

Conclusion: Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia.

Trial Registration: Trial registration number: jRCTs042180076.
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http://dx.doi.org/10.1007/s10157-020-01959-9DOI Listing
January 2021

Oncologic Outcomes of Complex Segmentectomy: A Multicenter Propensity Score-Matched Analysis.

Ann Thorac Surg 2021 03 12;111(3):1044-1051. Epub 2020 Aug 12.

Department of Surgical Oncology, Hiroshima University, Hiroshima, Japan. Electronic address:

Background: Complex segmentectomy creates several intricate intersegmental planes; however, it has not been fully established in lung cancer treatment. We compared the oncologic outcomes of complex segmentectomy and lobectomy through a large cohort, multicenter database using propensity score-matched analysis.

Methods: We retrospectively analyzed data from 1517 patients with clinical stage I lung cancer with a solid component size 2.0 cm or less, who underwent surgical resection at 3 institutions between 2010 and 2018. Complex segmentectomy (n = 240) and location-adjusted lobectomy (n = 851) as well as surgical results were analyzed for all patients and their propensity score-matched pairs.

Results: The prognosis of patients undergoing complex segmentectomy was not significantly different from that of patients undergoing lobectomy (5-year cancer-specific survival [CSS] rate, 96.4% versus 97.2%, P = .69; and 5-year recurrence-free interval [RFI] rate, 95.8% versus 93.4%, P = .19). This trend was also identified in subanalyses for pure solid tumors. However, there were major differences in clinicopathologic features between the 2 groups. After propensity score-matched analysis, proper matching of patients was ascertained. In 219 propensity score-matched pairs, long-term outcomes were similar between patients undergoing complex segmentectomy (5-year CSS, 96.0%; 5-year RFI, 95.5%) and lobectomy (5-year CSS, 97.8%; 5-year RFI, 95.9%). Propensity score-adjusted multivariable analysis for RFI revealed that prognosis associated with complex segmentectomy was comparable to the prognosis obtained with lobectomy (hazard ratio = 0.98; 95% confidence interval, 0.33-2.40; P = .98).

Conclusions: Complex segmentectomy provides acceptable oncologic outcomes in clinical stage I lung cancer treatment.
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http://dx.doi.org/10.1016/j.athoracsur.2020.06.020DOI Listing
March 2021

Study protocol for daiobotanpito combined with antibiotic therapy for treatment of acute diverticulitis: a study protocol for a randomized controlled trial.

Trials 2020 Jun 16;21(1):531. Epub 2020 Jun 16.

Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 3-2-17-2F Imabashi, Chuo-ku, Osaka, 541-0042, Japan.

Background: Colonic diverticular disease has been increasing in prevalence due to the rapidly aging global population, but standard treatment has not changed dramatically in recent years. Daiobotanpito (DBT; Da Huang Mu Dan Tang in Chinese) has been used in medical treatment of acute abdominal abscesses, such as appendicitis or diverticulitis in traditional Japanese (Kampo) medicine for many years, based on more than 3000 years of experience. Prior to this study, a retrospective open-label trial was conducted to compare patients with acute diverticulitis who received oral DBT combined with intravenous antibiotics with those who received intravenous antibiotic alone; it showed a positive effect of DBT on acute diverticulitis. We aim to investigate whether moderate to severe acute diverticulitis shows greater improvement with intravenous antibiotics plus orally administered DBT compared with intravenous antibiotics plus placebo.

Methods: This is a two-group, randomized, double-blind, placebo-controlled, multi-center trial, which is designed to evaluate the efficacy and safety of DBT in patients with moderate to severe diverticulitis treated with intravenous antibiotics. Eligible participants will be randomized to either a treatment group receiving a 10-day oral DBT regimen plus conventional therapy or a control group receiving a 10-day placebo regimen plus conventional therapy. The primary outcome will be success in treating diverticulitis: the success rate will be defined as elimination of abdominal pain within 4 days in all patients, and in patients with fever (body temperature ≧ 37.5 °C) on inclusion into this study, fever relief with reduction in body temperature to < 37.5 °C within 3 days. Secondary endpoints will include the number of hospitalization days, changes in inflammatory response (C-reactive protein (CRP), white blood cell (WBC) and neutrophil counts), fever type, number of days before beginning food intake, recurrence rate (observation for 1 year after registration), and adverse event expression rate. Assessments will be performed at baseline and on the day of discharge. The recurrence rate will be recorded at 1 year after registration.

Discussion: This study is expected to provide evidence to support the clinical benefits of DBT in the treatment of acute diverticulitis. It may also provide evidence on the efficacy and safety of DBT in the recurrence of acute diverticulitis.

Trial Registration: UMIN-CTR: UMIN000027381. Registered on 27 April 2017. https://upload.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000031377, and changed to jRCTs041180063, registered on 30 July 2019; as a result of the revision of the domestic law in 2018 in Japan.
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http://dx.doi.org/10.1186/s13063-020-04370-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298760PMC
June 2020

Weekly paclitaxel plus ramucirumab versus weekly nab-paclitaxel plus ramucirumab for unresectable advanced or recurrent gastric cancer with peritoneal dissemination refractory to first-line therapy-the P-SELECT trial (WJOG10617G)-a randomised phase II trial by the West Japan Oncology Group.

BMC Cancer 2020 Jun 12;20(1):548. Epub 2020 Jun 12.

Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa-ku, Nagoya-shi, Aichi, Japan.

Background: Ramucirumab (RAM) with weekly paclitaxel (wPTX) is a standard second-line therapy for advanced or recurrent gastric cancer. Nanoparticle albumin-bound paclitaxel (nab-PTX), an albumin-bound form of PTX, was developed to improve the therapeutic index of taxane treatment. However, the ABSOLUTE trial showed the non-inferiority of weekly nab-PTX (w-nab-PTX) to wPTX with respect to overall survival (OS) as second-line therapy for advanced or recurrent gastric cancer, and subgroup analysis of patients with peritoneal dissemination showed favourable OS and progression-free survival (PFS) in the w-nab-PTX arm compared to those in the wPTX arm. This study evaluated whether w-nab-PTX plus RAM is more effective than wPTX plus RAM for patients with peritoneal dissemination.

Methods: The P-SELECT trial (WJOG10617G) is a prospective, open-label, multicentre, randomised phase II study evaluating wPTX plus RAM (arm A) versus w-nab-PTX plus RAM (arm B). Key eligibility criteria include the following: 1) histologically proven adenocarcinoma, 2) unresectable or recurrent gastric cancer, 3) peritoneal dissemination, 4) intolerance or refractory to first-line therapy including fluoropyrimidines, and 5) ECOG Performance Status (PS) 0-2. Patients are randomised to either arm at a 1:1 ratio stratified by institution, PS, and severity of ascites. PTX (80 mg/m; days 1, 8, and 15) and RAM (8 mg/kg; days 1 and 15) are administered every 4 weeks in arm A, while nab-PTX (100 mg/m; days 1, 8, and 15) instead of PTX is administered in arm B. The primary endpoint is OS, and the main secondary endpoints are PFS, objective response rate, safety, neuropathy-specific quality of life, and biomarkers. To maintain a probability of ≥70% to ensure the hazard ratio for OS in arm B is lower than 0.90, 105 subjects are required. The study was initiated in October 2018 and is being conducted in 58 centres of the West Japan Oncology Group.

Discussion: The results of this study will determine whether w-nab-PTX plus RAM has the potential to be a preferred therapeutic option for advanced and recurrent gastric cancer with peritoneal dissemination, compared to wPTX plus RAM.

Trial Registration: This study was prospectively registered in the Japan Registry of Clinical Trials (jRCTs031180022, October 1, 2018).
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http://dx.doi.org/10.1186/s12885-020-07047-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291575PMC
June 2020

Final Results from a Phase II Trial of Osimertinib for Elderly Patients with Epidermal Growth Factor Receptor t790m-Positive Non-Small Cell Lung Cancer That Progressed during Previous Treatment.

J Clin Med 2020 Jun 5;9(6). Epub 2020 Jun 5.

Department of Pulmonary Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for treating EGFR-mutated lung cancer, and osimertinib is effective in cases that acquired T790M mutations after treatment with the first- and second-generation EGFR-TKIs. However, no study has evaluated its safety and efficacy in older patients. This phase II trial (jRCTs071180002) evaluated osimertinib in T790M mutation-positive Japanese patients who were ≥75 years old and had experienced relapse or progression after previous EGFR-TKI treatment. Our previous report that enrolled 36 patients showed the overall response rate (58.3%) and disease control rate (97.2%), while this report describes the results for the progression-free survival (PFS), overall survival (OS), and safety analyses. The median PFS was 11.9 months (95% confidence interval (CI): 7.9-17.5), and the median OS was 22.0 months (95% CI: 16.0 months-not reached). The most frequent adverse events were anemia/hypoalbuminemia (27 patients, 75.0%), thrombocytopenia (21 patients, 58.3%), and paronychia/anorexia/diarrhea/neutropenia (15 patients, 41.7%). Pneumonitis was observed in four patients (11.1%), including two patients (5.6%) with Grade 3-4 pneumonitis. These results suggest that osimertinib was relatively safe and effective for non-small cell lung cancer that acquired T790M mutations after previous EGFR-TKI treatment, even among patients who were ≥75 years old.
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http://dx.doi.org/10.3390/jcm9061762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356339PMC
June 2020

Long-term survival outcomes following laparoscopic surgery for clinical stage 0/I rectal carcinoma.

Ann Gastroenterol Surg 2020 May 20;4(3):294-300. Epub 2020 May 20.

Department of Surgery Kitasato Institute Hospital Kitasato University Tokyo Japan.

Aim: To clarify and evaluate the long-term outcomes of laparoscopic surgery for clinical stage 0/I rectal carcinoma patients.

Methods: This single-arm phase II trial involved accredited surgeons from 43 Japanese institutions. Patients were registered preoperatively. The planned sample size was 490. The primary endpoint was overall survival, and long-term outcomes were evaluated.

Results: A total of 495 patients were registered between February 2008 and August 2010. Eight patients (1.6%) required conversion to open surgery. Sphincter-preserving procedures were performed in 477 (97%) patients. Positive radial resection margin was found in two (0.4%) patients. Of 490 patients, 22, 314, 38, 115, and one patient had final pathological stages (p-stage) 0, I, II, III, and IV, respectively. Pathologically, 31.4% (154/490) of the patients did not have p-stage 0/I. The 5-year overall survival (OS) rates in p-stages 0, I, II, and III were 100%, 98%, 97%, and 94%, respectively. The 5-year OS of all patients at 96.6% (95% CI 94.6-97.9) was significantly better than the expected 5-year OS of 81.1% (< .0001). The 5-year relapse-free survival in p-stages 0, I, II, and III were 100%, 93%, 81%, and 79%, respectively. The 5-year relapse-free survival of all patients was 90.1%. Fifty patients (10.2%) had recurrence; lung recurrence was found in 22 patients, local recurrence in 14, liver in seven, distant lymph node in nine, and bone in three.

Conclusions: Laparoscopic surgery for clinical stage 0/I rectal carcinoma has feasible long-term outcomes. (ClinicalTrials.gov No.NCT00635466.).
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http://dx.doi.org/10.1002/ags3.12333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240150PMC
May 2020

Very Long-Term Treatment with a Probiotic Preparation, Strain Shirota, Suppresses Weight Loss in the Elderly.

Nutrients 2020 May 29;12(6). Epub 2020 May 29.

Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto 602-0841, Japan.

Weight loss, often observed in the elderly, is associated with increased risks of various diseases. No large and long-term human study has been conducted to demonstrate the health maintenance-related effects of lactic acid bacteria preparations. To reveal the potential benefit of long-term lactic acid, the effects of bacteria-based probiotics for health maintenance were examined. This observational study included the participants from a previous clinical study designed to evaluate the effects of wheat bran biscuits or preparation, 3 g/day biolactis powder (BLP), in preventing colorectal tumor. The participants were provided an option to continue treatment with BLP on an outpatient basis after completion of the study. The 380 patients who completed the study were contacted and asked to participate in the present study and those who consented were surveyed for cancer incidence, treatment compliance, lifestyle, weight, and other variables. Informed consent was obtained from 237 of the 380 (62.4%) patients. The mean follow-up period was 7913 days (21.7 years). Cancer developed in 24 of 128 (18.8%) patients in the BLP extension group and 24 of 109 (22.0%) patients in the non-BLP extension group (risk ratio 0.88 [95% confidence interval 0.53-1.47]). Although no significant difference was observed, the cumulative cancer incidence rose at a slightly lower rate in the BLP extension group. Both groups showed a significant weight decrease over the course of 20 years, although the decrease in the BLP extension group was only 1.4 kg, compared with 2.8 kg in the non-BLP extension group. Very long-term treatment with a probiotic preparation suppressed weight loss in the elderly.
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http://dx.doi.org/10.3390/nu12061599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352285PMC
May 2020

WJOG10517G: a multicenter Phase II study of mFOLFOX6 in gastric cancer patients with severe peritoneal metastases.

Future Oncol 2020 Jul 29;16(20):1417-1424. Epub 2020 May 29.

Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.

Gastric cancer patients with severe peritoneal metastases, defined as massive ascites and/or inadequate oral intake, have been excluded from clinical trials of new treatments due to poor prognosis and tumor-related complications, such as ileus. Based on the results of the JCOG1108/WJOG7312G study, their prognosis when treated with 5-fluorouracil/-leucovorin or 5-fluorouracil/-leucovorin plus paclitaxel remained extremely poor in this setting. Retrospective studies have shown the promising efficacy of the modified FOLFOX6 (mFOLFOX6) regimen, with improved ascites and oral intake. Therefore, we planned a Phase II study of mFOLFOX6 in gastric cancer patients with severe peritoneal metastases (jRCTs041180007). The primary end point is overall survival, with an exploratory analysis comparing the findings with those of the JCOG1108/WJOG7312G study using Bayes' theorem. Trial registration Identifier: jRCTs041180007 (jRCTs: the Japan Registry of Clinical Trials).
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http://dx.doi.org/10.2217/fon-2020-0298DOI Listing
July 2020

Outcome and Late Complications of Hepatoblastomas Treated Using the Japanese Study Group for Pediatric Liver Tumor 2 Protocol.

J Clin Oncol 2020 08 18;38(22):2488-2498. Epub 2020 May 18.

Center for Integrated Medical Research, Hiroshima University Hospital, Hiroshima, Japan.

Purpose: We report here the outcomes and late effects of the Japanese Study Group for Pediatric Liver Tumors (JPLT)-2 protocol, on the basis of cisplatin-tetrahydropyranyl-adriamycin (CITA) with risk stratification according to the pretreatment extent of disease (PRETEXT) classification for hepatoblastoma (HB).

Patients And Methods: From 1999 to 2012, 361 patients with untreated HB were enrolled. PRETEXT I/II patients were treated with up-front resection, followed by low-dose CITA (stratum 1) or received low-dose CITA, followed by surgery and postoperative chemotherapy (stratum 2). In the remaining patients, after 2 cycles of CITA, responders received the CITA regimen before resection (stratum 3), and nonresponders were switched to ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC; stratum 4). Intensified chemotherapeutic regimens with autologous hematopoietic stem-cell transplantation (SCT) after resection were an optional treatment for patients with refractory/metastatic disease.

Results: The 5-year event-free and overall survival rates of HB patients were 74.2% and 89.9%, respectively, for stratum 1, 84.8% and 90.8%%, respectively, for stratum 2, 71.6% and 85.9%%, respectively, for stratum 3, and 59.1% and 67.3%%, respectively, for stratum 4. The outcomes for CITA responders were significantly better than those for nonresponders, whose outcomes remained poor despite salvage therapy with a second-line ITEC regimen or SCT. The late effects, ototoxicity, cardiotoxicity, and delayed growth, occurred in 61, 18, and 47 patients, respectively. Thirteen secondary malignant neoplasms (SMNs), including 10 leukemia, occurred, correlating with higher exposure to pirarubicin and younger age at diagnosis.

Conclusion: The JPLT-2 protocol achieved up-front resectability in PRETEXT I/II patients with no annotation factors, and satisfactory survival in patients who were CITA responders in the remaining patients. However, outcomes for CITA nonresponders were unsatisfactory, despite therapy intensification with ITEC regimens and SCT. JPLT-2 had a relatively low incidence of cardiotoxicity but high rates of SMNs.
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http://dx.doi.org/10.1200/JCO.19.01067DOI Listing
August 2020

The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database.

Pediatr Blood Cancer 2020 08 8;67(8):e28350. Epub 2020 May 8.

Division of Pediatric Surgery, University of Utah School of Medicine, Utah, Salt Lake City.

Purpose: Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification.

Methods: We evaluated 1605 patients with hepatoblastoma included in the CHIC database to assess the relationship between event-free survival (EFS) and age at diagnosis. Further analysis included the age distribution of additional risk factors and the interaction of age with other known prognostic factors.

Results: Risk for an event increases progressively with increasing age at diagnosis. This pattern could not be attributed to the differential distribution of other known risk factors across age. Newborns and infants are not at increased risk of treatment failure. The interaction between age and other adverse risk factors demonstrates an attenuation of prognostic relevance with increasing age in the following categories: metastatic disease, AFP < 100 ng/mL, and tumor rupture.

Conclusion: Risk for an event increased with advancing age at diagnosis. Increased age attenuates the prognostic influence of metastatic disease, low AFP, and tumor rupture. Age could be used to modify recommended chemotherapy intensity.
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http://dx.doi.org/10.1002/pbc.28350DOI Listing
August 2020

A Randomized Phase II Study of Maintenance Bevacizumab, Pemetrexed or Bevacizumab Plus Pemetrexed for Advanced Non-squamous Non-small Cell Lung Cancer.

Anticancer Res 2020 May;40(5):2981-2987

Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background/aim: Continuation maintenance therapy is standard for advanced nonsquamous non-small cell lung cancer; however, the optimal maintenance strategy has yet to be determined.

Patients And Methods: Patients without disease progression after four cycles of carboplatin (CBDCA)+ pemetrexed (PEM)+ bevacizumab (BEV) were randomized to maintenance therapy with BEV, PEM, or BEV+PEM. The primary endpoint was 1-year progression-free survival (PFS) rate.

Results: Of the 90 patients enrolled, 64 were randomly assigned to maintenance therapy. The 1-year PFS rate was 9.1% in the BEV arm, 19.1% in the PEM arm, and 19.1% in the BEV+PEM arm. The median PFS and overall survival (OS) were 4.0 and 43.1 months in the BEV arm, 4.5 and 32.0 months in the PEM arm, and 6.4 and 41.8 months in the BEV+PEM arm.

Conclusion: The median PFS was numerically better in the BEV+PEM arm, but the median OS was not significantly different among the three arms.
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http://dx.doi.org/10.21873/anticanres.14278DOI Listing
May 2020

A phase II study of Osimertinib for patients with radiotherapy-naïve CNS metastasis of non-small cell lung cancer: treatment rationale and protocol design of the OCEAN study (LOGIK 1603/WJOG 9116L).

BMC Cancer 2020 May 1;20(1):370. Epub 2020 May 1.

Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita, 879-5593, Japan.

Background: Patients with activating epidermal growth factor receptor (EGFR) mutations are highly responsive to EGFR-tyrosine kinase inhibitors (TKIs). However, it has been reported that approximately 15-30% of patients treated with EGFR-TKIs experience central nervous system (CNS) progression, and patients with EGFR mutations exhibit a higher incidence of brain metastasis than those without such mutations. The efficacy of osimertinib for treating CNS metastasis has been reported, but its efficacy for CNS metastasis in radiotherapy-naïve patients is unclear.

Methods: In the present prospective two-cohort phase II trial, 65 patients (T790M cohort, 40 patients; first-line cohort, 25 patients) with radiotherapy-naïve CNS metastasis of EGFR mutation-positive non-small cell lung cancer (NSCLC) will be included. Patients will be treated once-daily with osimertinib 80 mg. The primary endpoint is the response rate of brain metastasis as assessed using the PAREXEL criteria. Key secondary endpoints are progression-free survival and the response rate of brain metastasis as assessed using the RECIST criteria. We will exploratorily analyze the relationships of the blood concentration of osimertinib with its efficacy against brain metastasis of NSCLC and the accumulation of osimertinib in cerebrospinal fluid and evaluate tumor-derived DNA from plasma specimens for mutations in EGFR and other genes. Recruitment, which in October 2016, is ongoing.

Discussion: Although previous reports revealed the efficacy of osimertinib for CNS metastasis, these reports only involved subgroup analysis, and the efficacy of osimertinib for patients with previously untreated CNS metastasis remains unclear. The OCEAN study is the only trial of osimertinib for patients with untreated brain metastasis of NSCLC. This study should provide novel data about osimertinib. If the results of the OCEAN study are positive, then avoidance of radiotherapy will be recommended to patients harboring EGFR mutations and brain metastasis.

Trial Registration: UMIN identifier: UMIN000024218 (date of initial registration: 29 September 2016). jRCT identifier: jRCTs071180017 (date of initial registration: 13 February 2019).
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http://dx.doi.org/10.1186/s12885-020-06874-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195707PMC
May 2020

Early gastric cancer detection in high-risk patients: a multicentre randomised controlled trial on the effect of second-generation narrow band imaging.

Gut 2021 Jan 2;70(1):67-75. Epub 2020 Apr 2.

Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Objective: Early detection of gastric cancer has been the topic of major efforts in high prevalence areas. Whether advanced imaging methods, such as second-generation narrow band imaging (2G-NBI) can improve early detection, is unknown.

Design: This open-label, randomised, controlled tandem trial was conducted in 13 hospitals. Patients at increased risk for gastric cancer were randomly assigned to primary white light imaging (WLI) followed by secondary 2G-NBI (WLI group: n=2258) and primary 2G-NBI followed by secondary WLI (2G-NBI group: n=2265) performed by the same examiner. Suspected early gastric cancer (EGC) lesions in both groups were biopsied. Primary endpoint was the rate of EGC patients in the primary examination. The main secondary endpoint was the positive predictive value (PPV) for EGC in suspicious lesions detected (primary examination).

Results: EGCs were found in 44 (1.9%) and 53 (2.3%; p=0.412) patients in the WLI and 2G-NBI groups, respectively, during primary EGD. In a post hoc analysis, the overall rate of lesions detected at the second examination was 25% (n=36/145), with no significant differences between groups. PPV for EGC in suspicious lesions was 13.5% and 20.9% in the WLI (50/371 target lesions) and 2G-NBI groups (59/282 target lesions), respectively (p=0.015).

Conclusion: The overall sensitivity of primary endoscopy for the detection of EGC in high-risk patients was only 75% and should be improved. 2G-NBI did not increase EGC detection rate over conventional WLI. The impact of a slightly better PPV of 2G-NBI has to be evaluated further.

Trial Registration Number: UMIN000014503.
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http://dx.doi.org/10.1136/gutjnl-2019-319631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788198PMC
January 2021

Regenerative Therapy for Liver Cirrhosis Based on Intrahepatic Arterial Infusion of Autologous Subcutaneous Adipose Tissue-Derived Regenerative (Stem) Cells: Protocol for a Confirmatory Multicenter Uncontrolled Clinical Trial.

JMIR Res Protoc 2020 Mar 31;9(3):e17904. Epub 2020 Mar 31.

Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.

Background: Liver cirrhosis results from chronic hepatitis, and is characterized by advanced fibrosis due to long-term hepatic inflammation. Cirrhosis ultimately leads to manifestations of jaundice, ascites, and encephalopathy, and increases the risk of hepatocellular carcinoma. Once cirrhosis is established, resulting in hepatic failure, no effective treatment is available. Therefore, novel therapies to inhibit disease progression of cirrhosis are needed.

Objective: The objective of this investigator-initiated clinical trial is to assess the safety and efficacy of autologous adipose tissue-derived regenerative (stem) cell therapy delivered to the liver via the hepatic artery in patients with liver cirrhosis.

Methods: Through consultation with the Japan Pharmaceuticals and Medical Devices Agency, we designed a clinical trial to assess a therapy for liver cirrhosis based on autologous adipose tissue-derived regenerative (stem) cells, which are extracted using an adipose tissue dissociation device. The primary endpoints of the trial are the serum albumin concentration, prothrombin activity, harmful events, and device malfunction.

Results: Enrollment and registration were initiated in November 2017, and the follow-up period ended in November 2019. Data analysis and the clinical study report will be completed by the end of March 2020.

Conclusions: Completion of this clinical trial, including data analysis, will provide data on the safety and efficacy of this novel liver repair therapy based on autologous adipose tissue-derived regenerative (stem) cells using an adipose tissue dissociation device.

Trial Registration: UMIN Clinical Trials Registry UMIN000022601; https://tinyurl.com/w9uqw3q.

International Registered Report Identifier (irrid): DERR1-10.2196/17904.
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http://dx.doi.org/10.2196/17904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319609PMC
March 2020

Phase II Study of Consolidation Amrubicin After Concurrent Chemoradiotherapy in Patients With Limited-stage Small-cell Lung Cancer.

In Vivo 2020 Mar-Apr;34(2):897-902

Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Background: Concurrent chemoradiotherapy (CCRT) is the gold standard for limited-stage small-cell lung cancer (LS-SCLC); however, most patients inevitably experience relapse. We hypothesized consolidation amrubicin following CCRT to be a potential treatment for LS-SCLC.

Patients And Methods: All enrolled patients were treated using induction CCRT consisting of four cycles of etoposide and cisplatin plus concurrent thoracic radiotherapy. Eligible patients then received three cycles of amrubicin as consolidation therapy (consolidation population). The primary endpoint was the 2-year progression-free survival rate in the consolidation population.

Results: Of the 36 intention-to-treat patients, 28 (78%) received amrubicin and 24 (67%) completed all planned treatments. The 2-year progression-free survival rate and overall response rate were 35.7% and 86%, respectively. The median progression-free and overall survival were 14.3 and 60.9 months, respectively. There were no treatment-related deaths in the intention-to-treat population.

Conclusion: This study was terminated due to slow patient accrual; however, this treatment strategy was feasible and demonstrated promising efficacy.
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http://dx.doi.org/10.21873/invivo.11855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157837PMC
December 2020

Fasting and Non-Fasting Triglycerides and Risk of Cardiovascular Events in Diabetic Patients Under Statin Therapy.

Circ J 2020 02 6;84(3):509-515. Epub 2020 Feb 6.

Department of Cardiology, Kanazawa University Graduate School of Medicine.

Background: Few data specifically investigate associations between fasting/non-fasting triglycerides (TG) and cardiovascular (CV) events under statin therapy among Japanese diabetic patients.Methods and Results:We recruited 4,988 participants with diabetes from the EMPATHY study. Median follow-up was 3 years. We evaluated associations between serum fasting/non-fasting TG and first CV events in Cox-regression hazard models adjusted by classical risk factors. CV events were defined as (1) major adverse cardiac events (MACE) including myocardial infarction, stroke, or cardiac death; and (2) CV diseases (CVD) including myocardial infarction, unstable angina, ischemic stroke, or large artery disease or peripheral arterial disease. Fasting as well as non-fasting TG were associated with MACE (adjusted hazard ratio [HR]: 1.017 per 10 mg/dL; 95% confidence interval [CI]: 1.000-1.037; P=0.046, adjusted HR: 1.028 per 10 mg/dL; 95% CI: 1.006-1.050; P=0.0091) and CVD (adjusted HR: 1.024 per 10 mg/dL; 95% CI: 1.011-1.038; P=4.4×10, adjusted HR: 1.028 per 10 mg/dL; 95% CI: 1.010-1.046; P=4.9×10). Comparing the top quartile with the bottom quartile of non-fasting TG, adjusted HR significantly increased 5.18 (95% CI: 1.38-18.3, P=0.014) for MACE, and 2.40 (95% CI: 1.11-4.75, P=0.021) for CVD, while adjusted HR did not change when divided into quartile of fasting TG.

Conclusions: Non-fasting TG could be considered as a substitute for fasting TG as a risk stratification for future CV events among Japanese diabetic patients.
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http://dx.doi.org/10.1253/circj.CJ-19-0981DOI Listing
February 2020

Shortening antibiotic duration in the treatment of acute cholangitis: rationale and study protocol for an open-label randomized controlled trial.

Trials 2020 Jan 17;21(1):97. Epub 2020 Jan 17.

Department of Gastroenterology, Kobe University Graduate School of Medicine, Kusunokicho 7-5-2, Chuoku, Kobe, Hyogo, 650-0017, Japan.

Background: Antimicrobial therapy with appropriate biliary drainage is considered the standard of care for acute cholangitis, but the optimal duration of antimicrobial therapy remains unknown. Seven to 10 days of antimicrobial therapy are common for the treatment of acute cholangitis, but a recent retrospective cohort study suggested a shorter duration might be effective. A shorter duration of antimicrobial therapy can be beneficial in decreasing the length of hospital stay, improving patients' quality of life, decreasing adverse effects, and even contributing to a decrease in the occurrence of antimicrobial resistance.

Methods/design: We will conduct a multi-centre, open-label, randomized, non-inferiority trial to compare short-course therapy (SCT) with conventional long-course therapy (LCT) in treating patients with acute cholangitis. SCT consists of 5-day intravenous antimicrobial therapy if the patients had clinical improvement, while at least 7 days of intravenous antibiotics will be provided to the LCT group. The primary outcome is clinical cure at 30 days after onset. Patients will be randomly assigned in an open-label fashion. A total sample size of 150 was estimated to provide a power of 80% with a one-sided α level of 2.5% and a non-inferiority margin of 10%.

Discussion: This trial is expected to reveal whether SCT is non-inferior to conventional LCT or not, and may provide evidence that one can shorten the treatment duration for acute cholangitis for the benefit of patients.

Trial Registration: University Hospital Medical Information Network, UMIN000028382. Registered on 30 August 2017.
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http://dx.doi.org/10.1186/s13063-020-4046-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969404PMC
January 2020