Publications by authors named "Hiroaki Okamoto"

341 Publications

Loss of antibodies to hepatitis E virus in organ transplant patients with hepatitis E.

Hepatol Res 2021 Mar 21. Epub 2021 Mar 21.

Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, Japan.

Aim: Studies regarding changes in antibodies to hepatitis E virus (HEV) after HEV infection in organ transplant patients are limited. This study aimed to clarify HEV infection trends in organ transplant patients who contracted HEV using data from a previous Japanese nationwide survey.

Methods: This study was undertaken from 2012 to 2019. Among 4518 liver, heart, and kidney transplant patients, anti-HEV immunoglobulin G (IgG) antibodies were positive in 164; data were collected from 106 of these patients, who consented to participate in the study. In total, 32 liver transplant patients, seven heart transplant patients, and 67 kidney transplant patients from 16 institutions in Japan were examined for IgG, IgM, and IgM antibodies to HEV and the presence of HEV RNA in the serum. The χ -test was used to determine the relationship between the early and late postinfection groups in patients with anti-HEV IgG positive-to-negative conversion rates. The Mann-Whitney U-test was used to compare clinical factors.

Results: Anti-HEV IgG positive-to-negative conversion occurred in 25 (23.6%) of 106 organ transplant patients. Of eight patients with hepatitis E who tested positive for HEV RNA, one (14.0%) had anti-HEV IgG positive-to-negative conversion. Twenty-four (24.5%) of 98 patients negative for HEV RNA had anti-HEV IgG positive-to-negative conversion.

Conclusions: This study revealed, for the first time, the changes in HEV antibodies in organ transplant patients. Loss of anti-HEV IgG could often occur unexpectedly in organ transplant patients with previous HEV infection.
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http://dx.doi.org/10.1111/hepr.13637DOI Listing
March 2021

Complete Genome Sequences of Two Rat Pegivirus Strains in Indonesia.

Microbiol Resour Announc 2021 Mar 18;10(11). Epub 2021 Mar 18.

Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan

The entire genome sequences of two pegivirus strains recovered from serum samples of wild rats () in Indonesia were determined. They possessed 11,013 to 11,014 nucleotides and differed from the reported rodent pegivirus strains within the species of the genus by 12.7% to 40.9% in the near-entire coding region sequences.
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http://dx.doi.org/10.1128/MRA.00049-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975870PMC
March 2021

Identification and a full genome analysis of novel camel hepatitis E virus strains obtained from Bactrian camels in Mongolia.

Virus Res 2021 Mar 1:198355. Epub 2021 Mar 1.

Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, 329-0498, Japan. Electronic address:

Hepatitis E virus (HEV) infects humans and a wide variety of other mammalian hosts. Recently, HEV strains belonging to genotype 8 (G8) within the Orthohepevirus A species of the Hepeviridae family, were identified in Bactrian camels (Camelus bactrianus) in China. The Bactrian camel (also known as the Mongolian camel) is native to the steppes of Central Asia. However, the HEV strains of Mongolian camels have not been examined. Among 200 serum samples from domestic Bactrian camels raised on 6 farms, in 6 soums in 3 provinces; 71 (35.5%) were positive for anti-HEV IgG, with prevalence differing by farm (soum) (4.2-75.0%); and 2 camels (1.0%) that had been raised in Bogd, Bayankhongor Province, which had the highest seroprevalence among the six studied areas, were positive for HEV RNA. The two HEV strains (BcHEV-MNG140 and BcHEV-MNG146) obtained from the viremic camels in the present study shared 97.7% nucleotide identity. They were closest to the reported G8 Chinese camel HEV strains but differed from them by 13.9-14.3% over the entire genome, with a nucleotide difference of 24.0-26.5% from the reported G1-G7 HEV strains. A phylogenetic tree indicated that the BcHEV-MNG140 and BcHEV-MNG146 strains were located upstream of a clade consisting of the Chinese camel HEV strains and formed a cluster with them, with a bootstrap value of 100%, suggesting that they may represent a novel subtype within G8. These results indicate a high prevalence of HEV infection in Mongolian camels and suggest that the variability of camel HEV genomes is markedly high.
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http://dx.doi.org/10.1016/j.virusres.2021.198355DOI Listing
March 2021

Japanese Man with HCV Genotype 4 Infection and Cirrhosis Who was Successfully Treated by the Combination of Glecaprevir and Pibrentasvir.

Intern Med 2021 Feb 1. Epub 2021 Feb 1.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Japan.

A 74-year-old man with a history of transfusion at 35 years old in Egypt was referred to our hospital. He was infected with hepatitis C virus (HCV) genotype 4 (GT4), which is a rare HCV GT in Japan, and was also diagnosed with hepatic compensated cirrhosis. We safely treated the patient for 12 weeks with the combination of glecaprevir and pibrentasvir, and a sustained virologic response (SVR) was achieved. This is the first report of HCV GT4 infection in a treatment-naïve Japanese patient with cirrhosis in whom SVR was achieved with the combination treatment of glecaprevir and pibrentasvir.
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http://dx.doi.org/10.2169/internalmedicine.6728-20DOI Listing
February 2021

An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.

Intern Med 2021 Feb 1. Epub 2021 Feb 1.

Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Japan.

A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.
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http://dx.doi.org/10.2169/internalmedicine.6337-20DOI Listing
February 2021

Prognostic impact of geriatric assessment in elderly patients with non-small cell lung cancer: an integrated analysis of two randomized phase III trials (JCOG1115-A).

Jpn J Clin Oncol 2021 Jan 22. Epub 2021 Jan 22.

Department of Medical Oncology, Osaka City General Hospital, Osaka, Japan.

Objective: Patients' actual age and performance status do not always accurately identify the 'fit elderly' for chemotherapy. This study aimed to determine whether four geriatric assessment tools could predict prognosis.

Methods: This study were analyzed using the data of two randomized phase III trials (JCOG0207 and JCOG0803/WJOG4307L) for elderly patients with advanced non-small cell lung cancer and included all eligible patients who were assessed before treatment with four geriatric assessment tools: the Barthel activities of daily living index, Lawton instrumental activities of daily living scale, Mini-Mental State Examination, and Geriatric Depression Scale-15. Univariable and multivariable analyses for overall survival, adjusted for baseline factors, were performed using a stratified Cox regression model with treatment regimen as strata.

Results: This analysis included 330 patients aged 70-74, 75-79 or 80 or more (n = 95/181/54), with a performance status of 0 or 1 (n = 119/211). Patients were divided into three groups based on Mini-Mental State Examination and two groups based on Geriatric Depression Scale, but over 80% of patients had perfect scores for both activities of daily living and instrumental activities of daily living. In overall survival subgroup analyses by GA tool, only Mini-Mental State Examination scores were associated with substantial outcome differences (median survival times: 21.2, 13.5 and 12.2 months for scores 30, 29-24 and ≤23). After adjusting for baseline factors, the Mini-Mental State Examination, sex and performance status were tended to be worse overall survival.

Conclusion: MMSE scores, performance status and sex, but not chronological age, effectively predicted the prognosis of elderly patients. Further studies should confirm that the Mini-Mental State Examination is useful for determining the indication of chemotherapy in elderly patients with advanced non-small cell lung cancer.
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http://dx.doi.org/10.1093/jjco/hyaa257DOI Listing
January 2021

Randomized phase II trial of S-1 plus cisplatin or docetaxel plus cisplatin with concurrent thoracic radiotherapy for inoperable stage III non-small cell lung cancer.

Cancer Med 2021 Jan 14;10(2):626-633. Epub 2020 Dec 14.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Kanagawa, Japan.

Cisplatin-based chemoradiotherapy is considered standard treatment for unresectable locally advanced non-small-cell lung cancer (LA-NSCLC). This study examined two regimens of chemotherapy in concurrent chemoradiation. Eligible patients with unresectable, radically irradible LA-NSCLC were randomized to either the SP (S-1 and cisplatin) or DP (docetaxel and cisplatin) arms with concurrent thoracic radiotherapy of 60 Gy, comprising 2 Gy per daily fraction. The primary endpoint was the overall survival (OS) rate at 2 years (the 2-year OS rate). From May 2011 to August 2014, 110 patients were enrolled. Of 106 eligible patients, the 2-year OS rates were 79% (95% CI: 66%-88%) and 69% (95% CI: 55%-80%) the SP and DP arms, respectively. The median progression-free survival was 11.6 months for the SP arm and 19.9 months for the DP arm, while the median survival time was 55.2 months for the SP arm and 50.8 months for the DP arm. Grade 3/4 leukopenia were more frequent in DP arm. The incidences of febrile neutropenia and pneumonitis tended to be higher in DP arm. There were no treatment-related deaths in either arm. The primary endpoint was met in both arms. The SP arm as a future reference regimen will be chosen due to fewer toxicities and better OS.
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http://dx.doi.org/10.1002/cam4.3641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877366PMC
January 2021

Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type epidermal growth factor receptor (TORG1320).

Invest New Drugs 2021 Apr 7;39(2):530-536. Epub 2020 Nov 7.

Department of Respiratory Medicine, Kitasato University School of Medicine, 1-15-1, Kitasato, Minami-ku, Sagamihara city, Kanagawa, 252-0375, Japan.

Background Amrubicin (AMR) is a completely synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We conducted a phase I study of AMR and erlotinib (ERL) combination therapy in previously treated patients with advanced NSCLC and have already reported the safety and effectiveness. Methods We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC harboring wild-type EGFR, PS 0-1 and < 75 years of age. Patients were treated at 3-week intervals with AMR plus ERL. The primary endpoint was the PFS, and the secondary endpoints were the response rate (RR), disease control rate (DCR), overall survival (OS) and toxicity. The trough ERL concentration (C) was measured as an exploratory study to analyze the relationship between the efficacy/safety and pharmacokinetics. Results From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95% confidence interval 2.1-5.1). The RR and DCR were 24.0% and 64.0%, respectively. We had no treatment-related deaths in this study. Conclusions The PFS of AMR and ERL combination therapy was superior to that of AMR monotherapy in the historical setting, but the primary endpoint was not met in this trial. In our study, the pharmacokinetic analysis showed that the C of ERL was elevated with combination therapy. This combination therapy might be a viable treatment for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information UMIN 000010582.
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http://dx.doi.org/10.1007/s10637-020-01031-zDOI Listing
April 2021

Additive Effects of Zinc Chloride on the Suppression of Hepatitis A Virus Replication by Interferon in Human Hepatoma Huh7 Cells.

In Vivo 2020 Nov-Dec;34(6):3301-3308

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.

Background/aim: Hepatitis A virus (HAV) infection is still one of the serious health problems worldwide, despite the existence of effective vaccines for HAV. Zinc compounds have antiviral activities against various DNA and RNA viruses. Therefore, we investigated the effects of zinc compounds on the antiviral activity of interferon against HAV.

Materials And Methods: The effects of zinc compounds with or without interferon on HAV genotype IIIA HA11-1299 replication were examined in human hepatoma Huh7 cells. Cell viability was examined by the MTS assay. Inflammasome associated gene expression was examined by real-time reverse transcription-polymerase chain reaction.

Results: Both zinc sulfate and zinc chloride had an inhibitory effect on HAV replication. Zinc sulfate tended to enhance while zinc chloride significantly enhanced the anti-HAV effect induced by interferon-alpha-2a. Zinc chloride significantly up-regulated mitogen-activated protein kinase 12 (MAPK12) and down-regulated 6 related genes [baculoviral IAP repeat containing 3 (BIRC3), interleukin 1 beta (IL1B), proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1), prostaglandin-endoperoxide synthase 2 (PTGS2), PYD and CARD domain containing (PYCARD), and tumor necrosis factor (TNF)].

Conclusion: Zinc chloride inhibits HAV replication and has additive effects on the anti-HAV activities of interferon.
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http://dx.doi.org/10.21873/invivo.12168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811611PMC
September 2020

Hepatitis B virus reactivation after successful treatment of hepatitis C virus with sofosbuvir and ribavirin: A case report and literature review.

Medicine (Baltimore) 2020 Oct;99(41):e22650

Division of Hepatology, Department of Internal Medicine.

Rationale: Hepatitis B virus (HBV) reactivation caused by immunosuppressive therapy or chemotherapy is well known. The administration of direct-acting antiviral agents (DAAs) to treat hepatitis C virus (HCV) infection has also been reported to cause HBV reactivation. We report a rare case of HBV reactivation in a patient with HCV infection after DAA therapy.

Patient Concerns: In 1996, a 53-year-old female was identified as infected with HCV at a medical check-up, following which she visited our hospital. She was infected with HCV genotype 2b, and at follow up in 1997, was found to be hepatitis B surface antigen (HBsAg) and antibody against HBsAg negative, antibody against HBV core positive. She then experienced malignant lymphoma in 2001 at 58 years of age. Complete remission was achieved following chemotherapy and autologous peripheral blood stem cell transplantation. In 2014, she remained negative for HBsAg and antibody against HBsAg but positive for antibody against HBV core. In 2015, 12 weeks of sofosbuvir and ribavirin treatment for HCV was started. Serum HCV RNA levels rapidly decreased, and HCV elimination was confirmed at 24 weeks after cessation of DAA treatment. Acute hepatitis B developed at 15 weeks post- sustained virological response without any symptoms and physical examination findings.

Diagnoses: This case is speculated to represent HBV reactivation induced by DAA treatment in a patient with previously resolved HBV, based on virologic and clinical status. Genome sequencing revealed the HBV genotype as A2.

Interventions: The patient was treated with nucleotide analog for HBV reactivation once a day.

Outcomes: Serum HBV-DNA levels decreased, and serum liver enzymes improved following initiation of nucleotide analog treatment. Also, adverse events of nucleotide analog treatment were not observed.

Lessons: Although the risk may be very low, DAA therapy can cause HBV reactivation in chronic hepatitis C patients with prior HBV infection. Thus, those patients must be closely monitored for serum HBV DNA levels during and after DAA treatment.
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http://dx.doi.org/10.1097/MD.0000000000022650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544429PMC
October 2020

First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer: KEYNOTE-024 Japan subset.

Cancer Sci 2020 Dec 16;111(12):4480-4489. Epub 2020 Oct 16.

Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan.

This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD-L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression-free survival was 41.4 (95% confidence interval [CI], 4.2-42.5) months with pembrolizumab and 4.1 (95% CI, 2.8-8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11-0.65]; one-sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9-NR) and 21.5 (95% CI, 5.2-35.0) months, respectively (HR, 0.39 [95% CI, 0.17-0.91]; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 pembrolizumab-treated patients (52%) and four chemotherapy-treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.
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http://dx.doi.org/10.1111/cas.14647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734005PMC
December 2020

A Phase 2 Study of Atezolizumab for Pretreated NSCLC With Idiopathic Interstitial Pneumonitis.

J Thorac Oncol 2020 12 25;15(12):1935-1942. Epub 2020 Aug 25.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Kanagawa, Japan.

Introduction: Interstitial pneumonia (IP) is one of the most common and poor prognostic comorbidities in patients with NSCLC and a known risk factor for pneumonitis. Atezolizumab monotherapy is an established treatment for recurrent NSCLC and reported to have a lower risk of pneumonitis than programmed cell death protein 1 inhibitors. This study aimed to assess the safety and efficacy of atezolizumab monotherapy in patients with pretreated advanced or recurrent NSCLC with idiopathic IP.

Methods: Patients with advanced or recurrent NSCLC with comorbid idiopathic, chronic fibrotic IP with % forced vital capacity of greater than 70% and no history of immune checkpoint inhibitors were enrolled. The patients received atezolizumab (1200 mg) every 3 weeks until the discontinuation criteria were met. The primary end point of this study was the 1-year survival rate. A sample size of 38 patients was set.

Results: This study was terminated early owing to high incidence of pneumonitis. A total of 17 patients were enrolled, with a median age of 70 years. The median % forced vital capacity and % diffusing capacity for carbon monoxide at baseline were 85.4% and 54.4%, respectively. The incidence of pneumonitis was 29.4% (5 of 17) for all grades, 23.5% (4 of 17) for grade greater than or equal to 3, and 5.9% (1 of 17) for grade 5. A total of 57.1% patients (4 of 7) with honeycomb lung developed pneumonitis with a grade greater than or equal to 3, whereas only one patient (10%) without honeycomb lung (n = 10) with grade 1 pneumonitis was found.

Conclusions: Patients with NSCLC with comorbid IP as defined by the selection criteria for this study might have an increased risk of immune checkpoint inhibitor-induced pneumonitis.
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http://dx.doi.org/10.1016/j.jtho.2020.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446731PMC
December 2020

Phase I/II study of erlotinib plus S-1 for patients with previously treated non-small cell lung cancer: Thoracic Oncology Research Group (TORG) 0808/0913.

Invest New Drugs 2021 Feb 15;39(1):202-209. Epub 2020 Aug 15.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama, Kanagawa, 240-8555, Japan.

Introduction In preclinical data, the combination therapy with S-1 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) had a synergistic antitumor effect on non-small cell lung cancer (NSCLC), regardless of the EGFR mutation status. Patients and Methods Patients with previously treated NSCLC and adequate organ function regardless of EGFR mutation status were eligible for the phase I study, with wild-type EGFR were eligible for the phase II study. Treatment consisted of erlotinib 150 mg/body orally once every day and S-1 60 mg/m, 70 mg/m, or 80 mg/m (level 0, level 1, or level 2) orally on days 1-14 every three weeks. The primary endpoint for the phase I study was the determination of the recommended dose (RD), the phase II study was the overall response rate (ORR). Results A total of 7 patients with performance-status (PS) 0 or 1 were enrolled as subjects in phase I. Five of these subjects were EGFR-mutation positive. Four subjects were enrolled at S-1 dose level 1 and 3 were enrolled at S-1 dose level 2. No dose-limiting toxicities were observed in these subjects. The RD was decided as erlotinib 150 mg/body and S-1 80 mg/m. In phase I, 5 subjects achieved partial response, and the ORR was 71.4%. A total of 10 patients with PS 0, 1, or 2 EGFR-wild type NSCLC were enrolled in phase II. In phase II, the ORR was 10.0%, and the disease control rate (DCR) was 40.0%. After the enrollment of 10 subjects, enrollment was stopped based on two treatment-related deaths. Conclusion The combination therapy of erlotinib plus S-1 was not feasible in the EGFR wild-type NSCLC at least and early stopped. Trial registration: UMIN-CTR Identifier: 000003421 (2010/03/31, phase I), 000003422 (2010/03/31, Phase II).
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http://dx.doi.org/10.1007/s10637-020-00985-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851018PMC
February 2021

Prevalence and genotype/subtype distribution of hepatitis E virus (HEV) among wild boars in Japan: Identification of a genotype 5 HEV strain.

Virus Res 2020 10 7;287:198106. Epub 2020 Aug 7.

Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi-Ken 329-0498, Japan.

To further investigate the prevalence of hepatitis E virus (HEV) infection and characterize HEV genomes among Japanese wild boars (Sus scrofa leucomystax), 1880 boars captured in 17 prefectures in Japan from 2013 to 2019 were studied. Overall, anti-HEV IgG was detected in 8.9 % and HEV RNA was detected in 3.9 % of boars, which was comparable with our previous studies during 2003-2013 (10.3 % and 3.5 %, respectively). Among 74 boar HEV strains obtained from infected boars in the present study, 50 (68 %) were classified into genotype 3 (3a and 3b), 23 (31 %) were classified into genotype 4 (4i), and the remaining strain (wbJGF_19-1) was classified into genotype 5. The wbGF_19-1 strain shared 92.7 % identity over the entire genome with the prototype genotype 5 strain (JBOAR135-Shiz09). The identification of the second genotype 5 HEV strain in a place that is located only 100 km from the site at which JBOAR135-Shiz09 was identified, suggests that genotype 5 HEV circulates within a relatively close range in Japan. Genetically similar HEV strains forming a clade were identified from wild boars living in each area during the observation period of 11-13 years, although the nucleotide sequence changed gradually, accounting for up to 3.4-3.6 % within the 412-nucleotide ORF2 sequence. Eight groups of boars with a cluster of HEV infections were observed, consisting of two, three or four infected offspring, presumably born to the same mother or offspring with their mother. These results suggest that wild boars continue to be important reservoirs for HEV infection in humans in Japan.
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http://dx.doi.org/10.1016/j.virusres.2020.198106DOI Listing
October 2020

Open-label, multicenter, randomized phase II study on docetaxel plus bevacizumab or pemetrexed plus bevacizumab for treatment of elderly (aged ≥75 years) patients with previously untreated advanced non-squamous non-small cell lung cancer: TORG1323.

Transl Lung Cancer Res 2020 Jun;9(3):459-470

Department of Thoracic Oncology and Medicine, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime, Japan.

Background: The effectiveness of bevacizumab monotherapy in elderly patients with non-squamous non-small cell lung cancer (NSCLC) is unclear. The efficacy of the combinations for elderly patients was explored.

Methods: Untreated patients (≥75 years; performance status 0-1) with stage IIIB, IV, or recurrent non-squamous NSCLC were included. Patients with epidermal growth factor receptor () mutation or anaplastic lymphoma kinase () gene rearrangements were eligible even if they received tyrosine kinase inhibitors. Patients were randomized 1:1 to receive docetaxel (50 mg/m) (DB) or pemetrexed (500 mg/m) (PB) with bevacizumab (15 m/kg). The primary endpoint was progression-free survival (PFS). Treatment was administered every 3 weeks until disease progression or unacceptable toxicity.

Results: Overall, 103 patients (DB: n=51; PB: n=52) were enrolled. In the DB and PB arms, median ages [range] were 78 [75-88] and 79 [75-94] years, respectively; median PFS were 6.1 and 4.6 months, respectively [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.66-1.61]; and response rates were 43%, and 40%, respectively (P=0.840). Grade ≥3 leukopenia, neutropenia, and fatigue incidences were significantly higher in the DB arm. Febrile neutropenia incidence did not differ significantly (16% . 12%, P=0.578). One patient in the PB arm died from a ruptured abdominal aortic aneurysm. Quality of life (QoL) analysis revealed less deterioration in the PB arm.

Conclusions: In previously untreated elderly patients with non-squamous NSCLC, PB shows feasibility, better QoL, and promising efficacy in terms of PFS, and an objective response rate for further analysis (UMIN000012786).
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http://dx.doi.org/10.21037/tlcr.2020.03.29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354128PMC
June 2020

Persistent infection with a rabbit hepatitis E virus created by a reverse genetics system.

Transbound Emerg Dis 2020 Jul 10. Epub 2020 Jul 10.

Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.

Rabbit hepatitis E virus (HEV) is a novel zoonotic infectious agent. Although a cell culture system to grow the virus has been established, there is currently no reverse genetics system for generating the virus. In this study, capped genomic rabbit HEV RNAs generated by in vitro transcription were transfected into PLC/PRF/5 cells, and the recovered viruses were subsequently passaged in the cells. The cell culture supernatant was capable of infecting rabbits negative for anti-HEV antibody by intravenous and oral inoculation, indicating that rabbit HEV generated by the reverse genetics system is infectious. Genome-wide analyses indicated that no nucleotide sequence change occurred in the virus genomes that were recovered from the cell culture supernatant after transfection and passaged one time or in the virus genomes recovered from faecal specimens of the infected rabbits. Ribavirin, a broad-spectrum anti-viral inhibitor, efficiently abrogated virus replication ex vivo and transiently suppressed the virus growth in the virus-infected rabbits, suggesting that this reagent is a candidate for therapeutic treatment. In addition, transmission of rabbit HEV to rabbits caused persistent infection, suggesting that the virus-infected rabbit could be an animal model for virus-induced hepatitis. The infectious rabbit HEV produced by a reverse genetics system would be useful to elucidate the mechanisms of HEV replication and the pathogenesis of viral hepatitis.
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http://dx.doi.org/10.1111/tbed.13723DOI Listing
July 2020

Treatment Rationale and Design of a Phase III Study of Afatinib or Chemotherapy in Patients with Non-small-cell Lung Cancer Harboring Sensitizing Uncommon Epidermal Growth Factor Receptor Mutations (ACHILLES/TORG1834).

Clin Lung Cancer 2020 11 21;21(6):e592-e596. Epub 2020 May 21.

Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan.

We describe the treatment rationale and design of our randomized phase III study, the ACHILLES trial (Japan Registry of Clinical Trials: jRCTs031180175). The aim of this study is to investigate the superiority of afatinib over chemotherapy as first-line treatment in patients with advanced nonsquamous non-small-cell lung cancer with sensitizing uncommon or compound epidermal growth factor receptor (EGFR) mutations, with the exception of de novo T790M mutations and exon 20 insertions. Eligible patients will be randomized at a 1:2 ratio to receive either chemotherapy or afatinib until disease progression or unacceptable toxicity. Patients in the chemotherapy arm will receive pemetrexed 500 mg/m + cisplatin 75 mg/m or carboplatin area under the curve (AUC) 5 or 6 every 3 weeks × 4 cycles, followed by pemetrexed 500 mg/m every 3 weeks. In the afatinib arm, investigators will choose the starting dose of afatinib (30 mg or 40 mg orally daily). The primary endpoint is progression-free survival. A total of 106 patients will be enrolled in this trial over a 30-month registration period with a 15-month follow-up. Enrollment began in March 2019. The results of this trial will establish the superiority of afatinib over chemotherapy in a cohort with a large variety of EGFR mutations.
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http://dx.doi.org/10.1016/j.cllc.2020.05.011DOI Listing
November 2020

Clinical and virologic features of hepatitis E virus infection at a university hospital in Japan between 2000 and 2019.

J Med Virol 2020 Jul 1. Epub 2020 Jul 1.

Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Shimotsuke, Japan.

The clinical and virologic features of hepatitis E virus (HEV) infection seem to vary among regions even in developed countries. However, we have little information on the diversity of HEV infection. Here, we investigated the characteristics of 26 patients in our hospital located in Tochigi prefecture, 90 km north of Tokyo, between 2000 and 2019. The reported number of patients with acute hepatitis E is increasing in Japan because measurement of IgA-class anti-HEV antibody was commercially available from 2011. In contrast, the numbers at our hospital were 1.5/y and 1.0/y in 2000 to 2011 and 2012 to 2019, respectively. This is attributed to the fact that we have been investigating HEV as a cause of unknown hepatitis before 2011. Among isolated HEV subgenotypes, including 3a, 3b, 4b, 4c, and 4d, all three patients with subgenotype 4c infection presented acute liver failure. Four HEV strains shared more than or equal to 99% identity within the 412-nucleotide partial sequence, in which the time and place of HEV infection varied, except for one intrafamilial infection. In addition, some strains were similar to HEV strains isolated far from Tochigi prefecture. In conclusion, the number of patients with acute hepatitis E was not increasing at Jichi Medical University Hospital and some strains were found to circulate in Japan.
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http://dx.doi.org/10.1002/jmv.26248DOI Listing
July 2020

Phase I/II study of carboplatin plus weekly nab-paclitaxel in patients aged ≥75 years with squamous-cell lung cancer: TORG1322.

Lung Cancer 2020 08 19;146:182-188. Epub 2020 May 19.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Objectives: This phase I/II study assessed the efficacy and safety of combination therapy with carboplatin (CBDCA) and nab-paclitaxel (nab-PTX) in advanced elderly patients (aged ≥75 years) with advanced squamous cell lung cancer (SqCLC).

Materials And Methods: In this phase I study, the doses of carboplatin at an area under the curve (AUC) of 5 or 6 mg/mL/min on day 1 (levels 1 and 2, respectively) were administered along with weekly nab-PTX (100 mg/m) on days 1, 8, and 15 every 4 weeks for up to 6 cycles using a modified 3 + 3 design. The primary endpoint for the phase II study was the 6-month progression-free survival (6 m PFS) rate.

Results: A total of 46 patients were enrolled in this study. Ten patients were enrolled in the phase I part. At dose level 1, 2/7 patients showed dose-limiting toxicities (DLTs) of grade 3 diarrhea and febrile neutropenia; at dose level 2, 1/3 patient exhibited grade 3 anorexia as a DLT. The recommended dose was determined to be level 2. Efficacy was then evaluated in 39 patients enrolled in a phase II study. The median number of cycles was 4 (range, 1-6), and the median follow-up time was 17.5 months (range, 5.6-28.9 months). The 6 m PFS rate was 59.4% (90% confidence interval [CI], 44.8%-71.4%), and the primary endpoint was met. The median overall survival time was 23.5 months (95% CI, 11.6-35.4), and the median PFS was 6.8 months (95% CI, 5.4-9.1). The response rate was 54%, and the disease control rate was 92%. Sixteen patients (41%) received immune checkpoint inhibitors post-study. Common grade 3 or 4 toxicities were neutropenia (61.5%), anemia (46.2%), thrombocytopenia (17.9%), and febrile neutropenia (15.4%).

Conclusion: Combination chemotherapy consisting of CBDCA with weekly nab-PTX had a promising efficacy and acceptable toxicities in elderly patients (aged ≥75 years) with advanced SqCLC.
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http://dx.doi.org/10.1016/j.lungcan.2020.05.005DOI Listing
August 2020

Rationale and protocol design for the TORG1835/NEXT-SHIP study: a phase II study of carboplatin, etoposide and nintedanib for unresectable limited/extensive disease small cell lung cancer with idiopathic pulmonary fibrosis.

Ther Adv Med Oncol 2020 18;12:1758835920923431. Epub 2020 May 18.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Background: Interstitial pneumonia (IP) is one of the most common and poor prognostic comorbidities in patients with small cell lung cancer (SCLC). The pharmacotherapy for SCLC occasionally induces fatal acute exacerbation of comorbid IP, especially in patients with idiopathic pulmonary fibrosis (IPF). Safe and effective pharmacotherapy is of greater importance in patients with SCLC and IPF, because SCLC presents a poor prognosis without systemic treatment. Nintedanib is expected to restrain acute exacerbation and present angiogenesis-inhibiting effects.

Methods: The TORG1835/NEXT-SHIP study is the world's first multi-center, single-arm, phase II trial for unresectable limited or extensive disease SCLC with IPF. The patients receive carboplatin (area under the curve 5, day 1), etoposide (<75 years old: 100 mg/m; ⩾75 years old: 80 mg/m; days 1-3), and nintedanib (150 mg twice a day) every 3 weeks for four cycles. After completion or discontinuation of carboplatin plus etoposide, the patients continue nintedanib until the discontinuation criteria are met. The primary endpoint is the incidence of acute exacerbation of IPF at 28 days after last administration of cytotoxic anti-cancer agents. We set an expected value of 5% and a threshold value of 20%. Taking statistical points (a/b errors: 0.05/0.75) and ineligible patients into account, the sample size was set at 33. The key secondary endpoints are time to first acute exacerbation of IPF, overall response rate, progression-free survival, overall survival, and toxicities.

Discussion: Because there is no clinical trial for unresectable SCLC with IPF, our study would provide a major impact on clinical practice.

Trial Registration: Japan Registry of Clinical Trials, jRCTs031190119, registered date: October 18, 2019 - Retrospectively registered, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190119.
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http://dx.doi.org/10.1177/1758835920923431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238300PMC
May 2020

Update: proposed reference sequences for subtypes of hepatitis E virus (species ).

J Gen Virol 2020 07;101(7):692-698

Centers for Disease Control and Prevention, National Center for HIV/Hepatitis/STD/TB Prevention, Division of Viral Hepatitis, Atlanta, Georgia, USA.

In this recommendation, we update our 2016 table of reference sequences of subtypes of hepatitis E virus (HEV; species , family ) for which complete genome sequences are available (Smith ., 2016). This takes into account subsequent publications describing novel viruses and additional proposals for subtype names; there are now eight genotypes and 36 subtypes. Although it remains difficult to define strict criteria for distinguishing between virus subtypes, and is not within the remit of the International Committee on Taxonomy of Viruses (ICTV), the use of agreed reference sequences will bring clarity and stability to researchers, epidemiologists and clinicians working with HEV.
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http://dx.doi.org/10.1099/jgv.0.001435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660235PMC
July 2020

A phase II study of atezolizumab for pretreated advanced/recurrent non-small cell lung cancer with idiopathic interstitial pneumonias: rationale and design for the TORG1936/AMBITIOUS study.

Ther Adv Med Oncol 2020 8;12:1758835920922022. Epub 2020 May 8.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama-city, Kanagawa Prefecture, Japan.

Background: Approximately 10% of patients with non-small cell lung cancer (NSCLC) are complicated with comorbid interstitial pneumonia (IP) with a poor prognosis. The pharmacotherapy for advanced lung cancer occasionally induces fatal acute exacerbation of pre-existing IP. Due to the lack of prospective studies, there is an urgent need to establish a safe and effective pharmacotherapy, especially for second-line or later settings. Atezolizumab, an anti-programmed cell death-ligand 1 antibody, is thought to be the safest candidate for second-line therapy among various immune checkpoint inhibitors. Moreover, compared with patients without IP, the patients with comorbid IP may have higher tumor mutation burden (TMB) or microsatellite instability (MSI), which are partly associated with a more favorable response to immune checkpoint inhibitors.

Methods: The Thoracic Oncology Research Group 1936/AMBITIOUS study is an ongoing, multicenter, single-arm, phase II trial to assess the safety and efficacy of atezolizumab for pretreated advanced/recurrent patients with NSCLC complicated with idiopathic, chronic fibrotic IP with a forced vital capacity of >70%. The patients will receive atezolizumab (1200 mg, day 1) every 3 weeks until the discontinuation criteria are met. The primary end point of this study is the 1-year survival rate, and a sample size of 38 patients is set. As a translational research, we will perform the analysis of TMB, somatic mutations, and MSI for nucleic acids extracted from archival tumor samples.

Discussion: Since there is no standard second-line or later therapy of advanced NSCLC with IP, the results of this study are expected to have a major impact on clinical practice.

Trial Registration: Japan Registry of Clinical Trials, jRCTs031190084, registered 26 August 2019 - retrospectively registered, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190084.
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http://dx.doi.org/10.1177/1758835920922022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222231PMC
May 2020

Low-Dose Erlotinib Treatment in Elderly or Frail Patients With EGFR Mutation-Positive Non-Small Cell Lung Cancer: A Multicenter Phase 2 Trial.

JAMA Oncol 2020 07 9;6(7):e201250. Epub 2020 Jul 9.

Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Importance: Although the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for EGFR gene mutation-positive non-small cell lung cancer is well established, optimal dosing remains to be established, especially in elderly or frail patients.

Objective: To investigate the efficacy and safety of low-dose erlotinib in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer.

Design, Setting, And Participants: Single-arm phase 2 trial with the Southwest Oncology Group (SWOG) 2-stage design that enrolled frail patients from 21 Japanese institutions after meeting the inclusion criteria. Chemotherapy-naive patients with EGFR-activating mutation-positive non-small cell lung cancer who were considered frail based on age, the Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status were eligible for the study.

Interventions: Patients were initially administered 50 mg/d erlotinib for 4 weeks, which was modified based on response or adverse events. Dose increase was permitted for patients with stable disease after 4 weeks.

Main Outcomes And Measures: The primary end point was the independent review committee-confirmed objective response rate (ORR) at the dose of 50 mg/d. The study also evaluated the pharmacokinetics of low-dose erlotinib and influence of ABCB1 gene polymorphisms.

Results: Eighty patients were enrolled, with a median (range) age of 80 (49-90) years; 54 (68%) were men. An independent review committee confirmed a significant ORR of 60.0% (90% CI, 50.2%-69.2%). The disease control rate was 90.0% (90% CI, 82.7%-94.9%), median progression-free survival was 9.3 months (95% CI, 7.2-11.4 months), and median overall survival was 26.2 months (95% CI, 21.9-30.4 months). Mild adverse events were observed in some participants, with few patients exhibiting grade 3 or greater adverse events. Low-dose erlotinib treatment was temporarily suspended for 10 patients owing to adverse events. Five of 80 patients (6%) had their erlotinib dose reduced to 25 mg because of oral mucositis, paronychia, erythema multiforme, diarrhea, and anorexia. Two patients discontinued treatment because of adverse events (cutaneous ulcer and bone infection, and oral mucositis, respectively). There were no cases of interstitial lung disease or treatment-related deaths. The median (range) erlotinib plasma concentration was measured at 685 (153-1950) ng/mL. Seventy-three patients discontinued study treatment owing to disease progression (n = 60), death (n = 3), AEs (n = 4), and patient requests (n = 6). No clear association was observed between the pharmacokinetics of low-dose erlotinib and the treatment outcome.

Conclusions And Relevance: Low-dose erlotinib appears to be safe and effective in elderly or frail patients with EGFR mutation-positive non-small cell lung cancer and can be a valid treatment option.

Trial Registration: UMIN-CTR Identifier: UMIN000015949.
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http://dx.doi.org/10.1001/jamaoncol.2020.1250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226294PMC
July 2020

Randomized Phase III Study of Pemetrexed Plus Cisplatin Versus Vinorelbine Plus Cisplatin for Completely Resected Stage II to IIIA Nonsquamous Non-Small-Cell Lung Cancer.

J Clin Oncol 2020 07 14;38(19):2187-2196. Epub 2020 May 14.

Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.

Purpose: To evaluate the efficacy of pemetrexed plus cisplatin versus vinorelbine plus cisplatin as postoperative adjuvant chemotherapy in patients with pathologic stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC).

Patients And Methods: We performed a randomized, open-label, phase III study at 50 institutions within 7 clinical study groups in Japan. Patients with completely resected pathologic stage II-IIIA (TNM 7th edition) nonsquamous NSCLC were randomly assigned to receive either pemetrexed (500 mg/m, day 1) plus cisplatin (75 mg/m, day 1) or vinorelbine (25 mg/m, days 1 and 8) plus cisplatin (80 mg/m, day 1) with stratification by sex, age, pathologic stage, mutation, and institution. These treatments were planned to be given every 3 weeks for 4 cycles. The primary end point was recurrence-free survival in the modified intent-to-treat population, excluding ineligible patients.

Result: Between March 2012 and August 2016, 804 patients were enrolled (402 assigned to vinorelbine plus cisplatin and 402 assigned to pemetrexed plus cisplatin). Of 784 eligible patients, 410 (52%) had stage IIIA disease and 192 (24%) had -sensitive mutations. At a median follow-up of 45.2 months, median recurrence-free survival was 37.3 months for vinorelbine plus cisplatin and 38.9 months for pemetrexed plus cisplatin, with a hazard ratio of 0.98 (95% CI, 0.81 to 1.20; 1-sided = .474). Grade 3-4 toxicities reported more frequently for vinorelbine plus cisplatin than for pemetrexed plus cisplatin were febrile neutropenia (11.6% 0.3%, respectively), neutropenia (81.1% 22.7%, respectively), and anemia (9.3% 2.8%, respectively). One treatment-related death occurred in each arm.

Conclusion: Although this study failed to show the superiority of pemetrexed plus cisplatin for patients with resected nonsquamous NSCLC, this regimen showed a better tolerability as adjuvant chemotherapy.
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http://dx.doi.org/10.1200/JCO.19.02674DOI Listing
July 2020

Association between elcatonin use and cancer risk in Japan: A follow-up study after a randomized, double-blind, placebo-controlled study of once-weekly elcatonin in primary postmenopausal osteoporosis.

Osteoporos Sarcopenia 2020 Mar 5;6(1):15-19. Epub 2020 Mar 5.

Eikokai Ono Hospital, Ono, Hyogo, Japan.

Objectives: On July 20, 2012, the European Medicines Agency (EMA) provided a recommendation that limits the long-term use of calcitonin. Based on this recommendation, we investigate the presence or absence of a cancer diagnosis in subjects who participated in the ongoing clinical trial of elcatonin.

Methods: When the EMA gave this recommendation, we were conducting "a 3-year placebo-controlled clinical study for elcatonin" (hereinafter, referred to as "the original study"). In accordance with the recommendation of EMA, we performed an intermediate analysis on the subjects of the original study to assess whether the study could be safely continued. We also added a 2-year follow-up study to investigate the risk of carcinogenesis for 5 years from the start of administration. We compared the risk of carcinogenesis estimated by person-year method in elcatonin group with that in placebo group.

Results: In the original study, there were 433 subjects in the elcatonin group and 437 in the placebo group, of whom 322 and 323, respectively, agreed to participate in the additional follow-up study. The average cancer incidence rate per 100 person-years 5 years from the start of administration was 1.02 in the elcatonin group and 1.08 in the placebo group, respectively, and there was no clear difference.

Conclusions: Since the number of cases in this study was small, we cannot completely deny the cancer risk due to long-term administration of this drug. However, the results do not suggest that once-weekly administration of 20 units of elcatonin increases the carcinogenic risk.
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http://dx.doi.org/10.1016/j.afos.2020.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093680PMC
March 2020

Comparison of Carboplatin Plus Pemetrexed Followed by Maintenance Pemetrexed With Docetaxel Monotherapy in Elderly Patients With Advanced Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

JAMA Oncol 2020 05 14;6(5):e196828. Epub 2020 May 14.

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

Importance: Few clinical trials have been specifically designed for elderly patients with advanced non-small cell lung cancer (NSCLC), and the anticipated increase in the number of such patients has prompted a search for new treatment options that provide a greater palliative benefit.

Objective: To determine whether treatment with carboplatin plus pemetrexed followed by pemetrexed maintenance is noninferior compared with docetaxel monotherapy with regard to overall survival (OS) for elderly patients with advanced nonsquamous NSCLC.

Design, Setting, And Participants: This open-label, multicenter, noninferiority phase 3 randomized clinical trial was conducted at 79 institutions in Japan. Cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and age of 75 years or older were enrolled between August 2013 and February 2017. Data were analyzed from November 2018 to February 2019.

Interventions: Patients were randomized to receive either docetaxel monotherapy (60 mg/m2) every 3 weeks or 4 cycles of carboplatin (area under the curve of 5) plus pemetrexed (500 mg/m2) administered every 3 weeks followed by maintenance therapy with the same dose of pemetrexed for 3 weeks.

Main Outcomes And Measures: The primary end point was OS analyzed on an intention-to-treat basis with a noninferiority margin of 1.154 for the upper limit of the 95% CI of the hazard ratio (HR) estimated with a stratified Cox regression model.

Results: Of the 433 enrolled patients, 250 (57.7%) were male, and the median (range) age was 78 (75-88) years. The median OS was 15.5 months (95% CI, 13.6-18.4) in the docetaxel group (n = 217) and 18.7 months (95% CI, 16.0-21.9) in the carboplatin-pemetrexed group (n = 216), with a stratified HR for OS of 0.850 (95% CI, 0.684-1.056; P for noninferiority = .003). Progression-free survival was also longer in the carboplatin-pemetrexed group (unstratified HR, 0.739; 95% CI, 0.609-0.896). Compared with those in the docetaxel group, those in the carboplatin-pemetrexed had lower rates of leukopenia (60 of 214 [28.0%] vs 147 of 214 [68.7%]) and neutropenia (99 of 214 [46.3%] vs 184 of 214 [86.0%]) of grade 3 or 4 and of febrile neutropenia (9 of 214 [4.2%] vs 38 of 214 [17.8%]) and higher rates of thrombocytopenia (55 of 214 [25.7%] vs 3 of 214 [1.4%]) and anemia (63 of 214 [29.4%] vs 4 of 214 [1.9%]) of grade 3 or 4. Dose reductions were less frequent with carboplatin-pemetrexed.

Conclusion And Relevance: Carboplatin-pemetrexed treatment followed by pemetrexed maintenance is a valid option for first-line treatment of elderly patients with advanced nonsquamous NSCLC.

Trial Registration: University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000011460.
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http://dx.doi.org/10.1001/jamaoncol.2019.6828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068674PMC
May 2020

Bronchial Sleeve Resection and Double-Barreled Reconstruction for a Carcinoid Tumor.

Ann Thorac Surg 2020 07 28;110(1):e67-e69. Epub 2020 Feb 28.

Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Yokohama, Japan.

Sleeve resection and double-barreled reconstruction are very rarely adopted for peripheral bronchial tumors. This surgical procedure was used for a carcinoid tumor in the bifurcation of the left upper and lower lobe bronchi. Bronchoplasty was accomplished by suturing the upper and basal bronchi together and anastomosing them to the left main bronchus. The techniques for double-barreled reconstruction described in this report obtained a successful result. These manipulations may be applicable to resection of other bronchial and tracheal bifurcations.
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http://dx.doi.org/10.1016/j.athoracsur.2020.01.032DOI Listing
July 2020

Efficacy of PD-1 Inhibitors in Older Non-small Cell Lung Cancer Patients.

Anticancer Res 2020 Feb;40(2):923-928

Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan.

Background/aim: We assessed the efficacy of immune checkpoint inhibitors (ICIs) in older patients because of the limited information regarding these patients.

Patients And Methods: We retrospectively analyzed 66 consecutive patients ≥70 years old with advanced non-small cell lung cancer (NSCLC). A total of 31 patients received ICIs (ICIs group) and 35 patients received only cytotoxic regimens (No ICIs group).

Results: Patients with squamous cell carcinoma who received ICIs had better overall survival (OS) than those who did not (9.7 versus 4.7 months, p=0.027). In multivariate analysis, treatment with ICIs [hazard ratio (HR)=0.54, 95% confidence interval (CI)=0.30-0.98, p=0.044], good performance status (HR=0.30, 95%CI=0.16-0.57, p=0.0003), and histology other than squamous cell carcinoma (HR=0.41, 95%CI=0.19-0.83, p=0.014) were significantly favorable factors for OS.

Conclusion: ICIs may be effective for older patients with NSCLC, especially squamous cell carcinoma patients.
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http://dx.doi.org/10.21873/anticanres.14025DOI Listing
February 2020

Multivesicular body sorting and the exosomal pathway are required for the release of rat hepatitis E virus from infected cells.

Virus Res 2020 03 18;278:197868. Epub 2020 Jan 18.

Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken, 329-0498, Japan. Electronic address:

Recent reports have shown that rat hepatitis E virus (HEV) is capable of infecting humans. We also successfully propagated rat HEV into human PLC/PRF/5 cells, raising the possibility of a similar mechanism shared by human HEV and rat HEV. Rat HEV has the proline-rich sequence, PxYPMP, in the open reading frame 3 (ORF3) protein that is indispensable for its release. However, the release mechanism remains unclear. The overexpression of dominant-negative (DN) mutant of vacuolar protein sorting (Vps)4A or Vps4B decreased rat HEV release to 23.9 % and 18.0 %, respectively. The release of rat HEV was decreased to 8.3 % in tumor susceptibility gene 101 (Tsg101)-depleted cells and to 31.5 % in apoptosis-linked gene 2-interacting protein X (Alix)-depleted cells. Although rat HEV ORF3 protein did not bind to Tsg101, we found a 90-kDa protein capable of binding to wild-type rat HEV ORF3 protein but not to ORF3 mutant with proline to leucine mutations in the PxYPMP motif. Rat HEV release was also decreased in Ras-associated binding 27A (Rab27A)- or hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs)-depleted cells (to 20.1 % and 18.5 %, respectively). In addition, the extracellular rat HEV levels in the infected PLC/PRF/5 cells were increased after treatment with Bafilomycin A1 and decreased after treatment with GW4869. These results indicate that rat HEV utilizes multivesicular body (MVB) sorting for its release and that the exosomal pathway is required for rat HEV egress. A host protein alternative to Tsg101 that can bind to rat HEV ORF3 should be explored in further study.
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http://dx.doi.org/10.1016/j.virusres.2020.197868DOI Listing
March 2020

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

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

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

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

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

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

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