Publications by authors named "Hidetoshi Itani"

10 Publications

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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

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

Pulmonary nocardiosis caused by in an immunocompetent patient.

Respir Med Case Rep 2020 25;29:101005. Epub 2020 Jan 25.

Department of Respiratory Medicine and Allergy, Tosei General Hospital, 160 Nishioiwake-cho, Seto, Aichi, 489-8642, Japan.

A subset of isolates, previously belonging to has recently been given the new species designation . Here we report a case of pulmonary nocardiosis caused by in a 52-year-old immunocompetent woman presenting with low-grade fever and fatigue. The isolated strain was resistant to sulfamethoxazole-trimethoprim and amikacin, but susceptible to amoxicillin-clavunate, ceftriaxone, clarithromycin and linezolid. With amoxicillin-clavunate treatment, the patient recovered and her condition remained stable, although recurrence occurred after cessation of the initial treatment. While infection by is rare, clinicians should be aware of its resistance to antimicrobials including amikacin and sulfamethoxazole-trimethoprim.
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http://dx.doi.org/10.1016/j.rmcr.2020.101005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997618PMC
January 2020

Interstitial pneumonitis associated with dasatinib: two case reports and literature review.

Respir Investig 2019 Sep 13;57(5):506-509. Epub 2019 Jul 13.

Department of Hematology, Japanese Red Cross Ise Hospital, 1-471-2 Funae, Ise 516-8512, Japan. Electronic address:

Dasatinib has increasingly been used to treat chronic myeloid leukemia (CML), although interstitial pneumonitis has been found as a complication in large clinical trials. In the present study, 23 patients received dasatinib for CML between 2012 and 2017 at our institution, of whom 2 developed symptomatic interstitial pneumonitis. Notably, the first patient developed interstitial pneumonitis five years after initiating dasatinib. Interstitial pneumonitis should be considered as a complication in patients receiving dasatinib for CML, which may even occur after a long period of uncomplicated administration.
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http://dx.doi.org/10.1016/j.resinv.2019.06.002DOI Listing
September 2019

Chronic Nodular Pulmonary Aspergillosis in a Patient with Rheumatoid Arthritis.

Intern Med 2019 1;58(7):979-984. Epub 2019 Apr 1.

National Institute of Infectious Diseases, Japan.

Chronic pulmonary aspergillosis, which features nodular lesions known as Aspergillus nodules, is a relatively uncommon disorder. We herein report a case of slowly progressing chronic multiple nodular pulmonary aspergillosis in a 59-year-old man with rheumatoid arthritis, dyspnea, and fatigue. One nodule was surgically resected. The surgical specimen featured central necrosis and was located adjacent to a respiratory bronchiole and pulmonary artery, without parenchymal invasion. Branching septate hyphae, compatible with Aspergillus, were seen inside this necrotic nodule. Chronic pulmonary aspergillosis should therefore be considered in the differential diagnosis of patients who present with slowly progressing pulmonary multiple nodules.
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http://dx.doi.org/10.2169/internalmedicine.1918-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478981PMC
May 2019

Prospective exosome-focused translational research for afatinib study of non-small cell lung cancer patients expressing EGFR (EXTRA study).

Thorac Cancer 2019 02 8;10(2):395-400. Epub 2018 Dec 8.

Division of Medical Oncology, Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) exhibit resistance to EGFR-tyrosine kinase inhibitors (TKIs) within 9-14 months of therapy. Recently, EGFR-mutated NSCLC has demonstrated the potential for heterogeneity; therefore, the manner of clonal heterogeneity may impact the duration of progression-free and overall survival and other parameters affecting EGFR-TKI treatment efficacy. However no predictive biomarker of these favorable treatment efficacies has been identified to date. The exosome-focused translational research for afatinib (EXTRA) study aims to identify a novel predictive biomarker and a resistance marker for afatinib by analyzing data from association studies of the clinical efficacy of afatinib and four "OMICs" (genomics, proteomics, epigenomics, and metabolomics) using peripheral blood from patients treated with afatinib. This study aims to: (i) conduct comprehensive multi-OMIC analyses in a prospective clinical trial, and (ii) focus on both sera/plasma and exosome as a source for OMIC analyses to identify a novel predictor of the efficacy of a specific drug. To eliminate the carryover bias of prior treatment, systemic treatment-naïve patients were enrolled. The candidates to be screened for biomarkers comprise a discovery cohort of 60 patients and an independent validation cohort of 40 patients. The EXTRA study is the first trial to screen novel biomarkers of longer treatment efficacy of EGFR-TKIs using four-OMICs analyses, focusing on both "naked or free" molecules and "capsulated" exosomal components in serially collected peripheral blood.
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http://dx.doi.org/10.1111/1759-7714.12923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360199PMC
February 2019

Ovarian Metastases from ALK-rearranged Lung Adenocarcinoma: A Case Report and Literature Review.

Intern Med 2018 Nov 6;57(22):3271-3275. Epub 2018 Jul 6.

Department of Respiratory Medicine, Japanese Red Cross Ise Hospital, Japan.

We herein report a 37-year-old woman with lung adenocarcinoma with brain metastases and an asymptomatic ovarian tumor. Immunohistochemistry and a fluorescent in situ hybridization analysis of the biopsied lung tumor revealed anaplastic lymphoma kinase (ALK) gene rearrangement. Although the origin of the ovarian tumor remained unclear, alectinib administration was initiated, and radiological responses were observed in all lesions, which confirmed that the ovarian tumor was a metastasis from lung cancer. Although differentiating the origin of an ovarian tumor is difficult in lung cancer patients due to the rarity of ovarian metastases, alectinib therapy can replace an invasive biopsy, especially in ALK-rearranged lung cancer patients.
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http://dx.doi.org/10.2169/internalmedicine.0538-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287983PMC
November 2018

Lung abscess caused by serotype 6B.

Respir Med Case Rep 2018 20;23:71-73. Epub 2017 Dec 20.

Department of Respiratory Medicine, Ise Red Cross Hospital, Ise, Japan.

Lung abscess has been considered to be a rare complication of pneumococcal infection, and most cases are reported to be serotype 3. A 67-year-old man presented with fever and was diagnosed to have lung abscess caused by serotype 6B. The minimal inhibitory concentration (MIC) of penicillin for the isolate was 1 μg/mL. He was treated with high-dose intravenous sulbactam/ampicillin as definitive therapy based on susceptibility testing for and recovered successfully without surgical intervention. serotype 6B can cause lung abscess.
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http://dx.doi.org/10.1016/j.rmcr.2017.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805848PMC
December 2017

Sequential Therapy with Crizotinib and Alectinib in ALK-Rearranged Non-Small Cell Lung Cancer-A Multicenter Retrospective Study.

J Thorac Oncol 2017 02 4;12(2):390-396. Epub 2016 Aug 4.

Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan.

Introduction: Alectinib and crizotinib have been approved for the therapy of NSCLC caused by anaplastic lymphoma kinase gene (ALK) rearrangement. The effect of alectinib or crizotinib on overall survival (OS) in patients with ALK-rearranged NSCLC remains unknown.

Methods: A multicenter retrospective study was conducted to compare OS between patients receiving alectinib and crizotinib and between patients treated with alectinib and those treated sequentially with crizotinib and then alectinib after crizotinib failure. The time to treatment failure (TTF), progression-free survival (PFS), and OS were compared.

Results: Sixty-one patients with ALK-rearranged NSCLC were enrolled. Forty-six patients were treated with anaplastic lymphoma kinase (ALK) inhibitors (31 with crizotinib, 28 with alectinib, and 13 with both ALK inhibitors). The response rate was 66.7% for the crizotinib-treated group and 80.8% for the alectinib-treated group. Among all patients, TTF and PFS were significantly prolonged in the alectinib-treated group compared with in the crizotinib-treated group. Subgroup analyses revealed significantly prolonged TTF for alectinib compared with crizotinib therapy in the ALK inhibitor-naive population. OS was significantly longer in the alectinib-treated group than in the crizotinib-treated group. The TTF and OS of patients treated sequentially with crizotinib and then with alectinib after crizotinib failure tended to be longer than those of patients treated with alectinib alone.

Conclusions: Therapy with alectinib alone was significantly superior to therapy with crizotinib alone in terms of TTF, PFS, and OS, and sequential therapy with crizotinib and alectinib after crizotinib failure tended to provide a better OS benefit than did therapy with alectinib alone in patients with ALK-positive NSCLC. However, large-scale prospective studies are needed to confirm these observations.
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http://dx.doi.org/10.1016/j.jtho.2016.07.022DOI Listing
February 2017

Short hydration in chemotherapy containing cisplatin (≥75 mg/m2) for patients with lung cancer: a prospective study.

Jpn J Clin Oncol 2013 Nov 4;43(11):1105-9. Epub 2013 Sep 4.

*Division of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan.

Objective: We previously reported that 22% of lung cancer patients experienced a Grade 2 or 3 elevation in creatinine after chemotherapy containing cisplatin. We conducted a Phase II trial to evaluate the safety and efficacy of short hydration.

Methods: The major eligibility criteria included patients with lung cancer for whom a ≥75 mg/m(2) cisplatin-based regimen was indicated and adequate organ function. Cisplatin was administered with pre- and post-hydration containing 10 mEq of potassium chloride in 500 ml of fluid over a 60-min period. Immediately before the administration of cisplatin, mannitol (20%, 200 ml) was administered as forced diuresis over 30 min. And magnesium sulfate (8 mEq) was added to pre-hydration.

Results: Forty-four patients were enrolled between April and December 2011. The patients included 29 men and 15 women with a median (range) age of 64 (42-74) years. Twenty patients received cisplatin and pemetrexed as their most frequent regimen and 38 patients received three to four cycles of chemotherapy. The median (range) duration and volume of the chemotherapies were 4.0 (3.3-6.8) h and 1600 (1550-2050) ml, respectively. Of the 44 patients, 43 (97.8%) completed the cisplatin-based chemotherapy without Grade 2 or higher renal dysfunction. The only patient who had Grade 2 elevation in creatinine (maximum value 1.7 mg/dl) had prompt improvement in creatinine levels and completed four cycles of chemotherapy.

Conclusions: The short hydration is safe without severe renal toxicities in regimens containing cisplatin (≥75 mg/m(2)) for patients with lung cancer.
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http://dx.doi.org/10.1093/jjco/hyt122DOI Listing
November 2013