16 results on '"Toshiyuki Nakai"'
Search Results
2. Pleural staging using local anesthetic thoracoscopy in dry pleural dissemination and minimal pleural effusion
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Tatsuya Imabayashi, Yuji Matsumoto, Toshiyuki Nakai, Midori Tanaka, and Takaaki Tsuchida
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Male ,non‐small cell lung cancer ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,medicine.drug_class ,Pleural effusion ,Dry pleural dissemination ,lcsh:RC254-282 ,03 medical and health sciences ,0302 clinical medicine ,minimal pleural effusion ,Blunt dissection ,Thoracoscopy ,Humans ,Medicine ,interventional pulmonology ,Anesthetics, Local ,Aged ,Neoplasm Staging ,Lung ,medicine.diagnostic_test ,business.industry ,Local anesthetic ,Original Articles ,General Medicine ,respiratory system ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,respiratory tract diseases ,Pleural Effusion ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Adenocarcinoma ,Female ,Original Article ,Non small cell ,Radiology ,local anesthetic thoracoscopy ,business ,Pleural biopsy - Abstract
Background Dry pleural dissemination (DPD) and minimal (, Local anesthetic thoracoscopy using a single‐puncture technique with a flex‐rigid pleuroscope might be a useful tool for accurate pleural staging in cases wherein dry pleural dissemination and minimal pleural effusion were suspected radiologically.
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- 2021
3. Feasibility study of cryobiopsy for practical pathological diagnosis of primary lung cancer including immunohistochemical assessment
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Shinji Sasada, Yuichiro Ohe, Ryuta Fukai, Toshiyuki Nakai, Yuji Matsumoto, Midori Tanaka, Tomoki Nishida, Shun-ichi Watanabe, and Noriko Motoi
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Adult ,Male ,0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Biopsy ,Concordance ,Adenocarcinoma ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Biomarkers, Tumor ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Lung cancer ,Lung ,Pathological ,Aged ,Tumor marker ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Thyroid ,General Medicine ,Middle Aged ,medicine.disease ,Immunohistochemistry ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Feasibility Studies ,Female ,business ,Cryoultramicrotomy - Abstract
Background Precision medicine in non-small cell lung cancer requires attainment of a sufficient amount of high-quality tumor tissue. Transbronchial cryobiopsy has emerged as a new diagnostic method for non-neoplastic lung disease with a better potential to assess morphology compared with conventional methods. However, the influence of cryobiopsy on specimen quality, particularly detection of protein expression, is unknown. We performed a comparative immunohistochemical study in specimens obtained by cryobiopsy versus conventional sampling to evaluate the feasibility of cryobiopsy for lung cancer diagnosis. Methods Pairs of artificial biopsy specimens, collected using a cryoprobe or conventional scalpel, were obtained from 43 surgically resected primary lung tumors. Formalin-fixed, paraffin-embedded blocks were prepared in an ISO15189-certified laboratory. Immunohistochemical staining of thyroid transcription factor-1, p40, Ki67 and programmed death-ligand 1 (22C3) was performed. The H-scores for thyroid transcription factor-1 and p40, labeling index for Ki67 and tumor proportion score for programmed death-ligand 1 were assessed. Pearson’s correlation coefficients between two sampling types were calculated. Results The thyroid transcription factor-1 and p40 H-scores showed perfect correlations between the cryobiopsy and conventional scalpel-obtained specimens (R2 = 0.977 and 0.996, respectively). Ki67 labeling index and PD-L1 tumor proportion score also showed strong correlations between the two sample types (R2 = 0.896 and 0.851, respectively). Five cases (11.6%) exhibited differences in tumor proportion score category between sample types, potentially because of intratumoral heterogeneity. Conclusions Immunohistochemical expression of certain tumor markers showed a high concordance between cryobiopsy and conventional scalpel sampling. Cryobiopsy is feasible for pathological diagnostics including PD-L1 evaluation.
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- 2020
4. Phase II Study of the Modified Weekly Nab-paclitaxel Regimen in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer
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Kazuhisa Asai, Kazuto Hirata, Tatsuo Kimura, Yoshiya Matsumoto, Takashi Yana, Tomoya Kawaguchi, Kenji Sawa, Toshiyuki Nakai, Shigeki Mitsuoka, and Naruo Yoshimura
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Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Paclitaxel ,Phases of clinical research ,Neutropenia ,Gastroenterology ,Drug Administration Schedule ,Internal medicine ,Albumins ,Carcinoma, Non-Small-Cell Lung ,medicine ,Clinical endpoint ,Humans ,Lung cancer ,Aged ,Aged, 80 and over ,Leukopenia ,business.industry ,Middle Aged ,medicine.disease ,Chemotherapy regimen ,Antineoplastic Agents, Phytogenic ,Progression-Free Survival ,Regimen ,Treatment Outcome ,Oncology ,Female ,medicine.symptom ,business ,Febrile neutropenia - Abstract
Objectives We conducted a clinical phase II study to evaluate the modified weekly nanoparticle albumin-bound paclitaxel (nab-paclitaxel) regimen in pretreated patients with advanced non-small cell lung cancer (NSCLC). Materials and methods This multicenter single-arm phase II study enrolled patients with advanced NSCLC who had previously received >1 chemotherapy regimen. Patients received nab-paclitaxel at 80 mg/m2 on days 1, 8, and 15 (21-d cycle). The primary endpoint was the investigator-assessed overall response rate (ORR). Secondary endpoints included overall survival, progression-free survival (PFS), disease control rate, and safety. The planned enrollment was 30 patients according to a Simon 2-stage minimax design. Results Thirty patients were enrolled between November 2015 and August 2017. Seventeen patients (56.7%) had received >2 regimens. The ORR was 23.3% (95% confidence interval [CI], 8.2%-38.4%), meeting the primary objective of the study. Median PFS was 5.7 months (95% CI, 3.4-9.0 mo), and median overall survival was 12.6 months (95% CI, 8.7-20.8 mo). The median number of treatment cycles was 4 (range, 1 to 20) over the entire study period, and median dose intensity was 63.6 mg/m2/wk (range, 45.7 to 100.0 mg/m2/wk). No new safety signals were reported; the most common grade ≥3 adverse events were neutropenia (56.7%), leukopenia (23.3%), and infection (10.0%). No cases of febrile neutropenia were observed. Conclusions Nab-paclitaxel monotherapy with a dose and schedule suitable for outpatients showed high ORR, long median PFS, and acceptable toxicity for patients with previously treated NSCLC. This dosage method may be useful for selected patients.
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- 2021
5. Cryobiopsy during flex-rigid pleuroscopy: an emerging alternative biopsy method in malignant pleural mesothelioma. A comparative study of pathology
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Noriko Motoi, Yuji Matsumoto, Midori Tanaka, Yuichiro Ohe, Toshiyuki Nakai, Shinji Sasada, and Takaaki Tsuchida
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Male ,Mesothelioma ,Cancer Research ,medicine.medical_specialty ,Poor prognosis ,Lung Neoplasms ,Pleural effusion ,Biopsy ,Pleural Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Thoracoscopy ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Aged ,medicine.diagnostic_test ,Pleural mesothelioma ,business.industry ,Mesothelioma, Malignant ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,Oncology ,030220 oncology & carcinogenesis ,%22">Fish ,Female ,030211 gastroenterology & hepatology ,Radiology ,business ,Fluorescence in situ hybridization - Abstract
BACKGROUND Malignant pleural mesothelioma (MPM) is rarely an asbestos-related cancer with a poor prognosis that is difficult to distinguish from some benign conditions by using conventional biopsy techniques. The purpose of this study was to evaluate the utility of a novel biopsy technique using a cryoprobe during flex-rigid pleuroscopy for diagnosing MPM. METHODS Consecutive patients who underwent pleural cryobiopsy during flex-rigid pleuroscopy from June through November 2017 to diagnose the cause of pleural effusion were collected. From these, cases ultimately diagnosed as MPM were selected. Pleural biopsies were performed by using conventional instruments followed by a cryoprobe. The obtained samples were histologically examined and compared with regard to the quality (sample size, tissue depth, and crush rate), immunohistochemical (IHC) staining, and p16 by fluorescence in situ hybridization (FISH). RESULTS In total, five patients ultimately diagnosed as MPM were enrolled. The sample collected was significantly larger for cryobiopsy than conventional biopsy (18.9 mm2 vs. 6.7 mm2, P < 0.001). Full-thickness biopsies were achieved in four cases by using cryobiopsy compared with one case by conventional biopsy. Moreover, the crush rate was significantly less for cryobiopsy than conventional biopsy (9% vs. 35%, P < 0.001). The results of IHC staining and p16 by FISH were similar between biopsy techniques. Cryobiopsy successfully led to accurate diagnosis of MPM in all cases, whereas conventional biopsy was diagnostic in one case. No severe complications developed after either biopsy technique. CONCLUSION Cryobiopsy during flex-rigid pleuroscopy is a feasible and convenient biopsy technique that supports precise diagnosis of MPM.
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- 2019
6. Alectinib-Induced Erythema Multiforme and Successful Rechallenge with Alectinib in a Patient with Anaplastic Lymphoma Kinase-Rearranged Lung Cancer
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Toshiyuki Nakai, Kazuto Hirata, Masahiko Ohsawa, Tatsuo Kimura, Ayako Ohyama, Tomoya Kawaguchi, Junko Sowa-Osako, and Daisuke Tsuruta
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Alectinib ,medicine.medical_specialty ,Side effect ,EML4-ALK ,Case Report ,Rechallenge ,lcsh:RC254-282 ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Anaplastic lymphoma kinase ,Erythema multiforme ,Lung cancer ,Hypersensitivity syndrome ,business.industry ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Dermatology ,Lymphoma ,Hypersensitivity reaction ,Oncology ,030220 oncology & carcinogenesis ,Prednisolone ,business ,medicine.drug - Abstract
Background: Alectinib is an oral drug developed for the treatment of patients with fusion gene encoding echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK)-rearranged non-small cell lung cancer (NSCLC). Here, we present the case of a patient treated with alectinib who developed a hypersensitivity reaction with successful rechallenge treatment. Case Presentation: A 39-year-old woman who was a passive smoker was referred to Osaka City University Hospital for the evaluation of a skin event caused by treatment for NSCLC with the fusion gene EML4-ALK. The skin reaction was observed on the anterior chest, upper arms, and ear auricles on day 11 of treatment with oral alectinib. The skin event presented as widely distributed erythematous macules that were confluent, indicating a severe and life-threatening form. The skin lesions started to resolve after the initiation of treatment with 40 mg prednisolone. After regrowth of the tumor, she received a rechallenge program for alectinib for 2 weeks; thereafter, alectinib treatment was successfully reinitiated. Conclusion: To the best of our knowledge, we present the first case in which alectinib, which binds to the adenosine triphosphate site of EML4-ALK, induced erythema multiforme. Moreover, successful readministration of alectinib through our rechallenge program has not been reported so far.
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- 2016
7. C609T Polymorphism of NADPH Quinone Oxidoreductase 1 Correlates Clinical Hematological Toxicities in Lung Cancer Patients Treated with Amrubicin
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Shinzoh Kudoh, Kuniomi Matsuura, Naruo Yoshimura, Tomohiro Suzumura, Takako Oka, Misato Nagata, Yukimi Kira, Hidenori Tanaka, Kazuto Hirata, Shigeki Mitsuoka, Tatsuo Kimura, Toshiyuki Nakai, and Kanako Umekawa
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Drug ,Microarray ,business.industry ,media_common.quotation_subject ,SNP ,Pharmacology ,Bioinformatics ,medicine.disease ,Quinone oxidoreductase ,amrubicin ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,lung cancer ,Oncology ,Pharmacokinetics ,Plasma concentration ,Genotype ,Medicine ,NQO1 ,business ,Lung cancer ,Amrubicin ,hematological toxicity ,media_common ,Original Research - Abstract
Background Amrubicin hydrochloride (AMR) is a key agent for lung cancer. NADPH quinone oxidoreductase 1 (NQO1) metabolizes the quinone structures contained in both amrubicin (AMR) and amrubicinol (AMR-OH). We hypothesized that NQO1 C609T polymorphism may affect AMR-related pharmacokinetics and clinical outcomes. Methods Patients received AMR doses of 30 or 40 mg/m2/day on days 1–3. Plasma sampling was performed 24 hours after the first and third AMR injections. Concentrations of AMR and AMR-OH were determined by HPLC and the NQO1 C609T polymorphism was assayed by RT-PCR. Results A total of 35 patients were enrolled. At a dose of 40 mg/m2, the T/T genotype exhibited a tendency toward a relationship with decrease concentrations of AMR-OH on days 2 and 4. The genotype also showed a significant decrease of hematological toxicities ( P < 0.05). Conclusions NQO1 C609T polymorphism had a tendency of correlation with the plasma concentrations of AMR-OH, and thereby had significant correlations with hematologic toxicities.
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- 2013
8. Utility of rapid on-site cytologic evaluation during endobronchial ultrasound with a guide sheath for peripheral pulmonary lesions
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Toshiyuki Nakai, Yuji Matsumoto, Shinji Sasada, Takehiro Izumo, Takaaki Tsuchida, and Christine Chavez
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Papanicolaou stain ,Ground-glass opacity ,03 medical and health sciences ,0302 clinical medicine ,Bronchoscopy ,Cytology ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Endobronchial ultrasound ,Lung ,Aged ,Retrospective Studies ,Ultrasonography ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Retrospective cohort study ,General Medicine ,Middle Aged ,Peripheral ,medicine.anatomical_structure ,030228 respiratory system ,Oncology ,030220 oncology & carcinogenesis ,Female ,Radiology ,medicine.symptom ,business - Abstract
Objective The utility of rapid on-site evaluation during endobronchial ultrasound with a guide sheath for peripheral pulmonary lesions is unclear. The aim of this study was to evaluate the role of rapid on-site evaluation during endobronchial ultrasound with a guide sheath for peripheral pulmonary lesions. Methods Consecutive patients who underwent endobronchial ultrasound with a guide sheath for the diagnosis of peripheral pulmonary lesions at our hospital between September 2012 and July 2014 were included in this retrospective study. Cytology slides were air-dried, and modified Giemsa (Diff-Quik) staining was used for rapid on-site evaluation. Additional smears were prepared for Papanicolaou staining and tissue samples were placed in formalin for histologic evaluation. The results of rapid on-site evaluation were compared with the final diagnoses of endobronchial ultrasound with a guide sheath. Results A total of 718 cases were included in the study population. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of rapid on-site evaluation during endobronchial ultrasound with a guide sheath for peripheral pulmonary lesions was 88.6%, 65.9%, 81.2%, 77.7% and 80.1%, respectively. There were no procedure-related deaths. Conclusions Rapid on-site evaluation during endobronchial ultrasound with a guide sheath had high sensitivity for peripheral pulmonary lesions. When carrying out rapid on-site evaluation of transbronchial biopsy samples from peripheral pulmonary lesions, careful interpretation and clinical correlation are necessary.
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- 2016
9. Epidermal growth factor receptor tyrosine kinase inhibitors in previously treated advanced non-small-cell lung cancer with wild-type EGFR
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Shun-ichi Isa, Takako Oka, Akihito Kubo, Hidenori Tanaka, Shinzoh Kudoh, Kazuhisa Asai, Kazuto Hirata, Tatsuo Kimura, Kuniomi Matsuura, Tomoya Kawaguchi, Kenji Sawa, Tetsuya Watanabe, Naruo Yoshimura, Shigeki Mitsuoka, Naoki Yoshimoto, Toshiyuki Nakai, Tomohiro Suzumura, and Masato Uji
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Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Genotype ,Afatinib ,medicine.medical_treatment ,Antineoplastic Agents ,Docetaxel ,Biomarkers, Pharmacological ,Disease-Free Survival ,03 medical and health sciences ,Erlotinib Hydrochloride ,0302 clinical medicine ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Epidermal growth factor receptor ,Lung cancer ,neoplasms ,Protein Kinase Inhibitors ,Randomized Controlled Trials as Topic ,Pharmacology ,Chemotherapy ,biology ,business.industry ,General Medicine ,medicine.disease ,respiratory tract diseases ,ErbB Receptors ,030220 oncology & carcinogenesis ,biology.protein ,Quinazolines ,Taxoids ,Erlotinib ,business ,Tyrosine kinase ,medicine.drug - Abstract
While epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitors (TKIs) lead to longer progression-free survival (PFS) when compared with conventional chemotherapy in non-small-cell lung cancer (NSCLC) harboring activating EGFR mutations, the role of EGFR-TKI remains unclear in EGFR-wild-type (WT) NSCLC.This article reviews selected data from randomized trials regarding the use of TKIs in EGFR-WT NSCLC. Nine randomized phase III trials have compared EGFR-TKI with chemotherapy in NSCLC patients in a second or later line setting. Two of these trials, TAILOR and DELTA, which were designed to investigate treatment benefits according to EGFR genotype, demonstrated that docetaxel chemotherapy displayed significantly better in progression-free survival (PFS) when compared with the EGFR-TKI erlotinib. Biomarkers to predict clinical benefits of the drug against EGFR WT tumor, and the efficacy of combination regimens using erlotinib or single-use afatinib against tumors are also covered in this article.Considering the modest benefits of erlotinib for EGFR-WT tumors, future studies are warranted, including the exploration of useful biomarkers and new treatment strategies for EGFT-TKI use, as well as the development of more sensitive EGFR mutation tests.
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- 2016
10. Phase II study of a combination regimen of gefitinib and pemetrexed as first-line treatment in patients with advanced non-small cell lung cancer harboring a sensitive EGFR mutation
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Naruo Yoshimura, Kazuhisa Asai, Shinzoh Kudoh, Shigeki Mitsuoka, Kazuto Hirata, Tatsuo Kimura, Kuniomi Matusura, Takako Oka, Tomoya Kawaguchi, Tomohiro Suzumira, Naoki Yoshimoto, Yoshihiro Tochino, and Toshiyuki Nakai
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Pulmonary and Respiratory Medicine ,Male ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Phases of clinical research ,Pemetrexed ,Neutropenia ,Gastroenterology ,Disease-Free Survival ,Gefitinib ,Predictive Value of Tests ,Internal medicine ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lung cancer ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,Chemotherapy ,Leukopenia ,business.industry ,Middle Aged ,medicine.disease ,Surgery ,ErbB Receptors ,Regimen ,Oncology ,Quinazolines ,Female ,medicine.symptom ,business ,medicine.drug ,Follow-Up Studies - Abstract
Purpose Patients with advanced non-small cell lung cancer (NSCLC) harboring a sensitive epidermal growth factor receptor (EGFR) mutation have been shown to exhibit a marked response to EGFR-tyrosine kinase inhibitor (TKI) treatment. Pemetrexed and gefitinib were reported to have a schedule-dependent cytotoxic synergism. We evaluated the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in EGFR-mutated NSCLC patients. Patients and methods Systemic therapy-naive patients with advanced non-squamous NSCLC harboring a sensitive EGFR mutation were included in this study. Pemetrexed was administered on day 1 at a dose of 500mg/m 2 , and gefitinib was sequentially administered on days 2–16. This treatment regimen was repeated every 3 weeks until disease progression. Results Twenty-six patients were enrolled in this study. The median number of treatment cycles was 16 (range, 1–35). The overall response rate (ORR) was 84.6% (95% confidence interval [CI], 70.7–98.5%), and the disease control rate (DCR) was 96.2% (95% CI, 88.9–100%). Grade 3/4 hematological toxicities included neutropenia (15.4%), leukopenia (7.7%), and anemia (3.8%). No grade 4 non-hematological toxicities were observed. The main grade 3 non-hematological toxicities were infection (11.5%), increased alanine aminotransferase (11.5%) and aspartate aminotransferase (7.7%) levels, fatigue (3.8%), diarrhea (3.8%), and pneumonitis (3.8%). We observed a median progression-free survival (PFS) of 18.0 months (95% CI, 15.0–21.0 months) and a median survival time (MST) of 32.0 months (95% CI, 28.5–35.5 months). There were no treatment-related deaths. Conclusions The combination regimen used in this study showed a high ORR, long median PFS, and acceptable toxicity. A future randomized trial on pemetrexed plus gefitinib compared with gefitinib alone is warranted.
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- 2015
11. Increase of Plasma Adiponectin Levels and Decrease of Pro-Inflammatory Cytokines in Non-Small Cell Lung Cancer Patients Treated with EGFR-TKIS
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Misato Nagata, Kanako Umekawa, Naruo Yoshimura, Kazuto Hirata, Toshiyuki Nakai, S. Kudoh, Shigeki Mitsuoka, Kuniomi Matsuura, Tomohiro Suzumura, and T. Kimura
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medicine.medical_specialty ,Adiponectin ,business.industry ,Insulin ,medicine.medical_treatment ,Leptin ,Adipokine ,Adipose tissue ,Inflammation ,Hematology ,Proinflammatory cytokine ,Endocrinology ,Oncology ,Internal medicine ,medicine ,Resistin ,medicine.symptom ,business - Abstract
Background Malnutrition in non-small cell lung cancer (NSCLC) is associated with advanced stage of disease and is needed for careful choice of treatment. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are routinely used for the treatment of advanced NSCLC with EGFR active mutations, which are promising the excellent responses. Recently, pro-inflammatory cytokines have been proposed as mediators of cancer cachexia. Adipose tissue produces and release substances called adipokines which include tumor necrosis factor-alpha (TNF-α), leptin, adiponectin, and resistin. Adiponectin suppresses the secretion of inflammatory cytokines such as IL-8, TNF-α, and induces the secretion of anti-inflammatory cytokines such as IL-10. It has been hypothesized that EFGR-TKI therapy may affect this adipokine network. Methods The prospective study which evaluated correlations between the pre and post-treatment point of days 30 plasma adipokines and cytokines after EGFR-TKIs administration and clinical outcomes in advanced NSCLC was conducted at Osaka City University Hospital. Plasma adipokines and cytokines were analyzed by Luminex 200 PONENT system (Milliplex MAP kits; Millipore). Results A total of 33 patients were enrolled. We obtained plasma samples for analyses 33 patients on pre-treatment point, and 23 patients on days 30 point. Plasma adiponectin level on the pre-treatment point (40.34 ± 32.00ng/ml) was significantly lower than those on days 30 point (45.07 ± 26.38ng/ml, p = 0.01). On the pre-treatment point of plasma IL-8 (16.70 ± 16.01pg/ml), IL-10 (13.06 ± 29.69pg/ml), insulin (656.9 ± 514.6pg/ml) levels were significantly higher than those on days 30 point (7.154 ± 5.674 pg/ml p = 0.02; 11.53 ± 30.92pg/ml, p = 0.04; and 551.4 ± 520.2pg/ml, p = 0.02, respectively). The levels of leptin and resistin had no significant changes between pre and on days 30 points. Conclusions The EGFR-TKIs treatment for NSCLC increased the plasma adiponectin levels and decreased the plasma insulin, IL-8 and IL-10 levels. Increase of adiponectin levels by EGFR-TKIs may resolve the inflammation and increase insulin sensitivity with reduced output of insulin. Disclosure All authors have declared no conflicts of interest.
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- 2012
12. Gefitinib and Pemetrexed As a First Line Treatment in Patients with Egfr Mutant Advanced Nsclc: a Phase Ii Study
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Takako Oka, S. Kudoh, Shigeki Mitsuoka, Toshiyuki Nakai, Tomoya Kawaguchi, Naruo Yoshimura, Naoki Yoshimoto, Kuniomi Matsuura, T. Kimura, and Kazuto Hirata
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Oncology ,medicine.medical_specialty ,business.industry ,Phases of clinical research ,Hematology ,Neutropenia ,medicine.disease ,Chemotherapy regimen ,Surgery ,Gefitinib ,Pemetrexed ,Internal medicine ,medicine ,Clinical endpoint ,Progression-free survival ,business ,Progressive disease ,medicine.drug - Abstract
Aim: Gefitinib (G) is the key drug for patients (pts) with Non-Small Cell Lung Cancer (NSCLC) harboring mutations of EGFR as a first line treatment. However, they have disease progression in most cases. Pemetrexed (PEM) and G are reported to have a schedule-depended cytotoxic synergism. We evaluated the efficacy and safety of G and PEM as a first line chemotherapy in pts with NSCLC harboring mutations of EGFR. Methods: Eligibilities were histological or cytologically proven non-squamous NSCLC with EGFR active mutation, chemotherapy naive, measurable lesion, ECOG PS 0-1, adequate organ function, life expectancy longer than 12 weeks and written informed consent. G (250mg/body) was administered on day 2-16 and PEM (500mg/m2) was administered on day1. The combination was repeated every 3 weeks until progressive disease (PD). Primary endpoint was overall response rate (ORR) and secondary endpoints were toxicities, disease control rate (DCR), progression free survival (PFS), and overall survival (OS). The planed sample size was 26 pts. Results: From March 2010 to January 2013, 26 pts were enrolled and eligible: males/females 13/13; median age 66 (range 58-84); PS 0/1 3/23; stage III/IV 1/25; Adeno/Others 26/0. All pts were eligible for efficacy and toxicity; a total 398 cycles (median 16 cycles, range 1-35) were given. Major grade 3/4 toxicities were neutropenia, infection, and liver dysfunction. There was no treatment-related death. ORR was 84.6%, and DCR was 96.2%. Median PFS was18.0 months, and median OS was 32.0 months. Conclusions: This combination showed high ORR, long median PFS, and acceptable toxicity. Randomized trial of PEM + G compare with G alone is warranted. Disclosure: All authors have declared no conflicts of interest.
- Published
- 2014
13. Dose-escalation study of chemoradiotherapy with use of involved-field conformal radiotherapy and accelerated hyperfractionation for stage III non-small cell lung cancer
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Naruo Yoshimura, Kazuto Hirata, Tatsuo Kimura, Misato Nagata, Toshiyuki Nakai, Hidenori Tanaka, Shigeki Mitsuoka, Tomohiro Suzumura, Shinzoh Kudoh, Kanako Umekawa, Masako Hosono Hosono, and Takuhito Tada
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Conformal radiotherapy ,Stage III Non-Small Cell Lung Cancer ,Accelerated fractionation ,Internal medicine ,Dose escalation ,Medicine ,Stage (cooking) ,business ,Chemoradiotherapy - Abstract
7564 Background: To determine a recommended dose (RD) of chemoradiotherapy with use of involved-field conformal radiotherapy and accelerated hyperfractionation (AHF) for stage III non-small cell lung cancer (NSCLC). Methods: Eligible patients had unresectable stage III NSCLC, age of less than 75 years, PS: 0 or 1, V20 of 35% or less. PET was used for staging. Cisplatin (80mg/m2) was administered on day 1 and vinorelbine (20mg/m2) was administered on days 1 and 8 for two cycle. Twice-daily radiation therapy (1.5 Gy per fraction) without elective nodal irradiation started on day 1. Total doses were 60Gy in 40 fractions and 66Gy in 44 fractions at levels 1 and 2 respectively. After concurrent chemoradiotherapy, consolidation chemotherapy regimen was cisplatin (80mg/m2) on day 1 and vinorelbine (20mg/m2) on days 1 and 8 every 4 week for three cycles. The dose-limiting toxicity (DLT) was defined as grade ≥ 3 esophagitis, grade 3 neutropenic fever, grade ≥ 3 other non-hematologic toxicities and interruption of irradiation for more than 2 weeks. DLT was monitored for 90 days. Results: A total of 12 patients were enrolled (6 patients in Level 1, 6 patients in Levels 2). DLTs were noted in 2 patients at Level 1, which were grade 3 esophagitis and grade 3 febrile neutropenia. Radiation dose was escalated up to 66 Gy in 44 fractions (Level 2), and there was no DLT. In principle, Sixty-six Gy in 44 fractions (Level 2) should be the RD. Major toxicities were leucopenia, neutropenia, and anemia. The response rate, the median progression free survival time, and the median overall survival time was 83.3%, 10.4 months, and 36.3 months for all patients, respectively. Conclusions: The RD was 66 Gy in 44 fractions (Level 2). The toxicity of this chemoradiothrapy regimen was manageable and efficacy is promising. The efficacy and safety of this regimen should be confirmed in a phase II study. Clinical trial information: UMIN000003769.
- Published
- 2013
14. Correlation of C609T Polymorphism of NADPH Quinone Oxidoreductase 1 and Clinical Outcome in Amrubicin-Treated Lung Cancer Patients
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Hiroaki Tanaka, Kuniomi Matsuura, Kazuto Hirata, T. Kimura, Naruo Yoshimura, Tomohiro Suzumura, Kanako Umekawa, Misato Nagata, Toshiyuki Nakai, S. Kudoh, and Shigeki Mitsuoka
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medicine.medical_specialty ,business.industry ,Hematology ,medicine.disease ,Quinone oxidoreductase ,Gastroenterology ,In vitro ,Oncology ,Internal medicine ,Genotype ,Medicine ,Cytotoxic T cell ,Platelet ,Hemoglobin ,business ,Lung cancer ,Amrubicin - Abstract
Background Amrubicin hydrochloride (AMR) is a novel synthetic aminoanthracycline derivative. AMR is metabolized to amrubicinol (AMR-OH), and the cytotoxic activity of AMR-OH is 18–220 times more potent than that of AMR. NADPH quinone oxidoreductase 1 (NQO1) is a cytosolic flavoprotein that metabolizes the quinone structures which are contained in both AMR and AMR-OH. Recent report showed that C609T polymorphisms of NQO1 had a significant inverse correlation with in vitro AMR-OH cytotoxicity. Previously, we reported that the plasma concentration of AMR-OH on day 4 is correlated with hematological toxicities (anti-cancer drugs 2009). We hypothesized that the C609T polymorphisms of NQO1 may relate to the AMR-OH plasma concentrations and clinical outcomes. To test this hypothesis, a pharmacogenomics study was carried out on patients with lung cancer received AMR at a dose of 30 or 40 mg/m2/day on days 1–3. Plasma sampling was carried out at the time points of 24 h after the third AMR injection (AMR on day 4 and AMR-OH on day 4). Methods The concentrations of AMR and AMR-OH were determined by the HPLC method. DNA was isolated from blood and C609T was assayed using RT–PCR. Results Thirty-five patients were enrolled. The C/C, C/T and T/T were observed in 12 (34.3%), 16 (45.7%) and 7 (20%) patients, respectively. A dose of 30 mg/m2 was administered to 19 patients, and 40 mg/m2 was administered to 16 patients. The mean plasma concentrations of AMR-OH on day 4 at a dose of 30 and 40 mg/m2 were 11.02 ± 3.83 and 16.18 ± 6.17 ng/ml, respectively (P = 0.005). No significant correlations were observed between NQO1 genotypes and clinical outcomes in patients with AMR at a dose of 30 mg/m2. In patients with AMR at a dose of 40 mg/m2, the plasma concentrations of AMR-OH on day 4 exhibited a tendency toward a relationship with NQO1 genotypes with values of C/C 20.5 ± 5.89, C/T 15.9 ± 5.43 and T/T 11.2 ± 4.47 ng/ml (P = 0.066). The significant relations were observed between NQO1 genotypes and decrease percentage changes in WBC, hemoglobin and platelet counts (P = 0.01, 0.03 and 0.0005, respectively). Conclusions The NQO1 genotype appears to be the candidate biomarker of hematological toxicities of AMR treatment at a dose of 40 mg/m2.
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- 2012
15. Correlation of C609T Polymorphism of Nadph Quinone Oxidoreductase 1 and Hematological Toxicities in Lung Cancer Patients Treated With Amrubicin
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Misato Nagata, Tomohiro Suzumura, Toshiyuki Nakai, S. Kudoh, Shigeki Mitsuoka, Kazuto Hirata, T. Kimura, Yukimi Kira, Kanako Umekawa, and Kuniomi Matsuura
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medicine.medical_specialty ,business.industry ,Hematology ,medicine.disease ,Gastroenterology ,Oncology ,Pharmacokinetics ,Internal medicine ,Genotype ,Medicine ,Cytotoxic T cell ,Platelet ,Hemoglobin ,Allele ,business ,Lung cancer ,Amrubicin - Abstract
Background Amrubicin hydrochloride (AMR) is a novel synthetic aminoanthracycline derivative, that is metabolically activated to amrubicinol (AMR-OH) by carbonyl reductase. The cytotoxic activity of AMR-OH is promising for small cell lung cancer and considered as a key agent. NADPH Quinone Oxidoreductase 1 (NQO1) is a cytosolic flavoprotein that metabolizes the quinone structures contained in both AMR and AMR-OH. NQO1 expression genotyped homozygous for minor alleles (T/T) was low compared with homozygous for major alleles (C/C) or heterozygous (C/T). We hypothesized that NQO1 C609T polymorphisms may relate to the AMR pharmacokinetics and clinical outcomes. Methods The patients with lung cancer received AMR at a dose of 30 or 40mg/m2/day on day 1-3 at Osaka City University Hospital were enrolled. Plasma sampling was performed at the time points of 24h after the third AMR injection. The concentrations of AMR and AMR-OH were determined by HPLC method. NQO1 C609T polymorphism was assayed using real-time polymerase chain reaction methods. Results A total of 35 patients were enrolled. The C/C, C/T, and T/T were observed in 12 (34.3%), 16 (45.7%), and 7 (20%) patients, respectively. A dose of 30 mg/m2 was administered to 19 patients, and 40mg/m2 was administered to 16 patients. The mean plasma concentrations of AMR-OH on day4 at a dose of 30mg/m2 and 40mg/m2 were 11.02 ± 3.83 and 16.18 ± 6.17 ng/ml, respectively (p = 0.005). In patients with AMR at a dose of 40mg/m2, the plasma concentrations of AMR-OH on day4 exhibited a tendency toward a relationship with NQO1 genotypes with values of C/C 20.5 ± 5.89, C/T 15.9 ± 5.43, and T/T 11.2 ± 4.47ng/ml (p = 0.066). The C/C was related to decrease changes in WBC, hemoglobin, and platelet counts (p = 0.01, p = 0.03, and p = 0.0005, respectively). No significant correlations were observed between NQO1 genotypes and clinical outcomes at a dose of 30mg/m2. Conclusions NQO1 C609T polymorphism had a tendency of correlation with the plasma concentrations of AMR-OH, and thereby had significant correlations with hematologic toxicities. NQO1 genotype appears to be the candidate biomarker of hematological toxicities of AMR treatment at a dose of 40mg/m2. Disclosure All authors have declared no conflicts of interest.
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- 2012
16. Reduced CYP2D6 function is associated with gefitinib-induced rash in patients with non-small cell lung cancer
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Shinzoh Kudoh, Tomohiro Suzumura, Kanako Umekawa, Naruo Yoshimura, Kuniomi Matsuura, Hidenori Tanaka, Yukimi Kira, Kazuto Hirata, Tatsuo Kimura, Misato Nagata, Toshiyuki Nakai, and Shigeki Mitsuoka
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Male ,CYP2D6 ,Cancer Research ,Lung Neoplasms ,Genotype ,Antineoplastic Agents ,Real-Time Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,lcsh:RC254-282 ,Erlotinib Hydrochloride ,Gefitinib ,Non-small cell lung cancer ,Surgical oncology ,Carcinoma, Non-Small-Cell Lung ,medicine ,Odds Ratio ,Genetics ,Humans ,Genetic Predisposition to Disease ,heterocyclic compounds ,Adverse effect ,Lung cancer ,skin and connective tissue diseases ,neoplasms ,Aged ,business.industry ,Exanthema ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Rash ,respiratory tract diseases ,Cytochrome P-450 CYP2D6 ,Erlotinib ,Oncology ,Adverse events ,Cancer research ,Quinazolines ,Female ,medicine.symptom ,business ,medicine.drug ,Research Article - Abstract
Background Rash, liver dysfunction, and diarrhea are known major adverse events associated with erlotinib and gefitinib. However, clinical trials with gefitinib have reported different proportions of adverse events compared to trials with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib but not erlotinib. It has been hypothesized that CYP2D6 phenotypes may be implicated in different adverse events associated with gefitinib and erlotinib therapies. Methods The frequency of each adverse event was evaluated during the period in which the patients received gefitinib or erlotinib therapy. CYP2D6 phenotypes were determined by analysis of CYP2D6 genotypes using real-time polymerase chain reaction techniques, which can detect single-nucleotide polymorphisms. The CYP2D6 phenotypes were categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of the adverse events associated with each factor, including CYP2D6 activities and treatment types. Results A total of 232 patients received gefitinib therapy, and 86 received erlotinib therapy. Reduced function of CYP2D6 was associated with an increased risk of rash of grade 2 or more (OR, 0.44; 95% confidence interval [CI], 0.21–0.94; *p = 0.03), but not diarrhea ≥ grade 2 (OR, 0.49; 95% CI, 0.17–1.51; *p = 0.20) or liver dysfunction ≥ grade 2 (OR, 1.08; 95% CI, 0.52–2.34; *p = 0.84) in the gefitinib cohort. No associations were observed between any adverse events in the erlotinib cohort and CYP2D6 phenotypes (rash: OR, 1.77; 95% CI, 0.54–6.41; *p = 0.35/diarrhea: OR, 1.08; 95% CI, 0.21–7.43; *p = 0.93/liver dysfunction: OR, 0.93; 95% CI, 0.20–5.07; *p = 0.93). Conclusions The frequency of rash was significantly higher in patients with reduced CYP2D6 activity who treated with gefitinib compared to patients with functional CYP2D6. CYP2D6 phenotypes are a risk factor for the development of rash in response to gefitinib therapy.
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