Yuichi Takiguchi - Academia.edu (original) (raw)

Papers by Yuichi Takiguchi

European Respiratory Journal, 2012

Study objectives: The aim of this study was to clarify the usefulness of COPD screening by using ... more Study objectives: The aim of this study was to clarify the usefulness of COPD screening by using a community-based lung cancer screening program. Methods: In Japan, community-based lung cancer screening by chest X-ray has been established. Japanese residents who are 40 years old or higher can freely receive chest X-ray every year. We utilized this screening system in Chiba City in order to detect COPD. From April 2010 to March 2011, 83,924 participants received regular lung cancer screening by chest X-ray at the first examination centers, which was approximately 30% of objective residents. We set the criteria of suspicious of COPD indicating 60 years or older, positive smoking history and having any chronic respiratory symptoms. 1,170 (1.3%) were recognized as suspicious of COPD and 551 of them (56.2%) received further examination including pulmonary function test (PFT) and/or chest computed tomography (CT) as the second close examination at 39 second examination centers. Results: 1...

Lung Cancer, 2020

Introduction: The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors ... more Introduction: The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFRmutated non-adenocarcinoma (ADC) non-small cell lung cancer patients is not well established. Herein, we investigated key prognostic factors influencing the efficacy of EGFR-TKIs in these patients. Methods: A total of 12,320 lung cancer patients pathologically diagnosed in 2012 at teaching hospitals in Japan were retrospectively selected. The follow-up survey was closed in 2016. Results: EGFR-mutated non-ADC patients were more prone to malignant pleural effusion (MPE) and distant metastasis than ADC patients (P = 0.071 and 0.022, respectively). EGFR-mutated ADC patients were likely to have a longer median overall survival (OS) than non-ADC patients [hazard ratio (HR) 1.3 (95 % CI, 0.97-1.8, P = 0.072)-29.5 months (95 % CI, 27.9-31.1 months) versus 19.5 months (95 % CI, 10.8-28.2 months) (P = 0.068)]. There was no significant difference in median OS between EGFR-positive ADC and non-ADC patients receiving treatment with first-generation EGFR-TKI. Among EGFR-positive non-ADC patients, the median OS was significantly longer for patients receiving EGFR-TKI treatment than for those who did not [HR 4.5 (95 % CI, 2.1-9.8, P < 0.001)-25.5 months (95 % CI, 8.1-42.9 months) versus 7.5 months (95 % CI, 3.4-11.6 months) (P < 0.001)]. While there was no significant difference in the median OS for ADC patients with either 19 del or L858R mutations, the median OS was significantly longer for EGFR-mutated non-ADC patients with 19 del than for those with L858R mutation (HR 3.2 [95 % CI, 1.5-6.9, P = 0.004]; it was not reached for 19 del and was 15.5 months for L858R [95 % CI, 6.6-24.4 months], P = 0.002). Discussion: EGFR-mutated non-ADC patients were more prone to MPE and distant metastasis. Both ADC and EGFR del19-positive non-ADC patients can benefit from EGFR-TKI treatment, whereas EGFR L858R-positive non-ADC patients might require different therapeutic options.

Cancer Science, 2020

This study provides the benchmark statistics on medically treated patients with non–small cell lu... more This study provides the benchmark statistics on medically treated patients with non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in Japan. Demographic background, treatment, and prognosis were obtained from patients with lung cancer pathologically diagnosed in 2012, who received nonsurgical treatment. Descriptive statistics and their associations with survival were analyzed. In total, 12 320 patients were registered from 314 institutions in Japan. The median age was 70 years, and 73% of the patients were male. The number (%) of stages I, II, III, and IV diseases were 468 (3.8%), 421 (3.4%), 3260 (26.5%), and 8171 (66.3%), respectively. NSCLC and SCLC accounted for 9872 (80.1%) and 2353 (19.1%) patients, respectively. Thoracic radiotherapy‐based therapy, chemotherapy, and palliative care alone were administered to 2572 (20.9%), 7790 (63.2%), and 1952 (15.8%) patients, respectively. Clinical TNM stage was one of the strongest prognostic factors with the 3‐year surv...

The Lancet Oncology, 2019

Background Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell ... more Background Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC. Methods This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.

Journal of Clinical Oncology, 2019

PURPOSE Although gene expression profiling is a promising diagnostic technique to determine the t... more PURPOSE Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP. PATIENTS AND METHODS Comprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate. RESULTS One hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in ...

BMC Cancer, 2017

Background: PIK3CA mutations are expected to be potential therapeutic targets for esophageal squa... more Background: PIK3CA mutations are expected to be potential therapeutic targets for esophageal squamous cell carcinoma (ESCC). We aimed to clarify the concordance between PIK3CA mutations detected in endoscopic biopsy specimens and corresponding surgically resected specimens. Methods: We examined five hotspot mutations in the PIK3CA gene (E542K, E545K, E546K, H1047R, and H1047L) in formalin-fixed and paraffin-embedded tissue sections of paired endoscopic biopsy and surgically resected specimens from 181 patients undergoing curative resection for ESCC between 2000 and 2011 using a Luminex technology-based multiplex gene mutation detection kit. Results: Mutation analyses were successfully performed for both endoscopic biopsy and surgically resected specimens in all the cases. A PIK3CA mutation was detected in either type of specimen in 13 cases (7.2%, 95% confidence interval: 3.9-12.0). The overall concordance rate, positive predictive value, and negative predictive value were 98.3% (178/181), 90.9% (10/11), and 98.8% (168/170), respectively. Among patients with a PIK3CA mutation detected in both types of specimens, the concordance between PIK3CA mutation genotypes was 100%. There were three cases with a discordant mutation status between the types of specimens (PIK3CA mutation in surgically resected specimen and wild-type in biopsy specimen in two cases, and the opposite pattern in one case), suggesting possible intratumoral heterogeneity in the PIK3CA mutation status. Conclusions: The PIK3CA mutation status was highly concordant between endoscopic biopsy and surgically resected specimens from the same patient, suggesting that endoscopic biopsy specimens can be clinically used to detect PIK3CA mutations in patients with ESCC.

Journal of Thoracic Oncology, 2017

first time, the lung cancer patients groups network have launched since November on 2015 named JL... more first time, the lung cancer patients groups network have launched since November on 2015 named JLCA, Japan lung cancer alliance. One of the goals of JLCA is to improve the lung cancer patient literacy in Japan. I will report JLCA activities about attempts to improve patient literacy in 2016. Results: 1) Multiple lung cancer patients have participated in the project on 'Working with cancer' by NCCJ. They had actually carried out to work together with lung cancer. Results of comparison of the two surveys between project survey by NCCJ and the survey by Japanese Cabinet Office comes out clearly the difference. More ambitious to work with cancer in National Cancer Center projects survey. 2) JLCA has been in cooperation with The Japan Lung Cancer Society, The Japanese Society of Medical Oncology, and enthusiastic lung cancer doctors to advocates activities especially Dr. Sawa. JLCA has been held five more seminars to improve lung cancer patient literacy at various places of Japan in 2016. Conclusion: One of the goals for Japanese lung cancer patients is to improve the patient literacy nowadays. They have ambitions to improve the patient literacy. They have participated in various activities to improve the patient literacy. It was found for them to want to be 'Living with cancer' and 'Working with cancer.' The important points are two thing, effective advocates projects and trial of patient initiative.

Journal of Thoracic Oncology, 2017

2010. Collagen gel droplet-embedded culture drug sensitivity test (CD-DST) was performed on fresh... more 2010. Collagen gel droplet-embedded culture drug sensitivity test (CD-DST) was performed on fresh surgical specimen. The clinical utility and prognostic outcome of adjuvant chemotherapy with carboplatin/paclitaxel in patients who showed chemo-sensitivity on CD-DST were evaluated. The primary endpoint was disease-free survival, and the secondary endpoints were overall survival and adverse effects during chemotherapy. Results: Among 92 registered patients, 87 (p-Stage IB in 54, IIA in 4, IIB in 10, IIIA in 19) were eligible and were included in the analysis. All patients were followed up for more than 5 years. The median age was 66 years old. The success rate of CD-DST was 87% and chemo-sensitivity to carboplatin and/or paclitaxel was observed in 75% of patients. Adjuvant chemotherapy was completed in 70% and the 5-year disease-free and overall survival rates were 68% and 82%, respectively. The 5-year disease-free and overall survival rates in Stage IIeIIIA patients were 58% and 75%, respectively. As for the adverse effects during adjuvant chemotherapy, grade 4 neutropenia was found in 13%. Conclusion: Chemo-sensitivity could be evaluated using CD-DST after lung cancer surgery. CD-DST might contribute to individualized adjuvant chemotherapy for locally advanced lung cancer.

Journal of Thoracic Oncology, 2017

*n¼20 did not have measurable disease per IRC and were not included in the IRC REP; † 2 CR; ‡ 4 C... more *n¼20 did not have measurable disease per IRC and were not included in the IRC REP; † 2 CR; ‡ 4 CR; § 13 CR; k non-measurable disease classified as CR, non-CR/non-PD or PD; NE¼not evaluable/estimable. Conclusion: Alectinib demonstrated durable responses, encouraging OS findings, good tolerability and an acceptable safety profile consistent with previous reports in this update of the NP28761 study with extended follow-up.

Gastroenterology Research and Practice, 2015

Objective. Patients with gastroenteropancreatic neuroendocrine carcinoma (NEC) have a poor progno... more Objective. Patients with gastroenteropancreatic neuroendocrine carcinoma (NEC) have a poor prognosis. Platinum-based combination chemotherapy is commonly used as first-line treatment; however, the role of salvage chemotherapy remains unknown. This study aimed to analyze the efficacy and safety of amrubicin monotherapy in patients with platinum-refractory gastroenteropancreatic NEC.Methods. Among 22 patients with advanced gastroenteropancreatic NEC, 10 received amrubicin monotherapy between September 2007 and May 2014 after failure of platinum-based chemotherapy. The efficacy and toxicity of the treatment were analyzed retrospectively.Results. Eight males and two females (median age, 67 years (range, 52–78)) received platinum-based chemotherapy, including cisplatin plus irinotecan (n=7, 70%), cisplatin plus etoposide (n=2, 20%), and carboplatin plus etoposide (n=1, 10%) before amrubicin therapy. Median progression-free survival and overall survival after amrubicin therapy were 2.6 an...

The Annals of Thoracic Surgery, 2006

Background. Patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) have a very poor ... more Background. Patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) have a very poor prognosis, but the benefit of adjuvant chemotherapy for these patients has not been established. We performed a prospective analysis of adjuvant chemotherapy for patients with completely resected pulmonary LCNECs to assess the effect of adjuvant chemotherapy. Methods. The adjuvant mixture consisted of cisplatin and VP-16 and was administered after surgery to 15 patients with LCNECs from 2000 to 2005. We compared patient survival with historical data for LCNEC patients treated without platinum-based adjuvant chemotherapy after surgery. Results. There were no differences in age, gender, surgical methods, and staging between the adjuvant chemotherapy group and the control group. Median follow-up was 33 months for the adjuvant group and 42 months for the control group. Of the 15 patients in the adjuvant chemotherapy group, 2 patients had disease recurrence and 1 died of interstitial pneumonia. The overall survival rate at 2 and 5 years of patients with adjuvant chemotherapy was 88.9%. The overall survival rate between patients with adjuvant chemotherapy and the historical control group was significantly different. Conclusions. Adjuvant chemotherapy consisting of cisplatin and VP-16 after surgery appears promising for the improvement of the prognosis for patients with completely resected LCNECs, and it should be evaluated further in larger multi-institutional trials.

CancerSpectrum Knowledge Environment, 2002

Investigational New Drugs

In first-in-human (FIH) trials, sequential tumor biopsies, i.e., two consecutive tumor biopsies, ... more In first-in-human (FIH) trials, sequential tumor biopsies, i.e., two consecutive tumor biopsies, the first performed at baseline (pretreatment) and the second during the early treatment period (on-treatment), provide proof of concept in investigational new drugs. We evaluated the success of sequential tumor biopsies in FIH trials, and explored approaches for improved success rates. We retrospectively reviewed the sequential tumor biopsies required in 17 of 52 FIH trials conducted from 2015 to 2020. One hundred and thirty-eight patients were identified. Success of either pretreatment or on-treatment biopsy alone, and of sequential tumor biopsies, was defined as the acquisition of viable tumor cells and as obtaining tumor cells from both biopsy specimens, respectively. The success rates of pretreatment and on-treatment biopsy were 98.6% and 94.2%, respectively, and of sequential tumor biopsies was 70.3%. Adverse events associated with the pretreatment biopsies (33.3% positive; 72.0% n...

Igaku butsuri : Nihon Igaku Butsuri Gakkai kikanshi = Japanese journal of medical physics : an official journal of Japan Society of Medical Physics, 2001

The development of computerized tomography (CT) has made CT fluoroscopy possible with real-time C... more The development of computerized tomography (CT) has made CT fluoroscopy possible with real-time CT images. However examination are expected to have high medical and occupational exposures. Then, exposures to patients and operating and assisting physicians during the CT fluoroscopy-guided lung biopsy were estimated. And changes in the examination conditions to lower the dose were made. Patient exposure was measured using an anthropomorphic phantom by simulation of clinical examination conditions. The surface dose to the physician was measured during actual clinical examinations. The average effective dose for the patient was 34+/-22mSv. The highest surface dose amounted to 1.9 Gy, although this was in a very narrow field. Patient doses could be reduced by a factor of 2.5-3 by changing examination methods while still retaining diagnostic quality. The highest dose to the operating physician was 10mGy which was recorded on the back of the hand and the average effective dose was estimate...

Japanese Journal of Clinical Oncology, 2021

Background According to a questionnaire sent to Designated Cancer Care Hospitals in Japan in 2013... more Background According to a questionnaire sent to Designated Cancer Care Hospitals in Japan in 2013, only 39.4% of the institutes had medical oncology departments. Furthermore, most of these medical oncology departments were primarily responsible for the treatment of limited disease categories and the administration of newly developed therapeutic modalities, including molecular-targeted therapy. The aim of the present study was to update these previous findings and to clarify the changes over the intervening 7-year period. Methods The questionnaire was sent to all 393 Designated Cancer Care Hospitals on 13 March 2020. Similar to the previous questionnaires, questions were asked regarding the presence of a medical oncology department, the number of physicians in the department and the degrees of responsibility for drug therapies provided by medical oncologists to adult patients with solid cancers. Results In total, 270 institutions (68.7%) responded. Overall, 145 of these 270 instituti...

Oncology Reports, 2017

Resistance to anticancer medications often leads to poor outcomes. The present study explored an ... more Resistance to anticancer medications often leads to poor outcomes. The present study explored an effective approach for enhancing chemotherapy targeted against human cancer cells. Real-time quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed overexpression of members of aldo-keto reductase (AKR) 1C family, AKR1C1, AKR1C2, AKR1C3, and AKR1C4, in cisplatin, cis-diamminedichloroplatinum (II) (CDDP)resistant human cancer cell lines, HeLa (cervical cancer cells) and Sa3 (oral squamous cell carcinoma cells). The genes were downregulated using small-interfering RNA (siRNA) transfection, and the sensitivity to CDDP or 5-fluorouracil (5-FU) was investigated. When the genes were knocked down, sensitivity to CDDP and 5-FU was restored. Furthermore, we found that administration of mefenamic acid, a widely used non-steroidal anti-inflammatory drug (NSAID) and a known inhibitor of AKR1Cs, enhanced sensitivity to CDDP and 5-FU. The present study suggests that AKR1C family is closely associated with drug resistance to CDDP and 5-FU, and mefenamic acid enhances their sensitivity through its inhibitory activity in drug-resistant human cancer cells. Thus, the use of mefenamic acid to control biological function of AKR1C may lead to effective clinical outcomes by overcoming anticancer drug resistance.

BMC cancer, May 12, 2016

The addition of bevacizumab to cytotoxic agents prolongs survival in patients with nonsquamous no... more The addition of bevacizumab to cytotoxic agents prolongs survival in patients with nonsquamous non-small cell lung cancer (NSCLC). To date, there is no evidence to suggest that treatment with a cytotoxic agent plus bevacizumab is more effective than a cytotoxic agent alone for nonsquamous NSCLC in elderly patients. We conducted a feasibility study of pemetrexed plus bevacizumab as a first-line treatment for advanced or recurrent nonsquamous NSCLC in elderly patients. Major eligibility and exclusion criteria included: chemotherapy-naive status; non-fitness for bolus combination chemotherapy; stage III/IV or relapsed nonsquamous NSCLC; age ≥70; performance status 0-1; absence of brain metastasis; and no history of hemoptysis and thoracic irradiation. Pemetrexed (500 mg/m(2)) and bevacizumab (15 mg/kg) were administered intravenously on day 1, and repeated every 3 weeks thereafter. The primary endpoint was safety, and the secondary endpoints were objective response rate (ORR), progress...

Japanese journal of clinical oncology, Jan 10, 2016

Cisplatin is administered in combination with massive hydration to avoid renal toxicity, making i... more Cisplatin is administered in combination with massive hydration to avoid renal toxicity, making its administration difficult in an outpatient setting. Although a short hydration protocol for cisplatin has been recently developed, its safety is not fully understood. Consecutive patients with lung or other cancer and an Eastern Cooperative Oncology Group performance status of 0-2 who were receiving chemotherapy containing cisplatin at a dose of ≥60 mg/m(2) in a single administration were evaluated. Seventy-four patients were treated with a short hydration protocol consisting of 1750-2250 ml of hydration with mannitol and magnesium supplementation over a period of 3.75-4.75 h on Day 1. Sixty-nine patients were treated with a conventional hydration protocol consisting of 2100-2600 ml of hydration over 6.5-7.5 h on Day 1 with pre- and post-hydration on Days 0, 2 and 3. Toxicity was then compared between the two groups. An elevated serum creatinine level ≥grade 1 was significantly less fr...

European Respiratory Journal, Sep 1, 2012

European Respiratory Journal, 2012

Study objectives: The aim of this study was to clarify the usefulness of COPD screening by using ... more Study objectives: The aim of this study was to clarify the usefulness of COPD screening by using a community-based lung cancer screening program. Methods: In Japan, community-based lung cancer screening by chest X-ray has been established. Japanese residents who are 40 years old or higher can freely receive chest X-ray every year. We utilized this screening system in Chiba City in order to detect COPD. From April 2010 to March 2011, 83,924 participants received regular lung cancer screening by chest X-ray at the first examination centers, which was approximately 30% of objective residents. We set the criteria of suspicious of COPD indicating 60 years or older, positive smoking history and having any chronic respiratory symptoms. 1,170 (1.3%) were recognized as suspicious of COPD and 551 of them (56.2%) received further examination including pulmonary function test (PFT) and/or chest computed tomography (CT) as the second close examination at 39 second examination centers. Results: 1...

Lung Cancer, 2020

Introduction: The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors ... more Introduction: The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFRmutated non-adenocarcinoma (ADC) non-small cell lung cancer patients is not well established. Herein, we investigated key prognostic factors influencing the efficacy of EGFR-TKIs in these patients. Methods: A total of 12,320 lung cancer patients pathologically diagnosed in 2012 at teaching hospitals in Japan were retrospectively selected. The follow-up survey was closed in 2016. Results: EGFR-mutated non-ADC patients were more prone to malignant pleural effusion (MPE) and distant metastasis than ADC patients (P = 0.071 and 0.022, respectively). EGFR-mutated ADC patients were likely to have a longer median overall survival (OS) than non-ADC patients [hazard ratio (HR) 1.3 (95 % CI, 0.97-1.8, P = 0.072)-29.5 months (95 % CI, 27.9-31.1 months) versus 19.5 months (95 % CI, 10.8-28.2 months) (P = 0.068)]. There was no significant difference in median OS between EGFR-positive ADC and non-ADC patients receiving treatment with first-generation EGFR-TKI. Among EGFR-positive non-ADC patients, the median OS was significantly longer for patients receiving EGFR-TKI treatment than for those who did not [HR 4.5 (95 % CI, 2.1-9.8, P < 0.001)-25.5 months (95 % CI, 8.1-42.9 months) versus 7.5 months (95 % CI, 3.4-11.6 months) (P < 0.001)]. While there was no significant difference in the median OS for ADC patients with either 19 del or L858R mutations, the median OS was significantly longer for EGFR-mutated non-ADC patients with 19 del than for those with L858R mutation (HR 3.2 [95 % CI, 1.5-6.9, P = 0.004]; it was not reached for 19 del and was 15.5 months for L858R [95 % CI, 6.6-24.4 months], P = 0.002). Discussion: EGFR-mutated non-ADC patients were more prone to MPE and distant metastasis. Both ADC and EGFR del19-positive non-ADC patients can benefit from EGFR-TKI treatment, whereas EGFR L858R-positive non-ADC patients might require different therapeutic options.

Cancer Science, 2020

This study provides the benchmark statistics on medically treated patients with non–small cell lu... more This study provides the benchmark statistics on medically treated patients with non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in Japan. Demographic background, treatment, and prognosis were obtained from patients with lung cancer pathologically diagnosed in 2012, who received nonsurgical treatment. Descriptive statistics and their associations with survival were analyzed. In total, 12 320 patients were registered from 314 institutions in Japan. The median age was 70 years, and 73% of the patients were male. The number (%) of stages I, II, III, and IV diseases were 468 (3.8%), 421 (3.4%), 3260 (26.5%), and 8171 (66.3%), respectively. NSCLC and SCLC accounted for 9872 (80.1%) and 2353 (19.1%) patients, respectively. Thoracic radiotherapy‐based therapy, chemotherapy, and palliative care alone were administered to 2572 (20.9%), 7790 (63.2%), and 1952 (15.8%) patients, respectively. Clinical TNM stage was one of the strongest prognostic factors with the 3‐year surv...

The Lancet Oncology, 2019

Background Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell ... more Background Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC. Methods This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.

Journal of Clinical Oncology, 2019

PURPOSE Although gene expression profiling is a promising diagnostic technique to determine the t... more PURPOSE Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP. PATIENTS AND METHODS Comprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate. RESULTS One hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in ...

BMC Cancer, 2017

Background: PIK3CA mutations are expected to be potential therapeutic targets for esophageal squa... more Background: PIK3CA mutations are expected to be potential therapeutic targets for esophageal squamous cell carcinoma (ESCC). We aimed to clarify the concordance between PIK3CA mutations detected in endoscopic biopsy specimens and corresponding surgically resected specimens. Methods: We examined five hotspot mutations in the PIK3CA gene (E542K, E545K, E546K, H1047R, and H1047L) in formalin-fixed and paraffin-embedded tissue sections of paired endoscopic biopsy and surgically resected specimens from 181 patients undergoing curative resection for ESCC between 2000 and 2011 using a Luminex technology-based multiplex gene mutation detection kit. Results: Mutation analyses were successfully performed for both endoscopic biopsy and surgically resected specimens in all the cases. A PIK3CA mutation was detected in either type of specimen in 13 cases (7.2%, 95% confidence interval: 3.9-12.0). The overall concordance rate, positive predictive value, and negative predictive value were 98.3% (178/181), 90.9% (10/11), and 98.8% (168/170), respectively. Among patients with a PIK3CA mutation detected in both types of specimens, the concordance between PIK3CA mutation genotypes was 100%. There were three cases with a discordant mutation status between the types of specimens (PIK3CA mutation in surgically resected specimen and wild-type in biopsy specimen in two cases, and the opposite pattern in one case), suggesting possible intratumoral heterogeneity in the PIK3CA mutation status. Conclusions: The PIK3CA mutation status was highly concordant between endoscopic biopsy and surgically resected specimens from the same patient, suggesting that endoscopic biopsy specimens can be clinically used to detect PIK3CA mutations in patients with ESCC.

Journal of Thoracic Oncology, 2017

first time, the lung cancer patients groups network have launched since November on 2015 named JL... more first time, the lung cancer patients groups network have launched since November on 2015 named JLCA, Japan lung cancer alliance. One of the goals of JLCA is to improve the lung cancer patient literacy in Japan. I will report JLCA activities about attempts to improve patient literacy in 2016. Results: 1) Multiple lung cancer patients have participated in the project on 'Working with cancer' by NCCJ. They had actually carried out to work together with lung cancer. Results of comparison of the two surveys between project survey by NCCJ and the survey by Japanese Cabinet Office comes out clearly the difference. More ambitious to work with cancer in National Cancer Center projects survey. 2) JLCA has been in cooperation with The Japan Lung Cancer Society, The Japanese Society of Medical Oncology, and enthusiastic lung cancer doctors to advocates activities especially Dr. Sawa. JLCA has been held five more seminars to improve lung cancer patient literacy at various places of Japan in 2016. Conclusion: One of the goals for Japanese lung cancer patients is to improve the patient literacy nowadays. They have ambitions to improve the patient literacy. They have participated in various activities to improve the patient literacy. It was found for them to want to be 'Living with cancer' and 'Working with cancer.' The important points are two thing, effective advocates projects and trial of patient initiative.

Journal of Thoracic Oncology, 2017

2010. Collagen gel droplet-embedded culture drug sensitivity test (CD-DST) was performed on fresh... more 2010. Collagen gel droplet-embedded culture drug sensitivity test (CD-DST) was performed on fresh surgical specimen. The clinical utility and prognostic outcome of adjuvant chemotherapy with carboplatin/paclitaxel in patients who showed chemo-sensitivity on CD-DST were evaluated. The primary endpoint was disease-free survival, and the secondary endpoints were overall survival and adverse effects during chemotherapy. Results: Among 92 registered patients, 87 (p-Stage IB in 54, IIA in 4, IIB in 10, IIIA in 19) were eligible and were included in the analysis. All patients were followed up for more than 5 years. The median age was 66 years old. The success rate of CD-DST was 87% and chemo-sensitivity to carboplatin and/or paclitaxel was observed in 75% of patients. Adjuvant chemotherapy was completed in 70% and the 5-year disease-free and overall survival rates were 68% and 82%, respectively. The 5-year disease-free and overall survival rates in Stage IIeIIIA patients were 58% and 75%, respectively. As for the adverse effects during adjuvant chemotherapy, grade 4 neutropenia was found in 13%. Conclusion: Chemo-sensitivity could be evaluated using CD-DST after lung cancer surgery. CD-DST might contribute to individualized adjuvant chemotherapy for locally advanced lung cancer.

Journal of Thoracic Oncology, 2017

*n¼20 did not have measurable disease per IRC and were not included in the IRC REP; † 2 CR; ‡ 4 C... more *n¼20 did not have measurable disease per IRC and were not included in the IRC REP; † 2 CR; ‡ 4 CR; § 13 CR; k non-measurable disease classified as CR, non-CR/non-PD or PD; NE¼not evaluable/estimable. Conclusion: Alectinib demonstrated durable responses, encouraging OS findings, good tolerability and an acceptable safety profile consistent with previous reports in this update of the NP28761 study with extended follow-up.

Gastroenterology Research and Practice, 2015

Objective. Patients with gastroenteropancreatic neuroendocrine carcinoma (NEC) have a poor progno... more Objective. Patients with gastroenteropancreatic neuroendocrine carcinoma (NEC) have a poor prognosis. Platinum-based combination chemotherapy is commonly used as first-line treatment; however, the role of salvage chemotherapy remains unknown. This study aimed to analyze the efficacy and safety of amrubicin monotherapy in patients with platinum-refractory gastroenteropancreatic NEC.Methods. Among 22 patients with advanced gastroenteropancreatic NEC, 10 received amrubicin monotherapy between September 2007 and May 2014 after failure of platinum-based chemotherapy. The efficacy and toxicity of the treatment were analyzed retrospectively.Results. Eight males and two females (median age, 67 years (range, 52–78)) received platinum-based chemotherapy, including cisplatin plus irinotecan (n=7, 70%), cisplatin plus etoposide (n=2, 20%), and carboplatin plus etoposide (n=1, 10%) before amrubicin therapy. Median progression-free survival and overall survival after amrubicin therapy were 2.6 an...

The Annals of Thoracic Surgery, 2006

Background. Patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) have a very poor ... more Background. Patients with pulmonary large cell neuroendocrine carcinoma (LCNEC) have a very poor prognosis, but the benefit of adjuvant chemotherapy for these patients has not been established. We performed a prospective analysis of adjuvant chemotherapy for patients with completely resected pulmonary LCNECs to assess the effect of adjuvant chemotherapy. Methods. The adjuvant mixture consisted of cisplatin and VP-16 and was administered after surgery to 15 patients with LCNECs from 2000 to 2005. We compared patient survival with historical data for LCNEC patients treated without platinum-based adjuvant chemotherapy after surgery. Results. There were no differences in age, gender, surgical methods, and staging between the adjuvant chemotherapy group and the control group. Median follow-up was 33 months for the adjuvant group and 42 months for the control group. Of the 15 patients in the adjuvant chemotherapy group, 2 patients had disease recurrence and 1 died of interstitial pneumonia. The overall survival rate at 2 and 5 years of patients with adjuvant chemotherapy was 88.9%. The overall survival rate between patients with adjuvant chemotherapy and the historical control group was significantly different. Conclusions. Adjuvant chemotherapy consisting of cisplatin and VP-16 after surgery appears promising for the improvement of the prognosis for patients with completely resected LCNECs, and it should be evaluated further in larger multi-institutional trials.

CancerSpectrum Knowledge Environment, 2002

Investigational New Drugs

In first-in-human (FIH) trials, sequential tumor biopsies, i.e., two consecutive tumor biopsies, ... more In first-in-human (FIH) trials, sequential tumor biopsies, i.e., two consecutive tumor biopsies, the first performed at baseline (pretreatment) and the second during the early treatment period (on-treatment), provide proof of concept in investigational new drugs. We evaluated the success of sequential tumor biopsies in FIH trials, and explored approaches for improved success rates. We retrospectively reviewed the sequential tumor biopsies required in 17 of 52 FIH trials conducted from 2015 to 2020. One hundred and thirty-eight patients were identified. Success of either pretreatment or on-treatment biopsy alone, and of sequential tumor biopsies, was defined as the acquisition of viable tumor cells and as obtaining tumor cells from both biopsy specimens, respectively. The success rates of pretreatment and on-treatment biopsy were 98.6% and 94.2%, respectively, and of sequential tumor biopsies was 70.3%. Adverse events associated with the pretreatment biopsies (33.3% positive; 72.0% n...

Igaku butsuri : Nihon Igaku Butsuri Gakkai kikanshi = Japanese journal of medical physics : an official journal of Japan Society of Medical Physics, 2001

The development of computerized tomography (CT) has made CT fluoroscopy possible with real-time C... more The development of computerized tomography (CT) has made CT fluoroscopy possible with real-time CT images. However examination are expected to have high medical and occupational exposures. Then, exposures to patients and operating and assisting physicians during the CT fluoroscopy-guided lung biopsy were estimated. And changes in the examination conditions to lower the dose were made. Patient exposure was measured using an anthropomorphic phantom by simulation of clinical examination conditions. The surface dose to the physician was measured during actual clinical examinations. The average effective dose for the patient was 34+/-22mSv. The highest surface dose amounted to 1.9 Gy, although this was in a very narrow field. Patient doses could be reduced by a factor of 2.5-3 by changing examination methods while still retaining diagnostic quality. The highest dose to the operating physician was 10mGy which was recorded on the back of the hand and the average effective dose was estimate...

Japanese Journal of Clinical Oncology, 2021

Background According to a questionnaire sent to Designated Cancer Care Hospitals in Japan in 2013... more Background According to a questionnaire sent to Designated Cancer Care Hospitals in Japan in 2013, only 39.4% of the institutes had medical oncology departments. Furthermore, most of these medical oncology departments were primarily responsible for the treatment of limited disease categories and the administration of newly developed therapeutic modalities, including molecular-targeted therapy. The aim of the present study was to update these previous findings and to clarify the changes over the intervening 7-year period. Methods The questionnaire was sent to all 393 Designated Cancer Care Hospitals on 13 March 2020. Similar to the previous questionnaires, questions were asked regarding the presence of a medical oncology department, the number of physicians in the department and the degrees of responsibility for drug therapies provided by medical oncologists to adult patients with solid cancers. Results In total, 270 institutions (68.7%) responded. Overall, 145 of these 270 instituti...

Oncology Reports, 2017

Resistance to anticancer medications often leads to poor outcomes. The present study explored an ... more Resistance to anticancer medications often leads to poor outcomes. The present study explored an effective approach for enhancing chemotherapy targeted against human cancer cells. Real-time quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed overexpression of members of aldo-keto reductase (AKR) 1C family, AKR1C1, AKR1C2, AKR1C3, and AKR1C4, in cisplatin, cis-diamminedichloroplatinum (II) (CDDP)resistant human cancer cell lines, HeLa (cervical cancer cells) and Sa3 (oral squamous cell carcinoma cells). The genes were downregulated using small-interfering RNA (siRNA) transfection, and the sensitivity to CDDP or 5-fluorouracil (5-FU) was investigated. When the genes were knocked down, sensitivity to CDDP and 5-FU was restored. Furthermore, we found that administration of mefenamic acid, a widely used non-steroidal anti-inflammatory drug (NSAID) and a known inhibitor of AKR1Cs, enhanced sensitivity to CDDP and 5-FU. The present study suggests that AKR1C family is closely associated with drug resistance to CDDP and 5-FU, and mefenamic acid enhances their sensitivity through its inhibitory activity in drug-resistant human cancer cells. Thus, the use of mefenamic acid to control biological function of AKR1C may lead to effective clinical outcomes by overcoming anticancer drug resistance.

BMC cancer, May 12, 2016

The addition of bevacizumab to cytotoxic agents prolongs survival in patients with nonsquamous no... more The addition of bevacizumab to cytotoxic agents prolongs survival in patients with nonsquamous non-small cell lung cancer (NSCLC). To date, there is no evidence to suggest that treatment with a cytotoxic agent plus bevacizumab is more effective than a cytotoxic agent alone for nonsquamous NSCLC in elderly patients. We conducted a feasibility study of pemetrexed plus bevacizumab as a first-line treatment for advanced or recurrent nonsquamous NSCLC in elderly patients. Major eligibility and exclusion criteria included: chemotherapy-naive status; non-fitness for bolus combination chemotherapy; stage III/IV or relapsed nonsquamous NSCLC; age ≥70; performance status 0-1; absence of brain metastasis; and no history of hemoptysis and thoracic irradiation. Pemetrexed (500 mg/m(2)) and bevacizumab (15 mg/kg) were administered intravenously on day 1, and repeated every 3 weeks thereafter. The primary endpoint was safety, and the secondary endpoints were objective response rate (ORR), progress...

Japanese journal of clinical oncology, Jan 10, 2016

Cisplatin is administered in combination with massive hydration to avoid renal toxicity, making i... more Cisplatin is administered in combination with massive hydration to avoid renal toxicity, making its administration difficult in an outpatient setting. Although a short hydration protocol for cisplatin has been recently developed, its safety is not fully understood. Consecutive patients with lung or other cancer and an Eastern Cooperative Oncology Group performance status of 0-2 who were receiving chemotherapy containing cisplatin at a dose of ≥60 mg/m(2) in a single administration were evaluated. Seventy-four patients were treated with a short hydration protocol consisting of 1750-2250 ml of hydration with mannitol and magnesium supplementation over a period of 3.75-4.75 h on Day 1. Sixty-nine patients were treated with a conventional hydration protocol consisting of 2100-2600 ml of hydration over 6.5-7.5 h on Day 1 with pre- and post-hydration on Days 0, 2 and 3. Toxicity was then compared between the two groups. An elevated serum creatinine level ≥grade 1 was significantly less fr...

European Respiratory Journal, Sep 1, 2012