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Preoperative chemotherapy is a promising strategy in patients with early-stage resectable non-small-cell lung cancer (NSCLC); optimal chemotherapy remains unclear. Clinical (c-) stage IB/II NSCLC patients were randomised to receive either two cycles of docetaxel (D)-cisplatin (P) combination chemotherapy (D 60 mg m(-2) and P 80 mg m(-2) on day 1) every 3-4 weeks or three cycles of D monotherapy (70 mg m(-2)) every 3weeks. Thoracotomy was performed 4-5 weeks (DP) or 3-4 weeks (D) after chemotherapy. The primary end point was 1-year disease-free survival (DFS). From October 2002 to November 2003, 80 patients were randomised. Chemotherapy toxicities were mainly haematologic and well tolerated. There were two early postoperative deaths with DP (one intraoperative bleeding and one empyema). Pathologic complete response was observed in two DP patients. Docetaxel-cisplatin was superior to D in terms of response rate (45 vs 15%) and complete resection rate (95 vs 87%). Both DFS and overall survival were better in DP. Disease-free survival at 1, 2 and 4 years were 78, 65 and 57% with DP, and were 62, 44 and 36% with D, respectively. Preoperative DP was associated with encouraging resection rate and DFS data, and phase III trials for c-stage IB/II NSCLC are warranted. [ABSTRACT FROM AUTHOR]

Background Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data. Patients and methods Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan–Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model. Results OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883–1.775, P  = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312–0.673, P  <   0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively. Conclusion G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease. This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539. [ABSTRACT FROM AUTHOR]

Background Cigarette smoking is the major cause of lung cancer (LC). Although the time to first cigarette (TTFC) of the day is a distinct indicator of nicotine dependence, little information is available on its possible relation to LC. Patients and methods This case–control study includes a total of 1572 incident LC cases and 1572 non-cancer controls visiting for the first time the Aichi Cancer Center Hospital between 2001 and 2005. We estimated the odds ratio (OR) and 95% confidence interval (CI) for TTFC using a logistic regression model after adjustment for several potential confounders. Results TTFC was inversely associated with the risk of LC. This association was consistent across histological subtypes of LC. For all LCs considered among ever smokers and after accurate allowance for smoking quantity and duration, besides other relevant covariates, compared with TTFC >60 min, the adjusted ORs were 1.08 (95% CI, 0.73–1.61) for TTFC of 31–60 min, 1.40 (0.98–2.01) for 6–30 min and 1.86 (1.28–2.71) for within 5 min (Ptrend, < 0.001). Statistically marginally significant heterogeneity by histological subtype was observed (Pheterogeneity, 0.002). Conclusions Nicotine dependence, as indicated by the TTFC, is associated with increased risk of LC and is therefore an independent marker of exposure to tobacco smoking. [ABSTRACT FROM PUBLISHER]

In the open-label, phase III CheckMate 816 study (NCT02998528), neoadjuvant nivolumab plus chemotherapy demonstrated statistically significant improvements in event-free survival (EFS) and pathological complete response (pCR) versus chemotherapy alone in patients with resectable non-small-cell lung cancer (NSCLC). Here we report efficacy and safety outcomes in the Japanese subpopulation. Patients with stage IB-IIIA, resectable NSCLC were randomized 1:1 to nivolumab plus chemotherapy or chemotherapy alone for three cycles before undergoing definitive surgery within 6 weeks of completing neoadjuvant treatment. The primary end-points (EFS and pCR) and safety were assessed in patients enrolled at 16 centers in Japan. Of the Japanese patients randomized, 93.9% (31/33) in the nivolumab plus chemotherapy arm and 82.9% (29/35) in the chemotherapy arm underwent surgery. At 21.5 months' minimum follow-up, median EFS was 30.6 months (95% confidence interval [CI], 16.8-not reached [NR]) with nivolumab plus chemotherapy versus 19.6 months (95% CI, 8.5-NR) with chemotherapy; hazard ratio, 0.60 (95% CI, 0.30-1.24). The pCR rate was 30.3% (95% CI, 15.6-48.7) versus 5.7% (95% CI, 0.7-19.2), respectively; odds ratio, 7.17 (95% CI, 1.44-35.85). Grade 3/4 treatment-related adverse events were reported in 59.4% versus 42.9% of patients, respectively, with no new safety signals identified. Neoadjuvant nivolumab plus chemotherapy resulted in longer EFS and a higher pCR rate versus chemotherapy alone in Japanese patients, consistent with findings in the global population. These data support nivolumab plus chemotherapy as a neoadjuvant treatment option in Japanese patients with resectable NSCLC., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib were approved for metastatic or relapsed non-small cell lung cancer (NSCLC) in Japan in 2002 and 2007, respectively. EGFR mutation testing was also approved in 2007. Although clinical trials showed efficacy in NSCLC patients harboring activating EGFR mutations, these effects have rarely been reported in real-world practice. We evaluated changes in survival in NSCLC patients following introduction of these agents and EGFR mutation testing by extracting patients diagnosed with NSCLC from 1993 through 2011 from six prefectural population-based cancer registries in Japan. Relative survival (RS) was calculated by sex, histological subtype, and cancer stage. We conducted interrupted time series analysis to assess survival changes following introduction of EGFR-TKIs and EGFR mutation testing. 120,068 patients with NSCLC were analyzed. One- and three-year RS gradually increased in overall NSCLC for men and women. For adenocarcinoma, among men, slopes of 1- and 3-year RS increased steeply in patients diagnosed from 2007 through 2011; among women, significant level increases were seen in 1-year RS in patients diagnosed in 2002 (4.55% [95% confidence interval: 1.76-7.33]) and 2007 (3.40% [1.27-5.52]). These significant level increases were particularly obvious in women with adenocarcinoma at an advanced stage. Our results suggest that recent improvements in survival in men and women with adenocarcinoma are due at least partly to introduction of EGFR-TKIs into real-world practice, and to prescription based on appropriate patient selection following introduction of EGFR mutation testing into real-world practice in Japan., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose: To investigate the efficacy of gefitinib as an adjuvant therapy for non-small-cell lung cancer patients with EGFR mutation., Patients and Methods: IMPACT (WJOG6410L; University Hospital Medical Information Network Clinical Trials Registry: UMIN000006252), a randomized, open-label, phase III study, included patients with completely resected pathologic stage II-III non-small-cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R) during September 2011 to December 2015. Patients were randomly assigned to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m 2 on day 1) plus vinorelbine (25 mg/m 2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles. The primary end point was disease-free survival (DFS)., Results: Overall, 234 patients were randomly assigned. Among 232 eligible patients (116 each; excluding two who withdrew consent), the median DFS was 35.9 and 25.1 months in the gefitinib and cis/vin groups, respectively. However, Kaplan-Meier curves crossed around 4 years after surgery with no statistically significant difference (stratified log-rank P = .63; hazard ratio by stratified Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival (OS) was also not different (stratified log-rank P = .89; hazard ratio = 1.03; 95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in 0 and three patients in the gefitinib and cis/vin groups, respectively., Conclusion: Although adjuvant gefitinib appeared to prevent early relapse, it did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant gefitinib in the selected patient subsets, especially those deemed ineligible for platinum-doublet adjuvant therapy; however, this was not a noninferiority trial., Competing Interests: Hirohito TadaHonoraria: Chugai Pharma Tetsuya MitsudomiHonoraria: AstraZeneca, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Bristol Myers Squibb, Chugai Pharma, Taiho Pharmaceutical, Lilly, Novartis, MSD K.K., Kyowa Hakko Kirin, Amgen, Daiichi-Sankyo, Guardant Health, Ethicon, Thermofisher Scientific Biomarkers, Merck KGaA, Janssen Oncology, TakedaConsulting or Advisory Role: AstraZeneca, Pfizer, Boehringer Ingelheim, Chugai Pharma, Ono Pharmaceutical, MSD Oncology, Lilly, Novartis, Amgen, Daiichi Sankyo, Thermo Fisher ScientificResearch Funding: Boehringer Ingelheim (Inst), AstraZeneca (Inst), Pfizer (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Sanofi/Aventis (Inst), Daiichi Sankyo (Inst), MSD K.K. (Inst), Kyowa Hakko Kirin (Inst) Toshihiro MisumiSpeakers' Bureau: Chugai Pharma, AstraZeneca Kenji SugioHonoraria: AstraZeneca, Chugai PharmaResearch Funding: Covidien Japan, Lilly Japan Masahiro TsuboiHonoraria: AstraZeneca Japan, Chugai Pharma, Taiho Pharmaceutical, Teijin Pharma, Johnson & Johnson, Novartis, MSD K.K., Ono Pharmaceutical, Bristol Myers Squibb Japan, MedtronicResearch Funding: Boehringer Ingelheim (Inst), Merck (Inst) Isamu OkamotoHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD Oncology, Chugai Pharma, AstraZeneca, Boehringer Ingelheim, Pfizer, Taiho Pharmaceutical, Lilly JapanConsulting or Advisory Role: Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, PfizerResearch Funding: AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Ono Pharmaceutical (Inst), MSD Oncology (Inst), Lilly (Inst), Astellas Pharma (Inst), AbbVie (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Takeda (Inst), Chugai/Roche (Inst) Shunichi SugawaraHonoraria: AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Ono Pharmaceutical, MSD K.K., Yakult Honsha, Kyowa Kirin Shinji AtagiHonoraria: Chugai Pharma, MSD K.K., Ono Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Lilly Japan, Pfizer, Bristol Myers Squibb Japan, Hisamitsu Pharmaceutical, Kyowa Hakko Kirin, Merck, Novartis, Thermo Fisher ScientificResearch Funding: MSD K.K. (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Lilly Japan (Inst), Pfizer (Inst), Bristol Myers Squibb Japan (Inst), Roche (Inst), Merck (Inst) Toshiaki TakahashiHonoraria: AstraZeneca KK, Chugai Pharma, Lilly Japan, Ono Pharmaceutical, MSD K.K., Pfizer, Boehringer Ingelheim, Roche, Takeda Pharmaceutical Co Ltd, Yakult HonshaResearch Funding: AstraZeneca KK (Inst), Lilly Japan (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), MSD K.K. (Inst), Pfizer (Inst), Amgen (Inst), Boehringer Ingelheim (Inst) Hidetoshi HayashiHonoraria: Ono Pharmaceutical, Bristol Myers Squibb Japan, Lilly, Taiho Pharmaceutical, Boehringer Ingelheim, AstraZeneca Japan, Chugai Pharma, Pfizer, MSD, Novartis, Merck SeronoConsulting or Advisory Role: Lilly, AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Pfizer, Merck Serono, Shanghai HaiHe Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo/UCB JapanResearch Funding: Ono Pharmaceutical, Boehringer Ingelheim, AstraZeneca, AbbVie (Inst), AC Medical (Inst), Astellas Pharma (Inst), Bristol Myers Squibb (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Lilly Japan (Inst), EPS Associates Co, Ltd (Inst), GlaxoSmithKline (Inst), Japan Clinical Research Operations (Inst), Kyowa Hakko Kirin (Inst), Merck Serono (Inst), Novartis (Inst), Otsuka (Inst), Parexel (Inst), Pfizer (Inst), PPD-SNBL (Inst), Quintiles Inc (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), Yakult Honsha (Inst)Patents, Royalties, Other Intellectual Property: Sysmex Morihito OkadaSpeakers' Bureau: Taiho Pharmaceutical, Johnson & Johnson, Covidien, Lilly, Chugai Pharma, AstraZeneca, Ono Pharmaceutical, CSL BehringResearch Funding: Taiho Pharmaceutical (Inst), Nippon Kayaku (Inst), Chugai Pharma (Inst), Covidien (Inst), Johnson & Johnson (Inst), Daiichi Sankyo (Inst), Yakult Honsha (Inst), Lilly Japan (Inst), Nihon Medi-Physics (Inst), Pfizer (Inst), Mochida Pharmaceutical Co Ltd. (Inst), Shionogi (Inst), Ono Pharmaceutical (Inst), Kyowa Hakko Kirin (Inst) Hiroshige YoshiokaHonoraria: Lilly, Chugai Pharma, Boehringer Ingelheim, Taiho Pharmaceutical, AstraZeneca, Bristol Myers Squibb, Ono Pharmaceutical, MSD K.K., Novartis, Kyowa Kirin Co, Ltd, Daiichi Sankyo, Nippon Kayaku, Delta-Fly Pharma, PfizerConsulting or Advisory Role: Delta-Fly Pharma Kazuhisa TakahashiSpeakers' Bureau: AstraZeneca Ichiro YoshinoHonoraria: Johnson & Johnson, Pfizer, Chugai Pharma, Taiho Pharmaceutical, Shionogi, Astra Zeneca, Intuitive Surgical, Daiichi Sankyo, Boehringer Ingelheim, Covidien/MedtronicConsulting or Advisory Role: Astra Zeneca, Intuitive Surgical, Covidien/MedtronicResearch Funding: Chugai Pharma (Inst), Taiho Pharmaceutical (Inst), Pfizer (Inst), Shionogi (Inst) Kazuhiko NakagawaHonoraria: AstraZeneca KK, Ono Pharmaceutical, Chugai Pharma, Nippon Boehringer Ingelheim, Lilly, Pfizer, Bristol Myers Squibb, Novartis, CareNet, Taiho Pharmaceutical, Yodosha, Nikkei Business Publications, Inc, Kyorin, Takeda, Medical Review Co, Ltd, MSD K.K., AbbVie, Merck, Roche Diagnostics, Bayer Yakuhin, Nippon Kayaku, Amgen, Kyowa Kirin Co, Ltd, Medical Mobile Communications Co, Ltd, 3H Clinical Trial, Astellas Pharma, Yomiuri Telecasting Corporation, Medicus Shuppan, publishers Co, Ltd, Thermo Fisher Scientific, Hisamitsu Pharmaceutical Co, Inc, Nichi-iko, Nanzando Co, Ltd, Daiichi Sankyo Co, LtdConsulting or Advisory Role: Pfizer, Kyorin Pharmaceutical Co, Ltd, Lilly Japan, Ono Pharmaceutical, Astellas Pharma, TakedaResearch Funding: Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Daiichi Sankyo (Inst), Eisai (Inst), Pfizer (Inst), Takeda (Inst), Nippon Boehringer Ingelheim (Inst), Taiho Pharmaceutical (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Lilly (Inst), Parexel International Corp. (Inst), A2 Healthcare (Inst), Novartis (Inst), IQvia (Inst), SymBio Pharmaceuticals (Inst), AstraZeneca KK (Inst), Kissei Pharmaceutical (Inst), EPS Holdings (Inst), Bayer Yakuhin (Inst), MSD K.K. (Inst), Pfizer (Inst), Otsuka (Inst), Syneos Health (Inst), EPS International (Inst), PRA Health Sciences (Inst), PPD-SNBL (Inst), Covance (Inst), GlaxoSmithKline K.K. (Inst), Sysmex (Inst), Mochida Pharmaceutical Co Ltd. (Inst), Japan Clinical Research Operations (Inst), Sanofi (Inst), Medical Research Support (Inst), ICON (Inst), CMIC (Inst), Kyowa Kirin Co, Ltd (Inst)No other potential conflicts of interest were reported.

Background: The optimal mode of surgery for ground-glass opacity dominant peripheral lung cancer defined with thoracic thin-section computed tomography remains unknown., Methods: We conducted a single-arm confirmatory trial to evaluate the efficacy and safety of sublobar resection for ground-glass opacity dominant peripheral lung cancer. Lung cancer with maximum tumor diameter 2.0 cm or less and with consolidation tumor ratio 0.25 or less based on thin-section computed tomography were registered. The primary end point was 5-year relapse-free survival. The planned sample size was 330 with the expected 5-year relapse-free survival of 98%, threshold of 95%, 1-sided α of 5%, and power of 90%. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number University Hospital Medical Information Network 000002008., Results: Between May 2009 and April 2011, 333 patients were enrolled from 51 institutions. Median age was 62 years (interquartile range, 56-68), and 109 were smokers. Median maximum tumor diameter was 1.20 cm (1.00-1.54). Median maximum tumor diameter of consolidation was 0 (0.00-0.20). The primary end point, 5-year relapse-free survival, was estimated on 314 patients who underwent sublobar resection. Operative modes were 258 wide wedge resections and 56 segmentectomies. Median pathological surgical margin was 15 mm (0-55). The 5-year relapse-free survival was 99.7% (90% confidence interval, 98.3-99.9), which met the primary end point. There was no local relapse. Grade 3 or higher postoperative complications based on Common Terminology Criteria for Adverse Effect v3.0 were observed in 17 patients (5.4%), without any grade 4 or 5., Conclusions: Sublobar resection with enough surgical margin offered sufficient local control and relapse-free survival for lung cancer clinically resectable N0 staged by computed tomography with 3 or fewer peripheral lesions 2.0 cm or less amenable to sublobar resection and with a consolidation tumor ratio of 0.25 or less., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069)., Patients and Methods: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m 2 ] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%., Conclusion: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC., Competing Interests: Akira Hamada has received grants and personal fees from AstraZeneca, personal fees from Chugai, and grants from the Japan Society for the Promotion of Science. Junichi Soh has received grants from AstraZeneca, and grants from the Japan Society for the Promotion of Science. Akito Hata has received grants and personal fees from AstraZeneca, Eli Lilly, and Boehringer Ingelheim, personal fees from Chugai, and grants from MSD. Kiyoshi Nakamatsu has received grants from AstraZeneca. Yasushi Yatabe has received grants and personal fees from AstraZeneca, personal fees from MSD, Chugai-pharma, Pfizer, Roche/Ventana, Agilent/Dako, Thermo Fisher Science, ArcherCD, Novartis, Elli-Lily, and Daiichi Sankyo. Hiroyuki Oizumi has received grants from AstraZeneca and ONO Pharmaceutical Co., Ltd. Masahiro Tsuboi has received grants and personal fees from AstraZeneca, ONO Pharmaceutical Co., Ltd., Bristol-Myers Squibb KK, Eli Lilly Japan, MSD, and Novartis, and personal fees from Johnson and Johnson Japan, Chugai Pharmaceutical Co., Ltd., Teijin Pharma, Taiho Pharma, Medtronic Japan, and grants from Beohringer-Ingelheim Japan. Hidehito Horinouchi has received grants and personal fees from AstraZeneca, BMS, ONO, MSD, Janssen, and Chugai, personal fees from Lilly, Merck Biophama, Kyowa-Kirin, and Nihonkayaku, and grants from Daiichi-Sankyo, Abbvie, and Genomic Health. Ichiro Yoshino has received grants and personal fees from AstraZeneca. Masayuki Tanahashi has received grants from AstraZeneca. Shinichi Toyooka has received grants from AstraZeneca, Illumina, Eurofins, and Eli Lilly, grants and personal fees from Taiho, Kyorin, and Chugai, and personal fees from ONO, Daiichi-Sankyo, Medtronic, Johnson and Johnson. Morihito Okada has received grants and personal fees from AstraZeneca. Hiroyasu Yokomise has received grants from AstraZeneca. Motohiro Yamashita has received grants from AstraZeneca. Yasumasa Nishimura has received grants from AstraZeneca. Nobuyuki Yamamoto has received grants and personal fees from MSD K.K., AstraZeneca, ONO Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Boehringer-Ingelheim, Novartis, and Pfizer Inc., personal fees from Thermo Fisher Scientific, Bristol-Myers Squibb, Life Technologies Japan Ltd., Nippon Kayaku, and Merk Biopharma, and grants from Astellas Pharma Inc., Tsumura & Co., Shionogi Co., Ltd., AbbVie GK., Amgen Inc., Kyorin Pharmaceutical Co., Ltd., Eisai Co., Ltd., Terumo Corporation, Toppan Printing Co., Ltd., and Tosoh. Kazuhiko Nakagawa has received grants and personal fees from AstraZeneca K.K., Astellas Pharma Inc., MSD K.K., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K.K., Bristol Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Merck Serono Co., Ltd./Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Limited, and AbbVie Inc, grants, personal fees, and other from Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Eli Lilly Japan K.K., and Takeda Pharmaceutical Co., Ltd., personal fees from Clinical Trial Co., Ltd., Medicus Shuppan, Publishers Co., Ltd., Care Net, Inc., Reno, Medical K.K., Medical Review Co., Ltd., Roche Diagnostics K.K., Bayer Yakuhin, Ltd., Medical Mobile Communications Co., Ltd., 3H Clinical Trial Inc., Nichi-Iko Pharmaceutical Co., Ltd., Nanzando Co., Ltd., Yodosha Co., Ltd., Nikkei Business Publications, Inc., Thermo Fisher Scientific K.K., Yomiuri Telecasting Corporation, and Nippon Kayaku Co., Ltd., personal fees and other from Kyorin Pharmaceutical Co., Ltd., and grants from inVentiv Health Japan, ICON Japan K.K., Gritsone Oncology, Inc., Parexel International Corp., Kissei Pharmaceutical Co., Ltd., EPS Corporation, Syneos Health, Pfizer R&D Japan G.K., A2 Healthcare Corp., Quintiles Inc./IQVIA Services Japan K.K., EP-CRSU Co., Ltd., Linical Co., Ltd., Eisai Co., Ltd., CMIC Shift Zero K.K., Kyowa Hakko Kirin Co., Ltd, Bayer Yakuhin, Ltd., EPS International Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. Tetsuya Mitsudomi has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Chugai, personal fees from Bristol-Myers Squibb, Eli Lilly, Merck Sharp and Dohme, and Pfizer, grants from Daiichi Sankyo, Taiho, Ono Pharmaceutical, and the Japan Society for the Promotion of Science, and other from Novartis. The other authors have stated that they have no conflict of interest., (Copyright © 2021. Published by Elsevier Inc.)

Background: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors., Materials and Methods: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan., Results: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy., Conclusion: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs., Implications for Practice: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Backgrounds: Since the recent development of molecular targeted drugs and immune checkpoint inhibitors has improved lung cancer treatment options and outcomes, supporting patients in balancing work and pharmacotherapy have become even more important in the field of lung cancer treatment. This study sought to identify the current status and roles of doctors in balancing work and treatment for lung cancer patients., Methods: Patients and doctors were recruited to complete a web-based questionnaire survey by the Japan Lung Cancer Society., Results: About 287 lung cancer patients and 381 doctors were included in the analysis. About 42.9% of patients responded that "there was no discussion" about their working conditions or work before the initiation of pharmacotherapy, while 22.6% responded that "there was an inquiry from a doctor/health care provider and a discussion that included the doctor was held." About 45.3% of patients took leave or resigned from work at the time of diagnosis. The most common reasons for patients to resign before or during pharmacotherapy were "poor physical condition due to side effects of treatment or illness" and "concern about causing problems in the workplace." To assist in balancing work and pharmacotherapy, patients desired "increased opportunities to consult about work" (36.9%) and "provision of treatment options with few adverse events" (28.9%)., Conclusion: This study highlights the importance of doctor-initiated management of the balance between work and treatment for lung cancer patients. An important first step is for doctors themselves to take an interest in their patients' professions and initiate discussions of work-related topics with their patients., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are the standard of care for non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations. However, almost all patients develop resistance after approximately 1 y of treatment, with >50% of cases due to the T790M secondary mutation of the EGFR gene. A large global Phase III study (AURA3) demonstrated that osimertinib significantly prolonged progression-free survival (PFS) over platinum-doublet chemotherapy in patients with T790M-positive NSCLC who had progressed on previous EGFR-TKI therapy. However, it is not clear whether efficacy or safety of osimertinib in Japanese patients is similar to the overall population. We report a pre-planned subgroup analysis of pooled Phase II data from the AURA Extension and AURA2 trials to investigate the efficacy and safety of osimertinib in Japanese patients. This study included 81 Japanese patients. Patients were administered 80 mg osimertinib orally once daily until disease progression. The main endpoints were objective response rate (ORR), PFS, and safety. The ORR was 63.6% and median PFS was 13.8 mo. Overall survival rate at 36 mo was 54.0%. The most common all-cause adverse events (AEs) were rash (grouped term; 65.4%), diarrhea (51.9%), paronychia (grouped term; 49.4%), and dry skin (grouped term; 39.5%). Most AEs were grade 1-2. Five patients (6.2%) developed interstitial lung disease, resulting in two deaths (2.5%). Osimertinib demonstrated favorable ORR and PFS in Japanese patients, similar to the overall population. Additionally, osimertinib has good efficacy and a manageable safety profile in Japanese patients with NSCLC who had acquired resistance due to the T790M mutation., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

We exhibit our ongoing multicenter, prospective, single-arm, phase II trial of docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) support for chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (NSCLC) (University Hospital Medical Information Network database: UMIN000030598). Docetaxel monotherapy is the Japanese standard of care for chemotherapy-naive elderly patients with advanced NSCLC. Docetaxel plus ramucirumab showed superior survival benefit over docetaxel monotherapy in the second-line setting for NSCLC. A Japanese phase II study comparing docetaxel plus ramucirumab and docetaxel monotherapy in the second-line setting showed febrile neutropenia (FN) incidence of approximately one-third in the docetaxel plus ramucirumab arm. Docetaxel plus ramucirumab could be a promising candidate for elderly patients with NSCLC, but such high FN incidence is a clinically critical concern. To overcome this problem, we adopt a routine primary prophylactic PEG-G-CSF with docetaxel plus ramucirumab therapy. We hypothesize that primary prophylactic PEG-G-CSF reduces FN and maximizes the efficacy of docetaxel plus ramucirumab in Japanese elderly patients with NSCLC. Intravenous docetaxel (60 mg/m 2 , day 1) plus ramucirumab (10 mg/kg, day 1) with subcutaneous PEG-G-CSF (3.6 mg, day 2) every 3 weeks is administered until progression. The primary endpoint is overall response rate (ORR). We decided the threshold ORR to be 20%, and the expected ORR 35%. Taking statistical points (α/β errors: 0.05/0.80) and ineligible patients into account, the sample size was set at 65. When the study results are promising, we will conduct a phase III trial to compare docetaxel plus ramucirumab with PEG-G-CSF support versus docetaxel monotherapy for chemotherapy-naive elderly patients with NSCLC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: We determined the central nervous system (CNS) efficacy of alectinib by calculating time to CNS progression and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and death in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) enrolled in the J-ALEX phase III study., Materials and Methods: Japanese patients aged ≥20 years with ALK-positive NSCLC who were ALK inhibitor-naïve and chemotherapy-naïve, or who had received one previous chemotherapy regimen, were enrolled. Patients with treated or untreated asymptomatic CNS metastases were eligible. Treatment comprised oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death or withdrawal. Imaging scans (computed tomography/magnetic resonance imaging) were taken at baseline and at regular intervals throughout the study. The CIRs for CNS progression, non-CNS progression and death were calculated for patients with and without baseline CNS metastases using a competing risks method., Results: The hazard ratio for time to CNS progression in patients with and without baseline CNS metastases was 0.51 (95% confidence interval [CI]: 0.16-1.64; P = 0.2502) and 0.19 (95% CI: 0.07-0.53; P = 0.0004), respectively. The CIRs of CNS progression and non-CNS progression were lower in the alectinib group than in the crizotinib group at all time points. The 1-year CIRs of CNS progression were 16.8% and 5.9% with crizotinib and alectinib, respectively, and the 1-year CIRs of non-CNS progression were 38.4% and 17.5%, respectively. Comparable findings were obtained in patients with or without baseline CNS metastases., Conclusion: Alectinib appears to avert the progression of CNS metastases in patients with ALK-positive NSCLC and baseline CNS metastases, and to prevent the development of new CNS lesions in patients without baseline CNS disease., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34-1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10(-14) ) even after removing rs2736100 (p value = 4.81 × 10(-3) ), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk., (Published 2014. This article is a US Government work and, as such, is in the public domain of the United States of America.)

Objective: The study objective was to examine the incidence, risk factors, and mortality rate of acute exacerbation of interstitial lung diseases in patients with lung cancer undergoing pulmonary resection in a large-scale multi-institutional cohort., Methods: We retrospectively analyzed 1763 patients with non-small cell lung cancer who had undergone pulmonary resection and presented with a clinical diagnosis of interstitial lung diseases between January 2000 and December 2009 at 61 hospitals in Japan. The incidence and outcomes of acute exacerbation within 30 days from the operation were investigated. Univariate and multivariate logistic regression analyses were used to identify independent risk factors of acute exacerbation., Results: Acute exacerbation occurred in 164 patients (9.3%; 95% confidence interval, 8.0-10.8), with a mortality rate of 43.9%, and was the top cause of 30-day mortality (71.7%). The following 7 independent risk factors of acute exacerbation were identified: surgical procedures, male sex, history of exacerbation, preoperative steroid use, serum sialylated carbohydrate antigen KL-6 levels, usual interstitial pneumonia appearance on computed tomography scan, and reduced percent predicted vital capacity. Surgical procedures showed the strongest association with acute exacerbation (using wedge resection as the reference, lobectomy or segmentectomy: odds ratio, 3.83; 95% confidence interval, 1.94-7.57; bi-lobectomy or pneumonectomy: odds ratio, 5.70; 95% confidence interval, 2.38-13.7; P < .001). The effect of perioperative prophylactics, such as steroids and sivelestat, was not confirmed in this study., Conclusions: Pulmonary resection for patients with lung cancer with interstitial lung diseases may provoke acute exacerbation at a substantially high rate and has high associated mortality. Surgical procedures that proved to be a risk factor for acute exacerbation should be chosen cautiously for these high-risk patients., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Objective: The study objective was to evaluate the long-term survival of patients with radiographically determined noninvasive lung adenocarcinomas., Methods: A prospective, multi-institutional study on image diagnosis to define early (noninvasive) adenocarcinomas of the lung (Japan Clinical Oncology Group 0201) has shown that a consolidation/tumor ratio on thin-section computed tomography 0.25 or less in cT1a (≤2.0 cm) could be used as a better radiologic criterion for a noninvasive pathology than a consolidation/tumor ratio 0.50 or less in cT1a-b (≤3.0 cm). From the prognostic viewpoints, these criteria were evaluated for 545 patients with adenocarcinoma who underwent lobectomy and lymph node dissection., Results: The subjects consisted of 233 men and 312 women with a median age of 62 years. The median follow-up period among overall patients was 7.1 years (range, 0-8.5 years). The overall and relapse-free 5-year survivals of the overall patients were 90.6% and 84.7%, respectively. When a consolidation/tumor ratio 0.5 or less in cT1a-b was used as a cutoff, the 5-year overall survivals of radiologic noninvasive (121 patients, 22.2%) and invasive (424 patients, 77.8%) adenocarcinomas were 96.7% and 88.9%, respectively, and the difference was statistically significant (P < .001, log-rank test). With the use of a consolidation/tumor ratio 0.25 or less in cT1a, the 5-year overall survivals of radiologic noninvasive (35 patients, 12.1%) and invasive (254 patients, 87.9%) adenocarcinomas were 97.1% and 92.4%, respectively, and the difference was not statistically significant (P = .259)., Conclusions: The radiologic criteria of a consolidation/tumor ratio 0.25 or less in cT1a (≤2.0 cm) and 0.50 in cT1a-b (≤3.0 cm) were both able to define a homogeneous group of patients with an excellent prognosis before surgery., (Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Activating mutation in the kinase domain of the human EGF receptor 2 (HER2) gene (also known as ERBB2 or neu) is reported to be present in a small fraction of lung adenocarcinomas. However its prognostic and predictive implications are not yet established., Patients and Methods: We examined 504 Japanese lung cancer patients who underwent pulmonary resection for HER2 mutations by direct sequencing and evaluated their prognostic and predictive implications. Updated prognostic data of 14 Japanese patients with HER2 mutation from previous two reports were also gathered., Results: HER2 mutations were identified in 13 of 504 cases (2.6%). Patients with HER2 mutations were common in female, nonsmokers and adenocarcinomas as those with EGFR mutations. When confined to the subgroup of nonsmokers with adenocarcinoma or adenosquamous cell carcinoma without EGFR mutations, the frequency of HER2 mutations was 14.1% (11/78). There was no difference in the overall survival of patients with HER2 mutations, compared with patients harboring EGFR mutations and patients harboring wild types for both EGFR and HER2. Within the patients with HER2 mutation, two of three with TP53 mutation and one of 13 without TP53 mutation died of the disease, suggesting negative prognostic role of the TP53 mutation. Three patients with HER2 mutations did not respond to platinum-based chemotherapy and EGFR-TKIs. Of note, one patient with the most common HER2 mutations, YVMA776-779ins, responded to trastuzumab plus vinorelbine after failure of multiple round of platinum-based chemotherapy and gefitinib., Conclusion: HER2 mutations are present in a subset of patients with lung cancer having distinct clinical features. HER2 mutations were not associated with the prognosis of patients with lung cancers. Patients with HER2 mutations might benefit from anti-HER2 therapy., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Lung cancer staging system proposed in 2007 adopts detailed tumor size cut-off values. Alternatively, visceral pleural invasion is deemed an important prognosticator, but has not been easily incorporated into the staging system., Methods: We studied 1,245 patients with resected nonsmall-cell lung cancer. Among patients with current pathologic stage IB (pT2N0M0) disease, those with worse prognosis were reclassified as stage IIA based on tumor size and degree of visceral pleural invasion defined by the Japan Lung Cancer Society: P0 = no pleural involvement beyond elastic layer; P1 = infiltration beyond elastic layer without exposure to pleural surface; and P2 = exposure to pleural surface., Results: The current pT2 category was divided into five groups based on size ( 3 to 5 cm) and degree of visceral pleural invasion (P0-1 or P2). Five-year survival rates in patients with P0-1 tumors greater than 3 cm to 5 cm or less were significantly better (59.5%) than those with tumors greater than 5 cm or P2 tumors (37.5% to 47.3%; p = 0.0014); we defined these two groups as T2a and T2b, respectively, and classified T2aN0M0 as stage IB and T2bN0M0 as stage IIA together with the current T1N1M0. Five-year survival rates for the modified IB and IIA diseases were 70.6% and 60.4%, respectively (p = 0.0414)., Conclusions: Modified subcategorization of the pT2 category resulted in T2a (> 3 to 5 cm or P2). Detailed assessment of the degree of visceral pleural invasion could provide more information on tumor characteristics and complement the pathologic staging of lung cancer.

Mutation of the LKB1 gene (also known as STK11) is regarded as a cause of Peutz-Jeghers syndrome. In Caucasian patients, LKB1 somatic mutations occur in approximately one-third of lung adenocarcinomas. The aim of the present study was to examine the LKB1 gene in Japanese patients with lung cancer and to evaluate its clinical and pathological implications. We sequenced the LKB1 gene in 22 lung cancer cell lines and 100 Japanese patients with lung cancer (including 81 adenocarcinomas, 14 squamous cell carcinomas and five other histological types) who had undergone curative pulmonary resection. We also determined expression levels of the LKB1 gene by quantitative real-time reverse transcription-polymerase chain reaction and correlated these results with the clinical and pathological features of patients. Among the 22 cell lines, four had mutations and three of these were in adenocarcinoma cells. Of 100 primary lung cancers, only three had LKB1 gene mutations (3%). All of them were male smokers with adenocarcinomas. Hence, when confined to this subset of patients, the mutation frequency was 9% (3/33). No significant correlation was observed between the expression level of LKB1 and patient clinicopathological features. In conclusion, LKB1 gene mutations were relatively rare in Japanese patients with lung cancer compared with Caucasian patients. LKB1 gene mutations appear to be frequent in male, smoking patients of Caucasian origin, in contrast to EGFR or HER2 mutations that are frequent in non-smoking, female patients of Asian origin.

There is substantial evidence that the decreased risk of lung cancer with high intake of vegetables and fruits is linked to folate as a specific nutrient. Functional polymorphisms in genes encoding one-carbon metabolism enzymes, methylenetetrahydrofolate reductase (MTHFR C677T and A1,298C), methionine synthase (MTR A2,756G), methionine synthase reductase (MTRR A66G) and thymidylate synthase, influence folate metabolism and thus might be suspected of impacting on lung cancer risk. We therefore conducted a case-control study with 515 lung cancer cases newly and histologically diagnosed and 1,030 age- and sex-matched non-cancer controls to clarify associations with these five polymorphisms according to lung cancer subtype. Gene-environment interactions with smoking and drinking habit and folate consumption were also evaluated by logistic regression analysis. None of the polymorphisms showed any significant impact on lung cancer overall risk by genotype alone, but on histology-based analysis increase in MTHFR 677T and 1,298C alleles was associated with reduced risk of squamous/small cell carcinoma (P = 0.029), especially among heavy smokers (P = 0.035), whereas the MTHFR 677TT genotype was linked to decreased risk for these subtypes among heavy drinkers (odds ratio = 0.17, 95% confidence interval: 0.03-0.98). In addition, we found interactions between the MTRR A66G polymorphism and smoking (P = 0.015) and the MTHFR A1,298C polymorphism and alcohol consumption (P = 0.025) for risk of lung cancer overall. In conclusion, the results suggest that MTHFR polymorphisms contribute to risk of squamous/small cell carcinomas of the lung, along with possible interactions among folate metabolism-related polymorphisms and smoking/drinking habits. Further evaluation is warranted.

Dihydropyrimidine dehydrogenase (DPD) is the enzyme catalyzing the first step of pyrimidine metabolism. To date, genetic polymorphisms of pyrimidine-synthesizing enzymes have been reported to be associated with the risk of malignant lymphoma or colon cancer. Accordingly, there may be associations between dihydropyrimidine dehydrogenase (DPYD) polymorphism and the risk of malignancies. We conducted a prevalent case-control study to investigate the associations between a functional polymorphism of dihydropyrimidine dehydrogenase, DPYD T85C, and the risk of six malignancies. Controls were 445 Nagoya City inhabitants without a history of malignancy who had participated in a health check-up between August and September 2000. Case subjects were 901 patients with malignancies (99 esophageal, 131 gastric, 143 colon, 179 lung, 243 breast, and 106 malignant lymphomas) who had visited Aichi Cancer Center Hospital between March 1999 and December 2000. No DPYD CC individuals were found in either cases or controls. The frequency of DPYD TC genotype was 6.3% in control subjects and 5.9% in all case subjects (not significant). In a subgroup analysis, the frequency of TC genotype was highest in patients with gastric cancer (9.1%), followed by those with lung cancer (8.3%), with the lowest frequency in those with malignant lymphoma (1.9%). The gender- and age- adjusted odds ratios and 95% confidence intervals for the TC genotype of gastric cancer and malignant lymphoma were 1.52 (0.71-3.28) and 0.31 (0.71-1.34), respectively. Although prevalent cases were used, this study suggested that the influence of DPYD T85C posed only a limited risk for the six malignancies.

Phospholipase D plays an important role in transmembrane signaling in a variety of cell types and its activity is increased in certain cancers, suggesting that it also contributes to tumorigenesis. A C-->T transition at nucleotide 1814 of the human phospholipase D(2) gene, which results in a Thr-->Ile substitution at amino acid 577, was noted in the GenBank database. The relationship of this polymorphism to the prevalence of cancer of the esophagus, stomach, colon-rectum, lung, and breast in Japanese was investigated in a case-control study. The genotype of the phospholipase D(2) gene was determined by the polymerase chain reaction with confronting two-pair primers. Multivariate logistic regression analysis with adjustment for age, gender, and smoking status revealed that the frequency of the T allele of the 1814C-->T polymorphism was significantly higher in individuals with colorectal cancer than in controls. A significant association of the polymorphism with the prevalence of colorectal cancer was found in analyses assuming either dominant (TT+CT vs. CC) or additive (CT vs. CC) effects of the T allele, but the T allele was not associated with the prevalence of esophageal, gastric, lung, or breast cancer. The activities of phospholipase D in cell lysates or membrane fractions did not differ between cells transfected with cDNAs encoding the Thr-577 or Ile-577 variants of phospholipase D(2). These results suggest that the phospholipase D(2) gene is a susceptibility locus for colorectal cancer in Japanese individuals, although a functional effect of the 1814C-->T (Thr577Ile) polymorphism was not detected.

The 8-oxoguanine DNA glycosylase (OGG1) repairs DNA by removing 8-hydroxyguanine, a highly mutagenic oxidative DNA adduct. Recently, the gene for OGG1 was cloned and several polymorphisms have been reported. Because environmental carcinogens produce 8-hydroxyguanine residues that potentially cause oncogenic mutations by mismatching to this modified base, the capacity to repair these lesions can be involved in cancer susceptibility. This study investigated the association between OGG1 Ser326Cys polymorphism and risk of the lung adenocarcinoma for Japanese by a prevalent case-control study in Japan. The subjects comprised 138 cases and 241 non-cancer outpatients as controls. OGG1 gene polymorphism was genotyped by a PCR-CTPP (polymerase chain reaction with confronting two-pair primers) method. The distribution of OGG1 Ser326Cys genotype among controls (Ser/Ser, 28.3%; Ser/Cys, 49.2%; and Cys/Cys, 22.5%) was not different from that among cases (Ser/Ser, 29.0%; Ser/Cys, 51.4%; and Cys/Cys, 24.0%). The sex-age adjusted odds ratio (OR) was 1.06 with 95% confidence interval (CI) 0.64-1.76 for Ser/Cys genotype and 0.81 with 0.44-1.52 for Cys/Cys genotype. The ORs according to the interval between diagnosis and study enrollment were also examined because the polymorphism was a potential prognostic factor of lung cancer. The ORs of Ser/Cys and Cys/Cys genotypes in the cases less than 3 years after diagnosis were higher than overall ORs; 1.86 (95%CI, 0.91-3.77), and 1.46 (0.64-3.35), respectively. The OR for smoking was not statistically different among genotype, though the sample size was too small to detect even a moderate interaction. This study supported the first study by Sugimura et al (Cancer Epidemiol Biomarkers Prev, 1999; 8: 669-674), that the association of OGG1 Ser326Cys polymorphism was limited for the risk of lung adenocarcinoma.

Background: The prognosis of patients with resected non-small cell lung cancer without carcinomatous pleuritis whose intrapleural cancer cells were detected by means of a cytologic examination of pleural lavage fluid obtained immediately after a thoracotomy has been reported to be poor., Methods: The Japan Clinical Oncology Group conducted a phase III trial for a 3-year period starting from October 1994 to determine whether intraoperative intrapleural hypotonic cisplatin treatment could effectively control pleural disease and thereby prolong the survival of these patients. The patients were randomized to receive either intraoperative intrapleural hypotonic cisplatin treatment or no treatment before closure of the open thorax. The intraoperative intrapleural hypotonic cisplatin treatment consisted of exposing the entire thorax to cisplatin (50 microg/mL) in distilled water for 15 minutes., Results: Because of the slow registration pace, the study was prematurely terminated in January 1998. During the 41-month period from the start of the registration, 49 patients were entered into the study, and all were eligible. Twenty-five and 24 patients were randomly assigned to the treatment and control groups, respectively. No statistically significant difference in the overall survival and disease-free survival between the 2 groups was observed. However, the appearance of carcinomatous pleuritis was suppressed by the hypotonic cisplatin treatment (42% of the control group vs 8% of the treatment group, P =.008)., Conclusions: Although the randomized trial was prematurely terminated, the intraoperative intrapleural hypotonic cisplatin treatment was found to effectively suppress the appearance of carcinomatous pleuritis in resected patients who demonstrated a positive pleural lavage cytology finding.

To investigate risk modification for lung cancer with diet in Japanese, we conducted a hospital-based case-control study and evaluated variation in influence with the histological type. We recruited 367 male and 240 female cases with adenocarcinomas, and 381 male and 57 female cases with squamous cell and small cell carcinomas. Controls comprised 2964 male and 1189 female cancer-free outpatients matched for sex and age with the cases. Odds ratios (ORs) and their 95% confidence intervals (CIs) for lung cancer were calculated with adjustment for potential confounding factors, using an unconditional logistic model. We found decreased ORs for adenocarcinomas in both males (OR = 0.51, 95% CI 0.31-0.84) and females (OR = 0.48, 95% CI 0.24-0.94) who consumed cooked/raw fish, but not dried/salted fish at the highest quartile frequency, compared with the lowest. Soybean curd consumption was associated with a decreased OR for female adenocarcinomas. Decreased ORs for squamous cell and small cell carcinomas were observed in males with frequent consumption of raw and green vegetables, fruit and milk, but consumption of carrot, pumpkin, egg and coffee was associated with increased ORs. This study suggests cooked/raw fish consumption lowers the risk of adenocarcinoma of the lung in Japanese., (Copyright 2001 Cancer Research Campaign http://www.bjcancer.com.)

Recently, we demonstrated that elevated expression of cyclooxygenase 2 (COX-2) is frequently seen in a specific type of lung cancer, i.e., adenocarcinoma, and is possibly associated with its invasion and metastasis. Here, the prognostic significance of elevated COX-2 expression was evaluated in a cohort of 130 adenocarcinoma patients who had consecutively undergone potentially curative resections. Immunohistological examination showed the presence of tumor cells with markedly increased COX-2 immunoreactivity in 93 of 130 (72%) cases. No relationship was found between the increase in COX-2 expression and clinical outcomes when the entire cohort was considered (P = 0.099). Reasoning that the influence of the increase in COX-2 expression may have been obscured by the clinical and molecular pathogenetic complexities in cases with an advanced disease, we also separately analyzed the prognostic significance of increased COX-2 expression after stratification according to the disease stage. A significant relationship between elevated COX-2 expression and shortened patient survival was observed only in a cohort of patients with stage I disease (P = 0.034). These findings suggest that an increase in COX-2 expression may be clinically significant for the prognosis of patients undergoing surgical resection of early-stage adenocarcinomas and, thus, warrant further conclusive studies involving a larger cohort.

The charts of 62 patients with primary lung cancer who underwent a pneumonectomy at our department from 1979 through 1992 were reviewed for the evaluation of postoperative morbidity and mortality. The 30-day mortality was 3/62 or 4.8%. Postoperative complication occurred in 37 of 62 patients (60%). The most common complication was a supraventricular tachyarrythmia. A major complication, which was defined as one necessitating re-thoracotomy or one which caused death, occurred in 19 patients (31%). We analyzed 43 perioperative variables for their predictive value of postoperative morbidity and mortality. Univariate analysis indicated that an elevated serum LDH, low predicted forced vital capacity, low predicted forced expiratory volume in 1 sec (FEV1) were significantly associated with the occurrence of a major complication. A multivariate logistic regression model indicated that a high LDH level, a low predicted FEV1 and no extubation following surgery were associated independently with a postoperative major complication. Since only the complete removal of a tumor offers a chance for cure for the treatment of non-small cell lung cancer, it is sometimes necessary to perform a pneumonectomy for these high-risk patients. Patients identified as being at high risk of a major complication should be candidates for intensive preoperative evaluation and perioperative care.

Isoleucine (Ile)-valine (Val) polymorphism, which is caused by a point mutation from A to G in exon 7, is reported to be associated with an elevated risk of lung cancer among Japanese. Because CYP1A1 catalyzes bioactivation of environmental procarcinogens, such as benzo[a]pyrene, it is very important to study the clinical meaning of Ile-Val polymorphism using an epidemiological study. In an epidemiological study, easy, economical, rapid and reliable identification of the CYP1A1 genotype is necessary. The present study shows that the new method, designed restriction fragment length polymorphism (designed RFLP), can detect Ile-Val polymorphism of CYP1A1. The Ile-Val polymorphism detected using this new method was consistent with that found by the allele-specific PCR amplifications (ASA) method in six cases tested. This new method detected Ile-Val polymorphism of CYP1A1 using 240 healthy Japanese who lived in the northern Kyusyu region. The frequency of the genotypes was as follows: Ile/Ile 159 (66.2%); Ile/Val, 65 (27.1%); Val/Val, 16 (6.7%). The frequency of the Ile gene was 0.798 and that of the Val gene, 0.202. There was no difference in Ile-Val polymorphism based on sex or age. Racial differences influenced the distribution of this polymorphism, but Japanese regional differences did not. Since this new method, designed RFLP, is rapid, reliable and suitable for large-scale screening of polymorphisms, it may be used routinely to detect Ile-Val polymorphism of CYP1A1. Furthermore, it will help to evaluate the relationship between CYP1A1 polymorphism and individual sensitivity to xenobiotics that may affect the incidence of lung cancer.

In a 7 1/2-year period (from 1 January 1980 to 30 June 1987), 997 patients with gastric cancer underwent gastric resection at the Department of Surgery, Matsuyama Red Cross Hospital, Japan. We studied clinicopathologically 83 patients (182 lesions) with synchronous multiple gastric cancer and compared them with patients who had solitary cancers only in the same period. We found that elderly men had a relatively high incidence of multiple gastric cancer, and that early cancer of the elevated well differentiated type was the most common. Of the 182 lesions, as many as 42 (23.1 per cent) were missed in the preoperative examination. Eighteen of these 42 lesions were found only with the aid of a microscope in sections almost incidentally excised. Small flat lesions tended to be missed. We should always be conscious that other gastric lesions may be present when treating patients with gastric cancer.