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Background and objective: Osimertinib as first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR) mutations remains controversial. Sequential EGFR-tyrosine kinase inhibitor (TKI) might be superior to the first line osimertinib in patients at risk of developing acquired T790M mutations.Methods: We enrolled consecutive patients with EGFR-mutated (deletion 19 or L858R) advanced NSCLC treated with first-line drugs and evaluated predictive markers using classification and regression tree (CART) for the detection of T790M mutations based on patient backgrounds prior to initial treatment.Results: Patients without acquired T790M mutations had worse outcomes than those with T790M mutations (median OS: 798 days vs. not reached; HR: 2.70; P

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 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.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.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.

Background: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. Methods: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres)in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO)stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1)using a permuted block method (block size of six patients)to receive six cycles of paclitaxel (175 mg/m2)and carboplatin (area under the serum concentration-time curve 5 or 6)every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. Findings: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7–34·2), 626 patients had progression-free survival events (405 [60%]of 678 in the trebananib group and 221 [66%]of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0–17·6])and the placebo group (15·0 months [12·6–16·1])groups (hazard ratio 0·93 [95% CI 0·79–1·09]; p=0·36). 512 (76%)of 675 patients in the trebananib group and 237 (71%)of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%]vs placebo 126 [38%])anaemia (76 [11%]vs 40 [12%]), and leucopenia (81 [12%]vs 35 [10%]). 269 (40%)patients in the trebananib group and 104 (31%)in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. Interpretation: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. Funding: Amgen. © 2019 Elsevier Ltd

Background Third-generation regimens with chemoradiotherapy has been established as one of a standard treatment in the phase III study WJTOG0105 even 10 years after starting treatment. We conducted an additional analysis by the histological type (Non-squamous [Non-Sq] vs. Squamous [Sq]) to examine differences of efficacy and patterns of initial failure. Methods Patients received the following treatments: MVP, mitomycin (8 mg/m2 on day 1, 29), vindesine (3 mg/m2 on day 1, 8, 29, 36), and cisplatin (80 mg/m2 on day 1, 29) with concurrent TRT (60 Gy), followed by 2 courses of MVP; IC, weekly irinotecan (20 mg/m2)/carboplatin (AUC 2) for 6 weeks with concurrent TRT (60 Gy), followed by 2 courses of irinotecan (50 mg/m2)/carboplatin (AUC 5); PC, weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks with concurrent TRT (60 Gy), followed by 2 courses of paclitaxel (200 mg/m2)/carboplatin (AUC 5). Overall survival (OS), progression free survival (PFS), and patterns of initial failure were compared by the histological type. Results From September 2001 to September 2005, 440 patients (arm A, n = 146; arm B arm, n = 147; arm C, n = 147) were enrolled. The median follow-up time 140 months. The median OS and PFS were 23.5, 8.3 months in Non-Sq and 19.7, 8.3 months in Sq. The efficacy of PC and IC was compared with MVP in each histological type. For Non-Sq, the median OS and PFS were 25.1, 8.3 months in PC and 20.3, 8.3 months in IC and 25.2, 8.4 months in MVP. For Sq, the median OS and PFS were 20.5, 9.9 months in PC and 17.1, 7.8 months in IC and 19.4, 8.3 months in MVP. There was no statistically significant difference in OS and PFS between PC, IC and MVP in each histological type. In the patterns of initial failure, out-field recurrence rate in Non-Sq (51.1%) was higher than Sq (26.1%). Furthermore, the patterns of initial failure were similar between PC, IC and MVP. Conclusions Weekly PC with concurrent TRT showed similar efficacy to MVP with concurrent TRT, with no correlation to the histological type in 10-years follow-up with WJTOG0105. In the pattern of initiated failure, out-field recurrence in Non-Sq was tend to be higher than in Sq. Clinical trial identification Clinical trial information: 000030811. Legal entity responsible for the study The authors. Funding West Japan Oncology Group (WJOG). Disclosure M. Tsuboi: Honoraria (institution): Bristol-Myers Squibb. M. Satouchi: Honoraria (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Bristol-Myers Squibb. D. Fujimoto: Honoraria (self): Bristol-Myers Squibb. T. Hirashima: Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (institution): Bristol-Myers Squibb. N. Yamamoto: Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (institution): Bristol-Myers Squibb. K. Nakagawa: Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (institution): Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Background Pembrolizumab (Pem) for NSCLC and PD-L1 TPS ≥50% as a first-line therapy showed the longer PFS and OS compared with chemotherapy in some clinical trial. However, only limited patients in good general condition without organ failure can participate in them and their outcomes may not be entirely representative of real-world setting. Methods We conducted a multicenter retrospective study across 11 medical centers (Hanshin Oncology clinical Problem Evaluation group (HOPE)). We analyzed clinical data from NSCLC patients receiving Pem as a first-line therapy between February 1st 2017 and April 30th 2018. We aimed to evaluate the efficacy and safety and to identify which patients will become more suitable candidates for Pem monotherapy. Results 213 patients were enrolled in this study. The median age was 71 years. Out of 213 patients, 176 (82.6%) were male, 20 (9.4%) were never smokers (Median brinkman index: 900), 172 (80.8%) had ECOG PS of 0-1, 55 (25.8%) had SQ, and PD-L1 TPS were 50-74%: 97 (45.5%), 75-89%: 55 (22.1%), and 90-100%: 69 (32.4%). 39 (18.3%) of all had AEs of grades ≥3. The most frequently severe AEs was pneumonitis (10 (4.7%) including in 1 grade 4), and no patient died of severe AEs. The overall RR/DCR were 51.2%/73.2%, the median PFS/OS was 8.3/18.4 months (M). In the univariate analysis, the ECOG PS (0-1 vs. ≥2: 9.0 vs. 4.0 M, HR: 2.11, p = 0.00061), CRP/ALB ( Conclusions Our results was consistent with the efficacy and safety of previous key clinical trials, although our study had various backgrounds. Furthermore, poor PS, high inflammatory state (CRP/ALB≥0.3), and steroid usage at the time of Pem treatment commencement were independently correlated with a shorter PFS of Pem. On the other hands, higher PD-L1 TPS (90-100%) was independently correlated with a longer PFS of Pem. Clinical trial identification UMIN (University Hospital Medical Information Network in Japan; number 000032470). Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure M. Tamiya: Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Taiho Pharmaceutical. A. Tamiya: Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Taiho Pharmaceutical. Y. Taniguchi: Speaker Bureau / Expert testimony: MSD. T. Yokoyama: Speaker Bureau / Expert testimony: Taiho Phermaceutical. K. Hirano: Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Taiho Phermaceutical. T. Hirashima: Speaker Bureau / Expert testimony: Taiho Phermaceutical. M. Kanazu: Speaker Bureau / Expert testimony: MSD. T. Kumagai: Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Taiho Phermaceutical. D. Fujimoto: Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Taiho Phermaceutical. All other authors have declared no conflicts of interest.

Background A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). Methods A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. Results Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade ≥3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). Conclusions This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR. Trial registration number NCT01377376.

Background Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for advanced non-small cell lung cancer (NSCLC) with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with uncommon EGFR mutations remains unclear. Methods We retrospectively surveyed a consecutive database of patients with NSCLC with EGFR mutations. We analyzed the data of patients with NSCLC with uncommon mutations, including single or compound mutations, who were treated with EGFR-TKIs between May 2016 and October 2018. Results Data from 543 patients were collected from five institutions, among whom 23 had EGFR uncommon mutations. Twenty-one patients who were treated with any EGFR-TKIs were analyzed in this study, 18 of whom were treated with EGFR-TKIs as first-line therapy (gefitinib 5, erlotinib 3, afatinib 10 patients). In contrast, three patients underwent cytotoxic chemotherapy as first-line therapy and were treated with EGFR-TKIs as second- and third-line therapy (gefitinib 1, erlotinib 1, afatinib 1 patient). According to the Response Evaluation Criteria in Solid Tumors, the overall response rate was 56%, and the disease control rate was 78%. The median progression-free survival (PFS) was 14.0 months in all patients with uncommon mutations. The median PFS of patients who were treated with first and second generation EGFR-TKIs were 14.0 months (n = 10) and 7.3 months (n = 11), respectively. Moreover, the PFS of patients with the G719X mutation (n = 12, median PFS: 32.9 months) was longer than that of patients with the L861Q mutation (n = 4, median PFS: 11.1) and compound mutations (n = 4, median PFS 7.3 months). Conclusions First and second generation EGFR-TKIs are effective treatments for patients with NSCLC with uncommon mutations. Notably, a greater favorable response was observed in patients with G719X mutations than those with L861Q and compound mutations. Clinical trial identification UMIN000028989. Legal entity responsible for the study Fumio Imamura. Funding AstraZeneca. Disclosure F. Imamura: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent a highly effective treatment for advanced non-small-cell lung cancer (NSCLC) with active mutations of the EGFR gene. However, most patients develop acquired resistance to EGFR-TKIs. The T790M mutation has been found to be associated with almost 50% of patients who acquired resistance to first- or second- generation EGFR-TKIs. The role of immune checkpoint inhibitors (ICIs) for patients without a T790M mutation or patients with a T790M mutation who have progressed after T790M inhibitor therapy remains unclear. Methods We retrospectively evaluated the clinical effects of ICIs for EGFR mutated non- squamous NSCLC patients who were treated after developing resistance to first- or second- generation EGFR-TKIs at five institutions in Japan. Patients treated with EGFR-TKI between May 2016 and October 2018 were enrolled. Patients who used a third-generation EGFR-TKI before using prior generations were excluded. Results Of the 58 patients identified, 21 were positive for T790M, and all were developing resistance to both third- and prior generation EGFR-TKIs. The objective response and disease control rates for ICIs were 13.8% and 55.2% respectively, and T790M-negative patients had numerically greater responses than T790M-positive patients (16.2% versus 9.5% and 62.1% versus 42.9%, p = 0.70 and p = 0.18, respectively). T790M-negative patients were associated with a clinically meaningfully longer median progression-free survival than were T790M-positive patients (4.4 months versus 1.8 months, p = 0.061). Conclusions T790M-negative status after development of acquired resistance to EGFR-TKIs tended to be associated with benefit from immunotherapy in this retrospective analysis. Clinical trial identification UMIN000028989. Legal entity responsible for the study The authors. Funding AstraZeneca K. K. Disclosure F. Imamura: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

Background Little is known about the associations between treatment outcome for immune checkpoint inhibitors and metastatic sites in patients with advanced non-small cell lung cancer (NSCLC). Furthermore, these previous studies included patients irrespective of their PD-L1 status and treatment lines. Therefore, we conducted a multicentered retrospective study to investigate the predictive factors of metastatic sites as first-line pembrolizumab efficacy in patients with PD-L1 tumor proportion score (TPS) ≥50% advanced NSCLC. Methods We retrospectively analyzed patients with advanced NSCLC and PD-L1 TPS ≥ 50% who received pembrolizumab as the first-line therapy at 11 institutions between February 2017 and April 2018. Clinical data including metastatic sites at the time of administering pembrolizumab treatment were collected. Treatment outcome of pembrolizumab was assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Results In total, 213 patients were included in the study. The median age was 71 years (range 39-91). Of the 213 patients, 176 (83%) were men, 172 (81%) had Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1. The major metastatic sites were thoracic lymph nodes metastasis (77%), intrapulmonary metastasis (31%), bone metastasis (28%), and malignant pleural effusion (26%). In multivariate analysis, poor PS (hazard ratio: 1.82, 95.0% confidence interval: 1.15–2.30; P = 0.046) and malignant pleural effusion (hazard ratio: 1.52, 95.0% confidence interval: 1.01–2.30; P = 0.046) was identified as an independent predictor of shorter progression free survival in patients treated with pembrolizumab. Conclusions In patients with advanced NSCLC and PD-L1 TPS ≥50% who received first-line pembrolizumab, poor PS and malignant pleural effusion are independent predictors of pembrolizumab efficacy. Clinical trial identification UMIN000032470. Legal entity responsible for the study Hanshin Oncology clinical Problem Evaluation group (HOPE). Funding Has not received any funding. Disclosure H. Kawachi: Honoraria (self): Taiho Pharmaceutical Co., Ltd.; Honoraria (self): Merck Sharp & Dohme, Corp. M. Tamiya: Honoraria (self): Taiho Pharmaceutical Co., Ltd.; Honoraria (self): Merck Sharp & Dohme, Corp. A. Tamiya: Honoraria (self): Taiho Pharmaceutical Co., Ltd.; Honoraria (self): Merck Sharp & Dohme, Corp. K. Hirano: Honoraria (self): Taiho Pharmaceutical Co., Ltd.; Honoraria (self): Merck Sharp & Dohme, Corp. T. Yokoyama: Honoraria (self): Taiho Pharmaceutical Co., Ltd. T. Ishida: Honoraria (self): Merck Sharp & Dohme, Corp. D. Fujimoto: Honoraria (self): Taiho Pharmaceutical Co., Ltd.; Honoraria (self): Merck Sharp & Dohme, Corp. T. Hirashima: Honoraria (self): Taiho Pharmaceutical Co., Ltd. M. Kanazu: Honoraria (self): Merck Sharp & Dohme, Corp. T. Kumagai: Honoraria (self): Taiho Pharmaceutical Co., Ltd.; Honoraria (self): Merck Sharp & Dohme, Corp. All other authors have declared no conflicts of interest.

Background: A previous clinical study in non-small cell lung cancer (NSCLC) patients in Western countries suggested the potential for combination of a first-in-class non-ATP-competitive c-Met inhibitor tivantinib with an epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib. Polymorphisms of CYP2C19, the key metabolic enzyme for tivantinib, should be addressed to translate the previous Western study to Asian population, because higher incidence of poor metabolisers (PMs) is reported in Asian population. Methods: Japanese patients with advanced/metastatic NSCLC received tivantinib in combination with erlotinib to evaluate safety and pharmacokinetics. Doses of tivantinib were escalated separately for extensive metabolisers (EMs) and PMs. Results: Tivantinib, when combined with erlotinib, was well tolerated up to 360 mg BID for EMs and 240 mg BID for PMs, respectively. Among 25 patients (16 EMs and 9 PMs), the adverse events (AEs) related to tivantinib and/or erlotinib (>20%, any grade) were rash, diarrhoea, dry skin and nausea. Grade ⩾3 AEs were leukopenia, anaemia and neutropenia. No dose-limiting toxicity was observed. Pharmacokinetics profile of tivantinib was not clearly different between the combination and monotherapy. Three partial response and three long-term stable disease (⩾24 weeks) were reported. Conclusion: Two doses of tivantinib in combination with erlotinib were recommended based on CYP2C19 genotype: 360 mg BID for EMs and 240 mg BID for PMs.

Small cell lung cancer with interstitial lung disease (ILD-SCLC) is difficult to treat because of the risk of fatal pneumonitis. Our study aims to evaluate the validity of topotecan (TOP) as chemotherapy for patients with relapsed ILD-SCLC. Overall survival was compared between TOP and other drugs as second-line treatments for ILD-SCLC patients. Forty-seven patients began chemotherapy and second-line treatment was administered in 48.5% of relapsed cases. The response rate of TOP for second-line therapy was 16.7%. Hematologic toxicities were grade 4 anemia, grade 3 neutropenia and grade 3 thrombocytopenia. Mild pulmonary toxicity was observed in 1 case. Patients receiving TOP as second-line treatment showed no significant difference in survival when compared to patients who underwent other regimens (median survival time 179 vs. 76 days; p =0.76). TOP is a well tolerated drug and is a viable candidate for second-line treatment of ILD-SCLC patients.

The purpose of this study was to evaluate the efficacy of gefitinib and the feasibility of screening for epidermal growth factor receptor (EGFR) mutations among select patients with advanced non-small cell lung cancer (NSCLC). Stage IIIB/IV NSCLC, chemotherapy-naive patients or patients with recurrences after up to two prior chemotherapy regimens were eligible. Direct sequencing using DNA from tumour specimens was performed by a central laboratory to detect EGFR mutations. Patients harbouring EGFR mutations received gefitinib. The primary study objective was response; the secondary objectives were toxicity, overall survival (OS), progression-free survival (PFS), 1-year survival (1Y-S) and the disease control rate (DCR). Between March 2005 and January 2006, 118 patients were recruited from 15 institutions and were screened for EGFR mutations, which were detected in 32 patients – 28 of whom were enrolled in the present study. The overall response rate was 75%, the DCR was 96% and the median PFS was 11.5 months. The median OS has not yet been reached, and the 1Y-S was 79%. Thus, gefitinib chemotherapy in patients with advanced NSCLC harbouring EGFR mutations was highly effective. This trial documents the feasibility of performing a multicentre phase II study using a central typing laboratory, demonstrating the benefit to patients of selecting gefitinib treatment based on their EGFR mutation status.

The types and properties of separators used for lead–acid batteries are reviewed. Attention is focused on the pocket-type polyethylene (PE) separator as this is widely used in present-day automotive batteries, i.e. in low-maintenance batteries with expanded lead–calcium grids. An improved PE separator has been developed by using a PE resin of high molecular weight. The resistance of the separator to attack by hot sulphuric acid is increased by a factor of 1.5. Batteries using the improved separator show a 40% increase in lifetime under the SAE 75 °C life-cycle test.

A phase II trial was conducted to evaluate the efficacy and toxicity of the Egorin's carboplatin dosing formula with 14-day oral etoposide in 38 elderly patients with small-cell lung cancer (SCLC). The overall response rate was 81%. Median survival times were 15.1 months for 16 limited-disease (LD) and 8.6 months for 22 extensive-disease (ED) patients. Myelosuppression was the principal side-effect. This regimen is an active regimen in the treatment of elderly SCLC patients.

Purpose: To evaluate the usefulness of transcutaneous needle biopsy (TCNB). Material and Methods: From May 1988 to December 1994, we performed TCNB under fluoroscopic control in 408 patients with mass lesions of the peripheral lung. The Surecut needle (1.5 mm) was selected mainly because of its ability to obtain specimens large enough for histological examination. Of the 408 patients, 286 had had previous bronchofiberscopic examinations but no definite diagnosis had been reached. Results: A definite diagnosis was obtained by TCNB in 305 (74.7%) of 408 cases (251 malignant neoplasms, 54 benign lesions). In malignant neoplasms, the pathological diagnosis based on cytology and histology together was more reliable than that based on cytology alone. Although the complications of this procedure (such as pneumothorax) were within the range of acceptability, care should be taken to avoid air embolism and the seeding of cancer cells along the needle tract. Conclusion: TCNB with the Surecut needle is a useful procedure with relatively low risk.

A compact re-entrant coaxial type electron accelerator (inner size: height 650 mm, diameter 550 mm) has been developed for electron beam processing. The resonant frequency of the resonator is 175 MHz and the Q-value 15000. The resonator is capacitively coupled to a feeder line and powered by a new type self-excited oscillator using a tetrode. The cathode of the electron gun consists of a single crystal of lanthanum hexa-boride (LaB6) that can emit the beam current of more than 400 mA. The maximum beam energy is 900 keV and the energy resolution (FWHM) is better than 5% by the use of a new type buncher integrated into the accelerating electrode.

Despite recent advances in control of acute emesis following cisplatin-based chemotherapy regimens, delayed emesis remains a significant cause of treatment-related morbidity and factors associated with delayed emesis have not yet been evaluated. A prospective randomised trial was conducted to compare the efficacy and toxicity of granisetron, dexamethasone plus prochlorperazine with granisetron alone in controlling cisplatin-induced delayed emesis and to identify the important factors that influence its occurrence and severity. Seventy cisplatin-naive patients with inoperable solid tumors participated in the trial. Patients who received 80 mg m-2 or 100 mg m-2 of cisplatin were randomly assigned to receive either granisetron 40 micrograms kg-1 intravenously (i.v.) on day 1, dexamethasone 20 mg i.v. on days 2 and 3 and prochlorperazine 5 mg orally thrice daily on days 1-5 or granisetron 40 micrograms kg-1 i.v. on day 1 alone. There was no difference in their acute antiemetic efficacy. A combination regimen was more effective than granisetron alone in preventing delayed symptoms, with superior rates of complete plus major responses of 77% vs 51% (P = 0.0460). Treatment arm was the only determinant factor for the occurrence of delayed emesis (P = 0.0101).

Friction Spot Joining (FSJ) process has been used to join aluminum sheets in transportation equipments. The metal flow in FSJ plays important role for successful joining. In this paper, the smoothed particle hydrodynamics (SPH) is employed to simulate the metal flow produced by FSJ. To simplify the numerical model for metal flow simulation, only the local joining zone of worksheets was selected as an object in which temperature is assumed to be quite high and materials are in softened state. The three dimensional movement of metal particles was visualized by simulation. The metal flow produced by axial movement and rotational movement of the FSJ welding tool was discussed based on the simulated results.

Two phase I trials of irinotecan (CPT-11) in combination with cisplatin were conducted. In both cases, the dose-limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twenty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 60 mg/m2. The other 13 patients received CPT-11 at 80 or 90 mg/m2 plus cisplatin at 80 mg/m2 with the granulocyte colony-stimulating factor support (2 micrograms/kg x 16 days). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT-11 was 90 mg/m2 in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h after the start of CPT-11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3-4 diarrhea than those with a lower SN-38 level (P = 0.0003). Stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the development of diarrhea (P = 0.0021). We conclude that there is a clear relationship between the SN-38 concentration and diarrhea during chemotherapy with CPT-11 plus cisplatin.

The separation of human serum lipoproteins were studied by hydroxyapatite chromatograhy with gradient or stepwise elution using potassium phosphate (KPi) buffers at pH 7.4. The low-density (LDL) and very low-density (VLDL) lipoproteins were separated from human serum on Tiselius-type hydroxyapatite (Bio-Gel HTP DNA grade) column (25 × 1.0 cm) by four stepwise elutions with 75, 200, 300 and 650 mM KPi buffers. The fractions eluted by 300 and 650 mM KPi contained 4.49 mg LDL and 0.68 mg VLDL, respectively. High-density (HDL) lipoprotein was eluted by 75 mM KPi together with the serum proteins such as albumin, globulin etc..

PURPOSE Since leukopenia was one of the dose-limiting toxicities of the combination of irinotecan (CPT-11) and cisplatin in a previous trial, we conducted a phase I trial to investigate whether support with recombinant human granulocyte colony-stimulating factor (rhG-CSF) would permit further intensification of the CPT-11 dose in combination with a fixed cisplatin dose. PATIENTS AND METHODS Twenty previously untreated patients with stage IIIB or IV non-small-cell lung cancer (NSCLC) were treated with CPT-11 on days 1, 8, and 15 in combination with cisplatin 80 mg/m2 intravenously on day 1. In addition, rhG-CSF (2 micrograms/kg/d) was administered on days 4 to 21, except on the days of CPT-11 treatment. The starting dose of CPT-11 was 70 mg/m2, and the CPT-11 dose was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS Diarrhea was the dose-limiting toxicity at 90 mg/m2. Two of six patients experienced either grade 3 or 4 diarrhea or grade 3 leukopenia during the first course of therapy at this dose level. Modest escalation of the CPT-11 dose from 80 to 90 mg/m2 resulted in a marked increase in the plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38). Occurrence of diarrhea was well correlated with the peak plasma concentration (Cmax) of SN-38 (P = .035). There were 10 partial responses (50%) among 20 patients. CONCLUSION The recommended dose for phase II studies is 80 mg/m2 of CPT-11, and 80 mg/m2 of cisplatin plus rhG-CSF. With the use of rhG-CSF, the CPT-11 dose can be increased 33% above that in the original regimen (60 mg/m2 of CPT-11 and 80 mg/m2 of cisplatin).

We have conducted a Phase I trial to determine the maximum tolerated dose of CPT-11 together with a fixed dose of cisplatin in patients with advanced lung cancer, and the dose-limiting toxicities of this combination. Fourteen previously untreated patients with stage IIIB or IV disease were treated with CPT-11 (90-min intravenous infusion on days 1, 8, and 15) plus cisplatin (60 mg m-2, intravenously on day 1). The starting dose of CPT-11 was 60 mg m-2, and diarrhea was the dose-limiting toxicity at the 90 mg m-2 dose level. All three patients (all four cycles) given 90 mg m-2 of CPT-11 experienced grade 3 diarrhea. Hematologic toxicity was relatively mild. Elimination of CPT-11 was biphasic with a mean (+/- s.d.) beta half-life of 11.36 +/- 7.26 h. The mean terminal half-life of the major metabolite (7-ethyl-10-hydroxycamptothecin; SN-38) was 22.13 +/- 13.28 (s.d.) h, and modest escalation of the CPT-11 dose from 80 mg m-2 to 90 mg m-2 resulted in a statistically significant apparent increase in the plasma concentrations of SN-38. There were one complete response (7%) and five partial responses (36%) among the 14 patients for an overall response rate of 43%. The recommended dose for Phase II studies is 80 mg m-2 of CPT-11 and 60 mg m-2 of cisplatin.

We have proposed the re-entrant resonant cavity applicator system for non-invasive brain tumor hyperthermia treatment. In this method, a human head is placed in the gap of the inner electrodes. A brain tumor is heated with the electromagnetic field stimulated in the cavity without contact between the human head and the applicator. We have already presented the effectiveness of the heating properties of this system with cylinder-type agar phantoms and by computer simulations. This paper discusses the heating properties of the developed system with the human head-type agar phantom for brain tumor hyperthermia treatment. First, in order to heat deep brain tumors, we tried to heat the human head-type agar phantom by using several electromagnetic field patterns of the resonant frequency. We found that the temperature distributions can be controlled inside the agar phantom by changing the resonant frequencies. Second, to heat local and deep areas of the agar phantom, we tried to achieve heating using the two different resonant frequencies. We found distinct heating properties by changing the electromagnetic field patterns of resonant frequencies. From these results, it was found that our developed heating system can be applied to hyperthermia treatments of deep-seated brain tumors. Further, by changing resonant frequency, treatment can very correspond to the size and the position of a tumor.

In this paper, we discuss the improvement of the speed of AIMS (Automatic Impedance Matching System) to automatically make impedance matching for a re-entrant resonant cavity applicator for non-invasive deep brain tumors hyperthermia treatments. We have already discussed the effectiveness of the heating method using the AIMS, with experiments of heating agar phantoms. However, the operating time of AIMS was about 30 minutes. To develop the ATT System (Automatic Totally Tuning System) including the automatic frequency tuning system, we must improve this problem. Because, when using the ATTS, the AIMS is used repeatedly to find the resonant frequency. In order to improve the speed of impedance matching, we developed the new automatic impedance matching system program (AIMS2). In AIMS, the stepping motors were connected to the impedance matching unit's dials. These dials were turned to reduce the reflected power. AIMS consists of two phases: all range searching and detailed searching. We focused on the three factors affecting the operating speed and improved them. The first factor is the interval put between the turning of the motors and AD converter. The second factor is how the steps of the motor when operating all range searching. The third factor is the starting position of the motor when detail searching. We developed the simple ATT System (ATT-beta) based on the AIMS2. To evaluate the developed AIMS2 and ATT- beta, experiments with an agar phantom were performed. From these results, we found that the operating time of the AIMS2 is about 4 minutes, which was approximately 12% of AIMS. From ATT-beta results, it was shown that it is possible to tune frequency and automatically match impedance with the program based on the AIMS2.

A 72-year-old woman was pointed out a right pleural effusion and thickening pleura on the chest computed tomography. The patient underwent semiflexible thoracoscopy under local anesthesia at the endoscopy room. The patient was placed in the lateral decubitus position, and flexible trocar was inserted with the single puncture technique. At the macroscopic findings, the parietal pleura were thickened prominently, and patchy plaques were occasionally recognized. A standard biopsy forceps hardly grasped pleura because of presence of scar, so we performed pleural biopsy using Insulation-tipped Diathermic (IT) knife. A subpleural injection of saline containing 0.5% lidokine and 0.005% epinephrine was performed for raising the affected parietal pleura with an injection needle. After a pin hole was made, the pleural lesion was incised in a circle by manipulating the IT knife, and the incised pleura were removed. Pathology revealed extensive fibrosis and epithelial mesothelioma by the specimen. This biopsy technique using IT knife through semiflexible thoracoscopy enabled to obtain a full-thickness pleura It is thought to be useful for the diagnosis of malignant pleural mesothelioma (MPM) in which standard forceps are difficult to grasp.

In this paper, we discuss a new system to make impedance matching automatically for a re-entrant resonant cavity applicator for brain tumor hyperthermia treatment non-invasively. We have already discussed about the effectiveness of the heating method using manual type impedance matching controller, with experiments of heating an agar phantom and computer simulations. However, it becomes difficult to perform an accurate impedance matching as resonant frequency becomes high. Here, in order to make a more accurate impedance matching, we developed the automatic impedance matching system (AIMS). We noticed that the reflected power was generated when the impedance matching was not complete. In this system, therefore, to reduce the reflected power fed back, the stepping motor to turn the dial of variable capacitors is controlled by developed software. To evaluate the developed AIMS, the experiments of heating the agar phantom were performed. From these results, we found that the temperature rise of the agar phantom by using AIMS was about 180% of using manual type controller under the same heating condition. It was found that the proposed system was very effective for hyperthermia treatment using resonant cavity applicator even when the resonant frequency was high.

In this paper, application advantages, development, and fabrication process of aQFN/HMT is introduced. Identical functions are intentionally designed in both CSP- BGA and aQFN/HMT packaging structures so that thermal and electrical performances of these two structures can be reasonably compared and demonstrated. Our calculations indicate that thermal and electrical performances of aQFN/HMT are much better than CSP-BGA, when the same functions are designed in.

The 200MeV proton synchrotron of circumference of 9.54m is being developed for medical radiotherapy. The rf system has been carried out with a wide bandwidth of frequency sweeping from 2.0MHz to 17.8MHz. The rf cavity is designed of a compact dimension and a high acceleration gradient. The high power test of the rf system has been successfully performed and maximal acceleration gradient of 60kV/m has been achieved. The experiments with rf feedback control system tracking to the exciting current of bending magnets are being studied In this paper, the recent progress of the rf system and test results will be presented in detail.

A project to build a compact proton synchrotron is now underway. Protons will be accelerated from 2 MeV to 200 MeV within 5 ms with an operation repetition rate of 10 Hz, in the synchrotron ring with a circumference of 11.9 m. The acceleration system is required to be of a wide bandwidth, with the frequency sweeping from 1.64 MHz to 14.26 MHz, and of a high gradient, with the maximum acceleration voltage of 20 kV. The acceleration section, consisting of a 2-cell rf cavity loaded with 4 high-permeability magnetic alloy cores in each cell, has been designed. A push-pull power amplifier with two 35 kW tetrode tubes will be used to drive the 2 cavities in parallel. Calculations and test results on the cavity characteristics will be presented and discussed, including the cavity impedance and equivalent circuit. The simulation results of the amplifier system using the ICAP code will also be given. The prototype of the rf system is being developed, and a high power test will be performed soon.

Background Cancer is the leading cause of death in Japan. Recently, the number of patients with lung cancer has been increasing. Most terminal cancer patients wish to die at home, but in fact, most nevertheless die in a hospital. The place of death is important to many patients, and home death may be best in terms of the patients' QOL, family satisfaction, and also regarding the overall cost. Purpose We retrospectively clarified the predictors of home deaths in terminal lung cancer patients. [Patients and Methods] We examined the patients with lung cancer who were introduced to about 30 home palliative care clinics between January 2009 and March 2010. We collected various data from their clinical records as follows; baseline demographics information including sex, PS, stage, and histology, patient's symptoms, patient's desire for home death, the family's wish for the patient's home death, the main caregivers, the number of caregivers, and the presence of a central vein access port (CV port). The survival time and the period of home palliative care were defined as the time from the first visit by the home palliative care team to the date of death, and the period of time after subtracting the total duration of hospitalization from the survival time, respectively. We confirmed the date of home death by a questionnaire given to the home palliative clinics. Results Ninety-one patients were introduced to home palliative care between 1 January 2009 and 31 March 2010, and 78 of them died of lung cancer. Of these 78 patients, 31 died at home (39.7%) and 47 died in a hospital. There were no significant differences in the median survival time between the group of subjects who died in a hospital (53 days) and those who died at home (50 days), and the period of home palliative care in the former (36 days) tended to be shorter than that in the later (50 days). According to a multivariate analysis, the patient's desire for home death and the presence of a CV port were significant factors associated with home death (P = 0.001 and P = 0.041, respectively). Conclusion The patient's desire for home death and the use of a CV port may therefore promote home death in terminal lung cancer patients.