Final overall survival results of WJTOG3405, a randomized phase III trial comparing gefitinib versus cisplatin with docetaxel as the first-line treatment for patients with stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer.

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.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study).

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.

CYP2C19 genotype-based phase I studies of a c-Met inhibitor tivantinib in combination with erlotinib, in advanced/metastatic non-small cell lung cancer.

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.

The effect of CYP2C19 polymorphism on the safety, tolerability, and pharmacokinetics of tivantinib (ARQ 197): results from a phase I trial in advanced solid tumors.

BACKGROUND: Tivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ~20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs). PATIENTS AND METHODS: Forty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid. RESULTS: Tivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC(0-12) compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients. CONCLUSION: Two different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined.

Efficacy and safety analysis according to histology for S-1 in combination with carboplatin as first-line chemotherapy in patients with advanced non-small-cell lung cancer: updated results of the West Japan Oncology Group LETS study.

BACKGROUND: A phase III study (Lung Cancer Evaluation of TS-1) previously demonstrated noninferiority in terms of overall survival (OS) at interim analysis for carboplatin-S-1 compared with carboplatin-paclitaxel for first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 564 patients were randomly assigned to receive either carboplatin on day 1 plus oral S-1 on days 1-14 or carboplatin-paclitaxel on day 1 every 21 days. Updated results and post hoc subgroup analysis according to tumor histology are presented. RESULTS: The updated analysis revealed a median OS of 15.2 months in the carboplatin-S-1 arm and 13.1 months in the carboplatin-paclitaxel arm, with a hazard ratio (HR) of 0.956 [95% confidence interval (CI) 0.793-1.151], consistent with the previous primary analysis. Median OS was 14.0 months in the carboplatin-S-1 arm and 10.6 months in the carboplatin-paclitaxel arm (HR 0.713; 95% CI 0.476-1.068) for patients with squamous cell carcinoma (SCC), with corresponding values of 15.5 and 13.9 months (HR 1.060; 95% CI 0.859-1.308) for those with non-SCC. CONCLUSIONS: These results establish the efficacy and safety of carboplatin-S-1 in patients with advanced NSCLC regardless of tumor histology.

Dose escalation study of carboplatin-pemetrexed followed by maintenance pemetrexed for elderly patients with advanced nonsquamous nonsmall-cell lung cancer.

BACKGROUND: This study was designed to determine the recommended dose of carboplatin-pemetrexed in elderly (≥75 years old), chemotherapy-naive patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received escalated doses of carboplatin and pemetrexed every 3 weeks for four cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed. RESULTS: The combination of carboplatin at an area under the concentration-time curve (AUC) of 5, and 500 mg/m(2) pemetrexed, was determined to be the recommended dose for elderly patients with advanced nonsquamous NSCLC. Of 17 patients, 10 received a median of five cycles of pemetrexed maintenance therapy without unexpected or cumulative toxic effects. The study had an overall response rate of 47.1%. The median progression-free survival time was 142 days (95% confidence interval [CI] 68-216 days) and the median overall survival time was 461 days (95% CI 168-754 days). CONCLUSIONS: This combination was a tolerable and effective regimen, and recommended dose (RD) was carboplatin [area under the curve (AUC) of 5]/pemetrexed (500 mg/m(2)) every 3 weeks, in chemotherapy-naïve, elderly (≥75 years old) patients with advanced nonsquamous NSCLC.

Effect of topotecan as second-line chemotherapy for small cell lung cancer patients with interstitial lung disease.

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.

Heating properties of the re-entrant type cavity applicator for brain tumor with several resonant frequencies.

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.

Improvement of the matching speed of AIMS for development of an automatic totally tuning system for hyperthermia treatment using a resonant cavity applicator.

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.

Disruption of the EGFR E884-R958 ion pair conserved in the human kinome differentially alters signaling and inhibitor sensitivity.

Targeted therapy against epidermal growth factor receptor (EGFR) represents a major therapeutic advance in lung cancer treatment. Somatic mutations of the EGFR gene, most commonly L858R (exon 21) and short in-frame exon 19 deletions, have been found to confer enhanced sensitivity toward the inhibitors gefitinib and erlotinib. We have recently identified an EGFR mutation E884K, in combination with L858R, in a patient with advanced lung cancer who progressed on erlotinib maintenance therapy, and subsequently had leptomeningeal metastases that responded to gefitinib. The somatic E884K substitution appears to be relatively infrequent and resulted in a mutant lysine residue that disrupts an ion pair with residue R958 in the EGFR kinase domain C-lobe, an interaction that is highly conserved within the human kinome as demonstrated by our sequence analysis and structure analysis. Our studies here, using COS-7 transfection model system, show that E884K works in concert with L858R in-cis, in a dominant manner, to change downstream signaling, differentially induce Mitogen-activated protein kinase (extracellular signaling-regulated kinase 1/2) signaling and associated cell proliferation and differentially alter sensitivity of EGFR phosphorylation inhibition by ERBB family inhibitors in an inhibitor-specific manner. Mutations of the conserved ion pair E884-R958 may result in conformational changes that alter kinase substrate recognition. The analogous E1271K-MET mutation conferred differential sensitivity toward preclinical MET inhibitors SU11274 (unchanged) and PHA665752 (more sensitive). Systematic bioinformatics analysis of the mutation catalog in the human kinome revealed the presence of cancer-associated mutations involving the conserved E884 homologous residue, and adjacent residues at the ion pair, in known proto-oncogenes (KIT, RET, MET and FAK) and tumor-suppressor gene (LKB1). Targeted therapy using small-molecule inhibitors should take into account potential cooperative effects of multiple kinase mutations, and their specific effects on downstream signaling and inhibitor sensitivity. Improved efficacy of targeted kinase inhibitors may be achieved by targeting the dominant activating mutations present.

[Full-thickness pleural biopsy using an Insulation-tipped Diathermic Knife in a patient with malignant pleural mesothelioma].

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.

Multicentre prospective phase II trial of gefitinib for advanced non-small cell lung cancer with epidermal growth factor receptor mutations: results of the West Japan Thoracic Oncology Group trial (WJTOG0403).

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.

Development of automatic impedance matching system for hyperthermia treatment using resonant cavity applicator.

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.

Heating properties of re-entrant resonant cavity applicator for brain tumor with simple head model.

We have already confirmed the effectiveness of the re-entrant resonant cavity applicator system with non-invasive experiments of heating cylindrical agar phantoms and computer simulations. This paper discusses the heating properties of the developed heating system with a human head model made of agar for brain tumor hyperthermia treatment. First, we present the results of heating a uniform agar head model with the developed heating system. In the experiments, the temperature rise at the center of the agar was about 8 degrees C, it was found that the center of the agar is heated to maximum temperature non-invasively. Second, we present the results of heating a non-uniform agar head model having an oral cavity and a nasal cavity. We found that the center of the agar can be heated to maximum temperature as well as uniform agar head model. From these results, it is confirmed that the possibility of effective hyperthermia for various types of deep-seated brain tumors.

Substitution of Dmo1 with normal alleles results in decreased manifestation of diabetes in OLETF rats.

AIM: Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes in the Otsuka Long Evans Tokushima Fatty (OLETF) rat strain. To evaluate possible metabolic and pathological improvements generated by correction of the Dmo1 genetic pathway, we produced congenic lines, in which both OLETF Dmo1 alleles are replaced by the F344-derived genome. METHODS: Congenic animals were produced by introgressing F344-derived Dmo1 alleles into the OLETF rat. Congenic animals of the fourth generation (BC4) were intercrossed to obtain F1 animals (BC4:F1). Animals of the next generation, BC4:F2, were used for this study. We used 23 BC4:F2 males harbouring homozygous replacement of the OLETF Dmo1 region with the F344-derived genome. Seven animals with OLETF-derived Dmo1 alleles were used as controls. RESULTS: Dmo1-F344/F344 congenic rats showed significant decreases in body weight, abdominal fat weight, serum triacylglycerols, total cholesterol, food consumption and blood glucose after glucose loading (13%, 39%, 45%, 27%, 18% and 27% respectively; p < 0.05) compared with Dmo1-OLETF/OLETF animals. Furthermore, histopathological analysis of the kidney showed that mesangial sclerosis, hyalin deposits and deposition of PAS-positive substance were significantly lower in Dmo1-F344/F344 animals (p < 0.05). CONCLUSION: Improvements in metabolic parameters and histopathological scores show that correction of the Dmo1 genetic pathway in the diabetic and mildly obese OLETF rat strain produces wide-ranging therapeutic effects. Thus, this pathway might represent a new drug target also applicable to humans.

Carboplatin calculated with Chatelut's formula plus etoposide for elderly patients with small-cell lung cancer.

OBJECTIVE: This dose escalation was conducted to evaluate the applicability of Chatelut's dosing, and to determine the efficacy and toxicity of carboplatin with etoposide in previously untreated elderly patients (>70 years) with small cell lung cancer. PATIENTS AND METHODS: Seventeen patients were treated with etoposide for 3 days and carboplatin calculated dose using Chatelut's formula on day 1 intravenously. The starting doses of etoposide on days 1 to 3, and carboplatin using the area under the concentration versus time curve (AUC) were 90 mg/m2 and 4 mg/ml x min, respectively. RESULTS: The median age was 77 years (range 71 to 87). Dose-limiting toxicity (DLT) was seen at level 4 (AUC 5 mg/ml x min of carboplatin and etoposide 100 mg/m2). Hematologic toxicity was the primary DLT. Grade 4 thrombocytopenia and Grade 4 leukopenia were observed at level 4. Non-hematologic toxicity was insignificant. The overall response rate was 94%. CONCLUSION: Etoposide at 100 mg/m2 and AUC of carboplatin of 4.5 mg/ml x min as calculated using Chatelut's formula every four weeks is the recommended dose for further phase II trials for elderly patients with small cell lung cancer.

Telomerase activity in endoscopically visible lung cancer.

To examine the correlation between telomerase activity and clinical features in patients with lung cancer, we examined 86 patients with endoscopically visible lung cancer including 61 with non-small cell lung cancer (NSCLC) and 25 with small cell lung cancer (SCLC). Telomerase activity was detected by using Telomerase ELISA Kit (Böhringer Manheim, Germany). The median and interquartile ranges of telomerase activity in normal lung, NSCLC and SCLC were 65 and 51-75, 106 and 58-349 and 285 and 117-2214, respectively. Normal lung, NSCLC and SCLC had significantly different telomerase activity (p < or = 0.0001). Between NSCLC and SCLC, SCLC exhibited higher telomerase activity than did NSCLC (p=0.0029). A cut-off level of absorbance [A450nm-A690nm] of 86 derived from 90% specificity in normal lung was used; sensitivity for overall lung cancer, NSCLC and SCLC was 62.8%, 54.1% and 84.0%, respectively. There was no significant difference in telomerase activity between each stage in NSCLC (p=0.9243). In SCLC, however, the median and interquartile range of telomerase activity in extensive disease (2128 and 292-2681) was significantly higher than those in limited disease (207 and 97-252) (p=0.0285).

[Analyses of factors preventing returning home in elderly patients on dialysis].

A significant number of elderly patients who begin dialysis are not able to return home even after attaining stable dialysis. The aim of the present study is to clarify the factors preventing returning home. Patients aged over 60 years who had newly started dialysis (103 cases) were studied. These were 58 men and 45 women. The age was 73 +/- 7 years (mean +/- standard deviation). In each patient, the cause of renal failure (non-diabetes/diabetes), nutritional state, complications, ambulation, cognitive function, urgency of the initiation into dialysis therapy, occurrence of access failure, presence or absence of the partner, presence or absence of members of the younger generation living in the same house, and the outcome (returning home or prolonged hospitalization) were surveyed. Of the 103 patients, 80 could return home, and 23 could not. First, we investigated the influence of the differences in each factor on the outcome. The subjects were divided into two groups by two categories in each factor. The numbers of patients who could not return home was calculated respectively. Comparisons were carried out by the chi 2 test. Statistically significant factors were ambulation (p < 0.0001), cognitive function (p < 0.0001), and cause of renal failure (p: 0.049). Multivariant logistic regression analysis was also performed using back-ground factors as explanatory variables and the outcome as a dependent variable. The factors presented by the nominal scale were converted to dummy variables. Statistically significant factors were ambulation (p < 0.0001), cognitive function (p: 0.001), and presence or absence of a partner (p: 0.012). Inability to walk, impaired cognitive function, and absence of a partner were the factors preventing returning home.

[Risk factors of anastomotic leak following operations for gastric cancer in the elderly].

The risk factors of anastomotic leak in the elderly following operations for gastric cancer were evaluated by multiple logistic model analysis. Data were taken from 705 operations over a 14-year period. The mean age of patients was 75.8 +/- 7.6 years. The significant risk factors for anastomotic leak were amounts of intra-operative bleeding and male gender. No other factors were significant, including age, preoperative associated diseases, preoperative nutritional states and postoperative complications, some of which were, however, significant factors by univariate analyses. We conclude that we should make every endeavor to lower the amount of intra-operative bleeding in order to prevent postoperative anastomotic leaks in the elderly, especially in male patients.