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The aging characteristics of recently developed SAW-resonator-coupled filters are discussed. The rejection level of the filter was decreased by applying power. This result means that the Q-factor of the surface acoustic wave (SAW) resonator decreases with applied power. This change was studied by means of resistivity measurement and microscopic observation. It was found that the resistivity of the thin film increases by stress-induced migration. The decrease of rejection level and the decrease of the resonator's Q-factor are explained by the measurement resistivity. Voids and hillocks were observed on thin-film electrodes. These observations also support the resistivity increase caused by stress-induced migration. It was seen that the formation of voids and hillocks induced the resistivity increase in thin-film electrodes. It is concluded that the cause of electrical characteristics change is the resistivity increase in the thin-film electrodes. >

A HDTV (high-definition television) rear projector using p-silicon TFT (thin-film transistor) LCD (liquid crystal display) panels has been developed. The authors present the conditions which should be satisfied in the HDTV display, especially in the LCD panel, and the fabricated display system and the specification. More compact rear projector equipment was fabricated using p-Si-TFT-LCD panels compared to those in CRTs. The picture size is 55 in diagonally and the system depth is 55 cm. A poly-silicon TFT process makes a small LCD panel possible. About 1,400,000 dots with a high aperture ratio of 30% are used in a 4.55-in LCD panel. A telecentric optical system and a retro-focus lens make the system size more compact. Moire disturbance is present in the LCD rear projector system. A method to decrease this picture quality degradation was realized using a finer pitch screen and diffusion board. >

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

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 (por = 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).

Aim: A multicenter randomized phase III study designed to demonstrate non-inferiority of G to E was conducted. Methods: Eligible pts were those with pathologically proven LA with stage IIIB/IV (AJCC version 6) or recurrence, previously treated with at least one chemotherapy regimen, evaluable disease, age ≥20 years and ECOG PS 0-2. Pts were randomized 1:1 to E (150 mg, daily), or G (250mg, daily) according to gender, stage, EGFR mutation status, performance status, smoking history, CT line, and institution. Target sample size was 560 based on the assumption that G was not inferior to E in PFS (2 – 4 months, a =0.025 [one sided], b =0.80). Non-inferiority was to be concluded if the upper CI limit was Results: From 2009/7 to 2012/10, 561 pts were accrued, and 280 and 279 were randomly assigned to E and G, respectively, including 185 (66.1%, E) and 186 (66.7%, G) with EGFR mutated tumors. Other baseline factors were balanced between arms except PS: median age 67/68 years; % female 54/55; % PS = 0, 50/40; PS = 1, 43/54; % stage IV, 69/69; % 2nd line, 69/71, % smoker, 50/50; for E/G. Median PFS, TTF and OS for E/G were 7.5 m/6.5 m (p = 0.257, HR = 1.125, 95% CI: 0.940-1.347), 5.3 m/5.6 m (HR = 1.032, 95% CI: 0.866-1.231), and 24.5 m/22.8 m (HR = 1.038, 95% CI: 0.833-1.294), respectively. RR and DCR for E/G were 43.9%/46.1% and 75.0%/71.2%, respectively. Median PFS and OS in pts with EGFR mutation for E/G were 10.1 m/8.9 m (p = 0.532), and 32.0 m/26.6 m (p = 0.111), respectively. Exploratory subset analysis revealed the prolongation of PFS of E compared with that of G in pts aged Conclusions: Non-inferiority in PFS between E and G was not demonstrated according to predefined criteria; however, there was no statistically significant difference in PFS, OS, RR, DCR and TTF. Disclosure: S. Morita: other substantive relationships: Chugai, AstraZeneka; T. Seto: corporate-sponsored research: AstraZeneka other substantive relationships: AstraZeneka, Chugai; T. Hirashima: corporate-sponsored research: Astrazeneca, Chugai-pharm; M. Okada: corporate-sponsored research: AstraZeneka, Chugai, Roche other substantive relationships: AstraZeneka, Chugai, Roche; Y. Urata: other substantive relationships: Chugai, AstraZeneka; N. Yamamoto: other substantive relationships: AstraZeneka, Chugai; K. Nakagawa: corporate-sponsored research: AstraZeneka, Chugai other substantive relationships: AstraZeneka, Chugai; Y. Nakanishi: corporate-sponsored research: Chugai other substantive relationships: Chugai. All other authors have declared no conflicts of interest.

This study was performed to evaluate the prognostic significance of alteration in telomere length in pathological stage (p-stage) I-IIIA non-small cell lung cancer (NSCLC). Paired cancer and normal lung tissues were obtained from 72 patients with histologically confirmed p-stage I-IIIA NSCLC. Terminal restriction fragment (TRF) length, which indicates telomere length, was measured by Southern blot analysis. Tumor telomerase activity was also assayed by non-radioactive PCR-ELISA in 55 patients. TRF length (mean +/- SD) in normal tissue was 6.2 +/- 1.1 Kb. Therefore, upper and lower limits of normal range in TRF length was set at 8.4 (mean + 2SD) Kb and 4.0 (mean-2SD) Kb, respectively. A tumor showing TRF length over normal range was defined as positive for the alteration. In 72 patients, 25 (34.7%) with alteration in TRF length had significantly shorter survival durations than those of the others. Telomerase activity did not correlate with survival duration. In multivariate analysis, alteration in TRF length (P = 0.0033) was second to p-stage (P = 0.0004) in importance among the various parameters.

GPI-anchored molecule-like protein (GML) has been identified as a new target molecule of p53. In esophageal cancer cell lines, expression of GML mRNA, which was found to be significantly correlated with in vitro anti-cancer drug sensitivity, was observed only in the presence of wild-type p53.The relationship between expression of GML mRNA and p53 gene status in 24 non-small cell lung cancer (NSCLC) cell lines was examined using RT-PCR and PCR-SSCP followed by direct DNA sequencing.Expression of GML mRNA was observed in only 3 of 24 cell lines. In contrast to previous studies showing p53-dependent GML expression, of the 3 cell lines expressing GML mRNA, one had a p53 gene mutation (codon 245: Gly to Cys).These findings suggest that the expression of GML mRNA is infrequent and regulated in a p53-independent manner in NSCLC.

Between July 1991 and February 1993, CYFRA 21-1 levels of 149 newly diagnosed patients with histologically proven non-small cell lung cancer (NSCLC) at Osaka Prefectural Habikino Hospital were measured with an enzyme immunoassay method developed by Boeringer Mannheim (Enzymun-Test CYFRA 21-1). NSCLC patients with CYFRA 21-1 serum levels over 3.5 ng/ml had a significantly poorer prognosis than did patients with normal CYFRA 21-1 levels (P0.001). Univariate analysis revealed that CYFRA 21-1 levels above 3.5 ng/ml, poor PS, advanced stage and serum LDH over 450 U/l strongly correlated with survival period. In multivariate analysis, however, only CYFRA 21-1 was found to be an independent prognostic factor compatible with Stage and PS (P = 0.0040 for CYFRA 21-1, P0.001 for PS, P = 0.0052 for Stage).

p53 abnormalities appear to play critical roles in human carcinogenesis. Many studies have indicated that p53 alteration is responsible for the differences in clinical characteristics of non-small cell lung cancer (NSCLC). The purpose of this review is to evaluate and summarize the significance of p53 alteration in the diagnosis and therapy of NSCLC. After assessing the principles of each approach to detecting p53 alteration, we reviewed the literature describing the impact of p53 alteration on clinical modalities such as diagnosis, prediction of prognosis, and response to treatment. We also reviewed p53 gene replacement therapy for NSCLC. Although p53 appears to be the most important gene in the development of NSCLC, it is not known whether p53 abnormalities are useful markers for clinicians. A multicenter, prospective study of p53 immunohistochemistry should therefore be performed. Replacement of the p53 gene has been shown to be effective in a clinical trial for patients with NSCLC. In addition to simple gene replacement, combination treatments of gene transfer and chemotherapy are now being tested in clinical trials.

Non-insulin-dependent diabetes mellitus (NIDDM) is a prototypical multifactorial disease. Genetic predisposition and obesity are major risk factors for NIDDM development and the interactions between these factors are likely to be important in the etiology of this disease. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is one of the best animal models of NIDDM, since the OLETF rat develops NIDDM with mild obesity that is very similar to human NIDDM. Therefore, the OLETF rat is a powerful model for investigating the interaction between genetic susceptibility to NIDDM and obesity. In this study, our goal was to clarify the relationship between an individual NIDDM susceptibility locus and obesity in the OLETF using a molecular genetics approach. We identified four novel quantitative trait loci (QTLs) that contribute to the susceptibility to NIDDM, none of which shows significant linkage with body weight. However, Nidd1/of on chromosome 7 and Nidd2/of on chromosome 14 have an interaction with body weight. In contrast, one locus was mapped to chromosome 10 for body weight, but not to fasting or postprandial glucose levels. These data illustrate that NIDDM and body weight are under separate genetic control in the OLETF yet interact to yield the final disease phenotype in the two Nidd/of loci. In addition, body weight could be used in place of body mass index as an indicator of obesity in our experimental system of genetic study. This study will facilitate the understanding of the complex interaction between genetic susceptibility to NIDDM and obesity.

Although p21 WAF1/Cip1 expression has been detected immunohistochemically in non-small cell lung cancer (NSCLC), the associations between p21 expression and clinical characteristics are unknown. To determine the association between p21 expression and clinical features, p21 expression was immunohistochemically analyzed in paraffin-embedded tumor samples from 137 patients with curatively resected NSCLC. p21 expression, indicating normal p21 function, was detected in 48 (35.0%) of the 137 patients with curatively resected NSCLC and was detected more frequently in patients with stage I or II disease (40.2%) than in those with stage IIIA disease (22.5%; P = 0.0483). There was no difference in the positive rate between squamous cell carcinoma [SCC; 15 of 48 (31.3%)] and adenocarcinoma [30 of 77 (39.0%)]. For SCC, patients with tumors expressing p21 survived longer than did those with tumors negative for p21 expression; however, the corresponding survival time was not significant for adenocarcinoma. On the other hand, p53 expression, detected in 58 (42.3%) of these patients, did not act as any predictor for prognosis in either SCC or adenocarcinoma. Our findings suggest that the presence of p21 expression is associated with favorable prognosis in SCC and may be useful in obtaining candidates for adjuvant therapies from among patients with SCC.

The purpose of this study was to evaluate the correlation between alteration in telomere length and prognosis in patients with pathological stage I-II non-small cell lung cancer. We measured telomeric repeat length and telomerase activity by use of southern blot analysis of terminal restriction fragments and a non-radioactive ELISA-based assay, respectively.Alterations in TRF lengths were present in 17(29.8%) of 57 patients. Patients with altered TRF length had significantly shorter survival than did patients without (P = 0.0051). In multivariate analysis, only alteration in TRF length independently correlated with shortened survival (P = 0.0033).

To improve the quality of life in cancer patients at a near-terminal stage, we assisted patients to stay home using a system for home infusion therapy (HIT) established at Osaka Prefectural Habikino Hospital in 1994. From April in 1995 to April in 1996, 25 patients were treated at home using the HIT system for longer than 7 days. Thirteen out of 25 patients still stayed at home even at a terminal stage and died in their residences. There was no difference either in the mean age or in the HIT duration between 13 patients who died at home and the remaining 12 patients who were readmitted to their hospitals before death. However, 47% of the patients who died at home had been told their diagnoses by doctors and realized their own prognoses, while only 17% of the patients who died in the hospital knew their diagnoses and prognoses. Seventy-seven percent of the patients who died at home were given home oxygen therapy (HOT), against 33% of the patients who died in the hospital. Furthermore, the patients who died at home were given more intensive care than the patients who died in the hospital, because the former had a larger family than the latter. In conclusion, HIT at a near-terminal stage and death at home may be more readily accepted by patients who know their diagnoses and prognoses and have a large family.

The prognostic significance of serum p53-Abs positivity for non-small cell lung cancer (NSCLC) is still unknown.To determine the prognostic value of serum p53-Abs status, we determined serum p53-Abs and immunohistochemistry in 140 patients with stage I-IIIA NSCLC.p53-Abs were detected in 12.1% of all patients and in 17.6% of those with squamous cell carcinoma (SCC). Neither p53-Abs nor p53 overexpression alone was correlated with survival for all patients. When these factors were combined for SCC, seronegative patients with tumors overexpressing p53 survived significantly longer than did those with p53-Abs or p53-nonexpressing tumors. In multivariate analysis, p53-Abs status and p53 overexpression were independent prognostic factors for SCC (p = 0.0337).These findings suggest that the combination of p53Abs seropositivity and p53 overexpression may be a prognostic factor for SCC.

To improve the quality of life in patients with malignant diseases at the near-terminal stage, we established a system for home infusion therapy (HIT) in Osaka Prefectural Habikino Hospital in 1994. Thirty-three patients were taken care of at home using the HIT system from January, 1995 to May, 1996. Their average age was 70 years old. The duration of HIT varied from 1 to 105 days (mean:25.5 days). Twenty-four cases received parenteral nutrition. The others received agents for brain edema (4 cases), morphine hydrochloride (2 cases), and anti-fungal agents (3 case). Additionally, 63% of these patients required home oxygen therapy (HOT) with HIT. Questionnaires to their families revealed that they were afraid of the progress of the disease in patients and their physical burden became heavier after the start of HIT. However, they were quite satisfied with the results of HIT.

Reverse transcription-PCR-single-strand conformation polymorphism analysis was performed to detect topoisomerase IIalpha mutations using total RNA from 19 bronchial biopsy specimens obtained from 13 patients with small cell lung cancer. An abnormally migrating single-strand conformation polymorphism band was observed in one tumor sample from a patient treated with etoposide-containing chemotherapy. DNA sequence analysis of this tumor showed two transversions at codons 486 (G to A) and 494 (A to G), resulting in two missense mutations (Arg to Lys and Glu to Gly, respectively). The codon 486 mutation was identical to that previously found in two cell lines selected for amsacrine resistance. These results demonstrate that mutations of topoisomerase IIalpha occur in patients with small cell lung cancer. The significance of these mutations in the development of resistance to etoposide needs further investigation.

Background The prognosis of gastric cancer with peritoneal metastasis is extremely poor. Neither systemic chemotherapy nor surgery alone prolongs survival of patients significantly. Methods Patients diagnosed with advanced gastric cancer underwent staging laparoscopy and received chemotherapy when peritoneal dissemination and/or cancer cells on peritoneal cytology were confirmed. The chemotherapy regimen consisted of S-1, weekly intravenous and intraperitoneal paclitaxel, which was verified in our phase II trial (Ann Oncol 2009). S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7 days rest. Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8. Clinical response of chemotherapy was assessed by computed tomography, gastroendoscopy, peritoneal cytology and second-look laparoscopy. Radical gastrectomy was carried out when macroscopic curative resection was made achievable by chemotherapy. Chemotherapy was restarted after operation as soon as possible. Overall survival, relapse free survival, morbidity and mortality of gastrectomy were evaluated. Results Out of 100 patients with peritoneal metastasis who received chemotherapy, 60 patients underwent gastrectomy after response to chemotherapy, including 54 with macroscopic metastasis and 6 with positive peritoneal cytology only. A median of three courses were administered preoperatively (range 1–16). Total or distal gastrectomy with lymphnode dissection was carried out in 54 or 6 patients, respectively. The median survival time was 34.5 months. The median relapse-free survival was 16.7 months. The first site of relapse was the peritoneum in 24 patients and the other organ site in 17 patients. Postoperative complications included anastomotic leakage and pancreatic fistula in two patients each, which were healed conservatively. There were no treatment-related deaths. Conclusions Gastrectomy combined with S-1, intravenous and intraperitoneal paclitaxel is safe and active for gastric cancer patients with peritoneal metastasis.

Background With the recent remarkable developments in anti-cancer agents such as targeted molecular therapies, treating patients with malignancies while keeping a balance among effect, safety, and QOL has become complicated. Methods From the perspective of the role of a board-certified specialist oncology pharmacist, we analyzed the future prospects of medical teams in cancer chemotherapy by examining the current practices of the medical team at our hospital. Results In 2011, our hospital became an authorized base hospital for lung cancer therapy in Osaka Prefecture. The medical team for cancer chemotherapy and supportive therapy at this hospital consists of two medical oncologists, two oncology pharmacists, one certified specialist cancer nurse, one certified cancer chemotherapy nurse, two certified palliative care nurses, and one psychologist. Three departments—thoracic oncology, outpatient chemotherapy, and gynecology—perform cancer chemotherapy. The total number of cancer chemotherapies carried out in 2011 was1433 (thoracic malignancies: 88.4%; breast cancer: 5.1%; gastrointestinal cancer: 6.5%) in outpatients and 1572 (thoracic malignancy: 83.3%; gynecological cancer: 11.8%; gastrointestinal cancer: 4.3%; breast cancer: 0.6%) in inpatients. In 2011, the oncology pharmacist carried out the following important functions in medical team: (i) sitting on a review board four times a year for approval of cancer chemotherapy; (ii) daily management of the ordering system for cancer chemotherapeutic agents; (iii) holding meetings four times a year to educate other specialists about new regimens or anti-cancer agents; (iv) monitoring the dose, schedule and patient's information about cancer chemotherapy to prevent severe toxic effects or treatment death; (v) each day, instructing patients who are receiving cancer chemotherapy; and (vi) consulting daily about side-effects and supportive therapy. Conclusions The oncology pharmacist currently plays an important role in the medical team and will become more important in the future.

SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly post-translational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand–glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family.

Objective The aim of this study was to evaluate the efficacy and toxicity of S-1, with adjusted doses based on body surface area (BSA) and creatinine clearance (Ccr), in chemonaive elderly patients with advanced non-small-cell lung cancer (NSCLC). Pharmacokinetic analysis was also carried out to evaluate the adequacy of the tailored S-1 dose. Methods Twenty-three patients with age 75 or older were enrolled from December 2007 to October 2009. S-1 was administered orally on days 1–28 twice daily (q42 days) until the first occurrence of disease progression, unacceptable toxicity or patient refusal. Doses of S-1 were adjusted based on individual Ccr and BSA. Pharmacokinetic studies were also carried out in 8 patients on day 7 of the first cycle. The primary objective is disease control rate (DCR; CR + PR + SD) and the secondary objectives are objective response rate (ORR), safety, overall survival (OS), progression-free survival (PFS) and clinical benefit rate (CBR; the rate of CR + PR + SD >24 weeks). Results The ORR was 8.7% (2/23), DCR was 69.6% (16/23) and the CBR was 30.4% (7/23). The median survival time (MST) was 228 days and the median PFS was 117 days. As for safety, grade 3/4 hematologic toxic effects have never been observed. As non-hematologic toxic effects, only one patient (4.3%) has experienced grade 3 anorexia and nausea/vomiting. In the pharmacokinetic study group (n = 8), the maximum plasma concentration (Cmax) and the area under the plasma concentration curve (AUC) of 5-FU were similar among eight patients irrespective of Ccr values which were comparable with the reported values in patients with normal renal function who received a standard dose of S-1 (80 mg/m2/day). Conclusions Our results suggest that tailored S-1 monotherapy is useful and tolerable as the first-line treatment in elderly patients with advanced NSCLC even when their renal functions are impaired.

Background Pemetrexed (PEM) to be a multitargeted antifolate agent is effective for non-squamous (non-sq) NSCLC. Functional polymorphisms of thymidylate synthase (TS), the reduced folate carrier (SCL19A1) and methylenetetrahydrofolate reductase (MTHFR), which are important enzymes in folate metabolism, have been shown to be correlated with the outcome in patients receiving methotrexate. Recently, the single-nucleotide polymorphism (SNP) of MTHFR was reported to be correlated with a good prognosis in patients receiving PEM. Purpose We retrospectively examined the significance of SNP in MTHFR, SCL19A1 or variable number of tandem repeat (VNTR) in TS as the prognostic factor or the predictive marker for side-effects of PEM. Method Non-Sq NSCLC patients treated with PEM were included in this study. After the PCR amplification of extracted lymphocyte DNA, analysis of sequencing or VNTR in target region was carried out. This study was approved on IRB (#504). Results The frequency of SNP in 35 cases is A1298C (A/A, 37%; A/C, 57%; C/C, 6%), C677T (C/C, 34%; C/T, 57%; T/T, 9%), SCL19A1 (G/G, 24%; G/A, 55%; A/A, 21%), TS tandem repeat (3R/3R, 63%; 2R/3R, 34%; 2R/2R, 3%). The final result of the correlation between PEM and response, overall survival, progression-free survival or side-effects will be reported in this congress.

Background The cell surface receptor tyrosine kinase c-Met and its ligand, the hepatocyte growth factor (HGF), are implicated in tumor cell migration, invasion, survival and proliferation. EMD 1214063 is a novel potent and highly selective reversible, ATP-competitive small molecule c-Met inhibitor. Methods This is a phase I, first in human (FIH) clinical trial with escalating doses of EMD 121406(NCT 01014936). The primary objective is to determine the MTD. Secondary objectives include evaluation of safety, pharmacokinetics, anti-tumor effect and pharmacodynamics (Pd). Eligible patients had advanced solid tumors not amenable to standard therapies. Following a classical 3 + 3 dose escalation scheme, successive cohorts of patients were treated with once daily oral EMD 1214063 according to two 21-day-cycle schedules, either days 1-14 followed by a 7-day rest(regimen 1, R1), or continuous three times weekly administration (regimen 2, R2). Pd markers were evaluated in paired tumor biopsies. Results As of 30 March 2011, a total of 41 patients had been enrolled, 21 in R1 and 20 in R2. The dose was escalated from 30 mg/day to 115 mg/day in R2 and to 230 mg/day in R1. One DLT was reported in R1 at 115 mg/day, an asymptomatic, grade 4 lipase and G3 amylase elevation. No other DLTs or treatment-related SAEs were observed. The remaining treatment-related AEs of grade 2 or higher included nausea (n = 1), vomiting (n = 1), anorexia (n = 1), diarrhea (n = 1), and fatigue (n = 1) in R1, and neutropenia (n = 1) in R2. 37 patients (90%) had no drug-related toxicity greater than grade 1. At the dose levels investigated, median Cmax and AUC values increased with dose. Immunohistochemical analysis of a patient with pre- and on-treatment biopsies showed a decrease in phospho-c-Met staining intensity under treatment. Preliminary anti-tumor activity has been observed, including an unconfirmed PR in one patient and stable disease lasting for at least 4 months in 5 patients. One patient with sarcomatoid bladder carcinoma and multiple MET copies due to polysomy of chromosome 7 achieved SD for 16+ months. Conclusions The MTD has not yet been reached and dose escalation of EMD 1214063 continues. Updated results of this FIH study will be presented.

Background There is controversy regarding palliative chemotherapy for large cell neuroendocrine carcinoma (LCNEC). We evaluated whether advanced LCNEC should be treated similarly as small-cell lung cancer (SCLC) or non-small-cell lung cancer (NSCLC). Methods The clinical reports and tumor specimens of 45 consecutive patients who were diagnosed with advanced LCNEC were reviewed. They were divided into SCLC (n = 11) and NSCLC regimen groups (n = 34) according to first-line chemotherapeutic regimens. Results Most patients were male (96%) and smokers (93%) with a median age of 64 years. Neuroendocrine differentiation was established in 42 (93%) tumors by immunohistochemical analyses. Regarding the efficacy of first-line chemotherapy in the SCLC and NSCLC regimen group, the response rates were 72.7% and 50% (P = 0.19), and the median progression-free survival times were 6.1 and 4.9 months (P = 0.41), respectively. The difference in overall survival between the two treatment groups was 7.3 months (16.5 versus 9.2 months, P = 0.10). There was also a contrasting difference in the type and efficacy of salvage chemotherapeutic regimens between the two groups: salvage regimens with irinotecan, platinum, or taxanes were commonly used with relatively high objective responses in the SCLC regimen group, whereas frequently used agents in the NSCLC regimen group such as pemetrexed, gefitinib, or erlotinib were associated with no objective response. Conclusions Regarding palliative chemotherapy, advanced LCNEC should be treated similarly as SCLC rather than NSCLC.

We present the rationale and study design of the phase II trial of carboplatin plus S-1 plus gefitinib followed by S-1 plus gefitinib, which the multicenter trial on safety and efficacy of first-line therapies in advanced non-small cell lung cancer (NSCLC) patients harboring activating mutation of the EGFR gene. Treatment consists of up to 4 cycles of induction therapy followed by maintenance therapy until disease progression or treatment discontinuation in 28 patients. The primary end points of the present study are the efficacy objectives are to assess the 1 year progression free survival rate, the overall survival (OS), response rates, progression-free survival (PFS). In addition, safety will be investigated in the present study. If the primary objective (1 year progression free survival rate) is achieved and this treatment has good tolerability, this study will provide robust results on an alternative treatment option, carboplatin plus S-1 plus gefitinib followed by maintenance therapy with S-1 plus gefitinib, for patients with advanced nonsquamous NSCLC harboring activating mutation of the EGFR gene.

Background The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid, nitrogen-containing bisphosphonate, in combination with docetaxel in previously treated NSCLC patients with bone metastases. Material and methods Previously treated NSCLC patients with bone metastases were randomly assigned to receive either docetaxel 60 mg/m2 with or without zoledronic acid 4 mg on day 1 every 21 days. The study treatment was repeated until disease progression, or intolerable toxicity. The primary end point was progression-free survival (PFS), and secondary end points were overall survival (OS), objective response rate (ORR), skeletal-related event (SRE) rate, SRE-free survival, and safety. All patients were followed-up for 1 year after the last patient enrollment. Results From May 2007 to March 2010, 100 patients were enrolled from 15 institutions; 50 patients were randomly assigned to docetaxel plus zoledronic acid (DZ) and 50 to docetaxel alone (D). Patient characteristics were well balanced between the two arms. Forty-nine patients in the DZ group received zoledronic acid with a median of three cycles (range 1–19). Of 94 patients for efficacy analysis (48 for DZ and 46 for D), the median OS was 10.4 (95% CI, 7.0–15.8) months in the DZ group, when compared with 9.7 (95% CI, 6.1–12.5) months in the D group (stratified log-rank test, P = 0.62). The median PFS were 2.7 and 2.6 months in DZ and D, respectively (stratified log-rank test, P = 0.89), with corresponding ORRs of 8% (95% CI, 2–20) and 4% (95% CI, 1–14). The median SRE-free survival in the two groups was 7.2 and 6.0 months, respectively (stratified log-rank test, P = 0.84). The SRE rates at 1 year were 30% (95% CI, 18–48) for the DZ group and 39% (95% CI, 24–57) for the D group. There were no clinically relevant differences in the frequencies of grade 3–4 adverse events between the two groups. No treatment-related death was observed in the DZ group. Conclusions The addition of zoledronic acid to docetaxel was well tolerated, but did not improve PFS and OS in NSCLC patients with bone metastases.

The clinical significance of the serum crosslinked N-telopeptide of type I collagen (NTx) as a prognostic marker for non-small-cell lung cancer (NSCLC) was evaluated. We have revealed that a high serum NTx level (>22 nmol bone collagen equivalents (BCE)/L) appears to be a risk factor for a reduction in overall survival in patients with NSCLC. Introduction: Lung cancer is the leading cause of cancer-related death. Many patients with lung cancer are in its advanced stages at the time of diagnosis. The 5-year survival rate for lung cancer is 10% to 20%, and the prognosis for patients with lung cancer is still poor. The crosslinked N-terminal telopeptide of type I collagen (NTx) is a metabolite of type I collagen, the main constituent of bone matrix. Patients and Methods: We measured serum NTx levels in patients who underwent staging during hospitalization for the initial treatment of lung cancer in our department. We examined whether serum NTx levels would be relevant to the prognosis of non-small-cell lung cancer (NSCLC). Results: This study included 176 patients with lung cancer (125 men and 51 women), including 109 with adenocarcinoma, 53 with squamous cell carcinoma, 6 with large-cell carcinoma, and 8 with other cancer types. Univariate and multivariate analysis using the Cox proportional hazards model revealed a particularly close associ- ation between sex, performance status, disease stage, and serum NTx levels and overall survival (OS). A median OS of 368 days was observed for patients with a serum NTx level 22 nmol BCE/L, which was significantly longer than the 197 days for patients with a serum NTx level 22 nmol BCE/L (hazard ratio (HR), 2.02; 95% confidence interval (CI), 1.36-2.99; log-rank P.00037). Conclusions: We have revealed that a high serum NTx level ( 22 nmol BCE/L) appears to be a risk factor for a reduction in OS in patients with NSCLC.

We present the rationale and study design of the phase I and II trials of carboplatin plus pemetrexed followed by pemetrexed, which the multicenter trial on safety and efficacy of first-line therapies in elderly (75 years old or more) advanced non-small-cell lung cancer (NSCLC) patients. Treatment consists of up to four cycles of induction therapy followed by maintenance therapy until disease progression or treatment discontinuation in 3–6 patients/cohort (Phase I), and 34 patients (phase II). The primary end points of the present study are to determine the recommended dose (RD) and maximum tolerance dose (MTD) of carboplatin plus pemetrexed in phase I, and, in phase II, the efficacy objectives are to assess the 1-year survival rate, the overall survival (OS), response rates, progression-free survival (PFS). In addition, safety will be investigated in phase II study. If the primary objective (recommended dose and 1-year survival rate) is achieved, this study will provide robust results on an alternative treatment option, carboplatin plus pemetrexed followed by maintenance therapy with pemetrexed, for patients with elderly (75 years old or more) advanced nonsquamous NSCLC.

Background Gefitinib is an effective agent for use in treating patients suffering from non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations. However, no optimal strategies have been established for treating these patients after gefitinib fails. Here, we conducted a retrospective study to assess the survival benefit of continued gefitinib treatment in these cases. Patients and methods We analyzed gefitinib responders with activating EGFR mutations who developed progressive disease (PD) during the course of therapy. Prognostic variables were analyzed using a Cox proportional-hazards model. Results Among the 146 patients retrospectively reviewed, exon-19 deletion mutations and L858R point mutations were detected in 78 and 68 patients, respectively. Median survival time after PD confirmation was 14.9 months (95% confidence interval [CI]: 7.9-21.9), and the median duration of continued gefitinib therapy beyond PD was 3.4 months. Statistical analysis showed that good performance status (0-1) (hazard ratio [HR]: 0.7), progression of previously evaluated lesion (HR: 0.6), and at least 3 months of continued treatment (HR: 0.4) were independent prognostic factors. Conclusion Continuation of gefitinib beyond PD is an effective optional treatment in EGFR-mutated patients. Disclosure All authors have declared no conflicts of interest.

e18036 Background: The bone resorption biomarkers urinary NTx (uNTx) and serum NTx (sNTx) have been shown to aid in the diagnosis of bone metastasis in patients with lung cancer. Patients with metastatic bone disease from lung cancer (MBDLC) are often treated with zoledronic acid. Zoledronic acid reduces the levels of bone resorption biomarkers and also the risk of skeletal adverse events in patients with MBDLC. We studied the effects of treatments including zoledronic acid on levels of sNTx during disease progression. Methods: Patients with MBDLC at the initial diagnosis were entered to this study. sNTx was measured once a month using the sNTx assay OSTEOMARK serum NTx (Alere Medical). MBDLC was characterized by monthly physical examination and by bone scintigraphy every 3 months for 12 months. All patients were required to provide written informed consent. Results: Twenty patients were enrolled between June and December 2010. The mean +/- 1 SD of the sNTx concentrations was 19.8 +/- 5.8 nM BCE/L at baseline. In the 16 patients receiving zoledronic acid, the levels of sNTx showed a significant decrease in the first month of treatment (baseline: 21.3 +/- 5.5 nM BCE/L; one month later: 13.6 +/- 2.7 nM BCE/L; p

Introduction Public health checkups are conducted on 3-year-old children in Japan. However, it is often difficult to detect or provide ongoing support to children with developmental disorders without MR. Therefore we have conducted health checkups on 5 year olds. Objectives The objectives are to describe the results and follow-up of health checkups in 5-year-old children and examine the utility of such checkups. Aims The aims are to make clear the utility of health checkups in 5-year-old children for screening for developmental disorders. Method The subjects were 303 children of 5-year-old that lived in Kanie-cho and participated in health checkups. In the checkups, a child psychiatrist examined the children, and made a provisional diagnosis of a developmental disorder. Results Eighty-two children were provisionally diagnosed as having developmental disorders. The follow-up allowed final diagnosis of developmental disorders (suspect diagnosis included) to be made in 39 children (12.9%), and pinpointed 19 children with ADHD, 9 children with PDD, 9 children with mild MR, and 2 children with motor skills disorder. All children with PDD had already been informed about the possible occurrence of developmental disorders at 3 years of age. However, most of ADHD, mild MR, and motor function disorder were diagnosed in these children during the checkups at the age of 5 years. Conclusion The health checkup in 5-year-old children is useful not only as a tool to detect developmental disorders that are difficult to diagnose at the age of 3 years but also as an approach in patients lost to follow-up.

PURPOSE We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) support because of the overlapping neutrophil toxicity of both drugs. The aim was to determine the maximum-tolerated dose of CPT-11 combined with a fixed dose of etoposide in patients with advanced lung cancer, as well as the dose-limiting toxicities of this combination. PATIENTS AND METHODS Twenty-five patients with stage III or IV lung cancer, 15 (60%) with prior chemotherapy, were treated at 4-week intervals using CPT-11 (90-minute intravenous infusion on days 1, 8, and 15) plus etoposide (80 mg/m2 intravenously on days 1 to 3). In addition, rhG-CSF (2 micrograms/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. The starting dose of CPT-11 was 60 mg/m2, and it was escalated in 10-mg/m2 increments until the maximum-tolerated dose was reached. RESULTS The maximum-tolerated dose of CPT-11 was 90 mg/m2, since two of the three patients developed grade 3 to 4 leukopenia or grade 3 to 4 diarrhea during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the dose-limiting toxicities, while thrombocytopenia was only a moderate problem. Elimination of CPT-11 was biphasic, with a mean +/- SD beta half-life of 18.17 +/- 9.09 hours. The mean terminal half-life of 7-ethyl-10-hydroxycamptothecin (SN-38; the major metabolite of CPT-11) was 43.40 +/- 37.84 hours. There was one complete response (5%) and eight partial responses (38%) among 21 assessable patients, for an overall response rate of 43%. The response rates for small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) were 58% (seven of 12 patients) and 22% (two of nine patients), respectively. CONCLUSION The combination of CPT-11 and etoposide with rhG-CSF support seems to be active against lung cancer, especially SCLC, with acceptable toxicity. The recommended dose for phase II studies in previously untreated patients is 80 mg/m2 of CPT-11 (days 1, 8, and 15) and 80 mg/m2 of etoposide (days 1 to 3) plus 2 micrograms/kg of rhG-CSF (days 4 to 21, except when CPT-11 is given). In addition, 70 mg/m2 of CPT-11 appears to be the appropriate dose for previously treated patients receiving this regimen.

e18044 Background: Many cancers metastasize to bone. Bone metastasis may cause an increase in bone resorption due to direct effects of the tumor itself or osteoclastic activation. This study evaluates the bone resorption biomarkers urinary NTx (uNTx) and serum NTx (sNTx) for the diagnosis of bone metastasis in patients with lung cancer. Methods: uNTx and sNTx were measured in 100 patients with lung cancer and 50 control patients with benign respiratory diseases using the uNTx:OSTEOMARKTM and sNTx:OSTEOMARKTM serum NTx assays (Inverness Medical Japan). Bone metastasis was characterized by scintigraphy. The extent of disease (EOD) was determined by the number of sites of bone metastasis. Area under the curve (AUC) for receiver operating characteristic (ROC) analysis was used to evaluate the detection of bone metastasis. Sensitivity and specificity of uNTx and sNTx to detect bone metastasis were calculated using cutpoints of 64 nM BCE/mM Cr for uNTx and 22 nM BCE/mM Cr for sNTx. All patients were required to...

2516 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-MET, a receptor tyrosine kinase implicated in tumor cell migration, invasion and proliferation. ARQ 197 is mainly metabol...

7552 Background: In 2010, the results of the LETS study demonstrated noninferiority for overall survival (OS) less than a predefined stopping boundary at the preplanned interim analysis (protocol-specified noninferiority margin, 1.33) (JCO 2010 28:5240). At the start of this study, we determined that a 2-year follow up would be required. Here, we report the updated results of OS. Methods: In the LETS study, chemotherapy-naive patients with advanced stage (IIIB/IV) non-small cell lung cancer (NSCLC), Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1, and adequate organ functions were randomly assigned to receive either carboplatin AUC (5 mg/ml/min) on day 1 plus oral S-1 (80 mg/m2/day; 40 mg/m2 b.i.d.) on days 1–14 or carboplatin AUC (6 mg/ ml/min) plus paclitaxel (200 mg/m2) on day 1 every 21 days. OS was evaluated as the primary endpoint (ITT; n = 564) in the carboplatin/S-1 arm (n = 282) and carboplatin/paclitaxel arm (n = 282). This analysis used a Cox proportional hazards model ad...

The patient was a 57-year-old male with long-standing bronchiectasis who developed severe respiratory failure and died in 1991. Autopsy revealed multiple broncholithiasis in both lungs, but no calcified lymph nodes in the hilar region. Since histological examination of the broncholiths showed only stratified structures but no tissue structure, most likely cause was considered to be calcification of mucus in the bronchi. Analysis of the stone components revealed 78% calcium and 22% protein. This patient represents a case of multiple broncholithiasis caused by mucus retention, which is thought to be very rare.

e18095 Background: Bone metastasis is an important factor for determining the appropriate treatment for lung cancer patients; further bone metastasis influences prognosis as well as the quality of ...