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Background Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1–3 every 3 weeks) or docetaxel (60 mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P= 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel. Clinical trial registration NCT01207011 (ClinicalTrials.gov)

Oral S-1 plus cisplatin is noninferior to docetaxel plus cisplatin in terms of overall survival with favorable QoL data. S-1 plus cisplatin is an option for the first-line treatment of patients with advanced NSCLC., Background Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL). Patients and methods Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0–1 and adequate organ function were randomized to receive either oral S-1 80 mg/m2/day on days 1–21 plus cisplatin 60 mg/m2 on day 8 every 4–5 weeks, or docetaxel 60 mg/m2 on day 1 plus cisplatin 80 mg/m2 on day 1 every 3–4 weeks, both up to six cycles. Results A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837–1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin. Conclusion Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC. Clinical trial number UMIN000000608.

Objective: This study reports the findings of a Phase I/II, cohort, dose-escalation trial of amru- bicin and irinotecan with the support of granulocyte colony-stimulation factor. This study aimed to determine the dose-limiting toxicity of the combination and to define the maximum-tolerated dose, as a recommended dose for Phase II trials. We also sought to obtain preliminary data on the efficacy of this combination as a frontline therapy for extensive-disease small-cell lung cancer. Methods: We included 23 chemo-naive patients with extensive-disease small-cell lung cancer in the trial. The amrubicin dose was escalated from 35 to 40 mg/m 2 (Levels 1 and 2, respectively) to determine the dose-limiting toxicity, with an unchanged dose of irinotecan at 50 mg/m 2 . Results: Of nine patients, three experienced dose-limiting toxicities at Level 1 of prolonged Grade 4 neutropenia, Grade 3 febrile neutropenia and Grade 3 febrile neutropenia with Grade 3 diarrhea. At Level 2, two patients experienced dose-limiting toxicities of Grade 4 neutropenia and Grade 3 neutropenia with Grade 4 diarrhea. The maximum-tolerated doses and recommended doses for amrubicin and irinotecan were therefore determined to be 35 and 50 mg/m 2 , respective- ly. The Level 1 trial was then expanded to 21 patients, 14 (70%) of whom showed partial responses to the recommended dose. The median progression-free and overall survival times were 6.37 and 15.21 months, respectively. Conclusions: The combination of amrubicin and irinotecan with the support of granulocyte colony-stimulation factor produced a potent effect in chemo-naive extensive-disease small-cell lung cancer patients. The use of biomarkers for this regimen may identify patients who are likely to suffer from treatment-ending severe adverse effects.

Background: Erythropoietin-stimulating agents (ESAs) effectively decrease the transfusion requirements of patients with chemotherapy-induced anaemia (CIA). Recent studies indicate that ESAs increase mortality and accelerate tumour progression. The studies also identify a 1.6-fold increased risk of venous thromboembolism. The ESA labelling was thus revised in Europe and the United States in 2008. This is the first randomised, phase III trial evaluating the efficacy and safety of epoetin-β (EPO), an ESA, dosed in accordance with the revised labelling, which specifies that ESAs should be administered to CIA patients with a haemoglobin level of ⩽10 g dl–1 and that a sustained haemoglobin level of >12 g dl–1 should be avoided. Methods: A total of 186 CIA patients (8.0 g dl–1⩽ haemoglobin ⩽10.0 g dl–1) with lung or gynaecological cancer were randomised to receive EPO 36 000 IU or placebo weekly for 12 weeks. Results: The proportion of patients receiving transfusions or with haemoglobin

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.

Thermally assisted magnetic recording (TAMR) is a promising technology to achieve a recording density of over several Tbit/inch2. We analyzed the use of a plasmon antenna as well as the effect of a particle medium with Finite-Difference Time-Domain (FDTD) method. Using a plasmon antenna, we analyzed the dependence of flying height (FH) on the power intensity (E2). FH is the distance between the medium and the antenna. We also analyzed the dependence of full width half maximum (FWHM) on near-field optics. We investigated the influence of different compositions of the antenna and of the media on plasmon resonance. Three compositions of the particle medium were Au, Pt, and Co. For metallic particles, the FWHM was less than 15 nm when FH was 5 nm to 20 nm. The peak intensity for the particle medium was higher than that of the continuous film across various values for FH. Furthermore, the overall power distribution was higher as well. These results show that particles positioned at the apex of the antenna can be heated by a small, concentrated spot.

We compared the efficacy and the safety of a carboplatin plus etoposide regimen (CE) vs split doses of cisplatin plus etoposide (SPE) in elderly or poor-risk patients with extensive disease small-cell lung cancer (ED-SCLC). Eligibility criteria included: untreated ED-SCLC; age/=70 and performance status 0-2, or age70 and PS 3. The CE arm received carboplatin area under the curve of five intravenously (IV) on day 1 and etoposide 80 mg m(-2) IV on days 1-3. The SPE arm received cisplatin 25 mg m(-2) IV on days 1-3 and etoposide 80 mg m(-2) IV on days 1-3. Both regimens were given with granulocyte colony-stimulating factor support in a 21-28 day cycle for four courses. A total of 220 patients were randomised. Median age was 74 years and 74% had a PS of 0 or 1. Major grade 3-4 toxicities were (%CE/%SPE): leucopenia 54/51, neutropenia 95/90, thrombocytopenia 56/16, infection 7/6. There was no significant difference (CE/SPE) in the response rate (73/73%) and overall survival (median 10.6/9.9 mo; P=0.54). Palliation scores were very similar between the arms. Although the SPE regimen is still considered to be the standard treatment in elderly or poor-risk patients with ED-SCLC, the CE regimen can be an alternative for this population considering the risk-benefit balance.

The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of pemetrexed with folate and vitamin B12 supplementation (FA/VB(12)) in Japanese patients with solid tumours and to investigate the safety, efficacy, and pharmacokinetics of pemetrexed. Eligible patients had incurable solid tumours by standard treatments, a performance status 0-2, and adequate organ function. Pemetrexed from 300 to 1,200 mg m(-2) was administered as a 10-min infusion on day 1 of a 21-day cycle with FA/VB(12). Totally, 31 patients were treated. Dose-limiting toxicities were alanine aminotransferase (ALT) elevation at 700 mg m(-2), and infection and skin rash at 1,200 mg m(-2). The MTD/RD were determined to be 1,200/1,000 mg m(-2), respectively. The most common grade 3/4 toxicities were neutropenia (grade (G) 3:29, G4:3%), leucopenia (G3:13, G4:3%), lympopenia (G3:13%) and ALT elevation (G3:13%). Pemetrexed pharmacokinetics in Japanese were not overtly different from those in western patients. Partial response was achieved for 5/23 evaluable patients (four with non-small cell lung cancer (NSCLC) and one with thymoma). The MTD/RD of pemetrexed were determined to be 1,200/1,000 mg m(-2), respectively, that is, a higher RD than without FA/VB(12) (500 mg m(-2)). Pemetrexed with FA/VB(12) showed a tolerable toxicity profile and potent antitumour activity against NSCLC in this study.

Recently, for the high recording density technology that aims at recording density of 1Tbit/inch2, heat assisted hybrid recording has been suggested. Near-field optics is one of the important factors for the hybrid recording to shrink an optical spot to a diameter of 50 nm or below. In this study, we analyzed a double layered plasmon antenna for hybrid recording by Finite Difference Time Domain (FDTD). The double layered plasmon antenna was designed on the resonance wavelength which itself depends on the materials and the shape of the antenna. The results of the calculation showed high power intensity and focused optical spot at the nanosize level.

Background The purpose of this study was to evaluate the toxicity and antitumor effect of cisplatin, irinotecan and etoposide combinations on two schedules, arms A and B, for previously untreated extensive small-cell lung cancer (E-SCLC), and to select the right arm for phase III trials. Patients and methods Sixty patients were randomized to receive either arm A (cisplatin 25 mg/m2 day 1, weekly for 9 weeks, irinotecan 90 mg/m2 day 1, on weeks 1, 3, 5, 7 and 9, and etoposide 60 mg/m2 days 1–3, on weeks 2, 4, 6, 8), or arm B (cisplatin 60 mg/m2 day 1, irinotecan 60 mg/m2 days 1, 8, 15, and etoposide50 mg/m2 days 1–3, every 4 weeks for four cycles). Prophylactic granulocyte colony-stimulating factor support was provided in both arms. Results Full cycles were delivered to 73% and 70% of patients in arms A and B, respectively. Incidences of grade 3–4 neutropenia, anemia, thrombocytopenia, infection and diarrhea were 57, 43, 27, 7 and 7%, respectively, in arm A, and 87, 47, 10, 13 and 10%, respectively, in arm B. A treatment-related death developed in one patient in arm A. Complete and partial response rates were 7% and 77%, respectively, in arm A, and 17% and 60%, respectively, in arm B. Median survival time was 8.9 months in arm A, and 12.9 months in arm B. Conclusions Arm B showed a promising complete response rate and median survival with acceptable toxicity in patients with E-SCLC, and should be selected for the investigational arm in phase III trials.

To determine a standard combination chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC), we conducted a phase III trial of irinotecan (CPT-11) to test the hypotheses that CPT-11+cisplatin is superior to cisplatin+vindesine and that CPT-11 monotherapy is not inferior to cisplatin+vindesine. A total of 398 patients with previously untreated NSCLC were randomised to receive cisplatin+CPT-11 (CPT-P), cisplatin+vindesine (VDS-P) or CPT-11 alone (CPT). In the CPT-P arm, CPT-11 60 mg m(-2) was administered on days 1, 8 and 15, and cisplatin 80 mg m(-2) was administered on day 1. In the VDS-P arm, cisplatin 80 mg m(-2) was administered on day 1, and vindesine 3 mg m(-2) was administered on days 1, 8 and 15. In the CPT arm, CPT-11 100 mg m(-2) was administered on days 1, 8 and 15. The median survival time was 50.0 weeks for patients on CPT-P, 45.6 weeks for those on VDS-P and 46.0 weeks for those on CPT (P=0.115, CPT-P vs VDS-P; P=0.089, CPT vs VDS-P), and the hazard ratio was 0.85 (95% confidence interval (CI): 0.65-1.11) for CPT-P vs VDS-P and 0.83 (0.64-1.09) for CPT vs VDS-P. The response rate was 43.7% for patients on CPT-P, 31.7% for those on VDS-P and 20.5% for those on CPT. Major adverse reactions were grade 4 neutropenia observed in 37, 54 and 8% of the patients on CPT-P, VDS-P and CPT, respectively; and grades 3 and 4 diarrhoea observed in 12, 3 and 15% of the patients, respectively. CPT-P therapy produces comparable survival to VDS-P in patients with advanced NSCLC. CPT-11 monotherapy is not inferior to VDS-P in terms of survival. The CPT-11-containing regimen is one of the most efficacious and well tolerated in the treatment of advanced NSCLC.

Dose-escalation study was performed to evaluate the maximum tolerated dose, recommended dose and toxicity profile of weekly irinotecan with daily carboplatin and concurrent thoracic radiotherapy in patients with locally advanced non-small-cell lung cancer. Thirty-one previously untreated patients with unresectable stage III non-small-cell lung cancer were enrolled in this study. Patients received weekly irinotecan plus carboplatin (20 mg m−2 daily for 5 days a week) for 4 weeks and thoracic radiotherapy (60 Gy in 30 fractions). The irinotecan dose was escalated from 30 mg m−2 in increments of 10 mg m−2. Four irinotecan dose levels were given and 30 patients were assessable. Their median age was 62 years (range: 52–72 years), 28 had a performance status of 0–1 and two had a performance status of 2, 12 had stage IIIA disease and 18 had IIIB disease. There were 19 squamous cell carcinomas, 10 adenocarcinomas, and one large cell carcinoma. The dose-limiting toxicities were pneumonitis, esophagitis, thrombocytopenia and neutropenia. The maximum tolerated dose of irinotecan was 60 mg m−2, with two patients developing grade 4 pulmonary toxicity and one patient died of pneumonitis (grade 5). The recommended dose of irinotecan was 50 mg m−2. Other grade 3 or 4 toxicities were nausea and vomiting. Three patients achieved complete remission and 15 had partial remission, for an objective response rate of 60.0%. The median survival time was 14.9 months, and the 1- and 2-year survival rates were 51.6% and 34.2%, respectively. The study concluded that the major toxicity of this regimen was pneumonitis. This therapy may be active against unresectable non-small-cell lung cancer and a phase II study is warranted. British Journal of Cancer (2002) 87, 258–263. doi:10.1038/sj.bjc.6600464 www.bjcancer.com © 2002 Cancer Research UK

Dyspnea is a major clinical symptom of various respiratory diseases. However, no objective assessment of dyspnea on exertion (DOE) in elderly subjects has been established yet. Furthermore, the factors which may influence DOE in healthy elderly subjects have not yet been precisely elucidated. An oxygen cost diagram (OCD), which was originally developed by McGavin (1978), is one of the methods of assessing dyspnea on exertion in a semi-quantitative way, although it is still uncertain which factor (s) might influence the changes in OCD values. The present study was, therefore, undertaken to study; 1) whether OCD values are useful for the assessment of DOE in elderly subjects, and 2) the possible factors (s) which might contribute to changes in OCD values in these patients. The total number of subjects which were enrolled in the present study was 818, consisting of 355 men and 463 women, whose mean age was 76.4 years old, was studied. Spirometry, arterial blood gases and OCD values were measured on the same day. The OCD value and FEV(1.0) declined linearly with advanced aging. It was found that the factors which significantly reduce OCD values were as follows: aging, vital capacity, FEV(1.0), and maximal voluntary ventilation (MVV). The odd ratio which contributes to changes in OCD values was calculated. It appeared that there was a gender difference: when the odd ratio of OCD values of less than 70 was taken as 1 in the men, the odd ratio in women was calculated as 1.42. The odd ratio increased with advancing age; when the value in the 65~69 year-old group was 1, the odd ratios in the 85~89 year-old and 90~94 year-old groups were in approximately 6 and 8, respectively. Similarly, the odd ratio increased parallel with reduction in MVV. From these results, we conclude that the OCD value is reliable, simple and the best method of evaluating dyspnea in elderly subjects semi-quantitatively, and both the minute ventilatory volume and age are closely related with changes in OCD values.

Sporadic cases have developed pulmonary toxicity after receiving chemotherapy and granulocyte colony-stimulating factor (G-CSF). However, because such cases received chemotherapy that alone frequently causes pulmonary toxicity, the role of G-CSF in this toxicity has been unclear. CHOP therapy (cyclophosphamide, doxorubicin, vincristine and prednisolone) only slightly induces pulmonary toxicity. However, we observed a considerable incidence of this toxicity in non-Hodgkin's lymphoma subjects receiving CHOP therapy and G-CSF (6 out of 52 subjects, 11.5%). In this cohort, among various characteristics, including the dose and interval of CHOP therapy, only the mean peak leucocyte count (MPLC) with each therapy cycle was associated with development of this toxicity (MPLC > or = 23.0 x 10(9) l(-1), 6 out of 29 cases; MPLC < 23.0 x 10(9) l(-1), 0 out of 23 cases; P = 0.020). These findings suggest that the effect of G-CSF is the main determinant of the pulmonary toxicity in these cases. Because the toxicity was associated with a large MPLC and did not recur in cases readministered G-CSF, an idiosyncratic reaction to G-CSF is unlikely to be the pathogenesis of this toxicity. Thus, lowering the G-CSF dose seems to be useful in the prevention of this toxicity. In all six cases, the time course of manifestation of the toxicity was the same, and early application of high-dose corticosteroid led to cure. This knowledge will be helpful in the care of similar cases. Images Figure 2

PURPOSE Irinotecan (CPT-11) is effective against small-cell lung cancer (SCLC) as monotherapy. Cisplatin is also a key drug against SCLC. We conducted a phase II study of CPT-11 combined with cisplatin to evaluate the efficacy and toxicity of this regimen in patients with previously untreated SCLC. PATIENTS AND METHODS Seventy-five patients with previously untreated SCLC were enrolled onto the study. CPT-11 60 mg/m2 was administered intravenously on days 1, 8, and 15 in combination with cisplatin 60 mg/m2 on day 1 every 28 days. Four courses of chemotherapy followed by thoracic irradiation were given to patients with limited disease (LD) and six courses to patients with extensive disease (ED). RESULTS The overall response rate was 84%, with a complete response (CR) rate of 29%. Forty patients with LD achieved an overall response rate of 83% and a CR rate of 30% and 35 patients with ED achieved an overall response rate of 86% and a CR rate of 29%. The median response duration was 8.0 months for LD patients and 6.6 months for ED patients. The median survival was 14.3 months for LD patients and 13.0 months for ED patients. The major grade 3 or 4 toxicities were neutropenia (77%), leukopenia (45%), diarrhea (19%), and anemia (39%). Two patients died with concomitant neutropenia and diarrhea. CONCLUSION This is a new active regimen for SCLC, especially ED-SCLC, with acceptable toxicity. A phase III study that compares CPT-11/cisplatin with etoposide/cisplatin for ED-SCLC is now being conducted.

The seasonal development of algal biomass and dissolved organic carbon (DOC) in bottom ice was determined for two widely separated areas of annual sea ice, Saroma-ko in northern Japan and Resolute Passage in the Canadian High Arctic, to determine the importance of DOC to estimates of primary production in sea ice communities. As algal biomass, measured either as chlorophyll a (Chl a) or particulate organic carbon (POC), increased, DOC concentrations increased to extremely high values (up to 40 mg Cl−1 DOC). The highest algal biomass and DOC concentrations were observed at Resolute under thin (4–8 cm) snow cover. Highly significant double-log linear relationships (r2 = 62–80%, p < 0.01) existed between DOC and both Chl a and POC, suggesting much of the DOC originated from the ice algae. A highly significant global relationship between DOC and POC (r2 = 74%, p

The massive development of the ice algal community commonly observed under first-year sea ice was studied with particular attention to photosynthetic and respiratory characteristics of ice algae at low temperature and low light conditions. Field experiments were carried out in April and May 1992 at Resolute Passage in the Canadian Arctic. Under ca. 200 cm of sea ice with a snow cover of less than 7 cm, ice algal biomass increased from 3.7 to 88.7 Chl a m −2 with growth rates increasing from 0.17 to 0.23 doublings d −1 , although the development was disturbed between 1 and 6 May. The photosynthetically active radiation (PAR) measured at the bottom of the sea ice near midday was between 8.6 and 1.5 μmol photons m −2 s −1 (1.0 and 0.1% of the surface irradiance), and the water temperature was near −1.8°C. In response to these low irradiance levels, ice algae exhibited a high α (the initial slope of the photosynthesis vs. irradiance relationship) of 0.26 μg C μg Chl a −1 h −1 (μ mol photons m −2 s −1 ) −1 . The dark respiration contributed up to 35% of the gross photosynthetic rare and was estimated to be 0.22 μg C μg Chl a −1 h −1 on average. Considering the value of α and the dark respiration rate, light compensation was estimated to be 0.8 μmol photons m −2 s −1 for the ice algal community, which was enough for ice algae to maintain the positive photosynthesis at the bottom of the sea ice at the maximum daily irradiance. Using a numerical model with these estimated parameters, we evaluated the net positive diel photosynthesis under natural environmental conditions. The numerical model also suggested that the long day length in the late spring and summer in the Arctic region allowed the algae to maintain positive net photosynthesis even after the massive development of the ice algal community.

Recent studies have suggested that some cases of familial interstitial pneumonia are associated with mutations in the gene encoding surfactant protein C (SFTPC). We report here a case of familial interstitial pneumonia in an adolescent boy whose paternal grandfather and father suffered from idiopathic interstitial pneumonia (IIP). The patient was asymptomatic but showed an abnormal shadow in the chest at his medical check-up. The surgical biopsy of the patient revealed non-specific interstitial pneumonia and showed pathological findings similar to those in his father's autopsy. Genomic DNA from blood leucocytes of the patient was sequenced for the Thy104His (Y104H) SFTPC mutation. Based on these results, he was diagnosed with SFTPC mutation-associated familial interstitial pneumonia. There has been no clinical, physiologic and radiologic progression for 4 years since the diagnosis. The relation between clinical manifestation and the mutation site of the patient may broaden the spectrum of SFTPC mutation-associated interstitial pneumonia.

The Bacillus subtilis sleB gene, which codes for the enzyme homologous to the germination-specific amidase from Bacillus cereus, was cloned and its nucleotide sequence was determined. Sequence analysis showed that it had an open reading frame of 918 bp, coding for a polypeptide of 305 amino acids with a putative signal sequence of 29 residues. Enzyme activity was not found in germination exudate of B. subtilis spores, which differs from the case of B. cereus enzyme. A B. subtilis mutant with an insertionally inactivated sleB gene revealed normal behavior in growth and sporulation. However, the sleB mutant was unable to complete germination mediated by L-alanine.

Japanese pulmonologists, experienced in treating patients with diffuse panbronchiolitis (DPB) prior to the 1980s, have uniformly observed that new incidences of DPB are now a rare event in Japan. However, there is no epidemiological data to support this observation. We examined epidemiological trends of the number of patients with DPB in a large company.The computerized health records of JR East Company employees were used to identify patients with DPB and then these were followed up using the assessments of these patients in JR Tokyo General Hospital and two other JR hospitals. The whole study period was 27 years (1976-2003), although detailed analyses were carried out for three specific periods; the first was 1976-1980, the second was 1989-1993, and the third was 1999-2003.In the first period, 11 DPB cases (four incidence, and seven prevalence) were detected among a total of 355,572 workers. In the second period, three DPB cases (one incidence, and two prevalence) were identified from a total of 180,359 workers. In the third period, no case was found in a total of 144,485 workers.This epidemiological trend suggests that both the incidence and prevalence of DPB may have decreased.

Although tumor infiltrating lymphocytes (T-TIL) from B cell non-Hodgkins lymphoma patients contain tumor-reactive T cells, they display poor proliferation and IFN-gamma production when stimulated through the TCR-CD3. To determine if there was altered signaling linked to TCR-CD3 ligation, tyrosine phosphorylation was examined in T-TIL because it represents an early and critical event in T cell activation. After stimulation with anti-CD3 Ab, Western blotting with anti-phosphotyrosine showed reduced phosphorylation in T-TIL when compared with peripheral blood-derived T cells from normal individuals. The altered phosphorylation was not due to the reduced expression of signaling elements linked to the TCR-CD3 complex. T-TIL expressed normal levels of CD3 epsilon, TCR zeta chain, and the three tyrosine kinases, p56lck (Lck), p59fyn, and ZAP-70. However, in T-TIL, anti-Lck Ab reacted with a 60-kDa protein, which appears to be the phosphorylated form of Lck. Binding of anti-Lck Ab to the 60-kDa protein was blocked by Lck peptide. In addition, anti-Lck Ab immunoprecipitated a phosphorylated 60-kDa protein from gamma-32P-labeled T-TIL that was not seen in normal resting T cells. In vitro kinase assay studies also demonstrated that TCR-CD3 engagement increased the kinase activity of Lck in normal T cells but not in T-TIL. These results suggest that although T-TIL from B cell non-Hodgkins lymphoma patients contain the signal transduction molecules associated with TCR-CD3 activation pathway, they are impaired in tyrosine phosphorylation and Lck activity, which may contribute to the functional defects of these cells.

Angiotensin II (Ang II) regulates a variety of physiological functions, including contraction of smooth muscle. Peptide leukotrienes (LTs) have recently been reported to be potent bronchoconstrictors and may play a role in the pathogenesis of airway inflammation. However, the possibility that Ang II and peptide LTs interact in the control of airway function has not been studied. In this study, we showed that Ang II receptors are present on guinea pig airway, and that they are of the AT1 subtype. We showed the possibility that Ang II induced the release of peptide LTs from guinea pig airway by activation of the AT1 receptor pathway. Our findings thus suggest that interaction between Ang II and peptide LTs might increase airway inflammation in the guinea pig.

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.

PURPOSE The purpose of this study was to determine the maximum-tolerated dose and the dose-limiting toxicities of CPT-11, a new derivative of camptothecin, in combination with a fixed dose of cisplatin in patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Twenty-seven previously untreated patients with stage IIIB or IV NSCLC were assessable for toxicity, and 26 were assessable for response. The initial dose of CPT-11 was 30 mg/m2 given as a 90-minute intravenous (IV) infusion on days 1, 8, and 15 in combination with cisplatin (80 mg/m2 IV on day 1) given every 4 weeks. The dose of CPT-11 was escalated in increments of 10 mg/m2 until severe or life-threatening toxic effects were observed. RESULTS Significant toxicity was infrequent up to 60 mg/m2 of CPT-11. The maximum-tolerated toxicity was reached at a dose of 70 mg/m2. Three of six patients either had leukocyte count nadirs of less than 2,000/microL or experienced grade 4 diarrhea during the first cycle of therapy at 70 mg/m2. The major toxic effects were leukopenia and diarrhea. There were 14 partial responses (54%) among the 26 patients. CONCLUSIONS A combination of CPT-11 and cisplatin seems to be effective against NSCLC with acceptable toxicities. The recommended dose for phase II studies is 60 mg/m2 of CPT-11 on days 1, 8, and 15, and 80 mg/m2 of cisplatin on day 1 every 4 weeks.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease without proven effective therapy. A multicentre, double-blind, placebo-controlled, randomised phase III clinical trial was conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of pirfenidone, a novel antifibrotic oral agent, over 52 weeks. Of 275 patients randomised (high-dose, 1,800 mg x day(-1); low-dose, 1,200 mg x day(-1); or placebo groups in the ratio 2:1:2), 267 patients were evaluated for the efficacy of pirfenidone. Prior to unblinding, the primary end-point was revised; the change in vital capacity (VC) was assessed at week 52. Secondary end-points included the progression-free survival (PFS) time. Significant differences were observed in VC decline (primary end-point) between the placebo group (-0.16 L) and the high-dose group (-0.09 L) (p = 0.0416); differences between the two groups (p = 0.0280) were also observed in the PFS (the secondary end-point). Although photosensitivity, a well-established side-effect of pirfenidone, was the major adverse event in this study, it was mild in severity in most of the patients. Pirfenidone was relatively well tolerated in patients with IPF. Treatment with pirfenidone may decrease the rate of decline in VC and may increase the PFS time over 52 weeks. Additional studies are needed to confirm these findings.

Background This trial evaluated whether a combination of docetaxel and gemcitabine provides better survival than docetaxel alone in patients with previously treated non-small-cell lung cancer (NSCLC). Patients and methods Eligibility included pathologically or cytologically proven NSCLC, failure of one platinum-based regimen, performance status of zero or one, 20–75 years old, and adequate organ function. Patients received docetaxel 60 mg/m2 (day 1) or docetaxel 60 mg/m2 (day 8) and gemcitabine 800 mg/m2 (days 1 and 8), both administered every 21 days until disease progression. Results Sixty-five patients participated in each arm. This trial was terminated early due to an unexpected high incidence of interstitial lung disease (ILD) and three treatment-related deaths due to ILD in the combination arm. Docetaxel plus gemcitabine compared with docetaxel-alone patients experienced similar grade and incidence of toxicity, except for ILD. No baseline factor was identified for predicting ILD. Median survival times were 10.3 and 10.1 months (one-sided P = 0.36) for docetaxel plus gemcitabine and docetaxel arms, respectively. Conclusion Docetaxel alone is still the standard second-line treatment for NSCLC. The incidence of ILD is higher for docetaxel combined with gemcitabine than for docetaxel alone in patients with previously treated NSCLC.

Patients with inoperable non-small-cell lung cancer (NSCLC) were randomly assigned to receive one of three dosage regimens: (1) vindesine and cisplatin (VP); (2) mitomycin, vindesine, and cisplatin (MVP); or (3) etoposide and cisplatin alternating with vindesine and mitomycin (EP/VM). In 199 assessable patients, the response rates were VP, 33%; MVP, 43%; and EP/VM, 19%. The addition of mitomycin to the VP regimen did not significantly improve the response rate. The response rate was significantly lower with the EP/VM regimen than with the MVP regimen (P less than .01). The median survival times were VP, 50 weeks; MVP, 42 weeks; and EP/VM, 40 weeks. These differences were not significant. Grade III or IV thrombocytopenia was significantly greater (P less than .01) in MVP patients (22%) than in the VP (5%). Other toxicities were similar in the three groups. Analyses of prognostic factors showed that treatment with MVP, sex, and histologic classification (squamous cell carcinoma) were predictive of improved response. Important factors for improved survival, according to the Cox regression analysis, were the stage of disease, performance status, sex, weight loss before diagnosis, and hemoglobin concentration.

A 44-year-old previously healthy male was diagnosed as anemic and treated at a nearby hospital. A year later, he was admitted to our hospital for precise examination of the progression of refractory anemia. Blood examination showed hemolytic anemia and more detailed examination of this hemolysis revealed pyruvate kinase deficiency. The activity was 15.1% of a normal control. Pyruvate kinase activities of his family members were normal or slightly decreased. Ten months after admission to our hospital, 2% of blast cells with Auer's body in the peripheral blood were noted which increased progressively. The bone marrow contained 17.3% of blast cells with a subsequent diagnosis of acute myelogenous leukemia being made. Although intensive chemotherapy was performed, the patient achieved a brief remission and died 2 years after admission to our hospital.

[1] The Biomass Burning and Lightning Experiment phase C (BIBLE-C) aircraft mission was carried out near Darwin, Australia (12°S, 131°E) in December 2000. This was the first aircraft experiment designed to estimate lightning NO production rates in the tropics, where production is considered to be most intense. During the two flights (flights 10 and 13 made on December 9 and 11–12, respectively) enhancements of NOx (NO + NO2) up to 1000 and 1600 parts per trillion by volume (pptv, 10-s data) were observed at altitudes between 11.5 and 14 km. The Geostationary Meteorological Satellite (GMS) cloud (brightness temperature) data and ground-based lightning measurements by the Global Positioning and Tracking System (GPATS) indicate that there were intensive lightning events over the coast of the Gulf of Carpentaria, which took place upstream from our measurement area 10 to 14 h prior to the measurements. For these two flights, air in which NOx exceeded 100 pptv extended over 620 × 140 and 400 × 170 km2 (wind direction × perpendicular direction), respectively, suggesting a significant impact of lightning NO production on NOx levels in the tropics. We estimate the amount of NOx observed between 11.5 and 14 km produced by the thunderstorms to be 3.3 and 1.8 × 1029 NO molecules for flights 10 and 13, respectively. By using the GPATS lightning flash count data, column NO production rates are estimated to be 1.9–4.4 and 21–49 × 1025 NO molecules per single flash for these two flight data sets. In these estimations, it is assumed that the column NO production between 0 and 16 km is greater than the observed values between 11.5 and 14 km by a factor of 3.2, which is derived using results reported by Pickering et al. (1998). There are however large uncertainties in the GPATS lightning data in this study and care must be made when the production rates are referred. Uncertainties in these estimates are discussed. The impact on the ozone production rate is also described.

There is sparse epidemiologic information regarding the role of dietary factors in the development of idiopathic pulmonary fibrosis (IPF).To examine the relationship between specific types of fatty acids and selected foods high in fat and IPF in Japan.Included were 104 cases agedor = 40 years who had been diagnosed in the last 2 years in accordance with the most recent criteria. Controls agedor = 40 years consisted of 56 hospitalised patients diagnosed as having acute bacterial pneumonia and four out-patients with common cold.Intake of saturated fatty acids, mono-unsaturated fatty acids, n-6 polyunsaturated fatty acids and meat was independently associated with an increased risk of IPF. Specifically, the multivariate OR for comparison of the highest with the lowest quartile of intake of saturated fatty acids was 6.26 (95%CI 1.79-24.96, P for trend = 0.01) and for meat it was 7.19 (95%CI 2.15-27.07, P for trend = 0.02). Intake of cholesterol, n-3 polyunsaturated fatty acids, fish, eggs and dairy products was not related to the risk.These findings suggest that consumption of saturated fatty acids and meat may increase the risk of IPF.

A gene (sleB) encoding a 24-kDa germination-specific spore cortex-lytic enzyme, probably an N-acetylmuramyl-L-alanine amidase, was cloned from Bacillus cereus, and its nucleotide sequence was determined. It was indicated that the enzyme is produced as a 259-residue protein with a signal sequence of 32 residues and is present in dormant spores in its active form. Sulfhydryl reagents inactivated the enzyme, but mutation of a single cysteine of the protein, Cys-258, to Gly did not cause complete inactivation of the enzyme, suggesting that the residue does not function as the catalytic center of enzyme.

Irinotecan is a topoisomerase I inhibitor that is highly active against small cell lung cancer (SCLC). Etoposide is another drug that is effective for SCLC. Since combination of these two topoisomerase inhibitors revealed a synergistic effect in vitro and showed a safety in phase I study, we conducted a phase II study in patients with previously un-treated extensive disease (ED) SCLC to evaluate the efficacy and toxicity of this combination. Fifty patients with previously untreated ED-SCLC were enrolled. Irinotecan was administered intravenously at 60mg/m(2) on days 1, 8, and 15, while etoposide was given at 80mg/m(2) on days 2-4. Treatment was repeated every 4 weeks for four cycles. The overall response rate was 66.0%, with a complete response rate of 10.0%. The median survival time was 11.5 months and the 1- and 2-year survival rates were 43.2 and 14.4%, respectively. The major toxicity of this regimen was myelosuppression, including grade 3 or 4 neutropenia (62.9%), leukopenia (28.0%), and anemia (14%). The other grade 3 toxicity was diarrhea (2%). This irinotecan and etoposide regimen is active against ED-SCLC with relatively mild toxicity.

To determine the maximum-tolerated dose (MTD) and the recommended dose (RD) of paclitaxel administered weekly with a fixed dose of cisplatin, and to assess the toxicity and activity of this combination, we conducted a phase I/II trial in patients with advanced non-small-cell lung cancer (NSCLC). In this study, patients with stage IIIB/IV NSCLC were eligible. Paclitaxel, at a starting dose of 40 mg x m(-2) week(-1) on days 1, 8, and 15, was combined with a fixed dose of cisplatin 80 mg x m(-2) on day 1. Chemotherapy was given in a 4-week cycle. In this phase I/II study, 38 patients were enrolled. Dose-limiting toxicities (DLT) were neutropenia, fatigue, and omission of treatment due to leucopenia, thrombocytopenia, or febrile neutropenia. The MTD and RD were estimated to be 70 mg x m(-2). Of the 37 assessable patients, 23 had a partial response and one had a complete response. Overall response rate was 62.1% (95% confidence interval (CI): 46.5-77.7%). The progression-free survival, the median survival time, and the 1-year survival rate were 5.5 months, 13.7 months, and 56.9%, respectively. This regimen is tolerable and very active against advanced NSCLC, and its efficacy should be confirmed in a phase III study.

Background This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’, ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included. Patients and methods Patients initially received a single oral dose of gefitinib followed by 10–14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT). Results Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. Cmax was reached within 3–7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8–79.7 h). A partial response (duration 35–361 days) was observed in five of the23 patients with non-small-cell lung cancer over a range of doses (225–700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40–127 days). Conclusions In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.

We conducted a prospective, randomized, double-blind, parallel study comparing the antiemetic activity and tolerability of treatment with droperidol (2.5 mg d.i.v. twice daily for 5 days) and placebo, both combined with granisetron (3 mg d.i.v. on the first day) and dexamethasone (16 mg d.i.v. on the first day, 8 mg d.i.v. on days 2, 3, and 4 mg d.i.v. on days 4, 5). A total of 180 lung cancer patients receiving high-dose cisplatin (80 mg/m(2))-containing chemotherapy were enrolled in the study, and 171 of them were capable of being evaluated. The clinical characteristics of the patients in the two treatment arms were well balanced. Complete protection from nausea and vomiting was recorded in the acute phase in 97% of patients who treated with droperidol versus 98% of patients who given the placebo (P=0.920), and in 42% versus 38% in the delayed phase (P=0.615). The multiple logistic regression analysis showed that a history of motion sickness was a significant risk factor for cisplatin-induced delayed emesis (odds ratio [OR]=5.98; 95% CI=2.15 to 16.7, P=0.0006). Droperidol-containing treatment was well tolerated by most patients, however, the incidence of sleepiness in the droperidol group was higher than in the placebo group (69% versus 30%, P0.0001). In conclusion, our data did not support the hypothesis that addition of droperidol to granisetron and dexamethasone reduces the delayed emesis induced by high-dose cisplatin.

Background Malnutrition in non-small cell lung cancer (NSCLC) is associated with advanced stage of disease and is needed for careful choice of treatment. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are routinely used for the treatment of advanced NSCLC with EGFR active mutations, which are promising the excellent responses. Recently, pro-inflammatory cytokines have been proposed as mediators of cancer cachexia. Adipose tissue produces and release substances called adipokines which include tumor necrosis factor-alpha (TNF-α), leptin, adiponectin, and resistin. Adiponectin suppresses the secretion of inflammatory cytokines such as IL-8, TNF-α, and induces the secretion of anti-inflammatory cytokines such as IL-10. It has been hypothesized that EFGR-TKI therapy may affect this adipokine network. Methods The prospective study which evaluated correlations between the pre and post-treatment point of days 30 plasma adipokines and cytokines after EGFR-TKIs administration and clinical outcomes in advanced NSCLC was conducted at Osaka City University Hospital. Plasma adipokines and cytokines were analyzed by Luminex 200 PONENT system (Milliplex MAP kits; Millipore). Results A total of 33 patients were enrolled. We obtained plasma samples for analyses 33 patients on pre-treatment point, and 23 patients on days 30 point. Plasma adiponectin level on the pre-treatment point (40.34 ± 32.00ng/ml) was significantly lower than those on days 30 point (45.07 ± 26.38ng/ml, p = 0.01). On the pre-treatment point of plasma IL-8 (16.70 ± 16.01pg/ml), IL-10 (13.06 ± 29.69pg/ml), insulin (656.9 ± 514.6pg/ml) levels were significantly higher than those on days 30 point (7.154 ± 5.674 pg/ml p = 0.02; 11.53 ± 30.92pg/ml, p = 0.04; and 551.4 ± 520.2pg/ml, p = 0.02, respectively). The levels of leptin and resistin had no significant changes between pre and on days 30 points. Conclusions The EGFR-TKIs treatment for NSCLC increased the plasma adiponectin levels and decreased the plasma insulin, IL-8 and IL-10 levels. Increase of adiponectin levels by EGFR-TKIs may resolve the inflammation and increase insulin sensitivity with reduced output of insulin. Disclosure All authors have declared no conflicts of interest.

Background G is the key drug for patient (pts) with NSCLC harboring mutations of EGFR as a first line treatment. However, they have disease progression in most cases. PEM and G are reported to have a schedule-depended cytotoxic synergism. Objectives We evaluated the efficacy and safety of G and PEM as a first line chemotherapy in pts with NSCLC harboring mutations of EGFR. Methods Eligibilities were histologically or cytologically proven non-squamous NSCLC with EGFR active mutation, chemotherapy naive, measurable lesion, ECOG PS0-1, adequate organ function, life expectancy longer than 12 weeks and written informed consent. G (250mg/body) was administered on days 2-16 and PEM (500mg/m2) was administered on day 1. This combination was repeated every 3 weeks until progressive disease (PD). Primary endpoint was overall response rate (ORR) and secondary endpoints were toxicities, disease control rate (DCR), progression free survival (PFS), and overall survival (OS). The planed sample size was 26 pts. Results From March 2010 to May 2012, 20 pts were enrolled and eligible: males/females 10/10; median age 66 (range 59-75); PS 0/2 2/18; stage III/IV 1/19; adeno/others 20/0. Nineteen pts were eligible for efficacy and toxicity; a total of 226 cycles (median 12 cycles, range 1-27) was given. Major grade 3/4 toxicities were neutropenia, leucopenia, liver dysfunction and infection, respectively. There was no treatment-related death. ORR was 68.8%, and DCR was 100%. Median PFS is 18.2 months and median OS is not reached. Conclusions This combination showed longer median PFS and acceptable toxicity. Randomized trial of PEM + G compare with G alone is warranted. Disclosure All authors have declared no conflicts of interest.

The General Measure of the Functional Assessment of Cancer Therapy scale (FACT-G) was developed in an English-speaking culture (USA). To determine if FACT-G could be used in Japan, a cross-cultural validation was performed. The Japanese version was created through an iterative forward-backward translation sequence used throughout the FACT multi-lingual translation project. In evaluating psychometric testing, its construct validity was investigated by factor analysis and multi-trait scaling analysis. Clinical validity was estimated by known-groups comparison using stage, performance score (PS) and patient location, and validated longitudinally by PS. The FACT-G (version 3) was given to 180 patients with lung cancer. Analyses showed that the scales of Physical, Functional, Emotional Well-Being, and Relationship with Doctors were constructively valid in Japan. Japanese patients felt that familial relationships were different than those with friends and neighbors, indicating that the Social/Family Well-Being scale needed cultural adaptation. Two items concerning coping with illness and acceptance of illness did not load predictably onto their respective scales and were considered to be cross-culturally problematic. However, clinical validity demonstrated its sensitivity. Japanese version 4 has been improved to address the weakness in an attempt to become an instrument that is applicable across cultures.

A 50-year-old man was admitted to our hospital because of an abnormal shadow, detected during an upper gastrointestinal examination. A chest radiograph showed an infiltrating shadow in the right middle lung field. A chest CT showed a fistula communicating between a bronchus (rt. B6) and the middle of the esophagus. Resection of the fistula was performed by video-assisted thoracoscopic surgery (VATS). Isolation of the fistula was straightforward, and there was no evidence of inflammation or adherent lymph nodes around it. Histologic examination of the resected specimen revealed that the fistula lumen was covered with squamous epithelium and muscularis mucosa. These findings suggested that this case could be categorized as Braimbridge type II. In this case, the chest CT showed the esophagobronchial fistula clearly, and was useful for the diagnosis.

This is a case of a 31-year-old man with a history of common cold. He had been suffering from productive cough and dyspnea on exertion. Squawks were heard through auscultation, and hyperinflation was also observed in his chest radiograph. Bronchiolitis was first suspected as a result of HRCT and TBLB. He was then treated with CAM for six months, but his symptoms showed little improvement. So we evaluated his squawks objectively by phonopneumograph, performed video assisted thoracoscopic surgery and diagnosed his illness as constrictive bronchiolitis. Based on the examinations, PSL therapy was applied to his case, which contributed improving his condition remarkably. The significance of this case is that proper auscultation led to the accurate diagnosis.

Although non-frozen storage of peripheral blood stem cells (PBSC) has been extensively studied and utilized clinically, the optimal storage conditions have not been determined. In order to improve the maintenance of clonogenic capacity during storage, we evaluated the feasibility of subzero non-freezing preservation of PBSC and attempted to determine the optimal conditions. Human PBSC were stored in different non-cryopreserved conditions. University of Wisconsin (UW) solution was used as the storage medium for PBSC. The stem cell integrity was optimally maintained when PBSC were preserved in a supercooled state at -2 degrees C in UW solution without any cryoprotectants, and the highest values for nucleated cell survival (91.6%), CFU-GM survival (67.3%) and trypan blue viability (92%) were achieved at 72 h. CFU-GM survival in our storage conditions was significantly better than the survival achieved with hypothermic preservation in autologous serum and ACD-A solution at 4 degrees C (67.3 +/- 9.2% vs 42.9 +/- 15.3%; P < 0.01) or cryopreservation at -80 degrees C (67.3 +/- 9.2% vs 52.7 +/- 10.7%; P < 0.01). Thus, the combination of supercooling and UW solution was the optimal non-freezing method of preserving transplantable PBSC tested here. This method is of clinical utility in peripheral blood stem cell transplantation (PBSCT) for its simplicity and storage efficiency, and has value as a short-term storage method for PBSC to support dose-intensive multicyclic chemotherapy.

Aim: DTX is one of the standard drugs for patients (pts) with previously treated NSCLC. However, its efficacy seems insufficient. The efficacy of AMR for NSCLC has been previously reported. Thus, we conducted a randomized phase III trial comparing AMR to DTX, sponsored by Dainippon Sumitomo Pharma Co., Ltd. Methods: We enrolled pts with NSCLC, Eastern Cooperative Oncology Group Performance Status 0-1, undergoing second- or third-line treatment, and aged 20–74 years. Pts were classified by histology, prior treatment, and institution into 2 groups and then randomly assigned (1:1 ratio) to treatment with AMR (35 mg/m2/day i.v., on days 1–3, q3w) or DTX (60 mg/m2/day i.v., on day 1, q3w). We planned a sample size of 100 patients per group, with a 2-sided alpha of 5% and power of 90%. We hypothesized a median progression-free survival (PFS) time of 3.3 and 2.0 months for AMR and DTX, respectively. The primary endpoint was PFS; secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and adverse events according to Common Terminology Criteria for Adverse Events v 4.03. Results: From October 2010 to June 2012, 202 pts were enrolled from 32 institutions. Patient characteristics were well balanced between both groups. OS was measured after a median follow-up of 13.5 months. Median PFS was 3.6 and 3.0 months with AMR and DTX, respectively (adjusted Hazard Rate (HR) 0.96, 95% Confidence Interval (CI) 0.69–1.34, p = 0.831). Median OS was 14.6 and 13.5 months with AMR and DTX, respectively (adjusted HR 1.02, 95% CI 0.72–1.43, p = 0.933). ORR was 14.8% and 18.8% with AMR and DTX, respectively (p = 0.544). DCR was 55.7% for both AMR and DTX (p = 1.000). The most frequent adverse events (≥grade 3) for AMR and DTX were neutropenia (82.7% and 78.8%, respectively) and leukopenia (63.3% and 70.7%, respectively). Two treatment-related deaths occurred in the DTX arm: a case of interstitial pneumonia and another of drowning in a bath. Conclusions: We were not able to demonstrate superiority of AMR over DTX for PFS, despite the 20-day PFS prolongation. Our results suggest that AMR may become a treatment option for patients with previously treated NSCLC. Disclosure: All authors have declared no conflicts of interest.