A prospective cohort study of patients with non-squamous non-small cell lung cancer treated with bevacizumab.

First-line chemotherapy regimens that include bevacizumab (Bev) have been hypothesized to improve outcomes in patients with advanced non-squamous non-small cell lung cancer (non-sq NSCLC). Although approved to treat NSCLC in 2009, insufficient data exist on the clinical uses of Bev in Japan. The present study prospectively evaluated the efficacy and safety of Bev-containing combination chemotherapy. Eligible patients exhibited histologically or cytologically documented advanced or recurrent non-sq NSCLC. Patients were administered 15 mg/kg Bev with standard chemotherapy followed by maintenance Bev. The primary endpoints were progression-free survival (PFS) and safety. A total of 102 patients with non-sq NSCLC were enrolled, 44.1% of whose tumor carried epidermal growth factor receptor (EGFR) mutations. The overall response rate to the intervention was 44.1%, and the median PFS was 8.3 months [95% confidence interval (CI)=6.4-10.2 months]. The median overall survival was 26.3 months (95% CI=22.2-30.4 months). The incidence of Bev-associated severe adverse events was similar to those in previous trials, excluding a grade 3-4 hypertension rate of 30.4% in the present study. Multivariate analysis revealed that a higher TNM classification of malignant tumor staging-T factor, adjusted hazard ratio (HR)=1.33 (95% CI=1.10-1.61), and poor performance status [adjusted HR=1.63 (1.02-2.60)] were associated with significantly shorter PFS, whilst the EGFR exon 19 deletion was significantly associated with prolonged PFS [adjusted HR=0.47 (0.25-0.87)]. Bev-containing chemotherapy was safe and effective for patients with non-sq NSCLC in clinical settings in Japan. The EGFR exon 19 deletion was suggested as a positive predictive factor for the efficacy of Bev-containing chemotherapy.

Enhancement of 5-fluorouracil-induced cytotoxicity by leucovorin in 5-fluorouracil-resistant gastric cancer cells with upregulated expression of thymidylate synthase.

BACKGROUND: Elucidation of the mechanisms by which gastric cancer cells acquire resistance to 5-fluorouracil (5FU) may provide important clues to the development of effective chemotherapy for 5FU-resistant gastric cancer METHODS: Four 5FU-resistant cell lines (MKN45/5FU, MKN74/5FU, NCI-N87/5FU, and KATOIII/5FU) were established by continuous exposure of the cells to progressively increasing concentrations of 5FU for about 1 year. Then, mRNA expression levels of four genes associated with 5FU metabolism, i.e., thymidylate synthase (TS), dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase, were quantitatively evaluated by real-time reverse transcriptase-polymerase chain reaction. In addition, TS protein expression was measured by Western blot analysis. RESULTS: As compared with the parent cell lines, the 5FU-resistant cell lines showed 3.8- to 11.6-fold higher resistance to 5FU, as well as 1.9- to 3.5-fold higher TS mRNA expression and 1.6- to 7.1-fold higher TS protein expression. In contrast, the expressions of other genes did not differ significantly among the cell lines. The cytotoxicity of 5FU was enhanced 2.3- to 2.8 fold by leucovorin (LV) against three of the four 5FU-resistant cell lines. CONCLUSIONS: Collectively, LV enhanced the cytotoxicity of 5FU not only against the parent gastric cancer cell lines, but also against the 5FU-resistant cell lines, even those with elevated TS expression levels. These results suggest that clinical studies of a combination of 5FU and LV are warranted in patients who have recurrent gastric cancer after 5FU-based therapy.

[Results of questionnaire on decision-making to treat advanced non-small cell lung cancer based on American and European practical guidelines].

During 2009, practical routine guidelines for advanced non-small cell lung cancer used in Europe or USA were updated because the clinical benefits of molecular target agents were confirmed through several pivotal clinical trials. These molecular target agents appeared in guidelines which became available in Japan by the end of 2009. We made a questionnaire for decision-making to treat advanced non-small cell lung cancer based on these practical guidelines. Oncologists of lung cancer working in the Shinjuku area of Tokyo in Japan were eligible. Between March 15th and April 9th in 2010, 28 oncologists from 12 departments in 7 hospitals completed this questionnaire. Most of them made the global standard decision-making according to the new guidelines, including new proposals such as usage of epidermal growth factor receptor-tyrosine kinase inhibitors. There were 3 differences from the guidelines. 1)Platinum doublets were selected even in 2nd- or 3rd-line treatment because of the expected tumor shrinkage. 2)Single cytotoxic agents were selected even for 3rd-line treatment. The tendency of a backward shift in decision-making was observed. 3)There were few selections of regimens including bevacizumab because of medical systems such as DPC(Diagnosis Procedure Combination)that is Japanese DRG(Diagnosis-Related Group)/PPS(Prospective Payment System).

[The efficacy of indisetron hydrochloride for the management of chemotherapy-induced nausea and vomiting for lung cancer].

We set out to determine the efficacy of indisetron hydrochloride for the management of chemotherapy-induced nausea and vomiting including carboplatin for lung cancer. Indisetron hydrochloride was given orally to 32 patients (indisetron group), and intravenous 5-HT3 receptor antagonists were given to 24 patients (control group). The number of patients with nausea or vomiting occurring within 24 hours and 24 to 72 hours after chemotherapy was measured. The complete inhibition of the vomiting within 24 hours after chemotherapy was 100% in the indisetron group and 95.8% in the control group. Twenty-four to 72 hours after chemotherapy, the complete inhibition of vomiting rate was 97.1% and 95.8%, respectively. In addition, the complete inhibition of nausea rate within 24 hours after chemotherapy was 87.5% in the indisetron group and that was 95.8% in the control group. The complete inhibition of nausea rate 24 to 72 hours after chemotherapy was 56.3% and 70.8%, respectively. No serious adverse events were observed. The comparison of the efficacy between the indisetron group and control groups did not reach statistical significance (p> 0.05). These findings suggest that prophylactic administration of indisetron hydrochloride is useful for the inhibition of acute and delayed nausea and vomiting caused by chemotherapy in lung cancer patients.

[Drug-induced pneumonia that may have been caused by imatinib mesylate administered for gastrointestinal stromal tumor].

The patient was a 64-year-old woman who had undergone partial enterectomy for a small intestinal tumor in August 2005, and gastrointestinal stromal tumor (GIST) was diagnosed. Administration of imanitib mesylate was initiated as postoperative chemotherapy in November 2005. In February 2006, a slight ground-glass opacity was noted in the right lower lobe on chest CT. In April, cough and dyspnea appeared, and non-segmental reticular ground-glass opacity was noted in bilateral lung fields. Drug-induced pneumonia associated with imatinib mesylate was suspected based on the clinical course, and administration of imatinib mesylate was discontinued. Oral administration of 30mg prednisolone was initiated, and the symptoms and shadows on X-ray films improved. The steroid dose was gradually reduced, and recovery of the patient was smooth. Imatinib mesylate is anticipated to be a good potential therapeutic drug for interstitial pneumonia because it blocks PDGF receptors. However, the risk of imatinib-induced interstitial pneumonia should be noticed.

[Acute form of eexogenous lipoid pneumonia caused by inhalation of liquid paraffin in a fire-eater].

We report a case of acute exogenous lipoid pneumonia in a 34-year-old-fire-eater. Six hours after inhalation of liquid paraffin, dyspnea, cough, fever, hemoptysis, and chest pain developed in this patient. Chest computed tomography showed nodular infiltrations with ground glass opacities (GGO) in the right middle lobes, GGO alone in the right lower lobes, and consolidations with GGO in the left lower lobes. Lipid-laden alveolar macrophages in bronchoalveolar lavage fluid were detected by lipid staining (Sudan III stain, oil-red-O stain) and transmission electron microscopy. The symptoms and lung infiltrations were improved by treatment with predonisolone, together with antibiotics and urinastatin.