Toshiaki Fujikane

Increased vascular endothelial growth factor in acute eosinophilic pneumonia

Acute eosinophilic pneumonia (AEP) is associated with the presence of diffuse pulmonary infiltrates on the chest radiograph and an increased number of eosinophils and an elevation of interleukin (IL)‐5 levels in bronchoalveolar lavage (BAL) fluid. Vascular endothelial growth factor (VEGF) is a constitutively expressed protein encoded by messenger ribonucleic acid in human eosinophils and is released following stimulation with IL‐5. However, the roles of IL‐5 and VEGF in the pathogenesis or activity of this disease have not been clarified. The authors investigated the cells and the levels of these two factors in BAL fluid in five AEP patients and five normal controls before and after corticosteroid treatment. The absolute number of eosinophils·mL−1, IL‐5 and VEGF levels in patients before treatment were higher than in controls (53.8 versus 0.3×104·mL−1, 490.1 versus 5.2 pg·mL−1 and 643.0 versus 133.9 pg·mL−1, respectively). IL‐5 and VEGF rapidly decreased to the control level in parallel with clinical improvement. The relationship between eosinophilia and IL‐5 and VEGF levels was strongly significant. Elevated interleukin‐5 in the lung may initiate the recruitment of eosinophils and enhance the release of mediators, such as vascular endothelial growth factor from eosinophils, which, in turn, increases the permeability of blood vessels.

A Phase III Comparison of Etoposide/Cisplatin with or without Added Ifosfamide in Small-Cell Lung Cancer

A total of 92 patients with small-cell lung cancer (SCLC) were randomized to receive cisplatin (80 mg/m2, day 1)/etoposide (100 mg/m2, days 1, 3, 5) (PE) or cisplatin (80 mg/m2, day 1)/etoposide (100 mg/m2, days 1, 3, 5)/ifosfamide (2 g/m2, days 1, 2, 3) (PEI) combination chemotherapy. After 2 courses of chemotherapy, patients with limited disease (LD) received chest irradiation of 40-50 Gy. Of the 89 patients who could be wholly evaluated, the overall response rate was 78% for PE and 74% for PEI therapy (NS). For all patients the complete response (CR) rates were 14 versus 21%, respectively, and 22 versus 30% for LD. However, the median survival times for all patients were 55 weeks for PE therapy versus 56 weeks for PEI therapy (NS). The 2-year survival rates were 15 and 17%, respectively, for all patients (NS). There was no difference in the duration of response between PE and PEI therapy in cases with CR or partial response. However, severe leukopenia (< 2,000/mm3) occurred more often after PEI (73%) than after PE (44%) therapy (p < 0.05). These results suggest that PEI is not superior to PE chemotherapy in SCLC. The use of ifosfamide in multimodality treatment regimens needs to be studied further.

Analysis of chest CT in patients with Mycobacterium avium complex pulmonary disease.

Background: The radiographic changes of Mycobacterium avium complex (MAC) pulmonary disease during therapy have not been studied well. Objective: To assess the efficacy of antituberculous drug therapy against MAC pulmonary disease using computed tomography (CT). Method: We analyzed chest CT scans before and after antituberculous therapy in 30 patients (21 women, 9 men) with MAC pulmonary disease. To evaluate radiographic changes during therapy, we defined a ‘degree of improvement’ (DI) that is calculated according to the CT appearance. Results: DI was better (1.35 ± 0.21) in patients who had converted sputum culture than in those who had not (0.44 ± 0.25) (p < 0.05). In patients who were diagnosed by bronchial washing, DI was better (1.60 ± 0.22) than in patients who were diagnosed by sputum (0.67 ± 0.20) (p < 0.01). We categorized the CT appearance into 6 types: small nodules, cavities, bronchial wall thickening, infiltration, pleural thickening and atelectasis. Patients who showed pleural thickening had a significantly worse DI (0.12 ± 0.40) than those who did not (1.23 ± 0.18) (p < 0.01). Most of the lesions that disappeared after therapy were small nodules. Conclusion: These results indicate that chest CT might be a useful tool for the prediction or assessment of drug therapy for MAC pulmonary disease.

Pentoxifylline Potentiates the Antitumor Effect of Cisplatin and Etoposide on Human Lung Cancer Cell Lines

The effect of pentoxifylline (PENT) on the sensitivity of two human lung adenocarcinoma cell lines, PC-9 and PC-14, to cisplatin (CDDP) and etoposide (ET) was studied. PENT at 0.5 and 1 mM enhanced the cytotoxicity of CDDP and ET on PC-14 and PC-9, respectively. Isobologram analyses of IC50 data, as well as combination index calculations, revealed that PENT had an additive or a synergistic effect when applied in combination with CDDP or ET, respectively. PENT potentiated the antitumor effect of ET in a nude-mouse xenograft model using PC-14 cells, when PENT was administered at 150 mg/kg subcutaneously for 6 days. Flow cytometry revealed that PENT decreased the accumulation of cells in the G2+M phase caused by CDDP when using PC-9 cells. However, PENT did not remarkably alter the accumulation of cells in G2+M caused by ET. These results suggest that PENT enhanced the antitumor effects of CDDP additively and those of ET synergistically. The enhancement mechanism probably differs between CDDP and ET. PENT needs more study to elucidate its potency as a new agent for combination chemotherapy.

Increased serum level of vascular endothelial growth factor in Mycobacterium avium complex infection.

Objective:  Pulmonary infection caused by Mycobacterium avium complex (MAC) is one of the granulomatous diseases which are associated with the expression of vascular endothelial growth factor (VEGF). The aim of the present study was to clarify the association of VEGF with the pathogenesis of MAC infection.

Evaluation of a Quantitative Serological Assay for Diagnosing Chronic Pulmonary Aspergillosis

ABSTRACT The purpose of this study was to evaluate the clinical utility of a quantitative Aspergillus IgG assay for diagnosing chronic pulmonary aspergillosis. We examined Aspergillus-specific IgG levels in patients who met the following criteria: (i) chronic (duration of >3 months) pulmonary or systemic symptoms, (ii) radiological evidence of a progressive (over months or years) pulmonary lesion with surrounding inflammation, and (iii) no major discernible immunocompromising factors. Anti-Aspergillus IgG serum levels were retrospectively analyzed according to defined classifications. Mean Aspergillus IgG levels were significantly higher in the proven group than those in the possible and control groups (P < 0.01). Receiver operating characteristic curve analysis revealed that the Aspergillus IgG cutoff value for diagnosing proven cases was 50 mg of antigen-specific antibodies/liter (area under the curve, 0.94; sensitivity, 0.98; specificity, 0.84). The sensitivity and specificity for diagnosing proven cases using this cutoff were 0.77 and 0.78, respectively. The positive rates of Aspergillus IgG in the proven and possible groups were 97.9% and 39.2%, respectively, whereas that of the control group was 6.6%. The quantitative Aspergillus IgG assay offers reliable sensitivity and specificity for diagnosing chronic pulmonary aspergillosis and may be an alternative to the conventional precipitin test.

The effect of suramin on human lung cancer cell line in vitro

Recently, several investigators reported the effects of suramin, a drug used in the treatment of trypanosomiasis, onchocerciasis, and an inhibition of the binding of some growth factors to cell surface receptors. In present study, therefore, we examined the effects of epidermal growth factor(EGF) and suramin on cell proliferation and cell cycle kinetics of an established cell line from human lung cancer(PC-13). EGF showed a stimulatory effect on cell proliferation of PC-13, suggesting EGF behaves as a growth factor of PC-13. On the other hand, suramin inhibited the stimulatory effect of EGF to PC-13 in a dose dependent manner. In addition, it was also observed that suramin inhibits the cell cycle progression from G0/G1 phase to S phase. These results indicate that suramin may withhold the cell proliferation and cell growth via suppression of the EGF cell stimulatory effects.

Rikkunshito for Preventing Chemotherapy-Induced Nausea and Vomiting in Lung Cancer Patients: Results from 2 Prospective, Randomized Phase 2 Trials

The herbal medicine rikkunshito has the potential to improve chemotherapy-induced nausea and vomiting (CINV) by stimulating ghrelin secretion. We aimed to evaluate the efficacy and safety of rikkunshito in preventing CINV for patients with lung cancer. Two separate prospective, randomized, phase II parallel design studies were conducted in patients with lung cancer. Fifty-eight and sixty-two patients scheduled to receive highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC), respectively, were randomized 1:1 to receive either standard antiemetic therapy in accordance with international guidelines (S group) or standard antiemetic therapy plus oral rikkunshito (R group). The primary endpoint was overall complete response (CR)—that is, no emesis and rescue medication in the first 120 h post-chemotherapy. Secondary endpoints included CR in the acute (0–24 h) and delayed (>24–120 h) phases and safety. Fifty-seven patients (S group, 28; R group, 29) receiving HEC and sixty-two patients (S group, 30; R group, 32) receiving MEC with comparable characteristics were evaluated. The CR rates were similar across the S and R groups for the HEC study in the overall (67.9% vs. 62.1%), acute (96.4% vs. 89.6%), and delayed (67.9% vs. 62.1%) phases, respectively, and for the MEC study in the overall (83.3% vs. 84.4%), acute (100% vs. 100%), and delayed (83.3% vs. 84.4%) phases, respectively. No severe adverse events were observed. Although rikkunshito was well tolerated, it did not demonstrate an additional preventative effect against CINV in lung cancer patients receiving HEC or MEC. Clinical Trial Registry Information: This study is registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry1, identification numbers UMIN 000014239 and UMIN 000014240.

Abstract 903: Long-term survivors in advanced non-small cell lung cancer

Background: It is known that chemotherapy for advanced non small-cell lung cancer (NSCLC) improves the prognosis, however, with regard to 2-year survival rate of inoperable stage III/IV patients is up to 20%. The contribution of chemotherapies for survival is not fully satisfied yet. Purpose: The aim of this study is to evaluate the rate of long-term survival of more than 2 years in patients with advanced NSCLC and elucidate clinical factors that affect long-term survival in those patients. Methods: We retrospectively reviewed 103 patients with inoperable, stage III/IV NSCLC treated with chemotherapy from January 2005 to December 2006 at Dohoku National Hospital. These included 69 adenocarcinomas, 22 squamous cell carcinomas, 9 large cell carcinomas and 3 others. These patients were divided into two groups: those who survived more than 2 years (long-term survivors; LTS) and the others (non long-term survivors; non LTS). We analyzed the prognostic factors that affect the survival in this setting. The difference of characteristics between two groups was tested with the Mann-Whitney U test, the chi-square test or Fisher9s exact test. Survival curves were calculated according to Kaplan-Meier method. The correlations of variables with survival were analyzed by multivariate analysis using a Cox proportional hazards model. Results: There were 27 (26.2%) patients who survived more than 2 years (LTS). All of them had performance status (PS) 0 or 1. These LTS included 13 females, 11 non-smoker, 21 adenocarcinomas and 17 stage IV disease. LTS showed significant correlation with gender, smoking status, intrapulmonary metastases, response of 1st-line chemotherapy (SD or better), and response of gefitinib (SD or better) (p=0.0008, p=0.0457, p=0.0317, p=0.0004 and p=0.0026, respectively). Patients who respond to initial chemotherapy (SD or better) as well as gefitinib showed favorable course. Univariate analyses showed that PS 0-1, intrapulmonary metastases, response of 1st-line chemotherapy (SD or better), response of gefitinib (SD or better) were significantly associated with better prognosis (p=0.0036, p=0.0203, p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 903.

Immunohistochemical Analysis of bcl-2 and p53 Protein Expresion in Non-Small Cell Lung Cancers with Reference to Histological Type and Pathological Stage.

原発性非小細胞肺癌手術例299例を対象としてbcl-2蛋白およびp53蛋白の発現と予後との関連を免疫組織化学的に検討した. 299例中, 64例 (21.4%) がbcl-2蛋白, 149例 (49.8%) がp53蛋白陽性であった. bcl-2蛋白およびp53蛋白の陽性率はいずれも腺癌に比し扁平上皮癌で高かった. 病理病期ではbcl-2蛋白の陽性率はIII, IV期に比べI, II期で高かった (p=0.032). 生存率はbcl-2蛋白陽性例は陰性例に比べ高く (p=0.012), p53蛋白陽性例が陰性例に比べ低かった (p=0.021). 病期別の検討ではI, II期ではbcl-2蛋白陽性例で有意に生存率が高かった (p=0.033). 組織型と生存率との関連では, 腺癌ではp53蛋白陰性例が, 扁平上皮癌ではbcl-2蛋白陽性例がいずれも有意 (それぞれp=0.012, p=0.012) に生存率が高かった. 腺癌におけるp53蛋白の発現, 扁平上皮癌におけるbcl-2蛋白の発現が予後因子として有用と考えられた.