Masanao Nakashima

Prognostic significance of the maspin tumor suppressor gene in pulmonary adenocarcinoma

Purpose Maspin is a member of the serpin family and has tumor suppressor activity. We evaluated maspin expression in pulmonary adenocarcinoma in relation to a number of clinicopathological features.Methods Maspin expression was examined immunohistochemically in a series of 78 pulmonary adenocarcinomas by the EnVision ChemMate method.Results Thirty-seven of 78 cases (47%) showed distinct maspin expression (maspin-positive group) and 41 (53%) did not (maspin-negative group). Maspin expression was not associated significantly with most clinicopathological variables including sex, age, tumor size, primary tumor, lymph node metastasis, visceral pleural invasion, pulmonary metastasis, and disease stage. However, the maspin-positive group had a better 5-year survival rate (62%) than did the maspin-negative group (42%). The difference in the 5-year survival rate was greatest in stage II patients (maspin-positive group, 69%; maspin-negative group, 17%; P = 0.048).Conclusion Our data indicate that maspin has prognostic significance for pulmonary adenocarcinoma. A better understanding of the role of maspin in tumor suppression may be helpful for development of novel chemotherapies for patients with this deadly tumor.

Patient satisfaction with sedation for flexible bronchoscopy

Background and objective:  Patient satisfaction with health care has increasingly been recognized as an important health outcome, but few studies have examined patient satisfaction with flexible bronchoscopy (FB). The purpose of this study was to assess patient satisfaction with FB conducted under conscious sedation and to identify the aspects of the procedure related to patient satisfaction.

Phase II trial of the combination of carboplatin and irinotecan in elderly patients with small-cell lung cancer

AIM The aim of the present phase II study was to assess the antitumour activity and safety of the combination of irinotecan and carboplatin in elderly patients with small-cell lung cancer (SCLC). MATERIAL AND METHODS Patients with previously untreated SCLC were eligible if they had a performance status of 0-2, were 70 years or older, and had adequate organ function. Patients were treated with carboplatin at an area under the plasma concentration versus time curve of 5 min/ml on day 1 and with irinotecan at 50mg/m(2) on days 1 and 8 every 3 weeks. RESULTS Thirty patients (26 men and 4 women; median age, 76 years; age range, 70-86 years) were enrolled. Eight patients had limited disease (LD) and 22 patients had extensive disease (ED). The overall response rate was 83.3% (95% confidence interval: 65.3-94.4%). Response rates did not differ significantly between patients with LD (87.5%) and those with ED (81.8%; p=0.71). The median survival time was 14 months overall and was significantly longer in patients with LD (26 months) than in patients with ED (11 months; p=0.025). The median progression free survival time was 6 months overall and was significantly longer in patients with LD (12 months) than in patients with ED (6 months; p=0.016). Grade 3-4 toxicities included neutropenia in 83% of patients, thrombocytopenia in 47%, anaemia in 60%, infection in 23%, and diarrhoea in 20%. There were no treatment-related deaths. CONCLUSIONS This chemotherapy is safe and effective for elderly patients with SCLC.

Phase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer.

Amrubicin is a novel, totally synthesized anthracycline derivative, and has antitumor activity against several human tumor xenografts. The combination of amrubicin with platinum derivative showed additive effect against a human small-cell lung cancer (SCLC) cell line. Until now, the combination of amrubicin plus carboplatin has not been studied in patients with previously treated SCLC. Therefore, we examined the safety and efficacy of the combination of amrubicin plus carboplatin in patients with sensitive or refractory relapsed SCLC. Patients with previously treated SCLC were eligible if they had a performance status of 2 or less, were 75 years or younger, and had adequate organ function. Twenty-five patients were enrolled (21 men and 4 women; median age, 65 years; age range 55-73 years). Patients received the combination of amrubicin (30 mg/m(2) on days 1-3) plus carboplatin (with a target area under the concentration-versus-time curve of 4 mg min/ml using the Calvert formula on day 1) every 3 weeks. The overall response rate was 36.0% (95% confidence interval [CI], 18.0-57.5%). Response rates differed significantly between patients with sensitive relapse (58.3%; 95% CI, 27.7-84.8%) and those with refractory relapse (15.4%; 95% CI, 1.9-15.4%; p=0.03). The median survival time (MST) from the start of this treatment was 7 months (range: 1-42 months); the MST of patients with sensitive relapse (10 months) was significantly longer than that of patients with refractory relapse (5 months: p=0.004). The median progression-free survival (PFS) time was 3 months (range: 1-14 months): the median PFS time of patients with sensitive relapse (5 months) was significantly longer than that of patients with refractory relapse (2 months; p=0.01). The most frequent grade 3-4 toxicity was myelosuppression, especially neutropenia, which developed in 88% of patients. Grade 3-4 thrombocytopenia developed in 44% of patients, and anemia developed in 56%. Nonhematologic toxicities were generally mild to moderately severe and temporary. None of the patients had cardiotoxicity. In conclusion, this therapy is effective and well tolerated for previously treated SCLC.

Association of pharmacokinetics and pharmacogenomics with safety and efficacy of gefitinib in patients with EGFR mutation positive advanced non-small cell lung cancer.

OBJECTIVES Gefitinib is a potent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and is a key drug for patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). The pharmacokinetics of orally administered gefitinib varies greatly among patients. We prospectively evaluated the association of pharmacokinetics and pharmacogenomics with the safety and efficacy of gefitinib in patients with EGFR mutation-positive advanced NSCLC. PATIENTS AND METHODS Pharmacokinetics was evaluated with samples of peripheral blood obtained on day 1 before treatment and 1, 3, 5, 8, and 24h after gefitinib (250 mg per day) was administered and on days 8 and 15 as the trough values. The plasma concentration of gefitinib was analyzed with high-performance liquid chromatography. The genotypes of ABCG2, ABCB1, CYP3A4, CYP3A5, and CYP2D6 genes were analyzed with direct sequencing. RESULTS The subjects were 35 patients (21 women; median age, 72 years; range, 53 to 90 years) with stage IV adenocarcinoma harboring EGFR mutations. The median peak plasma concentration (Cmax) was 377 (range, 168-781)ng/mL. The median area under the curve (AUC) of the plasma concentration of gefitinib from 0 to 24h was 4893 (range, 698-13991) ng/mL h. The common adverse events were skin toxicity (68% of patients), diarrhea (46%), and liver injury (63%). One patient died of drug-induced interstitial lung disease (ILD). The overall response rate was 82.9% (95% confidence interval, 66.4%-93.4%). The median progression-free survival time was 10 months, and the median survival time was 25 months. The pharmacokinetics and pharmacogenomics were not associated with significantly different toxicities, response rates, or survival times with gefitinib. However, the AUC and Cmax were highest and the trough value on day 8 was the second highest in one patient who died of drug-induced ILD. CONCLUSION Elevated gefitinib exposure might be associated with drug-induced ILD.

Evaluation of the Efficacy and Safety of the Combination of Gemcitabine and Nedaplatin for Elderly Patients with Advanced Non-Small-Cell Lung Cancer

Objective: The aim of the present study was to retrospectively assess the safety and efficacy of the combination of gemcitabine and nedaplatin in elderly patients with advanced non-small-cell lung cancer (NSCLC). Methods: Patients ≧75 years with previously untreated NSCLC who underwent chemotherapy consisting of gemcitabine (800 mg/m2 on days 1 and 8) and nedaplatin (80 mg/m2 on day 1) every 3 weeks were retrospectively analyzed. Results: Of the 35 patients, 28 were men and 7 were women, with a mean age of 78 years (range 75–87); 10 patients had stage IIIB disease and 25 patients had stage IV disease. The overall response rate was 45.7% (95% confidence interval 28.8–63.4). The median survival time was 14 months (range 3–44). Grade 3–4 toxicities included neutropenia in 74.3%, thrombocytopenia in 48.6%, anemia in 34.3%, hepatic dysfunction in 11.4%, and infection in 2.9%. There were no treatment-related deaths. There were no differences in response rate and survival between patients aged 75–79 years and patients ≧80 years, although grade 3–4 thrombocytopenia and anemia were significantly more frequent in patients ≧80 years. Conclusion: Our results suggest that the combination of gemcitabine and nedaplatin is effective and well tolerated for selected elderly patients with advanced NSCLC.

Cytopathologic and Histologic Features of Biphasic Pulmonary Blastoma

Background Biphasic pulmonary blastoma is a rare malignant neoplasm of debatable histogenesis. Although well described histologically, it is scarcely mentioned in the cytologic literature. Case A 78-year-old man reporting intermittent hemoptysis was admitted to the hospital. Chest radiography revealed a right-sided pulmonary mass. Cytologic examination of tumor specimens revealed 2 types of malignant cells. The smears were highly cellular, with a necrotic background. The stromal cells had predominantly round to ovoid or spindle-shaped nuclei and scant cytoplasm, and the nucleoli had slightly irregular borders with coarsely aggregated chromatin. The epithelial cells were arranged in sheets and glandular configurations. The cytoplasm of these cells was finely vacuolated or foamy, with indistinct cellular boundaries; eccentrically located nuclei were hyperchromatic and had irregularly shaped nucleoli. The cell block preparation showed a distinctly biphasic malignant tumor with the classic morphologic features of pulmonary blastoma. Conclusion A preoperative diagnosis of pulmonary blastoma is difficult to obtain by cytopathologic methods. A diagnosis of biphasic pulmonary blastoma should be considered whenever epithelial cells and a separate population of stromal cells are seen in a pulmonary exfoliative cytology specimen.

Immunohistochemical evaluation of tissue-specific proteolytic enzymes in adenomas containing foci of early carcinoma: correlations with cathepsin D expression and other malignant features.

Background: Cathepsin D (CD) is an aspartyl lysosomal protease, and the prognostic value of CD expression has been studied in a variety of tumors, however, its role in early adenocarcinomas remains unclear.Aim of the Study: We evaluated the expression of CD in a series of colorectal adenomas with severe dysplasia containing foci of early carcinoma and compared the results to several histopathological and immunohistochemical features.Methods: Adenomas were obtained by endoscopic polypectomy from 33 patients. Twenty-four of the 33 adenomas contained well-differentiated adenocarcinomas and nine adenomas contained moderately differentiated adenocarcinomas.Results: Positive CD expressions were observed in 25% of well-differentiated adenocarcinomas and in 66.7% of moderately differentiated adenocarcinomas (p<0.05). Of the 12 adenocarcinomas with positive CD expression, four had positive CD expression in their adenomas (p<0.01), 6 showed positive Ki-67 expression in their adenomas (NS), and 10 had positive p53 expression in their adenomas (p<0.05). No significant association was seen between the level of CD expression and adenoma size.Conclusions: The expression of CD in adenocarcinoma correlated significantly with differentiation, and with the levels of CD and p53 expression in the adenomas of the polyp.

Pneumonia induced by eribulin mesylate in a patient with recurrent breast cancer

A 48-year-old woman with breast cancer overexpressing human epidermal growth factor receptor type 2 was given eribulin mesylate, which induced pneumonia. Drug-induced pneumonia related to eribulin mesylate was diagnosed on the basis of clinical and radiographic findings and a positive reaction in the drug-induced lymphocyte stimulating test. The symptoms and radiographic findings improved without corticosteroid therapy. Careful attention should be paid to the possible signs and symptoms of lung injury in patients who receive eribulin mesylate or other chemotherapeutic agents.

Abstract 1208: Combination effect of afatinib and BI836845, a humanized IGF ligand-neutralizing antibody, on EGFR-TKI-resistant NSCLC cells

Insulin-like growth factor (IGF) signaling is thought to have a role in the cancer progression and survival, and many carcinomas are known to overexpress IGF-1 receptor (IGF1R). Furthermore, it was clarified that IGF1R signaling contributes to EGFR-TKI resistance in NSCLC. IGF1R is thought to be a therapeutic target for cancer chemotherapy. Previously, we screened the combination effect of afatinib and various anticancer drugs on a panel of NSCLC cell lines including gefitinib-resistant and afatinib-resistant PC-9 cells which we established. As the result, the combination of afatinib and small molecule IGF1R-TKIs (BMS754807, NVP-ADW742) has shown the most cytotoxicity on wide variety cancer cells. However, these IGF1R-TKIs have cross-reactivity to insulin receptor and, as a result, are known to cause hyperglycemia. Moreover, a phase III trial of the combination chemotherapy between erlotinib and IGF1R specific antibody, figitumumab, in advanced nonadenocarcinoma NSCLC patients (ADVIGO 1018)was closed early because of futility and an increased incidence of serious adverse events. BI836845 is a humanized IGF ligand-neutralizing antibody which is neutralizing both IGF-1 and IGF-2. The proliferation of several cell lines was reported to be potently inhibited by BI 836845 with lower than 100 μg/ml EC50 values. This antibody is thought to be a substitute approach to inhibit IGF1R signaling pathway other than previous IGF1R-TKIs. We evaluated the combination effect of afatinib and BI836845 on the same NSCLC panel by MTS assay. BI836845 had only a limited cytotoxicity by itself. The combination of afatinib and BI836845 had additive or synergistic cytotoxicity on most of the NSCLC cell lines including EGFR-TKIs-resistant cells except the cells overexpressing c-Met or expressing K-ras mutation. This combination significantly inhibited both EGFR and IGF1R autophosphorylation and their downstream signaling, especially Akt/mTOR pathway, as compared with each singular usage. These combination effects were attenuated when BI836845 combined with erlotinib. Since BI836845 cross-react to rodent IGFs, we examined pharmacological activity of this combination using SCID mice xenograft mode. The mice bearing tumor were given 6 mg/kg afatinib (5 times/week, p.o.) and 200 mg/kg BI836845 (1 time/week, i.p.) for 8 weeks. This combination synergistically inhibited afatinib-resistant tumor (PC-9Afa1, PC-9Afa2) and gefitinib-resistant tumor (PC-9ZD, expressed T790M mutant EGFR). This BI836845 administration completely inhibited IGFs activity in the mice serum without alteration of blood sugar level and insulin concentration. Though growth rate of the treated mice was slightly reduced, body weight loss and other serious adverse events were not observed. From these observations, this combination chemotherapy is thought to be a potential therapeutic strategy for NSCLC. Citation Format: Tohru Ohmori, Toshimitsu Yamaoka, Satoru Arata, Motoi Ohba, Yasunori Murata, Yasunari Kishida, Sojiro Kusumoto, Masanao Nakashima, Takashi Hirose, Tsukasa Ohnishi, Kazuto Nishio. Combination effect of afatinib and BI836845, a humanized IGF ligand-neutralizing antibody, on EGFR-TKI-resistant NSCLC cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1208.