Phase II trial of daily S-1 combined with weekly irinotecan in previously treated patients with advanced or recurrent squamous cell lung cancer: North Japan lung cancer group 1101.

BACKGROUND: This phase II trial was designed to evaluate the efficacy and safety of S-1 combined with weekly irinotecan as a second- or third-line treatment for patients with advanced or recurrent squamous cell lung cancer. METHODS: Patients with a body surface area <1.25, 1.25-1.50, and >1.50 m2 received oral S-1 on days 1-14 at 80, 100, and 120 mg/day, respectively, and irinotecan on days 1 and 8 at 70 mg/m2 every 3 weeks. The primary endpoint was the overall response rate, and the secondary endpoints were progression-free survival, overall survival, and the incidence and severity of adverse effects. RESULTS: Between September 2011 and December 2014, 30 patients were enrolled in this study. The overall response rate was 6.7% (95% confidence interval [CI]: 0.8%-22.1%), and the disease control rate was 73.3%. The median progression-free survival was 3.0 months (95% CI: 2.5-3.4 months), and the median overall survival was 10.5 months (95% CI: 5.6-13.7 months). Grade 3/4 treatment-related adverse events were reported in ≥10% of the patients, including leukopenia (21%), neutropenia (21%), anemia (17%), anorexia (10%), and hypokalemia (10%). CONCLUSIONS: Although the treatment-related adverse events were manageable, the combination of weekly irinotecan and S-1 did not have the expected effect.

Clinical Significance of Tumor Markers for Advanced Thymic Carcinoma: A Retrospective Analysis from the NEJ023 Study.

The optimal tumor marker for predicting the prognosis of advanced thymic carcinoma (ATC) remains unclear. We conducted a multi-institutional retrospective study of patients with ATC. A total of 286 patients were treated with chemotherapy. Clinicopathological information, including serum tumor markers, was evaluated to determine the overall survival (OS) and progression-free survival (PFS). The carcinoembryonic antigen, cytokeratin-19 fragment, squamous cell carcinoma (SCC) antigen, progastrin-releasing peptide, neuron-specific enolase (NSE), and alpha-fetoprotein levels were evaluated. In the Kaplan-Meier analysis, the OS was significantly shorter in the patients with elevated NSE levels than in those with normal NSE levels (median, 20.3 vs. 36.8 months; log-rank test p = 0.029; hazard ratio (HR), 1.55; 95% confidence interval (CI), 1.05-2.31 (Cox proportional hazard model)); a similar tendency regarding the PFS was observed (median, 6.4 vs. 11.0 months; log-rank test p = 0.001; HR, 2.04; 95% CI, 1.31-3.18). No significant differences in the OS and PFS were observed among the other tumor markers. In both univariate and multivariate analyses of the patients with SCC only, the NSE level was associated with the OS and PFS. Thus, the NSE level may be a prognostic tumor marker for thymic carcinoma, regardless of histology.

Phase I Study Evaluating the Combination of Afatinib with Carboplatin and Pemetrexed After First-line EGFR-TKIs.

BACKGROUND/AIM: Promising reports have described the combination of first-generation epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) with carboplatin plus pemetrexed or bevacizumab. However, no analysis of afatinib with platinum-doublet chemotherapies has been performed. PATIENTS AND METHODS: We evaluated the safety and antitumor efficacy of afatinib combined with carboplatin and pemetrexed in EGFR-mutated non-small-cell lung cancer (NSCLC) patients who progressed during first-generation EGFR-TKIs. RESULTS: Ten patients received 20 or 30 mg/day afatinib with carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2). Dose-limiting toxicities included delay of afatinib ≥14 days, grade 3 diarrhea, grade 3 hypokalemia, grade 3 serum amylase increase and grade 4 thrombocytopenia. The recommended dose of afatinib was 20 mg/day in this combination therapy. Overall response rate was 30% and median progression-free survival was 13.7 months. CONCLUSION: This is the first study to investigate the combination of afatinib, carboplatin and pemetrexed. At the recommended dose, this combination was well tolerated and had a good clinical efficacy.

Prognostic Factors and Efficacy of First-Line Chemotherapy in Patients with Advanced Thymic Carcinoma: A Retrospective Analysis of 286 Patients from NEJ023 Study.

BACKGROUND: The prognostic factors and the efficacy of first-line chemotherapy remain unclear in patients with advanced thymic carcinoma. MATERIALS AND METHODS: We conducted a multi-institutional retrospective study named NEJ023 for patients with advanced thymic carcinoma. All patients without any indication of curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions of the North East Japan Study Group. RESULTS: A total of 286 patients with advanced thymic carcinoma were analyzed. First-line chemotherapy included platinum-based doublets in 62.2% of the patients, monotherapy in 3.5%, and other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide [ADOC]) in 34.3%. The median follow-up period was 55.5 months, and the median overall survival (OS) from the start of first-line chemotherapy was 30.7 months (95% confidence interval, 25.9-35.9 months). There was no significant difference in OS among different first-line chemotherapy regimens (e.g., between carboplatin/paclitaxel and ADOC, median OS: 27.8 vs. 29.9 months). Masaoka-Koga stage IVa and volume reduction surgery were favorable prognostic factors for OS in the multivariate analysis using the Cox proportional hazards model. CONCLUSION: The efficacy of each first-line chemotherapy regimen for advanced thymic carcinoma did not vary significantly. Our results might support the adequacy of the use of carboplatin/paclitaxel as first-line chemotherapy for these patients. IMPLICATIONS FOR PRACTICE: Because of its rarity, there is limited information about prognostic factors and efficacy of chemotherapy in patients with advanced thymic carcinoma. This is the largest data set for those patients treated with chemotherapy. This study suggests there is no significant difference in efficacy between carboplatin/paclitaxel and cisplatin/doxorubicin/vincristine/cyclophosphamide for advanced thymic carcinoma. This result can support the adequacy of the selection of platinum doublets as treatment for those patients, rather than anthracycline-based multidrug regimen.

Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolongs overall survival compared with no prophylactic cranial irradiation in patients with extensive-disease small-cell lung cancer. However, because of the absence of brain imaging before enrolment and variations in chemotherapeutic regimens and irradiation doses, concerns have been raised about these findings. We did a phase 3 trial to reassess the efficacy of prophylactic cranial irradiation in the treatment of extensive-disease small-cell lung cancer. METHODS: We did this randomised, open-label, phase 3 study at 47 institutions in Japan. Patients with extensive-disease small-cell lung cancer who had any response to platinum-based doublet chemotherapy and no brain metastases on MRI were randomly assigned (1:1) to receive prophylactic cranial irradiation (25 Gy in ten daily fractions of 2·5 Gy) or observation. All patients were required to have brain MRI at 3-month intervals up to 12 months and at 18 and 24 months after enrolment. Randomisation was done by computer-generated allocation sequence, with age as a stratification factor and minimisation by institution, Eastern Cooperative Oncology Group performance status, and response to initial chemotherapy. The primary endpoint was overall survival, analysed in the intention-to-treat population. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000001755, and is closed to new participants. FINDINGS: Between April 3, 2009, and July 17, 2013, 224 patients were enrolled and randomly assigned (113 to prophylactic cranial irradiation and 111 to observation). In the planned interim analysis on June 18, 2013, of the first 163 enrolled patients, Bayesian predictive probability of prophylactic cranial irradiation being superior to observation was 0·011%, resulting in early termination of the study because of futility. In the final analysis, median overall survival was 11·6 months (95% CI 9·5-13·3) in the prophylactic cranial irradiation group and 13·7 months (10·2-16·4) in the observation group (hazard ratio 1·27, 95% CI 0·96-1·68; p=0·094). The most frequent grade 3 or worse adverse events at 3 months were anorexia (six [6%] of 106 in the prophylactic cranial irradiation group vs two [2%] of 111 in the observation group), malaise (three [3%] vs one [<1%]), and muscle weakness in a lower limb (one [<1%] vs six [5%]). No treatment-related deaths occurred in either group. INTERPRETATION: In this Japanese trial, prophylactic cranial irradiation did not result in longer overall survival compared with observation in patients with extensive-disease small-cell lung cancer. Prophylactic cranial irradiation is therefore not essential for patients with extensive-disease small-cell lung cancer with any response to initial chemotherapy and a confirmed absence of brain metastases when patients receive periodic MRI examination during follow-up. FUNDING: The Ministry of Health, Labour and Welfare of Japan.

Weekly irinotecan combined with carboplatin for patients with small-cell lung cancer: A phase I study.

BACKGROUND: We conducted a phase I dose escalation study to evaluate the feasibility, maximum tolerated dose (MTD), and recommended dose (RD) of weekly irinotecan combined with fixed-dose carboplatin for patients with untreated small-cell lung cancer (SCLC). METHODS: Fifteen patients with chemotherapy-naïve SCLC less than 75 years old were enrolled from 3 institutions. Patients received irinotecan (50-80mg/m(2) on days 1 and 8) and carboplatin (area under the curve, 5.0 on day 1) every 3 weeks, with 3-6 patients treated at each irinotecan dosage level (levels I-IV). The MTD was defined as the dose at which 33% of patients experienced dose-limiting toxicity. RESULTS: Eleven patients had a performance status of 1, and 7 patients were more than 70 years old. All but 1 patient were diagnosed with extensive disease. In total, 2 of 3 patients enrolled at level IV (80mg/m(2)) experienced grade 3 diarrhea. Therefore, the MTD was defined as the level IV dose, and the RD was defined as the level III dose (70mg/m(2)). Grade 3 or 4 neutropenia was observed in 60% of patients, and febrile neutropenia was observed in 13% of patients. Four patients experienced grade 3 or 4 anemia, and 6 patients experienced grade 3 or 4 thrombocytopenia. The most common non-hematological adverse events were nausea/vomiting, diarrhea, hypokalemia, and hyponatremia. CONCLUSIONS: The MTD of weekly irinotecan was 80mg/m(2), resulting in an RD of 70mg/m(2) for phase II trials.

A phase II study of erlotinib monotherapy in pre-treated non-small cell lung cancer without EGFR gene mutation who have never/light smoking history: re-evaluation of EGFR gene status (NEJ006/TCOG0903).

OBJECTIVES: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are particularly effective in non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations. However, some studies have reported survival benefits in NSCLC patients with wild-type EGFR upon erlotinib treatment. This trial was conducted to evaluate the efficacy of erlotinib monotherapy and investigate the predictive values of several biomarkers. PATIENTS AND METHODS: Patients with previously treated NSCLC but without EGFR gene mutations that had never or light smoked were eligible for this study. Gene status screening was performed using the PNA-LNA PCR clamp method. Erlotinib was administered until disease progression or unacceptable toxicities occurred. EGFR gene status was re-evaluated using the fragment method to detect exon 19 deletions and the Cycleave-PCR method to detect point mutations. Expression of hepatocyte growth factor (HGF), Met, and thymidylate synthase (TS) were evaluated using immunohistochemistry. RESULTS: Forty-seven patients were enrolled in the study between March 2010 and November 2011. Objective response rate (ORR) and disease control rate (DCR) were 15.2% and 41.3%. Re-evaluations for EGFR gene were performed in 32 tumor samples. EGFR gene mutations were found in eight samples (5:exon 19 deletion, 2:G719X, 1:L858R). Six patients had PR and two had SD among these eight patients. A total of 24 patients were confirmed as wild-type EGFR using different methods. ORR and DCR were 4.2% and 41.7%. The median progression free survival (PFS) and median survival times were 2.0 and 6.0 months, respectively. Patients with tumors expressing HGF showed shorter PFS but not MET or TS. CONCLUSIONS: Re-examination of EGFR gene status using different detecting method or different sample should be considered to grasp a chance of erlotinib treatment after first line treatment. In confirmed EGFR wild NSCLC, negative HGF staining could be a biomarker for longer PFS by erlotonib treatment.

Phase II study of amrubicin combined with carboplatin for refractory relapsed small-cell lung cancer: North Japan Lung Cancer Group Trial 0802.

BACKGROUND: Amrubicin (AMR), a new anthracycline agent, has shown promising results for advanced small-cell lung cancer (SCLC), although the efficacy of AMR alone against refractory relapsed SCLC is insufficient. This study was conducted to evaluate the safety and efficacy of the combination of AMR and carboplatin (CBDCA) in patients with refractory relapsed SCLC. METHODS: Patients with advanced SCLC who relapsed within 90 days after the completion of first-line chemotherapy received AMR (30mg/m(2), days 1-3) and CBDCA (area under the curve 4.0mgmL(-1)min(-1), day 1) every 3 weeks. The primary endpoint of this study was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival, and the toxicity profile. Assuming that an ORR of 45% in eligible patients would indicate potential usefulness and an ORR of 20% would be the lower limit of interest, with α=0.10 and ß=0.10, at least 24 patients were required. RESULTS: Among 29 eligible patients, the ORR was 34% (90% confidence interval, 20-48). The median PFS was 3.5 months, whereas the median survival time was 7.3 months. The most common grade 3-4 toxicity was neutropenia (79%), although only one patient (3%) suffered from febrile neutropenia. Non-hematological toxicities were of moderate severity and no treatment-related death was observed. CONCLUSIONS: This is the first prospective study of AMR combined with CBDCA for refractory relapsed SCLC, which was effective and well tolerated. However, further investigation of this regimen is warranted.

Randomized phase II trial comparing carboplatin plus weekly paclitaxel and docetaxel alone in elderly patients with advanced non-small cell lung cancer: north japan lung cancer group trial 0801.

BACKGROUND: Standard first-line chemotherapy for elderly non-small cell lung cancer (NSCLC) patients has been monotherapy with vinorelbine or gemcitabine. Docetaxel has also been considered as an alternative option for the elderly population in Japan. We have previously demonstrated the high efficacy of carboplatin plus weekly paclitaxel for elderly NSCLC patients. Consequently, we conducted a randomized phase II study to select the proper regimen for a future phase III trial. METHODS: Eligible patients were aged 70 years or older with newly diagnosed advanced NSCLC. Patients were randomly assigned either to a combination of carboplatin (area under the curve: 6 mg/mL per minute) with weekly paclitaxel (70 mg/m²) (CP regimen) or to single-agent docetaxel (60 mg/m²). The primary endpoint of this study was objective response rate. Secondary endpoints were progression-free survival, overall survival, and toxicity profile. RESULTS: Among 83 eligible patients (41 to CP, 42 to docetaxel), the objective response rates were 54% (95% confidence interval: 39%-69%) and 24% (95% confidence interval: 11%-37%) and median progression-free survival was 6.6 months and 3.5 months in the CP arm and the docetaxel arm, respectively. Severe neutropenia, febrile neutropenia, and nausea were significantly frequent in the docetaxel arm, whereas toxicities in the CP arm were generally moderate. One treatment-related death was observed in the docetaxel arm. CONCLUSION: The CP regimen achieved higher activity with less toxicity than single-agent docetaxel. Considering the results of this phase II trial and the IFCT-0501 trial, we have selected the CP regimen for a future phase III trial in elderly patients with advanced NSCLC.

Randomized phase II trial of uracil/tegafur and cisplatin versus vinorelbine and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage III non-small-cell lung cancer: NJLCG 0601.

INTRODUCTION: The optimal chemotherapy with thoracic radiotherapy (TRT) for locally advanced non-small-cell lung cancer (NSCLC) remains to be established. This randomized phase II study of concurrent chemoradiotherapy was conducted to compare uracil/tegafur (UFT) and cisplatin with vinorelbine and cisplatin for stage III NSCLC. PATIENTS AND METHODS: Patients with unresectable stage III NSCLC were randomized to receive UP (400 mg/m(2) UFT on days 1-14 and 29-42 and 80 mg/m(2) cisplatin on days 8 and 36) or NP (20 mg/m(2) vinorelbine on days 1, 8, 29, and 36 and 80 mg/m(2) cisplatin on days 1 and 29). TRT began on day 1 (total 60 Gy in 30 fractions). RESULTS: Of 70 enrolled patients, 66 were evaluable for efficacy and safety. The overall response rates were 80% (95% CI: 67-93%) and 71% (95% CI: 55-87%) for the UP arm and the NP arm. With a median follow-up of 20.2 months, the progression-free survival and median survival time were 8.8 and 26.9 months in the UP arm, and 6.8 and 21.7 months in the NP arm. The 2-/3-year survival rates were 51.0/34.3% and 46.9/33.4% for the UP arm and the NP arm, respectively. Grade 3/4 neutropenia occurred in 20% and 58% of patients in the UP and NP arms, respectively. CONCLUSION: Combined with concurrent TRT, the UP arm achieved better efficacy and safety compared with the NP arm, suggesting it to be a promising candidate as a standard regimen for locally advanced NSCLC. Further evaluation of the UP arm is warranted.

Phase II study of irinotecan as a third- or fourth-line treatment for advanced non-small cell lung cancer: NJLCG0703.

BACKGROUND: We aimed to evaluate the efficacy and safety of irinotecan monotherapy as a third- or fourth-line treatment for advanced non-small cell lung cancer (NSCLC) patients. METHODS: Patients with advanced NSCLC refractory to 2 or more previous regimens were treated with 80 mg/m2 irinotecan on days 1, 8, and 15, every 4 weeks. The primary endpoint was the overall response rate (ORR), whereas secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity profiles. RESULTS: From December 2007 to April 2009, 32 patients (median age, 60 years) were enrolled. Most of the patients (75.0%) were male, and 18.8% had a performance status of 2. Six partial responses to irinotecan monotherapy were observed (ORR, 18.8%: 95% confidence interval, 5.3%-32.3%). The disease control rate (DCR) was 78.1%, median PFS was 4.0 months, and median survival time (MST) was 10.4 months. Grade 3-4 neutropenia was observed in 22% of patients, but other toxic effects were moderate. No cases of grade 3-4 diarrhea or treatment-related death were noted. Of the 15 patients for whom progressive disease represented the best response to previous treatment regimens, 2 exhibited a partial response and 9 showed stable disease after irinotecan monotherapy, with a DCR of 73.3%, median PFS of 4.4 months, and MST of 8.2 months. CONCLUSIONS: Irinotecan monotherapy is effective for advanced NSCLC patients who have previously failed 2 or more treatment regimens.

Phase I study of daily S-1 combined with weekly irinotecan in patients with advanced non-small cell lung cancer.

BACKGROUND: S-1 is a novel oral fluorouracil prodrug active against non-small cell lung cancer (NSCLC). To determine the feasibility of S-1 combined with weekly irinotecan for patients with advanced NSCLC, we performed a phase I study to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan. METHODS: Patients with advanced NSCLC received S-1 (80 mg/m(2)) on days 1-14 and irinotecan (50-80 mg/m(2)) on days 1, 8, and 15 of each 28-day cycle. Three to six patients were treated with each dose of irinotecan, with the MTD defined as the dose at which dose-limiting toxicity (DLT) appeared in 33% of patients. RESULTS: At doses of 50-70 mg/m(2), no patients experienced any DLT, whereas, at a dose of 80 mg/m(2), two of four patients experienced DLTs. Two patients experienced grade 3 toxicities - neutropenia and diarrhea. CONCLUSION: The MTD of weekly irinotecan was 80 mg/m(2), making its RD for phase II trials 70 mg/m(2).

Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402.

PURPOSE: Amrubicin, a new anthracycline agent, and topotecan are both active for previously treated small-cell lung cancer (SCLC). No comparative study of these agents has been reported. This randomized phase II study was conducted to select amrubicin or topotecan for future evaluation. PATIENTS AND METHODS: Patients with SCLC previously treated with platinum-containing chemotherapy were randomly assigned to receive amrubicin (40 mg/m(2) on days 1 through 3) or topotecan (1.0 mg/m(2) on days 1 through 5). Patients were stratified by Eastern Cooperative Oncology Group performance status (0, 1, or 2) and type of relapse (chemotherapy sensitive or refractory). The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival, and toxicity profile. RESULTS: From February 2004 to July 2007, 60 patients were enrolled, and 59 patients (36 patients with sensitive and 23 patients with refractory relapse) were assessable for efficacy and safety evaluation. Neutropenia was severe, and one treatment-related death owing to infection was observed in the amrubicin arm. ORRs were 38% (95% CI, 20% to 56%) for the amrubicin arm and 13% (95% CI, 1% to 25%) for the topotecan arm. In sensitive relapse, ORRs were 53% for the amrubicin arm and 21% for the topotecan arm. In refractory relapse, ORRs were 17% for the amrubicin arm and 0% for the topotecan arm. Median PFS was 3.5 months for patients in the amrubicin arm and 2.2 months for patients in the topotecan arm. Multivariate analysis revealed that amrubicin has more influence than topotecan on overall survival. CONCLUSION: Amrubicin may be superior to topotecan with acceptable toxicity for previously treated patients with SCLC. Further evaluation of amrubicin for relapsed SCLC is warranted.

Adenocarcinoma with epidermal growth factor receptor gene mutations in three siblings.

Sensitivity to an inhibitor of epidermal growth factor receptor (EGFR) kinase strongly correlates with EGFR somatic mutations in non-small cell lung cancer. These mutations are frequently found in patients with adenocarcinoma, never- or light-smokers, women, and East Asians. In this study, we show an aggregation of three non-small cell lung cancer cases with EGFR gene mutations in one family. The subjects were all female, never- or light-smokers with adenocarcinoma. Two of the patients responded to treatment with gefitinib. A genetic study of these cases would be useful in elucidating genetic susceptibility to lung cancer in persons with EGFR mutations.

A phase II study of weekly paclitaxel combined with carboplatin for elderly patients with advanced non-small cell lung cancer.

We conducted this phase II study to explore the efficacy and safety of weekly paclitaxel combined with carboplatin in elderly patients with advanced non-small cell lung cancer (NSCLC). Elderly patients (> or = 70 years old) of stage IIIB, IV, or recurrent NSCLC with PS 0 or 1 were enrolled. Patients received paclitaxel at a dose of 70 mg/m2 on Days 1, 8, 15, and carboplatin at the target dose of the area under the curve (AUC) of six on Day 1 every 28 days for at least two cycles. Forty-two patients were enrolled and 40 patients were treated with a median of three cycles (range, 1-5). The overall response rate (ORR) was 45% (95% confidence interval, 30-60%). The median survival time (MST) was 14 months and the 1-year survival rate was 62%. Twenty-eight patients (70%) had grade 3/4 neutropenia and two patients (5%) experienced grade 3 febrile neutropenia. Non-hematological toxicities were generally mild to moderate and grade 3 peripheral neuropathy was seen in one patient (3%). There was one treatment-related death by infection due to neutropenia. Weekly paclitaxel and carboplatin combination chemotherapy was an effective and safe regimen in elderly patients with advanced NSCLC. A randomized trial comparing this treatment with the conventional tri-weekly regimen of paclitaxel and carboplatin is warranted.

Phase II study of carboplatin combined with biweekly docetaxel for advanced non-small cell lung cancer.

BACKGROUND: The combination of carboplatin and docetaxel has been considered one of the standard treatments for advanced non-small cell lung cancer (NSCLC). To investigate a safer and more convenient schedule for outpatient, we conducted a phase II study to evaluate the efficacy and the safety of carboplatin plus biweekly docetaxel for advanced NSCLC. PATIENTS AND METHODS: Patients with stage IIIB, IV, or postoperative recurrent NSCLC with good performance status were administered docetaxel at a dose of 35 mg/m on days 1 and 15 and carboplatin at an area under the curve (AUC) of 6 on day 1 every 4 weeks for at least three cycles. RESULTS: Fifty patients were treated with median of three cycles (range 1-6). Grade 3/4 toxicities included neutropenia in 18 patients (36%), thrombocytopenia in 4 patients (8%), and anemia in 10 patients (20%). No patient experienced febrile neutropenia. Nonhematological toxicities were also mild to moderate, and there were no treatment-related deaths. The overall response rate was 30%, and the disease control rate was 70%. Among the elderly population, 54% of patients achieved partial response. Median progression-free survival was 4.8 months, and median overall survival was 11.8 months. CONCLUSIONS: Biweekly docetaxel plus carboplatin has a similar efficacy and lower toxicity compared with a standard triweekly regimen of docetaxel plus carboplatin, which is a suitable regimen for outpatients, including elderly patients.

Granulocyte-macrophage colony-stimulating factor and lung immunity in pulmonary alveolar proteinosis.

The anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody is inferred to cause idiopathic pulmonary alveolar proteinosis (iPAP): the antibody neutralizes GM-CSF and thereby impairs differentiation of alveolar macrophages. Administration of GM-CSF improves respiratory function of patients with iPAP, as confirmed in this study using aerosolized GM-CSF. To elucidate its mechanism, we characterized bronchoalveolar lavage fluid and alveolar macrophages obtained from three patients with iPAP who were treated successfully with aerosolized GM-CSF. Cell number, expressions of surface mannose receptor and the transcription factor PU.1, and phagocytic ability of alveolar macrophages were all restored to control levels. With treatment, the neutralizing capacity of GM-CSF activity was reduced markedly, concomitant with the decreasing autoantibody levels. Interestingly, the amount of GM-CSF autoantibody complex also decreased. In one case in which the complex was analyzed, the majority of GM-CSF binding the complex was endogenous protein, suggesting that the complex is removed immediately from the lung after treatment. Our study shows that GM-CSF administration engenders a decrease in the neutralizing capacity against the protein in the lungs. Thereby, it facilitates restoration of the normal function of alveolar macrophages.

[Bronchial artery embolization can be effective for primary racemose hemangioma].

We report two cases of primary racemose hemangioma in patients with hemoptysis. In the first, a 59-year-old man had a pulsatile polypoid lesion in the bronchus of the lingula; and in the second, a 24-year-old woman had a nodule in the bronchus of the right lower lobe. In both patients, arteriography of the bronchial artery revealed enlargement and convolution of its branches. Primary racemose hemangioma was diagnosed in both patients. The arteriography also revealed a shunt between the pulmonary and bronchial arteries in the woman. Bronchial artery embolization (BAE) was an effective treatment for the hemoptysis. To date, eight months after the embolization, hemoptysis has not recurred. Bronchoscopy and arteriography of the bronchial artery are both useful for diagnosing primary racemose hemangioma. BAE seems to be effective in treating primary racemose hemangioma.

High level of vascular endothelial growth factor in hemorrhagic pleural effusion of cancer.

Angiogenic cytokines, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and angiogenin, are candidates for the induction of pleural effusions because they have been implicated in the induction of neovascularization, vascular permeability, and hemorrhage both in the inflammatory process and in tumor progression. Thus, we hypothesized that these angiogenic factors in effusion might be involved in the clinical manifestation of malignant pleural disease. We measured the levels of VEGF, bFGF, and angiogenin in pleural effusions and sera from 40 patients. Pleural effusions due to malignancy (1,350 pg/ml) contained significantly higher levels of VEGF than effusions due to inflammatory diseases (102 pg/ml; p = 0.034). Furthermore, hemorrhagic effusions showed significantly higher VEGF levels (1,942 pg/ml) than non-hemorrhagic effusions (202 pg/ml; p = 0.016) in malignant patients. In contrast, neither bFGF nor angiogenin were correlated with any clinical manifestation of pleural effusion. Immunohistochemical study revealed that malignant cells in the pleura were stained with anti-VEGF antibody. Our data suggest that VEGF secreted from tumor cells may be involved in the accumulation of pleural effusion in malignancy, and that increased levels of VEGF may induce hemorrhagic effusion.

Possible oncogenic potential of DeltaNp73: a newly identified isoform of human p73.

p73, a recently identified gene highly homologous to p53, can transactivate p53 target genes and induce apoptosis. Here we report the identification of an NH(2)-terminal truncated isoform of human p73, DeltaNp73, which is capable of suppressing p53- and p73-dependent transactivation. We speculate that this suppression is achieved by competing for the DNA binding site in the case of p53 and by direct association in the case of TAp73. Expression of DeltaNp73 in cancer cell lines also inhibited suppressive activity of p53 and TAp73 in colony formation, implying possible involvement of DeltaNp73 in oncogenesis by inhibiting the tumor-suppressive function of p53 and TAp73. Also reported is the identification of TAp73eta, a new member of the COOH-terminal truncated isoform of p73 and tissue-specific expression of these isoforms, along with other previously identified p73 isoforms.