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Introduction: First-line treatment with bevacizumab combined with chemotherapy has been shown to improve outcomes in patients with advanced, nonsquamous non-small cell lung cancer (NSNSCLC) in phase III clinical trials. SAiL (MO19390), an open-label, multicenter, single-arm study, evaluated the safety and efficacy of first-line bevacizumab-based treatment in clinical practice. This report presents the results of a preplanned subanalysis of Asian patients enrolled in SAiL., Methods: Patients with untreated, locally advanced, metastatic or recurrent NSNSCLC received bevacizumab 7.5 or 15 mg/kg every 3 weeks plus chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. Eligibility criteria for SAiL permitted enrolment of a broad patient population. The primary end point was safety; secondary end points included time to disease progression and overall survival., Results: The Asian intent-to-treat population comprised 314 of the 2212 patients enrolled in the SAiL trial. In the Asian subanalysis, patients received a median of nine cycles of bevacizumab, and the median follow-up was 16.4 months. The incidence of clinically significant adverse events (grade ≥3) of special interest was relatively low in this population (15.6% overall); proteinuria (7.6%), hypertension (4.8%), and bleeding (2.5%) were the most common. A total of five adverse events related to bevacizumab were reported as grade 5. Disease control rate was 94.1%, median time to disease progression was 8.3 months, and median overall survival was 18.9 months., Conclusions: The safety and efficacy of first-line bevacizumab-based treatment in Asian patients with advanced NSNSCLC is consistent with that demonstrated in phase III studies and in the overall SAiL population. There were no new safety signals.

Introduction: Four phase III randomized trials adding epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors to standard chemotherapeutics in patients with advanced non-small cell lung cancer (NSCLC) have failed to show benefits. The mechanism of these failures was examined., Methods: Fifteen previously untreated NSCLC cell lines were simultaneously treated with gefitinib plus cisplatin. Three exhibited sensitizing-EGFR mutations. Three selected lines were further tested with paclitaxel/cisplatin, paclitaxel/gefitinib, and paclitaxel/cisplatin/gefitinib combinations. The tetrazolium colorimetric assay with application of the classic isobole method was used, and dose-versus-log-response curves (DRCs) were analyzed to evaluate possible resistance mechanisms., Results: Of the 15 cell lines tested, combined gefitinib/cisplatin was significantly antagonistic in 10 wild-type and three sensitizing-EGFR mutant cell lines (group mean combination index = 1.184, 95% confidence interval = 1.12-1.24, p = 0.001). The mean combination index values of paclitaxel/cisplatin/gefitinib were higher than or comparable with those of paclitaxel/cisplatin and paclitaxel/gefitinib. DRC analysis consistently showed nonsaturable passive resistance, suggesting that gefitinib at 0.001 to 0.3 μM can interfere with cisplatin cell entry (at concentrations >1-3 μM) in a dose-dependent manner and lead to antagonism. This antagonism may or may not be schedule dependent in different cell lines., Conclusions: In most EGFR wild-type or sensitizing-mutant NSCLC cells, the concomitant gefitinib/cisplatin combination showed antagonism, likely because gefitinib interfered with cisplatin entry into the cell. The findings that three-drug combination was not better than the two-drug combinations are in accordance with the results of the randomized trials. The EGFR-tyrosine kinase inhibitor/platinum antagonism is a possible reason for the failure of those randomized trials.

Introduction: Epidermal growth factor receptor-tyrosine kinase inhibitors are used as effective first-line and salvage therapy in the treatment of advanced non-small cell lung cancer (NSCLC) patients in East Asia. The objective of this study was to compare the efficacy of gefitinib and erlotinib in Taiwanese patients with advanced NSCLC., Methods: Clinical data of NSCLC patients treated with gefitinib or erlotinib from January 2004 to December 2008 were collected retrospectively. Five tertiary referral centers in Taiwan participated in the study., Results: Of the 1122 patients enrolled, 506 (45%) were female, 594 (53%) were never smokers or former light smokers, and 867 (77%) were diagnosed with adenocarcinoma. Epidermal growth factor receptor-tyrosine kinase inhibitors were prescribed as first-line treatment in 465 (41%) patients and as second-line or salvage therapy in 657 patients (59%). The objective response rate was similar between the gefitinib and erlotinib treatment groups, while disease control rate was 58.9 and 65.8% (p = 0.025), respectively. Median progression-free survival of gefitinib and erlotinib groups was 3.6 and 4.6 months, respectively (p = 0.027). Median overall survival of gefitinib and erlotinib groups was 9.6 and 10.7 months, respectively (p = 0.013)., Conclusion: Taiwanese patients with advanced NSCLC treated with erlotinib reported higher disease control rate, longer progression-free survival, and overall survival compared with patients treated with gefitinib.

Objectives: The main goal of end-of-life care is to achieve the best quality of life (QOL) for patients. The purpose of this study was to investigate the impact of (1) the patients' awareness of their prognosis, (2) the extent of patient-family caregiver congruence on the preferences for end-of-life care options, and (3) the perceived caregiving burden of family caregivers when they provide end-of-life care to their dying relative, on the QOL for terminally ill cancer patients in Taiwan., Methods: A total of 1108 dyads of patient-family caregiver from 24 hospitals throughout Taiwan were one-time surveyed. Predictors of the QOL were identified by multiple regression analysis., Results: Controlling for the effects of age, financial status, and symptom distress, a novel finding of this study was that the patient awareness of prognosis, patient-family caregiver congruence on the preferred place of death, and the subjective family caregiving burden had a significant impact on the QOL of Taiwanese terminally ill cancer patients., Conclusions: QOL is not only related to the unavoidable decline in physical condition and daily functioning of the dying patient but is also related to domains that, as death approaches, have the potential to show improvement through the efforts of health-care professionals, such as presenting prognostic information to optimize the patients' understanding and assists them with psychological adjustments, facilitating patient-family caregiver congruence on the end-of-life care decision regarding the place of death and lightening the caregiving burden of family caregivers., ((c) 2008 John Wiley & Sons, Ltd.)

Background and Objective: A survey was carried out of peritoneal carcinomatosis (PC) in lung cancer., Methods: A retrospective analysis was conducted of all lung cancer patients with malignant ascites diagnosed between 1990 and 2005 at a general hospital in Taiwan., Results: There were 30 lung cancer patients with documented PC. The most frequent abdominal symptom was abdominal distension. The most common histological type of lung cancer with PC was adenocarcinoma. Eighty per cent of the patients developed malignant pleural effusions before the diagnosis of PC. The median survival after diagnosis of PC was 15 days. Two adenocarcinoma patients with PC benefited from treatment with gefitinib., Conclusions: Further study is warranted to investigate the use of gefitinib in treatment of patients with lung adenocarcinoma and PC.

Aims: The aim of this cross-sectional study was to explore fatigue levels and fatigue-coping strategies in Taiwanese lung cancer patients receiving chemotherapy., Background: Lung cancer is now recognized as one of the most common cancers in Taiwan, with a high prevalence of mortality. As chemotherapy progresses, fatigue is a common cause of symptom distress., Methods: Data on demographic and disease-related characteristics were gathered from the medical record, and data on fatigue and coping strategies were gathered by questionnaires administered to 101 lung cancer patients receiving chemotherapy., Results: The mean fatigue score for the total sample was 8.0 (SD = 5.0, range = 0-20), indicating light-to-moderate fatigue. The majority of patients (n = 76, 75.2%) had a baseline haemoglobin level of 12 g/dl (6.2 SD 5.7). Fatigue levels were significantly higher in patients receiving a third course of chemotherapy than in those receiving a first course (F = 3.7, p = 0.03). The most commonly used management category was energy conservation (n = 659), and the most commonly used strategy was sitting (n = 101) and lying down (n = 98). However, participants rated exercise (mean = 3.9), sleep (mean = 3.8) and walking (mean = 3.6) as the most effective., Conclusion: This study highlighted the management of fatigue problems in lung cancer patients receiving chemotherapy, especially in respecting patients' self-report of fatigue-management strategies. Relevance to clinical practice. Health care providers should carefully assess patients for fatigue while they are receiving chemotherapy. These patients and their caregivers should be taught to notice fatigue and encouraged to choose coping strategies that reduce fatigue level, thus improving their quality of life.

Interleukin-6 (IL-6) has been identified as an important growth regulator of lung cancer cells. Elevation of serum levels of IL-6 has been found in a subpopulation of lung cancer patients, but rarely in patients with benign lung diseases. Approximately 15% of non-small cell lung cancer (NSCLC) tumors exhibit neuroendocrine (NE) properties (NSCLC-NE) and have been suggested to have the biological characteristics similar to small cell lung cancer (SCLC) with early metastasis and initial responsiveness to chemotherapy. We recently showed that IL-6 promotes cell proliferation and downregulates the expression of neuron-specific enolase (NSE, one of the major NE markers) in NSCLC-NE cells. In this study, we show that IL-6 stimulates a transient increase of tyrosine phosphorylation of STAT3 in a dose-dependent fashion. Inhibition of STAT3 signaling pathway by either AG-490 (JAK2-specific inhibitor) or overexpression of STAT3Y705F (a dominant-negative STAT3) reverses NSE expression in IL-6- treated NSCLC-NE cells. In addition, IL-6 induces phosphorylation and activation of p38 MAPK. SB-203580, a p38 MAPK-specific inhibitor, inhibits IL-6-induced p38 MAPK phosphorylating activity and suppresses IL-6-stimulated cell proliferation. Together, our results indicate that STAT3 signaling pathway is involved in IL-6-induced NE differentiation and that p38 MAPK is associated with IL-6-stimulated growth regulation in NSCLC-NE cells. These data suggest that both kinase pathways play critical roles in the pathogenesis of NSCLC-NE malignancies, providing new molecular targets for future therapeutic approaches.

Interleukin-6 (IL-6) has been shown to regulate both growth and neuroendocrine (NE) differentiation in some types of human cancer cells, and erbB2 may be a critical component of IL-6 signaling. Non-small cell lung cancer (NSCLC) tumors that demonstrate NE properties have been suggested to have biological characteristics similar to small cell lung cancers with initial responsiveness to chemotherapy. We investigated whether IL-6 is implicated in the cell growth, NE differentiation, and chemosensitivity of NSCLC-NE cells. NSCLC-NE cells were treated with exogenous IL-6, and a subclone of an IL-6-transfected NSCLC cell line that constitutively expressed IL-6 receptor was also generated. These cells were assessed for cell proliferation by cell counting and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays, chemosensitivity to cisplatin and etoposide by MTT assays, and NE differentiation by observing morphological changes and immunoblotting for neuron-specific enolase (NSE). The IL-6-treated cells and the IL-6-transfected cells showed enhanced cell proliferation and downregulated NSE expression, but little change in chemosensitivity. In the culture medium, IL-6-transfected cells grew as looser aggregates than the parental cells. IL-6 could not activate the erbB genes. In conclusion, IL-6 can induce cell proliferation and NE dedifferentiation but has little effect on chemosensitivity in IL-6 receptor-expressing NSCLC-NE cells. The status of NSE expression is unlikely to be a crucial factor for chemosensitivity in NSCLC cells.

Background: The present study was designed to determine the different effects of cytokines or antibodies (IL-2, IL-4, IL-7, IL-10, IL-12, alphaCD3) in stimulating the cellular functions of mesothelial cells isolated from malignant pleural effusion., Methods: Mesothelial cells were isolated from 27 patients with malignant pleural effusion. The cultured cellular interferon-gamma (IFNgamma) and IL-10 production, proliferative response, and cytolytic activity against autologous tumors and K-562 cells were measured., Results: Stimulation with IL-2 alone significantly increased the mesothelial cells' proliferative response (p < 0.001) and cytolytic activity against autologous tumors (p = 0.025). The further addition of other cytokines did not increase these functions. The IFNgamma/IL-10 ratio data showed that the T-helper (Th) pathway was shifted from the Th-2 pathway to the Th-1 pathway (increase of IFNgamma/IL-10 ratio) when mesothelial cells were stimulated with IL-2. Further stimulation with IL-2 plus IL-12 or alphaCD3 shifted the Th pathway further in the Th-1 direction, but without statistical significance., Conclusions: The mesothelial cell proliferative response is enhanced with IL-2 stimulation alone. The T-helper pathway is also shifted from the Th-2 to the Th-1 response (increase of IFNgamma/IL-10 ratio) after IL-2 stimulation of mesothelial cells. Mesothelial cells had cytolytic activity against tumor cells, and this activity could be augmented by IL-2 stimulation.

Background: We conducted a phase II study of vinorelbine and cisplatin chemotherapy in non-small cell lung cancer (NSCLC) patients who had failed previous chemotherapy, to assess the response and toxicity of this combination chemotherapy., Methods: Twenty-two patients were enrolled from September 1999 to March 2001. The median age was 70 years. All patients had a performance status of 2. Vinorelbine was administered on days 1, 8 and 15, at a dose of 20 mg/m2; and cisplatin was given on day 1 at a dose of 50 mg/m2, every 4 weeks., Results: Sixty-eight cycles of treatment were given, with a median of 3 cycles. All patients were evaluable for toxicity profile, and 21 patients were evaluable for response rate. The major toxicity was myelosuppression. Grade 3 or 4 neutropenia occurred in 40.9% of the patients, and grade 3 or 4 anemia occurred in 13.6% of the patients during treatment. Uneventful febrile neutropenia occurred in 1 patient. Other toxicities were few and mild in severity. After 2 cycles of treatment, 2 of 21 patients (9.5%) had a partial response (95% confidence interval 0%-22%). The median time of disease progression was 3.7 months, the median survival was 7.6 months, and the one-year survival was 12.3%. Median survival was 8.7 and 4.9 months in those patients receiving this treatment as second-line and > or = third-line chemotherapy, respectively., Conclusions: Vinorelbine and cisplatin salvage chemotherapy produced a modest anti-tumor response, a mild toxicity profile, and reasonable survival in our elderly NSCLC patients with a poor performance status. This regimen deserves further study in elderly NSCLC patients who have failed previous chemotherapy.

This paper presents a novel binarization algorithm for color document images. Conventional thresholding methods do not produce satisfactory binarization results for documents with close or mixed foreground colors and background colors. Initially, statistical image features are extracted from the luminance distribution. Then, a decision-tree based binarization method is proposed, which selects various color features to binarize color document images. First, if the document image colors are concentrated within a limited range, saturation is employed. Second, if the image foreground colors are significant, luminance is adopted. Third, if the image background colors are concentrated within a limited range, luminance is also applied. Fourth, if the total number of pixels with low luminance (less than 60) is limited, saturation is applied; else both luminance and saturation are employed. Our experiments include 519 color images, most of which are uniform invoice and name-card document images. The proposed binarization method generates better results than other available methods in shape and connected-component measurements. Also, the binarization method obtains higher recognition accuracy in a commercial OCR system than other comparable methods.