Evaluation of Safety and Efficacy of Salvage Therapy With Sunitinib, Docetaxel (Tyxan) and Cisplatinum Followed by Maintenance Vinorelbine for Unresectable/Metastatic Nonsmall Cell Lung Cancer: Stage 1 of a Simon 2 Stage Clinical Trial. [Corrected].

Current chemotherapeutic regimens for nonsmall cell lung cancer (NSCLC) have reached a plateau over the last few years. Targeted therapy makes use of tyrosine kinase inhibitors (TKIs) to suppress a number of signaling pathways including epidermal growth factor receptor and vascular endothelial growth factor which are active in NSCLC biology. In this study, we used sunitinib, a multi-target receptor TKI, combined with chemotherapy for unresectable/metastatic NSCLC.This open label Simon's 2 stage clinical trial enrolled a total of 6 NSCLC patients who received docetaxel (40 mg) and cisplatin (50 mg) on day 1 of each cycle (14 day interval between cycles) and sunitinib (25 mg qd for 10 days between cycles) for a total of 12 cycles (24 weeks), after which patients received maintenance therapy with vinorelbine (30 mg TIW) until disease progression. The sample size was based on a Simon's Optimal Two-Stage Designs for Phase II clinical trials. The expected response rate was set as 35% for P0 and as 60% for P1. The study was designed for a minimum of 6 patients for first stage and 15 patients until second stage with a significance level alpha = 0.10 and power = 70%. Diagnosis of a poor response in the second of 6 patients in Stage I or seventh of the 15 patients in Stage II would lead to early termination of the trial.The overall response rate was 66.7%. Four patients had an overall survival >60 months. The time to PFS ranged from 3 to 42 months. The combination therapy was well-tolerated.Sunitinib combined with chemotherapy shows promise and warrants further investigation.

Glucose-regulated protein 94 modulates the therapeutic efficacy to taxane in cervical cancer cells.

Cervical cancer is an important health issue for women worldwide, and the endoplasmic reticulum stress pathway is important for determining the chemotherapeutic response to cancer. However, the role of glucose-regulated protein 94 (GRP94) in taxane therapy for cervical cancer remains unclear. In this study, we generated GRP94 knockdown (GRP94-KD) Hela cells using short hairpin RNAs and found that GRP94-KD cells were resistant to taxane treatment in an MTT assay. Scrambled control cells demonstrated higher levels of apoptosis when treated with taxanes in comparison to GRP94-KD cells, as determined by cell cycle profiling, 4',6-diamidino-2-phenylindole staining, and terminal deoxynucleotidyl transferase-mediated nick end labeling staining. Caspase 3 and caspase 7 activity was also higher in scrambled control cells treated with taxane in comparison to GRP94-KD cells. Moreover, we found that depletion of GRP94 altered the levels of the apoptosis-related proteins Bcl2 and Bad, leading to sensitivity to taxane. Exposure to taxane also induced the expression of Bad in scrambled cells but not in GRP94-KD cells. In addition, the expression of Bcl2 was increased dramatically in GRP94-KD cells, whereas only a small increase was observed in scrambled cells. Therefore, we conclude that silencing GRP94 may increase resistance to taxane treatment in cervical cancer cells by altering the activation of the apoptosis pathway. In addition, GRP94 may represent a key biomarker for determining the therapeutic efficacy of taxane treatment in cervical cancer patients.

NNK enhances cell migration through α7-nicotinic acetylcholine receptor accompanied by increased of fibronectin expression in gastric cancer.

BACKGROUND: In this study, we intended to dissect the mechanism of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-enhanced migration of gastric cancer. Smoking has been defined as a risk factor for gastric cancer. Tobacco-specific carcinogen, NNK, was reported to enhance cancer progression in gastric cancer. Currently, metastasis is the major issue for clinical cancer therapy, but the influence of NNK on the migration of gastric cancer remains to be determined. METHODS: The expression of nicotinic receptor in gastric cancer cells was identified by real-time polymerase chain reaction and Western blotting. The influence of NNK on migration of gastric cancer cells was evaluated by the transwell migration assay system. Receptor-mediated migration was studied by both inhibitor and small interfering RNA. RESULTS: Alpha7 nicotinic acetylcholine receptor, alpha7-nicotinic acetylcholine receptor (nAChR), was identified higher than alpha9-nAChR in gastric cancer cell lines, AGS cells. NNK enhanced significantly gastric cancer cell migration in transwell assay. We used inhibitor and siRNA to demonstrate that alpha7-nAChR mediated NNK-enhanced gastric cancer cell migration and upregulation of fibronectin were involved in NNK-enhanced migration of gastric cancer cells. Finally, we found that silenced fibronectin expression level inhibited the migratory ability in AGS cells. CONCLUSIONS: NNK enhanced gastric cancer metastasis through alpha7-nAChR and fibronectin-one of the hallmarks of epithelial mesenchymal transition.

Nicotine promotes cell migration through alpha7 nicotinic acetylcholine receptor in gastric cancer cells.

BACKGROUND: The objective was to study the mechanism of nicotine-enhanced migration of gastric cancer cells. Long-term cigarette smoking increases the risk of gastric cancer mortality. Tobacco-specific mitogen, nicotine, was reported to correlate with cancer progression on gastric cancer. Since metastasis is the major cause of cancer death, the influence of nicotine on the migration of gastric cancer cells remains to be determined. MATERIALS AND METHODS: The influence of nicotine on migration of gastric cancer cells was evaluated by transwell assay and wound-healing migration assay. Receptor-mediated migration was studied by both inhibitor and small interfering RNA. RESULTS: Alpha7 nicotinic acetylcholine receptor, alpha7-nAChR, was identified in gastric cancer cell lines, AGS cells. Nicotine enhanced AGS cell migration in transwell assay and wound-healing migration assay in a dose-dependent manner. We used inhibitor and siRNA to demonstrate that alpha7-nAChR mediated nicotine-enhanced gastric cancer cell migration through downregulation E-cadherin and upregulation ZEB-1 and snail. CONCLUSIONS: Tobacco-specific mitogen, nicotine, enhanced gastric cancer metastasis through alpha7-nAChR and suppression of E-cadherin level-one of the hallmarks of epithelial to mesenchymal transition. Therefore, patients with gastric cancer should avoid smoking.

EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF.

MicroRNAs (miRNA) mediate distinct gene regulatory pathways triggered by epidermal growth factor receptor (EGFR) activation, which occurs commonly in lung cancers with poor prognosis. In this study, we report the discovery and mechanistic characterization of the miRNA miR-7 as an oncogenic "oncomiR" and its role as a key mediator of EGFR signaling in lung cancer cells. EGFR activation or ectopic expression of Ras as well as c-Myc stimulated miR-7 expression in an extracellular signal-regulated kinase (ERK)-dependent manner, suggesting that EGFR induces miR-7 expression through a Ras/ERK/Myc pathway. In support of this likelihood, c-Myc bound to the miR-7 promoter and enhanced its activity. Ectopic miR-7 promoted cell growth and tumor formation in lung cancer cells, significantly increasing the mortality of nude mice hosts, which were orthotopically implanted with lung cancers. Quantitative proteomic analysis revealed that miR-7 decreased levels of the Ets2 transcriptional repression factor ERF, the coding sequence of which was found to contain a miR-7 complementary sequence. Indeed, ectopic miR-7 inhibited production of ERF messages with a wild-type but not a silently mutated coding sequence, and ectopic miR-7 rescued growth arrest produced by wild-type but not mutated ERF. Together, these results identified that ERF is a direct target of miR-7 in lung cancer. Our findings suggest that miR-7 may act as an important modulator of EGFR-mediated oncogenesis, with potential applications as a novel prognostic biomarker and therapeutic target in lung cancer.

Risk factors for 24-hour mortality after traumatic rib fractures owing to motor vehicle accidents: a nationwide population-based study.

BACKGROUND: Accurate identification of patients at high risk of death as a result of major chest trauma is essential within a trauma system. We used 3-year population-based data in Taiwan to evaluate risk factors associated with 24-hour mortality among adults with obvious rib fractures and needing hospitalization after traffic accidents. METHODS: Pooled data from Taiwan's National Health Insurance Research Database for the years 2002 through 2004 were used. A total of 18,856 patients hospitalized with rib fractures after traffic accidents were included. Multivariate logistic regression using generalized estimating equations was performed to explore the relationship between 24-hour mortality and patients' age, sex, and comorbid conditions, as well as hospital characteristics, adjusting for social factors and any clustering of the sampled patients by hospital. RESULTS: Of patients in the sample, 459 (2.4%) died within 24 hours of admission. Patients who had six or more rib fractures were three times more likely to die within 24 hours of admission compared with patients with only one rib fracture (odds ratio [OR], 3.16; p < 0.001). The adjusted odds of death within 24 hours were higher for patients who had hemopneumothorax (OR, 3.15; p < 0.001), extremity fractures (OR, 1.74; p < 0.001), pelvic fractures (OR, 2.92; p < 0.001), head injuries (OR, 4.29; p < 0.001), spleen injury (OR, 1.83; p < 0.05), hepatic injury (OR, 4.39; p < 0.001), heart injury (OR, 4.48; p < 0.001), and diaphragm injury (OR, 3.16; p < 0.05) compared with patients who had none of these injuries. CONCLUSIONS: We concluded that more than six ribs fractured, heart injuries, hepatic injuries, head injuries, and advanced age are the most important determinants of 24-hour mortality after thoracic trauma from traffic accidents.

Does high surgeon and hospital surgical volume raise the five-year survival rate for breast cancer? A population-based study.

This study sets out to examine the relationship between both surgeon and hospital volume and five-year survival rates for breast cancer patients. We performed Cox proportional hazard regressions on a pooled population-based database linking the Taiwan National Health Insurance Research Database with the 'cause of death' data file, covering the three-year period from January 1997 to December 1999. Of the 13,360 breast cancer resection patients in our study sample, the five-year survival rates, by surgeon volume, were 77.3% in the high-volume group (>201 cases), 76.9% in the medium-volume group (45-200), and 69.5% in the low-volume group (585 cases), 74.5% for medium-volume hospitals (259-585) and 72.1% for low-volume hospitals (

Association between surgeon and hospital volume and in-hospital fatalities after lung cancer resections: the experience of an Asian country.

BACKGROUND: We used 4-year nationwide population-based data to explore the volume-outcome relationships for lung cancer resections in Taiwan and to determine whether there is any association between high-volume hospitals or high-volume surgeons and lower in-hospital mortality rates. METHODS: We use pooled data for the years 2001 through 2004 obtained from the National Health Insurance Research Database in Taiwan. A total of 4,841 patients, identified as having undergone pulmonary resections for lung or bronchial tumors during the period of this study, were treated by 377 surgeons in 79 hospitals. Multivariate logistic regression analyses were then employed to assess the crude and adjusted odds ratio of in-patient fatalities between surgeon and hospital lung cancer resection volume groups. RESULTS: Patients treated by low-volume surgeons had significantly higher in-hospital fatality rates than those treated by either medium-volume surgeons (2.3% versus 1.0%; p < 0.001) or high-volume surgeons (2.3% versus 0.6%; p < 0.001). However, hospital case volume alone is not a significant predictor of hospital in-patient fatalities for lung cancer resections. With increasing surgeon volume, there was a decline in the adjusted odds ratio of hospital in-patient deaths. The odds of hospital in-patient deaths for those patients treated by low-volume surgeons were 2.04 times those of medium-volume surgeons, and 2.63 times those of high-volume surgeons. CONCLUSIONS: We conclude that after adjusting for patient, surgeon, and hospital characteristics, an inverse volume-outcome relationship does exist for surgeons, but not for hospitals, in Taiwan.

Preoperative serum albumin level is a prognostic indicator for adenocarcinoma of the gastric cardia.

Among patients with adenocarcinoma of the gastric cardia, we noted that patients with higher preoperative serum albumin levels appeared to survive longer than patients with lower levels. Thus, we evaluated serum albumin as a prognostic factor for patient survival. From 1987 to 1997, 314 patients with adenocarcinoma of the gastric cardia underwent curative resection. Patient serum albumin levels were evaluated on the second day after admission, before any nutritional support. Patients were divided into two groups: those with normal serum albumin levels (>3.5 g/dl) and those with abnormal serum albumin levels. The perioperative mortality and morbidity were 5.7% (18 of 314) and 22.3% (70 of 314), respectively. The surgical resectability rate was significantly better among patients with normal serum albumin levels (P < 0.001). The 5-year overall survival rate of patients with normal serum albumin levels was also better than those with abnormally low serum albumin levels (38.4% versus 19.1%, P=0.0003). In each cancer stage, the 5-year survival rate of patients with normal serum albumin levels was better than that among those with hypoalbuminemia. By multivariate analysis, serum albumin level and the pathologic T, N statuses were independent factors correlated with prognosis. Preoperative serum albumin level correlated highly with resectability and survival. Patients with abnormal serum albumin levels had worse survival than did those with normal serum albumin levels. We recommend that postoperative adjuvant therapy be given to all patients with hypoalbuminemia preoperatively.

Prognostic significance of nm23-H1 expression in esophageal squamous cell carcinoma.

OBJECTIVES: Tumor recurrence and metastasis are major causes of treatment failure in esophageal squamous cell carcinoma (ESCC). Recently, nm23, originally considered to be an anti-metastatic gene, has been reported to associate with various roles in different human cancers. We therefore investigated the clinical significance of nm23-H1 expression in ESCC. METHODS: Pathological sections were immunohistochemically stained with monoclonal antibody that was specific to nm23-H1. Expression of positive nm23-H1 staining was further confirmed by Western blot and reverse transcription-polymerase chain reaction (RT-PCR). The relationship between nm23-H1 expression and clinicopathological variables was examined by statistical analysis. Except for 11 (7%) surgical morality, the remaining 145 patients entered the prognostic analysis. The cisplatin-based chemotherapy was established for the patients with tumor stages at or beyond IIb, or with tumor recurrence. Survival difference between groups was compared by log rank test. RESULTS: Immunohistochemically, nm23-H1 expression was detected in 39.3% (57/145) of the pathological sections. It was positively correlated with tumor stage (P = 0.002), evident lymphovascular invasion (P < 0.001) and tumor recurrence (P = 0.02). Survival of nm23-H1 positive group was statistically superior to nm23-H1 negative group (P < 0.0001) By multivariate survival analysis, tumor stage, the number of lymph node metastasis and expression of nm23-H1 were the independent prognostic factors for ESCC patients. CONCLUSIONS: Our study demonstrated that nm23-H1 expression was associated with disease progression in ESCC. However, survival of nm23-H1 positive group was superior to nm23-H1 negative group. This paradoxical result could suppose that nm23-H1 expression might increase cisplatin chemosensitivity and hence improve survival. Screening for nm23-H1 expression in tumor cells may be a potential therapeutic strategy in ESCC patients.

Pulmonary hamartoma.

BACKGROUND: Pulmonary hamartoma is the most common type of benign lung tumors. We retrospectively reviewed the clinicopathological features of 61 patients with pulmonary hamartomas undergoing surgical resection in our institution. METHODS: From 1971 to 2002, 61 patients with 62 pulmonary hamartomas underwent surgical resection in the Division of Thoracic Surgery, Taipei Veterans General Hospital. 45 were men and 16 were women (approximately in 3:1 ratio). Their mean age was 56.9 years (range 20 to 77 years). The medical records of these patients were reviewed. The information collected using a standardized data-collection form consisted of the age at presentation, gender, initial manifestations or symptoms, history of tobacco consumption, location of hamartoma, size of the lesions, state of calcification in the hamartoma, the results of preoperative bronchoscopic examination, operative procedures and pathological report of intra-operative frozen section. All available histological slides were reviewed by the same pathologist to reconfirm the diagnosis of pulmonary hamartoma. RESULTS: Of the 61 patients with pulmonary hamartoma, 41 patients were clinically asymptomatic, 16 patients had new onset of respiratory symptoms and 4 patients had chronic cough. One patient had synchronous 2 separate lesions. The hamartomas were equally distributed in the pulmonary lobes with the mean transverse diameter of 1.8 cm measured in operation (range 0.2 to 5.0). No tumor recurrence developed after resection in our series. The mean follow-up was 8.9 years. CONCLUSIONS: The vast majority of pulmonary hamartomas represent as solitary pulmonary nodule. Definite diagnosis and the treatment can be achieved by surgical resection with minimal morbidity. No tumor recurrence was encountered in the follow-up period.