Molecular mechanisms for the regulation of Nrf2-mediated cell proliferation in non-small-cell lung cancers.

We previously demonstrated that the transcription factor NF-E2-related factor2 (Nrf2), expressed abundantly in non-small-cell lung cancer (NSCLC) cells, plays a pivotal role in the proliferation and chemoresistance of NSCLC. Here we show that Nrf2-mediated NSCLC cell proliferation is dually regulated by epidermal growth factor receptor (EGFR) signaling and an Nrf2 repressor protein Keap1 (Kelch-like ECH-associated protein-1). NSCLC cells expressing wild-type EGFR and Keap1 genes show enhanced proliferation on stimulation with EGFR ligand under non-stress conditions. Exposure to cigarette smoke extract (CSE) enhanced cell proliferation by modification of the Nrf2/Keap1 interaction. Although EGFR-tyrosine kinase inhibitor (TKI) inhibited the proliferation of these cells, exposure to CSE attenuated its efficacy. In NSCLC cells with Keap1 gene mutations, Nrf2 was constitutively activated owing to dysfunction of Keap1 and cells proliferated independently of EGFR signaling. Furthermore, EGFR-TKI was unable to inhibit their proliferation. In NSCLC cells with EGFR gene mutations, Nrf2 was constitutively activated by EGFR signaling. In these cells, proliferation was largely dependent on the EGFR signaling pathway. Although these cells were highly sensitive to EGFR-TKI, exposure to CSE or knockdown of Keap1 mRNA reduced sensitivity to EGFR-TKI. We found a case of NSCLC showing resistance to EGFR-TKI despite having EGFR-TKI-sensitive EGFR gene mutation because of dysfunctional mutation in Keap1 gene. Results indicate that oxidative stress reduces the anticancer effects of EGFR-TKI in wild-type Keap1 NSCLC cells. Analysis of Keap1 dysfunction may become a novel molecular marker to predict resistance to EGFR-TKI in NSCLC cells having EGFR-TKI-sensitive EGFR mutations. Finally, as the downstream molecule of both EGFR and Keap1 signaling, Nrf2 is an important molecular target for the treatment of NSCLC, where cells have mutations in EGFR, KRAS or Keap1 genes.

Increased levels of KL-6 and subsequent mortality in patients with interstitial lung diseases.

OBJECTIVES: KL-6 is a specific marker in patients with interstitial lung diseases (ILDs); however, the relationship between elevated levels of KL-6 and subsequent mortality is not well defined. To determine if elevated serum levels of KL-6 are associated with increased mortality, and to identify the most suitable cut-off level of KL-6 by which to distinguish between good prognosis and poor prognosis, we evaluated the prognostic significance of serum KL-6 levels in patients with stable-state ILDs. METHODS: Two hundred and nineteen patients diagnosed with ILDs (152 with idiopathic interstitial pneumonia and 67 with collagen disease-associated pulmonary fibrosis) at Tsukuba University Hospital from April 1999 to October 2005 were entered in this study. Serum KL-6 levels in patients with ILDs were measured with a commercially available enzyme immunoassay kit, and these patients were then followed up. RESULTS: During the follow-up period, 58 of the 219 patients died of respiratory failure. Patients who died during this period had higher levels of KL-6 than did those who did not (P = 0.0004). The receiver operating characteristic curve analysis showed 1000 U mL(-1) as the most suitable cut-off level by which to distinguish between the two groups of patients. The 95% specificity serum KL-6 level with poor outcome was 2750 U mL(-1). In univariate and multivariate analysis, elevated serum KL-6 (>1000 U mL(-1)) in the stable state indicated poor prognosis (P = 0.0005, log-rank test; P = 0.0001, Cox proportional hazard model). CONCLUSIONS: Elevated KL-6 level may provide simple, yet valuable information by which to identify patients with ILDs who are at increased risk for subsequent mortality.

Lung cancer patients with cardio- and cerebrovascular diseases.

Cardio- and cerebrovascular diseases (CCVD) and cancer are the leading causes of death for humans. The aim of this study was to demonstrate clinicopathological features of lung cancer patients with CCVD. Nine hundred and sixty-six patients with lung cancer were consecutively admitted to our division over a 24-year period. Among them, 254 (26.3%) patients were diagnosed as having CCVD based on medical records. One hundred and ninety-one were men and 143 were 70 years of age or older. There was a difference in smoking habit (p=0.0029) and 30 pack year or more history of smoking (p<0.0001) between lung cancer patients with or without CCVD. Among the 254 patients, 97 patients had stage IA-IIIA disease, however, 27 patients received chest irradiation or supportive care because of coexistence of CCVD. In 157 patients with locally advanced or metastatic disease, 58 patients had less intensive therapy. In multivariate analysis, existence of CCVD in patients with non-small cell lung cancer (NSCLC) was proven to be a prognostic factor (p=0.0466). Our results imply that existing CCVD do adversely affect the outcome of NSCLC. When we decide whether or not to offer an intensive therapy which may increase treatment-related mortality, patients' medical condition including CCVD should be taken into consideration.

Peritoneal carcinomatosis in lung cancer patients.

Metastatic involvement of the peritoneum is not a very rare autopsy finding. Clinically, however, peritonitis carcinomatosis from a lung cancer is infrequently encountered and the pattern of the metastasis has not been studied. A total of 1041 patients with lung cancer who were admitted to our division over a 26-year period were retrospectively analyzed. Twelve (1.2%) of the 1041 patients with advanced lung cancer developed peritoneal carcinomatosis in their clinical courses. The incidence of peritoneal carcinomatosis was high in patients with large cell carcinoma and adenocarcinoma. Six and 9 of the 12 patients had metastases in intra-abdominal sites and pleural seeding, respectively. The median survival time from the diagnosis of peritoneal carcinomatosis was 2 months. Ascites accompanying metastasis to abdominal organs and pleural seeding in a patient with a known lung cancer would be regarded as a metastasis.

Patterns of brain metastasis in lung cancer.

Brain metastasis as the only site of spread in lung cancer was studied. Ninety-two (13.1%) of 701 lung cancer patients had brain metastasis at the time of diagnosis. Eighteen and 16 patients had small primary lesion and were N0-1 disease, respectively. Thirty-two patients had sole brain metastasis. Patients with sole brain metastasis had more favorable survival than patients with other metastatic sites (p=0.0165). Brain metastasis may occur even with small primary lesion and/or without regional lymph node involvement. Well-planned surgery or stereotactic radiosurgery will result in enhanced survival.

Lung cancer in middle-aged patients.

Clinicopathological features of middle-aged lung cancer patients were investigated in 1016 consecutive patients. Among them, 22.8% of patients were in their forties and fifties. The preponderance of adenocarcinomas and the higher female/male ratio in middle-aged groups compared with the older group were findings similar to those observed in younger patients. Smoking habit increased according to the age groups. Middle-aged patients had a propensity for advanced stage, however, survival was not inferior to younger patients. Middle-aged patients consisted of two different groups of patients, whose characteristics were similar to those observed in either younger or elderly patients.

Lung cancer in the octogenarian.

BACKGROUND: Older patients with lung cancer tend to have significant coexisting diseases and less aggressive treatment is often advisable. OBJECTIVE: To investigate the clinicopathological features of lung cancer in patients aged 80 years and over. METHODS: The medical records of 966 patients with lung cancer between 1976 and 1999 were reviewed retrospectively. RESULTS: There were 56 (5.8%) patients 80 years old or over. Thirty-nine (70%) were male, and 22 (39%) patients had poor performance status (2-4). Some of the patients had a medical history of cardiovascular disease (n = 23; 41%), cerebrovascular disease (n = 5; 9%), diabetes mellitus (n = 11; 20%), or malignant disease (n = 8; 14%). Twenty-one (35%) patients were diagnosed as having surgically resectable disease and 20 patients underwent radiotherapy, but 25 patients only received supportive care because of concomitant illnesses. Only 9 and 2 patients, respectively, had chemotherapy and surgery. There was no statistical difference in the survival rate of the two groups of patients receiving radiotherapy or supportive care. CONCLUSION: Adequate palliative care to provide prolonged quality survival is an appropriate primary goal of therapy for lung cancer in the octogenarian until less invasive treatments are developed.

Lung cancer patients with chronic obstructive pulmonary disease.

The aim of this study is to evaluate characteristics in lung cancer patients with chronic obstructive pulmonary disease (COPD). Among 966 lung cancer patients admitted to our division over a period of 24 years, 73 patients were diagnosed as having COPD. There were 68 (93.2%) men and 5 women; of the tumors 43 (58.9%) were squamous cell carcinomas. Although 41 (56.2%) patients had stage IA-IIIA, only 11 (15.1%) had surgery. Coexistence of COPD was proved to be a prognostic factor (p=0.0451). Adequate palliative care to provide quality survival would be the primary goal of therapy for lung cancer patients with COPD.