miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer.

INTRODUCTION: The ability to diagnose non-small cell lung cancer (NSCLC) at an early stage may lead to improved survival. The aim of this study was to identify differentially expressed serum-based microRNAs (miRNAs) between patients with early-stage NSCLC and controls. These miRNAs may serve as biomarkers for NSCLC early detection. METHODS: miRNA profiling was performed on total RNA extracted from serum obtained from 22 individuals (11 controls and 11 patients with early-stage NSCLC). Quantitative polymerase chain reaction (qPCR) was used to validate the profiling results in the discovery set and in a validation set of 31 controls and 22 patients with early-stage NSCLC. Additionally, six matched plasma samples (four NSCLC cases and two controls) and three serum mesothelioma samples were analyzed by qPCR. Receiver operating characteristic curves were generated for each possible combination of the miRNAs measured by qPCR. RESULTS: The expression of hsa-miR-1254 and hsa-miR-574-5p was significantly increased in the early-stage NSCLC samples with respect to the controls. Receiver operating characteristic curves plotting these two miRNAs were able to discriminate early-stage NSCLC samples from controls with 82% and 77% of sensitivity and specificity, respectively, in the discovery cohort and with 73% and 71% of sensitivity and specificity, respectively, in the validation cohort. The mesothelioma and plasma samples did not seem to classify into either NSCLC or control groups. CONCLUSIONS: Serum miRNAs are differentially expressed between patients with early-stage NSCLC and controls. The utility of miR-1254 and miR-574-5p serum-based biomarkers as minimally invasive screening and triage tools for subsequent diagnostic evaluation warrants additional validation.

Association of CYP19A1 polymorphisms with risks for atypical adenomatous hyperplasia and bronchioloalveolar carcinoma in the lungs.

Estrogen has been indicated to play an etiological role in the development of lung adenocarcinoma (ADC), particularly bronchioloalveolar carcinoma (BAC), a type of ADC that develops from a benign adenomatous lesion, atypical adenomatous hyperplasia (AAH). Polymorphisms in the CYP19A1 gene cause interindividual differences in estrogen levels. Here, 13 CYP19A1 single-nucleotide polymorphisms (SNPs) were examined for associations with lung AAH risk. AAH is detected as ground-glass opacity (GGO) by computed tomography (CT) examination, and this study consisted of 100 individuals diagnosed with GGO in their lungs among 3088 CT-based cancer screening examinees and 424 without. Minor allele carriers for the rs3764221 SNP showed an elevated risk for GGO [odds ratio (OR) = 1.72, P = 0.017]. Associations of this SNP with risks for lung AAH and BAC in the lungs were next examined using 359 ADC cases whose resected lung lobes were subjected to a histological examination for AAH accompaniment and the presence of BAC components and 330 controls without cancer. The ORs were also increased for lung ADC accompanied by AAH (OR = 1.74, P = 0.029) as well as lung ADC with BAC components (OR = 1.41, P = 0.091). The minor allele was associated with an increased circulating estradiol level (P = 0.079) in a population of 363 postmenopausal women without cancer. These results indicate that CYP19A1 polymorphisms are involved in the risk for lung AAH and BAC in the lungs by causing differences in estrogen levels.

FTY720 treatment in experimentally urethane-induced lung tumors.

FTY720 has been shown to prevent cancer development in experimental models but there is no report whether this beneficial effect is associated with the time point of the drug administration. Lung adenoma was induced in mice by urethane injection followed by different periods of FTY720 administration in order to evaluate lung tumor development. BALB/c mice received two doses (1, 5 g/kg) of urethane intraperitoneally and were submitted to five daily doses of FTY720 (1 mg/kg/day) starting just after urethane injection (G2 n=5), 4 weeks after urethane injection (G3 n=10), 8 weeks after urethane injection (G4 n=10) and no FTY720 administration (G1 n=5). Twenty-four weeks after urethane administration mice were evaluated for leukocyte numbers in blood, lymphocytes in spleen, and lungs were evaluated for changes in histology and PCNA expression. Lung nodules were present in higher numbers both in non treated (G1; 0.0-7.0) and FTY720 treated 8 weeks after urethane injection (G4; 0.0-6.0). G4 Group also presented the highest number of papillary nodules. There was a decrease in PCNA staining in early time FTY720 treated mice. Therefore, our data suggest that FTY720 treatment in early periods after lung tumor induction is beneficial and impairs adenoma development.

A multiparametric serum kallikrein panel for diagnosis of non-small cell lung carcinoma.

PURPOSE: Human tissue kallikreins are a family of 15 secreted serine proteases. We have previously shown that the expression of several tissue kallikreins is significantly altered at the transcriptional level in lung cancer. Here, we examined the clinical value of 11 members of the tissue kallikrein family as potential biomarkers for lung cancer diagnosis. EXPERIMENTAL DESIGN: Serum specimens from 51 patients with non-small cell lung cancer (NSCLC) and from 50 healthy volunteers were collected. Samples were analyzed for 11 kallikreins (KLK1, KLK4-8, and KLK10-14) by specific ELISA. Data were statistically compared and receiver operating characteristic curves were constructed for each kallikrein and for various combinations. RESULTS: Compared with sera from normal subjects, sera of patients with NSCLC had lower levels of KLK5, KLK7, KLK8, KLK10, and KLK12, and higher levels of KLK11, KLK13, and KLK14. Expression of KLK11 and KLK12 was positively correlated with stage. With the exception of KLK5, expression of kallikreins was independent of smoking status and gender. KLK11, KLK12, KLK13, and KLK14 were associated with higher risk of NSCLC as determined by univariate analysis and confirmed by multivariate analysis. The receiver operating characteristic curve of KLK4, KLK8, KLK10, KLK11, KLK12, KLK13, and KLK14 combined exhibited an area under the curve of 0.90 (95% confidence interval, 0.87-0.97). CONCLUSIONS: We propose a multiparametric panel of kallikrein markers for lung cancer diagnosis with relatively good accuracy. This model requires validation with a larger series and may be further improved by addition of other biomarkers.

Preoperative serum carcinoembryonic antigen level is a prognostic factor in women with early non-small-cell lung cancer.

BACKGROUND: Carcinoembryonic antigen (CEA) is one of the markers evaluated in patients with non-small cell lung cancer (NSCLC). The significance of the preoperative serum CEA level in female patients with NSCLC is seldom discussed. In this study, we conducted a retrospective review to investigate the prognostic significance of the preoperative CEA level in female patients with stage I NSCLC. METHODS: In this study, we looked at 163 female patients with stage I NSCLC. Patient charts were reviewed to collect patient data, including the age of the patient, tumor location, tumor size, visceral pleural invasion, the stage of disease, and the preoperative serum CEA level. The cutoff value of serum CEA level was 6.0 ng/mL. The significance of preoperative CEA level in the prognosis of female patients with stage I NSCLC was evaluated. RESULTS: Among the 163 female patients with stage I NSCLC, 47 patients (28.8%) had abnormal preoperative serum CEA level (>6 ng/mL). Diagnosis of adenocarcinoma and bronchoalveolar carcinoma accounted for 83.4% of these 163 female patients. In-hospital mortality was encountered in 1 patient. Univariate analysis of survival in the other 162 female patients with stage I NSCLC showed that age, stage, tumor size, and preoperative CEA level were prognostic factors. Visceral pleural invasion had no impact on the prognosis of these patients. Multivariate analysis revealed that tumor size and preoperative CEA level were independent prognostic factors in female patients with stage I NSCLC. CONCLUSIONS: Preoperative serum CEA level and tumor size are independent prognostic factors in female patients with stage I NSCLC. In contrast, visceral pleural invasion was not associated with the prognosis. Importantly, these results suggest that female patients with abnormally high preoperative CEA level and tumor size larger than 3 cm may need a thorough preoperative evaluation and careful postoperative follow-up to rule out occult metastasis of early NSCLC.

Multiple bronchioloalveolar carcinomas in acromegaly: a potential role of insulin-like growth factor I in carcinogenesis.

The molecular pathogenesis of lung cancer, especially multiple and synchronous bronchioloalveolar carcinomas (BACs), is still unknown. Here, we report two cases of multiple BACs associated with acromegaly, and discuss about the possible relationship between these two pathological condition. The first patient was a 52-year-old female with a history of Hardy's surgery for pituitary growth hormone cell adenoma 2 years earlier. The second patient was a 57-year-old female with acromegaly and obstructive sleep apnea syndrome. Both patients were non-smokers and showed a high serum level of insulin-like growth factor I (IGF-I) at the time of admission, even though the level of growth hormone had decreased. High-resolution computed tomography (HRCT) revealed multiple small nodules with pure ground-glass opacity (GGO) in both lungs of the first patient and a small nodule with pure GGO in the right lung of the second one. Partial resection for these tumors were performed under video-assisted thoracoscopic surgery. Resected lung specimens of the first case revealed one papillary adenocarcinoma, seven BACs, and 11 atypical adenomatous hyperplasias (AAHs). The second case showed two foci of BACs. Immunohistochemically, all BACs were strongly positive for IGF-IR which is a specific receptor for IGF-I, and all AAHs were also weakly positive for IGF-IR. Since IGF-I is known as a potent growth factor for normal as well as cancerous cells, it might play an important role for tumorigenesis and/or tumor progression of BACs through its interaction with and/or upregulation of IGF-IR. In addition, much attention should be paid to detect lung lesions in acromegaly with high serum level of IGF-I.

[Blood gas analysis in bronchiolo-alveolar carcinoma]. / Blutgasanalyse bei bronchiolo-alveolärem Karzinom.

A 44-year old patient is presented with bronchiolo-alveolar carcinoma which had set multiple metastases into the lung. Basic lung function was normal. It is of interest that only blood gases were borderline. There was a huge discrepancy between the extension of the pulmonary tumour and the impairment of lung function. Hence, blood gas analysis at rest and under exercise is a necessary tool in such cases.

Clinical investigation of bronchioloalveolar carcinoma: a retrospective analysis of 53 patients in a single institution.

BACKGROUND: Bronchioloalveolar carcinoma (BAC) has been reported to have unique clinicopathological features. PATIENTS AND METHODS: This retrospective study was performed using data base including 871 patients treated for primary lung cancer between 1981 and 1995. RESULTS: The patients with BAC included a larger proportion of female (P = 0.029) and smoked less (P = 0.002) than those with non-BAC. There was no difference in survival between surgically resected patients with BAC and those with non-BAC. Clinical Stage IV patients with BAC had a better response to chemotherapy than did those with non-BAC. Survival in the former group was better than that in the latter on univariate analysis, but the significance of this difference was not confirmed multivariate analysis. CONCLUSION: The patients with BAC included a larger proportion of females and smoked less than those with non-BAC. Treatment results for BAC was comparable to those for non-BAC.

Double lung cancer combined with idiopathic thrombocytopenic purpura. A case report.

A 68-year-old woman was admitted because of two abnormal lung shadows, which later proved to be differentiated double cancer. Preoperative hematology tests showed a low platelet count and the result of bone marrow aspiration was compatible with idiopathic thrombocytopenic purpura (ITP). A normal platelet count was once obtained by preoperative percutaneous partial splenic arterial embolization (PSE). However, as there was a tendency for the platelet count to decrease just before surgery, one shot high-dose immunoglobulin (Ig) was administered, which is thought to have a short term effect. The operation was performed successfully. After resection of lung cancer, her platelet count was maintained at around 15x10(4) mm3 without taking drugs for ITP. These findings suggest a relationship between lung cancer and ITP.

Amylase-producing lung cancer.

A bronchioloalveolar carcinoma of lung associated with hyperamylasemia occurring in a 40-year-old woman is described. Another 13 cases of such a tumor from the English literature are reviewed. A majority of the lung tumors associated with hyperamylasemia were adenocarcinomas. When the amylase isoenzymes were determined, the amylase appeared to be salivary-gland type (S-type). Electron microscopic studies had revealed membrane-bound electron-dense granules within the tumor cells.

Disseminated intravascular coagulation in prostatic disease.

DIC may complicate prostatic disease either in its acute type during resection of the prostate causing excessive intra- or postoperative bleeding, or in its chronic type in cases with adenocarcinoma of the prostate with haematogenous metastases. Pathogenesis, diagnosis, clinical course, differentiation of the condition against consumption of clotting factors by primary fibrinolysis, and treatment are discussed. The course in four characteristic cases is demonstrated.