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Repeat mediastinoscopy in all its indications: experience with 96 patients and 101 procedures.

To evaluate the accuracy of repeat mediastinoscopy (reMS) in all its indications, and to analyse survival in the group of patients who underwent induction chemotherapy or chemoradiotherapy for pathologically proven stage III-N2 non-small-cell lung cancer (NSCLC).

Methods: From July 1992 to February 2009, 96 patients (87 men; median age: 61.3 years), underwent 101 reMSs (five patients required a second reMS) for the following

indications: restaging after induction therapy for pathologically proven N2 disease (84 cases), inadequate first mediastinoscopy (five), metachronous second primary (six) and recurrent lung cancer (six). Patients with N2-NSCLC, who had received induction therapy and had positive reMS, underwent definitive chemotherapy or chemoradiotherapy. Patients in whom reMS was negative underwent thoracotomy for lung resection and systematic nodal dissection (SND). SND was considered the gold standard to compare the negative results of reMS. Pathologic findings were reviewed and staging values were calculated using the standard formulas. Follow-up data were completed in January 2010, and survival analysis was performed by the Kaplan-Meier method.

Results: In the group of reMS for restaging after induction therapy, the staging values were: sensitivity 0.74, specificity 1, positive predictive value 1, negative predictive value 0.79 and diagnostic accuracy 0.87. We also determined the diagnostic value of this technique according to the type of induction treatment. In terms of accuracy, no statistically significant differences were found. Median survival time in patients with true negative reMS was 51.5 months (95% confidence interval (CI) 0-112), and in the combined group of patients with positive and false-negative reMS, median survival time was 11 months (95% CI 7.6-14.1) (p=0.0001). In the group of miscellaneous indications, all staging values were 1.

Conclusion: ReMS is feasible in all the indications described. After induction therapy, it is a useful procedure to select patients for lung resection with high accuracy, independently of the induction treatment used or the intensity of the first mediastinoscopy. The persistence of lymph node involvement after induction therapy has a poor prognosis. Therefore, techniques providing cytohistological evidence of nodal downstaging are advisable to avoid unnecessary thoracotomies.

Plasma microRNAs as potential biomarkers for non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death. Developing minimally invasive techniques that can diagnose NSCLC, particularly at an early stage, may improve its outcome.

Using microarray platforms, we previously identified 12 microRNAs (miRNAs) the aberrant expressions of which in primary lung tumors are associated with early-stage NSCLC. Here, we extend our previous research by investigating whether the miRNAs could be used as potential plasma biomarkers for NSCLC.

We initially validated expressions of the miRNAs in paired lung tumor tissues and plasma specimens from 28 stage I NSCLC patients by real-time quantitative reverse transcription PCR, and then evaluated diagnostic value of the plasma miRNAs in a cohort of 58 NSCLC patients and 29 healthy individuals. The altered miRNA expressions were reproducibly confirmed in the tumor tissues.

The miRNAs were stably present and reliably measurable in plasma. Of the 12 miRNAs, five displayed significant concordance of the expression levels in plasma and the corresponding tumor tissues (all r>0.850, all P<0.05). A logistic regression model with the best prediction was defined on the basis of the four genes (miRNA-21, -126, -210, and 486-5p), yielding 86.22% sensitivity and 96.55% specificity in distinguishing NSCLC patients from the healthy controls. Furthermore, the panel of miRNAs produced 73.33% sensitivity and 96.55% specificity in identifying stage I NSCLC patients. In addition, the genes have higher sensitivity (91.67%) in diagnosis of lung adenocarcinomas compared with squamous cell carcinomas (82.35%) (P<0.05).

Altered expressions of the miRNAs in plasma would provide potential blood-based biomarkers for NSCLC.

Third-line therapy for advanced non-small-cell lung cancer patients: feasible drugs for feasible patients.

The proven benefit of third-line treatment in advanced non-small cell lung cancer (NSCLC) is still unclear. We retrospectively evaluated the outcome of advanced NSCLC patients treated with third-line therapies in our institution, especially focusing on efficacy and toxicity between mono-therapy and doublets chemotherapy, aiming to assess the value of third-line treatment and evaluate the efficacy of different regimens in third-line treatment.

Three hundred and seventeen patients received a second-line treatment among 620 advanced NSCLC after failure of first-line chemotherapy. One hundred and twenty-six patients from this group were offered third-line or further-line treatments. Survival analysis was conducted based on Kaplan-Meier method, and Chi-square was used to compare data between second-line and third-line group.

There were significant differences in overall survival between second-line and third-line treatments (17.70 months vs. 24.03 months, P < 0.0001). Twenty-four patients received single chemotherapy, epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) were used to treat thirty-three patients and sixty-nine patients received doublet chemotherapy in third-line treatment. The progression-free survival (PFS) after third-line therapy was 2.37 months in all patients and 2.30 months, 2.80 months, 2.97 months, in the doublet chemotherapy, single-agent chemotherapy, and EGFR-TKIs arms, respectively (P = 0.033). Cancer-related symptom relief improvement was confirmed in 78.9% patients (60/78). Forty-eight patients had no symptoms as confirmed by imaging examination.

Patients with advanced NSCLC could get benefits from third-line treatments. Those patients could obtain a moderate progression-free survival and conspicuous improvement in the cancer-related symptom. Mono-therapy was recommended in third-line treatment.

Biomarkers of DNA repair and related pathways: significance in non-small cell lung cancer.

To review selected biomarkers of DNA repair and related pathways as they relate to the management of patients with non-small cell lung cancer (NSCLC), emphasizing the role of individualized, chemotherapy for advanced disease, and discussing potential applications in early disease.

RECENT FINDINGS: The activity of molecular-targeted agents in NSCLC patients whose tumor possesses relevant biomarkers [such as epidermal growth factor receptor (EGFR) activating mutations and ALK translocations] has made personalized therapy possible. In addition, preclinical and clinical studies have shown that histopathological and biomolecular factors can correlate with clinical outcome in patients with NSCLC treated with chemotherapy. As a result, tumor histology is now routinely considered in selecting chemotherapy for NSCLC patients, such as pemetrexed for nonsquamous histology. Molecular tumor and host factors, including genes involved in DNA-repair and synthesis, are potentially even more relevant as predictive biomarkers of tumor response to chemotherapy. However, individual molecular markers and gene signatures need further validation and standardization, before routine use in the clinic can be recommended.

SUMMARY: In the era of molecular-targeted agents, individualized therapy based on molecular biomarkers has become a reality in the treatment of patients with advanced NSCLC. Further studies are needed to optimize current treatment algorithms with regard to biomarkers for chemotherapy benefit, to refine molecular markers, and to translate these findings to early stage NSCLC.

Targeting non-malignant disorders with tyrosine kinase inhibitors.

Receptor and non-receptor tyrosine kinases are involved in multiple proliferative signalling pathways. Imatinib, one of the first tyrosine kinase inhibitors (TKIs) to be approved, revolutionized the treatment of chronic myelogenous leukaemia, and other TKIs with different spectra of kinase inhibition are used to treat renal cell carcinoma, non-small-cell lung cancer and colon cancer.

Studies also support the potential use of TKIs as anti-proliferative agents in non-malignant disorders such as cardiac hypertrophy, and in benign-proliferative disorders including pulmonary hypertension, lung fibrosis, rheumatoid disorders, atherosclerosis, in-stent restenosis and glomerulonephritis.

In this Review, we provide an overview of the most recent developments - both experimental as well as clinical - regarding the therapeutic potential of TKIs in non-malignant disorders.

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