Overexpression of filamin-A protein is associated with aggressive phenotype and poor survival outcomes in NSCLC patients treated with platinum-based combination chemotherapy.

An actin-binding protein filamin A connects the actin filament network to cell membrane receptors, and acts as a scaffold for various signaling pathways related to cancer growth and progression. Recently, it has been reported that filamin A is required for efficient regulation of early stages of DNA repair process. Moreover, some in vitro studies showed that the overexpression of filamin A determines resistance to various cytotoxic drugs, including cisplatin. We aimed to analyse the expression of filamin A protein in resected NSCLC (Non Small Cell Lung Cancer) specimens, to investigate the association of the level of filamin A protein expression and other clinicopathological features, and possible relationship between the expression of filamin A and survival outcome in NSCLC patients, treated with platinum-based combination chemotherapy. We performed filamin A protein immunohistochemistry on formalin-fixed and paraffin-embedded (FFPE) tissue sections from 135 NSCLC patients, using EP2405Y antibody against C-terminus of filamin A. Cytoplasmic, membranous and nuclear positivity of filamin A was evaluated semi-quantitatively and correlated with available clinicopathological data. Patients were divided into two groups for survival analysis (I group - patients treated with adjuvant platinum-based chemotherapy, II group - patients with surgical treatment only). We found significant positive correlation between filamin A protein expression and NSCLC stage (r=0.249; p<0,05), presence of lymph node (N)(r=0.205; p<0,05) and distant metastases (M) (r=0.332; P<0.01). Increased filamin A protein expression was significantly related with poor survival outcomes in patients with adjuvant platinum-based chemotherapy: OS (HR=1.005, 95%CI[1.000;1.010], p=0.037), DFS (HR=1.004, 95%CI [1.001:1.008], p=0,017). Multivariate Cox proportional hazards regression analysis also showed that overexpression of filamin A represents an independent risk factor for disease relapse, in addition to tumor size, stage, and metastases status (HR=1.723, 95%CI [1.021:2.909], p<0.05). Thus, filamin A expression might be a new prognostic marker in patients with NSCLC.

[Neoadjuvant chemotherapy and surgical treatment in advanced stages of non-small cell lung cancer]. / Neoadjuvantní chemoterapie a chirurgická lécba u pokrocilých stadií nemalobunecného karcinomu plic.

INTRODUCTION: Lung cancer takes first place in both incidence and mortality in the Czech Republic. This is associated with the disease being diagnosed in late stages, which limits the possibility of radical therapy. Five-year survival of patients operated on with stage IIIA is low and doesn't even reach 20%. These poor results and the development of systemic chemotherapy in the 1990's led to an effort to treat locally advanced disease by administering chemotherapy before the surgical procedure- induction chemotherapy. Its benefit, however, unlike that of adjuvant chemotherapy, remains unclear. AIM: To analyze and compare the results between a set of patients with non-small cell lung cancer (NSCLC) with stage III A-B, operated on at the I. Department of Surgery at the University Hospital and Palacky Medical Faculty in Olomouc between the years 2000-2008, who underwent preoperative chemotherapy with the results of patients with stage III A-B diagnosed after the operation based on histological findings. Three- and five-year survivals, as well as survival median, were evaluated in both groups. RESULTS: A statistically significant difference in survival between the two groups was not observed. CONCLUSION: Neoadjuvant chemotherapy remains controversial in the treatment of NSCLC. The initially promising results have not been unequivocally confirmed in later studies and its role remains a question to be answered in future extensive randomized studies.

[Importance of neoadjuvant chemotherapy in the treatment of advanced bronchogenic carcinoma]. / Význam neoadjuvantní chemoterapie v lécbe pokrocilého bronchogenního karcinomu.

BACKGROUND: The basic task of induction (neo-adjuvant) therapy is elimination of occult micrometastatic dissemination found in some cases already in localized stages of non-small cell pulmonary cancer (stage I-IIIA NSCLC). An equally important effect is also cytoreduction in primary tumours which have before the local intervention an intact vascular supply. A difficult problem remains the correct selection of patients who from the long-term aspect may profit from such a procedure. MATERIAL AND METHODS: The authors evaluated perspectively aspects of oncological treatment and circumstances of surgical intervention after induction chemotherapy in 81 and 87 patients resp. in stage IIIA NSCLC evaluated before initiated neo-adjuvant chemotherapy. RESULTS: Complete remission was recorded in 4.9%, partial remission in 50.6%, stabilized disease in 23.5% and progression in 21% patients. Down-staging was recorded in 26%, 70.3% patients were indicated for surgery. In the group of 87 patients operated after induction therapy pneumonectomies predominated--41 (46%), only one operated patient died within 30 days after surgery (1.1%), complications were neither frequent nor serious. The median of survival after radical resection is 26 months. CONCLUSIONS: Neo-adjuvant chemotherapy by modern cytostatics is usually well tolerated and creates satisfactory conditions for successful complete resection. The operation proper may be more difficult but need not be associated with serious complications. By this treatment it is probably possible to influence long-term results not only in stage IIIA but to reduce also the risk of a later more remote metastatic dissemination in some patients operated in lower stages of lung cancer. Our present aim is to test parameters which will be able to predict possible failure of induction therapy, and seek factors predicting risk behaviour of the tumour also in lower stages (stage I and II TNM classification).

[Assessment of metastatic potential of pulmonary carcinoma]. / Odhad metastatického potenciálu plicního karcinomu.

The authors evaluated in a group of 25 patients after radical lung resection on account of a non-small cell carcinoma the correlation between tumour grading, invasion into lymphatic and blood vessels, proliferation markers (Ki-67, PCNA), ploidy, cell polymorphism and mitotic cell activity of the lung tumour and the lymphogenic or haematogenic metastatizing proved before or during surgery. From the investigation patients after induction chemotherapy were eliminated. It was of interest that the great majority of investigated parameters was positive or elevated in patients with lymphogenic or haematogenic metastases. Conversely in patients where the majority of these parameters was negative on the day of the operation, no metastases were detected. In the group of patients where the investigated indicators were positive and no metastasis was found, similarly as in both previous sub-groups, the author will continue to follow-up the following: recurrence, median survival and five-year survival. From the assembled parameters a table was prepared stratifying the risk of metastases.

Lung resection in a neoadjuvant protocol.

Neoadjuvant therapy was defined as a cytoreductive therapy administered prior to a definitive locoregional treatment--surgical resection. While surgical resection can be curative in patients diagnosed with localized early-stage non-small cell lung cancer, patients with nodal (N1, N2) disease are generally not candidates for exclusive surgery. Inductive therapy can improve the microscopic metastatic disease, eradicate the primary tumor and thereby improve survival.