Pablo Martinez

Fluorescence In Situ Hybridization and Immunohistochemistry as Diagnostic Methods for ALK Positive Non-Small Cell Lung Cancer Patients

Background Anaplastic Lymphoma Kinase (ALK) positivity represents a novel molecular target in a subset of Non-Small Cell Lung Cancers (NSCLC). We explore Fluorescence in situ Hybridization (FISH) and Immunohistochemistry (IHC) as diagnostic methods for ALK positive patients and to describe its prevalence and outcomes in a population of NSCLC patients. Methods NSCLC patients previously screened for Epidermal Growth Factor Receptor (EGFR) at our institution were selected. ALK positive patients were identified by FISH and the value of IHC (D5F3) was explored. Results ninety-nine patients were identified. Median age was 61.5 years (range 35–83), all were caucasians, eighty percent were adenocarcinomas, fifty-one percent were male and thirty-eight percent were current smokers. Seven (7.1%) patients were ALK positive by FISH, thirteen (13.1%) were EGFR mutant, and 65 (65.6%) were negative/Wild Type (WT) for both ALK and EGFR. ALK positivity and EGFR mutations were mutually exclusive. ALK positive patients tend to be younger than EGFR mutated or wt patients. ALK positive patients were predominantly never smokers (71.4%) and adenocarcinoma (71.4%). ALK positive and EGFR mutant patients have a better outcome than negative/WT. All patients with ALK FISH negative tumours were negative for ALK IHC. Out of 6 patients positive for ALK FISH with more tissue available, 5 were positive for ALK IHC and 1 negative. Conclusions ALK positive patients represent 7.1% of a population of selected NSCLC. ALK positive patients have different clinical features and a better outcome than EGFR WT and ALK negative patients. IHC is a promising method for detecting ALK positive NSCLC patients.

Exploratory analysis of activation of PTEN–PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM)

BACKGROUND Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with elevated AKT/mTOR activity. We aimed to identify the expression and phosphorylation status of PTEN, PI3K and downstream signaling in MPM. PATIENTS AND METHODS Thirty consecutive MPM patients were identified. Clinical data analyzed: sex, age, histology, performance status (PS), white blood count, and neutrophil-lymphocyte ratio (NLR). Paraffin-embedded biopsies were used for immunohistochemical analysis. RESULTS Overexpression of PTEN, pMAPK, mTOR, pAKT, 4E-BP1, p4E-BP1, eIF-4E, peIF-4E, p-S6 and FOXO3a in MPM was found in 90%, 100%, 93.3%, 80%, 100%, 43.3%, 96.7%, 100%, 63.3% and 100% of tumors respectively. There was a significant correlation between low pS6 protein expression and longer progression free survival (PFS: 7.9 vs 5.6 months; p = 0.04) and overall survival (OS: 23.4 vs 5.6 months; p = 0.05). Patients with concomitant low expression of pS6 and p4E-BP1 and overexpression of FOXO3a had significantly better prognosis (34.6 vs 1.9 months; p = 0.004). In multivariate analysis, histology and NLR were independent prognostic factors (p = 0.02 and p = 0.04 respectively), but pS6 only showed a trend (p = 0.8). CONCLUSIONS This study shows PI3K pathway and downstream proteins in MPM are frequently activated and provides prognostic information. The role of PI3K pathway is worth of prospective validation in future studies on MPM.

Phase I Safety and Pharmacokinetic Study of the PI3K/mTOR Inhibitor SAR245409 (XL765) in Combination with Erlotinib in Patients with Advanced Solid Tumors

Introduction: The primary objectives of this phase I study were to evaluate the safety and maximum tolerated dose (MTD) of SAR245409, a pan-class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin inhibitor, combined with erlotinib in patients with advanced solid tumors. Methods: Forty-six patients with advanced solid tumors were enrolled. Patients with lung cancer (n = 37) had received an epidermal growth factor receptor (EGFR) inhibitor before study entry. SAR245409 30, 50, 70, or 90 mg once daily (QD) or 20 or 30 mg twice daily (BID) was administered, in combination with erlotinib 100 mg QD, in 28-day cycles. Dose escalation of SAR245409 followed a standard 3 + 3 design. Patients were evaluated for adverse events (AEs). Additional evaluations included pharmacokinetics, pharmacodynamic effects on PI3K and EGFR/mitogen-activated protein kinase signaling pathways in tumor and skin samples, and tumor response. Results: The MTDs of SAR245409, in combination with erlotinib 100 mg QD, were 70 mg QD and 20 mg BID. The most frequently reported treatment-related AEs (any grade) were diarrhea (35%), rash (35%), and nausea (28%). No treatment-related AE occurred at grade 3/4 in more than one patient (2.2%). No major pharmacokinetic interaction between SAR245409 and erlotinib was noted. Suppression of PI3K and EGFR/mitogen-activated protein kinase signaling pathway biomarkers was observed in skin and tumor samples. Stable disease was the best overall response reported, occurring in 12 of 32 (37.5%) evaluable patients. Conclusion: MTDs of SAR245409 and erlotinib were below the single-agent doses of either agent, despite the lack of major pharmacokinetic interaction.

Adjuvant treatment of resected nonsmall cell lung cancer: state of the art and new potential developments.

Purpose of review Approximately 50% of surgically resected early stage lung cancer patients will relapse and die of recurrent disease within 5 years. In order to reduce the risk of relapse and improve survival, efforts have been focused on the use of chemotherapy before or after surgery. The benefit of adjuvant cisplatin-based chemotherapy is widely accepted for patients with resected stage II–IIIA, although its impact on survival is limited. There is, therefore, a need to find other strategies to further improve survival outcomes. Recent findings In recent years, there has been a marked increase in the development of novel therapeutic strategies targeting signaling pathways, such as epidermal growth factor receptor, angiogenesis, and immunotherapy in stage IV nonsmall cell lung cancer. The potential contribution of these strategies in the adjuvant setting is now being analyzed in randomized clinical trials. Summary At present, the challenge for research in early stage disease is to define subsets of patients who benefit from certain targeting agents and establish how to integrate such agents into the adjuvant setting.

Molecular targeted therapy for early-stage non-small-cell lung cancer: Will it increase the cure rate?

Non-small-cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases, with a world-wide annual incidence of around 1.3 million. Surgery remains the corner stone of treatment in early-stage NSCLC when feasible, and the addition of adjuvant cisplatin-based chemotherapy has improved these results in resected NSCLC patients. For those patients with non-metastatic NSCLC not suitable for complete surgical resection, chemotherapy plus radiotherapy remains the best treatment option. For patients with metastatic NSCLC, molecular targeted agents have become part of the therapeutic arsenal in recent years. However, to date no targeted agent has been approved for patients with early or locally-advanced stages of NSCLC. Here, we review the rationale, literature and studies addressing the role of targeted agents used in the adjuvant setting or as part of chemoradiotherapy regimens.

Cabazitaxel Versus Topotecan in Patients with Small-Cell Lung Cancer with Progressive Disease During or After First-Line Platinum-Based Chemotherapy.

Introduction: Patients with small-cell lung cancer (SCLC) typically respond well to initial chemotherapy. However, relapse invariably occurs, and topotecan, the only approved second-line treatment option, has limited efficacy. Taxanes have activity in SCLC, and cabazitaxel is a second-generation taxane with potential for enhanced activity in chemorefractory malignancies. Methods: Patients with SCLC who relapsed after initial platinum-based chemotherapy were randomly assigned to receive cabazitaxel 25 mg/m2 every 21 days or topotecan 1.5 mg/m2 on days 1–5 every 21 days. Two patient subgroups, defined by chemosensitive and chemo-resistant/refractory disease, were assessed in combination and separately. Results: The safety profile of cabazitaxel and topotecan was consistent with previous studies, and despite considerable toxicity in both arms, no new safety concerns were identified. Patients receiving cabazitaxel had inferior progression-free survival compared with topotecan (1.4 versus 3.0 months, respectively; two-sided p < 0.0001; hazard ratio = 2.17, 95% confidence interval = 1.563–3.010), and results were similar in both the chemosensitive and chemorefractory subgroups. No complete responses were observed in either arm, and no partial responses were observed in the cabazitaxel group. The partial response rate in the topotecan arm was 10%. Median overall survival was 5.2 months in the cabazitaxel arm and 6.8 months in the topotecan arm (two-sided p = 0.0125; hazard ratio = 1.57, 95% confidence interval = 1.10–2.25). Conclusion: Cabazitaxel, a next-generation taxane, had inferior efficacy when compared with standard-dose topotecan in the treatment of relapsed SCLC. Topotecan remains a suboptimal therapy, and continued efforts to develop improved second-line treatments are warranted.

Experiencia de los Servicios de Cirugía Torácica españoles en el tratamiento del pectus excavatum mediante la técnica de Nuss

INTRODUCTION Although the Nuss technique revolutionized the surgical treatment of pectus excavatum, its use has not become widespread in our country. The aim of this study was to analyze the current use of this technique in a sample of Thoracic Surgery Departments in Spain. METHODS Observational rectrospective multicentric study analyzing the main epidemiological aspects and clinical results of ten years experience using the Nuss technique. RESULTS Between 2001 and 2010 a total of 149 patients were operated on (mean age 21.2 years), 74% male. Initial aesthetic results were excellent or good in 93.2%, mild in 4.1% and bad in 2.7%. After initial surgery there were complications in 45 patients (30.6%). The most frequent were wound seroma, bar displacement, stabilizer break, pneumothorax, haemothorax, wound infection, pneumonia, pericarditis and cardiac tamponade that required urgent bar removal. Postoperative pain appeared in all patients. In 3 cases (2%) it was so intense that it required bar removal. After a mean follow-up of 39.2 months, bar removal had been performed in 72 patients (49%), being difficult in 5 cases (7%). After a 1.6 year follow-up period good results persisted in 145 patients (98.7%). CONCLUSION Nuss technique in adults has had good results in Spanish Thoracic Surgery Departments, however its use has not been generalized. The risk of complications must be taken into account and its indication must be properly evaluated. The possibility of previous conservative treatment is being analyzed in several departments at present.

Bone metastases with nerve root compression as a late complication in patient with epithelial pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor with dismal prognoses and poor response to treatments. The most frequent symptoms are due to local invasion. Distant metastases are not uncommon and usually appear at late stage of the disease. However, metastases in bone have rarely been well documented. Here we report the case of a MPM patient with nerve root compression due to bone metastases 18 months after the first diagnoses of MPM.