Expression of phosphorylated ribosomal protein S6 in mesothelioma patients - correlation with clinico-pathological characteristics and outcome: results from the European Thoracic Oncology Platform (ETOP) Mesoscape project.

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p < 0.001, 10.7 versus 16.9 months) and PFS (p < 0.001, 6.2 versus 10.8 months). In subgroup analysis, in non-epithelioid PM patients high pS6 expression was associated with significantly shorter OS and PFS. These exploratory findings suggest a clinically relevant PI3K pathway activation in non-epithelioid PM which might lay the foundation for future targeted treatment strategies.

Giant tuberculin reaction associated with the homeopathic drug tuberculinum: a case report.

Giant reactions to the tuberculin skin test are extremely rare and have been previously reported almost exclusively in patients with lepromatous leprosy. We herein report a giant tuberculin reaction associated with the homeopathic drug Tuberculinum in a patient with no evidence of active tuberculosis or leprosy.

European Epidemiology of Pleural Mesothelioma-Real-Life Data From a Joint Analysis of the Mesoscape Database of the European Thoracic Oncology Platform and the European Society of Thoracic Surgery Mesothelioma Database.

INTRODUCTION: Pleural mesothelioma (PM) is an aggressive malignancy with increasing prevalence and poor prognosis. Real-life data are a unique approach to reflect the reality of PM epidemiology, treatment, and prognosis in Europe. METHODS: A joint analysis of the European Thoracic Oncology Platform Mesoscape and the European Society of Thoracic Surgeons (ESTS) databases was performed to better understand the characteristics and epidemiology of PM, including histologic subtype, staging, and treatment. Overall survival (OS) was assessed, adjusting for parameters of clinical interest. RESULTS: The analysis included 2766 patients (Mesoscape: 497/10 centers/ESTS: 2269/77 centers). The primary histologic subtype was epithelioid (71%), with 57% patients on stages III to IV. Within Mesoscape, the patients received either multimodality (59%) or palliative intention treatment (41%). The median follow-up was 47.2 months, on the basis of 1103 patients (Mesoscape: 491/ESTS: 612), with 823 deaths, and median OS was 17.4 months. In multivariable analysis, female sex, epithelioid subtype, and lower stage were associated with longer OS, when stratifying by cohort, age, and Eastern Cooperative Oncology Group Performance Status. Within Mesoscape, multimodality treatment including surgery was predictive of longer OS (hazard ratio = 0.56, 95% confidence interval: 0.45-0.69), adjusting for sex, histologic subtype, and Eastern Cooperative Oncology Group Performance Status. Overall, surgical candidates with a macroscopic complete resection had a significantly longer median OS compared with patients with R2 (25.2 m versus 16.4 m; log-rank p < 0.001). CONCLUSIONS: This combined European Thoracic Oncology Platform/ESTS database analysis offers one of the largest databases with detailed clinical and pathologic outcome. Our finding reflects a benefit for selected patients that undergo multimodality treatment, including macroscopic complete resection, and represents a valuable resource to inform the epidemiology and treatment options for individual patients.

Triplet combination of carboplatin, irinotecan, and etoposide in the first-line treatment of extensive small-cell lung cancer: a single-institution phase II study.

Small-cell lung cancer is a rapidly progressive tumor and median survival is less than 10 months in patients with extensive stage of the disease. This study aims to evaluate the efficacy and tolerability of the carboplatin, etoposide, and irinotecan triplet as a first-line treatment in extensive small-cell lung cancer. Chemonaive patients with documented diagnosis of extensive small-cell lung cancer, performance status 0-2, and adequate organ function were eligible. Patients received triweekly carboplatin area under the curve 5 on day 1, irinotecan 150 mg/m on day 2, and etoposide 75 mg/m on days 1, 2, and 3 for up to six cycles. A total of 54 patients were enrolled. Forty-seven of 54 patients (87%) had a performance status of 0-1. The response rate was 75% and complete response was achieved in 10 of 54 patients (18%). The median time to progression was estimated at 8 months (95% confidence interval: 6.6-8.9) and median overall survival at 12 months (95% confidence interval: 10.3-13.9). Patients with one site of metastases had prolonged survival as compared with those with two or more sites. Normalization of lactate dehydrogenase values after treatment was not correlated to survival. Grade 3-4 neutropenia occurred in nine patients (16.7%) and grade 3 fetal thrombocytopenia in one patient (1.9%). Two toxic deaths (3.7%) were reported. The carboplatin, irinotecan, and etoposide triplet is a very effective and well-tolerated combination for the poor prognosis group of extensive-stage small-cell lung cancer patients.

Therapy-induced toxicity of the lungs: an overview.

UNLABELLED: Pulmonary toxicity induced by novel antineoplastic agents has not been well characterized because of the simultaneous or sequential use of drugs and a multimodality therapeutic approach. To further investigate this topic, relevant studies were identified through Medline. The generic names of novel antineoplastic agents and the key words pulmonary toxicity, dyspnea and pneumonitis were used for the search. References from the articles identified were also reviewed for additional sources. Most novel antineoplastic drugs may induce pulmonary toxicity. The most recognized patterns of lung toxicity consist of unspecified dyspnea and interstitial lung disease (ILD). Exclusion diagnosis of possible underlying diseases is necessary. Genetic predisposition, autoimmune conditions or superimposed disease may also be involved in the development of lung toxicity. CONCLUSION: Clinicians should be aware of potential pulmonary toxicity as a complication in the treatment of cancer and focus on its early detection or prediction.

Cardiopulmonary exercise testing (CPET) as preoperative test before lung resection.

Lung resection is still the only potentially curative therapy for patients with localized non-small lung cancer (NSCLC). However, the presence of cardiovascular comorbidities and underlying lung disease increases the risk of postoperative complications. Various studies have evaluated the use of different preoperative tests in order to identify patients with an increased risk for postoperative complications, associated with prolonged hospital stay and increased morbidity and mortality. In this topic review, we discuss the role of cardiopulmonary exercise testing (CPET) as one of the preoperative tests suggested for lung cancer patients scheduled for lung resection. We describe different types of exercise testing techniques and present algorithms of preoperative evaluation in lung cancer patients. Overall, patients with maximal oxygen consumption (VO2max) <10 mL/kg/min or those with VO2max <15 mL/kg/min and both postoperative FEV1 and DLCO<40% predicted, are at high risk for perioperative death and postoperative cardiopulmonary complications, and thus should be offered an alternative medical treatment option.

Endoscopic and endobronchial ultrasound-guided needle aspiration in the mediastinal staging of non-small cell lung cancer.

Invasive staging of mediastinal lymph nodes is recommended for the majority of patients with potentially resectable non-small cell lung cancer. In the past, 'blind' transbronchial needle aspiration during bronchoscopy and mediastinoscopy, a surgical procedure conducted under general anesthesia, were the only diagnostic methods. The latter is still considered the 'gold standard'; however, two novel, minimally-invasive techniques have emerged for the evaluation of the mediastinum: endoscopic (transesophageal) and endobronchial ultrasound--both performed using a dedicated echoendoscope, facilitating the ultrasound-guided, real-time aspiration of mediastinal lymph nodes. These methods are well-tolerated under local anesthesia and moderate sedation, with very low complication rates. Current guidelines on the invasive mediastinal staging of lung cancer still state that a negative needle aspiration result from these methods should be confirmed by mediastinoscopy. As more experience is gathered and echoendoscopes evolve, a thorough endosonographic evaluation of the mediastinum by both techniques, will obviate the need for surgical staging in the vast majority of patients and reduce the number of futile thoracotomies.

Measurement of exhaled alveolar nitrogen oxide in patients with lung cancer: a friend from the past still precious today.

Nitric oxide (NO) is a marker of airway inflammation and indirectly a general indicator of inflammation and oxidative stress. NO is a contributing factor in lung cancer at an early stage and also after chemotherapy treatment of lung cancer. We studied whether exhaled NO levels were altered by three cycles of chemotherapy at diagnosis and after chemotherapy, and whether, directly or indirectly, these changes were related to the course of disease. Also, a correlation of NO levels with other markers of inflammation was performed. We studied 42 patients diagnosed early: 26 men and 16 women with lung cancer. We analyzed blood tests for control of inflammatory markers, functional pulmonary tests, and alveolar exhaled NO. We recorded a decrease in exhaled NO after three cycles of chemotherapy in all patients, regardless of histological type and stage: there were 42 patients with mean 9.8 NO after three cycles (average 7.7). Also, a strong correlation appeared between NO measurements before and after chemotherapy and C-reactive protein (P < 0.05, r = 0.42, before) and (P < 0.045, r = 0.64, after). NO alveolar measurement as an indicator of airway inflammation indicates response to chemotherapy in lung cancer. Also, the inflammatory process in lung cancer was confirmed and indicated response to chemotherapy through an index that is sensitive to inflammatory disease of the airways.

The role of endobronchial ultrasound in lung cancer diagnosis and staging: a comprehensive review.

Endobronchial ultrasound (EBUS) technology is a relatively new bronchoscopic method of visualizing the tracheobronchial tree, the surrounding pulmonary parenchyma, and the mediastinal structures, with a particular role in lung cancer diagnosis, staging, and treatment. There are 2 types of probes used in EBUS: the peripheral or radial probe (RP) and the linear or convex probe (CP) EBUS, which have technical differences and distinct diagnostic abilities. Both are used for EBUS-guided biopsies and transbronchial needle aspirations (TBNA), which increases the diagnostic yield over conventional bronchoscopic techniques, thus providing advanced information on staging, diagnosis, and treatment. Complications of EBUS are rare, and they are usually related to the underlying biopsy procedure and the operator's experience. EBUS examination duration is usually short, and it can be performed as an outpatient procedure. Interestingly, EBUS combinations with other current and evolving techniques, eg, electromagnetic navigation, are feasible and have a role in therapeutic interventions and molecular diagnostics. In conclusion, EBUS is a safe and accurate technique that is comparable with current criterion standard procedures, eg, mediastinoscopy. More training is required for the vast majority of respiratory physicians, and precise diagnostic algorithms are needed so that more patients benefit from this development.

Metastin is not involved in metastatic potential of non-small cell lung cancer.

Metastin, the product of the KISS-1 gene, seems to represent a strong suppressant of metastasis for some types of cancer. The aim of this study is to explore whether circulating levels of metastin could be used as a marker for the metastatic potential of non-small cell lung cancer (NSCLC) as well as a diagnostic marker in NSCLC patients. The possible correlation between metastin and leptin circulating levels was also evaluated. Fasting serum levels of metastin and leptin were determined in 96 NSCLC patients at diagnosis (76 with metastatic disease and 21 with locally advanced disease) and 49 healthy volunteers using commercial available ELISA. Serum metastin levels presented no differences between NSCLC patients and healthy volunteers (1.18 ± 0.98 vs. 1.17 ± 0.39 ng/ml, P = 0.979) as well as between patients with metastatic and locally advanced disease (1.17 ± 1.05 vs. 1.21 ± 0.64 ng/ml, P = 0.872). There was no statistically significant correlation between circulating metastin and leptin levels in NSCLC patients and patients with locally advanced and metastatic disease. This study shows a lack of direct involvement of metastin in the diagnosis and metastatic potential of NSCLC.

Phase II study of gemcitabine plus docetaxel as second-line treatment in malignant pleural mesothelioma: a single institution study.

OBJECTIVE: The combinations of cisplatin-pemetrexed and cisplatin-gemcitabine are considered the standard systemic therapy for malignant pleural mesothelioma (MPM), which is a rapidly progressive tumor. The purpose of the present study is to evaluate the efficacy, safety, and clinical benefit of the gemcitabine plus docetaxel regimen in the second-line treatment of this disease. PATIENTS AND METHODS: A total of 37 patients with MPM were treated with the combination of docetaxel (80 mg/m) and gemcitabine (1000 mg/m) on day 1 and 14 of a 28-day cycle. The regimen was repeated for a maximum of 6 cycles or until disease progression or unacceptable toxicity. RESULTS: There was partial response of the disease in 7 patients (18.9%), whereas it remained stable in 23 patients (62.2%) and progressed in 7 patients (18.9%). The median time to disease progression was 7 months (range: 5.8-8.2 months) with a mean survival of 16.2 months (range: 13-19.3 months). CONCLUSION: The biweekly administration of docetaxel and gemcitabine, along with granulocyte colony-stimulating factor support, constitutes a safe, tolerable, and convenient regimen for the treatment of MPM, suggesting that this combination may be a viable option, especially in previously treated patients.

Prolonged survival after splenectomy in Wiskott-Aldrich syndrome: a case report.

Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency disorder that is characterized by a variable clinical phenotype. Matched donor bone marrow transplantation is currently the only curative therapeutic option. We present the case of a 24-year-old male who was diagnosed at the age of seven with Wiskott-Aldrich syndrome. He did not respond to intravenous gammaglobulin and he experienced recurrent pulmonary infections despite prophylactic antibiotics. The patient had no matched donor. At the age of nine, he was submitted to splenectomy and his platelet count was normalized. Fifteen years later, the patient remains asymptomatic with a normal platelet count. He is still receiving prophylactic antibiotics and no bleeding episodes or septic complications have been reported. This case demonstrates that splenectomy can represent a safe therapeutic option in selected WAS patients, provided that there is a tight follow-up program, patient education and adherence to guidelines regarding post-splenectomy prophylaxis.