Virtual Library

Abstract
Neuroendocrine Tumours of the Lung encompass low grade tumors (typical and atypical carcinoids) and high grade carcinomas (large cell neuroendocrine lung carcinoma and small cell lung carcinoma). Typical carcinoids (TC) and atypical carcinoids (AC) are usually diagnosed in front of symptoms (bleeding or pneumonia) or abnormal chest Xray or CT scan. Patients with TC are younger. Association with MEN1 syndrom is rare. Bronchial endoscopy often shows the tumor and biopsies made with caution usually confirms the diagnosis of carcinoid. However, the pathological analysis of the whole tumour is necessary to distinguish TC and AC, according to WHO criteria based on mitotic count (less or more than 2 per 2mm[2]) and necrosis. Staging differs from that of other lung cancers, including somatostatin receptor scintigraphy (SRS), hepatic MRI and bone MRI. Treatment of typical or atypical bronchial carcinoid is implemented in the multidisciplinary setting after an in depth characterization of host and tumor presentations. Goals of the treatment are both to control hormone-related symptoms if they exist, and tumor growth. Surgery remains the gold standard of treatment of bronchial carcinoids. Thoracic surgery should not differ from that of lung cancer, while it should be conservative for young patients, with complete resection and lymph node dissection. In case of lymph node involvement, there is no consensus about adjuvant treatment, which is not recommended by ENETS. Prognostic heterogeneity and absence of cure at the metastatic stage make quality of life a key issue of advanced bronchial carcinoid management. Advanced atypical carcinoids are more aggressive than typical carcinoids. The spontaneous slope without treatment, the number of tumor organs including the primary, SRS grade of uptake and quality of control of hormone-related symptoms are key parameters to be characterized before any therapeutic decision. Based on the limited number of studies available in patients with bronchial primary, recommendations of treatment also take into account data established from the field of digestive NET. Treatment is based on locoregional therapies for bone and liver metastasis, and/or systemic treatment (somatostatin analogues, everolimus, chemotherapy, Peptide receptor radionuclide therapy). Large cell neuroendocrine carcinomas (LCNEC) are high grade malignant tumours. Their behavior is very different from that of bronchial carcinoids. Patients are usually male and smokers. Locally advanced or metastatic stages are usual at presentation. Brain metastases are frequent. Surgery is possible only in one third of patients. Adjuvant chemotherapy with platinum-etoposide based chemotherapy is recommended. For more advanced LCNEC, prognosis is poor and treatment does not differ from that of SCLC, without any significant progress made these last years.

Abstract
Most patients affected by malignant pleural mesothelioma (MPM) are candidates for chemotherapy during the course of the disease, as single modality treatment or within the context of a multimodality approach. Following the results of a large phase III trial, the combination of cisplatin and pemetrexed has become the preferred first-line chemotherapy, although there is also evidence for the activity of the combination with carboplatin. Unfortunately, nearly all MPM patients progress during or after first-line treatment. Second-line therapies are being increasingly used in the clinical practice because patients are frequently still in good clinical conditions at the time of disease progression. However, the role of these treatments in MPM is unproven, and the optimal regimens still remain to be defined. In pemetrexed-naïve patients, data from a randomized trial vs. best supportive care suggest the use of single-agent pemetrexed as a standard second-line treatment. This evidence is supported also by the results of the Expanded Access Programs. To date, there is no standard approach for pemetrexed-pre-treated patients. Several phase II and a few phase III trials have been performed or are ongoing, and this remains a field of active research. Unfortunately, studies available until now have frequently severe limitations, due to the small number and to the heterogeneity of patients included, and often to the design of the studies themselves. In selected cases with a prolonged response to first-line pemetrexed-containing chemotherapy (less than 25% of the whole population of MPM patients treated in first-line), re-treatment with a pemetrexed-based regimen should be considered, based on preliminary evidence reported in small case series. Clinicians should be aware of the risk of hypersensitivity reactions when carboplatin is used in combination with pemetrexed in the re-treatment setting. For the remaining patients the evidence is still limited. Targeted therapies with agents such as EGFR and PDGFR inhibitors, anti-angiogenic compounds, and histone-deacetylase inhibitors have so far achieved disappointing results. Trials with small molecules or monoclonal antibodies that target different molecular pathways are ongoing. Patients should be encouraged to participate in these trials. When a trial is not available or patients are not eligible for an experimental approach, second-line chemotherapy can be a reasonable option for palliation. Gemcitabine and vinorelbine are the most commonly administered agents. However, prospective studies in this setting are sparse, and most evidence comes from retrospective reports. Gemcitabine has been studied mainly in combination with other compounds in small studies. Overall, all these studies showed a modest activity, with a response rate of 10% or less and a disease control (including also stable disease) in about half of patients. The incidence of severe toxicity was low, and mainly related to hematological adverse events. Vinorelbine has been studied in the second-line setting mainly as a single agent. There are at least 4 studies available, 2 of them with a retrospective design. These studies are difficult to compare, because of different patient selection and drug schedules. In the largest study patients were pretreated with various chemotherapy regimens, including pemetrexed-based regimens, while in the other studies all patients were pemetrexed-pretreated. Two studies included also patients treated beyond second line, while the others were pure second-line trials. Treatment schedules were different, and this was reflected by the higher hematological toxicity in studies with the higher vinorelbine dose-intensity. Overall, response rate ranged from 0 to 15%, with disease control rates variable according to patient selection. When gemcitabine and vinorelbine were used in combination, no survival benefit was observed as compared to single-agent chemotherapy, with a higher (mainly hematological) toxicity. In conclusion, evidence for a benefit of second-line chemotherapy in MPM patients is weak, and should be confirmed in prospective studies. A few trials with new chemotherapeutic compounds (e.g. trabectedin) are ongoing. Ideally, future second-line trials in MPM should be designed as at least randomized phase II trial and according to strict eligibility criteria, mainly as far as pre-treatment is concerned (prior regimens and numbers of treatment lines). Patients should be stratified according to the outcome of first-line therapy and to known prognostic factors (like EORTC prognostic score). Time-related events (median PFS or 3-month PFS) should be the primary endpoints. Finally, second-line setting is the ideal field for high-quality correlative studies aimed to identify the patients who will benefit from treatment, and to improve the knowledge of MPM biology.

Abstract
Malignant pleural mesothelioma (MPM) is an asbestos-related disease with a very poor prognosis because of late-stage diagnosis due to unspecific imaging techniques and non-specific symptoms resembling pleural effusions such as chest pain and dyspnea. Early diagnosis could improve the disease’s outcome by reducing the diagnostic delay. Serum tumor biomarkers for early MPM screening are attractive because of their non-invasive and low-cost nature. Nevertheless, MPM is a heterogeneous disease suggesting an ideal biomarker should be capable of capturing all the MPM subtypes and to distinguish MPM from benign or metastatic pleural conditions. To have a clinical impact, biomarkers should predict the development of the disease in which a positive test could enrich the at-risk population eligible for further screening and reduce the economical burden of wild screening. In order rule in MPM, a biomarker should have a positive predictive value of minimally 10%, and the low MPM prevalence urges the need for a high test specificity. Many candidate blood biomarkers have been studied such as hyaluronic acid, carcinoembryonic antigen, CYFRA 21.1 and cancer antigen 125. Nonetheless, their accuracy is insufficient and based upon small-sized retrospective studies without further validation. Hence, they are of little use in clinical practice. More recently, the cell adhesion proteins soluble mesothelin (SM), megakaryocyte potentiating factor (MPF) and osteopontin (OPN) were investigated. OPN functions in cancer progression, bone matrix formation and immunologic responses. Despite 78% sensitivity and 88% specificity found by Pass et al., subsequent validation studies revealed contradictory accuracy findings with AUCs ranging from 0.64 to 0.89. Furthermore, OPN lacks specificity because it is overexpressed in other tumor types, limiting its use as a diagnostic mesothelioma marker. SM has been found the best available serum marker for MPM. It is derived from a mesothelin gene-encoded precursor protein, which is cleaved into a soluble fraction (MPF) and a membrane-bound fraction (mesothelin) involved in cancerous growth, proliferation and migration and present on the pleural, peritoneal and pericardial mesothelial cells. SM enters the circulation by shedding of the membrane-bound mesothelin or frameshift mutations and is highly expressed in mesothelioma and other malignancies. The first determined serum MPF levels differentiated MPM from healthy controls with 91% sensitivity and 100% specificity. Subsequent studies resulted in diagnostic accuracies with AUCs between 0.79 and 0.88. MPF and SM are highly correlated and have equal diagnostic performances. SM was elevated in MPM patients compared to controls and had discriminative power with 84% sensitivity and 100% specificity. A commercial MesoMark[TM] ELISA assay for SM was developed and evaluated by different groups gaining diagnostic accuracies with AUCs from 0.72 to 0.81. The use of SM as diagnostic marker is still under debate because of large intergroup inconsistencies. An individual patient data meta-analysis was performed, yielding an AUC of 0.77 representing the overall SM diagnostic performance. When SM was used to rule in or rule out diagnosis, the specificities and sensitivities were respectively 95% and 32% and 22% and 95%. SM has low specificity and is only selective for epithelioid and biphasic MPM, hampering its use as a stand-alone marker and possible replacement of the current gold standard of invasive histopathologic diagnosis. Hence a combination of several tumor markers might improve the diagnostic performance. However, combining SM, OPN and MPF did not outperform the accuracy of SM alone and it is necessary to take GFR, BMI and age into account as confounding effects because they influence the biomarker levels. New markers like HMGB1 and fibulin-3 were investigated and were found upregulated in patients sera compared to sera from healthy controls. Although both are promising, a long and cumbersome validation process will need to be executed comparing the accuracy of both biomarkers with serum SM. In the past, several programs have been conducted to screen asbestos-exposed individuals for lung disease with annual chest X-rays. Besides demonstrating the presence of benign asbestos-related diseases, these modalities have not proven to be effective at detecting early malignancies. CT has a superior sensitivity, and its use in screening has been examined in several large-scale studies (Table). Results predominantly illustrate the low prevalence of mesothelioma, and the high background noise (non-calcified nodules) in asbestos-exposed populations. In addition, the standardization of reading both chest X-ray and CT has proven to be difficult, while the cost and radiation doses represent other problematic issues. PET and MRI are currently not applied in screening, and their cost is likely to be prohibitive. Altogether, it is now generally accepted that the use of imaging has not made any impact on the early detection of mesothelioma, and their use is not recommended by the different (inter)national guidelines. In the future, the ‘Holy Grail’ could be sniffed out thanks to the innovative field of exhaled breath analysis. Volatile organic compounds (VOCs) arise from the cells’ metabolism and are released in exhaled breath, making these promising diagnostic MPM markers obtained via high-throughput non-invasive techniques. Electronic nose (eNose) analysis has shown promising results for diagnosing MPM with diagnostic accuracies ranging from 80.8% to 95% in discriminating MPM patients from asbestos-exposed and healthy individuals. However, eNoses work as blackboxes and do not identify VOCs as possible biomarkers. GC-MS analysis identified cyclohexane to discriminate MPM patients from asbestos-exposed and healthy persons. Although this research field opens new perspectives for biomarker discovery, a lot of small-sized studies were performed in order to identify new biomarkers for screening, urging the need for large-scale validation studies. Although different routes of discovering biomarkers for early screening have been paved, the way to a validated and clinically useful screening biomarker panel still has to be constructed. Table: Prospective screening studies using chest CT in asbestos-exposed cohorts to detect asbestos-related malignancies.