Morphologic-Molecular Transformation of Oncogene Addicted Non-Small Cell Lung Cancer.

Patients with non-small cell lung cancer, especially adenocarcinomas, harbour at least one oncogenic driver mutation that can potentially be a target for therapy. Treatments of these oncogene-addicted tumours, such as the use of tyrosine kinase inhibitors (TKIs) of mutated epidermal growth factor receptor, have dramatically improved the outcome of patients. However, some patients may acquire resistance to treatment early on after starting a targeted therapy. Transformations to other histotypes-small cell lung carcinoma, large cell neuroendocrine carcinoma, squamous cell carcinoma, and sarcomatoid carcinoma-have been increasingly recognised as important mechanisms of resistance and are increasingly becoming a topic of interest for all specialists involved in the diagnosis, management, and care of these patients. This article, after examining the most used TKI agents and their main biological activities, discusses histological and molecular transformations with an up-to-date review of all previous cases published in the field. Liquid biopsy and future research directions are also briefly discussed to offer the reader a complete and up-to-date overview of the topic.

Tissue and circulating biomarkers of benefit to immunotherapy in extensive-stage small cell lung cancer patients.

Extensive stage-Small-Cell Lung Cancer (ES-SCLC) is an aggressive cancer with dismal prognosis. The addition of immune-checkpoint inhibitors (ICIs) to platinum-based chemotherapy have been consistently demonstrated to improve outcomes and survival, becoming the new standard in first - line treatment of ES-SCLC patients. However, despite positive results reported in the pivotal trials, longer benefit appears evident only for a selected group of patients. Several predictive biomarkers have been studied so far but the prospective identification of patients more likely to experience better outcome seems to be challenging in SCLC. Indeed, classical immune predictive biomarkers as PD-L1 and tumor mutational burden (TMB) seem not to correlate with outcomes. Recently, a new molecular classification of SCLC based on differential expression of genes associated with specific clinical behaviors and therapeutic vulnerability have been presented suggesting a new field to be investigated. Despite the achievements, these studies focused mainly on inter-tumoral heterogeneity, limiting the exploration of intra-tumoral heterogeneity and cell to cell interactions. New analysis methods are ongoing in order to explore subtypes plasticity. Analysis on single biopsies cannot catch the whole genomic profile and dynamic change of disease over time and during treatment. Moreover, the availability of tissue for translational research is limited due to the low proportion of patients undergoing surgery. In this context, liquid biopsy is a promising tool to detect reliable predictive biomarkers. Here, we reviewed the current available data on predictive role of tissue and liquid biomarkers in ES-SCLC patients receiving ICIs. We assessed latest results in terms of predictive and prognostic value of gene expression profiling in SCLC. Finally, we explored the role of liquid biopsy as a tool to monitor SCLC patients over time.

Extensive-stage small-cell lung cancer in patients receiving atezolizumab plus carboplatin-etoposide: stratification of outcome based on a composite score that combines gene expression profiling and immune characterization of microenvironment.

PURPOSE: Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only in a patient subgroup. Thus, the identification of predictive biomarkers is an urgent unmet medical need. EXPERIMENTAL DESIGN: Tumor samples from naive extensive-stage (ES) SCLC patients receiving atezolizumab plus carboplatin-etoposide were analyzed by gene expression profiling and two 9-color multiplex immunofluorescence panels, to characterize the immune infiltrate and SCLC subtypes. Associations of tissue biomarkers with time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS), were assessed. RESULTS: 42 patients were included. Higher expression of exhausted CD8-related genes was independently associated with a longer TTF and PFS while increased density of B lymphocytes correlated with longer TTF and OS. Higher percentage of M2-like macrophages close to tumor cells and of CD8+T cells close to CD4+T lymphocytes correlated with increased risk of TF and longer survival, respectively. A lower risk of TF, disease progression and death was associated with a higher density of ASCL1+tumor cells while the expression of POU2F3 correlated with a shorter survival. A composite score combining the expression of exhausted CD8-related genes, B lymphocyte density, ASCL1 tumor expression and quantification of CD163+macrophages close to tumor cells, was able to stratify patients into high-risk and low-risk groups. CONCLUSIONS: In conclusion, we identified tissue biomarkers and a combined score that can predict a higher benefit from chemoimmunotherapy in ES-SCLC patients.

Increased Levels of Endothelin-1 in Cerebrospinal Fluid Are a Marker of Poor Visual Recovery after Optic Neuritis in Multiple Sclerosis Patients.

BACKGROUND: Multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the central nervous system, typically features immune-mediated focal demyelination and secondary axonal degeneration. Cerebral hypoperfusion of the normal-appearing white matter (NAWM) has been reported in MS patients and may be mediated by elevated levels of endothelin-1 (ET-1), a most potent vasoconstrictive peptide released from reactive astrocytes in MS focal lesions. Optic neuritis (ON) is one of the most frequent manifestations of MS and also shows peripapillary vascular hypoperfusion in combination with disc swelling. AIMS: We aimed to compare serum and cerebrospinal fluid (CSF) levels of ET-1 as a potential prognostic marker of MS-ON in two groups of patients differing for severity of MS-ON clinical presentation. MATERIALS AND METHODS: A cross-sectional study to compare serum and CSF levels of ET-1 between patients with clinically aggressive MS-ON (A-MS-ON) and nonaggressive MS-ON (NA-MS-ON) according to conventional ophthalmological criteria, including optical coherence tomography. CSF and serum concentrations of ET-1 were measured using a commercially available ELISA method. RESULTS: Sixteen patients consecutively referred to the Units of Neurology for visual disturbances attributable to MS were recruited, 11 (69%) patients with A-MS-ON and 5 (31%) with NA-MS-ON. Median CSF ET-1 levels and CSF/serum ET-1 quotient were significantly higher in patients with A-MS-ON (0.30 vs. 0.56 ng/ml) as compared to NA-MS-ON (0.16 vs. 0.16). CONCLUSIONS: Severity and failure in the recovery from ON in MS patients may depend from vascular hypoperfusion of the optic nerve induced by high intrathecally produced ET-1, a potential prognostic marker of ON recovery in MS. The detection of CSF ET-1 levels may allow identifying groups of ON patients potentially benefitting from treatment with ET-1 antagonists (e.g., bosentan).