EGFR-Mutated Non-Small Cell Lung Cancer and Resistance to Immunotherapy: Role of the Tumor Microenvironment

Lung cancer is a leading cause of cancer-related deaths worldwide. About 10-30% of patients with non-small cell lung cancer (NSCLC) harbor mutations of the EGFR gene. The Tumor Microenvironment (TME) of patients with NSCLC harboring EGFR mutations displays peculiar characteristics and may modulate the antitumor immune response. EGFR activation increases PD-L1 expression in tumor cells, inducing T cell apoptosis and immune escape. EGFR-Tyrosine Kinase Inhibitors (TKIs) strengthen MHC class I and II antigen presentation in response to IFN-gamma, boost CD8+ T-cells levels and DCs, eliminate FOXP3+ Tregs, inhibit macrophage polarization into the M2 phenotype, and decrease PD-L1 expression in cancer cells. Thus, targeted therapy blocks specific signaling pathways, whereas immunotherapy stimulates the immune system to attack tumor cells evading immune surveillance. A combination of TKIs and immunotherapy may have suboptimal synergistic effects. However, data are controversial because activated EGFR signaling allows NSCLC cells to use multiple strategies to create an immunosuppressive TME, including recruitment of Tumor-Associated Macrophages and Tregs and the production of inhibitory cytokines and metabolites. Therefore, these mechanisms should be characterized and targeted by a combined pharmacological approach that also concerns disease stage, cancer-related inflammation with related systemic symptoms, and the general status of the patients to overcome the single-drug resistance development

Modafinil restores memory performance and neural activity impaired by sleep deprivation in mice.

The original aims of our study have been to investigate in sleep-deprived mice, the effects of modafinil administration on spatial working memory, in parallel with the evaluation of neural activity level, as compared to non-sleep-deprived animals. For this purpose, an original sleep deprivation apparatus was developed and validated with continuous electroencephalography recording. Memory performance was evaluated using spontaneous alternation in a T-maze, whereas the neural activity level was estimated by the quantification of the c-Fos protein in various cerebral zones. This study allowed altogether: First, to evidence that a diurnal 10-h sleep deprivation period induced an impairment of spatial working memory. Second, to observe a decrease in c-Fos expression after sleep deprivation followed by a behavioural test, as compared to non-sleep-deprived mice. This impairment in neural activity was evidenced in areas involved in wake-sleep cycle regulation (anterior hypothalamus and supraoptic nucleus), but also in memory (frontal cortex and hippocampus) and emotions (amygdala). Finally, to demonstrate that modafinil 64 mg/kg is able to restore on the one hand memory performance after a 10-h sleep deprivation period, and on the other hand, the neural activity level in the very same brain areas where it was previously impaired by sleep deprivation and cognitive task

New Horizons in Metastatic Colorectal Cancer: Prognostic Role of CD44 Expression

Background: The transmembrane glycoprotein CD44, the major hyaluronan (HA) receptor, has been proven to regulate cell growth, survival, differentiation, and migration. It is therefore widely considered to be involved in carcinogenesis. Its role as a new therapeutic target in solid tumors is under evaluation in clinical trials. The prognostic value remains controversial. Here, we aimed to investigate the correlation between CD44 expression and the clinicopathological features and survival in metastatic colorectal cancer (mCRC) patients. Methods: Data from 65 mCRC patients of the Medical Oncology Unit, University Hospital and University of Cagliari were retrospectively collected from 2008 to 2021. Immunohistochemical analysis was performed at the Pathology Division, University Hospital of Cagliari on 3 μm thick sections obtained from paraffin blocks. The intensity of immunohistochemical staining was subclassified into four groups: score 0 if negative or weak membrane staining in less than 10% of tumor cells; score 1+ if weak membrane staining in at least 10% of tumor cells or moderate membrane staining in less than 10% of tumor cells; score 2+ if moderate membrane staining in at least 10% of tumor cells or intensive membrane staining in less than 10% of tumor cells; score 3+ if intense membrane staining in at least 10% of tumor cells. Based on this score, we distinguished patients into low CD44 expression (score 0, 1+, 2+) and high CD44 expression (score 3+). Statistical analysis was performed with MedCalc (survival distribution: Kaplan-Meier; survival comparison: log-rank test; association between categorical variables: Fisher's exact test). Results: Patients' median age was 66 years (range 49-85). Regarding CD44 expression, score was 0 in 18 patients, 1+ in 15 patients, 2+ in 18 patients, and 3+ in 14 patients. Median overall survival (mOS) was 28.1 months (95%CI: 21.3-101). CD44 overexpression (3+) was correlated with poor prognosis (p = 0.0011; HR = 0.2), with a mOS of 14.5 months (95%CI 11.7 to 35.9) versus 30.7 months (95%CI 27.8 to 101) in lower CD44 expression. Higher CD44 expression was associated with clinically poor prognostic features: age ≥ 70 years (p = 0.0166); inoperable disease (p = 0.0008); stage IV at diagnosis (p = 0.0241); BRAF mutated (p = 0.0111), high-grade tumor (p = 0.0084). Conclusions: CD44 markedly correlated with aggressive tumor behavior and contributed to the earlier progression of disease, thus suggesting its role as a novel prognostic marker and potential therapeutic target for mCRC patients

Prediction of Response to Anti-Angiogenic Treatment for Advanced Colorectal Cancer Patients: From Biological Factors to Functional Imaging

Colorectal cancer (CRC) is a leading tumor worldwide. In CRC, the angiogenic pathway plays a crucial role in cancer development and the process of metastasis. Thus, anti-angiogenic drugs represent a milestone for metastatic CRC (mCRC) treatment and lead to significant improvement of clinical outcomes. Nevertheless, not all patients respond to treatment and some develop resistance. Therefore, the identification of predictive factors able to predict response to angiogenesis pathway blockade is required in order to identify the best candidates to receive these agents. Unfortunately, no predictive biomarkers have been prospectively validated to date. Over the years, research has focused on biologic factors such as genetic polymorphisms, circulating biomarkers, circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and microRNA. Moreover, research efforts have evaluated the potential correlation of molecular biomarkers with imaging techniques used for tumor assessment as well as the application of imaging tools in clinical practice. In addition to functional imaging, radiomics, a relatively newer technique, shows real promise in the setting of correlating molecular medicine to radiological phenotypes

Immunotherapy in small bowel adenocarcinoma: a potential role?

AbstractSmall bowel adenocarcinoma (SBA) is a rare tumor with an unfavorable prognosis, and due to its rarity, few studies on its treatment are available. Chemotherapy remains the standard of treatment in advanced disease. Recently immunotherapy has demonstrated to be a valid therapeutic option for many solid tumors. We reviewed the data published in literature to understand the impact of immunotherapy in this cancer

How to improve metastatic pancreatic ductal adenocarcinoma patients' selection: Between clinical trials and the real-world

As underlined in the minireview by Blomstrand et al, given the poor prognosis and the paucity of data on a therapeutic sequence in pancreatic ductal adenocarcinoma (PDAC), additional randomized controlled trials and real-world evidence studies addressing current and novel regimens are needed. The real-world outcomes of first-line chemotherapy regimens such as FOLFIRINOX and gemcitabine/nab-paclitaxel are thoroughly reviewed and seem to be largely generalizable in a real-world context. Regarding second-line chemotherapy, the key question about the optimal sequence of regimens remains uncertain. Precisely in this setting, it is therefore useful to encourage the implementation of clinical studies that may contribute to the scarcity of data available up to now. We report our experience with a small group of patients treated with second-line liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin. To improve the treatment of patients affected by PDAC, it is useful to identify subgroups of patients who may benefit from target treatments (e.g., BRCA mutant) and it is also important to focus on any prognostic factors that may affect the survival and treatment of these patients

Does immunotherapy change the treatment paradigm in metastatic gastric cancer?

Gastric cancer represents one of the leading causes of cancer-related death worldwide. Even if the last decade has witnessed an improvement in surgical and systemic treatments, with an increase of overall life expectancy, survival rates still remain unsatisfactory, especially for patients with metastatic disease. Systemic therapies represent the gold standard in the management of stage IV gastric cancer. In this scenario, the availability of effective second and third lines has represented for a long time the only hope to offer an overall survival improvement to these patients. Recently, the advent of immune checkpoint inhibitors has involved also gastric cancer with encouraging efficacy data in the metastatic setting, becoming integral part of the management of selected patients

Uncovering key targets of success for immunotherapy in pancreatic cancer

Introduction: Despite available treatment options, pancreatic ductal adenocarcinoma (PDAC) is frequently lethal. Recent immunotherapy strategies have failed to yield any notable impact. Therefore, research is focussed on unearthing new drug targets and therapeutic strategies to tackle this malignancy and attain more positive outcomes for patients. Areas covered: In this perspective article, we evaluate the main resistance mechanisms to immune checkpoint inhibitors (ICIs) and the approaches to circumvent them. We also offer an assessment of concluded and ongoing trials of PDAC immunotherapy. Literature research was performed on Pubmed accessible through keywords such as: 'pancreatic ductal adenocarcinoma,' 'immunotherapy,' 'immunotherapy resistance,' 'immune escape,' 'biomarkers.' Papers published between 2000 and 2021 were selected. Expert opinion: The tumor microenvironment is a critical variable of treatment resistance because of its role as a physical barrier and inhibitory immune signaling. Promising therapeutic strategies appear to be a combination of immunotherapeutics with other targeted treatments. Going forward, predictive biomarkers are required to improve patient selection. Biomarker-driven trials could enhance approaches for assessing the role of immunotherapy in PDAC

Retreatment With Anti-EGFR Antibodies in Metastatic Colorectal Cancer Patients: A Multi-institutional Analysis

On the basis of retrospective analyses and phase 2 studies, metastatic colorectal cancer patients whose disease responded to a first-line regimen containing an anti-epidermal growth factor receptor (EGFR) agent may experience benefit from anti-EGFR readministration in later therapy lines. While the analysis of circulating tumor DNA seems a promising tool to select the best candidates for this strategy, identifying clinical predictors of anti-EGFR sensitivity would be useful to drive treatment choices in daily practice