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The majority of patients with resected stage II‐IIIA non‐small cell lung cancer (NSCLC) are treated with platinum‐based adjuvant chemotherapy (ACT) in a one‐size‐fits‐all approach. However, a significant number of patients do not derive clinical benefit, and no predictive patient selection biomarker is currently available. Using mass spectrometry‐based proteomics, we have profiled tumour resection material of 2 independent, multi‐centre cohorts of in total 67 patients with NSCLC who underwent ACT. Unsupervised cluster analysis of both cohorts revealed a poor response/survival sub‐cluster composed of ~ 25% of the patients, that displayed a strong epithelial‐mesenchymal transition signature and stromal phenotype. Beyond this stromal sub‐population, we identified and validated platinum response prediction biomarker candidates involved in pathways relevant to the mechanism of action of platinum drugs, such as DNA damage repair, as well as less anticipated processes such as those related to the regulation of actin cytoskeleton. Integration with pre‐clinical proteomics data supported a role for several of these candidate proteins in platinum response prediction. Validation of one of the candidates (HMGB1) in a third independent patient cohort using immunohistochemistry highlights the potential of translating these proteomics results to clinical practice.

Background/Objectives: Monoclonal antibodies (mAbs) have revolutionized multiple myeloma (MM) treatment. However, post-marketing data on their neuropsychiatric safety are limited. This study aimed to evaluate neuropsychiatric adverse events (AEs) related to mAbs used for MM through a retrospective pharmacovigilance analysis using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS) database. Methods: Individual case safety reports (ICSRs) from 2015 to 2023 with at least one neuropsychiatric AE and one of the MM-approved mAbs as the suspected drug (i.e., daratumumab, elotuzumab, isatuximab, belantamab mafodotin, teclistamab, elranatamab, and talquentamab) were analyzed using descriptive and disproportionality approaches. Results: Unknown signals of disproportionate reporting (SDR) included the following: cerebral infarction for daratumumab (n = 45; reporting odds ratio (ROR) = 2.39, 95% confidence interval (CI) = 1.79–3.21; information component (IC) = 1.54, IC025–IC075 = 1.05–1.9), elotuzumab (25; 7.61, 5.13–11.28; 3.03, 2.37–3.51), and isatuximab (10; 2.56, 1.38–4.76; 1.67, 0.59–2.4); mental status changes for daratumumab (40; 2.66, 1.95–3.63; 1.67, 1.14–2.04) and belantamab mafodotin (10; 4.23, 2.28–7.88; 2.3, 1.22–3.03); an altered state of consciousness for daratumumab (32; 1.97, 1.39–2.78; 1.32, 0.73–1.74) and belantamab mafodotin (6; 2.35, 1.05–5.23; 1.6, 0.19–2.52); Guillain-Barre syndrome (GBS) for daratumumab (23; 6.42, 4.26–9.69; 2.81, 2.11–3.3), isatuximab (8; 10.72, 5.35–21.48; 3.57, 2.35–4.37), and elotuzumab (3; 4.74, 1.53–14.7; 2.59, 0.52–3.8); and orthostatic intolerance for daratumumab (10; 12.54, 6.71–23.43; 3.75, 2.67–4.48) and elotuzumab (4; 28.31, 10.58–75.73; 5, 3.24–6.08). Conclusions: Our analysis highlighted several previously unacknowledged SDRs for MM-approved mAbs. Given the complex and not entirely understood etiology of some neuropsychiatric AEs, including GBS, further investigations are necessary.

Lung cancer (LC) is one of the most prevalent cancers in both men and women and today is still characterized by high mortality and lethality. Several biomarkers have been identified for evaluating the prognosis of non-small cell lung cancer (NSCLC) patients and selecting the most effective therapeutic strategy for these patients. The introduction of innovative targeted therapies and immunotherapy with immune checkpoint inhibitors (ICIs) for the treatment of NSCLC both in advanced stages and, more recently, also in early stages, has revolutionized and significantly improved the therapeutic scenario for these patients. Promising evidence has also been shown by analyzing both micro-RNAs (miRNAs) and the lung/gut microbiota. MiRNAs belong to the large family of non-coding RNAs and play a role in the modulation of several key mechanisms in cells such as proliferation, differentiation, inflammation, and apoptosis. On the other hand, the microbiota (a group of several microorganisms found in human orgasms such as the gut and lungs and mainly composed by bacteria) plays a key role in the modulation of inflammation and, in particular, in the immune response. Some data have shown that the microbiota and the related microbiome can modulate miRNAs expression and vice versa by regulating several intracellular signaling pathways that are known to play a role in the pathogenesis of lung cancer. This evidence suggests that this axis is key to predicting the prognosis and effectiveness of ICIs in NSCLC treatment and could represent a new target in the treatment of NSCLC. In this review, we highlight the most recent evidence and data regarding the role of both miRNAs and the lung/gut microbiome in the prediction of prognosis and response to ICI treatment, focusing on the link between miRNAs and the microbiome. A new potential interaction based on the underlying modulated intracellular signaling pathways is also shown.

Lung cancer is the leading cause of cancer deaths in the world. Surgery is the most potentially curative therapeutic option for patients with early-stage non-small cell lung cancer (NSCLC). The five-year survival for these patients remains poor and variable, depending on the stage of disease at diagnosis, and the risk of recurrence following tumor resection is high. During the last 20 years, there has been a modest improvement in the therapeutic strategies for resectable NSCLC. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, have become the cornerstone for the treatment of metastatic NSCLC patients. Recently, their clinical development has been shifted in the neoadjuvant and adjuvant settings where they have demonstrated remarkable efficacy, leading to improved clinical outcomes. Based on the positive results from phase III trials, ICIs have become a therapeutic option in neoadjuvant and adjuvant settings. On October 2021 the Food and Drug Administration (FDA) approved atezolizumab as an adjuvant treatment following surgery and platinum-based chemotherapy for patients with NSCLC whose tumors express PD-L1 ≥ 1%. In March 2022, nivolumab in combination with platinum-doublet chemotherapy was approved for adult patients with resectable NSCLC in the neoadjuvant setting. The current review provides an updated overview of the clinical trials exploring the role of immunotherapy in patients with early-stage NSCLC, focusing on the biological rationale for their use in the perioperative setting. We will also discuss the role of potential predictive biomarkers to personalize therapy and optimize the incorporation of immunotherapy into the multimodality management of stage I-III NSCLC.

IntroductionNew oral tyrosine kinase inhibitors (TKIs) are approved for metastatic colorectal cancer (mCRC). The aim of this study was to assess the neuropsychiatric adverse drug reactions (ADRs) of these drugs reported in the FDA Adverse Event Reporting System (FAERS) database.MethodsAll reports with regorafenib (REG) and encorafenib (ENC) as the primary suspect, and reported in the FAERS between 2012 and 2022, were collected. A descriptive and disproportionality analyses were conducted.ResultsOut of 4,984 cases, 1,357 (30.2%) reported at least one neuropsychiatric ADR. New potential signals for REG included neuropathy peripheral (n = 265; reporting odds ratio, ROR = 19.48, 95% confidence interval, CI 95% = 17.52-22.47; information component, IC = 2.89, IC025-IC075 = 2.77-3.02), hyperesthesia (n = 18; ROR = 12.56, CI 95% = 7.90-19.96; IC = 2.25, IC025-IC075 = 1.79-2.72), taste disorder (n = 41; ROR = 9.91, CI 95% = 7.29-13.49; IC = 2.18, IC025-IC075 = 1.88-2.49), poor quality sleep (n = 18; ROR = 6.56, CI 95% = 4.13-10.42; IC = 1.74, IC025-IC075 = 1.27-2.20), altered state of consciousness (n = 15; ROR = 5.50, CI 95% = 3.31-9.14; IC = 1.57, IC025-IC075 = 1.06-2.07), depressed mood (n = 13; ROR = 1.85, CI 95% = 1.07-3.19; IC = 0.58, IC025-IC075 = 0.04-1.13) and insomnia (n = 63; ROR = 1.48, CI 95% = 1.15-1.89; IC = 0.38, IC025-IC075 = 0.13-0.63). For ENC comprised depressed mood (n = 4; ROR = 5.75, CI 95% = 2.15-15.39; IC = 1.74, IC025-IC075 = 0.76-2.73) and cognitive disorders (n = 3; ROR = 4.71, CI 95% = 1.51-14.66; IC = 1.54, IC025-IC075 = 0.41-2.68).DiscussionThis study identified new unknown potential neuropsychiatric ADRs. Further investigations are required to better define the neurotoxicity of TKIs in mCRC patients.

IntroductionNon-small cell lung cancer (NSCLC) is often caused by molecular alterations that can be detected by predictive biomarkers including mutations or amplifications of several genes. Several tyrosine kinase inhibitors (TKIs) have been approved in Europe by the European Medicines Agency (EMA) for NSCLC. The aim of this study was to analyze the onset of adverse drug reactions (ADRs) related to TKIs in NSCLC through a spontaneous reporting system (SRS) database.MethodsAll ADR reports having as suspected drug afatinib (AFT), alectinib (ALEC), brigatinib (BRG), ceritinib (CER), crizotinib (CRIZ), erlotinib (ERL), gefitinib (GEF), lorlatinib (LORL), nintedanib (NTB), and osimertinib (OSI) recorded into the Report Reazioni Avverse dei Medicinali (RAM) system database for national data and into the Italian SRS database for Sicilian data and collected from 2006 to 2021 have been evaluated. A descriptive analysis of basal demographic and drug-related characteristics was performed. A case-by-case methodology was conducted paying particular attention to all serious ADR reports collected in Sicily, focusing on type of seriousness, age, sex, concomitant drugs, and comorbidities.ResultsOf the 3,048 Italian reports, most of ADRs were related to ERL (n = 1,448), followed by AFT (n = 435) and GEF (n = 366). ADR reports were slightly more frequent in females (52.2%) and in the age group >65 years (53.0%). A higher number of cases were related to skin disorders (n = 1,766; 57.9%), followed by gastrointestinal disorders (n = 1,024; 33.6%), general disorders and administration site conditions (n = 536; 17.6%), and infections (n = 483; 15.8%). The case-by-case assessment of Sicilian ADRs showed that 33 cases were serious (12.5%) and mainly involved ERL (n = 17; 51.5%), occurring in males with a higher onset of respiratory diseases (30.3%) such as respiratory failure, interstitial lung disease and dyspnea.DiscussionThe analysis of spontaneous ADR reports of TKIs confirmed, in general, well-known risks, which often include skin, gastrointestinal, general, liver, and respiratory diseases as well as infections. However, more attention should be paid to the occurrence of serious life-threatening ADRs including respiratory failure, interstitial lung disease, and cardiogenic shock, especially in young patients.

Background: this study assessed the nephrotoxicity of regorafenib (REG) and encorafenib (ENC) in metastatic colorectal cancer (mCRC) through an analysis of reports from the US Food and Drug Administration’s Adverse Event Reporting System (FAERS) database. Methods: descriptive and disproportional analyses were performed for all reports using ENC and REG as the primary suspect. Results: A total of 379 reports had at least one renal adverse drug reaction (ADR), and these ADRs were mainly related to REG (93.1%). Potential safety signals for REG included chromaturia (n = 44; ROR = 12.00, CI 95% = 8.92–16.16; IC = 2.36, IC025–IC075 = 2.06–2.66), hydronephrosis (10; 8.70, 4.67–16.19; 1.85, 1.23–2.47), nephrotic syndrome (7; 5.73, 2.73–12.03; 1.47, 0.73–2.21), renal impairment (53; 4.16, 3.17–5.45; 1.39, 1.12–1.66), dysuria (19; 3.06, 1.95–4.81; 1.06, 0.61–1.52), renal failure (38; 1.66, 1.20–2.28; 0.49, 0.17–0.81), and acute kidney injury (AKI) (43; 1.46, 1.08–1.97; 0.37, 0.07–0.67). For ENC, consistent disproportionalities were observed for AKI (n = 11; ROR = 3.79, CI 95% = 2.09–6.90; IC = 1.32, IC025–IC075 = 0.72–1.91) and dysuria (4; 6.50, 2.43–17.39; 1.86, 0.88–2.85). Conclusions: these findings highlight some not extensively reported renal ADRs that require further investigations to better characterize the safety profiles of REG and ENC in patients with mCRC.

In recent years, we have seen the development and approval for clinical use of an increasing number of therapeutic agents against actionable oncogenic drivers in metastatic non-small cell lung cancer (NSCLC). Among them, selective inhibitors, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting the mesenchymal–epithelial transition (MET) receptor, have been studied in patients with advanced NSCLC with MET deregulation, primarily due to exon 14 skipping mutations or MET amplification. Some MET TKIs, including capmatinib and tepotinib, have proven to be highly effective in this molecularly defined subgroup of patients and are already approved for clinical use. Other similar agents are being tested in early-stage clinical trials with promising antitumor activity. The purpose of this review is to provide an overview of MET signaling pathways, MET oncogenic alterations primarily focusing on exon 14 skipping mutations, and the laboratory techniques used to detect MET alterations. Furthermore, we will summarize the currently available clinical data and ongoing studies on MET inhibitors, as well as the mechanisms of resistance to MET TKIs and new potential strategies, including combinatorial approaches, to improve the clinical outcomes of MET exon 14-altered NSCLC patients.

Dendritic cell (DC)-based immunotherapy has increased interest among anti-cancer immunotherapies. Nevertheless, the immunosuppressive mechanisms in the tumor milieu, e.g., inhibitory immune checkpoint molecules, have been implicated in diminishing the efficacy of DC-mediated anti-tumoral immune responses. Therefore, the main challenge is to overcome inhibitory immune checkpoint molecules and provoke efficient T-cell responses to antigens specifically expressed by cancerous cells. Among the inhibitory immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression on DCs diminishes their maturation and antigen presentation capability. Accordingly, we hypothesized that the expression of CTLA-4 on DCs inhibits the T cell-mediated anti-tumoral responses generated following the presentation of tumor antigens by DCs to T lymphocytes. In this study, we loaded colorectal cancer (CRC) cell lysate on DCs and inhibited the expression of CTLA-4 by small interfering RNA (siRNA) in them to investigate the DCs’ functional and phenotypical features, and T-cell mediated responses following DC/T cell co-culture. Our results demonstrated that blockade of CTLA-4 could promote stimulatory properties of DCs. In addition, CTLA-4 silenced CRC cell lysate-loaded DCs compared to the DCs without CTLA-4 silencing resulted in augmented T cell proliferation and cytokine production, i.e., IFN-γ and IL-4. Taken together, our findings suggest CTLA-4 silenced CRC cell lysate-loaded DCs as a promising therapeutic approach however further studies are needed before this strategy can be used in clinical practice.

The majority of epidermal growth factor receptor (EGFR) mutations (85–90%) are exon 19 deletions and L858R point mutations of exon 21, characterized by high sensitivity to EGFR-tyrosine kinase inhibitors (TKIs). Less is known about uncommon mutations (10–15% of EGFR mutations). The predominant mutation types in this category include exon 18 point mutations, exon 21 L861X, exon 20 insertions, and exon 20 S768I. This group shows a heterogeneous prevalence, partly due to different testing methods and to the presence of compound mutations, which in some cases can lead to shorter overall survival and different sensitivity to different TKIs compared to simple mutations. Additionally, EGFR-TKI sensitivity may also vary depending on the specific mutation and the tertiary structure of the protein. The best strategy remains uncertain, and the data of EGFR-TKIs efficacy are based on few prospective and some retrospective series. Newer investigational agents are still under study, and there are no other approved specific treatments targeting uncommon EGFR mutations. Defining the best treatment option for this patient population remains an unmet medical need. The objective of this review is to evaluate existing data on the outcomes, epidemiology, and clinical characteristics of lung cancer patients with rare EGFR mutations, with a focus on intracranial activity and response to immunotherapy.

Autophagy is conserved cellular machinery that degrades un-usable proteins and cellular components and has a crucial role in the pathogenesis and drug resistance of various diseases such as lung cancer (LC). Multiple types of endogenous molecules (i.e. miRNAs) have been found to regulate multiple biological processes, such as autophagy. Dysfunction of these molecules is associated with the onset and progression of a variety of human malignancies. Several studies had shown that some miRNAs could mediate autophagy activity in LC cells, which would affect drug resistance as a major problem in LC therapy. Therefore, identifying the underlying molecular targets of miRNAs and their function in autophagy pathways could develop new treatment interventions for LC patients. In this review, we will summarize the interplay between miRNAs, autophagy, and drug resistance of LC patients, as well as the genes and molecular pathways that are involved.

Background: Several serious attempts to treat colorectal cancer have been made in recent decades. However, no effective treatment has yet been discovered due to the complexities of its etiology. Methods: we used Weighted Gene Co-expression Network Analysis (WGCNA) to identify key modules, hub-genes, and mRNA-miRNA regulatory networks associated with CRC. Next, enrichment analysis of modules has been performed using Cluepedia. Next, quantitative real-time PCR (RT-qPCR) was used to validate the expression of selected hub-genes in CRC tissues. Results: Based on the WGCNA results, the brown module had a significant positive correlation (r = 0.98, p-value=9e-07) with CRC. Using the survival and DEGs analyses, 22 genes were identified as hub-genes. Next, three candidate hub-genes were selected for RT-qPCR validation, and 22 pairs of cancerous and non-cancerous tissues were collected from CRC patients referred to the Gastroenterology and Liver Clinic. The RT-qPCR results revealed that the expression of GUCA2B was significantly reduced in CRC tissues, which is consistent with the results of differential expression analysis. Finally, top miRNAs correlated with GUCA2B were identified, and ROC analyses revealed that GUCA2B has a high diagnostic performance for CRC. Conclusions: The current study discovered key modules and GUCA2B as a hub-gene associated with CRC, providing references to understand the pathogenesis and be considered a novel candidate to CRC target therapy.