Epidermal growth factor receptor status and Notch inhibition in non-small cell lung cancer cells.

BACKGROUND: Notch may behave as an oncogene or a tumor suppressor gene in lung cancer cells. Notch receptor undergoes cleavage by enzymes, including γ-secretase, generating the active Notch intracellular domain (NICD). The aim of the present study was to investigate the effect of DAPT, a γ-secretase inhibitor, in non-small cell lung cancer (NSCLC) cells, as well as the impact of epidermal growth factor (EGF) that is over-expressed by NSCLC cells, on Notch signaling. H23, A549, H661 and HCC827 human NSCLC cell lines were used, expressing various NICD and EGF receptor (EGFR) protein levels. RESULTS: DAPT decreased the number of H661 cells in a concentration-dependent manner, while it had a small effect on H23 and A549 cells and no effect on HCC827 cells that carry mutated EGFR. Notch inhibition did not affect the stimulatory effect of EGF on cell proliferation, while EGF prevented DAPT-induced NICD decrease in H23 and H661 cells. The type of cell death induced by DAPT seems to depend on the cell type. CONCLUSIONS: Our data indicate that inhibition of Notch cleavage may not affect cell number in the presence of EGFR mutations and that EGFR may affect Notch signalling suggesting that a dual inhibition of these pathways might be promising in NSCLC.

PIOS (Patras Immunotherapy Score) Score Is Associated with Best Overall Response, Progression-Free Survival, and Post-Immunotherapy Overall Survival in Patients with Advanced Non-Small-Cell Lung Cancer (NSCLC) Treated with Anti-Program Cell Death-1 (PD-1) Inhibitors.

Immunotherapy with immune checkpoint inhibitors (ICIs) has changed the therapeutic management of advanced non-small cell lung cancer (aNSCLC) over the last decade. However, there is an unmet need for clinically useful biomarkers in this patient subgroup. The aim of this study was to combine baseline clinical characteristics of aNSCLC patients, in the form of a scoring system, and to investigate its predictive and prognostic value in NSCLC patients treated with ICIs. A total of 112 patients with advanced (stages IIIA to IV) NSCLC, treated with nivolumab or pembrolizumab, were enrolled in this study. Patras Immunotherapy Score (PIOS) was developed based on four of the studied parameters (performance status (PS), body mass index (BMI), age, and lines of treatment (LOT), which were incorporated into our formula (PS × BMI/ LOT × age). PIOS score was strongly associated with best overall responses (BOR), with those patients having benefit/good response (stable disease (SD) or partial (PR) or complete response (CR), achieving a higher score compared to patients who developed progressive disease (PD) (p < 0.001). Furthermore, PIOS score was associated with progression-free survival (PFS), since high-score patients had longer PFS (p < 0.001, hazard ratio (HR) = 0.469). Moreover, PIOS was associated with post-immunotherapy overall survival (OS), with high-score patients having improved OS (log-rank p = 0.019). This study suggests that a combination of baseline parameters, which give rise to PIOS score, may predict the best response of NSCLC patients treated with anti-program cell death -1 (PD-1) monotherapy as well as it may have a potent prognostic value for PFS and post immunotherapy OS.

Real-world clinical outcome and toxicity data and economic aspects in patients with advanced breast cancer treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy: the experience of the Hellenic Cooperative Oncology Group.

BACKGROUND: We evaluated real-world clinical outcomes and toxicity data and assessed treatment-related costs in patients with advanced breast cancer who received treatment with cyclin-dependent kinase inhibitors (CDKi). PATIENTS AND METHODS: We conducted a prospective-retrospective analysis of patients with advanced hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who received a CDKi, in combination with endocrine therapy, at any line of treatment. The primary endpoint was progression-free survival (PFS). Cost analysis was conducted from a public third-payer (National Organization for Healthcare Services Provision (EOPYY)) perspective, assessing only costs related to direct medical care, including drug therapy costs and adverse drug reaction (ADR)-related costs. RESULTS: From July 2015 to October 2019, 365 women received endocrine therapy combined with CDKi; median age was 61 years, postmenopausal 290 (80.6%) patients. CDKi were administered as first-line treatment in 149 (40.9%) patients, second-line treatment in 96 (26.4%) and third-line treatment and beyond in 119 (32.7%) patients. The most common adverse events were neutropenia, anaemia, thrombocytopenia and fatigue. Grade 3-4 adverse events occurred in 86 (23.6%) patients, whereas 8 (2.2%) patients permanently discontinued treatment due to toxicity. The median PFS for patients who received CDKi as first-line, second-line and third-line treatment and beyond was 18.7, 12 and 7.4 months, respectively. The median overall survival since the initiation of CDKi treatment was 29.9 months (95% CI: 23.0-not yet reached (NR)). The mean pharmaceutical therapy cost estimated per cycle was 2 724.12 € for each patient, whereas the main driver of the ADR-related costs was haematological adverse events. CONCLUSIONS: Treatment with CDKi was well tolerated, with a low drug discontinuation rate. Patients who received CDKi as first-line treatment had improved PFS and OS compared with second-line treatment and beyond. The main component of direct medical costs assessed in the cost analysis comprises CDKi pharmaceutical therapy costs. TRIAL REGISTRATION NUMBER: NCT04133207.

A Case of Serratia marcescens Endocarditis in a Nonintravenous Drug-Using Male Patient and Review of Literature.

INTRODUCTION: Serratia marcescens is a rare cause of infective endocarditis and has almost exclusively been associated with intravenous drug use and hospital-acquired infections. Here, we present a case of infective endocarditis caused by Serratia marcescens in an otherwise healthy, nonintravenous drug-using male patient. CASE REPORT: A 41-year-old man presented with hypertension and hemoptysis. Blood cultures were obtained that showed bacteremia by Serratia marcescens. An echocardiogram was carried out that revealed severe mitral regurgitation accompanying ruptured mitral chordae tendineae. The patient received the appropriate antibiotic treatment, without further surgical intervention. DISCUSSION: Hospital-acquired infections by Serratia species are a common problem in medical practice and have been attributed to specialized interventional procedures. Taking into consideration the patient's immunocompetence and lack of intravenous drug use, it is possible that bacteremia could be attributed to a medical procedure. Moreover, in contrast to most cases described in the literature, no surgery was performed.

Seasonal variability in the incidence of carcinomatous meningitis.

OBJECT: The aim of the study was to investigate whether there are seasonal differences in the occurrence of carcinomatous meningitis (CM), with a greater prevalence of the disease in months with higher temperatures. METHODS: The authors searched the records of all patients with a diagnosis of CM from 1998 until 2013 at the University Hospital of Patras, Greece. The date of hospitalization was extracted for each patient. The cases were divided into 2 categories depending on the time of CM diagnosis. Based on the official data regarding the annual temperature distribution in this region, the authors divided the patients into 2 groups. The first group consisted of cases diagnosed with CM from October 15 to April 15 (cold climate and shorter daytime duration), whereas the second group comprised patients diagnosed between April 15 and October 15 (warm climate and longer daytime duration). RESULTS: Overall, 44 confirmed cases of CM were found. The most common type of malignancy associated with the development of CM was breast cancer (27 patients), while the second most common tumor was lung carcinoma (11 patients). The median interval between the time of initial cancer diagnosis and CM was 4.5 years. Thirty-one patients were diagnosed with CM during the period between April 15 and October 15, while the remaining 13 patients developed CM between October 15 and April 15, a significant difference (p = 0.01). CONCLUSIONS: Significantly more patients developed CM during the warm season of the year. To the authors' knowledge, this is the first study to provide evidence for the potential seasonal variability in CM incidence. However, these results should be validated prospectively in larger cohorts.

Targeted therapies for advanced non-small cell lung cancer.

The incorporation of targeted agents has considerably improved the management of patients with advanced non-small cell lung cancer (NSCLC) over the last years. The main targets include the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF). Currently available agents with established role in NSCLC include the anti-EGFR tyrosine-kinase inhibitors (TKIs) erlotinib/gefitinib and the anti-VEGF monoclonal antibody bevacizumab. Moreover, several other agents targeting critical pathways in lung carcinogenesis are currently under preclinical or clinical evaluation. This review presents an update on the role of targeted agents in advanced NSCLC. In addition, we present the main clinical studies investigating the activity of these agents in NSCLC and we provide recent data with respect to future therapeutic strategies.