Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions.

Background: In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).

Patients And Methods: Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue.

Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer.

Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance.

Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy.

The discovery of epidermal growth factor receptor () mutations and subsequent demonstration of the efficacy of genotype-directed therapies with EGFR tyrosine kinase inhibitors (TKIs) marked the advent of the era of precision medicine for non-small-cell lung cancer (NSCLC). First- and second-generation EGFR TKIs, including erlotinib, gefitinib and afatinib, have consistently shown superior efficacy and better toxicity compared with first-line platinum-based chemotherapy and currently represent the standard of care for -mutated advanced NSCLC patients. However, tumors invariably develop acquired resistance to EGFR TKIs, thereby limiting the long-term efficacy of these agents.

Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy.

The identification of echinoderm microtubule-associated protein-like 4 () and anaplastic lymphoma kinase () fusion gene in non-small cell lung cancer (NSCLC) has radically changed the treatment of a subset of patients harboring this oncogenic driver. Crizotinib was the first ALK tyrosine kinase inhibitor to receive fast approval and is currently indicated as the first-line therapy for advanced, -positive NSCLC patients. However, despite crizotinib's efficacy, patients almost invariably progress, with the central nervous system being one of the most common sites of relapse.

Activation of signal transducer and activator of transcription 3 (STAT3) signaling in EGFR mutant non-small-cell lung cancer (NSCLC).

Gefitinib, erlotinib or afatinib are the current treatment for non-small-cell lung cancer (NSCLC) harboring an activating mutation of the epidermal growth factor receptor (EGFR), but less than 5% of patients achieve a complete response and the median progression-free survival is no longer than 12 months. Early adaptive resistance can occur as soon as two hours after starting treatment by activating signal transducer and activation of transcription 3 (STAT3) signaling. We investigated the activation of STAT3 in a panel of gefitinib-sensitive EGFR mutant cell lines, and gefitinib-resistant PC9 cell lines developed in our laboratory.

Second-line therapy of squamous non-small cell lung cancer: an evolving landscape.

The treatment of lung cancer has radically changed over the last few years. The discovery of druggable oncogenic alterations and the introduction of immunotherapy have provided lung cancer patients with the possibility of more efficient and less toxic therapeutic alternatives than chemotherapy. In the case of lung squamous cell carcinoma (LSCC), the treatment progress is slower than adenocarcinoma, for which several targeted agents have been already approved.

Anaplastic lymphoma kinase inhibitors in phase I and phase II clinical trials for non-small cell lung cancer.

Crizotinib is a first-in-class ALK tyrosine kinase inhibitor (TKI), which has proven its superiority over standard platinum-based chemotherapy for the first-line therapy of ALK-rearranged non-small cell lung cancer (NSCLC) patients. The development of acquired resistance to crizotinib represents an ongoing challenge with the central nervous system being one of the most common sites of relapse. Ceritinib and alectinib are approved second-generation ALK TKIs.

Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial.

Background: The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation.

Pharmacological management of relapsed/refractory NSCLC with chemical drugs.

Lung cancer is the leading cause of cancer death in both genders. In the early stages the disease is asymptomatic and most patients appear with metastasis at the time of the diagnosis. The discovery of key oncogenic events mainly in lung adenocarcinoma, like EGFR mutations or ALK rearrangements has changed the treatment landscape and has improved the prognosis of lung cancer patients.

Identification of , , and Fusions by a Multiplexed mRNA-Based Assay in Formalin-Fixed, Paraffin-Embedded Samples from Advanced Non-Small-Cell Lung Cancer Patients.

Background: Anaplastic lymphoma receptor tyrosine kinase (), ROS proto-oncogene 1, receptor tyrosine kinase (), and ret proto-oncogene () fusions are present in 5%-7% of patients with advanced non-small-cell lung cancer (NSCLC); their accurate identification is critical to guide targeted therapies. FISH and immunohistochemistry (IHC) are considered the gold standards to determine gene fusions, but they have limitations. The nCounter platform is a potentially useful genomic tool for multiplexed detection of gene fusions, but has not been validated in the clinical setting.

HER3 as a Therapeutic Target in Cancer.

Targeting members of the human epidermal growth factor receptor family, especially EGFR and HER2, has been an established strategy for the treatment of tumors with abnormally activated receptors due to overexpression, mutation, ligand-dependent receptor dimerization and ligand-independent activation. Less attention has been paid to the oncogenic activity of HER3, although there is growing evidence that it mediates resistance to EGFR and HER2 pathway directed therapies. The main caveat for the development of effective HER3 targeted therapies is the absence of a strong enzymatic activity to target, as well as the limited potential for single-agent activity.

Usefulness of circulating free DNA for monitoring epidermal growth factor receptor mutations in advanced non-small cell lung cancer patients: a case report.

Genomic analysis of circulating tumor DNA (ctDNA) released from cancer cells into the bloodstream has been proposed as a useful method to capture dynamic changes during the course of the disease. In particular, the ability to monitor epidermal growth factor receptor () mutation status in cell-free circulating DNA (cfDNA) isolated from advanced non-small cell lung cancer (NSCLC) patients can help to the correct management of the disease and overcome the challenges associated with tumor heterogeneity and insufficient biopsied material to perform key molecular diagnosis. Here, we report a case of long term monitorization of mutation status in cfDNA from peripheral blood in an NSCLC patient in, with excellent correlation with clinical evolution.

Fusion gene and splice variant analyses in liquid biopsies of lung cancer patients.

Obtaining a biopsy of solid tumors requires invasive procedures that strongly limit patient compliance. In contrast, a blood extraction is safe, can be performed at many time points during the course disease and encourages appropriate therapy modifications, potentially improving the patient's clinical outcome and quality of life. Fusion of the tyrosine kinase genes anaplastic lymphoma kinase (), C-ROS oncogen 1 (), rearranged during transfection () and neurotrophic tyrosine kinase 1 () occur in 1-5% of lung adenocarcinomas and constitute therapeutic targets for tyrosine kinase inhibitors.

Dermanyssus gallinae (chicken mite): an underdiagnosed environmental infestation.

Dermanyssus gallinae is a mite that normally parasitizes small birds but may occasionally bite humans. We report an unusual case of an 82-year-old woman who presented with pruritus and bite-like lesions over her trunk. Other members of the household were also affected.

Orbital cellulitis and endogenous endophthalmitis secondary to Proteus mirabilis cholecystitis.

We report the first case of orbital cellulitis and endogenous endophthalmitis secondary to Proteus mirabilis bacteremia that resulted from a calculus cholecystitis. Despite resolution of the gallbladder infection with antimicrobial therapy, the patient required evisceration of the affected eye. The pathogenesis of hematogenous endophthalmitis due to Gram-negative bacilli is discussed.

Ventilator-associated pneumonia.

Purpose Of Review: Ventilator-associated pneumonia (VAP) is the main nosocomial infection in patients receiving mechanical ventilation. Despite numerous advances in the understanding of this disorder, the incidence rate continues in an unacceptable range. In this review, we discuss some important findings of recently published studies on diagnosis, prevention and treatment.