Role of liquid biopsy in oncogene-addicted non-small cell lung cancer

none7noThe discovery of actionable oncogene in non-small cell lung cancer (NSCLC) allowed the identification of a subgroup of patients who benefit from targeted tyrosine kinase inhibitors more than others. Mutations in the epidermal growth factor receptor (EGFR), translocations in the anaplastic lymphoma kinase (ALK) and rearrangements in the ROS proto-oncogene 1 (ROS1) must be identified in tumor tissue to guide the proper treatment choice. Liquid biopsy is based on the analysis of tumor materials released in the circulation. Liquid biopsy can be complementary to tissue biopsy, both at baseline and at progression, especially in the detection of somatic gene alterations emerging during the treatment with tyrosine kinase inhibitors (TKIs). Particularly, circulating DNA is used to find mutations in driver oncogenes, while circulating tumor cells, extracellular vesicles (EVs) and cell-free microRNAs (cfmiRNAs) are still under investigation. To help the unbiased use of liquid biopsy in the choice of the appropriate therapy, some recommendations were delivered by expert panels. Currently, analysis of EGFR mutations in cell-free DNA (cfDNA) is recommended at baseline when tissue biopsy harbors scarce tumor cells, and at progression before performing tissue biopsy; liquid biopsy analysis for other oncogenic drivers is not indicated in the clinical practice.openCanale M.; Pasini L.; Bronte G.; Delmonte A.; Cravero P.; Crino L.; Ulivi P.Canale, M.; Pasini, L.; Bronte, G.; Delmonte, A.; Cravero, P.; Crino, L.; Ulivi, P

Receptor-Coupled Phosphoinositide Hydrolysis in Human Retinal Pigment Epithelium

Carbachol and histamine stimulated phosphoinositide (PPI) hydrolysis in cultured human retinal pigment epithelium (RPE), as reflected by an accumulation of 3 H-inositol phosphates in the presence of 10 m M Li + . Carbachol increased PPI hydrolysis to greater than 600% of basal with an EC 50 of 60 Μ M ; stimulation was linear up to 60 min. This activation likely occurred via the M 3 muscarinic cholinergic receptor based on the IC 50 values for 4-diphenylacetoxy- N -methylpiperidine methiodide (0.47 n M ), pirenzepine (280 n M ), and 11-[[2-[(diethylamino)methyl]-1-piperidinyl]-acetyl]-5,11-dihydro-6 H -pyrido[2,3- b ][1,4]benzodiazepin-6-one (1.4 Μ M ). Carbachol-mediated PPI hydrolysis was decreased by 80% in the absence of extracellular Ca 2+ . Histamine stimulated PPI turnover in a linear manner by 180% with an EC 50 of 20 Μ M by the H 1 histaminergic receptor. Serotonin, glutamate, norepinephrine, and dopamine were inactive. In human RPE, the resting cytoplasmic Ca 2+ concentration, as determined by fura-2 fluorescence, was 138 ± 24 n M . On the addition of carbachol, there was a 180% increase in peak intracellular Ca 2+ ; addition of histamine increased intracellular Ca 2+ by 187%. These results suggest receptor-mediated, inositol lipid hydrolysis is coupled to intracellular Ca 2+ flux in human RPE.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66430/1/j.1471-4159.1991.tb03471.x.pd

Immunoglobulin-resistant delayed hemolytic transfusion reaction treated with rituximab in an adult sickle cell patient.

Clinical presentation of the immunoglobulin (Ig)-resistant DHTR episode in a adult patient with SC

An unusual case of sarcoidosis in an adult patient with sickle cell disease: Management with methotrexate and low dose of steroid

No abstract is available for this article

Synthesis and crystal structure of C2/c Ca(Co, Mg)Si2O6 pyroxenes : effect of the cationic substitution on the cell volume

A series of clinopyroxenes along the CaMgSi2O6-CaCoSi2O6 join was synthesized by quenching from melt at 1500\ub0C and subsequent annealing at 1250\ub0C (at 0.0001 GPa). This protocol proved to be the most effective to obtain homogenous, impurity free and stoichiometric pyroxenes as run products. Electron microprobe analyses in energy-dispersive mode were conducted and single-crystal X-ray diffraction data were collected on the Ca(CoxMg1-x)Si2O6 pyroxenes, with x = 0.2, 0.4, 0.5, 0.6; anisotropic structure refinements were performed. The effects of the cation substitution at the M1 site are described at the atomic level. The experimental findings of this study allowed us to extend the comparative analysis of the structural features of pyroxenes with divalent cations at the M1 and M2 sites

Case Report: Stevens-Johnson Syndrome and Hepatotoxicity Induced by Osimertinib Sequential to Pembrolizumab in a Patient With EGFR-Mutated Lung Adenocarcinoma

Background: Lung cancer is a complex disease with many subtypes. However, histochemical characteristics, and genetic mutation determinations are contributing to better define therapeutic targets and new drugs. Although this guarantees patients the possibility of obtaining tailored treatment, it makes it more difficult for clinicians patient management more difficult for clinicians who have to define the most suitable therapeutic strategy and to deal with new treatment-related adverse events (TRAEs). It has been seen that the administration of a tyrosine kinase inhibitor (TKI) sequential to an immune checkpoint inhibitor (ICI) can lead to a higher rate of severe and life-threatening TRAEs. We report the case of a patient with advanced non-small cell lung cancer (NSCLC) who experienced severe hepatotoxicity and Stevens-Johnson syndrome (SJS) induced by osimertinib sequential to pembrolizumab. Case presentation: A 54-year-old woman with advanced NSCLC received one cycle of chemotherapy plus pembrolizumab after diagnosis. Ten days later she began osimertinib 80 mg daily because epidermal growth factor receptor (EGFR) analysis had revealed an exon 19 deletion. On day 23 of osimertinib the patient experienced an episode of grade (G) 3 hepatotoxicity resolved by discontinuing osimertinib and corticosteroid therapy. The patient restarted osimertinib 80 mg daily after the remission of symptoms but was hospitalized 14 days later following a second episode of severe G3 hepatotoxicity and the onset of SJS, successfully treated with high-dose corticosteroids. Despite the short exposure to osimertinib, the patient obtained a good pathological response. Conclusion: It is important to alert clinicians to carefully evaluate the sequential therapeutic strategy in patients with NSCLC who are candidates for TKI- or ICI-based treatment. Our experience suggests that the use of tyrosine kinase inhibitors (TKIs) as front-line treatment is a more reasonable and safe option for EGFR-mutated lung adenocarcinoma, with ICIs considered as a possible further treatment in sequential approaches

New generation anaplastic lymphoma kinase inhibitors

Anaplastic lymphoma kinase (ALK) gene translocations are pro-tumoral driver alterations that encompass 3*7% of non-squamous non-small cell lung cancer (NSCLC) with specific, clinic and histologic features. The therapeutic strategy depends on anti-ALK tyrosine kinase inhibitors (TKIs) of which crizotinib was the first approved for clinical use. Despite its use improved significantly progression-free survival, overall response rate and duration of response of this illness, after a median period of 10.9 months all patients progress due to the development of acquired resistance mutations in the ALK tyrosine kinase domain in approximately one third of patients. Moreover, 60-90% of patients treated with crizotinib has a progression in the central nervous system (CNS) in absence of extracranial worsening of the disease. This is primarily attributed to poor CNS penetration by crizotinib as many pre-clinical and clinical models suggest. For instance, in order to overtake acquired resistance to crizotinib, prolong the control of the disease and manage CNS localizations, several II and III generation TKIs have been developed. Some of them were approved after the failure of crizotinib (ceritinib, alectinib, brigatinib and lorlatinib) and in first line setting (ceritinib, alectinib and brigatinib) while others are still under evaluation for TKI-naive patients such as lorlatinib, ensartinib and entrectinib. In this review we will discuss the most recent results of new TKIs in order to describe a fast growing therapeutic landscape in this setting

Bionics-based surgical training using 3D printed photopolymers and smart devices

Additive manufacturing technologies support the realization of surgical training devices using, typically, photopolymers-based materials. Unfortunately, the material jetting family, able to print a large range of soft and hard polymers, requires expensive machines and materials, which are not always available. On the other hand, vat polymerization fails in the resolution/volume ratio and in the mechanical properties reconstruction. Stereolithographic 3D printers, mostly used in dental surgery, make possible to realize cheap and sustainable models for training activity using only one material, reducing the possibility to obtain different mechanical characteristics. Moreover, the printed objects have to be treated (i.e. curing post-processing) in order to obtain the required performances, that could be preserved for long term storing. The aim of the proposed approach is to assure the surgeons' skills improvement through bionic-based surgical 3D printed models and smart devices, able to reproduce the same perception of a real surgical activity. We demonstrated how it is possible develop smart devices capable to take into account the same characteristics of different materials (i.e. bone and spongy bone) even if stored for a long time

Advances in molecular mechanisms and immunotherapy involving the immune cell-promoted epithelial-to-mesenchymal transition in lung cancer

none8noImmunotherapy has offered a new opportunity for the treatment of many malignancies. In patients with lung cancer, immune checkpoint inhibitors have significantly improved survival. However, little is known about predictive factors or primary and acquired resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is a complex of phenotypic changes involved in carcinogenesis and resistance to cancer treatments. Specifically, immune cells in the tumor microenvironment can promote EMT, and mesenchymal phenotype acquisition negatively regulates the anticancer immune response. EMT is associated with higher expression of PD-L1 and other immune checkpoints. In this review, we focused on the role of EMT in the interplay between tumor cells and the immune system, with particular emphasis on lung cancer. On the basis of our findings, we hypothesize that the effects of EMT on immune cells could be overcome in this disease by a new combination of immune checkpoint inhibitors.openDe Matteis S.; Canale M.; Verlicchi A.; Bronte G.; Delmonte A.; Crino L.; Martinelli G.; Ulivi P.De Matteis, S.; Canale, M.; Verlicchi, A.; Bronte, G.; Delmonte, A.; Crino, L.; Martinelli, G.; Ulivi, P

Liquid biopsy for egfr mutation analysis in advanced non-small-cell lung cancer patients: Thoughts drawn from a real-life experience

none12noBackground: Liquid biopsy analysis for EGFR detection in cell-free DNA (cfDNA) from NSCLC patients has become routine. The aim of this study was to explore its applicability in clinical practice. Methods: We collected data of EGFR-mutated NSCLC patients with liquid biopsy analysis. Data included test timing, concomitant tissue re-biopsy, therapy change, histology, stage, smoking habits, gender and age. All analyses were performed via a real-time PCR method to analyze EGFR mutations at exons 18, 19, 20 and 21. Variant allele frequency was performed for patients with available sequential EGFR mutation analysis in cfDNA. Overall survival was analyzed through the Kaplan–Meier method. We designed flow charts to show the real-life application of liquid biopsy. Results: We found that liquid biopsy is used in treatment-naïve patients as an alternative to EGFR detection in tumor tissue, and in patients with positive or negative EGFR from tumor biopsy. The majority of liquid biopsy analyses were performed in NSCLC patients who were disease progressive during TKI therapy. The presence of EGFR mutation in cfDNA was associated with a worse prognosis. In two patients, VAF of EGFR mutations in cfDNA was concordant with tumor volume changes. Conclusion: These findings suggest that liquid biopsy for EGFR detection can continue to be useful.openUlivi P.; Petracci E.; Canale M.; Priano I.; Capelli L.; Calistri D.; Chiadini E.; Cravero P.; Rossi A.; Delmonte A.; Crino L.; Bronte G.Ulivi, P.; Petracci, E.; Canale, M.; Priano, I.; Capelli, L.; Calistri, D.; Chiadini, E.; Cravero, P.; Rossi, A.; Delmonte, A.; Crino, L.; Bronte, G