Setting of Optimal Algorithm for Effective Diagnostics of Non-Small Cell Lung Carcinoma with ALK Gene Rearrangement

(Identification of optimal algorithm for effective diagnostics of non-small cell lung carcinoma with ALK gene rearrangement - implementation of the method and practical experience with routine diagnostics) INTRODUCTION: Smaller subgroup of non-small cell lung carcinoma (NSCLC) is represented by tumours with carcinogenesis iniciated by fusion of ALK gene with another partner (usually EML4). Patients with ALK gene rearrangement treated with ALK inhibitors have significantly prolonged survival. Since ALK gene rearrangement is described according to the current WHO classification in 4-5% of NSCLC, it is necessary to find the optimal way of identifying patients eligible for this targeted therapy in routine diagnostic practice. AIM: In the retrospective part of the study a) to find an immunohistochemical (IHC) detection procedure of ALK protein with specificity and sensitivity high enough to use this antibody as screening method for selecting NSCLC cases for fluorescence in situ hybridization (FISH) testing of ALK gene rearrangement and b) to determine diagnostic yield of "small" biopsies, i.e. endobronchial, transbronchial and transthoracic biopsies and cytoblocks, for ALK gene rearrangement testing. In the prospective part of the study a) verification of the selected IHC method of ALK protein detection..

Encorafenib Acts as a Dual-Activity Chemosensitizer through Its Inhibitory Effect on ABCC1 Transporter In Vitro and Ex Vivo

Encorafenib (LGX818, trade name Braftovi), a novel BRAF inhibitor, has been approved for the treatment of melanoma and colorectal cancer. In the present work, we evaluated encorafenib’s possible antagonistic effects on the pharmacokinetic mechanisms of multidrug resistance (MDR), as well as its perpetrator role in drug interactions. Firstly, encorafenib potently inhibited the efflux function of the ABCC1 transporter in drug accumulation assays, while moderate and null interaction levels were recorded for ABCB1 and ABCG2, respectively. In contrast, the mRNA expression levels of all the tested transporters were not altered by encorafenib. In the drug combination studies, we found that daunorubicin and topotecan resistances were synergistically attenuated by the encorafenib-mediated interaction in A431-ABCC1 cells. Notably, further experiments in ex vivo patient-derived explants confirmed the MDR-modulating ability of encorafenib. Advantageously, the overexpression of tested drug efflux transporters failed to hinder the antiproliferative activity of encorafenib. In addition, no significant modulation of the CYP3A4 enzyme’s activity by encorafenib was observed. In conclusion, our work indicated that encorafenib can act as an effective chemosensitizer targeting the ABCC1-induced MDR. Our in vitro and ex vivo data might provide valuable information for designing the novel effective scheme applicable in the clinical pharmacotherapy of BRAF-mutated/ABCC1-expressing tumors

CASE 2–2012: a 57-Year-Old Woman with Post-Transplant Lymphoproliferative Disorder after Allogeneic Stem Cell Transplantation for Primary Myelofibrosis

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