[The significance of C-KIT gene mutations in the diagnosis and prognosis of malignant tumors]. / Znachenie mutatsii gena C-KIT v diagnostike i prognoze techeniya zlokachestvennykh opukholei.

Mutations in the C-KIT gene encoding type III receptor tyrosine kinase that regulates cellular processes, such as differentiation, survival, proliferation, migration, and apoptosis, are found in some neoplasms: gastrointestinal stromal tumor, mastocytosis, melanoma, breast carcinomas, myeloid leukemias, and a number of others. Tumors that exhibit these mutations are sensitive to therapy with tyrosine kinase inhibitors, which makes it necessary to correctly identify the mutation status by C-KIT in order to apply a personalized approach to therapy. This literature review shows that the type and localization of the C-KIT gene mutation are of crucial prognostic value and significance in choosing drugs for antitumor therapy, but traditional diagnostic methods fail to determine accurate mutation characteristics. Routine sequencing techniques focus on identifying the gene mutations associated with specific cellular processes, such as DNA damage and repair. The emergence of next-generation sequencing techniques has solved this problem, making it possible to fully analyze the genome of a malignant neoplasm, with constant screening for new mutations that appear as the tumor develops, affect the prognosis of the disease, and change its sensitivity to the antitumor therapy.

Conjunctival Melanoma: Update on Genetics, Epigenetics and Targeted Molecular and Immune-Based Therapies.

PURPOSE: To present the molecular mechanisms involved in the pathogenesis of conjunctival melanoma (CM) and review the existing literature on targeted molecular inhibitors as well as immune checkpoint inhibitors for the management of locally advanced and metastatic disease. METHODS: A comprehensive review of the literature was performed using the keywords "conjunctival melanoma", "immune checkpoint inhibitors", "BRAF inhibitors", "MEK inhibitors", "CTLA4 inhibitors", "PD1 inhibitors", "c-KIT mutations", "BRAF mutations", "NRAS mutations", "dabrafenib", "trametinib", "vemurafenib", "ipilimumab", "pembrolizumab", and "nivolumab". A total of 250 articles were reviewed and 120 were included in this report. RESULTS: Mutations of mediators in the MAP kinase pathway, such as RAS, BRAF, MEK and ERK, and mutations of the PI3K/AKT/mTOR pathway play a major role in the pathogenesis of conjunctival melanoma. In addition, alterations of c-KIT, NF1, TERT, chemokine receptors as well as chromosomal copy number alterations and micro RNAs are thought to have a causative association with CM development. Targeted molecular inhibitors, such as BRAF and MEK inhibitors, are currently being implemented in the therapy of BRAF-mutated CM. Furthermore, immune checkpoint PD-1 and CTLA4 inhibitors with favorable clinical outcomes in the treatment of cutaneous melanoma have increased recurrence-free survival and reduced metastatic spread in CM cases. CONCLUSION: The complex molecular mechanisms that contribute to the development of CM can be targeted both by molecular inhibitors of oncogenic pathways as well as immune checkpoint inhibitors in order to halt progression of the disease and increase survival.

Gastrointestinal stromal tumor after tyrosine kinase inhibition therapy: a review of biopsies of 34 patients with clinically suspected relapse and/or progression of the tumor.

Implementation of combined surgical and targeted therapy strategies using tyrosine kinase inhibitors improved the prognosis of patients with aggressive GISTs. The therapeutic answer may be individually different, some patients do not respond properly, or even progress in spite of the therapy. This together with intratumoral heterogeneity and possible development of secondary phenotypical and genetical changes represents a challenge for pathologists examining a biopsy of relapsed tumors and/or their metastases. For this study biopsy files of the national Slovak GIST registry were reviewed to identify patients examined bioptically both prior the therapy and during the TKI treatment due to suspected tumor relapse and/or progression. All the GIST biopsies were analyzed using a standardized algorithm of histological, immunohistochemical and molecular analyses of exon 7, 9, 11, 13 of c-KIT and exons 12, 14, and 18 of PDGFRA genes, with the aim to identify posttherapeutical changes of these parameters. From 34 patients fulfilling the criteria of selection, all were histologically examined during their clinically suspicious first GIST relaps, eight during the 2nd, three during 3rd and one during 4th and 5th relapse resp. All but one posttherapeutical biopsies showed "viable" GIST tissue and so 44 relapses of 33 patients could be evaluated in comparison with identical parameters of diagnostic biopsies. Distinguishing three major histological types (spindle-, epitheloid-cell and mixed cell type), a change of the GIST type was identified in 1/3 of 1st relapse and » of all relapse biopsies. Evaluation of three phenotypical GIST parameters CD117, CD34 and DOG-1, showed that phenotype alteration was always represented by a single change. The most common was either a gain or loss of CD34 positivity appearing in 1/3 of 1st relapse biopsies, while a loss of CD117 positivity was identified in one patient´s biopsy only. Altogether, the phenotypical changes were in » of all relapses. A changed mutational profile was recognized in 38,2% first relaps biopsies and in 33% of all relapses, the change was mostly isolated (in 10/45 relapses) and less often (in 4/45 relapses) it represented a gain of a new mutation in association with persisting original one. In conclusion, the biopsies of patients showing relapse and/or progression on TKI treatment show predominance of viable GIST cells with limited or even absent signs of scaring, as well as relatively low incidence of morphological, pheno- and genotypical changes.

Anaphylaxis after hymenoptera sting: is it venom allergy, a clonal disorder, or both?

A 47-year-old man presented with loss of consciousness 5 minutes after being stung by a yellow jacket in his backyard. Epinephrine and fluids were required for resuscitation. Allergy evaluation revealed specific IgE to yellow jacket and honeybee, and the patient was started on venom immunotherapy. He had systemic reactions during buildup and a severe anaphylactic episode requiring 3 doses of intramuscular epinephrine at maintenance doses. Immunotherapy was discontinued. Serum tryptase level after 1 such episode was 29 ng/mL, with a baseline level of 25 ng/mL 4 weeks later. The physical examination was unremarkable including no skin lesions of cutaneous mastocytosis. Because of elevated baseline tryptase level, a bone marrow biopsy was performed, which revealed multifocal dense infiltrates of mast cells. A diagnosis of systemic mastocytosis was made. The patient was treated with omalizumab and was able to tolerate immunotherapy and is currently maintained on lifelong immunotherapy. He was restung in the field and has not had anaphylaxis.

Prevalence and prognostic significance of c-KIT mutations in core binding factor acute myeloid leukemia: a comprehensive large-scale study from a single Chinese center.

To clarify the prevalence and prognostic significance of c-KIT mutations in patients with core binding factor acute myeloid leukemia (CBF-AML), a total of 351 patients who were categorized as pediatric t(8;21), adult t(8;21), pediatric inv(16), or adult inv(16) were screened at diagnosis for c-KIT mutations in exons 17 and 8 using direct sequencing. A total of 250 patients underwent follow-up. Overall, 36.5% of the patients had a c-KIT mutation. Adult t(8;21) and inv(16) patients had mutations predominantly in exons 17 and 8, respectively. Higher White blood cell (WBC) count, WBC index, and AML1-ETO transcript levels in adult t(8;21) patients were significantly associated with c-KIT mutations and mutations in exon 17 (P≤0.030). c-KIT mutations in adult t(8;21) patients were significantly correlated with a high cumulative incidence of relapse (CIR, P=0.0070) at 2 years and a low 2-year disease-free survival (DFS, P=0.013) and overall survival (OS, P=0.0055). However, no significant difference was revealed in the effect of c-KIT mutations on outcome of adult inv(16) and pediatric t(8;21) patients (all P>0.05). Multivariate analysis revealed that c-KIT mutation is an independent prognostic factor for relapse, DFS, and OS (P≤0.016) in adult t(8;21) AML patients. Therefore, with regard to c-KIT mutation, CBF-AML is a heterogeneous disease. c-KIT mutations have a strong adverse effect on the relapse and survival of adult t(8;21) AML patients.