Sructural rearrangements of NTRK genes: characteristics, methods of detection and targeted therapy for cancer

Background. The first-generation trk inhibitors, larotrectinib and entrectinib, were approved by the u.s. Food and drug administration (Fda) for the treatment of advanced solid tumors harboring NTRK gene fusions in November 2018 and in august 2019, respectively. The purpose of the study was to present upto-date data on the structure and functions of ntrk genes, the frequency of occurrence of rearrangements with their participation, the consequences of their occurrence at the cellular level, methods of detecting such rearrangements, as well as targeted drugs used in the presence of chimeric NTRK genes. Material and methods. A systemic literature search was conducted in pubmed ncbi, Web of science, scopus databases. Results. The products of NTRK genes are receptors for neurotrophins, and their high expression is normally observed only in a narrow range of tissue types. Intrachromosomal or interchromosomal rearrangements lead to a significant increase in the level of expression of the chimeric gene regulated by the strong promoter of the partner gene. The high transcriptional activity of such a gene, along with the constant activation of the kinase activity of the protein product, leads to the activation of metabolic pathways responsible for cell escape from apoptosis and disruption of the regulation of the cell cycle. The occurrence of chimeric NTRK genes varies between different types of tumors, with the highest (up to 90 %) in rare cancers (secretory carcinoma of the breast, secretory carcinoma of the salivary glands, congenital mesoblastic nephroma, children’s fibrosarcoma). Larotrectinib and entrectinib are highly effective targeted drugs in suppressing the growth of a tumor carrying NTRK rearrangements, regardless of the type of tumor. In this regard, the introduction of new high-precision methods for the detection of chimeric NTRK genes, as well as the study of the mechanisms of the development of resistance with the assumption of ways to overcome it, seems relevant. Conclusion. Rearrangements of NTRK genes are quite common in various types of oncology and are an effective target for modern targeted drugs.

Non-Wilms' Renal Tumors In Children:A 139 Cases Series

Background:Pediatric non-Wilms renal tumors (NWRTs) which comprise a small proportion of renal tumors,are a heterogeneous group of neoplasms with variable malignant potential, mortality, and response to treatment.This study aimed to determine the clinical characteristics, management and prognosis of children with non-Wilms' renal tumors(NWRTs). Methods:Medical records of all patients (n = 139) treated for NWRTs over a 12-year period (2008.01–2019.10) at a single center were reviewed retrospectively.Results:The histopathological groups of NWRTs included malignant rhabdoid tumor of the kidney(MRTK)(n: 30, 21.6%), renal cell cancer(RCC)(n: 26,18.7%), clear cell sarcoma of the kidney(CCSK)(n: 24,17.3%), congenital mesoblastic nephroma(CMN)(n: 21,15.1%), cystic nephroma(CN)(n: 16,11.5%),metanephric tumours(n: 12, 8.6%), renal angiomyoliporma(RAML)(n: 3, 2.2%), renal primitive neuroectodermal tumor(rPNET)(n: 2, 1.4%), renal hemangioma(n: 2, 1.4%), inflammatory myofibroblastic tumor(IMT)(n: 2, 1.4%), ossifying renal tumor of infancy(ORTI)(n: 1, 0.7%). 123 children were followed up with an average of 42 months. 16 children were lost to follow-up. Tumor-free survival was observed in 94 children. 28 children(22.8%) were died.Conclusions:Pediatric NWRTs comprises 19.1% of all renal tumors in our single center. Accurate diagnoses along with appropriate management are important factors in improving patients outcome. The mainstay treatment of malignant NWRTs including MRTK,CCSK,RCC and PNET is comprehensive treatment. The mainstay treatment of benign NWRTs including RAML,CN, ORTI, CMN,metanephric tumours, and renal hemangioma is surgical resection alone.

Surgical management of cellular congenital mesoblastic nephroma in a neonate: a case report and review of literature

Background Congenital mesoblastic nephroma (CMN) is the most common type of renal stromal tumor in neonates. It is classified into cellular, classical, and mixed types. The multidisciplinary management approach is the mainstay of management. We are reporting a case of neonatal congenital mesoblastic nephroma in a full-term boy with intrauterine growth restriction and hypertension managed effectively in our institution. Case presentation A full-term boy with intrauterine growth restriction (IUGR) with a birth weight of 2.3 kg, referred at birth with an abdominal mass. His antenatal scan at 35 weeks showed a cystic abdominal mass. On delivery, a huge visible abdominal mass of cystic consistency and smooth surface was noticed at the right side of the abdomen. blood pressure was 98/75 mmHg. It was responsive to hydralazine. Aldosterone and renin were significantly elevated at more than 100 and 500 ng/dl, respectively. Serum neurone-specific enolase (NSE) was 35 ng/ml while alfa feto protein was (AFP) 50,000 kIU/L. An abdominal ultrasound scan revealed an ill-defined large heterogeneous mass of 6.09 × 6.5 × 5.77 cm that arises from the right kidney. A computed tomography scan confirmed a right kidney mass with peripheral claw sign of the normal right renal tissue. It was crossing the midline and causing a mass effect on the adjacent structures. The right renal artery and vein were compressed and shifted posteriorly and inferomedially. Right radical nephrectomy was performed via a right lower transverse incision. The tumor was completely excised with a tumor weight of 270 g and a size of 10.5 × 8 × 5.5 cm. Histopathological diagnosis was mesoblastic nephroma of a cellular type which was confirmed by immunohistochemistry. Post-operatively, the blood pressure has significantly reduced and antihypertensive medications were eventually weaned off. The multidisciplinary team decided to preserve chemotherapy only in case of recurrence. At 3 months follow-up, no features of recurrence were noticed based on surveillance ultrasonography. Conclusion Mesoblastic nephroma should be considered in any newborn with renal mass. The multidisciplinary team approach with aggressive management of hypertension, detailed radiological investigation, and complete tumor resection is fundamental for obtaining an excellent outcome for such entities.

A novel case of an infantile fibrosarcoma-like tumor with KIAA1549-BRAF translocation and an oncogenic NF2p.Q459* SNV with potential clinical significance

We report a case of a right gluteal mass from the sacroiliac joint to the knee of an infant girl. Biopsy showed histopathological features similar to infantile fibrosarcoma (IFS). However, unlike most IFS, no ETV6-NTRK3 fusion gene abnormality was detected. Molecular analysis with TruSight RNA Pan-Cancer Panel detected the presence of KIAA1549-BRAF translocation and an oncogenic NF2p.Q459* SNV with potential clinical significance. A review revealed that the combination of this patient’s tumor site with the presence of a KIAA1549-BRAF translocation abnormality and an accompanying single nucleotide variant has not been previously described. The detection of this translocation abnormality raises the possibility that the spindle cell tumors in infants with an absence of the ETV6-NTRK3 fusion gene abnormality might have a distinct pathogenetic mechanism different from the previously known IFS and congenital mesoblastic nephroma. Furthermore, the discovery of BRAF translocation and its aberrant signaling of the mitogen-activated protein kinase (MAPK) pathway in this tumor contributes to the promise of clinical benefit of using the MEKi trametinib for the treatment of progressive disease that is refractory to conventional chemotherapy.