PURPOSE: Tropomyosin receptor kinase (TRK) fusions are detected in less than 2% of central nervous system tumors. There are limited data on the clinical course of affected patients. EXPERIMENTAL DESIGN: We conducted an international retrospective cohort study of patients with TRK fusion-driven central nervous system tumors. RESULTS: A total of 119 patients were identified. The median age at the time of diagnosis was 4.5 years. The majority were reported to have a histology consistent with a diagnosis of high-grade glioma (HGG; 57.1%) followed by low-grade glioma (LGG; 27.7%). Pediatric patients had a better prognosis, with a median overall survival of 185.5 months compared with 24.8 months in adults (P < 0.0001). Patients with LGG also had a better outcome when compared with HGG (P = 0.0012). The objective response was 68.8% with larotrectinib compared with 38.1% for nontargeted treatment. CONCLUSIONS: Children with LGG had a favorable outcome compared with adult glioma and HGG. TRK inhibitors seem to improve tumor control.

• MeSH
• dítě MeSH
• dospělí MeSH
• fúze genů MeSH
• fúzní onkogenní proteiny * genetika   MeSH
• gliom * genetika   patologie   mortalita   terapie   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory centrálního nervového systému * genetika   terapie   mortalita   patologie   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• pyrazoly terapeutické užití   MeSH
• pyrimidiny terapeutické užití   MeSH
• receptor trkA * genetika   antagonisté a inhibitory   MeSH
• receptor trkB genetika   antagonisté a inhibitory   MeSH
• receptor trkC genetika   antagonisté a inhibitory   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• stupeň nádoru MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

This study was undertaken to determine the frequency, and the clinicopathologic and genetic features, of colon cancers driven by neurotrophic receptor tyrosine kinase (NTRK) gene fusions. Of the 7008 tumors screened for NTRK expression using a pan-Trk antibody, 16 (0.23%) had Trk immunoreactivity. ArcherDx assay detected TPM3-NTRK1 (n=9), LMNA-NTRK1 (n=3), TPR-NTRK1 (n=2) and EML4-NTRK3 (n=1) fusion transcripts in 15 cases with sufficient RNA quality. Patients were predominantly women (median age: 63 y). The tumors involved the right (n=12) and left colon unequally and were either stage T3 (n=12) or T4. Local lymph node and distant metastases were seen at presentation in 6 and 1 patients, respectively. Lymphovascular invasion was present in all cases. Histologically, tumors showed moderate to poor (n=11) differentiation with a partly or entirely solid pattern (n=5) and mucinous component (n=10), including 1 case with sheets of signet ring cells. DNA mismatch repair-deficient phenotype was seen in 13 cases. Tumor-infiltrating CD4/CD8 lymphocytes were prominent in 9 cases. Programmed death-ligand 1 positive tumor-infiltrating immune cells and focal tumor cell positivity were seen in the majority of cases. CDX2 expression and loss of CK20 and MUC2 expression were frequent. CK7 was expressed in 5 cases. No mutations in BRAF, RAS, and PIK3CA were identified. However, other genes of the PI3K-AKT/MTOR pathway were mutated. In several cases, components of Wnt/β-catenin (APC, AMER1, CTNNB1), p53, and TGFβ (ACVR2A, TGFBR2) pathways were mutated. However, no SMAD4 mutations were found. Two tumors harbored FBXW7 tumor suppressor gene mutations. NTRK fusion tumors constitute a distinct but rare subgroup of colorectal carcinomas.

• MeSH
• adenokarcinom diagnóza   genetika   patologie   MeSH
• fúzní onkogenní proteiny genetika   metabolismus   MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny genetika   metabolismus   MeSH
• nádorové biomarkery genetika   metabolismus   MeSH
• nádory tračníku diagnóza   genetika   patologie   MeSH
• následné studie MeSH
• onkogenní fúze MeSH
• receptor trkA genetika   metabolismus   MeSH
• receptor trkB genetika   metabolismus   MeSH
• receptor trkC genetika   metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• tyrosinkinasové receptory genetika   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Larotrectinib je prvním registrovaným léčivým přípravkem protinádorové agnostické léčby pro tumory s fúzemi genů NTRK. Publikovaná analýza 159 dospělých i pediatrických pacientů se solidními tumory s fúzí NTRK léčených larotrectinibem prokázala medián trvání léčebné odpovědi 35,2 měsíce a medián doby do progrese onemocnění 28,3 měsíce. Jednalo se o značně heterogenní skupinu pokročilých předléčených nádorů. Larotrectinib má dobrý bezpečnostní profil; dávka byla redukována u 8 % nemocných a k přerušení terapie došlo u 2 % pacientů z důvodů nežádoucích účinků.

Larotrectinib is a registered anticancer drug for antitumor therapy for tumors with NTRK gene fusions. A published analysis of 159 adult and pediatric patients with solid NTRK fusion tumors treated with larotrectinib showed a median duration of response of 35.2 months and a median time to disease progression of 28.3 months. These were highly heterogeneous groups of advanced pretreated tumors. Larotrectinib has a good safety profile; the dose was reduced in 8% of patient, in 2% due to side effects.

• MeSH
• fúze genů MeSH
• lidé MeSH
• mutace * MeSH
• protinádorové látky imunologicky aktivní * škodlivé účinky   terapeutické užití   MeSH
• receptor trkA genetika   terapeutické užití   MeSH
• receptor trkB genetika   terapeutické užití   MeSH
• receptor trkC genetika   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH

RNAscope® technology provided by Advanced Cell Diagnostics (ACD) allows the detection and evaluation of coinciding mRNA expression profiles in the same or adjacent cells in unprecedented quantitative detail using multicolor fluorescent in situ hybridization (FISH). While already extensively used in thinly sectioned material of various pathological tissues and, to a lesser extent, in some whole mounts, we provide here a detailed approach to use the fluorescent RNAscope method in the mouse inner ear and thick brain sections by modifying and adapting existing techniques of whole mount fluorescent in situ hybridization (WH-FISH). We show that RNAscope WH-FISH can be used to quantify local variation in overlaying mRNA expression intensity, such as neurotrophin receptors along the length of the mouse cochlea. We also show how RNAscope WH-FISH can be combined with immunofluorescence (IF) of some epitopes that remain after proteinase digestion and, to some extent, with fluorescent protein markers such as tdTomato. Our WH-FISH technique provides an approach to detect cell-specific quantitative differences in developing and mature adjacent cells, an emerging issue revealed by improved cellular expression profiling. Further, the presented technique may be useful in validating single-cell RNAseq data on expression profiles in a range of tissue known or suspected to have locally variable mRNA expression levels.

• MeSH
• fluorescenční protilátková technika metody   MeSH
• hybridizace in situ fluorescenční MeSH
• kochlea metabolismus   MeSH
• messenger RNA genetika   metabolismus   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• neurotrofin 3 metabolismus   MeSH
• receptor trkB genetika   metabolismus   MeSH
• receptor trkC genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• zobrazování trojrozměrné MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH