AIMS: Embryonal tumours with PLAGL1 or PLAGL2 amplification (ET, PLAGL) show substantial heterogeneity regarding their clinical characteristics and have been treated inconsistently, resulting in diverse outcomes. In this study, we aimed to evaluate the clinical behaviour of ET, PLAGL and elucidate their response pattern across the different applied treatment regimens. METHODS: We conducted an in-depth retrospective analysis of clinical and serial imaging data of 18 patients with ET, PLAGL (nine each of PLAGL1 and PLAGL2 amplified). RESULTS: Patients with PLAGL1-amplified tumours (ET, PLAGL1) had fewer relapses (3/9), while PLAGL2-amplified tumours (ET, PLAGL2) were prone to early relapse or progression (8/9) and to distant, leptomeningeal and intraventricular relapses. Progression-free survival differed significantly between the subtypes (log-rank test, p = 0.0055). Postoperative treatment included chemotherapy (n = 17, various protocols), alone (n = 8) or combined with radiotherapy (n = 9). Responses to chemotherapy were observed in both subtypes, and incomplete resection was not associated with inferior survival. All three survivors with ET, PLAGL2 were treated with induction and high-dose chemotherapy with (n = 1-low-dose CSI and boost) or without (n = 2) radiotherapy, whereas five patients with less intensive chemotherapy relapsed. All six survivors with ET, PLAGL1 were treated with conventional chemotherapy regimens, with (n = 4-local radiotherapy n = 3; CSI and boost n = 1) or without (n = 2) radiotherapy. Two patients with ET, PLAGL1 relapsed after 8 years. CONCLUSIONS: Adjuvant therapy should be considered for all ET, PLAGL patients: Patients with ET, PLAGL2 might benefit from intensified chemotherapy regimens. In contrast, patients with ET, PLAGL1 showed superior outcomes without high-dose chemotherapy or craniospinal irradiation.

• MeSH
• amplifikace genu MeSH
• dítě MeSH
• DNA vazebné proteiny * genetika   MeSH
• dospělí MeSH
• germinální a embryonální nádory * genetika   terapie   patologie   diagnostické zobrazování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory centrálního nervového systému * genetika   terapie   patologie   diagnostické zobrazování   MeSH
• nádory mozku * genetika   terapie   MeSH
• předškolní dítě MeSH
• retrospektivní studie MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

BACKGROUND AND PURPOSE: CNS embryonal tumor with pleomorphic adenoma gene-like 1 (PLAGL1)/pleomorphic adenoma gene-like 2 (PLAGL2) amplification (ET, PLAGL) is a newly identified, highly malignant pediatric tumor. Systematic MRI descriptions of ET, PLAGL are currently lacking. MATERIALS AND METHODS: MRI data from 19 treatment-naïve patients with confirmed ET, PLAGL were analyzed. Evaluation focused on anatomic involvement, tumor localization, MRI signal characteristics, DWI behavior, and the presence of necrosis and hemorrhage. Descriptive statistics (median, interquartile range, percentage) were assessed. RESULTS: Ten patients had PLAGL1 and nine had PLAGL2 amplifications. The solid components of the tumors were often multinodular with heterogeneous enhancement (mild to intermediate in 47% and intermediate to strong in 47% of cases). Nonsolid components included cysts in 47% and necrosis in 84% of the cases. The tumors showed heterogeneous T2WI hyper- and isointensity (74%), relatively little diffusion restriction (ADC values less than contralateral normal-appearing WM in 36% of cases with available DWI), and tendencies toward hemorrhage/calcification (42%). No reliable distinction was found between PLAGL1- and PLAGL2-amplified tumors or compared with other embryonal CNS tumors. CONCLUSIONS: The study contributes to understanding the imaging characteristics of ET, PLAGL. It underscores the need for collaboration in studying rare pediatric tumors and advocates the use of harmonized imaging protocols for better characterization.

• MeSH
• amplifikace genu MeSH
• dítě MeSH
• DNA vazebné proteiny genetika   MeSH
• germinální a embryonální nádory diagnostické zobrazování   patologie   MeSH
• kojenec MeSH
• lidé MeSH
• magnetická rezonanční tomografie * metody   MeSH
• mladiství MeSH
• nádorové supresorové proteiny MeSH
• nádory centrálního nervového systému diagnostické zobrazování   patologie   MeSH
• nádory mozku diagnostické zobrazování   patologie   MeSH
• předškolní dítě MeSH
• proteiny buněčného cyklu MeSH
• proteiny vázající RNA MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

GLI1 -altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1 -altered mesenchymal neoplasms to date, including 23 GLI1- amplified and 15 GLI1 -rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1- rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1 -amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1 -amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1- amplified tumors. GLI1 -amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1 -amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1 -rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1 -amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1- rearranged group. Despite comparable progression rates, GLI1 -amplified tumors had a shorter median progression-free survival compared with GLI1 -rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1 -altered mesenchymal tumors.

• MeSH
• amplifikace genu * MeSH
• časové faktory MeSH
• dospělí MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• genová přestavba * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery * genetika   MeSH
• nádory měkkých tkání genetika   patologie   mortalita   MeSH
• protein Gli1 * genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Metastatický kolorektální karcinom je v současnosti stále nevyléčitelné onemocnění. Nicméně díky pokrokům v systémové terapii se medián přežití pacientů významně prodlužuje. Prodlužování celkového přežití je podmíněno více personalizovanou terapií dle ne/přítomnosti molekulárních alterací. Jednou z těchto relativně nově zkoumaných alterací a novým cílem terapie je HER2 pozitivní metastatický kolorektální karcinom. Cílem tohoto článku je podat stručný přehled současných možností léčby této specifické podskupiny.

Metastatic colorectal cancer is currently still an incurable disease. However, thanks to advances in systemic therapy, the median survival of patients is increasing. The prolongation of overall survival is due to more personalized therapy according to the absence/presence of molecular alterations. One of these relatively newly investigated alterations and a novel target for therapy is HER2-positive metastatic colorectal cancer. The aim of this article is to provide a brief overview of current therapeutic options for this specific subset of metastatic disease.

• MeSH
• amplifikace genu MeSH
• cílená molekulární terapie metody   MeSH
• geny erbB-2 MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• klinická studie jako téma MeSH
• klinické laboratorní techniky MeSH
• kolorektální nádory * diagnóza   farmakoterapie   genetika   MeSH
• kombinovaná farmakoterapie metody   MeSH
• lidé MeSH
• prognóza MeSH
• protinádorové látky imunologicky aktivní terapeutické užití   MeSH
• protinádorové látky terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian carcinoma characterized by unique biological features and highly malignant characteristics including low chemosensitivity. Therefore, new therapeutic targets are needed. These could include the downstream pathways of receptor tyrosine kinases, especially the human epidermal growth factor receptor 2 (HER2). Our main objective was to characterize the HER2 status using immunohistochemistry (IHC) and FISH on 118 OCCCs, also considering the novel paradigm of HER2-zero and HER2-low status. Other aims included determination of the association between HER2 status and survival, HER2 gene DNA and RNA NGS analysis, HER2 gene expression analysis, and correlation between IHC and gene expression in HER2-zero and HER2-low cases. Cases with HER2 overexpression/amplification accounted for 5.1% (6/118), with additional 3% harbouring HER2 gene mutation. The remaining 112 (94.9%) cases were HER2-negative. Of these, 75% were classified as HER2-zero and 25% as HER2-low. This percentage of HER2 aberrations is significant concerning their possible therapeutic influence. Cases from the HER2-zero group showed significantly better survival. Although this relationship lost statistical significance in multivariate analysis, the results have potential therapeutic significance. HER2 gene expression analysis showed a significant correlation with HER2 IHC status in the entire cohort (HER2-positive vs. HER2-negative), while in the cohort of only HER2-negative cases, the results did not reach statistical significance, suggesting that gene expression analysis would not be suitable to confirm the subdivision into HER2-low and HER2-zero. Our results also emphasize the need for standardized HER2 testing in OCCC to determine the best predictor of clinical response.

• MeSH
• amplifikace genu MeSH
• epiteliální ovariální karcinom genetika   MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie MeSH
• lidé MeSH
• nádory prsu * genetika   MeSH
• nádory vaječníků * patologie   MeSH
• receptor erbB-2 metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Receptors of the large HER family play an important role in breast cancer, which is undergoing a gradual development in connection with biological development, both in the fi eld of diagnostics and therapy. Dimerization of HER-2 with other HER members, such as HER-3, is the biggest driver of tumor cell growth and survival. Numerous studies show that HER-3 gene overexpression correlates with poor prognosis. However, other studies have shown HER-3 overexpression to be a positive prognostic factor. HER-3 may confer resistance to certain EGFR or HER-2 receptor therapeutics. An interesting fact, however, is that HER-3 expression can serve as a marker in immunotherapy for triple-negative breast cancer (TNBC). It is thought to be involved not only in cell survival and proliferation, but also in the regulation of PD-L1 expression. In breast cancer, PD-L1 expression is heterogeneous and is generally associated with the presence of tumor-infi ltrating lymphocytes and a number of factors with poor prognosis such as young age, hormone receptor negativity, and high HER-2 expression and proliferation index. Our results showed amplifi cation of HER-3 (CERB3) in 2 out of a sample of 20 patients with TNBC, and 13 of 20 HER-2-positive patients. PD-L1 expression was demonstrated in 3 out of 13 HER-3-positive patients and 2 out of 2 HER-3-positive TNBC patients. There was a strong correlation between positive HER-3 and PD-L1 TNBC expression (p = < 0.001). Thus, the view of the HER-3 receptor will be much more complex, and the overexpression of this receptor appears to have both negative and positive prognostic and clinical impacts (Tab. 1, Ref. 17).

• MeSH
• amplifikace genu MeSH
• antigeny CD274 biosyntéza   MeSH
• cytogenetické vyšetření MeSH
• dospělí MeSH
• erbB receptory škodlivé účinky   MeSH
• imunoanalýza MeSH
• lidé středního věku MeSH
• lidé MeSH
• proteosyntéza * MeSH
• senioři MeSH
• triple-negativní karcinom prsu * etiologie   genetika   imunologie   patofyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• Publikační typ
• klinická studie MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Despite constant advances in the field of pediatric oncology, the survival rate of high-risk neuroblastoma patients remains poor. The molecular and genetic features of neuroblastoma, such as MYCN amplification and stemness status, have established themselves not only as potent prognostic and predictive factors but also as intriguing targets for personalized therapy. Novel thiosemicarbazones target both total level and activity of a number of proteins involved in some of the most important signaling pathways in neuroblastoma. In this study, we found that di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) potently decreases N-MYC in MYCN-amplified and c-MYC in MYCN-nonamplified neuroblastoma cell lines. Furthermore, DpC succeeded in downregulating total EGFR and phosphorylation of its most prominent tyrosine residues through the involvement of NDRG1, a positive prognostic marker in neuroblastoma, which was markedly upregulated after thiosemicarbazone treatment. These findings could provide useful knowledge for the treatment of MYC-driven neuroblastomas that are unresponsive to conventional therapies.

• MeSH
• amplifikace genu účinky léků   MeSH
• biologické modely MeSH
• chelátory železa farmakologie   MeSH
• down regulace účinky léků   MeSH
• erbB receptory metabolismus   MeSH
• fosforylace účinky léků   MeSH
• fyziologický stres účinky léků   MeSH
• intracelulární signální peptidy a proteiny metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• neuroblastom metabolismus   patologie   MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• protoonkogen n-myc metabolismus   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• pyridiny farmakologie   MeSH
• signální transdukce * MeSH
• thiosemikarbazony farmakologie   MeSH
• tvar buňky účinky léků   MeSH
• umlčování genů účinky léků   MeSH
• upregulace účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Salivary gland carcinomas represent a heterogeneous group of poorly characterized head and neck tumors. The purpose of this study was to evaluate ALK gene and protein aberrations in a large, well-characterized cohort of these tumors. A total of 182 salivary gland carcinomas were tested for anaplastic lymphoma kinase (ALK) positivity by immunohistochemistry (IHC) using the cut-off of 10% positive cells. ALK positive tumors were subjected to FISH analysis and followed by hybrid capture-based next generation sequencing (NGS). Of the 182 tumors, 8 were ALK positive by IHC. Further analysis using hybrid capture NGS analysis revealed a novel MYO18A (Exon1-40)-ALK (exon 20-29) gene fusion in one case of intraductal carcinoma. Additional genomic analyses resulted in the detection of inactivating mutations in BRAF and TP53, as well as amplifications of ERBB2 and ALK. ALK rearrangements are a rare entity in salivary gland carcinomas. We identified a potentially targetable novel ALK fusion in an intraductal carcinoma of minor salivary glands.

• MeSH
• amplifikace genu MeSH
• anaplastická lymfomová kináza genetika   MeSH
• dítě MeSH
• dospělí MeSH
• fúze genů MeSH
• hybridizace in situ fluorescenční MeSH
• imunohistochemie MeSH
• intraduktální neinfiltrující karcinom enzymologie   genetika   patologie   MeSH
• karcinom enzymologie   genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádorové biomarkery genetika   MeSH
• nádory slinných žláz enzymologie   genetika   patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Long-term complications such as radiation-induced second malignancies occur in a subset of patients following radiation-therapy, particularly relevant in pediatric patients due to the long follow-up period in case of survival. Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). We perform comprehensive (epi-) genetic and expression profiling of RIGs arising after cranial irradiation for MB (n = 23) and ALL (n = 9). Our study reveals a unifying molecular signature for the majority of RIGs, with recurrent PDGFRA amplification and loss of CDKN2A/B and an absence of somatic hotspot mutations in genes encoding histone 3 variants or IDH1/2, uncovering diagnostic markers and potentially actionable targets.

• MeSH
• amplifikace genu * MeSH
• chromozomální delece MeSH
• dítě MeSH
• dospělí MeSH
• genetická transkripce MeSH
• genom lidský MeSH
• genová přestavba genetika   MeSH
• gliom genetika   patologie   MeSH
• inhibitor p15 cyklin-dependentní kinasy metabolismus   MeSH
• inhibitor p16 cyklin-dependentní kinasy metabolismus   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru patologie   MeSH
• metylace DNA genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• regulace genové exprese u nádorů MeSH
• růstový faktor odvozený z trombocytů - receptor alfa genetika   metabolismus   MeSH
• shluková analýza MeSH
• záření MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

PURPOSE: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. MATERIALS AND METHODS: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). RESULTS: Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P < .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. CONCLUSION: Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.

• MeSH
• amplifikace genu * MeSH
• anaplastická lymfomová kináza genetika   MeSH
• klinické zkoušky, fáze III jako téma MeSH
• kojenec MeSH
• lidé MeSH
• míra přežití MeSH
• mutační rychlost * MeSH
• následné studie MeSH
• neuroblastom genetika   MeSH
• předškolní dítě MeSH
• prognóza MeSH
• protoonkogen n-myc genetika   MeSH
• randomizované kontrolované studie jako téma MeSH
• rizikové faktory MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH