• MeSH
• adenom diagnóza   terapie   MeSH
• anastomóza chirurgická MeSH
• dospělí MeSH
• familiární adenomatózní polypóza * chirurgie   diagnostické zobrazování   komplikace   MeSH
• kolektomie MeSH
• lidé MeSH
• meduloblastom * chirurgie   diagnóza   terapie   MeSH
• peritonitida diagnóza   terapie   MeSH
• pouch MeSH
• tlusté střevo chirurgie   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Neuropatologická diagnostika nádorů centrální nervové soustavy se v posledních letech výrazně posunula díky molekulárně biologickým poznatkům i novým metodám, jako je metylační profilování. V současné WHO klasifikaci se na jejich podkladě změnil jednak obecný přístup ke gradingu a reportování nádorů. Také byly vytvořeny nové skupiny nádorů a nové jednotky, zdůrazňující rozdíly mezi morfologicky obdobnými nádory s rozdílným molekulárně patologickým pozadím. Tento edukativní článek předkládá aktuální pohled na členění nejčastějších dětských nádorů CNS a jeho vliv na současné diagnostické postupy.

Neuropathological diagnostics of central nervous system tumours has advanced significantly in recent years thanks to molecular biological insights and new methods such as methylation profiling. In the current WHO classification, the general approach to grading and reporting of tumours has changed as a result. New tumour groups and new units have also been created, highlighting the differences between morphologically similar tumours with different molecular pathological backgrounds. This educative article gives actual view on groups of the most frequent pediatric CNS tumours and its impact on diagnostic approaches.

• MeSH
• diagnostické techniky molekulární MeSH
• ependymom diagnóza   patologie   MeSH
• gliom diagnóza   genetika   patologie   MeSH
• lidé MeSH
• meduloblastom diagnóza   patologie   MeSH
• metylace DNA MeSH
• nádory centrálního nervového systému * diagnóza   genetika   klasifikace   MeSH
• nádory mozku diagnóza   genetika   klasifikace   MeSH
• stupeň nádoru MeSH
• Check Tag
• lidé MeSH

PURPOSE: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007). CONCLUSION: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

• MeSH
• chronická nemoc MeSH
• dítě MeSH
• kohortové studie MeSH
• kojenec MeSH
• kraniospinální iradiace * škodlivé účinky   MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• meduloblastom * radioterapie   MeSH
• nádory mozečku * radioterapie   MeSH
• nádory mozku * terapie   MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• proteiny hedgehog MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Tumors of the fourth ventricle are frequently treated pathologies in pediatric neurosurgery. Data regarding predictors for permanent neurological deficits, long-term functional outcomes, cerebellar mutism (CM), the extent of resection (EOR), and oncological outcomes are scarce. We attempt to contribute to this topic with an analysis of our institutional cohort. METHODS: A retrospective single-center study of patients aged ≤ 19 years who underwent primary surgical resection of a fourth ventricular tumor over a 15-year period (2006-2021). Predictors analyzed included age, gender, surgical approach, anatomical pattern, tumor grade, EOR, tumor volume, and others as appropriate. RESULTS: One hundred six patients were included (64 males, mean age 7.3 years). The rate of permanent neurological deficit was 24.2%; lateral tumor extension (p = 0.036) and tumor volume greater than 38 cm3 (p = 0.020) were significant predictors. The presence of a deficit was the only significant predictor of reduced (less than 90) Lansky score (p = 0.005). CM occurred in 20.8% of patients and was influenced by medulloblastoma histology (p = 0.011), lateral tumor extension (p = 0.017), and male gender (p = 0.021). No significant difference between the transvermian and telovelar approach in the development of CM was detected (p = 0.478). No significant predictor was found for the EOR. EOR was not found to be a significant predictor of overall survival for both low-grade and high-grade tumors; however, gross total resection (GTR) was protective against tumor recurrence compared to near-total or subtotal resection (p < 0.001). In addition, survival was found to be better in older patients (≥ 7.0 years, p = 0.019). CONCLUSION: The overall rate of postoperative complications remains high due to the eloquent localization. Older patients (> 7 years) have been found to have better outcomes and prognosis. Achieving GTR whenever feasible and safe has been shown to be critical for tumor recurrence. CM was more common in patients with medulloblastoma and in patients with tumors extending through the foramen of Luschka. The telovelar approach uses a safe and anatomically sparing corridor; however, it has not been associated with a lower incidence of CM and neurological sequelae in our series, showing that each case should be assessed on an individual basis.

• MeSH
• čtvrtá mozková komora diagnostické zobrazování   chirurgie   MeSH
• dítě MeSH
• lidé MeSH
• lokální recidiva nádoru chirurgie   MeSH
• meduloblastom * chirurgie   MeSH
• nádory mozečku * chirurgie   etiologie   MeSH
• neurochirurgické výkony škodlivé účinky   MeSH
• pooperační komplikace epidemiologie   etiologie   chirurgie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

IMPORTANCE: Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. OBJECTIVE: To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). DESIGN, SETTING, AND PARTICIPANTS: This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. INTERVENTIONS: Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. MAIN OUTCOMES AND MEASURES: The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. RESULTS: Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. CONCLUSIONS AND RELEVANCE: This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01356290.

• MeSH
• dítě MeSH
• etoposid MeSH
• kvalita života MeSH
• lidé MeSH
• meduloblastom * farmakoterapie   etiologie   MeSH
• metronomické podávání léků MeSH
• mladiství MeSH
• nádory mozečku * farmakoterapie   etiologie   MeSH
• nádory mozku * farmakoterapie   MeSH
• předškolní dítě MeSH
• protokoly antitumorózní kombinované chemoterapie škodlivé účinky   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky kontrolované MeSH
• multicentrická studie MeSH

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.

• MeSH
• lidé MeSH
• meduloblastom * genetika   MeSH
• myši MeSH
• nádory mozečku * genetika   MeSH
• nádory mozku * MeSH
• proteiny nervové tkáně MeSH
• proteiny vázající RNA genetika   MeSH
• proteomika MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Cerebelární mutismus patří ke komplikacím operačních výkonů v zadní jámě lební. Vyskytuje se především v dětském věku, nejčastěji po resekci tumoru v oblasti vermis mozečku. Klinické charakteristiky tohoto syndromu jsou v zahraniční literatuře dobře popsány, patofyziologický mechanismus jeho vzniku však zůstává neobjasněn. Cílem našeho sdělení je prostřednictvím kazuistiky upozornit na zajímavou klinickou jednotku, které je dosud v českých neurologických odborných publikacích věnována pouze ojedinělá zmínka.

Cerebellar mutism is a postoperative complication after an intervention in posterior cranial fossa. It can particularly be seen in children following tumor resection of cerebellar vermis. Clinical features of this syndrome are well described in foreign literature while its pathophysiology stays unclear. The goal of our case report is to point this interesting phenomenon out mainly because it is only sporadicly mentioned in Czech neurological publications.

• Klíčová slova
• cerebelární mutismus,
• MeSH
• dítě MeSH
• lidé MeSH
• meduloblastom * chirurgie   diagnóza   MeSH
• pooperační komplikace MeSH
• výsledek terapie MeSH
• zadní jáma lební chirurgie   patologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

• MeSH
• antigen Ki-67 metabolismus   MeSH
• buněčná diferenciace * genetika   MeSH
• buněčný rodokmen MeSH
• histondemethylasy MeSH
• lidé MeSH
• meduloblastom * klasifikace   genetika   patologie   MeSH
• metencephalon * embryologie   patologie   MeSH
• mozeček embryologie   patologie   MeSH
• mutace MeSH
• nádory mozečku * klasifikace   genetika   patologie   MeSH
• proteiny hedgehog metabolismus   MeSH
• proteiny T-boxu metabolismus   MeSH
• represorové proteiny MeSH
• svalové proteiny MeSH
• transkripční faktory Otx nedostatek   genetika   MeSH
• transkripční faktory PEBP2A genetika   MeSH
• transkripční faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

• MeSH
• dítě MeSH
• dospělí MeSH
• genetická variace MeSH
• genové regulační sítě MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• meduloblastom genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nádory mozečku genetika   MeSH
• předškolní dítě MeSH
• proteiny hedgehog genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• signální transdukce genetika   MeSH
• transkriptom * 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
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

• Klíčová slova
• kranifaryngeom,
• MeSH
• dítě MeSH
• ependymom chirurgie   epidemiologie   terapie   MeSH
• germinální a embryonální nádory klasifikace   patologie   terapie   MeSH
• gliom diagnóza   terapie   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• meduloblastom diagnóza   klasifikace   MeSH
• mozek diagnostické zobrazování   MeSH
• nádory centrálního nervového systému * diagnóza   genetika   klasifikace   terapie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• přehledy MeSH