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1.
Neuropathol Appl Neurobiol ; 47(2): 236-250, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32779246

RESUMEN

AIMS: Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalized, risk-adapted therapies. METHODS: We characterized the iMB molecular landscape, including second-generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). RESULTS: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second-generation subtypes II/III/IV. Subtype II strongly associated with large-cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very-high-risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4 ) and subtype IV tumours were standard risk (80% OS) using upfront CSI-based therapies; randomized-controlled trials of upfront radiation-sparing and/or second-line radiotherapy should be considered. Seventy-five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non-DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH . iMBSHH harboured two distinct subtypes (iMBSHH-I/II ). Within the discriminated favourable-risk iMBSHH DN/MBEN patient group, iMBSHH-II had significantly better progression-free survival than iMBSHH-I , offering opportunities for risk-adapted stratification of upfront therapies. Both iMBSHH-I and iMBSHH-II showed notable rescue rates (56% combined post-relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. CONCLUSIONS: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup-dependent survival models highlight opportunities for biomarker-directed therapies.


Asunto(s)
Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Meduloblastoma/genética , Meduloblastoma/patología , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico , Estudios Retrospectivos
2.
Neuropathol Appl Neurobiol ; 45(4): 410-420, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-29770465

RESUMEN

AIMS: To evaluate the relationship between expression of myxovirus-resistance protein A (MxA) protein on muscle biopsies by immunohistochemistry and disease activity in juvenile dermatomyositis (JDM) patients. Also, another aim was to investigate whether the expression of MxA is related with myositis-specific autoantibodies (MSA) status in JDM patients. METHODS: 103 patients (median aged 6.3, interquartile range 0.5-15.9) enrolled in the Juvenile Dermatomyositis Cohort and Biomarker Study (JDCBS). Muscle biopsies were stained with MxA and scored. Clinical data at initial presentation were collected and autoantibodies were analysed. Multiple linear regression analysis was performed to estimate the association between MxA expression on muscle fibres and muscle disease activity, and MSA status. RESULTS: Expression of MxA protein on JDM samples was identified in 61.2%. There was a significant association between MxA scores and Childhood Myositis Assessment Scale (CMAS) (P = 0.002), and Manual Muscle Testing of Eight Muscles (MMT8) (P = 0.026). CMAS and MMT8 scores were significantly lower in the group of patients with strong MxA expression. MxA scores differed according to MSA subgroups (P = 0.002). Patients with positive nuclear matrix protein 2 autoantibodies had strong MxA expression, whereas anti-melanoma differentiation-associated gene 5 positive patients had no or weak MxA expression. CONCLUSIONS: This study reveals the significant association between level of MxA expression on muscle fibres and clinical measures of muscular disease activity in JDM patients and MSA status. This confirms type I interferonopathies in muscle fibres of JDM patients which could help with improving treatment outcome in JDM patients and underscoring the distinct pathophysiological pathways in different MSA status.


Asunto(s)
Dermatomiositis/metabolismo , Enfermedades Musculares/inmunología , Miositis/metabolismo , Proteínas de Resistencia a Mixovirus/metabolismo , Adolescente , Autoanticuerpos/metabolismo , Biomarcadores/análisis , Niño , Preescolar , Estudios de Cohortes , Dermatomiositis/inmunología , Femenino , Humanos , Lactante , Masculino , Miositis/inmunología , Proteínas de Resistencia a Mixovirus/inmunología
3.
Neuropathol Appl Neurobiol ; 45(5): 495-512, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30378704

RESUMEN

AIM: Juvenile idiopathic inflammatory myopathies have been recently reclassified into clinico-serological subgroups. Myopathological correlates of the subgroups are incompletely understood. METHODS: We studied muscle biopsies from 101 children with clinically and serologically defined juvenile idiopathic inflammatory myopathies from the UK JDM Cohort and Biomarker Study by applying the international JDM score tool, myopathological review and C5b-9 complement analysis. RESULTS: Autoantibody data were available for 90/101 cases with 18/90 cases positive for anti-TIF1γ, 15/90 anti-NXP2, 11/90 anti-MDA5, 5/90 anti-Mi2 and 6/90 anti-PmScl. JDM biopsy severity scores were consistently low in the anti-MDA5 group, high in the anti-Mi2 group, and widely distributed in the other groups. Biopsies were classified histologically as perifascicular atrophy (22/101), macrophage-rich necrosis (6/101), scattered necrosis (2/101), clustered necrosis (2/101), inflammatory fibre invasion (2/101), chronic myopathic change (1/101), diffuse endomysial macrophage infiltrates (40/101) and minimal change (24/101). MDA5 cases segregated with the minimal change group and showed no capillary C5b-9-deposition. The Mi2 group displayed high severity scores and a tendency towards sarcolemmal complement deposition. NXP2 and TIF1γ groups showed a variety of pathologies with a high proportion of diffuse endomysial macrophage infiltrates and a high proportion of capillary C5b-9 deposition. CONCLUSION: We have shown that juvenile idiopathic inflammatory myopathies have a spectrum of histopathological phenotypes and show distinct complement attack complex deposition patterns. Both correlate in some cases with the serological subtypes. Most cases do not show typical histological features associated with dermatomyositis (e.g. perifascicular atrophy). In contrast, more than half show relatively mild histopathological changes.


Asunto(s)
Autoanticuerpos/inmunología , Miositis/inmunología , Miositis/patología , Autoantígenos/inmunología , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Masculino , Fenotipo
4.
Neuropathol Appl Neurobiol ; 45(2): 95-107, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30326153

RESUMEN

Low-grade epilepsy-associated brain tumours (LEAT) are the second most common cause for drug-resistant, focal epilepsy, that is ganglioglioma (GG) and dysembryoplastic neuroepithelial tumours (DNT). However, molecular pathogenesis, risk factors for malignant progression and their frequent association with drug-resistant focal seizures remain poorly understood. This contrasts recent progress in understanding the molecular-genetic basis and targeted treatment options in diffuse gliomas. The Neuropathology Task Force of the International League Against Epilepsy examined available literature to identify common obstacles in diagnosis and research of LEAT. Analysis of 10 published tumour series from epilepsy surgery pointed to poor inter-rater agreement for the histopathology diagnosis. The Task Force tested this hypothesis using a web-based microscopy agreement study. In a series of 30 LEAT, 25 raters from 18 countries agreed in only 40% of cases. Highest discordance in microscopic diagnosis occurred between GG and DNT variants, when oligodendroglial-like cell patterns prevail, or ganglion cells were difficult to discriminate from pre-existing neurons. Suggesting new terminology or major histopathological criteria did not satisfactorily increase the yield of histopathology agreement in four consecutive trials. To this end, the Task Force applied the WHO 2016 strategy of integrating phenotype analysis with molecular-genetic data obtained from panel sequencing and 450k methylation arrays. This strategy was helpful to distinguish DNT from GG variants in all cases. The Task Force recommends, therefore, to further develop diagnostic panels for the integration of phenotype-genotype analysis in order to reliably classify the spectrum of LEAT, carefully characterize clinically meaningful entities and make better use of published literature.


Asunto(s)
Neoplasias Encefálicas/patología , Epilepsia/patología , Ganglioglioma/patología , Glioma/patología , Oligodendroglía/patología , Neoplasias Encefálicas/clasificación , Epilepsia/clasificación , Ganglioglioma/clasificación , Ganglioglioma/diagnóstico , Glioma/clasificación , Glioma/diagnóstico , Humanos , Oligodendroglía/clasificación , Fenotipo
5.
Neuropathol Appl Neurobiol ; 44(2): 151-162, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28949028

RESUMEN

Embryonal tumours of the central nervous system (CNS) present a significant clinical challenge. Many of these neoplasms affect young children, have a very high mortality and therapeutic strategies are often aggressive with poor long-term outcomes. There is a great need to accurately diagnose embryonal tumours, predict their outcome and adapt therapy to the individual patient's risk. For the first time in 2016, the WHO classification took into account molecular characteristics for the diagnosis of CNS tumours. This integration of histological features with genetic information has significantly changed the diagnostic work-up and reporting of tumours of the CNS. However, this remains challenging in embryonal tumours due to their previously unaccounted tumour heterogeneity. We describe the recent revisions made to the 4th edition of the WHO classification of CNS tumours and review the main changes, while highlighting some of the more common diagnostic testing strategies.


Asunto(s)
Neoplasias del Sistema Nervioso Central/clasificación , Neoplasias de Células Germinales y Embrionarias/clasificación , Neoplasias del Sistema Nervioso Central/patología , Humanos , Neoplasias de Células Germinales y Embrionarias/patología , Organización Mundial de la Salud
6.
Neuropathol Appl Neurobiol ; 44(1): 56-69, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29315734

RESUMEN

Brain tumours are the second most common cause of seizures identified in epilepsy surgical series. While any tumour involving the brain has the potential to cause seizures, specific subtypes are more frequently associated with epilepsy. Tumour-related epilepsy (TRE) has a profound impact on patients with brain tumours and these seizures are often refractory to anti-epileptic treatments, resulting in long-term disability and patient morbidity. Despite the drastic impact of epilepsy-associated tumours on patients, they have not traditionally enjoyed as much attention as more malignant neoplasms. However, recently a number of developments have been achieved towards further understanding of the molecular and developmental backgrounds of specific epilepsy-associated tumours. In addition, the past decade has seen an expansion in the literature on the pathophysiology of TRE. In this review, we aim to summarize the mechanisms by which tumours may cause seizures and detail recent data regarding the pathogenesis of specific developmental epilepsy-associated tumours.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Encéfalo/metabolismo , Epilepsia/metabolismo , Biomarcadores de Tumor/metabolismo , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Encéfalo/patología , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/patología , Epilepsia/etiología , Epilepsia/patología , Humanos
7.
Neuropathol Appl Neurobiol ; 44(7): 663-672, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-29533475

RESUMEN

AIMS: To develop an expert consensus statement regarding appropriate clinical and forensic post mortem neurological imaging. METHODS: An expert panel of clinicians were recruited from registered members of the British Neuropathological Society (BNS) and the International Society of Forensic Radiology and Imaging (ISFRI) with post mortem expertise. Following a focus group meeting, 16 core statements were incorporated into an online modified Delphi survey and each panellist was asked to score their level of agreement. Following the first iteration, two statements that failed to reach consensus were modified and re-rated. Consensus was predefined as 75% agreement across responders. RESULTS: Seventeen experts joined the panel and 12 (70.6%) attended the focus group meeting; 14 (82%) completed both iterations of the survey. Consensus was reached for need of adequate clinical history, multidisciplinary discussion, establishment of special interest groups to discuss cases, gathering further evidence to inform imaging choices, establishment of methods for quality assessment in reporting standards and adequate funding for imaging services. The panel agreed that pathologists should be responsible for neuroimaging referrals, collating results of ancillary tests, and producing the final post mortem report. Areas requiring further discussion include the impact of double reporting, indications for neuroimaging and utilities of three-dimensional printing. CONCLUSION: The BNS/ISFRI statement represents current views of an expert panel of health professionals engaged in post-mortem neuroimaging. We hope this provides a working guideline for less experienced operators, stimulates discussion and highlights the most pressing clinical and research questions.


Asunto(s)
Autopsia/métodos , Encéfalo/diagnóstico por imagen , Neuroimagen , Encéfalo/patología , Consenso , Humanos , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X
8.
Clin Radiol ; 72(12): 1025-1037, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28821323

RESUMEN

Post-mortem magnetic resonance (PMMR) imaging is rapidly emerging as an alternative, "less invasive", and more widely accepted investigative approach for perinatal deaths in the UK. PMMR has a high diagnostic accuracy for congenital and acquired fetal neuropathological anomalies compared to conventional autopsy, and is particularly useful when autopsy is non-diagnostic. The main objectives of this review are to describe and illustrate the range of common normal and abnormal central nervous system (CNS) findings encountered during PMMR investigation. This article covers the standard PMMR sequences used at our institution, normal physiological post-mortem findings, and a range of abnormal developmental and acquired conditions. The abnormal findings include diseases ranging from neural tube defects, posterior fossa malformations, those of forebrain and commissural development as well as neoplastic, haemorrhagic, and infectious aetiologies. Neuropathological findings at conventional autopsy accompany many of the conditions we describe, allowing readers to better understand the underlying disease processes and imaging appearances.


Asunto(s)
Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética , Neuroimagen , Encéfalo/anomalías , Encéfalo/embriología , Encéfalo/patología , Diagnóstico , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética/métodos , Neuroimagen/métodos , Cambios Post Mortem
12.
Clin Radiol ; 70(8): 872-80, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26050535

RESUMEN

AIM: To compare the diagnostic accuracy of non-invasive cerebral post-mortem magnetic resonance imaging (PMMRI) specifically for cerebral and neurological abnormalities in a series of fetuses and children, compared to conventional autopsy. MATERIALS AND METHODS: Institutional ethics approval and parental consent was obtained. Pre-autopsy cerebral PMMRI was performed in a sequential prospective cohort (n = 400) of fetuses (n = 277; 185 ≤ 24 weeks and 92 > 24 weeks gestation) and children <16 years (n = 123) of age. PMMRI and conventional autopsy findings were reported blinded and independently of each other. RESULTS: Cerebral PMMRI had sensitivities and specificities (95% confidence interval) of 88.4% (75.5 to 94.9), and 95.2% (92.1 to 97.1), respectively, for cerebral malformations; 100% (83.9 to 100), and 99.1% (97.2 to 99.7) for major intracranial bleeds; and 87.5% (80.1 to 92.4) and 74.1% (68 to 79.4) for overall brain pathology. Formal neuropathological examination was non-diagnostic due to maceration/autolysis in 43/277 (16%) fetuses; of these, cerebral PMMRI imaging provided clinically important information in 23 (53%). The sensitivity of PMMRI for detecting significant ante-mortem ischaemic injury was only 68% (48.4 to 82.8) overall. CONCLUSIONS: PMMRI is an accurate investigational technique for identifying significant neuropathology in fetuses and children, and may provide important information even in cases where autolysis prevents formal neuropathological examination; however, PMMRI is less sensitive at detecting hypoxic-ischaemic brain injury, and may not detect rarer disorders not encountered in this study.


Asunto(s)
Autopsia/métodos , Encefalopatías/diagnóstico , Encéfalo/anomalías , Feto/anomalías , Imagen por Resonancia Magnética/métodos , Adolescente , Niño , Preescolar , Humanos , Hipoxia-Isquemia Encefálica/diagnóstico , Lactante , Recién Nacido , Hemorragias Intracraneales/diagnóstico , Estudios Prospectivos , Sensibilidad y Especificidad
13.
Childs Nerv Syst ; 31(4): 625-9, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25348811

RESUMEN

Pilomyxoid astrocytomas are a more aggressive variant of pilocytic astrocytoma. Over the last 14 years, there has been increasing evidence to suggest that these tumours are distinct pathological entities to pilocytic astrocytomas. Radiological features of these tumours are slowly emerging in the neuroradiological literature. We report a unique radiological appearance of a multicystic, disseminated astrocytoma with pilomyxoid characteristics presenting in a 4-year-old boy and highlight the importance of considering this diagnosis with similar imaging.


Asunto(s)
Astrocitoma/diagnóstico , Neoplasias Hipotalámicas/diagnóstico , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Astrocitoma/complicaciones , Preescolar , Humanos , Hidrocefalia/etiología , Neoplasias Hipotalámicas/complicaciones , Antígeno Ki-67/metabolismo , Imagen por Resonancia Magnética , Masculino , Proteínas del Tejido Nervioso , Médula Espinal/patología , Tercer Ventrículo/patología , Tomografía Computarizada por Rayos X , Proteína p53 Supresora de Tumor/metabolismo
14.
Neuropathol Appl Neurobiol ; 44(2): 135-136, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29464792

Asunto(s)
Neuropatología , Humanos
16.
AJNR Am J Neuroradiol ; 42(5): 961-968, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33664107

RESUMEN

BACKGROUND AND PURPOSE: Primary posterior fossa tumors comprise a large group of neoplasias with variable aggressiveness and short and long-term outcomes. This study aimed to validate the clinical usefulness of a radiologic decision flow chart based on previously published neuroradiologic knowledge for the diagnosis of posterior fossa tumors in children. MATERIALS AND METHODS: A retrospective study was conducted (from January 2013 to October 2019) at 2 pediatric referral centers, Children's Hospital of Philadelphia, United States, and Great Ormond Street Hospital, United Kingdom. Inclusion criteria were younger than 18 years of age and histologically and molecularly confirmed posterior fossa tumors. Subjects with no available preoperative MR imaging and tumors located primarily in the brain stem were excluded. Imaging characteristics of the tumors were evaluated following a predesigned, step-by-step flow chart. Agreement between readers was tested with the Cohen κ, and each diagnosis was analyzed for accuracy. RESULTS: A total of 148 cases were included, with a median age of 3.4 years (interquartile range, 2.1-6.1 years), and a male/female ratio of 1.24. The predesigned flow chart facilitated identification of pilocytic astrocytoma, ependymoma, and medulloblastoma sonic hedgehog tumors with high sensitivity and specificity. On the basis of the results, the flow chart was adjusted so that it would also be able to better discriminate atypical teratoid/rhabdoid tumors and medulloblastoma groups 3 or 4 (sensitivity = 75%-79%; specificity = 92%-99%). Moreover, our adjusted flow chart was useful in ruling out ependymoma, pilocytic astrocytomas, and medulloblastoma sonic hedgehog tumors. CONCLUSIONS: The modified flow chart offers a structured tool to aid in the adjunct diagnosis of pediatric posterior fossa tumors. Our results also establish a useful starting point for prospective clinical studies and for the development of automated algorithms, which may provide precise and adequate diagnostic tools for these tumors in clinical practice.


Asunto(s)
Algoritmos , Neoplasias Infratentoriales/diagnóstico , Imagen por Resonancia Magnética/métodos , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Neoplasias Infratentoriales/patología , Masculino
18.
Exp Cell Res ; 315(16): 2835-46, 2009 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-19523942

RESUMEN

The heterogeneity of tumours and uncertainties surrounding derived short-term cell cultures and established cell lines fundamentally challenge the research and understanding of tumour growth and development. When tumour cells are cultured, changes are inevitably induced due to the artificial growth conditions. Several recent studies have questioned how representative established cell lines or derived short-term cell cultures are of the tumour in situ. We have characterised gene expression changes induced by short-term culture in astrocytoma in order to determine whether derived short-term cell cultures are representative of the tumour in situ. In comparison to the majority of studies, paired biopsies and derived short-term cultures were investigated to reduce the effects of long-term culture and inter-tumour variability when comparing biopsies and derived cultures from tumours with the same histology from different individuals. We have used the Affymetrix GeneChip U133A to generate gene expression profiles of 6 paediatric pilocytic astrocytoma (PA) biopsies and derived short-term cell cultures and 3 adult glioblastoma multiforme (GBM) biopsies and derived short-term cultures. Significant differential gene expression is induced by short-term culture. However, when the biopsy and derived short-term cell culture samples were grouped according to tumour type (PA and GBM) a molecular signature of 608 genes showed significant differential expression between the groups. This gene cohort can distinguish PA and GBM tumours, regardless of the sample source, suggesting that astrocytoma derived short-term cultures do retain key aspects of the global tumour expression profile and are representative of the tumour in situ. Furthermore, these genes are involved in pathways and functions characteristic of adult GBM including VEGF signalling, hypoxia and TP53 signalling.


Asunto(s)
Astrocitoma , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas , Células Tumorales Cultivadas/metabolismo , Adulto , Animales , Astrocitoma/metabolismo , Astrocitoma/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Niño , Análisis por Conglomerados , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Transducción de Señal/fisiología
19.
Cytopathology ; 20(4): 256-60, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19659957

RESUMEN

OBJECTIVES: To evaluate whether there are any factors that predict malignant cells being found in paediatric cerebrospinal fluid (CSF) samples. To determine whether CSF provides useful staging information not provided by magnetic resonance imaging (MRI) in paediatric patients with primary central nervous system (CNS) malignancy. METHODS: We compared the CSF cytology and spinal MRI staging results in paediatric patients with primary CNS malignancy at a UK tertiary referral centre, over a decade. RESULTS: Of 159 CSF samples, 72 samples were from 72 patients with primary CNS malignancy with spinal MRI available for comparison. Eight of these 72 had positive cytology (seven malignant and one suspicious). All had a high clinical suspicion of tumour at the time of sampling. Of the 72 patients, only two had evidence of CSF spread on MRI spinal staging and CSF cytology; ten had MRI without cytological evidence and six had cytological without MRI evidence. CONCLUSIONS: In paediatric patients with primary CNS tumours, CSF cytology provides useful staging information. Spinal MRI alone may miss some patients with CSF spread who would be identified with CSF cytology.


Asunto(s)
Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Neoplasias del Sistema Nervioso Central/diagnóstico , Líquido Cefalorraquídeo/citología , Adolescente , Niño , Preescolar , Técnicas Citológicas , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Médula Espinal/patología
20.
Endocr Relat Cancer ; 26(3): 355-366, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30645190

RESUMEN

Pharmacological inhibition of the sonic hedgehog (SHH) pathway can be beneficial against certain cancers but detrimental in others. Adamantinomatous craniopharyngioma (ACP) is a relevant pituitary tumour, affecting children and adults, that is associated with high morbidity and increased mortality in long-term follow-up. We have previously demonstrated overactivation of the SHH pathway in both human and mouse ACP. Here, we show that this activation is ligand dependent and induced by the expression of SHH protein in a small proportion of tumour cells. We investigate the functional relevance of SHH signalling in ACP through MRI-guided preclinical studies using an ACP mouse model. Treatment with vismodegib, a clinically approved SHH pathway inhibitor, results in a significant reduction in median survival due to premature development of highly proliferative and vascularised undifferentiated tumours. Reinforcing the mouse data, SHH pathway inhibition in human ACP leads to a significant increase in tumour cell proliferation both ex vivo, in explant cultures, and in vivo, in a patient-derived xenograft model. Together, our results demonstrate a protumourigenic effect of vismodegib-mediated SHH pathway inhibition in ACP.


Asunto(s)
Craneofaringioma/fisiopatología , Proteínas Hedgehog/antagonistas & inhibidores , Adolescente , Animales , Proliferación Celular , Niño , Preescolar , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Neoplasias Hipofisarias , Transducción de Señal
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