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1.
Cell ; 187(18): 4926-4945.e22, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38986619

RESUMO

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in the 3D nuclear space with surprising strength. TULIPs occur in all PFA samples and recur at predictable genomic coordinates, and their formation is induced by expression of EZHIP. The universality of TULIPs across PFA samples suggests a conservation of molecular principles that could be exploited therapeutically.


Assuntos
Ependimoma , Ependimoma/genética , Humanos , Neoplasias Infratentoriais/genética , Neoplasias Infratentoriais/patologia , Genoma Humano , Lactente , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Criança , Masculino , Feminino
2.
Cell ; 181(2): 219-222, 2020 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-32302564

RESUMO

Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of "cancer neuroscience" and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.


Assuntos
Neoplasias/metabolismo , Sistema Nervoso/metabolismo , Humanos , Neurociências
3.
Cell ; 155(3): 567-81, 2013 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-24139898

RESUMO

Mutation is a fundamental process in tumorigenesis. However, the degree to which the rate of somatic mutation varies across the human genome and the mechanistic basis underlying this variation remain to be fully elucidated. Here, we performed a cross-cancer comparison of 402 whole genomes comprising a diverse set of childhood and adult tumors, including both solid and hematopoietic malignancies. Surprisingly, we found that the inactive X chromosome of many female cancer genomes accumulates on average twice and up to four times as many somatic mutations per megabase, as compared to the individual autosomes. Whole-genome sequencing of clonally expanded hematopoietic stem/progenitor cells (HSPCs) from healthy individuals and a premalignant myelodysplastic syndrome (MDS) sample revealed no X chromosome hypermutation. Our data suggest that hypermutation of the inactive X chromosome is an early and frequent feature of tumorigenesis resulting from DNA replication stress in aberrantly proliferating cells.


Assuntos
Cromossomos Humanos X , Mutação , Neoplasias/genética , Inativação do Cromossomo X , Adulto , Idoso , Replicação do DNA , Feminino , Humanos , Masculino , Meduloblastoma/genética , Meduloblastoma/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Polimorfismo de Nucleotídeo Único , Fase S
4.
Cell ; 153(5): 1064-79, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23706743

RESUMO

Metabolic adaptation is essential for cell survival during nutrient deprivation. We report that eukaryotic elongation factor 2 kinase (eEF2K), which is activated by AMP-kinase (AMPK), confers cell survival under acute nutrient depletion by blocking translation elongation. Tumor cells exploit this pathway to adapt to nutrient deprivation by reactivating the AMPK-eEF2K axis. Adaptation of transformed cells to nutrient withdrawal is severely compromised in cells lacking eEF2K. Moreover, eEF2K knockdown restored sensitivity to acute nutrient deprivation in highly resistant human tumor cell lines. In vivo, overexpression of eEF2K rendered murine tumors remarkably resistant to caloric restriction. Expression of eEF2K strongly correlated with overall survival in human medulloblastoma and glioblastoma multiforme. Finally, C. elegans strains deficient in efk-1, the eEF2K ortholog, were severely compromised in their response to nutrient depletion. Our data highlight a conserved role for eEF2K in protecting cells from nutrient deprivation and in conferring tumor cell adaptation to metabolic stress. PAPERCLIP:


Assuntos
Caenorhabditis elegans/metabolismo , Quinase do Fator 2 de Elongação/metabolismo , Neoplasias/fisiopatologia , Elongação Traducional da Cadeia Peptídica , Transdução de Sinais , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Neoplasias Encefálicas/fisiopatologia , Caenorhabditis elegans/genética , Sobrevivência Celular , Transformação Celular Neoplásica , Quinase do Fator 2 de Elongação/genética , Privação de Alimentos , Glioblastoma/fisiopatologia , Células HeLa , Humanos , Camundongos , Camundongos Nus , Células NIH 3T3 , Transplante de Neoplasias , Fator 2 de Elongação de Peptídeos/metabolismo , Transplante Heterólogo
5.
Nature ; 612(7941): 787-794, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36450980

RESUMO

Medulloblastoma (MB) is the most common malignant childhood brain tumour1,2, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella3-5 have not fully defined the compositional heterogeneity of MBs. Here we undertook single-cell profiling of freshly isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group 3 and metastatic tumours. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group 3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group 3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group 3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs show potential cell populations predisposed to transformation and regulatory circuitries underlying tumour cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.


Assuntos
Neoplasias Encefálicas , Transformação Celular Neoplásica , Feto , Meduloblastoma , Humanos , Neoplasias Encefálicas/patologia , Transformação Celular Neoplásica/patologia , Neoplasias Cerebelares/patologia , Cerebelo/citologia , Cerebelo/patologia , Feto/citologia , Feto/patologia , Meduloblastoma/patologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/patologia , Prognóstico
6.
Cell ; 148(1-2): 59-71, 2012 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-22265402

RESUMO

Genomic rearrangements are thought to occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving massive chromosome rearrangements in a one-step catastrophic event termed chromothripsis. We report the whole-genome sequencing-based analysis of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome), uncovering massive, complex chromosome rearrangements. Integrating TP53 status with microarray and deep sequencing-based DNA rearrangement data in additional patients reveals a striking association between TP53 mutation and chromothripsis in SHH-MBs. Analysis of additional tumor entities substantiates a link between TP53 mutation and chromothripsis, and indicates a context-specific role for p53 in catastrophic DNA rearrangements. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings connect p53 status and chromothripsis in specific tumor types, providing a genetic basis for understanding particularly aggressive subtypes of cancer.


Assuntos
Neoplasias Encefálicas/genética , Rearranjo Gênico , Meduloblastoma/genética , Proteína Supressora de Tumor p53/genética , Animais , Criança , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Modelos Animais de Doenças , Humanos , Leucemia Mieloide Aguda/genética , Síndrome de Li-Fraumeni/fisiopatologia , Camundongos , Pessoa de Meia-Idade
7.
Nature ; 574(7780): 712-716, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31597163

RESUMO

Cancers are caused by genomic alterations known as drivers. Hundreds of drivers in coding genes are known but, to date, only a handful of noncoding drivers have been discovered-despite intensive searching1,2. Attention has recently shifted to the role of altered RNA splicing in cancer; driver mutations that lead to transcriptome-wide aberrant splicing have been identified in multiple types of cancer, although these mutations have only been found in protein-coding splicing factors such as splicing factor 3b subunit 1 (SF3B1)3-6. By contrast, cancer-related alterations in the noncoding component of the spliceosome-a series of small nuclear RNAs (snRNAs)-have barely been studied, owing to the combined challenges of characterizing noncoding cancer drivers and the repetitive nature of snRNA genes1,7,8. Here we report a highly recurrent A>C somatic mutation at the third base of U1 snRNA in several types of tumour. The primary function of U1 snRNA is to recognize the 5' splice site via base-pairing. This mutation changes the preferential A-U base-pairing between U1 snRNA and the 5' splice site to C-G base-pairing, and thus creates novel splice junctions and alters the splicing pattern of multiple genes-including known drivers of cancer. Clinically, the A>C mutation is associated with heavy alcohol use in patients with hepatocellular carcinoma, and with the aggressive subtype of chronic lymphocytic leukaemia with unmutated immunoglobulin heavy-chain variable regions. The mutation in U1 snRNA also independently confers an adverse prognosis to patients with chronic lymphocytic leukaemia. Our study demonstrates a noncoding driver in spliceosomal RNAs, reveals a mechanism of aberrant splicing in cancer and may represent a new target for treatment. Our findings also suggest that driver discovery should be extended to a wider range of genomic regions.


Assuntos
Mutação , Neoplasias/genética , RNA Nuclear Pequeno/genética , Spliceossomos/genética , Humanos , Neoplasias/patologia , Neoplasias/fisiopatologia , Sítios de Splice de RNA , Splicing de RNA , Fatores de Processamento de RNA/genética
9.
Nature ; 572(7767): 67-73, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31043743

RESUMO

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.


Assuntos
Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Evolução Molecular , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Transcrição Gênica , Animais , Neoplasias Cerebelares/classificação , Cerebelo/citologia , Cerebelo/embriologia , Cerebelo/metabolismo , Criança , Feminino , Feto/citologia , Glioma/classificação , Glioma/genética , Glioma/patologia , Humanos , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Análise de Sequência de RNA , Análise de Célula Única , Fatores de Tempo , Transcriptoma/genética
10.
Nature ; 576(7786): 274-280, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31802000

RESUMO

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC2-4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.


Assuntos
MicroRNAs/genética , Neoplasias Embrionárias de Células Germinativas/genética , RNA Helicases DEAD-box/genética , DNA Topoisomerases Tipo I/genética , Humanos , Mutação , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante , Recidiva , Ribonuclease III/genética
11.
Pediatr Blood Cancer ; 71(11): e31275, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39152641

RESUMO

BACKGROUND: Few studies have characterized the burden of late effects among childhood ependymoma survivors. To address this gap, we examined these sequelae using real-world health services data in a population-based ependymoma survivor cohort. METHODS: All individuals younger than 18 years diagnosed with an ependymoma in Ontario, Canada between 1987 and 2015 who had survived at least 5 years from their latest pediatric cancer event (index date) were matched 1:5 with population controls. Following linkage with provincial health services data, the cumulative incidences of multiple medical and functional outcomes between survivors and controls were compared. RESULTS: Among 96 survivors, 77.1% had been irradiated and 9.4% had received cisplatin. At 10 years post-index, survivors were at significantly higher risk of all-cause mortality (7.1%, 95% confidence interval [CI]: 1.0-13.3 vs. 0.3%, 95% CI: 0.0-1.0; p = .0002), non-obstetric hospitalization (45.1%, 95% CI: 32.6-56.7 vs. 10.6%, 95% CI: 7.6-14.1; p < .0001), stroke (6.5%, 95% CI: 2.3-13.7 vs. 0%; p < .0001), severe hearing loss requiring an amplification device (7.5%, 95% CI: 2.7-15.7 vs. 0%; p < .0001), receiving homecare service (27.6%, 95% CI: 18.5-37.5 vs. 7.7%, 95% CI: 5.3-10.7; p < .0001), and submitting a disability support prescription claim (24.0%, 95% CI: 14.8-34.3 vs. 5.4%, 95% CI: 3.5-7.8; p < .0001) compared to controls. CONCLUSIONS: Pediatric ependymoma survivors are highly vulnerable to severe late sequelae, including death, stroke, severe hearing loss, and disability. Urgent efforts are needed to improve risk-stratification approaches that mitigate exposure to toxic therapies for children with lower risk disease. Interventions to prevent or decrease the risk of developing late sequelae are critical to optimizing survivor long-term health.


Assuntos
Sobreviventes de Câncer , Ependimoma , Humanos , Ependimoma/mortalidade , Ependimoma/epidemiologia , Ependimoma/terapia , Masculino , Feminino , Criança , Sobreviventes de Câncer/estatística & dados numéricos , Ontário/epidemiologia , Adolescente , Pré-Escolar , Lactente , Seguimentos , Taxa de Sobrevida , Estudos de Casos e Controles , Prognóstico
13.
Nature ; 561(7723): 331-337, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30185905

RESUMO

Successful T cell immunotherapy for brain cancer requires that the T cells can access tumour tissues, but this has been difficult to achieve. Here we show that, in contrast to inflammatory brain diseases such as multiple sclerosis, where endothelial cells upregulate ICAM1 and VCAM1 to guide the extravasation of pro-inflammatory cells, cancer endothelium downregulates these molecules to evade immune recognition. By contrast, we found that cancer endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which allowed us to overcome this immune-evasion mechanism by creating an ALCAM-restricted homing system (HS). We re-engineered the natural ligand of ALCAM, CD6, in a manner that triggers initial anchorage of T cells to ALCAM and conditionally mediates a secondary wave of adhesion by sensitizing T cells to low-level ICAM1 on the cancer endothelium, thereby creating the adhesion forces necessary to capture T cells from the bloodstream. Cytotoxic HS T cells robustly infiltrated brain cancers after intravenous injection and exhibited potent antitumour activity. We have therefore developed a molecule that targets the delivery of T cells to brain cancer.

14.
Lancet ; 399(10329): 1049-1058, 2022 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-35279258

RESUMO

BACKGROUND: Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients with Duchenne muscular dystrophy, aged 10 years or older with moderate upper limb impairment, were enrolled at seven centres in the USA. Patients were randomly assigned (1:1) using stratified permuted blocks to receive CAP-1002 (1·5 × 108 CDCs) or placebo intravenously every 3 months for a total of four infusions. Clinicians, caregivers, patients, and clinical operations personnel were fully masked to treatment groups. The primary outcome was the change in mid-level elbow Performance of Upper Limb version 1.2 (PUL 1.2) score at 12 months, assessed in the intention-to-treat population. Safety was assessed in all individuals who received an investigational product. This trial is registered with ClinicalTrials.gov, NCT03406780. FINDINGS: Between March 1, 2018, and March 31, 2020, 26 male patients with Duchenne muscular dystrophy were enrolled, of whom eight were randomly assigned to the CAP-1002 group and 12 to the placebo group (six were not randomised due to screening failure). In patients who had a post-treatment PUL 1.2 assessment (eight in the CAP-1002 group and 11 in the placebo group), the mean 12-month change from baseline in mid-level elbow PUL1.2 favoured CAP-1002 over placebo (percentile difference 36·2, 95% CI 12·7-59·7; difference of 2·6 points; p=0·014). Infusion-related hypersensitivity reactions without long-term sequelae were observed in three patients, with one patient discontinuing therapy due to a severe allergic reaction. No other major adverse reactions were noted, and no deaths occurred. INTERPRETATION: CAP-1002 cell therapy appears to be safe and effective in reducing deterioration of upper limb function in patients with late-stage Duchenne muscular dystrophy. Various measures of cardiac function and structure were also improved in the CAP-1002 group compared with the placebo group. Longer-term extension studies are needed to confirm the therapeutic durability and safety of CAP-1002 beyond 12 months for the treatment of skeletal myopathy and cardiomyopathy in Duchenne muscular dystrophy. FUNDING: Capricor Therapeutics.


Assuntos
Cardiomiopatias , Distrofia Muscular de Duchenne , Cardiomiopatias/complicações , Terapia Baseada em Transplante de Células e Tecidos , Criança , Método Duplo-Cego , Humanos , Masculino , Distrofia Muscular de Duchenne/tratamento farmacológico , Resultado do Tratamento
15.
J Magn Reson Imaging ; 2023 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-37855257

RESUMO

BACKGROUND: Breath-holding (BH) for cine balanced steady state free precession (bSSFP) imaging is challenging for patients with impaired BH capacity. Deep learning-based reconstruction (DLR) of undersampled k-space promises to shorten BHs while preserving image quality and accuracy of ventricular assessment. PURPOSE: To perform a systematic evaluation of DLR of cine bSSFP images from undersampled k-space over a range of acceleration factors. STUDY TYPE: Retrospective. SUBJECTS: Fifteen pectus excavatum patients (mean age 16.8 ± 5.4 years, 20% female) with normal cardiac anatomy and function and 12-second BH capability. FIELD STRENGTH/SEQUENCE: 1.5-T, cine bSSFP. ASSESSMENT: Retrospective DLR was conducted by applying compressed sensitivity encoding (C-SENSE) acceleration to systematically undersample fully sampled k-space cine bSSFP acquisition data over an acceleration/undersampling factor (R) considering a range of 2 to 8. Quality imperceptibility (QI) measures, including structural similarity index measure, were calculated using images reconstructed from fully sampled k-space as a reference. Image quality, including contrast and edge definition, was evaluated for diagnostic adequacy by three readers with varying levels of experience in cardiac MRI (>4 years, >18 years, and 1 year). Automated DL-based biventricular segmentation was performed commercially available software by cardiac radiologists with more than 4 years of experience. STATISTICAL TESTS: Tukey box plots, linear mixed effects model, analysis of variance (ANOVA), weighted kappa, Kruskal-Wallis test, and Wilcoxon signed-rank test were employed as appropriate. A P-value <0.05 was considered statistically significant. RESULTS: There was a significant decrease in the QI values and edge definition scores as R increased. Diagnostically adequate image quality was observed up to R = 5. The effect of R on all biventricular volumetric indices was non-significant (P = 0.447). DATA CONCLUSION: The biventricular volumetric indices obtained from the reconstruction of fully sampled cine bSSFP acquisitions and DLR of the same k-space data undersampled by C-SENSE up to R = 5 may be comparable. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 1.

16.
J Neurooncol ; 161(3): 573-582, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36757527

RESUMO

PURPOSE: The overall survival and prognostic factors for children with multiply recurrent posterior fossa ependymoma are not well understood. We aimed to assess prognostic factors associated with survival for relapsed pediatric posterior fossa ependymoma. METHODS: An institutional database was queried for children with a primary diagnosis of posterior fossa ependymoma from 2000 to 2019. Kaplan-Meier survival analysis and Cox-proportional hazard regression were used to assess the relationship between treatment factors and overall survival. RESULTS: There were 60 patients identified; molecular subtype was available for 56, of which 49 (87.5%) were PF-A and 7 (12.5%) were PF-B. Relapse occurred in 29 patients (48%) at a mean time of 24 months following primary resection. Median 50% survival was 12.3 years for all patients and 3.3 years following diagnosis of first relapsed disease. GTR was associated with significantly improved survival following primary resection (HR 0.373, 95% CI 0.14-0.96). Presence of recurrent disease was significantly associated with worse survival (p < 0.0001). At recurrent disease diagnosis, disseminated disease was a negative prognostic factor (HR 11.0 95% CI 2.7-44) while GTR at first relapse was associated with improved survival HR 0.215 (95% CI: 0.048-0.96, p = 0.044). Beyond first relapse, the impact of GTR was not significant on survival, though surgery compared to no surgery was favorable with HR 0.155 (95% CI: 0.04-0.59). CONCLUSIONS: Disseminated disease at recurrence and extent of resection for first relapsed disease were important prognostic factors. Surgery compared to no surgery was associated with improved survival for the multiply recurrent ependymoma cohort.


Assuntos
Neoplasias Encefálicas , Ependimoma , Criança , Humanos , Recidiva Local de Neoplasia , Estimativa de Kaplan-Meier , Ependimoma/cirurgia , Ependimoma/diagnóstico , Prognóstico
17.
J Cardiovasc Magn Reson ; 25(1): 39, 2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-37400886

RESUMO

BACKGROUND: Multiple right ventricular (RV) metrics have prognostic value in pulmonary hypertension (PH). A cardiac magnetic resonance imaging (CMR) derived global ventricular function index (GFI) provided improved prediction of composite adverse outcome (CAO) in adults with atherosclerosis. GFI has not yet been explored in a PH population. We explored the feasibility of GFI as a predictor of CAO in a pediatric PH population. METHODS: Two center retrospective chart review identified pediatric PH patients undergoing CMR from Jan 2005-June 2021. GFI, defined as the ratio of the stroke volume to the sum of mean ventricular cavity and myocardial volume, was calculated for each patient. CAO was defined as death, lung transplant, Potts shunt, or parenteral prostacyclin initiation after CMR. Cox proportional hazards regression was used to estimate associations and assess model performance between CMR parameters and CAO. RESULTS: The cohort comprised 89 patients (54% female, 84% World Health Organization (WHO) Group 1; 70% WHO-FC ≤ 2; and 27% on parenteral prostacyclin). Median age at CMR was 12 years (IQR 8.1-17). Twenty-one (24%) patients experienced CAO during median follow up of 1.5 years. CAO cohort had higher indexed RV volumes (end systolic-145 vs 99 mL/m2, p = 0.003; end diastolic-89 vs 46 mL/m2, p = 0.004) and mass (37 vs 24 gm/m2, p = 0.003), but lower ejection fraction (EF) (42 vs 51%, p < 0.001) and GFI (40 vs 52%, p < 0.001). Higher indexed RV volumes (hazard ratios [HR] 1.01, CI 1.01-1.02), lower RV EF (HR 1.09, CI 1.05-1.12) and lower RV GFI (HR 1.09, CI 1.05-1.11) were associated with increased risk of CAO. In survival analysis, patients with RV GFI < 43% demonstrated decreased event-free survival and increased hazard of CAO compared to those with RV GFI ≥ 43%. In multivariable models, inclusion of GFI provided improved prediction of CAO compared to models incorporating ventricular volumes, mass or EF. CONCLUSIONS: RV GFI was associated with CAO in this cohort, and inclusion in multivariable models had increased predictive value compared to RVEF. GFI uses readily available CMR data without additional post-processing and may provide additional prognostic value in pediatric PH patients beyond traditional CMR markers.


Assuntos
Hipertensão Pulmonar , Disfunção Ventricular Direita , Adulto , Humanos , Feminino , Criança , Adolescente , Masculino , Estudos Retrospectivos , Fatores de Risco , Valor Preditivo dos Testes , Volume Sistólico , Função Ventricular Direita
18.
Pediatr Blood Cancer ; 70 Suppl 4: e29955, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36083866

RESUMO

Cardiac tumors in children are rare and the majority are benign. The most common cardiac tumor in children is rhabdomyoma, usually associated with tuberous sclerosis complex. Other benign cardiac masses include fibromas, myxomas, hemangiomas, and teratomas. Primary malignant cardiac tumors are exceedingly rare, with the most common pathology being soft tissue sarcomas. This paper provides consensus-based imaging recommendations for the evaluation of patients with cardiac tumors at diagnosis and follow-up, including during and after therapy.


Assuntos
Neoplasias Cardíacas , Rabdomioma , Esclerose Tuberosa , Criança , Humanos , Ressonância de Plasmônio de Superfície , Neoplasias Cardíacas/diagnóstico por imagem , Neoplasias Cardíacas/complicações , Rabdomioma/diagnóstico por imagem , Rabdomioma/complicações , Diagnóstico por Imagem
19.
Nature ; 543(7643): 122-125, 2017 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-28178237

RESUMO

Human cells have twenty-three pairs of chromosomes. In cancer, however, genes can be amplified in chromosomes or in circular extrachromosomal DNA (ecDNA), although the frequency and functional importance of ecDNA are not understood. We performed whole-genome sequencing, structural modelling and cytogenetic analyses of 17 different cancer types, including analysis of the structure and function of chromosomes during metaphase of 2,572 dividing cells, and developed a software package called ECdetect to conduct unbiased, integrated ecDNA detection and analysis. Here we show that ecDNA was found in nearly half of human cancers; its frequency varied by tumour type, but it was almost never found in normal cells. Driver oncogenes were amplified most commonly in ecDNA, thereby increasing transcript level. Mathematical modelling predicted that ecDNA amplification would increase oncogene copy number and intratumoural heterogeneity more effectively than chromosomal amplification. We validated these predictions by quantitative analyses of cancer samples. The results presented here suggest that ecDNA contributes to accelerated evolution in cancer.


Assuntos
Variações do Número de Cópias de DNA/genética , Evolução Molecular , Amplificação de Genes/genética , Heterogeneidade Genética , Modelos Genéticos , Neoplasias/genética , Oncogenes/genética , Cromossomos Humanos/genética , Análise Citogenética , Análise Mutacional de DNA , Genoma Humano/genética , Humanos , Metáfase/genética , Neoplasias/classificação , RNA Mensageiro/análise , RNA Neoplásico/genética , Reprodutibilidade dos Testes , Software
20.
Nature ; 549(7671): 227-232, 2017 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-28854171

RESUMO

Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare 'outlier' clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy.


Assuntos
Diferenciação Celular , Linhagem da Célula , Rastreamento de Células , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células , Células Clonais/efeitos dos fármacos , Células Clonais/patologia , Epigênese Genética , Feminino , Glioblastoma/tratamento farmacológico , Xenoenxertos , Humanos , Camundongos , Invasividade Neoplásica , Transplante de Neoplasias , Células-Tronco Neoplásicas/efeitos dos fármacos , Fenótipo , Processos Estocásticos
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