RESUMO
Diffuse intrinsic pontine glioma (DIPG) is a rare childhood malignancy with poor prognosis. There are no effective treatment options other than external beam therapy. We conducted a pilot, first-in-human study using 124I-omburtamab imaging and theranostics as a therapeutic approach using a localized convection-enhanced delivery (CED) technique for administering radiolabeled antibody. We report the detailed pharmacokinetics and dosimetry results of intratumoral delivery of 124I-omburtamab. Methods: Forty-five DIPG patients who received 9.0-370.7 MBq of 124I-omburtamab intratumorally via CED underwent serial brain and whole-body PET/CT imaging at 3-5 time points after injection within 4, 24-48, 72-96, 120-144, and 168-240 h from the end of infusion. Serial blood samples were obtained for kinetic analysis. Whole-body, blood, lesion, and normal-tissue activities were measured, kinetic parameters (uptake and clearance half-life times) estimated, and radiation-absorbed doses calculated using the OLINDA software program. Results: All patients showed prominent activity within the lesion that was retained over several days and was detectable up to the last time point of imaging, with a mean 124I residence time in the lesion of 24.9 h and dose equivalent of 353 ± 181 mSv/MBq. Whole-body doses were low, with a dose equivalent of 0.69 ± 0.28 mSv/MBq. Systemic distribution and activities in normal organs and blood were low. Radiation dose to blood was very low, with a mean value of 0.27 ± 0.21 mGy/MBq. Whole-body clearance was monoexponential with a mean biologic half-life of 62.7 h and an effective half-life of 37.9 h. Blood clearance was biexponential, with a mean biologic half-life of 22.2 h for the rapid α phase and 155 h for the slower ß phase. Conclusion: Intratumoral CED of 124I-omburtamab is a novel theranostics approach in DIPG. It allows for delivery of high radiation doses to the DIPG lesions, with high lesion activities and low systemic activities and high tumor-to-normal-tissue ratios and achieving a wide safety margin. Imaging of the actual therapeutic administration of 124I-omburtamab allows for direct estimation of the therapeutic lesion and normal-tissue-absorbed doses.
Assuntos
Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Radioisótopos do Iodo , Radiometria , Humanos , Masculino , Feminino , Criança , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/radioterapia , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/radioterapia , Pré-Escolar , Adolescente , Convecção , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Glioma/diagnóstico por imagem , Glioma/radioterapia , Distribuição Tecidual , Lactente , Adulto JovemRESUMO
PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor. Radiation therapy (RT) is the standard treatment, with reirradiation considered in case of progression. However, the prognostic factors for reirradiation are not well understood. This study aims to investigate the outcomes of DIPG patients undergoing reirradiation and identify clinical and radiomic prognostic factors. METHODS: We conducted a retrospective analysis of patients with DIPG who underwent reirradiation at our institution between January 2016 and December 2023. Using PyRadiomics, we extracted radiomic features of tumors at the time of progression from FLAIR MRI images and collected clinical data. We used the least absolute shrinkage and selection operator (lasso) for Cox's proportional hazard model with leave-one-out cross-validation to select optimal prognostic factors for survival after reirradiation. RESULTS: The study included 18 patients who underwent reirradiation at first progression, receiving a total dose of 20â¯Gy or 24â¯Gy in 2Gy fractions. Reirradiation was well tolerated, with no severe toxicity. Most patients (78%) showed neurological improvement after treatment. Median survival after progression was 29.2 weeks. The Cox model demonstrated a concordance of 0.81 (95% CI: 0.75-0.88), revealing that tumor sphericity and structural gray-level heterogeneity in FLAIR MRI images were associated with longer survival of reirradiated patients. CONCLUSION: Reirradiation is a safe and effective approach for patients with DIPG. MRI-based radiomic models could be helpful in predicting survival after reirradiation.
Assuntos
Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Progressão da Doença , Imageamento por Ressonância Magnética , Reirradiação , Humanos , Neoplasias do Tronco Encefálico/radioterapia , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Masculino , Feminino , Criança , Estudos Retrospectivos , Prognóstico , Pré-Escolar , Glioma Pontino Intrínseco Difuso/radioterapia , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Adolescente , Modelos de Riscos Proporcionais , Dosagem Radioterapêutica , RadiômicaRESUMO
PURPOSE: This study aimed to describe 11C-methionine (11C-MET) PET imaging characteristics in patients with paediatric diffuse intrinsic pontine glioma (DIPG) and correlate them with survival and H3 K27M mutation status. METHODS: We retrospectively analysed 98 children newly diagnosed with DIPG who underwent 11C-MET PET. PET imaging characteristics evaluated included uptake intensity, uniformity, metabolic tumour volume (MTV), and total lesion methionine uptake (TLMU). The maximum, mean, and peak of the tumour-to-background ratio (TBR), calculated as the corresponding standardised uptake values (SUV) divided by the mean reference value, were also recorded. The associations between the PET imaging characteristics and clinical outcomes in terms of progression-free survival (PFS) and overall survival (OS) and H3 K27M mutation status were assessed, respectively. RESULTS: In univariate analysis, imaging characteristics significantly associated with shorter PFS and OS included a higher uniformity grade, higher TBRs, larger MTV, and higher TLMU. In multivariate analysis, larger MTV at diagnosis, shorter symptom duration, and no treatment were significantly correlated with shorter PFS and OS. The PET imaging features were not correlated with H3 K27M mutation status. CONCLUSION: Although several imaging features were significantly associated with PFS and OS, only MTV, indicating the size of the active tumour, was identified as a strong independent prognostic factor.
Assuntos
Neoplasias Encefálicas , Glioma Pontino Intrínseco Difuso , Glioma , Humanos , Criança , Metionina/genética , Neoplasias Encefálicas/genética , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/metabolismo , Estudos Retrospectivos , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/genética , Racemetionina , Tomografia por Emissão de Pósitrons , MutaçãoRESUMO
OBJECTIVE: Unlike its pediatric counterpart, adult diffuse intrinsic pontine glioma (DIPG) remains largely unelucidated. In this study, the authors examined the clinical, radiological, pathological, molecular, and clinical aspects of 96 adult DIPGs. METHODS: The National Brain Tumor Registry of China (April 2013-December 2019) was used to collect data on radiologically diagnosed adult DIPG patients. Survival analysis was conducted using Kaplan-Meier curves and univariate and multivariate Cox regression. The chi-square test/Wilcoxon rank-sum test and multivariable logistic regression were used to examine the clinical and radiological characteristics of patients with long-term survival (LTS). Interaction analyses between clinical factors were also conducted. RESULTS: The median age at symptom onset was 33.5 years, and the median duration of symptoms was 4.5 months. The frequencies of H3K27M and IDH1 mutations were 37.2% and 26.5%, respectively. All adult DIPG patients had a median overall survival (OS) of 19.5 months, with 1-, 2-, and 3-year survival rates of 67.0%, 42.8%, and 36.0%, respectively. The median OS of 40 patients who did not undergo treatment was 13.4 months. Patients with H3K27M-mutant tumors had a poorer prognosis than those with IDH-mutant tumors (p < 0.001) and H3K27M(-)/IDH-wild-type tumors (p = 0.002), with a median OS of 11.4 months. The median OSs of patients with H3K27M-mutant tumors who received treatment and those who did not were 13.8 months and 7.5 months, respectively (p = 0.016). Among patients with and without a pathological diagnosis, H3K27M mutation (p < 0.001) and contrast enhancement on MRI (p = 0.003), respectively, imparted a worse prognosis. Treatments were the predictive factor for patients with H3K27M-mutant tumors (p = 0.038), whereas contrast enhancement on MRI was the prognostic factor for the H3K27M(-) group (p = 0.038). In addition, H3K27M mutation and treatment were significant predictors for patients with symptom duration ≤ 4 months (H3K27M, p = 0.020; treatment, p = 0.014) and tumors with no contrast enhancement (H3K27M, p = 0.003; treatment, p = 0.042). Patients with LTS were less likely to have cranial nerve palsy (p = 0.002) and contrast enhancement on MRI at diagnosis (p = 0.022). CONCLUSIONS: It is recommended that all adult DIPG patients undergo genomic testing for H3K27M and IDH mutations. Despite the low prevalence, additional study is needed to better characterize the efficacy of various treatment modalities in adults with DIPG.
Assuntos
Astrocitoma , Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Glioma , Adulto , Humanos , Criança , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/terapia , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/terapia , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/terapia , MutaçãoRESUMO
OBJECTIVE: Delivery of drugs intraarterially to brain tumors has been demonstrated in adults. In this study, the authors initiated a phase I trial of superselective intraarterial cerebral infusion (SIACI) of bevacizumab and cetuximab in pediatric patients with refractory high-grade glioma (diffuse intrinsic pontine glioma [DIPG] and glioblastoma) to determine the safety and efficacy in this population. METHODS: SIACI was used to deliver mannitol (12.5 ml of 20% mannitol) to disrupt the blood-brain barrier (BBB), followed by bevacizumab (15 mg/kg) and cetuximab (200 mg/m2) to target VEGF and EGFR, respectively. Patients with brainstem tumors had a balloon inflated in the distal basilar artery during mannitol infusion. RESULTS: Thirteen patients were treated (10 with DIPG and 3 with high-grade glioma). Toxicities included grade I epistaxis (2 patients) and grade I rash (2 patients). There were no dose-limiting toxicities. Of the 10 symptomatic patients, 6 exhibited subjective improvement; 92% showed decreased enhancement on day 1 posttreatment MRI. Of 10 patients who underwent MRI at 1 month, 5 had progressive disease and 5 had stable disease on FLAIR, whereas contrast-enhanced scans demonstrated progressive disease in 4 patients, stable disease in 2, partial response in 2, and complete response in 1. The mean overall survival for the 10 DIPG patients was 519 days (17.3 months), with a mean posttreatment survival of 214.8 days (7.2 months). CONCLUSIONS: SIACI of bevacizumab and cetuximab was well tolerated in all 13 children. The authors' results demonstrate safety of this method and warrant further study to determine efficacy. As molecular targets are clarified, novel means of bypassing the BBB, such as intraarterial therapy and convection-enhanced delivery, become more critical. Clinical trial registration no.: NCT01884740 (clinicaltrials.gov).
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/administração & dosagem , Bevacizumab/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias do Tronco Encefálico/tratamento farmacológico , Cetuximab/administração & dosagem , Cetuximab/uso terapêutico , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Adolescente , Antineoplásicos Imunológicos/efeitos adversos , Bevacizumab/efeitos adversos , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Cetuximab/efeitos adversos , Criança , Pré-Escolar , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Sistemas de Liberação de Medicamentos , Feminino , Glioblastoma/tratamento farmacológico , Humanos , Injeções Intra-Arteriais , Imageamento por Ressonância Magnética , Masculino , Análise de Sobrevida , Resultado do TratamentoRESUMO
An adequate understanding of the relationships between radiographic and genomic features in diffuse intrinsic pontine glioma (DIPG) is essential, especially in the absence of universal biopsy, to further characterize the molecular heterogeneity of this disease and determine which patients are most likely to respond to biologically-driven therapies. Here, a radiogenomics analytic approach was applied to a cohort of 28 patients with DIPG. Tumor size and imaging characteristics from all available serial MRIs were evaluated by a neuro-radiologist, and patients were divided into three radiographic response groups (partial response [PR], stable disease [SD], progressive disease [PD]) based on MRI within 2 months of radiotherapy (RT) completion. Whole genome and RNA sequencing were performed on autopsy tumor specimens. We report several key, therapeutically-relevant findings: (1) Certain radiologic features on first and subsequent post-RT MRIs are associated with worse overall survival, including PD following irradiation as well as present, new, and/or increasing peripheral ring enhancement, necrosis, and diffusion restriction. (2) Upregulation of EMT-related genes and distant tumor spread at autopsy are observed in a subset of DIPG patients who exhibit poorer radiographic response to irradiation and/or higher likelihood of harboring H3F3A mutations, suggesting possible benefit of upfront craniospinal irradiation. (3) Additional genetic aberrations were identified, including DYNC1LI1 mutations in a subgroup of patients with PR on post-RT MRI; further investigation into potential roles in DIPG tumorigenesis and/or treatment sensitivity is necessary. (4) Whereas most DIPG tumors have an immunologically "cold" microenvironment, there appears to be a subset which harbor a more inflammatory genomic profile and/or higher mutational burden, with a trend toward improved overall survival and more favorable radiographic response to irradiation, in whom immunotherapy should be considered. This study has begun elucidating relationships between post-RT radiographic response with DIPG molecular profiles, revealing radiogenomically distinct subgroups with unique clinical trajectories and therapeutic targets.
Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/genética , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/genética , Genômica por Imageamento , Adolescente , Antineoplásicos/uso terapêutico , Neoplasias do Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/radioterapia , Quimioterapia Adjuvante , Criança , Pré-Escolar , Dineínas do Citoplasma/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma Pontino Intrínseco Difuso/patologia , Glioma Pontino Intrínseco Difuso/radioterapia , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Receptores ErbB/genética , Feminino , Histonas/genética , Humanos , Imageamento por Ressonância Magnética , Masculino , Projetos Piloto , Terapia com Prótons , Radiossensibilizantes/uso terapêutico , Radioterapia , Análise de Sequência de RNA , Taxa de Sobrevida , Microambiente Tumoral/genética , Proteínas Supressoras de Tumor/genética , Sequenciamento Completo do Genoma , Adulto JovemRESUMO
PURPOSE: Diffuse intrinsic pontine gliomas (DIPGs) are the most fatal primary brainstem tumors in pediatric patients. The identification of new molecular features, mediating their formation and progression, as non-coding RNAs (ncRNAs), would be of great importance for the development of effective treatments. METHODS: We analyzed the DIPGs transcriptome with the HTA2.0 array and it was compared with pediatric non-brainstem astrocytoma expression profiles (GSE72269). RESULTS: More than 50% of the differentially expressed transcripts were ncRNAs and based on this, we proposed a DIPGs ncRNA signature. LncRNAs XIST and XIST-210, and the HBII-52 and HBII-85 snoRNA clusters were markedly downregulated in DIPGs. qPCR assays demonstrated XIST downregulation in all non-brainstem astrocytomas, in a gender, age, and brain location-independent manner, as well as in DIPGs affecting boys; however, DIPGs affecting girls showed both downregulation and upregulation of XIST. Girls' with longer survival positively correlated with XIST expression. CONCLUSIONS: The involvement of ncRNAs in DIPGs is imminent and their expression profile is useful to differentiate them from non-neoplastic tissues and non-brain stem astrocytomas, which suggests their potential use as DIPG biomarkers. In fact, XIST and XIST-210 are potential DIPG prognostic biomarkers.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias do Tronco Encefálico/diagnóstico , Glioma Pontino Intrínseco Difuso/diagnóstico , RNA não Traduzido/metabolismo , Transcriptoma , Adolescente , Fatores Etários , Processamento Alternativo , Astrocitoma/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/mortalidade , Criança , Pré-Escolar , Bases de Dados Genéticas , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/genética , Glioma Pontino Intrínseco Difuso/mortalidade , Regulação para Baixo , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , RNA Nucleolar Pequeno/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores Sexuais , Regulação para CimaRESUMO
BACKGROUND AND PURPOSE: Pediatric CNS tumors commonly present challenges for radiographic interpretation on conventional MR imaging. This study sought to investigate the safety and tolerability of hyperpolarized carbon-13 (HP-13C) metabolic imaging in pediatric patients with brain tumors. MATERIALS AND METHODS: Pediatric patients 3 to 18 years of age who were previously diagnosed with a brain tumor and could undergo MR imaging without sedation were eligible to enroll in this safety study of HP [1-13C]pyruvate. Participants received a one-time injection of HP [1-13C]pyruvate and were imaged using dynamic HP-13C MR imaging. We assessed 2 dose levels: 0.34 mL/kg and the highest tolerated adult dose of 0.43 mL/kg. Participants were monitored throughout imaging and for 60 minutes postinjection, including pre- and postinjection electrocardiograms and vital sign measurements. RESULTS: Between February 2017 and July 2019, ten participants (9 males; median age, 14 years; range, 10-17 years) were enrolled, of whom 6 completed injection of HP [1-13C]pyruvate and dynamic HP-13C MR imaging. Four participants failed to undergo HP-13C MR imaging due to technical failures related to generating HP [1-13C]pyruvate or MR imaging operability. HP [1-13C]pyruvate was well-tolerated in all participants who completed the study, with no dose-limiting toxicities or adverse events observed at either 0.34 (n = 3) or 0.43 (n = 3) mL/kg. HP [1-13C]pyruvate demonstrated characteristic conversion to [1-13C]lactate and [13C]bicarbonate in the brain. Due to poor accrual, the study was closed after only 3 participants were enrolled at the highest dose level. CONCLUSIONS: Dynamic HP-13C MR imaging was safely performed in 6 pediatric patients with CNS tumors and demonstrated HP [1-13C]pyruvate brain metabolism.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Isótopos de Carbono , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Ácido Pirúvico , Adolescente , Criança , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Projetos PilotoRESUMO
OBJECTIVE: While the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single-dose drug infusions, agents for oncological therapy may require repeated or chronic infusions to maintain therapeutic drug concentrations. Repeat and chronic CED infusions have rarely been described for oncological purposes. Currently available CED devices are not approved for extended indwelling use, and the only potential at this time is for sequential treatments through multiple procedures. The authors report on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of diffuse intrinsic pontine glioma. METHODS: Patients in this study were enrolled in a phase I single-center clinical trial using 124I-8H9 monoclonal antibody (124I-omburtamab) administered by CED (clinicaltrials.gov identifier NCT01502917). A retrospective chart and imaging review were used to assess demographic data, CED infusion data, and postoperative neurological and surgical outcomes. MRI scans were analyzed using iPlan Flow software for volumetric measurements. Target and catheter coordinates as well as radial, depth, and absolute error in MRI space were calculated with the ClearPoint imaging software. RESULTS: Seven patients underwent 2 or more sequential CED infusions. No patients experienced Clinical Terminology Criteria for Adverse Events grade 3 or greater deficits. One patient had a persistent grade 2 cranial nerve deficit after a second infusion. No patient experienced hemorrhage or stroke postoperatively. There was a statistically significant decrease in radial error (p = 0.005) and absolute tip error (p = 0.008) for the second infusion compared with the initial infusion. Sequential infusions did not result in significantly different distribution capacities between the first and second infusions (volume of distribution determined by the PET signal/volume of infusion ratio [mean ± SD]: 2.66 ± 0.35 vs 2.42 ± 0.75; p = 0.45). CONCLUSIONS: This series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural workflow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncological purposes.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Neoplasias do Tronco Encefálico/cirurgia , Glioma Pontino Intrínseco Difuso/cirurgia , Sistemas de Liberação de Medicamentos/métodos , Radioisótopos do Iodo/uso terapêutico , Procedimentos Neurocirúrgicos/métodos , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/farmacocinética , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Criança , Pré-Escolar , Convecção , Doenças dos Nervos Cranianos/induzido quimicamente , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Feminino , Humanos , Infusões Intravenosas , Radioisótopos do Iodo/administração & dosagem , Radioisótopos do Iodo/farmacocinética , Imageamento por Ressonância Magnética , Masculino , Estudos Retrospectivos , Distribuição Tecidual , Resultado do TratamentoRESUMO
Optimising the conduct of clinical trials for diffuse intrinsic pontine glioma involves use of consistent, objective disease assessments and standardised response criteria. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. A working group was formed specifically to address response assessment in children and young adults with diffuse intrinsic pontine glioma and to develop a consensus on recommendations for response assessment. Response should be assessed using MRI of brain and spine, neurological examination, and anti-inflammatory or antiangiogenic drugs. Clinical imaging standards are defined. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.
Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/terapia , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/terapia , Determinação de Ponto Final/normas , Imageamento por Ressonância Magnética/normas , Neuroimagem/normas , Idade de Início , Neoplasias do Tronco Encefálico/epidemiologia , Neoplasias do Tronco Encefálico/patologia , Glioma Pontino Intrínseco Difuso/epidemiologia , Glioma Pontino Intrínseco Difuso/patologia , Humanos , Gradação de Tumores , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do Tratamento , Carga TumoralRESUMO
Diffuse intrinsic pontine glioma with H3 K27M mutation is a rare brain tumor that primarily affects children. It is extremely lethal, and our understanding of the natural course of this disease, and how it progresses, is lacking. We have presented a case that demonstrates how aggressive this disease can be after progression, with remarkable spread throughout the brain and spine despite upfront radiotherapy. Although rarely reported, widespread dissemination of metastatic diffuse intrinsic pontine glioma throughout the brain and spine is possible.
Assuntos
Neoplasias Encefálicas/secundário , Neoplasias do Tronco Encefálico/patologia , Glioma Pontino Intrínseco Difuso/secundário , Neoplasias da Coluna Vertebral/secundário , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Criança , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Feminino , Humanos , Imageamento por Ressonância Magnética , Neoplasias da Coluna Vertebral/diagnóstico por imagemRESUMO
BACKGROUND AND PURPOSE: Recent advances in molecular techniques have characterized distinct subtypes of diffuse intrinsic pontine gliomas. Our aim was the identification of MR imaging correlates of these subtypes. MATERIALS AND METHODS: Initial MRIs from subjects with diffuse intrinsic pontine gliomas recruited for a prospective clinical trial before treatment were analyzed. Retrospective imaging analyses included FLAIR/T2 tumor volume, tumor volume enhancing, the presence of cyst and/or necrosis, median, mean, mode, skewness, kurtosis of ADC tumor volume based on FLAIR, and enhancement at baseline. Molecular subgroups based on EGFR and MGMT mutations were established. Histone mutations were also determined (H3F3A, HIST1H3B, HIST1H3C). Univariate Cox proportional hazards regression was used to test the association of imaging predictors with overall and progression-free survival. Wilcoxon rank sum, Kruskal-Wallis, and Fisher exact tests were used to compare imaging measures among groups. RESULTS: Fifty patients had biopsy and MR imaging. The median age at trial registration was 6 years (range, 3.3-17.5 years); 52% were female. On the basis of immunohistochemical results, 48 patients were assigned to 1 of 4 subgroups: 28 in MGMT-/epidermal growth factor receptor (EGFR)-, 14 in MGMT-/EGFR+, 3 in MGMT+/EGFR-, and 3 in MGMT+/EGFR+. Twenty-three patients had histone mutations in H3F3A, 8 in HIST1H3B, and 3 in HIST1H3C. Enhancing tumor volume was near-significantly different across molecular subgroups (P = .04), after accounting for the false discovery rate. Tumor volume enhancing, median, mode, skewness, and kurtosis ADC T2-FLAIR/T2 were significantly different (P ≤ .048) between patients with H3F3A and HIST1H3B/C mutations. CONCLUSIONS: MR imaging features including enhancement and ADC histogram parameters are correlated with molecular subgroups and mutations in children with diffuse intrinsic pontine gliomas.
Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/genética , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/genética , Neuroimagem/métodos , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA/métodos , Receptores ErbB/genética , Feminino , Histonas/genética , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Mutação , Estudos Prospectivos , Estudos RetrospectivosAssuntos
Antineoplásicos/administração & dosagem , Barreira Hematoencefálica/efeitos dos fármacos , Neoplasias do Tronco Encefálico/tratamento farmacológico , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Animais , Antineoplásicos/metabolismo , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Humanos , Fragmentos de Peptídeos/administração & dosagem , Terapia por Ultrassom/métodosRESUMO
BACKGROUND AND PURPOSE: 2D measurements of diffuse intrinsic pontine gliomas are limited by variability, and volumetric response criteria are poorly defined. Semiautomated 2D measurements may improve consistency; however, the impact on tumor response assessments is unknown. The purpose of this study was to compare manual 2D, semiautomated 2D, and volumetric measurement strategies for diffuse intrinsic pontine gliomas. MATERIALS AND METHODS: This study evaluated patients with diffuse intrinsic pontine gliomas through a Phase I/II trial (NCT02607124). Clinical 2D cross-product values were derived from manual linear measurements (cross-product = long axis × short axis). By means of dedicated software (mint Lesion), tumor margins were traced and maximum cross-product and tumor volume were automatically derived. Correlation and bias between methods were assessed, and response assessment per measurement strategy was reported. RESULTS: Ten patients (median age, 7.6 years) underwent 58 MR imaging examinations. Correlation and mean bias (95% limits) of percentage change in tumor size from prior examinations were the following: clinical and semiautomated cross-product, r = 0.36, -1.5% (-59.9%, 56.8%); clinical cross-product and volume, r = 0.61, -2.1% (-52.0%, 47.8%); and semiautomated cross-product and volume, r = 0.79, 0.6% (-39.3%, 38.1%). Stable disease, progressive disease, and partial response rates per measurement strategy were the following: clinical cross-product, 82%, 18%, 0%; semiautomated cross-product, 54%, 42%, 4%; and volume, 50%, 46%, 4%, respectively. CONCLUSIONS: Manual 2D cross-product measurements may underestimate tumor size and disease progression compared with semiautomated 2D and volumetric measurements.
Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Neuroimagem/métodos , Adolescente , Aminopiridinas/uso terapêutico , Neoplasias do Tronco Encefálico/tratamento farmacológico , Quimiorradioterapia/métodos , Quimioterapia Adjuvante/métodos , Criança , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Purinas/uso terapêutico , Software , Carga Tumoral/efeitos dos fármacos , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a lethal childhood brain cancer with dismal prognosis and MR imaging is the primary methodology used for diagnosis and monitoring. Our aim was to determine whether advanced diffusion, perfusion, and permeability MR imaging metrics predict survival and pseudoprogression in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: A clinical trial using the poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor veliparib concurrently with radiation therapy, followed by maintenance therapy with veliparib + temozolomide, in children with diffuse intrinsic pontine glioma was conducted by the Pediatric Brain Tumor Consortium. Standard MR imaging, DWI, dynamic contrast-enhanced perfusion, and DSC perfusion were performed at baseline and approximately every 2 months throughout treatment. ADC histogram metrics of T2-weighted FLAIR and enhancing tumor volume, dynamic contrast-enhanced permeability metrics for enhancing tumors, and tumor relative CBV from DSC perfusion MR imaging were calculated. Baseline values, post-radiation therapy changes, and longitudinal trends for all metrics were evaluated for associations with survival and pseudoprogression. RESULTS: Fifty children were evaluable for survival analyses. Higher baseline relative CBV was associated with shorter progression-free survival (P = .02, Q = 0.089) and overall survival (P = .006, Q = 0.055). Associations of higher baseline mean transfer constant from the blood plasma into the extravascular extracellular space with shorter progression-free survival (P = .03, Q = 0.105) and overall survival (P = .03, Q = 0.102) trended toward significance. An increase in relative CBV with time was associated with shorter progression-free survival (P < .001, Q < 0.001) and overall survival (P = .004, Q = 0.043). Associations of longitudinal mean extravascular extracellular volume fraction with progression-free survival (P = .03, Q = 0.104) and overall survival (P = .03, Q = 0.105) and maximum transfer constant from the blood plasma into the extravascular extracellular space with progression-free survival (P = .03, Q = 0.102) trended toward significance. Greater increases with time were associated with worse outcomes. True radiologic progression showed greater post-radiation therapy decreases in mode_ADC_FLAIR compared with pseudoprogression (means, -268.15 versus -26.11, P = .01.) CONCLUSIONS: ADC histogram, perfusion, and permeability MR imaging metrics in diffuse intrinsic pontine glioma are useful in predicting survival and pseudoprogression.
Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Neuroimagem/métodos , Neuroimagem/normas , Adolescente , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benchmarking , Benzimidazóis/administração & dosagem , Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/terapia , Quimiorradioterapia/métodos , Criança , Glioma Pontino Intrínseco Difuso/mortalidade , Glioma Pontino Intrínseco Difuso/terapia , Progressão da Doença , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Interpretação de Imagem Assistida por Computador/normas , Imageamento por Ressonância Magnética/métodos , Masculino , Imagem de Perfusão/métodos , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Temozolomida/administração & dosagemAssuntos
Neoplasias do Tronco Encefálico/genética , Glioma Pontino Intrínseco Difuso/genética , Ependimoma/genética , Proteínas Oncogênicas/genética , Biópsia , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/patologia , Pré-Escolar , Metilação de DNA , Diagnóstico Diferencial , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/patologia , Ependimoma/patologia , Humanos , Imuno-Histoquímica , Neoplasias Infratentoriais/genética , Neoplasias Infratentoriais/patologia , Imageamento por Ressonância Magnética , Masculino , Técnicas de Diagnóstico Molecular , Patologia Molecular , RNA-Seq , Sequenciamento do ExomaRESUMO
BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a devastating childhood cancer that despite being primarily diagnosed by MR imaging alone, lacks robust prognostic imaging features. This study investigated patterns and quantification of extrapontine lesion extensions as potential prognostic imaging biomarkers for survival in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: Volumetric analysis of baseline MR imaging studies was completed in 131 patients with radiographically defined typical diffuse intrinsic pontine gliomas. Extrapontine tumor extension was classified according to the direction of extension: midbrain, medulla oblongata, and right and left middle cerebellar peduncles; various extrapontine lesion extension patterns were evaluated. The Kaplan-Meier method was used to estimate survival differences; linear regression was used to evaluate clinical-radiographic variables prognostic of survival. RESULTS: At least 1 extrapontine lesion extension was observed in 125 patients (95.4%). Of the 11 different extrapontine lesion extension patterns encountered in our cohort, 2 were statistically significant predictors of survival. Any extension into the middle cerebellar peduncles was prognostic of shorter overall survival (P = .01), but extension into both the midbrain and medulla oblongata but without extension into either middle cerebellar peduncle was prognostic of longer overall survival compared with those having no extension (P = .04) or those having any other pattern of extension (P < .001). CONCLUSIONS: Within this large cohort of patients with typical diffuse intrinsic pontine gliomas, 2 specific extrapontine lesion extension patterns were associated with a significant overall survival advantage or disadvantage. Our findings may be valuable for risk stratification and radiation therapy planning in future clinical trials.
Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/patologia , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/patologia , Adolescente , Neoplasias do Tronco Encefálico/mortalidade , Criança , Pré-Escolar , Glioma Pontino Intrínseco Difuso/mortalidade , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Masculino , Prognóstico , Estudos RetrospectivosRESUMO
PURPOSE: Optimal radiation therapy (RT) target margins for diffuse intrinsic pontine glioma (DIPG) are unknown. We sought to define disease progression patterns in a contemporary cohort treated with conformal RT using different clinical target volume (CTV) margins. METHODS AND MATERIALS: We reviewed 105 patients with newly diagnosed DIPG treated with conformal conventionally fractionated RT at our institution from 2006 to 2014. CTV margins were classified as standard (1 cm) for 60 patients and extended (2-3 cm) for 45 patients. Survival and cumulative incidence of progression in treatment groups were compared by log-rank and Gray's tests, respectively. Cox proportional hazard models identified predictors of survival. RESULTS: For 97 patients evaluated with magnetic resonance imaging at progression, the cumulative incidences of isolated local, isolated distant, and synchronous disease progression at 1 year were 62.6%, 12.3%, and 7.2%, respectively, and did not differ significantly according to the CTV margin. Central dosimetric progression (Vprogression95% ≥95%) was observed in 80 of 81 evaluable patients. Median progression-free survival and overall survival (OS) were 7.6 months (95% confidence interval, 6.9-8.2) and 11.3 months (95% confidence interval, 10.0-12.8), respectively, and did not differ significantly according to margin status. DIPG survival prediction risk group (standard vs high, P = .02; intermediate vs high, P = .009) and development of distant metastasis (P = .003) were independent predictors of OS. For the 41 patients (39%) with a pathologic diagnosis, H3.3 K27M mutation was associated with shorter OS (hazard ratio [HR], 0.41; P =.02), whereas H3.1 K27M and ACVR1 mutations were associated with longer OS (HR, 3.56; P =.004 and HR, 2.58; P =.04, respectively). CONCLUSIONS: All patients who experienced local failure showed progression within the high-dose volume, and there was no apparent survival or tumor-control benefit to extending the CTV margins beyond 1 cm. Given the increasing use of reirradiation, standardizing the CTV margin to 1 cm may improve retreatment tolerance.
Assuntos
Neoplasias do Tronco Encefálico/radioterapia , Glioma Pontino Intrínseco Difuso/radioterapia , Radioterapia Conformacional , Neoplasias do Tronco Encefálico/diagnóstico por imagem , Neoplasias do Tronco Encefálico/patologia , Criança , Pré-Escolar , Glioma Pontino Intrínseco Difuso/diagnóstico por imagem , Glioma Pontino Intrínseco Difuso/patologia , Progressão da Doença , Feminino , Humanos , Masculino , Estudos Retrospectivos , Análise de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
Dissemination of diffuse intrinsic pontine glioma (DIPG) outside the central nervous system is exceptional. Here, we present a child diagnosed with DIPG who developed seeding along the track of the ventriculoperitoneal shunt and review the literature on this unusual occurrence.