Cellular hemangioma is a subtype of hemangioma that is associated with cellular immaturity and the potential for recurrence. Intracranial location of these lesions is extremely rare, and definitive ...treatment often requires radical neurosurgical resection. The authors report a case of a 12-year-old boy with a subtemporal cellular hemangioma. He underwent gross-total resection of the tumor, but within 1.5 months the tumor recurred, necessitating a second resection. Because of its proximity to vascular structures, only subtotal resection was possible. Repeat MRI 1 month after the second surgery showed significant tumor recurrence. Given the tumor's demonstrated capacity for recurrence and its proximity to the vein of Labbé and sigmoid sinus, further resection was not indicated. In an effort to limit radiation therapy for this young patient, treatment with bevacizumab and temozolomide was chosen and achieved a complete response that has proven durable for 36 months after cessation of therapy. This is the first report of the successful use of chemotherapy to treat an intracranial hemangioma, a rare condition with limited therapeutic options.
Biologically accurate mouse models of human cancer have become important tools for the study of human disease. The anatomical location of various target organs, such as brain, pancreas, and prostate, ...makes determination of disease status difficult. Imaging modalities, such as magnetic resonance imaging, can greatly enhance diagnosis, and longitudinal imaging of tumor progression is an important source of experimental data. Even in models where the tumors arise in areas that permit visual determination of tumorigenesis, longitudinal anatomical and functional imaging can enhance the scope of studies by facilitating the assessment of biological alterations, (such as changes in angiogenesis, metabolism, cellular invasion) as well as tissue perfusion and diffusion. One of the challenges in preclinical imaging is the development of infrastructural platforms required for integrating in vivo imaging and therapeutic response data with ex vivo pathological and molecular data using a more systems-based multiscale modeling approach. Further challenges exist in integrating these data for computational modeling to better understand the pathobiology of cancer and to better affect its cure. We review the current applications of preclinical imaging and discuss the implications of applying functional imaging to visualize cancer progression and treatment. Finally, we provide new data from an ongoing preclinical drug study demonstrating how multiscale modeling can lead to a more comprehensive understanding of cancer biology and therapy.
Spatial heterogeneity in medulloblastoma Morrissy, A Sorana; Cavalli, Florence M G; Remke, Marc ...
Nature genetics,
05/2017, Letnik:
49, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of ...targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.
Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative ...radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.
Learning Objectives
After completing this course, the reader will be able to:
Recognize the classification, clinical presentation, and diagnosis of embryonal CNS tumors.
Explain the important ...molecular genetic alterations identified in embryonal CNS tumors.
Describe the current management and novel treatment strategies for embryonal CNS tumors.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
Embryonal central nervous system (CNS) tumors are the most common group of malignant brain tumors in children. The diagnosis and classification of tumors belonging to this family have been controversial; however, utilization of molecular genetics is helping to refine traditional histopathologic and clinical classification schemes. Currently, this group of tumors includes medulloblastomas, supratentorial primitive neuroectodermal tumors, atypical teratoid/rhabdoid tumors, ependymoblastomas, and medulloepitheliomas. While the survival of older children with nonmetastatic medulloblastomas has improved considerably within the past two decades, the outcomes for infants and for those with metastatic medulloblastomas or other high‐risk embryonal CNS tumors remain poor. It is anticipated that the emerging field of molecular biology will greatly aid in the future stratification and therapy for pediatric patients with malignant embryonal tumors. In this review, recent advances in the diagnosis, molecular genetics, and treatment of the most common pediatric embryonal CNS tumors are discussed.
DNA methylation and epigenetic inactivation of the O6-methylguanine methyltransferase (MGMT) gene induces MGMT deficiency, reducing the tumor cell's DNA repair capacity and increasing its ...susceptibility to alkylating chemotherapeutic agents. Consequently, adult patients whose tumors are deficient in MGMT have better outcomes with alkylator chemotherapy, and MGMT methylation has been proposed as a screening marker of deficient tumors. In order to test the feasibility of this approach for medulloblastoma, a common brain tumor in children, we determined the methylation status, mRNA expression pattern, and protein expression of MGMT in a panel of clinical specimens. Methylation-specific polymerase chain reaction analysis revealed methylation of MGMT in 28 of 37 tumor samples. Quantitative real-time reverse transcriptase-polymerase chain reaction showed a range of expression of MGMT mRNA varying more than 20-fold. However, there was no correlation found between MGMT methylation and mRNA expression. Immunohistochemistry demonstrated that all tumors were immunoreactive for MGMT in the nucleus of the medulloblastoma cells in a heterogeneous pattern. The intercell variability of MGMT complement explained the discordance between methylation and expression. Therefore, MGMT methylation as determined by methylation-specific polymerase chain reaction cannot be used as a marker for MGMT deficiency in medulloblastoma. Further, these findings support the use of pharmacological MGMT depletion as a rational approach for intensification of alkylator chemotherapy in the treatment of medulloblastoma.
Pediatric brain and spinal cancers are collectively the leading disease-related cause of death in children; thus, we urgently need curative therapeutic strategies for these tumors. To accelerate such ...discoveries, the Children’s Brain Tumor Network (CBTN) and Pacific Pediatric Neuro-Oncology Consortium (PNOC) created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to establish OpenPBTA, an open collaborative project with over 40 scalable analysis modules that genomically characterize 1,074 pediatric brain tumors. Transcriptomic classification reveals universal TP53 dysregulation in mismatch repair-deficient hypermutant high-grade gliomas and TP53 loss as a significant marker for poor overall survival in ependymomas and H3 K28-mutant diffuse midline gliomas. Already being actively applied to other pediatric cancers and PNOC molecular tumor board decision-making, OpenPBTA is an invaluable resource to the pediatric oncology community.
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•OpenPBTA collaborative analyses establish resource for 1,074 pediatric brain tumors•NGS-based WHO-aligned integrated diagnoses generated for 644 of 1,074 tumors•RNA-Seq analysis infers medulloblastoma subtypes, TP53 status, and telomerase activity•OpenPBTA will accelerate therapeutic translation of genomic insights
The OpenPBTA is a global, collaborative open-science initiative that brought together researchers and clinicians to genomically characterize 1,074 pediatric brain tumors and 22 patient-derived cell lines. Shapiro et al. create over 40 open-source, scalable modules to perform cancer genomics analyses and provide a richly annotated somatic dataset across 58 brain tumor histologies. The OpenPBTA framework can be used as a model for large-scale data integration to inform basic research, therapeutic target identification, and clinical translation.
Metastasis is the leading cause of treatment failure in medulloblastoma. Understanding the genetic regulation of metastasis may aid in the development of novel treatments. We therefore performed in ...silico analysis of the mRNA expression of 83 medulloblastomas compiled from two independent microarray studies by focusing on 135 genes most frequently linked to metastasis in other tumors. We then asked whether expression of these genes correlated with metastasis in the medulloblastoma array data sets. We found the platelet-derived growth factor receptor alpha, early growth response protein 1 and insulin-like growth factor 2 genes as well as several genes associated with MYCC and ERBB2 overexpressed by at least 2-fold in metastatic tumors in both array data sets. We conclude that these genes may interact to promote prometastatic signaling in medulloblastoma.
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