71 results on '"Hawkins, Cynthia"'
Search Results
2. MRI-Based End-To-End Pediatric Low-Grade Glioma Segmentation and Classification.
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Vafaeikia, Partoo, Wagner, Matthias W., Hawkins, Cynthia, Tabori, Uri, Ertl-Wagner, Birgit B., and Khalvati, Farzad
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DEEP learning , *CONFIDENCE intervals , *MAGNETIC resonance imaging , *GLIOMAS , *TUMORS in children , *RADIOMICS , *COMPARATIVE studies , *GENETIC markers , *TRANSFERASES , *RESEARCH funding , *PREDICTION models , *RECEIVER operating characteristic curves , *TUMOR grading - Abstract
Purpose: MRI-based radiomics models can predict genetic markers in pediatric low-grade glioma (pLGG). These models usually require tumour segmentation, which is tedious and time consuming if done manually. We propose a deep learning (DL) model to automate tumour segmentation and build an end-to-end radiomics-based pipeline for pLGG classification. Methods: The proposed architecture is a 2-step U-Net based DL network. The first U-Net is trained on downsampled images to locate the tumour. The second U-Net is trained using image patches centred around the located tumour to produce more refined segmentations. The segmented tumour is then fed into a radiomics-based model to predict the genetic marker of the tumour. Results: Our segmentation model achieved a correlation value of over 80% for all volume-related radiomic features and an average Dice score of.795 in test cases. Feeding the auto-segmentation results into a radiomics model resulted in a mean area under the ROC curve (AUC) of.843, with 95% confidence interval (CI) [.78-.906] and.730, with 95% CI [.671-.789] on the test set for 2-class (BRAF V600E mutation BRAF fusion) and 3-class (BRAF V600E mutation BRAF fusion and Other) classification, respectively. This result was comparable to the AUC of.874, 95% CI [.829-.919] and.758, 95% CI [.724-.792] for the radiomics model trained and tested on the manual segmentations in 2-class and 3-class classification scenarios, respectively. Conclusion: The proposed end-to-end pipeline for pLGG segmentation and classification produced results comparable to manual segmentation when it was used for a radiomics-based genetic marker prediction model. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Diffuse intrinsic pontine glioma ventricular peritoneal shunt metastasis: a case report and literature review.
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Gelder, Chloé Louise, Hawkins, Cynthia, Zapotocky, Michal, Dirks, Peter, Bartels, Ute, and Bouffet, Eric
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LITERATURE reviews , *CENTRAL nervous system , *OLIGODENDROGLIOMAS , *METASTASIS - Abstract
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. [ABSTRACT FROM AUTHOR]
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- 2019
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4. cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAFV600E mutation.
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Ellison, David W., Hawkins, Cynthia, Jones, David T. W., Pfister, Stefan M., Onar-Thomas, Arzu, Reifenberger, Guido, and Louis, David N.
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GLIOMAS , *BRAF genes , *MYB gene - Abstract
The article discusses the IDH-wt?H3-wt diffuse gliomas arising mainly in middle-aged adults and grading for it by World Health Organization (WHO) which is characterized by BRAF mutation, FGFR alteration or MYB or MYBLI rearrangement.
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- 2019
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5. A 3‐year‐old male with an extramedullary, intra‐ and extradural mass at T11‐L1.
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Sagga, Aziz, Mehta, Vivek, Hawkins, Cynthia, and van Landeghem, Frank K. H.
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MULTINUCLEATED giant cells , *LANGERHANS-cell histiocytosis , *NON-langerhans-cell histiocytosis , *JUVENILE xanthogranuloma , *CELL morphology - Published
- 2023
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6. JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma.
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Tiffany Sin Yu Chan, Hawkins, Cynthia, Krieger, Jonathan R., McGlade, C. Jane, and Annie Huang
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CARRIER proteins , *MEDULLOBLASTOMA , *CELL communication , *METASTASIS , *PHENOTYPES - Abstract
Substantial evidence links Myc-PI3K/AKT signaling to the most aggressive subtype of medulloblastoma and this axis in medulloblastoma therapy. In this study, we advance understanding of how Myc-PI3K/AKT signaling contributes to this malignancy, specifically, in identifying the Myc-interacting protein JPO2 and its partner binding protein LEDGF/p75 as critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma. JPO2 overexpression induced metastatic medulloblastoma in vivo through two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT that promote metastatic phenotypes in this setting. Overall, our findings highlight two novel prometastatic loci in medulloblastoma and point to the JPO2:LEDGF/p75 protein complex as a potentially new targetable component of PI3K/AKT signaling in medulloblastoma. Cancer Res; 76(9); 2802-12. [ABSTRACT FROM AUTHOR]
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- 2016
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7. Increased confidence of radiomics facilitating pretherapeutic differentiation of BRAF-altered pediatric low-grade glioma.
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Kudus, Kareem, Wagner, Matthias W., Namdar, Khashayar, Nobre, Liana, Bouffet, Eric, Tabori, Uri, Hawkins, Cynthia, Yeom, Kristen W., Ertl-Wagner, Birgit B., and Khalvati, Farzad
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MACHINE learning , *RADIOMICS , *GLIOMAS , *RANDOM forest algorithms , *RELATIONSHIP status - Abstract
Objectives: Currently, the BRAF status of pediatric low-grade glioma (pLGG) patients is determined through a biopsy. We established a nomogram to predict BRAF status non-invasively using clinical and radiomic factors. Additionally, we assessed an advanced thresholding method to provide only high-confidence predictions for the molecular subtype. Finally, we tested whether radiomic features provide additional predictive information for this classification task, beyond that which is embedded in the location of the tumor. Methods: Random forest (RF) models were trained on radiomic and clinical features both separately and together, to evaluate the utility of each feature set. Instead of using the traditional single threshold technique to convert the model outputs to class predictions, we implemented a double threshold mechanism that accounted for uncertainty. Additionally, a linear model was trained and depicted graphically as a nomogram. Results: The combined RF (AUC: 0.925) outperformed the RFs trained on radiomic (AUC: 0.863) or clinical (AUC: 0.889) features alone. The linear model had a comparable AUC (0.916), despite its lower complexity. Traditional thresholding produced an accuracy of 84.5%, while the double threshold approach yielded 92.2% accuracy on the 80.7% of patients with the highest confidence predictions. Conclusion: Models that included radiomic features outperformed, underscoring their importance for the prediction of BRAF status. A linear model performed similarly to RF but with the added benefit that it can be visualized as a nomogram, improving the explainability of the model. The double threshold technique was able to identify uncertain predictions, enhancing the clinical utility of the model. Clinical relevance statement: Radiomic features and tumor location are both predictive of BRAF status in pLGG patients. We show that they contain complementary information and depict the optimal model as a nomogram, which can be used as a non-invasive alternative to biopsy. Key Points: • Radiomic features provide additional predictive information for the determination of the molecular subtype of pediatric low-grade gliomas patients, beyond what is embedded in the location of the tumor, which has an established relationship with genetic status. • An advanced thresholding method can help to distinguish cases where machine learning models have a high chance of being (in)correct, improving the utility of these models. • A simple linear model performs similarly to a more powerful random forest model at classifying the molecular subtype of pediatric low-grade gliomas but has the added benefit that it can be converted into a nomogram, which may facilitate clinical implementation by improving the explainability of the model. [ABSTRACT FROM AUTHOR]
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- 2024
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8. An update on the CNS manifestations of brain tumor polyposis syndromes.
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Kim, Byungjin, Tabori, Uri, and Hawkins, Cynthia
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BRAIN tumors , *LI-Fraumeni syndrome , *GASTROINTESTINAL cancer , *SYNDROMES ,CENTRAL nervous system tumors - Abstract
Cancer predisposition syndromes are associated with an increased risk of developing primary malignancies. Here we discuss those which are associated with an increased risk of tumors of the central nervous system (CNS) and gastrointestinal (GI) tract. These can be grouped into those in which the CNS tumors predominate versus those in which the GI cancers predominate. The former include constitutional mismatch repair deficiency (CMMRD) syndrome, Li–Fraumeni syndrome (LFS), and Cowden syndrome (CS) while the latter include familial adenomatosis polyposis 1 (FAP1), Lynch syndrome and polymerase proofreading-associated polyposis syndrome (PPAP). Tumor specificity does exist as medulloblastoma occur in FAP, LFS and CMMRD while glioma are most commonly seen in all replication repair-deficient genes and LFS. Choroid plexus carcinoma is strictly observed in LFS while Cowden syndrome patients develop Lhermitte Duclos disease or meningioma. In each syndrome, specific types of low-grade and high-grade gastrointestinal cancers can occur, but these will be discussed elsewhere. Underlying cancer predisposition syndromes are important to consider when faced with brain tumors, particularly in the pediatric and young adult age groups, as identification of an underlying germ line mutation may change the upfront management of the patient and has implications for future cancer surveillance for both the patient and potentially affected family members. Considerations of family history, presence of skin lesions and consanguinity provide valuable information in identifying patients at potential increased risk. [ABSTRACT FROM AUTHOR]
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- 2020
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9. Pediatric low-grade glioma in the era of molecular diagnostics.
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Ryall, Scott, Tabori, Uri, and Hawkins, Cynthia
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GLIOMAS , *MOLECULAR diagnosis , *TUMORS in children , *BRAIN tumors , *SURGICAL excision , *MITOGEN-activated protein kinases , *MITOGEN-activated protein kinase phosphatases - Abstract
Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior – in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS–mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrella of pediatric-type low-grade glioma. In doing so we discuss the specific molecular drivers of pediatric low grade glioma and how to effectively test for them, review the newest therapeutic agents and their utility in treating this disease, and propose a risk-based stratification system that considers both clinical and molecular parameters to aid clinicians in making treatment decisions. [ABSTRACT FROM AUTHOR]
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- 2020
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10. Malignant transformation of adult-onset pilocytic astrocytoma to diffuse leptomeningeal glioneuronal tumor within the thoracic spine: a case report and review of the literature.
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Laghaei Farimani, Pedram, Rebchuk, Alexander D., Chang, Stephano J., Yip, Stephen, Hawkins, Cynthia, and Ailon, Tamir T.
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LITERATURE reviews , *THORACIC vertebrae , *ASTROCYTOMAS , *MENINGEAL cancer , *TUMORS , *SPINAL cord diseases - Abstract
We describe a 31-year-old male who presented with progressive myelopathy from a thoracic pilocytic astrocytoma (PA). Following multiple recurrences and resections, 10 years after his index surgery, pathology revealed diffuse leptomeningeal glioneuronal tumor (DLGNT) with high-grade features. We discuss his clinical course, management, histopathological findings, and present a comprehensive review of spinal PA undergoing malignant transformation in adults and adult-onset spinal DLGNT. To our knowledge, we present the first reported case of adult-onset spinal PA malignant transformation to DLGNT. Our case adds to the paucity of clinical data characterizing such transformations and highlights the importance of developing novel management paradigms. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Pakistan National Guidelines for Pediatric High-Grade Gliomas.
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Bashir, Farrah, Qureshi, Bilal Mazhar, Minhas, Khurram, Tabori, Uri, Bouffet, Eric, Hawkins, Cynthia, Enam, Ather, and Mushtaq, Naureen
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SOMATIC mutation , *HEALTH care teams , *GLIOMAS , *MIDDLE-income countries , *EARLY death ,CENTRAL nervous system tumors - Abstract
Pediatric high-grade glioma (pHGG) is highly malignant central nervous system tumor and constitute 10% of the pediatric gliomas. Effective treatment needs a functioning multi-disciplinary team including pediatric neuro oncologist, neurosurgeon, neuroradiologist, neuropathologist and radiation oncologist. Despite surgical resection, radiotherapy and chemotherapy, most HGG will recur resulting in early death. A significant proportion of HGG occurs in context of cancer predisposition syndromes like Constitutional Mismatch Repair Deficiency (CMMRD) also known as Biallelic Mismatch Repair Deficiency (bMMRD) characterized by high mutational burden. The incidence of HGG with CMMRD is one per million patients. bMMRD is caused by homozygous germline mutations in one of the four Mis Match Repair (MMR) genes (PMS2, MLH1, MSH2, and MSH6). The use of TMZ is now avoided in CMMRD related HGG due to its limited response and known ability to increase the accumulation of somatic mutations in these patients, increasing the risk of secondary tumors. HGG should be managed under the care of multidisciplinary team to receive optimum treatment. This is particularly important for low middle-income countries (LMIC) with limited resources like Pakistan. [ABSTRACT FROM AUTHOR]
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- 2023
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12. Maternal and childhood medical history and the risk of childhood brain tumours: a case–control study in Ontario, Canada.
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Cheng, Sierra, McLaughlin, John R., Brown, M. Catherine, Al-Sawaihey, Hamad, Rutka, James, Bouffet, Eric, Hawkins, Cynthia, Cairney, A. Elizabeth, Ranger, Adrianna, Fleming, Adam J., Johnston, Donna, Grenberg, Mark, Malkin, David, and Hung, Rayjean J.
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Background: Studies to date have yielded inconclusive results as to whether maternal medical history during pregnancy, and a child's early-life medical history contribute to the development of childhood brain tumours (CBTs). This study examined associations between maternal and childhood medical history and the risk of CBTs. Methods: The Childhood Brain Tumour Epidemiology Study of Ontario (CBREO) examined children 0–15 years of age with newly diagnosed CBTs from 1997 to 2003. Multivariable logistic regression analysis determined associations for prenatal medications and childhood medical history, adjusted for child's demographics, and maternal education. Analyses were stratified by histology. A latency period analysis was conducted using 12- and 24-month lead times. Results: Maternal intake of immunosuppressants during the prenatal period was significantly associated with glial tumours (OR 2.73, 95% CI 1.17–6.39). Childhood intake of anti-epileptics was significantly associated with CBTs overall, after accounting for 12-month (OR 8.51, 95% CI 3.35–21.63) and 24-month (OR 6.04, 95% CI 2.06–17.70) lead time before diagnosis. No associations for other medications were found. Conclusions: This study underscores the need to examine potential carcinogenic effects of the medication classes highlighted and of the indication of medication use. Despite possible reverse causality, increased CBT surveillance for children with epilepsy might be warranted. [ABSTRACT FROM AUTHOR]
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- 2023
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13. Mitochondrial POLG related disorder presenting prenatally with fetal cerebellar growth arrest.
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Inbar-Feigenberg, Michal, Blaser, Susan, Hawkins, Cynthia, Shannon, Patrick, Hewson, Stacy, and Chitayat, David
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MITOCHONDRIAL pathology , *CHORIONIC villus sampling , *GESTATIONAL age , *ULTRASONIC imaging , *GENETIC mutation , *DIAGNOSIS - Abstract
We report the prenatal findings of severe cerebellar growth arrest in two siblings with POLG1 mutations. The first presented with seizures and lactic acidosis immediately after premature birth and was diagnosed with mitochondrial disease on muscle biopsy. Molecular DNA analysis confirmed homozygous missense mutation in the POLG1 gene. The pregnancy of the second sibling was monitored closely by repeat fetal ultrasounds since the parents declined invasive testing. A detailed fetal ultrasound at 19 weeks gestation showed a small cerebellum with transcerebellar diameter (TCD) on axial cranial imaging, measuring below the 5th centile for gestational age. Molecular analysis confirmed the same homozygous familial mutation in the POLG1gene. This report further delineates the phenotypic features of the POLG related disorders and expands it to the prenatal era. Subsequent pregnancies were monitored by molecular analysis, using chorionic villus sampling (CVS). [ABSTRACT FROM AUTHOR]
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- 2018
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14. Pathological Findings of a Subependymal Giant Cell Astrocytoma Following Treatment With Rapamycin.
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Cheng, Sylvia, Hawkins, Cynthia, Taylor, Michael D., and Bartels, Ute
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ASTROCYTOMAS , *HYDROCEPHALUS , *RAPAMYCIN , *HERITABILITY , *MTOR protein , *CLINICAL trials , *THERAPEUTICS - Abstract
Background Tuberous sclerosis complex is a heritable multisystem disorder associated with genes involved in the formation of a tumor-suppressor complex acting through the Ras homologue enriched in brain protein to limit activation of the mammalian target of rapamycin complex I. Mutations in these genes result in enhanced mammalian target of rapamycin signaling and may cause neurological manifestations including brain tubers, subependymal nodules, and subependymal giant cell astrocytomas. These astrocytomas are tumors that arise near the foramen of Monro and may lead to obstructive hydrocephalus. Standard therapy has been surgical resection. More recently, mammalian target of rapamycin inhibitor, everolimus, has been approved for treatment after demonstration of efficacy in prospective clinical trials. Methods We report a 15 year-old girl with tuberous sclerosis complex who proceeded to surgical resection of her subependymal giant cell astrocytoma after 3 months of treatment with mammalian target of rapamycin inhibition. We compared her subependymal giant cell astrocytoma tissue specimen with 12 untreated subependymal giant cell astrocytomas accessed from The Hospital for Sick Children in Toronto, Canada. Results This girl's histopathological findings were consistent with subependymal giant cell astrocytomas with no exposure to mammalian target of rapamycin inhibitors. There were no major differences identified on immunohistochemistry at targets downstream of mammalian target of rapamycin complex 1 or in neighboring signaling pathways. The majority of cells were reactive to glial fibrillary acidic protein, mitogen-activated protein kinase, phospho-S6, caspase 3 (95% positivity), and NP-1. Conclusion In this one individual, rapamycin therapy did not change the histopathological characteristics of subependymal giant cell astrocytoma. Mammalian target of rapamycin inhibition involves complex signaling pathways inducing subependymal giant cell astrocytoma shrinkage. However, its effect is not easily characterized within tumor tissue. [ABSTRACT FROM AUTHOR]
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- 2015
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15. Consensus Recommendations to Optimize the Detection and Reporting of NTRK Gene Fusions by RNA-Based Next-Generation Sequencing.
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Stockley, Tracy L., Lo, Bryan, Box, Adrian, Gomez Corredor, Andrea, DeCoteau, John, Desmeules, Patrice, Feilotter, Harriet, Grafodatskaya, Daria, Hawkins, Cynthia, Huang, Weei Yuarn, Izevbaye, Iyare, Lepine, Guylaine, Papadakis, Andreas I., Park, Paul C., Sheffield, Brandon S., Tran-Thanh, Danh, Yip, Stephen, and Sound Tsao, Ming
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RNA sequencing , *MOLECULAR pathology , *ONCOLOGY - Abstract
The detection of gene fusions by RNA-based next-generation sequencing (NGS) is an emerging method in clinical genetic laboratories for oncology biomarker testing to direct targeted therapy selections. A recent Canadian study (CANTRK study) comparing the detection of NTRK gene fusions on different NGS assays to determine subjects' eligibility for tyrosine kinase TRK inhibitor therapy identified the need for recommendations for best practices for laboratory testing to optimize RNA-based NGS gene fusion detection. To develop consensus recommendations, representatives from 17 Canadian genetic laboratories participated in working group discussions and the completion of survey questions about RNA-based NGS. Consensus recommendations are presented for pre-analytic, analytic and reporting aspects of gene fusion detection by RNA-based NGS. [ABSTRACT FROM AUTHOR]
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- 2023
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16. Using comprehensive genomic and functional analyses for resolving genotype–phenotype mismatches in children with suspected CMMRD in Lebanon: an IRRDC study.
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Hamideh, Dima, Das, Anirban, Bianchi, Vanessa, Chung, Jiil, Negm, Logine, Levine, Adrian, Basbous, Maya, Sanchez-Ramirez, Santiago, Mikael, Leonie, Jabado, Nada, Atweh, Lamya, Lteif, Mireille, Mahfouz, Rami, Tarek, Nidale, Abboud, Miguel, Muwakkit, Samar, Hawkins, Cynthia, Tabori, Uri, and Saab, Raya
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GENOMICS , *FUNCTIONAL analysis , *SYMPTOMS , *IMMUNOHISTOCHEMISTRY , *CANCER diagnosis , *PHENOTYPES - Abstract
Constitutional mismatch repair deficiency (CMMRD) is an aggressive and highly penetrant cancer predisposition syndrome. Because of its variable clinical presentation and phenotypical overlap with neurofibromatosis, timely diagnosis remains challenging, especially in countries with limited resources. Since current tests are either difficult to implement or interpret or both we used a novel and relatively inexpensive functional genomic assay (LOGIC) which has been recently reported to have high sensitivity and specificity in diagnosing CMMRD. Here we report the clinical and molecular characteristics of nine patients diagnosed with cancer and suspected to have CMMRD and highlight the challenges with variant interpretation and immunohistochemical analysis that led to an uncertain interpretation of genetic findings in 6 of the 9 patients. Using LOGIC, we were able to confirm the diagnosis of CMMRD in 7 and likely exclude it in 2 patients, resolving ambiguous result interpretation. LOGIC also enabled predictive testing of asymptomatic siblings for early diagnosis and implementation of surveillance. This study highlights the varied manifestations and practical limitations of current diagnostic criteria for CMMRD, and the importance of international collaboration for implementing robust and low-cost functional assays for resolving diagnostic challenges. [ABSTRACT FROM AUTHOR]
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- 2023
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17. Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD).
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Briggs, Mayen, Das, Anirban, Firth, Helen, Levine, Adrian, Sánchez-Ramírez, Santiago, Negm, Logine, Ercan, Ayse B., Chung, Jill, Bianchi, Vanessa, Jalloh, Ibrahim, Phyu, Poe, Thorp, Nicky, Grundy, Richard G., Hawkins, Cynthia, Trotman, Jamie, Tarpey, Patrick, Tabori, Uri, Allinson, Kieren, and Murray, Matthew J.
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EPENDYMOMA , *POSTERIOR cranial fossa , *HEREDITARY nonpolyposis colorectal cancer - Published
- 2023
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18. Radiomic Features Based on MRI Predict Progression-Free Survival in Pediatric Diffuse Midline Glioma/Diffuse Intrinsic Pontine Glioma.
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Wagner, Matthias W., Namdar, Khashayar, Napoleone, Marc, Hainc, Nicolin, Amirabadi, Afsaneh, Fonseca, Adriana, Laughlin, Suzanne, Shroff, Manohar M., Bouffet, Eric, Hawkins, Cynthia, Khalvati, Farzad, Bartels, Ute, and Ertl-Wagner, Birgit B.
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CONFIDENCE intervals , *GLIOMAS , *MAGNETIC resonance imaging , *RETROSPECTIVE studies , *SURVIVAL analysis (Biometry) , *PROGRESSION-free survival - Abstract
Purpose: Biopsy-based assessment of H3 K27 M status helps in predicting survival, but biopsy is usually limited to unusual presentations and clinical trials. We aimed to evaluate whether radiomics can serve as prognostic marker to stratify diffuse intrinsic pontine glioma (DIPG) subsets. Methods: In this retrospective study, diagnostic brain MRIs of children with DIPG were analyzed. Radiomic features were extracted from tumor segmentations and data were split into training/testing sets (80:20). A conditional survival forest model was applied to predict progression-free survival (PFS) using training data. The trained model was validated on the test data, and concordances were calculated for PFS. Experiments were repeated 100 times using randomized versions of the respective percentage of the training/test data. Results: A total of 89 patients were identified (48 females, 53.9%). Median age at time of diagnosis was 6.64 years (range: 1–16.9 years) and median PFS was 8 months (range: 1–84 months). Molecular data were available for 26 patients (29.2%) (1 wild type, 3 K27M-H3.1, 22 K27M-H3.3). Radiomic features of FLAIR and nonenhanced T1-weighted sequences were predictive of PFS. The best FLAIR radiomics model yielded a concordance of.87 [95% CI:.86–.88] at 4 months PFS. The best T1-weighted radiomics model yielded a concordance of.82 [95% CI:.8–.84] at 4 months PFS. The best combined FLAIR + T1-weighted radiomics model yielded a concordance of.74 [95% CI:.71–.77] at 3 months PFS. The predominant predictive radiomic feature matrix was gray-level size-zone. Conclusion: MRI-based radiomics may predict progression-free survival in pediatric diffuse midline glioma/diffuse intrinsic pontine glioma. [ABSTRACT FROM AUTHOR]
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- 2023
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19. Expression and Clinical Correlation of PD-1/PD-L1 and VE1(BRAFp.V600E) in Pediatric Langerhans Cell Histiocytosis.
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Tandon, Sneha, Weitzman, Sheila, Joyce, Brooklyn, Mcguire, Bryan, Stephens, Derek, Whitlock, James, Hawkins, Cynthia, Bo Yee Ngan, and Abla, Oussama
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LANGERHANS-cell histiocytosis , *PROGRAMMED death-ligand 1 , *PROGRAMMED cell death 1 receptors , *MUTANT proteins - Abstract
Background And Objectives: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm with a wide spectrum of clinical presentations. Programmed Cell Death-1 (PD- 1) receptor and its ligand (PD-L1) are overexpressed in LCH, but their clinical significance is unknown. We performed a clinical correlation study of PD-1/PD-L1 and VE1(BRAFp.V600E) expression in 131 children with LCH. Methods: A total of 111 samples were tested for PD-1/PD-L1 and 109 for VE1(BRAFp.V600E) mutant protein by immunohistochemistry. Results: PD-1, PD-L1 and VE1(BRAFp.V600E) positivity was observed in 40.5%, 31.53% and 55%, respectively. PD-1/PD-L1 expression showed no significant effect on the rate of disease reactivations, early response to therapy or late sequelae. The 5-year EFS was not statistically different between patients with PD-1 positive compared to those with PD-1 negative tumours (47.7% vs.58.8%, p=0.17). Similar 5-year EFS rates were also seen in those who were PD-L1 positive compared to PD-L1 negative cases (50.5% vs.55.5%, p=0.61). VE1(BRAFp.V600E) positivity was associated with a significantly higher frequency of risk-organ involvement (p=0.0053), but no significant effect on early response to therapy or rates of reactivations or late sequelae. Conclusions: Our study showed no significant correlation between VE1(BRAFp.V600E) expression, PD-1 and PD-L1 and clinical outcome in pediatric LCH. [ABSTRACT FROM AUTHOR]
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- 2023
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20. The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers.
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Tatari, Nazanin, Khan, Shahbaz, Livingstone, Julie, Zhai, Kui, Mckenna, Dillon, Ignatchenko, Vladimir, Chokshi, Chirayu, Gwynne, William D., Singh, Manoj, Revill, Spencer, Mikolajewicz, Nicholas, Zhu, Chenghao, Chan, Jennifer, Hawkins, Cynthia, Lu, Jian-Qiang, Provias, John P., Ask, Kjetil, Morrissy, Sorana, Brown, Samuel, and Weiss, Tobias
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PROTEOMICS , *GLIOBLASTOMA multiforme , *SYMPTOMS , *DRUG target - Abstract
Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM–rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2–5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis. [ABSTRACT FROM AUTHOR]
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- 2022
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21. Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic targets in high grade glioma.
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Siddaway, Robert, Canty, Laura, Pajovic, Sanja, Milos, Scott, Coyaud, Etienne, Sbergio, Stefanie-Grace, Vadivel Anguraj, Arun Kumaran, Lubanszky, Evan, Yun, Hwa Young, Portante, Alessia, Carette, Sheyenne, Zhang, Cunjie, Moran, Michael F., Raught, Brian, Campos, Eric I., and Hawkins, Cynthia
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DRUG target , *GLIOMAS , *TRANSCRIPTION factors , *DNA repair , *CHROMATIN , *METHYLGUANINE , *CATECHOL-O-methyltransferase , *METHYLTRANSFERASES - Abstract
Histone H3 mutations at amino acids 27 (H3K27M) and 34 (H3G34R) are recurrent drivers of pediatric-type high-grade glioma (pHGG). H3K27M mutations lead to global disruption of H3K27me3 through dominant negative PRC2 inhibition, while H3G34R mutations lead to local losses of H3K36me3 through inhibition of SETD2. However, their broader oncogenic mechanisms remain unclear. We characterized the H3.1K27M, H3.3K27M and H3.3G34R interactomes, finding that H3K27M is associated with epigenetic and transcription factor changes; in contrast H3G34R removes a break on cryptic transcription, limits DNA methyltransferase access, and alters mitochondrial metabolism. All 3 mutants had altered interactions with DNA repair proteins and H3K9 methyltransferases. H3K9me3 was reduced in H3K27M-containing nucleosomes, and cis-H3K9 methylation was required for H3K27M to exert its effect on global H3K27me3. H3K9 methyltransferase inhibition was lethal to H3.1K27M, H3.3K27M and H3.3G34R pHGG cells, underscoring the importance of H3K9 methylation for oncohistone-mutant gliomas and suggesting it as an attractive therapeutic target. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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- View/download PDF
22. Surgical outcomes in children with drug-resistant epilepsy and hippocampal sclerosis.
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Alashjaie, Ream, Kerr, Elizabeth N., AlShoumer, Azhar, Hawkins, Cynthia, Yau, Ivanna, Weiss, Shelly, Ochi, Ayako, Otsubo, Hiroshi, Krishnan, Pradeep, Widjaja, Elysa, Ibrahim, George M., Donner, Elizabeth J., and Jain, Puneet
- Subjects
- *
TEMPORAL lobectomy , *HIPPOCAMPAL sclerosis , *CHILDREN with epilepsy , *CHILDHOOD epilepsy , *FOCAL cortical dysplasia , *TEMPORAL lobe - Abstract
Hippocampal sclerosis (HS) is a common surgical substrate in adult epilepsy surgery cohorts but variably reported in various pediatric cohorts. We aimed to study the epilepsy phenotype, radiological and pathological variability, seizure and neurocognitive outcomes in children with drug-resistant epilepsy and hippocampal sclerosis (HS) with or without additional subtle signal changes in anterior temporal lobe who underwent surgery. This retrospective study enrolled children with drug-resistant focal epilepsy and hippocampal sclerosis with or without additional subtle T2-Fluid Attenuated Inversion Recovery (FLAR)/Proton Density (PD) signal changes in anterior temporal lobe who underwent anterior temporal lobectomy with amygdalohippocampectomy. Their clinical, EEG, neuropsychological, radiological and pathological data were reviewed and summarized. Thirty-six eligible patients were identified. The mean age at seizure onset was 3.7 years; 25% had daily seizures at time of surgery. Isolated HS was noted in 22 (61.1%) cases and additional subtle signal changes in ipsilateral temporal lobe in 14 (38.9%) cases. Compared to the normative population, the group mean performance in intellectual functioning and most auditory and visual memory tasks were significantly lower than the normative sample. The mean age at surgery was 12.3 years; 22 patients (61.1%) had left hemispheric surgeries. ILAE class 1 outcomes was seen in 28 (77.8%) patients after a mean follow up duration of 2.3 years. Hippocampal sclerosis was noted pathologically in 32 (88.9%) cases; type 2 (54.5%) was predominant subtype where further classification was possible. Additional pathological abnormalities were seen in 11 cases (30.6%); these had had similar rates of seizure freedom as compared to children with isolated hippocampal sclerosis/gliosis (63.6% vs 84%, p=0.21). Significant reliable changes were observed across auditory and visual memory tasks at an individual level post surgery. Favourable seizure outcomes were seen in most children with isolated radiological hippocampal sclerosis. Patients with additional pathological abnormalities had similar rates of seizure freedom as compared to children with isolated hippocampal sclerosis/gliosis. • Subtle anterior temporal signal changes were noted in 38.9% children with hippocampal sclerosis (HS). • 77.8% children became seizure free after anterior temporal lobectomy with amygdalohippocampectomy. • Overall, 30.6% cases had additional pathological abnormalities. • Seizure freedom rates of children with additional pathological abnormalities similar to those with isolated HS. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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- View/download PDF
23. Understanding diffuse leptomeningeal glioneuronal tumors.
- Author
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Bajin, Inci Yaman, Levine, Adrian, Dewan, Michael C., Bennett, Julie, Tabori, Uri, Hawkins, Cynthia, and Bouffet, Eric
- Abstract
Intoduction: Diffuse leptomeningeal glioneuronal tumors (DLGNTs) pose a rare and challenging entity within pediatric central nervous system neoplasms. Despite their rarity, DLGNTs exhibit complex clinical presentations and unique molecular characteristics, necessitating a deeper understanding of their diagnostic and therapeutic nuances.This review synthesizes contemporary literature on DLGNT, encompassing epidemiology, clinical manifestations, pathological features, treatment strategies, prognostic markers, and future research directions. To compile the existing body of knowledge on DLGNT, a comprehensive search of relevant databases was conducted.DLGNT primarily affects pediatric populations but can manifest across all age groups. Its diagnosis is confounded by nonspecific clinical presentations and overlapping radiological features with other CNS neoplasms. Magnetic resonance imaging (MRI) serves as a cornerstone for DLGNT diagnosis, revealing characteristic leptomeningeal enhancement and intraparenchymal involvement. Histologically, DLGNT presents with low to moderate cellularity and exhibits molecular alterations in the MAPK/ERK signalling pathway. Optimal management of DLGNT necessitates a multidisciplinary approach encompassing surgical resection, chemotherapy, radiotherapy, and emerging targeted therapies directed against specific genetic alterations. Prognostication remains challenging, with factors such as age at diagnosis, histological subtypes, and genetic alterations influencing disease progression and treatment response. Long-term survival data are limited, underscoring the need for collaborative research efforts.Advancements in molecular profiling, targeted therapies, and international collaborations hold promise for improving DLGNT outcomes. Harnessing the collective expertise of clinicians, researchers, and patient advocates, can advance the field of DLGNT research and optimize patient care paradigms.Methods: Diffuse leptomeningeal glioneuronal tumors (DLGNTs) pose a rare and challenging entity within pediatric central nervous system neoplasms. Despite their rarity, DLGNTs exhibit complex clinical presentations and unique molecular characteristics, necessitating a deeper understanding of their diagnostic and therapeutic nuances.This review synthesizes contemporary literature on DLGNT, encompassing epidemiology, clinical manifestations, pathological features, treatment strategies, prognostic markers, and future research directions. To compile the existing body of knowledge on DLGNT, a comprehensive search of relevant databases was conducted.DLGNT primarily affects pediatric populations but can manifest across all age groups. Its diagnosis is confounded by nonspecific clinical presentations and overlapping radiological features with other CNS neoplasms. Magnetic resonance imaging (MRI) serves as a cornerstone for DLGNT diagnosis, revealing characteristic leptomeningeal enhancement and intraparenchymal involvement. Histologically, DLGNT presents with low to moderate cellularity and exhibits molecular alterations in the MAPK/ERK signalling pathway. Optimal management of DLGNT necessitates a multidisciplinary approach encompassing surgical resection, chemotherapy, radiotherapy, and emerging targeted therapies directed against specific genetic alterations. Prognostication remains challenging, with factors such as age at diagnosis, histological subtypes, and genetic alterations influencing disease progression and treatment response. Long-term survival data are limited, underscoring the need for collaborative research efforts.Advancements in molecular profiling, targeted therapies, and international collaborations hold promise for improving DLGNT outcomes. Harnessing the collective expertise of clinicians, researchers, and patient advocates, can advance the field of DLGNT research and optimize patient care paradigms.Results: Diffuse leptomeningeal glioneuronal tumors (DLGNTs) pose a rare and challenging entity within pediatric central nervous system neoplasms. Despite their rarity, DLGNTs exhibit complex clinical presentations and unique molecular characteristics, necessitating a deeper understanding of their diagnostic and therapeutic nuances.This review synthesizes contemporary literature on DLGNT, encompassing epidemiology, clinical manifestations, pathological features, treatment strategies, prognostic markers, and future research directions. To compile the existing body of knowledge on DLGNT, a comprehensive search of relevant databases was conducted.DLGNT primarily affects pediatric populations but can manifest across all age groups. Its diagnosis is confounded by nonspecific clinical presentations and overlapping radiological features with other CNS neoplasms. Magnetic resonance imaging (MRI) serves as a cornerstone for DLGNT diagnosis, revealing characteristic leptomeningeal enhancement and intraparenchymal involvement. Histologically, DLGNT presents with low to moderate cellularity and exhibits molecular alterations in the MAPK/ERK signalling pathway. Optimal management of DLGNT necessitates a multidisciplinary approach encompassing surgical resection, chemotherapy, radiotherapy, and emerging targeted therapies directed against specific genetic alterations. Prognostication remains challenging, with factors such as age at diagnosis, histological subtypes, and genetic alterations influencing disease progression and treatment response. Long-term survival data are limited, underscoring the need for collaborative research efforts.Advancements in molecular profiling, targeted therapies, and international collaborations hold promise for improving DLGNT outcomes. Harnessing the collective expertise of clinicians, researchers, and patient advocates, can advance the field of DLGNT research and optimize patient care paradigms.Conclusion: Diffuse leptomeningeal glioneuronal tumors (DLGNTs) pose a rare and challenging entity within pediatric central nervous system neoplasms. Despite their rarity, DLGNTs exhibit complex clinical presentations and unique molecular characteristics, necessitating a deeper understanding of their diagnostic and therapeutic nuances.This review synthesizes contemporary literature on DLGNT, encompassing epidemiology, clinical manifestations, pathological features, treatment strategies, prognostic markers, and future research directions. To compile the existing body of knowledge on DLGNT, a comprehensive search of relevant databases was conducted.DLGNT primarily affects pediatric populations but can manifest across all age groups. Its diagnosis is confounded by nonspecific clinical presentations and overlapping radiological features with other CNS neoplasms. Magnetic resonance imaging (MRI) serves as a cornerstone for DLGNT diagnosis, revealing characteristic leptomeningeal enhancement and intraparenchymal involvement. Histologically, DLGNT presents with low to moderate cellularity and exhibits molecular alterations in the MAPK/ERK signalling pathway. Optimal management of DLGNT necessitates a multidisciplinary approach encompassing surgical resection, chemotherapy, radiotherapy, and emerging targeted therapies directed against specific genetic alterations. Prognostication remains challenging, with factors such as age at diagnosis, histological subtypes, and genetic alterations influencing disease progression and treatment response. Long-term survival data are limited, underscoring the need for collaborative research efforts.Advancements in molecular profiling, targeted therapies, and international collaborations hold promise for improving DLGNT outcomes. Harnessing the collective expertise of clinicians, researchers, and patient advocates, can advance the field of DLGNT research and optimize patient care paradigms. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
24. Pediatric-type low-grade gliomas in adolescents and young adults—challenges and emerging paradigms.
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Bennett, Julie, Yeo, Kee Kiat, Tabori, Uri, Hawkins, Cynthia, and Lim-Fat, Mary Jane
- Abstract
Pediatric-type low-grade glioma (PLGG) encompasses a heterogeneous group of WHO grade 1 or 2 tumors and is the most common central nervous system tumor found in children. PLGG extends beyond pediatrics, into adolescents and young adults (AYA, ages 15–40). PLGG represents 25% of all gliomas diagnosed in AYA with differences in tumor location and molecular alterations compared to children, resulting in improved outcome for AYAs. Long-term outcome is excellent, though patients may suffer significant morbidity depending on tumor location. There are differences in treatment practices with radiation used to treat PLGG in AYAs more often than in children. Most PLGG in AYA harbor an alteration in the RAS/MAPK pathway, with limited insight into response to targeted therapy in this age group. This review discusses the epidemiology, current therapeutic approaches, and challenges in the management of PLGG in AYA. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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25. Combined MEK and JAK/STAT3 pathway inhibition effectively decreases SHH medulloblastoma tumor progression.
- Author
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Zagozewski, Jamie, Borlase, Stephanie, Guppy, Brent J., Coudière-Morrison, Ludivine, Shahriary, Ghazaleh M., Gordon, Victor, Liang, Lisa, Cheng, Stephen, Porter, Christopher J., Kelley, Rhonda, Hawkins, Cynthia, Chan, Jennifer A., Liang, Yan, Gong, Jingjing, Nör, Carolina, Saulnier, Olivier, Wechsler-Reya, Robert J., Ramaswamy, Vijay, and Werbowetski-Ogilvie, Tamra E.
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MEDULLOBLASTOMA , *CANCER invasiveness , *RNA sequencing , *BRAIN cancer , *CHILDHOOD cancer - Abstract
Medulloblastoma (MB) is the most common primary malignant pediatric brain cancer. We recently identified novel roles for the MEK/MAPK pathway in regulating human Sonic Hedgehog (SHH) MB tumorigenesis. The MEK inhibitor, selumetinib, decreased SHH MB growth while extending survival in mouse models. However, the treated mice ultimately succumbed to disease progression. Here, we perform RNA sequencing on selumetinib-treated orthotopic xenografts to identify molecular pathways that compensate for MEK inhibition specifically in vivo. Notably, the JAK/STAT3 pathway exhibits increased activation in selumetinib-treated tumors. The combination of selumetinib and the JAK/STAT3 pathway inhibitor, pacritinib, further reduces growth in two xenograft models and also enhances survival. Multiplex spatial profiling of proteins in drug-treated xenografts reveals shifted molecular dependencies and compensatory changes following combination drug treatment. Our study warrants further investigation into MEK and JAK/STAT3 inhibition as a novel combinatory therapeutic strategy for SHH MB. RNA sequencing of MEK inhibitor (selumetinib)-treated tumors reveals an upregulation of the JAK/STAT3 pathway, with combinatorial therapeutic strategies of JAK/STAT3 inhibitors and selumetinib investigated for the SHH subgroup of medulloblastoma. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
26. CAP-ACP Workload Model for Advanced Diagnostics in Precision Medicine.
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Park, Paul C, Kurek, Kyle C, DeCoteau, John, Howlett, Christopher J, Hawkins, Cynthia, Izevbaye, Iyare, Carter, Michael D, Redpath, Margaret, Lo, Bryan, Alex, Deepu, Yousef, George, Yip, Stephen, and Maung, Raymond
- Subjects
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EMPLOYEES' workload , *TUMORS , *ONCOLOGY - Abstract
Objectives: In precision medicine, where oncologic management is tailored to the individual's clinical and genetic profiles, advanced diagnostic testing provides prognostic information and guides management in a growing number of malignancies. There is a need to capture the work pathologists perform to meet this demand by providing medically relevant, timely, and accurate testing results. This work includes not only direct patient consults (interpretation of results and issuing reports) but the administrative and medical oversight as well as the research needed to provide the necessary quality assurance, quality control, direction, and framework for the laboratory.Methods: An expert panel of Canadian pathologists involved in advanced diagnostics was convened to establish and beta test a model for workload assessment in advanced diagnostics.Results: All aspects of the advanced diagnostics workload were detailed and applied to models based on members' experience, including medical oversight, administration, and the introduction of new testing and platforms. Models for biomarker testing were developed for simple and complex or multiplexed assays, and a detailed model was developed to assess the workload for next-generation sequencing-based assays.Conclusions: This paper provides the first detailed proposal for capturing an advanced diagnostic workload to enable appropriate pathologist allotment for performing all the steps required to run an advanced diagnostic service. [ABSTRACT FROM AUTHOR]- Published
- 2022
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- View/download PDF
27. Diffusely infiltrating astrocytomas: pathology, molecular mechanisms and markers.
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Ichimura, Koichi, Narita, Yoshitaka, and Hawkins, Cynthia
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ASTROCYTOMAS , *PATHOLOGY , *TUMORS , *MOLECULAR pathology , *ISOCITRATE dehydrogenase , *GLIOBLASTOMA multiforme - Abstract
Diffusely infiltrating astrocytomas include diffuse astrocytomas WHO grade II and anaplastic astrocytomas WHO grade III and are classified under astrocytic tumours according to the current WHO Classification. Although the patients generally have longer survival as compared to those with glioblastoma, the timing of inevitable malignant progression ultimately determines the prognosis. Recent advances in molecular genetics have uncovered that histopathologically diagnosed astrocytomas may consist of two genetically different groups of tumours. The majority of diffusely infiltrating astrocytomas regardless of WHO grade have concurrent mutations of IDH1 or IDH2, TP53 and ATRX. Among these astrocytomas, no other genetic markers that may distinguish grade II and grade III tumours have been identified. Those astrocytomas without IDH mutation tend to have a distinct genotype and a poor prognosis comparable to that of glioblastomas. On the other hand, diffuse astrocytomas that arise in children do not harbour IDH/ TP53 mutations, but instead display mutations of BRAF or structural alterations involving MYB/ MYBL1 or FGFR1. A molecular classification may thus help delineate diffusely infiltrating astrocytomas into distinct pathogenic and prognostic groups, which could aid in determining individualised therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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28. Immune Checkpoint Inhibition as Single Therapy for Synchronous Cancers Exhibiting Hypermutation: An IRRDC Study.
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Henderson, Jacob J., Das, Anirban, Morgenstern, Daniel A., Sudhaman, Sumedha, Bianchi, Vanessa, Chung, Jill, Negm, Logine, Edwards, Melissa, Kram, David E., Osborn, Michael, Hawkins, Cynthia, Bouffet, Eric, Cho, Yoon-Jae, and Tabori, Uri
- Subjects
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IMMUNE checkpoint inhibitors , *CANCER treatment - Abstract
Two targets with one arrow: #Immunotherapy as single treatment for synchronous RRD #glioblastoma and #metastatic cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
29. Immune Checkpoint Inhibition as Single Therapy for Synchronous Cancers Exhibiting Hypermutation: An IRRDC Study.
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Henderson, Jacob J., Das, Anirban, Morgenstern, Daniel A., Sudhaman, Sumedha, Bianchi, Vanessa, Chung, Jill, Negm, Logine, Edwards, Melissa, Kram, David E., Osborn, Michael, Hawkins, Cynthia, Bouffet, Eric, Cho, Yoon-Jae, and Tabori, Uri
- Subjects
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IMMUNE checkpoint inhibitors , *CANCER treatment - Abstract
Two targets with one arrow: #Immunotherapy as single treatment for synchronous RRD #glioblastoma and #metastatic cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
30. MetaFusion: a high-confidence metacaller for filtering and prioritizing RNA-seq gene fusion candidates.
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Apostolides, Michael, Jiang, Yue, Husić, Mia, Siddaway, Robert, Hawkins, Cynthia, Turinsky, Andrei L, Brudno, Michael, and Ramani, Arun K
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GENE fusion , *RNA sequencing - Abstract
Motivation Current fusion detection tools use diverse calling approaches and provide varying results, making selection of the appropriate tool challenging. Ensemble fusion calling techniques appear promising; however, current options have limited accessibility and function. Results MetaFusion is a flexible metacalling tool that amalgamates outputs from any number of fusion callers. Individual caller results are standardized by conversion into the new file type Common Fusion Format. Calls are annotated, merged using graph clustering, filtered and ranked to provide a final output of high-confidence candidates. MetaFusion consistently achieves higher precision and recall than individual callers on real and simulated datasets, and reaches up to 100% precision, indicating that ensemble calling is imperative for high-confidence results. MetaFusion uses FusionAnnotator to annotate calls with information from cancer fusion databases and is provided with a Benchmarking Toolkit to calibrate new callers. Availability and implementation MetaFusion is freely available at https://github.com/ccmbioinfo/MetaFusion. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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31. Upfront Adjuvant Immunotherapy of Replication Repair–Deficient Pediatric Glioblastoma With Chemoradiation-Sparing Approach.
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Larkin, Trisha, Das, Anirban, Bianchi, Vanessa, Sudhaman, Sumedha, Chung, Jiil, Alsafwani, Noor, Negm, Logine, Yachnis, Anthony, Blatt, Jason, Hawkins, Cynthia, Bouffet, Eric, Tabori, Uri, and Gururangan, Sridharan
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BRAIN tumors , *PHYSICIANS , *GLIOBLASTOMA multiforme , *IMMUNE checkpoint inhibitors , *MAGNETIC resonance imaging , *SINGLE nucleotide polymorphisms - Abstract
(A) Timeline of first surgery, tumor regrowth, second surgery, initiation of nivolumab, and follow-up. (B) Histopathology confirming glioblastoma and loss of staining of PMS2 and MLH1 in tumor cells only, and retained in normal cells, along with staining retained in tumor cells for MSH2 and MSH6. Pediatric glioblastoma (GBM) accounts for up to 15% of primary CNS neoplasms in children and is the leading cause of death among this group. As family history and clinical phenotypes may be insufficient to uncover RRD in GBM, molecular tumor analysis should be performed in all patients because of the potential therapeutic benefits. [Extracted from the article]
- Published
- 2021
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32. Giant choroid plexus cysts with calvarial erosion: a case report and literature review.
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Yang, Runze, Yan, Han, Dewan, Michael C., Tailor, Jignesh K., Santisukwongchote, Sakun, Hawkins, Cynthia, and Ibrahim, George M.
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CHOROID plexus , *LITERATURE reviews , *EROSION , *DIFFERENTIAL diagnosis , *CRANIOTOMY , *TOOTH erosion - Abstract
Choroid plexus cysts rarely grow to be symptomatic. Few large choroid plexus cysts have been reported in the pediatric population. The authors report a 15-month-old boy with increased head circumference and a bony deformity in the left parietal region due to mass effect from a giant choroid plexus cyst. The child had a craniotomy for open resection of the cyst, and made an excellent recovery. The differential diagnosis for intraventricular cysts and the literature surrounding choroid plexus cysts are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
33. Upfront Adjuvant Immunotherapy of Replication Repair–Deficient Pediatric Glioblastoma With Chemoradiation-Sparing Approach.
- Author
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Larkin, Trisha, Das, Anirban, Bianchi, Vanessa, Sudhaman, Sumedha, Chung, Jiil, Alsafwani, Noor, Negm, Logine, Yachnis, Anthony, Blatt, Jason, Hawkins, Cynthia, Bouffet, Eric, Tabori, Uri, and Gururangan, Sridharan
- Subjects
- *
BRAIN tumors , *PHYSICIANS , *GLIOBLASTOMA multiforme , *IMMUNE checkpoint inhibitors , *MAGNETIC resonance imaging , *SINGLE nucleotide polymorphisms - Abstract
(A) Timeline of first surgery, tumor regrowth, second surgery, initiation of nivolumab, and follow-up. (B) Histopathology confirming glioblastoma and loss of staining of PMS2 and MLH1 in tumor cells only, and retained in normal cells, along with staining retained in tumor cells for MSH2 and MSH6. As family history and clinical phenotypes may be insufficient to uncover RRD in GBM, molecular tumor analysis should be performed in all patients because of the potential therapeutic benefits. Pediatric glioblastoma (GBM) accounts for up to 15% of primary CNS neoplasms in children and is the leading cause of death among this group. [Extracted from the article]
- Published
- 2021
- Full Text
- View/download PDF
34. Cancer proteome and metabolite changes linked to SHMT2.
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Tong, Jiefei, Krieger, Jonathan R., Taylor, Paul, Bagshaw, Rick, Kang, Jae, Jeedigunta, Swathi, Wybenga-Groot, Leanne E., Zhang, Wen, Badr, Heba, Mirhadi, Shideh, Pham, Nhu-An, Coyaud, Étienne, Yu, Man, Li, Ming, Cabanero, Michael, Raught, Brian, Maynes, Jason T., Hawkins, Cynthia, Tsao, Ming Sound, and Moran, Michael F.
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MITOCHONDRIAL proteins , *GLUTAMATE dehydrogenase , *NUCLEOTIDE synthesis , *BENZOATES , *CELL proliferation , *GLYCINE - Abstract
Serine hydroxymethyltransferase 2 (SHMT2) converts serine plus tetrahydrofolate (THF) into glycine plus methylene-THF and is upregulated at the protein level in lung and other cancers. In order to better understand the role of SHMT2 in cancer a model system of HeLa cells engineered for inducible over-expression or knock-down of SHMT2 was characterized for cell proliferation and changes in metabolites and proteome as a function of SHMT2. Ectopic over-expression of SHMT2 increased cell proliferation in vitro and tumor growth in vivo. Knockdown of SHMT2 expression in vitro caused a state of glycine auxotrophy and accumulation of phosphoribosylaminoimidazolecarboxamide (AICAR), an intermediate of folate/1-carbon-pathway-dependent de novo purine nucleotide synthesis. Decreased glycine in the HeLa cell-based xenograft tumors with knocked down SHMT2 was potentiated by administration of the anti-hyperglycinemia agent benzoate. However, tumor growth was not affected by SHMT2 knockdown with or without benzoate treatment. Benzoate inhibited cell proliferation in vitro, but this was independent of SHMT2 modulation. The abundance of proteins of mitochondrial respiration complexes 1 and 3 was inversely correlated with SHMT2 levels. Proximity biotinylation in vivo (BioID) identified 48 mostly mitochondrial proteins associated with SHMT2 including the mitochondrial enzymes Acyl-CoA thioesterase (ACOT2) and glutamate dehydrogenase (GLUD1) along with more than 20 proteins from mitochondrial respiration complexes 1 and 3. These data provide insights into possible mechanisms through which elevated SHMT2 in cancers may be linked to changes in metabolism and mitochondrial function. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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- View/download PDF
35. cIMPACT‐NOW update 7: advancing the molecular classification of ependymal tumors.
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Ellison, David W., Aldape, Kenneth D., Capper, David, Fouladi, Maryam, Gilbert, Mark R., Gilbertson, Richard J., Hawkins, Cynthia, Merchant, Thomas E., Pajtler, Kristian, Venneti, Sriram, and Louis, David N.
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TUMOR classification , *INFRATENTORIAL brain tumors , *TUMOR suppressor genes , *EPENDYMOMA , *GENE fusion , *INTRACRANIAL tumors - Abstract
Advances in our understanding of the biological basis and molecular characteristics of ependymal tumors since the latest iteration of the World Health Organization (WHO) classification of CNS tumors (2016) have prompted the cIMPACT‐NOW group to recommend a new classification. Separation of ependymal tumors by anatomic site is an important principle of the new classification and was prompted by methylome profiling data to indicate that molecular groups of ependymal tumors in the posterior fossa and supratentorial and spinal compartments are distinct. Common recurrent genetic or epigenetic alterations found in tumors belonging to the main molecular groups have been used to define tumor types at intracranial sites; C11orf95 and YAP1 fusion genes for supratentorial tumors and two types of posterior fossa ependymoma defined by methylation group, PFA and PFB. A recently described type of aggressive spinal ependymoma with MYCN amplification has also been included. Myxopapillary ependymoma and subependymoma have been retained as histopathologically defined tumor types, but the classification has dropped the distinction between classic and anaplastic ependymoma. While the cIMPACT‐NOW group considered that data to inform assignment of grade to molecularly defined ependymomas are insufficiently mature, it recommends assigning WHO grade 2 to myxopapillary ependymoma and allows grade 2 or grade 3 to be assigned to ependymomas not defined by molecular status. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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- View/download PDF
36. cIMPACT‐NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT‐Utrecht meeting on future CNS tumor classification and grading.
- Author
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Louis, David N., Wesseling, Pieter, Aldape, Kenneth, Brat, Daniel J., Capper, David, Cree, Ian A., Eberhart, Charles, Figarella‐Branger, Dominique, Fouladi, Maryam, Fuller, Gregory N., Giannini, Caterina, Haberler, Christine, Hawkins, Cynthia, Komori, Takashi, Kros, Johan M., Ng, HK, Orr, Brent A., Park, Sung‐Hye, Paulus, Werner, and Perry, Arie
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TUMOR classification , *TUMOR grading , *MEETINGS , *WORKS councils - Abstract
cIMPACT‐NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT‐NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles—relating to classification categories, approaches to classification, nomenclature, and grading—that the group hopes will also inform the future classification of CNS neoplasms. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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- View/download PDF
37. BRAF V600E mutant oligodendroglioma‐like tumors with chromosomal instability in adolescents and young adults.
- Author
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Fukuoka, Kohei, Mamatjan, Yasin, Ryall, Scott, Komosa, Martin, Bennett, Julie, Zapotocky, Michal, Keith, Julia, Myrehaug, Sten, Hazrati, Lili‐Naz, Aldape, Kenneth, Laperriere, Norm, Bouffet, Eric, Tabori, Uri, and Hawkins, Cynthia
- Subjects
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TEENAGERS , *MULTIPLE tumors , *TUMORS , *TEMPORAL lobe , *GLIOMAS , *YOUNG adults , *MEIOSIS - Abstract
We performed genome‐wide methylation analysis on 136 pediatric low‐grade gliomas, identifying a unique cluster consisting of three tumors with oligodendroglioma‐like histology, BRAF p.V600E mutations and recurrent whole chromosome gains of 7 and loss of 10. Morphologically, all showed similar features, including a diffusely infiltrative glioma composed of round nuclei with perinuclear halos, a chicken‐wire pattern of branching capillaries and microcalcification. None showed astrocytic features or characteristics suggestive of high‐grade tumors including necrosis or mitotic figures. All tumors harbored multiple chromosomal copy number abnormalities (>10 chromosomes altered), but none showed 1p/19q co‐deletion or IDH1 p.R132H mutation. Hierarchical clustering and t‐stochastic neighbor embedding analyses from DNA methylation data cluster them more closely to previously described pediatric‐type low‐grade gliomas and separate from adult gliomas. These tumors exhibit distinct clinical features; they are temporal lobe lesions occurring in adolescents and young adults with a prolonged history of seizures and all are alive with no recurrence (follow‐up 3.2 to 13.2 years). We encountered another young adult case with quite similar pathological appearance and molecular status except for TERT promoter mutation. Although the series is small, these may represent a new category of IDH wild‐type low‐grade gliomas which may be confused with "molecular GBM." Further, they highlight the heterogeneity of IDH wild‐type gliomas and the relatively indolent behavior of "pediatric‐type" gliomas. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
38. Data Sets for the Reporting of Tumors of the Central Nervous System: Recommendations From The International Collaboration on Cancer Reporting.
- Author
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Louis, David N., Wesseling, Pieter, Brandner, Sebastian, Brat, Daniel J., Ellison, David W., Giangaspero, Felice, Hattab, Eyas M., Hawkins, Cynthia, Judge, Meagan J., Kleinschmidt-DeMasters, Bette, Komori, Takashi, McLean, Catriona, Paulus, Werner, Perry, Arie, Reifenberger, Guido, Weller, Michael, and Rous, Brian
- Subjects
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HISTOLOGICAL techniques , *INTERPROFESSIONAL relations , *MEDICAL care , *NOSOLOGY , *MOLECULAR pathology , *PATIENTS , *CONTENT mining ,BRAIN tumor diagnosis ,CENTRAL nervous system tumors - Abstract
Context.-- Standards for pathology reporting of cancer are foundational to national and international benchmarking, epidemiology, and clinical trials, with international standards for pathology reporting of cancer being undertaken through the International Collaboration on Cancer Reporting (ICCR). Objective.-- To develop standardized templates for brain tumor diagnostic pathology reporting. Design.-- As a response to the 2016 updated 4th edition of the WHO (World Health Organization) Classification of Tumours of the Central Nervous System (2016 CNS WHO), an expert ICCR committee developed data sets to facilitate reporting of brain tumors that are classified histologically and molecularly by the 2016 CNS WHO; as such, this represents the first combined histologic and molecular ICCR data set, and required a novel approach with 3 highly related data sets that should be used in an integrated manner. Results.-- The current article and accompanying ICCR Web site describe reporting data sets for central nervous system tumors in the hope that they provide easy-to-use and highly reproducible means to issue diagnostic reports in consort with the 2016 CNS WHO. Conclusions.-- The consistent use of these templates will undoubtedly prove useful for patient care, clinical trials, epidemiologic studies, and monitoring of neuro-oncologic care around the world. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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39. Correction: Maternal and childhood medical history and the risk of childhood brain tumours: a case–control study in Ontario, Canada.
- Author
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Cheng, Sierra, McLaughlin, John R., Brown, M. Catherine, Al-Sawaihey, Hamad, Rutka, James, Bouffet, Eric, Hawkins, Cynthia, Cairney, A. Elizabeth, Ranger, Adrianna, Fleming, Adam J., Johnston, Donna, Greenberg, Mark, Malkin, David, and Hung, Rayjean J.
- Published
- 2023
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40. cIMPACT‐NOW: a practical summary of diagnostic points from Round 1 updates.
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Louis, David N., Ellison, David W., Brat, Daniel J., Aldape, Kenneth, Capper, David, Hawkins, Cynthia, Paulus, Werner, Perry, Arie, Reifenberger, Guido, Figarella‐Branger, Dominique, Deimling, Andreas, and Wesseling, Pieter
- Subjects
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TUMOR classification , *ASTROCYTOMAS , *ADULT-child relationships , *GLIOMAS - Abstract
cIMPACT‐NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classifications. From 2016 to 2019 (Round 1), cIMPACT published four updates. Update 1 clarified the use of the term NOS (Not Otherwise Specified) and proposed use of the additional term NEC (Not Elsewhere Classified). Update 2 issued clarifications regarding two diagnoses: Diffuse Midline Glioma, H3 K27M‐mutant and Diffuse Astrocytoma/Anaplastic Astrocytoma, IDH‐mutant. Update 3 proposed molecular criteria that could be used in the setting of an IDH‐wildtype diffuse or anaplastic astrocytic glioma without histological features of glioblastoma to infer that the tumor would behave similarly to a grade IV glioblastoma. Update 4 suggested that, in children and young adults, subtypes of IDH‐wildtype/H3‐wildtype diffuse gliomas may have distinct clinical features in the setting of a BRAFV600E mutation, FGFR1 alteration, other MAPK pathway alteration, or a MYB or MYBL1 rearrangement. The practical diagnostic relevance of these cIMPACT proposals is highlighted in this summary. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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41. Survival and functional outcomes of molecularly defined childhood posterior fossa ependymoma: Cure at a cost.
- Author
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Zapotocky, Michal, Beera, Kiran, Adamski, Jenny, Laperierre, Normand, Guger, Sharon, Janzen, Laura, Lassaletta, Alvaro, Figueiredo Nobre, Liana, Bartels, Ute, Tabori, Uri, Hawkins, Cynthia, Urbach, Stacey, Tsang, Derek S., Dirks, Peter B., Taylor, Michael D., Bouffet, Eric, Mabbott, Donald J., and Ramaswamy, Vijay
- Subjects
- *
RADIOTHERAPY , *EPENDYMOMA , *INTELLIGENCE levels , *PROGRESSION-free survival , *CHILDREN - Abstract
Background: Posterior fossa ependymoma (PFE) comprises 2 groups, PF group A (PFA) and PF group B (PFB), with stark differences in outcome. However, to the authors' knowledge, the long‐term outcomes of PFA ependymoma have not been described fully. The objective of the current study was to identify predictors of survival and neurocognitive outcome in a large consecutive cohort of subgrouped patients with PFE over 30 years. Methods: Demographic, survival, and neurocognitive data were collected from consecutive patients diagnosed with PFE from 1985 through 2014 at the Hospital for Sick Children in Toronto, Ontario, Canada. Subgroup was assigned using genome‐wide methylation array and/or immunoreactivity to histone H3 K27 trimethylation (H3K27me3). Results: A total of 72 PFE cases were identified, 89% of which were PFA. There were no disease recurrences noted among patients with PFB. The 10‐year progression‐free survival rate for all patients with PFA was poor at 37.1% (95% confidence interval, 25.9%‐53.1%). Analysis of consecutive 10‐year epochs revealed significant improvements in progression‐free survival and/or overall survival over time. This pertains to the increase in the rate of gross (macroscopic) total resection from 35% to 77% and the use of upfront radiotherapy increasing from 65% to 96% over the observed period and confirmed in a multivariable model. Using a mixed linear model, analysis of longitudinal neuropsychological outcomes restricted to patients with PFA who were treated with focal irradiation demonstrated significant continuous declines in the full‐scale intelligence quotient over time with upfront conformal radiotherapy, even when correcting for hydrocephalus, number of surgeries, and age at diagnosis (‐1.33 ± 0.42 points/year; P = .0042). Conclusions: Data from a molecularly informed large cohort of patients with PFE clearly indicate improved survival over time, related to more aggressive surgery and upfront radiotherapy. However, to the best of the authors' knowledge, the current study is the first, in a subgrouped cohort, to demonstrate that this approach results in reduced neurocognitive outcomes over time. In a subgroup‐specific manner, the results of the current study demonstrate that survival among patients with posterior fossa ependymoma has improved over time, and this improvement clearly is related to a change in practice with regard to pursuing aggressive surgical resections with upfront postoperative radiotherapy in all patients. This significant improvement highlights an urgent need for the implementation of early intervention and neuroprotective strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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42. IL-13 receptors as possible therapeutic targets in diffuse intrinsic pontine glioma.
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Berlow, Noah E., Svalina, Matthew N., Quist, Michael J., Settelmeyer, Teagan P., Zherebitskiy, Viktor, Kogiso, Mari, Qi, Lin, Du, Yuchen, Hawkins, Cynthia E., Hulleman, Esther, Li, Xiao-Nan, Gultekin, Sakir H., and Keller, Charles
- Subjects
- *
INTERLEUKIN-13 , *GLIOMA treatment , *TREATMENT of brain cancer , *CANCER immunotherapy , *CHILDHOOD cancer - Abstract
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal childhood cancer of the brain. Despite the introduction of conventional chemotherapy and radiotherapy, improvements in survival have been marginal and long-term survivorship is uncommon. Thus, new targets for therapeutics are critically needed. Early phase clinical trials exploring molecularly-targeted therapies against the epidermal growth factor receptor (EGFR) and novel immunotherapies targeting interleukin receptor-13α2 (IL-13Rα2) have demonstrated activity in this disease. To identify additional therapeutic markers for cell surface receptors, we performed exome sequencing (16 new samples, 22 previously published samples, total 38 with 26 matched normal DNA samples), RNA deep sequencing (17 new samples, 11 previously published samples, total 28 with 18 matched normal RNA samples), and immunohistochemistry (17 DIPG tissue samples) to examine the expression of the interleukin-4 (IL-4) signaling axis components (IL-4, interleukin 13 (IL-13), and their respective receptors IL-4Rα, IL-13Rα1, and IL-13Rα2). In addition, we correlated cytokine and receptor expression with expression of the oncogenes EGFR and c-MET. In DIPG tissues, transcript-level analysis found significant expression of IL-4, IL-13, and IL-13Rα1/2, with strong differential expression of IL-13Rα1/2 in tumor versus normal brain. At the protein level, immunohistochemical studies revealed high content of IL-4 and IL-13Rα1/2 but notably low expression of IL-13. Additionally, a strong positive correlation was observed between c-Met and IL-4Rα. The genomic and transcriptional landscape across all samples was also summarized. These data create a foundation for the design of potential new immunotherapies targeting IL-13 cell surface receptors in DIPG. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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43. H3 K27M mutations are extremely rare in posterior fossa group A ependymoma.
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Ryall, Scott, Guzman, Miguel, Elbabaa, Samer, Luu, Betty, Mack, Stephen, Zapotocky, Michal, Taylor, Michael, Hawkins, Cynthia, and Ramaswamy, Vijay
- Subjects
- *
INFRATENTORIAL brain tumors , *EPENDYMOMA , *GLIOMAS , *GENETIC mutation , *HISTONES - Abstract
Background: Mutations in the tail of histone H3 (K27M) are frequently found in pediatric midline high-grade glioma's but have rarely been reported in other malignancies. Recently, recurrent somatic nucleotide variants in histone H3 (H3 K27M) have been reported in group A posterior fossa ependymoma (EPN_PFA), an entity previously described to have no recurrent mutations. However, the true incidence of H3 K27M mutations in EPN_PFA is unknown. Methods: In order to discern the frequency of K27M mutations in histone H3 in EPN_PFA, we analyzed 151 EPN_PFA previously profiled with genome-wide methylation arrays using a validated droplet digital PCR assay. Results: We identified only 1 case out of 151 EPN_PFA harboring the K27M mutation indicating that histone mutations are extremely rare in EPN_PFA. Morphologically, this single mutated case is clearly consistent with an ependymoma, and the presence of the K27M mutation was confirmed using immunohistochemistry. Discussion: K27M mutations are extremely rare in EPN_PFA. Routine evaluation of K27M mutations in EPN_PFA is of limited utility, and is unlikely to have any bearing on prognosis and/or future risk stratification. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
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44. Cribriform neuroepithelial tumor: molecular characterization of a SMARCB1-deficient non-rhabdoid tumor with favorable long-term outcome.
- Author
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Johann, Pascal D., Hovestadt, Volker, Thomas, Christian, Jeibmann, Astrid, Heß, Katharina, Bens, Susanne, Oyen, Florian, Hawkins, Cynthia, Pierson, Christopher R., Aldape, Kenneth, Kim, Sang‐Pyo, Widing, Eva, Sumerauer, David, Hauser, Péter, van Landeghem, Frank, Ryzhova, Marina, Korshunov, Andrey, Capper, David, Jones, David T.W., and Pfister, Stefan M.
- Subjects
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BRAIN tumor treatment , *METHYLATION , *DNA mutational analysis , *DIAGNOSTIC use of fluorescence in situ hybridization , *PHENOTYPES - Abstract
Rhabdoid phenotype and loss of SMARCB1 expression in a brain tumor are characteristic features of atypical teratoid/rhabdoid tumors (ATRT). Rare non-rhabdoid brain tumors showing cribriform growth pattern and SMARCB1 loss have been designated cribriform neuroepithelial tumor (CRINET). Small case series suggest that CRINETs may have a relatively favorable prognosis. However, the long-term outcome is unclear and it remains uncertain whether CRINET represents a distinct entity or a variant of ATRT. Therefore, 10 CRINETs were clinically and molecularly characterized and compared with 10 ATRTs of each of three recently described molecular subgroups (i.e. ATRT-TYR, ATRT-SHH and ATRT-MYC) using Illumina Infinium HumanMethylation450 arrays, FISH, MLPA, and sequencing. Furthermore, outcome was compared to a larger cohort of 27 children with ATRT-TYR. Median age of the 6 boys and 4 girls harboring a CRINET was 20 months. On histopathological examination, all CRINETs demonstrated a cribriform growth pattern and distinct tyrosinase staining. On unsupervised cluster analysis of methylation data, all CRINETs examined exclusively clustered within the ATRT-TYR molecular subgroup. As ATRT-TYR, CRINETs mainly showed large heterozygous 22q deletions (9/10) and SMARCB1 mutations of the other allele. In two patients, SMARCB1 mutations were also present in the germline. Estimated mean overall survival in patients with CRINETs was 125 months (95% confidence interval 100-151 months) as compared to only 53 (33-74) months in patients with ATRTs of the ATRT-TYR subgroup (Log-Rank P < 0.05). In conclusion, CRINET represents a SMARCB1-deficient non-rhabdoid tumor, which shares molecular similarities with the ATRT-TYR subgroup but has distinct histopathological features and favorable long-term outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
45. An integrative molecular and genomic analysis of pediatric hemispheric low-grade gliomas: an update.
- Author
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Lassaletta, Alvaro, Zapotocky, Michal, Bouffet, Eric, Hawkins, Cynthia, and Tabori, Uri
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- *
GLIOMAS , *TUMORS in children , *GENOMICS , *MOLECULAR biology ,EPITHELIAL cell tumors - Abstract
Hemispheric low-grade gliomas account for the second most common location in pediatric low-grade gliomas (PLGGs) after the cerebellum. The pathological spectrum includes gangliogliomas, dysembryoplastic neuroepithelial tumors (DNETs), diffuse astrocytomas, pilocytic astrocytomas, and pleomorphic xanthoastrocytomas (PXAs), among others. Clinically, hemispheric PLGGs represent a well-recognized cause of intractable epilepsy in children and adolescents. With an excellent long-term outcome, surgery remains the cornerstone and patients with gross total resection typically do not need any further therapies. The recent literature about hemispheric PLGGs was reviewed to provide an up-to-date overview of the molecular and cell biology of these tumors. Hemispheric PLGGs can harbor multiple alterations involving BRAFV600E, FGFR, NTRK, MYB/MYBL1, IDH, and BRAF-KIAA1549 fusions. However, the clinical significance of most of these alterations is still to be defined. The role of RAS/MAPK mutations and other alterations in hemispheric PLGGs is of interest from diagnostic, prognostic, and therapeutic perspectives. Molecular testing for these tumors should be encouraged, since the findings can have an important impact not only in prognosis but also in therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
46. Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma.
- Author
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Ryall, Scott, Krishnatry, Rahul, Arnoldo, Anthony, Buczkowicz, Pawel, Mistry, Matthew, Siddaway, Robert, Ling, Cino, Pajovic, Sanja, Man Yu, Rubin, Joshua B., Hukin, Juliette, Steinbok, Paul, Bartels, Ute, Bouffet, Eric, Tabori, Uri, and Hawkins, Cynthia
- Subjects
- *
THALAMUS , *GLIOMAS - Abstract
Paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due to their sensitive midline location. As such, genetic analysis for biomarkers to aid in the diagnosis, prognosis and treatment of these tumours is needed. Here, we identified 64 thalamic gliomas with clinical follow-up and characterized targeted genomic alterations using newly optimized droplet digital and NanoString-based assays. The median age at diagnosis was 9.25 years (range, 0.63-17.55) and median survival was 6.43 (range, 0.01-27.63) years. Our cohort contained 42 and 22 tumours reviewed as low and high grade gliomas, respectively. Five (12 %) low grade and 11 (50 %) high grade gliomas were positive for the H3F3A/HIST1H3B K27M (H3K27M) mutation. Kaplan-Meier survival analysis revealed significantly worse overall survival for patients harbouring the H3K27M mutation versus H3F3A/ HIST1H3B wild type (H3WT) samples (log-rank p < 0.0001) with a median survival of 1.02 vs. 9.12 years. Mitogen-activated protein kinase (MAPK) pathway activation via BRAF or FGFR1 hotspot mutations or fusion events were detected in 44 % of patients, and was associated with long-term survival in the absence of H3K27M (log-rank p < 0.0001). Multivariate analysis demonstrated H3K27M status and high grade histology to be the most significant independent predictors of poor overall survival with hazard ratios of 6.945 and 7.721 (p < 0.0001), respectively. In contrast, MAPK pathway activation is a predictor of favourable patient outcome, although not independent of other clinical factors. Importantly, we show that low grade malignancies may harbour H3K27M mutations and that these tumours show a dismal survival compared to low grade H3WT cases. Our data strongly supports the inclusion of targeted genetic testing in childhood thalamic tumours to most accurately stratify patients into appropriate risk groups. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
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47. Atypical Teratoid Rhabdoid Tumor Diagnosis after Partial Resection of Dysembryoplastic Neuroepithelial Tumor: Case Report and Review of the Literature.
- Author
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Nadi, Mustafa, ahmad, Tahani, Huang, annie, Hawkins, Cynthia, Bouffet, Eric, and Kulkarni, abhaya V.
- Subjects
- *
TUMOR growth - Abstract
Dysembryoplastic neuroepithelial tumors (DNETs) are generally considered benign, slow-growing epilepsy-associated lesions. While rare cases of malignant transformation of DNET to high-grade glial tumors have been reported, to our knowledge there have been no reports of transformation/emergence of DNET to atypical teratoid rhabdoid tumor (AT/RT), a highly aggressive embryonal brain tumor. Here, we report the case of an 8-year-old boy who presented with an incidental finding of a small right insular lesion which grew slowly over 3 years. The patient first underwent surgery with subtotal tumor resection at age 11. Pathology was consistent with DNET. Following surgery, further tumor growth was evident, requiring fractionated radiotherapy and eventually chemotherapy, but continued tumor growth was witnessed. Three years after radiation, imaging showed dramatic further tumor growth, and the patient underwent a second debulking surgery. The pathology revealed a malignant tumor with BAF47-negative cells, suggestive of AT/RT. This report adds to our knowledge about the poorly understood behavior and natural history of DNETs and emphasizes the importance of lifelong clinical and neuroimaging follow-up of these lesions. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
48. Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: A population-based study.
- Author
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Krishnatry, Rahul, Zhukova, Nataliya, Guerreiro Stucklin, Ana S., Pole, Jason D., Mistry, Matthew, Fried, Iris, Ramaswamy, Vijay, Bartels, Ute, Huang, Annie, Laperriere, Normand, Dirks, Peter, Nathan, Paul C., Greenberg, Mark, Malkin, David, Hawkins, Cynthia, Bandopadhayay, Pratiti, Kieran, Mark W., Manley, Peter E., Bouffet, Eric, and Tabori, Uri
- Subjects
- *
GLIOMAS , *NERVOUS system tumors , *ASTROCYTOMAS , *GLIOBLASTOMA multiforme , *MEDULLOBLASTOMA , *BRAIN tumor treatment , *GLIOMA treatment , *AGE distribution , *BRAIN tumors , *CANCER relapse , *CANCER invasiveness , *CONFIDENCE intervals , *DATABASES , *LONGITUDINAL method , *MULTIVARIATE analysis , *PROGNOSIS , *REGRESSION analysis , *SEX distribution , *SURVIVAL analysis (Biometry) , *TIME , *TUMOR classification , *ACQUISITION of data , *PROPORTIONAL hazards models , *RETROSPECTIVE studies , *KAPLAN-Meier estimator - Abstract
Background: The determinants of outcomes for adult survivors of pediatric low-grade glioma (PLGG) are largely unknown.Methods: This study collected population-based follow-up information for all PLGG patients diagnosed in Ontario, Canada from 1985 to 2012 (n = 1202) and determined factors affecting survival. The impact of upfront radiation treatment on overall survival (OS) was determined for a cohort of Ontario patients and an independent reference cohort from the Surveillance, Epidemiology, and End Results database.Results: At a median follow-up of 12.73 years (range, 0.02-33 years), only 93 deaths (7.7%) were recorded, and the 20-year OS rate was 90.1% ± 1.1%. Children with neurofibromatosis type 1 had excellent survival and no tumor-related deaths during adulthood. Adverse risk factors included pleomorphic xanthoastrocytoma (P < .001) and a thalamic location (P < .001). For patients with unresectable tumors surviving more than 5 years after the diagnosis, upfront radiotherapy was associated with an approximately 3-fold increased risk of overall late deaths (hazard ratio [HR], 3.3; 95% confidence interval [CI], 1.6-6.6; P = .001) and an approximately 4-fold increased risk of tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = .013). In a multivariate analysis, radiotherapy was the most significant factor associated with late all-cause deaths (HR, 3.0; 95% CI, 1.3-7.0; P = .012) and tumor-related deaths (HR, 4.4; 95% CI, 1.3-14.6; P = 0.014). A similar association between radiotherapy and late deaths was observed in the independent reference cohort (P < .001). In contrast to early deaths, late mortality was associated not with PLGG progression but rather with tumor transformation and non-oncological causes.Conclusions: The course of PLGG is associated with excellent long-term survival, but this is hampered by increased delayed mortality in patients receiving upfront radiotherapy. These observations should be considered when treatment options are being weighed for these patients. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
49. Rasmussen's encephalitis: advances in management and patient outcomes.
- Author
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Hoffman, Caitlin, Ochi, Ayako, Snead, Orlando, Widjaja, Elysa, Hawkins, Cynthia, Tisdal, Martin, and Rutka, James
- Subjects
- *
CHRONIC encephalitis , *HEMISPHERECTOMY , *MAGNETOENCEPHALOGRAPHY , *COGNITIVE ability , *IMMUNOTHERAPY , *HEALTH outcome assessment , *THERAPEUTICS - Abstract
Purpose: Rasmussen's encephalitis (RE) is a hemispheric inflammatory disorder resulting in progressive epilepsy, hemiparesis, and cognitive decline. Controversy surrounds the most effective timing of surgery with respect to language dominance, functional status, and seizure outcome. We describe our experience with RE to inform treatment decisions. Methods: A retrospective chart review was performed in children diagnosed with RE from 1983 to 2012. Results: Thirteen consecutive cases were identified: six males and seven females with a mean age of 10.6 years (range 5-18). Nine patients received immunotherapy, with transient benefit in three, treatment-associated complications in two, and no difference in their mean time to treatment (5.38 vs 6.37 years p = 0.74) or long-term outcome. Mean follow-up was 5.6 years (range 0.58-12.25). There was no difference in outcome based on pre-operative duration of seizures. At last follow-up, 63 % of surgically treated patients achieved seizure freedom, 100 % had improved seizure control, 90 % had improved cognitive function, 36 % stopped medication, and 63 % tapered medication. Language improved in 83 % of patients with dominant disease. These findings were not associated with age at treatment. All surgical patients were ambulatory at last follow-up. Conclusions: Hemispherotomy achieves good seizure control with cognitive improvement and ambulatory status post-operatively. Time to surgery and dominant disease were not associated with outcome, suggesting that hemispherotomy can be offered early or late, with expectations of good seizure control and functional outcome, even with dominant disease. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
50. Synchronous glioblastoma and medulloblastoma in a child with mismatch repair mutation.
- Author
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Amayiri, Nisreen, Al-Hussaini, Maysa, Swaidan, Maisa, Jaradat, Imad, Qandeel, Monther, Tabori, Uri, Hawkins, Cynthia, Musharbash, Awni, Alsaad, Khulood, and Bouffet, Eric
- Subjects
- *
DNA repair , *TRETINOIN - Abstract
Synchronous primary malignant brain tumors are rare. We present a 5-year-old boy with synchronous glioblastoma and medulloblastoma. Both tumor samples had positive p53 stain and loss of PMS2 and MLH1 stains. The child had multiple café au lait spots and a significant family history of cancer. After subtotal resection of both tumors, he received craniospinal radiation with concomitant temozolomide followed by chemotherapy, alternating cycles of cisplatin/lomustine/vincristine with temozolomide. Then, he started maintenance treatment with cis-retinoic acid (100 mg/m/day for 21 days). He remained asymptomatic for 34 months despite a follow-up brain MRI consistent with glioblastoma relapse 9 months before his death. Cis-retinoic acid may have contributed to prolong survival in this child with a probable biallelic mismatch repair syndrome. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
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