121 results on '"Hawkins, Cynthia"'
Search Results
2. 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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3. 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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4. 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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5. 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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6. 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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7. Association between radiographic Wallerian degeneration and neuropathological changes post childhood stroke.
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JONES, KEVIN C, HAWKINS, CYNTHIA, ARMSTRONG, DEREK, DEVEBER, GABRIELLE, MACGREGOR, DAUNE, MOHARIR, MAHENDRANATH, and ASKALAN, RAND
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NEURODEGENERATION , *PYRAMIDAL tract , *DIAGNOSTIC imaging , *MAGNETIC resonance imaging , *HISTOPATHOLOGY , *AUTOPSY , *HEMORRHAGIC diseases - Abstract
Aim Wallerian degeneration is a radiological finding thought to reflect corticospinal tract degeneration. This finding on magnetic resonance imaging (MRI) is routinely used as a predictor of poor prognosis in childhood stroke. However, its validity has never been established. Our objective was to correlate Wallerian degeneration seen on MRI with histopathology. Method We searched the databases of the Department of Pathology and Children's Stroke registry at the Hospital for Sick Children, Toronto for autopsy specimens exhibiting focal infarcts from children born at term who underwent MRI after a stroke. The specimens were examined for Wallerian degeneration and then correlated with the pre-mortem MRI findings. Results Seven children (four females, three males) with a median age of 11 years (1-17y) at the time of stroke met the inclusion criteria for this study. Of the seven children included in the study with ischaemic or haemorrhagic infarcts, six had concordant Wallerian degeneration findings on both MRI and post-mortem histopathological examination. The median time between stroke and death was 20 days (3-1825d). Interpretation Our results show for the first time that the radiographic finding of Wallerian degeneration is a valid biomarker of corticospinal tract degeneration in children who have had ischaemic or haemorrhagic stroke. [ABSTRACT FROM AUTHOR]
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- 2013
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8. Survival Benefit for Pediatric Patients With Recurrent Ependymoma Treated With Reirradiation
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Bouffet, Eric, Hawkins, Cynthia E., Ballourah, Walid, Taylor, Michael D., Bartels, Ute K., Schoenhoff, Nicholas, Tsangaris, Elena, Huang, Annie, Kulkarni, Abhaya, Mabbot, Donald J., Laperriere, Normand, and Tabori, Uri
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PEDIATRIC therapy , *CANCER relapse , *EPENDYMA , *CANCER radiotherapy , *HEALTH outcome assessment , *TREATMENT effectiveness , *DEMOGRAPHIC surveys , *COHORT analysis , *TUMORS - Abstract
Purpose: The outcome of recurrent ependymoma in children is dismal. Reirradiation has been proposed as an effective modality for ependymoma at relapse. However, the toxicity and outcome benefits of this approach have not been well established. Methods and Materials: We conducted a retrospective population-based study of all patients with recurrent ependymoma treated between 1986 and 2010 in our institution. Demographic, treatment, and outcome data were analyzed for the entire cohort. Results: Of 113 patients with intracranial ependymoma, 47 patients relapsed. At the time of relapse, 29 patients were treated with surgical resection and/or chemotherapy, and 18 patients received full-dose (≥54 Gy focal and/or craniospinal) reirradiation with or without surgery at recurrence. Reirradiation was tolerated well with no severe acute complications noticed. Three-year overall survival was 7% ± 6% and 81% ± 12% for nonreirradiated and reirradiated patients, respectively (p < 0.0001). Time to second progression after reirradiation was significantly longer than time to first progression. This surprising phenomenon was associated with improved progression-free survival for tumors with evidence of DNA damage (n = 15; p = 0.002). At a mean follow-up of 3.73 years, only 2/18 patients had endocrine dysfunction, and 1 patient required special education support. However, a decline in intellectual function from pre- to postreirradiation assessment was observed. Conclusions: Reirradiation is an effective treatment that may change the natural history of recurrent ependymoma in children. However, this change may be associated with increased neurocognitive toxicity. Additional follow-up is needed to determine the risk of late recurrence, secondary radiation-induced tumors, and long-term functional outcome of these patients. [ABSTRACT FROM AUTHOR]
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- 2012
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9. Diagnosis of limb-girdle muscular dystrophy 2A by immunohistochemical techniques.
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Kolski, Hanna K., Hawkins, Cynthia, Zatz, Mayana, De Paula, Flavia, Biggar, Doug, Alman, Ben, and Vajsar, Jiri
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IMMUNOHISTOCHEMISTRY techniques , *NEUROMUSCULAR diseases , *IMMUNOCHEMISTRY , *MUSCULAR dystrophy , *DIAGNOSIS - Abstract
The Western blot technique is currently the standard detection method for suspected limb girdle muscular dystrophy (LGMD) 2A (calpainopathy). This is the first report in the English literature of the successful application of immunohistochemical techniques to support a diagnosis of LGMD 2A. This approach is straightforward and appears to be reasonably specific. We propose that immunohistochemical methods should be re-evaluated for the screening of undiagnosed patients with suspected LGMD 2A. [ABSTRACT FROM AUTHOR]
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- 2008
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10. Diagnostic Yield of Brain Biopsies in Children Presenting to Neurology.
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Venkateswaran, Sunita, Hawkins, Cynthia, and Wassmer, Evangeline
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DIAGNOSIS of brain diseases , *BIOPSY , *VASCULITIS , *ELECTROENCEPHALOGRAPHY , *CLINICAL pathology , *PEDIATRIC neurology , *MOLECULAR genetics , *NEUROLOGY , *CHILDREN - Abstract
The role of brain biopsy is well established in patients with neoplastic lesions, with a diagnostic yield approaching 95%. The diagnostic yield of brain biopsy in adults with neurological decline varies from 20% to 43%. Only a few studies have examined the diagnostic yield of brain biopsy in children with idiopathic neurological decline. A retrospective analysis was conducted on all open and closed pediatric brain biopsies performed between January 1988 and May 2003. Biopsies were performed for diagnostic purposes in patients showing a progressively deteriorating neurologic course in whom less-invasive modalities such as neuroimaging, electroencephalography (EEG), and molecular genetic studies were either negative or inconclusive. Immunocompromised patients were included. Patients were excluded if the preoperative diagnosis was a neoplasm or if the patient was undergoing a resection as part of a work-up for intractable epilepsy. Each patient underwent numerous investigations before brain biopsy. The utility of each biopsy was analyzed. Sixty-six children had brain biopsies performed for diagnostic purposes during the study period. Patient ages ranged from 2 months to 16 years and 9 months at the time of biopsy. The diagnostic yield was 48.5% overall, with a yield of 68.8% between 1996 and 2003. Of the total, 26 (39.4%) biopsies were both diagnostic and useful. Patients most frequently presented with seizures (56. 1%) and encephalopathy (33%). The most frequently diagnosed disease was vasculitis (18,2%). A total of 71.9% of patients with diagnostic biopsies improved with appropriate treatment. Brain biopsy in children had a diagnostic yield of 48.5% in our series. A specific diagnosis may help in management and outcome, especially with a diagnosis of vasculitis. [ABSTRACT FROM AUTHOR]
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- 2008
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11. Expression patterns of the organic cation/carnitine transporter family in adult murine brain
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Lamhonwah, Anne Marie, Hawkins, Cynthia E., Tam, Carolyn, Wong, Jeannie, Mai, Lydia, and Tein, Ingrid
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CENTRAL nervous system , *NERVOUS system , *CELL nuclei , *ORGANELLES - Abstract
Abstract: Organic cation/carnitine transporters transport carnitine, drugs, and xenobiotics (e.g. choline, acetylcarnitine, betaine, valproic acid), and are expressed in muscle, heart, blood vessels, kidney, gut, etc. Objective. To characterize expression patterns of mOctn1, -2 and -3 in murine brain. Methods. We applied our transporter-specific antibodies to mOctn1, -2 and -3, followed by 20 antibody and DAB peroxidase detection to serial adult murine brain sections counterstained with hematoxylin. Results. All three transporters showed strong expression in the external plexiform layer of the olfactory bulb and in olfactory nerve, the molecular layer and neuronal processes of input fibres extending vertically in motor cortex, in the dendritic arborization of the cornu ammonis and dendate gyrus (hippocampus), neuronal processes in the arcuate nucleus (hypothalamus), choroid plexus cells, and neuronal cell bodies and dendrites of cranial nerve nuclei V and VII. In the cerebellum, all three transporters were strongly expressed in dendritic processes of Purkinje cells, but Octn1 and -2 were expressed more strongly than Octn3 in Purkinje cell bodies. In spinal cord, Octn1, -2 and -3 were prominent in axons and dendritic end-arborizations of spinal cord neurons in both ascending and descending white matter tracts, whereas Octn3 was also strongly expressed in grey matter, specifically in anterior horn cell bodies. Octn3 was weakly expressed in glomerular layer neuronal cell bodies of olfactory bulb. Conclusions. hOCTN2 deficiency presents with carnitine-responsive cardiomyopathy, myopathy and hypoglycemic, hypoketotic coma with strokes, seizures and delays. In mouse, Octn1, -2 and -3 are expressed in many regions throughout the central nervous system with a pattern suggestive of roles in modulating cerebral bioenergetics and in acetylcholine generation for neurotransmission in olfactory, satiety, limbic, memory, motor and sensory functions. This distribution may play a role in the pattern of neurological injury that occurs in hOCTN2 deficiency during catabolic episodes of hypoglycemic, hypoketotic encephalopathy and which may manifest with cognitive impairment, hypotonia and seizures. [Copyright &y& Elsevier]
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- 2008
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12. Loss of nicastrin elicits an apoptotic phenotype in mouse embryos
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Nguyen, Van, Hawkins, Cynthia, Bergeron, Catherine, Supala, Agnes, Huang, Jean, Westaway, David, St George-Hyslop, Peter, and Rozmahel, Richard
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HUMAN abnormalities , *GENETICS , *PHENOTYPES , *MOLECULAR weights , *HEREDITY , *BIOCHEMISTRY - Abstract
Abstract: Nicastrin is a member of the high molecular weight presenilin complex that plays a central role in gamma-secretase cleavage of numerous type-1 membrane-associated proteins required for cell signaling, proliferation and lineage development. We have generated a nicastrin-null mouse line by disruption of exon 3. Similar to previously described nicastrin-null mice, these animals demonstrate severe growth retardation, mortality beginning at embryonic age 10.5 days, and marked developmental abnormalities indicative of a severe Notch phenotype. Preceding their mortality, 10.5-day-old nicastrin-null embryos were found to also exhibit specific apoptosis within regions showing profound deformities, particularly in the developing heart and brain. This result suggests that complete disruption of presenilin complexes elicits programmed cell death, in addition to a Notch phenotype, which may contribute to the developmental abnormalities and embryonic mortality of nicastrin-null mice and possibly neurodegeneration in Alzheimer''s disease. [Copyright &y& Elsevier]
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- 2006
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13. Imaging findings in primary intracranial atypical teratoid/rhabdoid tumors.
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Parmar, Hemant, Hawkins, Cynthia, Bouffet, Eric, Rutka, James, and Shroff, Manohar
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TUMORS in children , *TERATOMA , *DIAGNOSTIC imaging , *FLUORESCENCE in situ hybridization , *IMMUNOHISTOCHEMISTRY , *DISEASE relapse - Abstract
Background: Intracranial atypical teratoid/rhabdoid tumors (AT/RT) are rare and extremely aggressive neoplasms seen primarily in childhood. Imaging features are often considered non-specific. However, correct diagnosis of AT/RT is important because these tumors have a markedly different clinical prognosis and require more aggressive therapy.Objective: To determine the imaging features of AT/RT.Materials and Methods: We retrospectively analyzed imaging findings in 11 patients with primary intracranial AT/RT presenting over a period of 5 years. CT (n=11), MR (n=7), clinical (n=11) and pathological (n=11) features were evaluated. FISH analysis showing monosomy of chromosome 22 (absence of bcr 22q11 locus) was available for three patients. Immunohistochemical staining for INI-1 (BAF47) was performed on all tumors.Results: There were 11 patients, 6 boys and 5 girls. The age of presentation varied from 1 month to 15 years (average age 3 years 8 months). Six tumors were located in the posterior fossa and five in the supratentorial compartment. The tumors showed a hyperdense solid component (64%) that showed moderate to marked enhancement with contrast medium. On MR imaging, the predominant signal pattern was isointensity on T1-weighted images (57%) and T2 shortening with heterogeneity on T2-weighted images (86%). All tumors were large in size (average 4.2 x 3.7 cm), and there was a tendency for calcification (36%), hemorrhage (46%), necrosis (46%) and perifocal edema (100%). There was also a high tendency for subarachnoid dissemination, with five patients (46%) demonstrating brain and/or spinal metastasis. At follow-up (n=7), six patients showed local recurrence. At the time of recurrence, all these patients showed extensive leptomeningeal spread of the disease in both intracranial and intraspinal compartments.Conclusion: There are no specific imaging features for intracranial AT/RT. But a high tendency toward large size, a hyperdense solid component on CT scan with calcification, hemorrhage, necrosis and subarachnoid spread suggest that this tumor should be considered in the differential diagnosis of large pediatric intracranial tumors. [ABSTRACT FROM AUTHOR]- Published
- 2006
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14. Identification of human brain tumour initiating cells.
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Singh, Sheila K., Hawkins, Cynthia, Clarke, Ian D., Squire, Jeremy A., Bayani, Jane, Hide, Takuichiro, Henkelman, R. Mark, Cusimano, Michael D., and Dirks, Peter B.
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STEM cells , *BRAIN tumors , *CANCER treatment , *TRANSPLANTATION of organs, tissues, etc. , *PEOPLE with diabetes , *XENOGRAFTS - Abstract
The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours, except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient's original tumour, whereas injection of 105 CD133- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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15. Rapidly Progressive Dementia Due to Mycobacterium neoaurum Meningoencephalitis.
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Heckman, George A., Hawkins, Cynthia, Morris, Andrew, Burrows, Lori L., and Bergeron, Catherine
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DEMENTIA , *MENINGOENCEPHALITIS , *MYCOBACTERIUM , *NEUROLOGIC manifestations of general diseases , *EMERGING infectious diseases - Abstract
Dementia developed in a patient with widespread neurologic manifestations; she died within 5 months. Pathologic findings showed granulomatous inflammation with caseation necrosis, foreign body-type giant cells, and proliferative endarteritis with vascular occlusions. Broad-range polymerase chain reaction identified Mycobacterium neoaurum as the possible pathogen. Central nervous system infection by M. neoaurum may result in rapidly progressive dementia. [ABSTRACT FROM AUTHOR]
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- 2004
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16. Beyond hand-crafted features for pretherapeutic molecular status identification of pediatric low-grade gliomas.
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Kudus, Kareem, Wagner, Matthias W., Namdar, Khashayar, Bennett, Julie, Nobre, Liana, Tabori, Uri, Hawkins, Cynthia, Ertl-Wagner, Birgit Betina, and Khalvati, Farzad
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IDENTIFICATION , *GLIOMAS , *CONVOLUTIONAL neural networks , *RADIOMICS , *MAGNETIC resonance imaging , *RANDOM forest algorithms - Abstract
The use of targeted agents in the treatment of pediatric low-grade gliomas (pLGGs) relies on the determination of molecular status. It has been shown that genetic alterations in pLGG can be identified non-invasively using MRI-based radiomic features or convolutional neural networks (CNNs). We aimed to build and assess a combined radiomics and CNN non-invasive pLGG molecular status identification model. This retrospective study used the tumor regions, manually segmented from T2-FLAIR MR images, of 336 patients treated for pLGG between 1999 and 2018. We designed a CNN and Random Forest radiomics model, along with a model relying on a combination of CNN and radiomic features, to predict the genetic status of pLGG. Additionally, we investigated whether CNNs could predict radiomic feature values from MR images. The combined model (mean AUC: 0.824) outperformed the radiomics model (0.802) and CNN (0.764). The differences in model performance were statistically significant (p-values < 0.05). The CNN was able to learn predictive radiomic features such as surface-to-volume ratio (average correlation: 0.864), and difference matrix dependence non-uniformity normalized (0.924) well but was unable to learn others such as run-length matrix variance (− 0.017) and non-uniformity normalized (− 0.042). Our results show that a model relying on both CNN and radiomic-based features performs better than either approach separately in differentiating the genetic status of pLGGs, and that CNNs are unable to express all handcrafted features. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Understanding diffuse leptomeningeal glioneuronal tumors.
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Bajin, Inci Yaman, Levine, Adrian, Dewan, Michael C., Bennett, Julie, Tabori, Uri, Hawkins, Cynthia, and Bouffet, Eric
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MENINGEAL cancer , *PROGNOSIS , *THERAPEUTICS , *CHILD patients , *SYMPTOMS ,CENTRAL nervous system tumors - 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. Methods: 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. Results: 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. Conclusion: 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]
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- 2024
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18. Viruses and human brain tumors: cytomegalovirus enters the fray.
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Hawkins, Cynthia and Croul, Sidney
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MEDULLOBLASTOMA , *BRAIN tumors , *MORTALITY , *ENDOCRINOLOGY , *CELL lines , *CYTOMEGALOVIRUSES , *ANIMAL experimentation , *COMPARATIVE studies , *GLIOMAS , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *RESEARCH funding , *EVALUATION research - Abstract
Medulloblastoma is the most common malignant brain tumor in children. Overall survival rates have improved in recent years as a result of risk-stratified treatment regimens. However, medulloblastoma remains associated with substantial mortality, and survivors often experience debilitating neurological, endocrinological, and social sequelae as a result of treatment. Targeted and less toxic therapeutic strategies are therefore needed. In this issue of the JCI, Baryawno et al. report their findings that a large percentage of primary medulloblastomas and medulloblastoma cell lines are infected with human cytomegalovirus (HCMV) and suggest that targeting this virus could provide a new way to treat individuals with medulloblastoma. [ABSTRACT FROM AUTHOR]
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- 2011
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19. 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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20. 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]
- Published
- 2020
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21. 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]
- Published
- 2020
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22. Developmental stage-specific transformation of neural progenitors.
- Author
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Muñoz, Diana Marcela and Hawkins, Cynthia
- Published
- 2014
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23. Malignant transformation of adult-onset pilocytic astrocytoma to diffuse leptomeningeal glioneuronal tumor within the thoracic spine: a case report and review of the literature.
- Author
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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]
- Published
- 2023
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24. 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]
- Published
- 2023
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25. 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.
- Abstract
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]
- Published
- 2023
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26. 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]
- Published
- 2015
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27. 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]
- Published
- 2018
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28. LETTERS.
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Hawkins, Cynthia, Russell, Sandra, Murphy, Idris, Glew, Adrian, Brotherton, Ben, Richards, J. H., Moss, Christopher, and Rees, Molly
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LETTERS to the editor , *ART exhibitions , *ARTISTS , *ARTS & society , *EXILES in art - Abstract
Several letters to the editor are presented in response to articles in the previous and latest issues including "The Wonderful Exile of the Artist" by Merlin James in the winter of 1999 issue, the review of the Morandi exhibition by Christopher Stock in the previous issue, and the review on Chardin's exhibition by Matthew Collins in the latest issue.
- Published
- 2001
29. 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
- Subjects
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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]
- Published
- 2023
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30. 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]
- Published
- 2023
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31. Radiomic Features Based on MRI Predict Progression-Free Survival in Pediatric Diffuse Midline Glioma/Diffuse Intrinsic Pontine Glioma.
- Author
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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]
- Published
- 2023
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32. Recurrent posterior fossa group A (PFA) ependymoma in a young child with constitutional mismatch repair deficiency (CMMRD).
- Author
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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.
- Subjects
- *
EPENDYMOMA , *POSTERIOR cranial fossa , *HEREDITARY nonpolyposis colorectal cancer - Published
- 2023
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33. Mycobacterium neoaurum Contamination.
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Heckman, George A., Hawkins, Cynthia, Morris, Andrew, Burrows, Lori L., and Bergeron, Catherine
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LETTERS to the editor , *MYCOBACTERIUM - Abstract
Presents a response to a letter to the editor about the article "Rapidly Progressive Dementia Due to Mycobacterium neoaurum Meningoencephalitis," in the "Emerging Infectious Diseases" journal.
- Published
- 2005
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34. Expression and Clinical Correlation of PD-1/PD-L1 and VE1(BRAFp.V600E) in Pediatric Langerhans Cell Histiocytosis.
- Author
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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]
- Published
- 2023
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35. The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers.
- Author
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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]
- Published
- 2022
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36. Oncohistone interactome profiling uncovers contrasting oncogenic mechanisms and identifies potential therapeutic targets in high grade glioma.
- Author
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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
- Subjects
- *
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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37. 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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38. 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
39. 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
- Full Text
- View/download PDF
40. Surgical outcomes in children with drug-resistant epilepsy and hippocampal sclerosis.
- Author
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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
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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
- Full Text
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41. Pediatric-type low-grade gliomas in adolescents and young adults—challenges and emerging paradigms.
- Author
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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
- Full Text
- View/download PDF
42. 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
- *
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
43. Immune Checkpoint Inhibition as Single Therapy for Synchronous Cancers Exhibiting Hypermutation: An IRRDC Study.
- Author
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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
- *
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
44. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumours: an integrative genomic analysis
- Author
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Picard, Daniel, Miller, Suzanne, Hawkins, Cynthia E, Bouffet, Eric, Rogers, Hazel A, Chan, Tiffany SY, Kim, Seung-Ki, Ra, Young-Shin, Fangusaro, Jason, Korshunov, Andrey, Toledano, Helen, Nakamura, Hideo, Hayden, James T, Chan, Jennifer, Lafay-Cousin, Lucie, Hu, Pingzhao, Fan, Xing, Muraszko, Karin M, Pomeroy, Scott L, and Lau, Ching C
- Subjects
- *
BIOMARKERS , *METASTASIS , *CENTRAL nervous system diseases , *BRAIN tumors , *GENOMICS , *COHORT analysis - Abstract
Summary: Background: Childhood CNS primitive neuro-ectodermal brain tumours (PNETs) are very aggressive brain tumours for which the molecular features and best treatment approaches are unknown. We assessed a large cohort of these rare tumours to identify molecular markers to enhance clinical management of this disease. Methods: We obtained 142 primary hemispheric CNS PNET samples from 20 institutions in nine countries and examined transcriptional profiles for a subset of 51 samples and copy number profiles for a subset of 77 samples. We used clustering, gene, and pathway enrichment analyses to identify tumour subgroups and group-specific molecular markers, and applied immunohistochemical and gene-expression analyses to validate and assess the clinical significance of the subgroup markers. Findings: We identified three molecular subgroups of CNS PNETs that were distinguished by primitive neural (group 1), oligoneural (group 2), and mesenchymal lineage (group 3) gene-expression signatures with differential expression of cell-lineage markers LIN28 and OLIG2. Patients with group 1 tumours were most often female (male:female ratio 0·61 for group 1 vs 1·25 for group 2 and 1·63 for group 3; p=0·043 [group 1 vs groups 2 and 3]), youngest (median age at diagnosis 2·9 years [95% CI 2·4–5·2] for group 1 vs 7·9 years [6·0–9·7] for group 2 and 5·9 years [4·9–7·8] for group 3; p=0·005), and had poorest survival (median survival 0·8 years [95% CI 0·5–1·2] in group 1, 1·8 years [1·4–2·3] in group 2 and 4·3 years [0·8–7·8] in group 3; p=0·019). Patients with group 3 tumours had the highest incidence of metastases at diagnosis (no distant metastasis:metastasis ratio 0·90 for group 3 vs 2·80 for group 1 and 5·67 for group 2; p=0·037). Interpretation: LIN28 and OLIG2 are promising diagnostic and prognostic molecular markers for CNS PNET that warrant further assessment in prospective clinical trials. Funding: Canadian Institute of Health Research, Brainchild/SickKids Foundation, and the Samantha Dickson Brain Tumour Trust. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
45. Milder phenotype of congenital muscular dystrophy in a novel POMT1 mutation.
- Author
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Al-Zaidy, Samiah A., Baskin, Berivan, Hawkins, Cynthia, Yoon, Grace, Ray, Peter N., and Vajsar, Jiri
- Abstract
Introduction: Congenital muscular dystrophies (CMD) with hypoglycosylated α-dystroglycan due to POMT1 mutations are associated with clinical phenotypes that vary in severity. Methods: We describe a patient with congenital hypotonia, generalized weakness, elevated creatine kinase (CK), and normal brain imaging. Results: Histochemical analysis of the index case's muscle showed deficiency of glycosylated α-dystroglycan and secondary merosin deficiency. Genetic testing revealed a novel mutation in exon 20 of the POMT1 gene. Conclusions: Our patient's milder form of CMD adds to the emerging evidence of an expanding phenotype caused by POMT1 mutations. The histopathological findings of the muscle biopsy in this case support the need for careful clinical, genetic, and histochemical diagnostic interpretation. Muscle Nerve 45: 752-755, 2012 [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
46. Brain biopsy in children with primary small-vessel central nervous system vasculitis.
- Author
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Elbers, Jorina, Halliday, William, Hawkins, Cynthia, Hutchinson, Clare, and Benseler, Susanne M.
- Abstract
Objective:: Primary angiitis of the central nervous system in childhood (cPACNS) is an immune-mediated inflammatory process directed toward blood vessels in the central nervous system. It has been associated with variable clinical and radiological presentations, and devastating consequences without treatment. Brain biopsy is required for definitive diagnosis. The objective of this study was to characterize the clinical and histopathological features of brain biopsies in small-vessel cPACNS (SVcPACNS). Methods:: A single-center prospective cohort study of children diagnosed with cPACNS from 1998 to 2008 was performed. All patients with negative cerebral angiography and brain biopsy were included. Patient data were reviewed for clinical, laboratory, and radiological characteristics at presentation. Standardized brain biopsy review protocols were established, with independent analysis by 2 neuropathologists. Histopathology was correlated with collected clinical data. Results:: A total of 13 SVcPACNS patients were included. Ages ranged from 5 to 17 years. Presenting features included seizures (85%), headache (62%), and cognitive decline (54%). Brain biopsy confirmed SVcPACNS in 11 patients with intramural lymphocytic infiltrate. Two had nonspecific perivascular inflammation only. All 6 nonlesional biopsies yielded a diagnosis of SVcPACNS. Lack of specific histological features correlated with prolonged time to biopsy, prior steroid treatment, and inadequate specimen sampling. Interpretation:: In children presenting with new onset severe headaches, seizures, or cognitive decline, SVcPACNS and brain biopsy should be considered. Lesional biopsies are preferred; however, nonlesional biopsies may succeed in yielding the diagnosis. Steroid treatment prior to biopsy and inadequate biopsy sampling may obscure the diagnosis in true cases of SVcPACNS. ANN NEUROL 2010;68:602-610 [ABSTRACT FROM AUTHOR]
- Published
- 2010
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- View/download PDF
47. Telomerase inhibition induces acute ATM-dependent growth arrest in human astrocytomas
- Author
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Wong, Vincent C.H., Ma, Jing, and Hawkins, Cynthia E.
- Subjects
- *
ASTROCYTOMAS , *TELOMERASE , *CHILDHOOD cancer , *DNA damage , *CELLULAR signal transduction , *TUMOR growth - Abstract
Abstract: The purpose of the study was to examine the degree of hTERT, the catalytic subunit of telomerase, expression in paediatric high-grade astrocytoma and to explore the potential of telomerase inhibition as a therapy for these tumours. hTERT was expressed at high levels in 36 of 44 paediatric astrocytomas. Telomerase inhibition induced acute DNA damage and ATM-pathway-dependent G2/M cell cycle arrest in astrocytomas in vitro, both occurring prior to telomere shortening itself. Our data suggest that telomerase inhibition could be a useful adjuvant therapy for high-grade astrocytomas, potentially inducing tumour growth arrest following short-term treatment. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
48. GATA6 is an astrocytoma tumor suppressor gene identified by gene trapping of mouse glioma model.
- Author
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Kamnasaran, Deepak, Baoping Qian, Hawkins, Cynthia, Stanford, William L., and Guha, Abhijit
- Subjects
- *
TUMOR suppressor genes , *ASTROCYTOMAS , *BRAIN tumors , *TRANSCRIPTION factors , *ASTROCYTES , *CELL proliferation , *CELL lines , *MUTAGENESIS - Abstract
Malignant astrocytomas are the most common and lethal adult primary brain tumor. Retroviral gene trapping of nontransformed neonatal astrocytes from a glial fibrillary acidic protein (GFAP):V12Ha-Ras murine astrocytoma model led to isolation of the transcription factor Gata6. Loss of Gata6 resulted in enhanced proliferation and transformation of astrocytes. Human malignant astrocytoma cell lines, explant xenografts, and operative specimens demonstrated loss of GATA6 expression. Loss-of-function GATA6 mutations with loss of heterozygosity of the GATA6 locus were found in human malignant astrocytoma specimens but not in lower-grade astrocytomas or normal adult astrocytes. Knockdown of Gata6 expression in V12Ha-Ras or p53-/- astrocytes, but not in parental murine or human astrocytes, led to acceleration of tumorgenesis. Knockin GATA6 expression in human malignant astrocytoma cells reduced their tumorgenic growth with decreased VEGF expression. Collectively, these data demonstrate that GATA6, isolated from a murine astrocytoma model, is a novel tumor suppressor gene that is a direct target of mutations during malignant progression of murine and human astrocytomas. This work also demonstrates the utility of random mutagenesis strategies, such as gene trapping, on murine cancer models toward discovery of novel genetic alterations in corresponding human cancers. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
49. Grandpa and I have Dystrophinopathy?: Approach to Asymptomatic HyperCKemia
- Author
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Saengpattrachai, Montri, Ray, Peter N., Hawkins, Cynthia E., Berzen, Alan, and Banwell, Brenda L.
- Subjects
- *
MEMBRANE proteins , *DYSTROPHIN , *GENETIC mutation , *BLOOD plasma - Abstract
This report describes three males from a single kinship, ages 7, 8, and 67 years with clinically asymptomatic dystrophinopathy. The index case was an 8-year-old male evaluated for asymptomatic but persistently elevated serum creatine kinase levels. Muscle biopsy demonstrated a mild myopathy, without necrotic fibers. Immunostaining for dystrophin revealed a slight reduction in sarcolemmal reactivity for the amino terminus of dystrophin. Dystrophin gene analysis revealed a deletion of exon 45 to exon 51. Genetic analysis identified two other affected males (age 7 years and 67 years), as well as four female carriers in the same family. The 7-year-old male had mildly increased creatine kinase levels with normal muscle strength. The 67-year-old grandfather had normal neuromuscular examination and serum creatine kinase levels. Asymptomatic dystrophinopathy in late adulthood is exceptionally rare, and highlights the importance of consideration of dystrophin mutation analysis in patients with hyperCKemia, even in the absence of muscle weakness. [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
- View/download PDF
50. MetaFusion: a high-confidence metacaller for filtering and prioritizing RNA-seq gene fusion candidates.
- Author
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Apostolides, Michael, Jiang, Yue, Husić, Mia, Siddaway, Robert, Hawkins, Cynthia, Turinsky, Andrei L, Brudno, Michael, and Ramani, Arun K
- Subjects
- *
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
- Full Text
- View/download PDF
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