46 results on '"Janss AJ"'
Search Results
2. A Pilot Study of Low-Dose Craniospinal Irradiation in Patients With Newly Diagnosed Average-Risk Medulloblastoma.
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Minturn JE, Mochizuki AY, Partap S, Belasco JB, Lange BJ, Li Y, Phillips PC, Gibbs IC, Fisher PG, Fisher MJ, and Janss AJ
- Abstract
Purpose: Medulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. Prior to advances in molecular subgrouping, we sought to reduce the late effects of radiation in patients with average-risk medulloblastoma., Methods: We performed a single-arm, multi-institution study, reducing the dose of craniospinal irradiation by 25% to 18 Gray (Gy) with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy., Results: Twenty-eight (28) patients aged 3-30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 79% (95% confidence interval [CI] 58% to 90%) and 93% (95% CI 74% to 98%), respectively. The 5-year RFS and OS were 71% (95% CI 50% to 85%) and 86% (95% CI 66% to 94%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities., Conclusions: Given the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from a reduced craniospinal radiation dose of 18 Gy without impacting relapse-free or overall survival., Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00031590., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Minturn, Mochizuki, Partap, Belasco, Lange, Li, Phillips, Gibbs, Fisher, Fisher and Janss.)
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- 2021
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3. Vision-related quality-of-life in pediatric primary brain tumor patients.
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Peragallo JH, Bruce BB, Vasseneix C, Jariyakosol S, Janss AJ, Newman NJ, and Biousse V
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- Child, Humans, Surveys and Questionnaires, Vision Disorders epidemiology, Vision Disorders etiology, Visual Acuity, Brain Neoplasms complications, Quality of Life
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Purpose: Brain tumors are the leading cause of death from childhood cancer. Although overall survival has improved due to earlier detection, better therapies, and improved surveillance, visual dysfunction and impaired vision-related quality-of-life (VR-QOL) are often unrecognized in children. This project investigated VR-QOL in pediatric brain tumor patients., Methods: We evaluated visual impairment and quality-of-life (QOL) in a quality improvement project at one tertiary care center. Patients ≤ 18, greater than 6 months from diagnosis of brain tumor, excluding intrinsic anterior visual pathway tumors, underwent standardized neuro-ophthalmologic examination. Health-related QOL (HR-QOL) (PedsQL Brain Tumor Module) and VR-QOL questionnaires [CVFQ (Children's Visual Function Questionnaire) in children < 8, and EYE-Q in children 8-18] were obtained from patients and parents., Results: Among 77 patients, craniopharyngiomas (n = 16, 21%) and astrocytomas (n = 15, 20%) were the most common tumors. Among 44/77 (57%) visually impaired children, 7 (16%) were legally blind. Eye-Q median score was 3.40 (interquartile range 3.00-3.75), worse than average scores for normal children. Eye-Q score decreased 0.12 with every 0.1 increase in logMAR visual acuity (p < 0.001). Patients who were legally blind had a significantly lower Eye-Q score than those who were not [0.70 vs. 3.44 (p < 0.001)]. Cognitive HR-QOL scores decreased 1.3 for every 0.1 increase in logMAR visual acuity (p = 0.02)., Conclusions: Pediatric brain tumor patients' vision, HR-QOL, and VR-QOL were often severely affected even when tumors were considered cured. Visual acuity and legal blindness correlated with VR-QOL. Systematic neuro-ophthalmologic examinations in pediatric primary brain tumor patients are necessary to facilitate early preventative and corrective ophthalmologic interventions., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2021
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4. Children's Oncology Group Phase III Trial of Reduced-Dose and Reduced-Volume Radiotherapy With Chemotherapy for Newly Diagnosed Average-Risk Medulloblastoma.
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Michalski JM, Janss AJ, Vezina LG, Smith KS, Billups CA, Burger PC, Embry LM, Cullen PL, Hardy KK, Pomeroy SL, Bass JK, Perkins SM, Merchant TE, Colte PD, Fitzgerald TJ, Booth TN, Cherlow JM, Muraszko KM, Hadley J, Kumar R, Han Y, Tarbell NJ, Fouladi M, Pollack IF, Packer RJ, Li Y, Gajjar A, and Northcott PA
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- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols pharmacology, Child, Child, Preschool, Female, Humans, Male, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Medulloblastoma drug therapy, Medulloblastoma radiotherapy
- Abstract
Purpose: Children with average-risk medulloblastoma (MB) experience survival rates of ≥ 80% at the expense of adverse consequences of treatment. Efforts to mitigate these effects include deintensification of craniospinal irradiation (CSI) dose and volume., Methods: ACNS0331 (ClinicalTrials.gov identifier: NCT00085735) randomly assigned patients age 3-21 years with average-risk MB to receive posterior fossa radiation therapy (PFRT) or involved field radiation therapy (IFRT) following CSI. Young children (3-7 years) were also randomly assigned to receive standard-dose CSI (SDCSI; 23.4 Gy) or low-dose CSI (LDCSI; 18 Gy). Post hoc molecular classification and mutational analysis contextualized outcomes according to known biologic subgroups (Wingless, Sonic Hedgehog, group 3, and group 4) and genetic biomarkers. Neurocognitive changes and ototoxicity were monitored over time., Results: Five hundred forty-nine patients were enrolled on study, of which 464 were eligible and evaluable to compare PFRT versus IFRT and 226 for SDCSI versus LDCSI. The five-year event-free survival (EFS) was 82.5% (95% CI, 77.2 to 87.8) and 80.5% (95% CI, 75.2 to 85.8) for the IFRT and PFRT regimens, respectively, and 71.4% (95% CI, 62.8 to 80) and 82.9% (95% CI, 75.6 to 90.2) for the LDCSI and SDCSI regimens, respectively. IFRT was not inferior to PFRT (hazard ratio, 0.97; 94% upper CI, 1.32). LDCSI was inferior to SDCSI (hazard ratio, 1.67%; 80% upper CI, 2.10). Improved EFS was observed in patients with Sonic Hedgehog MB who were randomly assigned to the IFRT arm ( P = .018). Patients with group 4 MB receiving LDCSI exhibited inferior EFS ( P = .047). Children receiving SDCSI exhibited greater late declines in IQ (estimate = 5.87; P = .021)., Conclusion: Reducing the radiation boost volume in average-risk MB is safe and does not compromise survival. Reducing CSI dose in young children with average-risk MB results in inferior outcomes, possibly in a subgroup-dependent manner, but is associated with better neurocognitive outcome. Molecularly informed patient selection warrants further exploration for children with MB to be considered for late-effect sparing approaches., Competing Interests: Jeff M. MichalskiStock and Other Ownership Interests: ViewRayConsulting or Advisory Role: Mevion Medical Systems, Boston Scientific, Merck Sharp & Dohme, Blue Earth DiagnosticsResearch Funding: Merck Sharp & DohmeTravel, Accommodations, Expenses: Boston Scientific, Merck Sharp & DohmeOpen Payments Link: https://openpaymentsdata.cms.gov/physician/221723 Kristina K. HardyEmployment: BayerHonoraria: BayerSpeakers' Bureau: BayerTravel, Accommodations, Expenses: Bayer Stephanie M. PerkinsConsulting or Advisory Role: Mevion Medical Systems Thomas E. MerchantTravel, Accommodations, Expenses: Philips Healthcare Nancy J. TarbellConsulting or Advisory Role: Mevion Medical Systems, Advanced OncoPatents, Royalties, Other Intellectual Property: Spouse is an editor for UpToDate Maryam FouladiResearch Funding: PTC Therapeutics, Bayer Schering Pharma Roger J. PackerHonoraria: NovartisConsulting or Advisory Role: Novartis, AstraZeneca Amar GajjarConsulting or Advisory Role: Roche/Genentech, QED TherapeuticsResearch Funding: Genentech, Kazia TherapeuticsNo other potential conflicts of interest were reported.
- Published
- 2021
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5. Guidelines for Treatment and Monitoring of Adult Survivors of Pediatric Brain Tumors.
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Janss AJ, Mazewski C, and Patterson B
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- Adult, Brain Neoplasms pathology, Child, Humans, Aftercare standards, Brain Neoplasms therapy, Cancer Survivors statistics & numerical data, Practice Guidelines as Topic standards, Quality of Life
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Opinion Statement: Pathologies of pediatric brain tumors are more varied than those diagnosed in adults and survival outcomes more optimistic. Therapies for pediatric brain tumors are also diverse and treatment options are expanding. The growing number of adult survivors of childhood brain tumors is quite diverse. Medical management of these adults requires understanding the tumor diagnosis and location, the modalities used to treat the tumor, the age of the survivor at the time of diagnosis and treatment, any complications of treatment, and, most importantly, the baseline medical condition and neurological function of each adult survivor. A network of medical, neurological, and mental health providers is critical in the care of a child with a brain tumor. A comparable network should be available to survivors of these tumors since they may transition to adulthood with medical and neurological deficits and can acquire additional late effects of treatments as they age. Optimally, each survivor will have an individualized survivor health plan (SHP) that concisely summarizes the tumor, treatments, potential late effects, and screening that may identify evolving late effects before they impact mental, social or physical functioning. This plan helps patients, families, and the medical team advocate for surveillance aiming to optimize the survivor's quality of life. Failure to support the health and function of these heroic cancer survivors renders the medical advances, the courage, and the struggle that permitted survival meaningless.
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- 2019
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6. Headache, elevated tumor markers, and pituitary mass.
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Shanker K, Janss AJ, and Patterson BC
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- Biomarkers, Tumor blood, Child, Female, Humans, Hypothyroidism drug therapy, Magnetic Resonance Imaging, Obesity etiology, Pituitary Gland diagnostic imaging, Pituitary Gland pathology, Thyroxine therapeutic use, Tomography, X-Ray Computed, alpha-Fetoproteins, Headache etiology, Hypothyroidism complications, Hypothyroidism diagnosis
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- 2015
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7. Diffuse leptomeningeal neuroepithelial tumor: 9 pediatric cases with chromosome 1p/19q deletion status and IDH1 (R132H) immunohistochemistry.
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Schniederjan MJ, Alghamdi S, Castellano-Sanchez A, Mazewski C, Brahma B, Brat DJ, Brathwaite CD, and Janss AJ
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- Child, Child, Preschool, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 19 genetics, Female, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Isocitrate Dehydrogenase analysis, Isocitrate Dehydrogenase biosynthesis, Male, Meningeal Carcinomatosis genetics, Meningeal Carcinomatosis metabolism, Neoplasms, Neuroepithelial genetics, Neoplasms, Neuroepithelial metabolism, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Chromosome Deletion, Meningeal Carcinomatosis pathology, Neoplasms, Neuroepithelial pathology
- Abstract
Leptomeningeal dissemination in children is typical of high-grade, and occasionally low-grade, neoplasms. Rare cases of widely disseminated oligodendroglia-like leptomeningeal tumors, sometimes with associated spinal cord lesions, have been described that respond to treatment and follow an indolent course. Whether these lesions represent an established tumor category or are a unique entity remains to be established. We present 9 pediatric cases of such diffuse leptomeningeal neuroepithelial tumors (DLNT), 8 with assessment of 2 common genetic alterations seen in oligodendrogliomas, 1p and 19q chromosomal deletions and isocitrate dehydrogenase-1 (IDH1) R132H mutations. Four patients were male and 5 female, with a mean age at presentation of 4 years (range, 2 to 7 y). All presented with signs of increased intracranial pressure and diffuse contrast enhancement of the leptomeninges by magnetic resonance imaging. Three had a cervical or upper thoracic spinal cord tumor, and another had a small cerebellar lesion. Leptomeningeal biopsies showed a thickened and fibrotic arachnoid infiltrated by monotonous cells with round nuclei and prominent perinuclear clearing. All cases were strongly immunoreactive for S100 protein, and most showed faint granular synaptophysin reactivity. Six of 8 cases showed deletions of chromosome arm 1p by fluorescence in situ hybridization, 2 of which also had loss of 19q. None of the lesions reacted with IDH1-R132H antibodies. Although the clinicopathologic features show overlap of these DLNT lesions with oligodendroglioma and extraventricular neurocytoma, they do not exactly match either one, suggesting that DLNTs are a distinct tumor entity.
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- 2013
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8. Transient enlargement of craniopharyngioma after radiation therapy: pattern of magnetic resonance imaging response following radiation.
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Shi Z, Esiashvili N, Janss AJ, Mazewski CM, MacDonald TJ, Wrubel DM, Brahma B, Schwaibold FP, Marcus RB, Crocker IR, and Shu HK
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- Adolescent, Brain diagnostic imaging, Child, Child, Preschool, Craniopharyngioma mortality, Dose Fractionation, Radiation, Female, Follow-Up Studies, Humans, Magnetic Resonance Imaging, Male, Pituitary Neoplasms mortality, Radiography, Retrospective Studies, Survival Analysis, Young Adult, Craniopharyngioma pathology, Craniopharyngioma radiotherapy, Pituitary Neoplasms pathology, Pituitary Neoplasms radiotherapy, Radiosurgery methods
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Clinical experience suggests that craniopharyngiomas may temporarily increase in size after radiation therapy (RT). The study goal is to determine the incidence and natural history of this response in a cohort of patients managed at Children's Healthcare of Atlanta (CHOA) or Emory Healthcare (EHC). Between 08/1998 and 06/2009, 41 children and young adults were diagnosed with craniopharyngioma at CHOA and/or EHC. Of these, 21 received external-beam radiation and were included in our analysis. Serial magnetic resonance imaging (MRI) studies were evaluated volumetrically to assess response to RT. Median age at diagnosis was 8.2 years (range 3.2-23.5 years). Median radiation dose was 54.0 Gy using standard fractionation (1.8-2.0 Gy/day). With median follow-up of 41.3 months (range 7.2-121.8 months), actuarial local control and overall survival rates at 5 years were 78.7 % and 100 %, respectively. Of subjects, 52.4 % of subjects (11 of 21) were noted on serial MRI evaluation to have tumor enlargement (mostly cystic component) after radiation before eventual shrinkage without further intervention. For tumors that expanded, the median volume increase was 33.9 % (range 15.6-224.4 %). Median time to maximal tumor/cyst expansion was 1.5 months (range 1.0-5.0 months). Finally, nearly all patients (20 of 21) showed a measurable objective response to therapy by MRI regardless of ultimate disease control. Median time to maximal response post-radiation, as defined by MRI, was 9.5 months (range 3.5-39.9 months). In summary, RT is effective for managing craniopharyngioma. However, despite good ultimate responses, approximately 50 % of the patients show tumor/cyst expansion on MRI over the first few months post-radiation. Caution should be taken not to subject these patients to "salvage surgery" or cyst aspiration during this early time unless there are other overriding surgical indications. Understanding the natural history of this phenomenon could potentially help guide the management of these craniopharyngioma patients.
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- 2012
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9. A phase II study of metronomic oral topotecan for recurrent childhood brain tumors.
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Minturn JE, Janss AJ, Fisher PG, Allen JC, Patti R, Phillips PC, and Belasco JB
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- Brain Stem Neoplasms drug therapy, Child, Disease-Free Survival, Ependymoma drug therapy, Female, Glioma drug therapy, Humans, Male, Neuroectodermal Tumors, Primitive drug therapy, Topoisomerase I Inhibitors therapeutic use, Topotecan toxicity, Treatment Outcome, Brain Neoplasms drug therapy, Topotecan administration & dosage
- Abstract
Background: The prognosis for recurrent or refractory brain tumors in children is poor with conventional therapies. Topotecan is a topoisomerase I inhibitor with good central nervous system (CNS) penetration following oral administration. Increased efficacy of topotecan has been demonstrated with prolonged low-dose daily treatment in pre-clinical models. To investigate further this drug delivered orally in pediatric CNS malignancies, a phase II study in children with recurrent or refractory brain tumors was performed., Procedure: Patients ≤ 21 years of age at diagnosis with a recurrent, progressive, or refractory primary CNS malignancy and measurable disease, were eligible. Patients enrolled into four strata: ependymoma (N = 4), high-grade glioma (HGG) (N = 6), brainstem glioma (BSG) (N = 13), and primitive neuroectodermal tumor (PNET) (N = 8). Oral topotecan was administered once daily at a dose of 0.8 mg/m(2)/day for 21 consecutive days repeated every 28 days. Response and toxicity profiles were evaluated., Results: Twenty-six patients were evaluable (median age 9.2 years; 10 males). Two objective responses were observed in PNET patients with disseminated tumor at study entry. These two patients remain alive and in remission 7 and 9.5 years off study. Four other patients (two BSG, one PNET, and one HGG) had stable disease (median 4.6 months). The most common toxicities were hematologic., Conclusions: Daily oral topotecan at a dose of 0.8 mg/m(2)/day can be safely administered to children with recurrent or refractory brain tumors. This regimen identified activity in recurrent PNET. The prolonged progression free survival (PFS) in two PNET patients justifies consideration of this regimen in more advanced clinical trials.
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- 2011
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10. Seventeen-year-old adolescent with pituitary abscess.
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Lin MI, Janss AJ, Wrubel D, and Meacham LR
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- Adolescent, Brain Abscess complications, Brain Abscess therapy, Diabetes Insipidus etiology, Drainage, Humans, Hypopituitarism etiology, Male, Pituitary Diseases etiology, Brain Abscess pathology, Diabetes Insipidus pathology, Hypopituitarism pathology, Magnetic Resonance Imaging, Pituitary Diseases pathology
- Abstract
Pituitary abscess is a rare but potentially life-threatening infectious process. Diagnosis is challenging as symptoms are non-specific and signs of infection may be absent. We report the case of a previously healthy 17-year-old male who presented with worsening headaches, polyuria, polydipsia and no clinical signs of infection. On evaluation, he was found to have hypopituitarism with diabetes insipidus, hypothyroidism and adrenal insufficiency. An imaging study revealed a pituitary mass. He underwent transsphenoidal biopsy to rule out tumor. The abscess was drained transsphenoidally and he was treated with parental antibiotics. Magnetic resonance imaging one year later revealed a normal pituitary without any evidence of abscess or mass. He continues to require thyroid, adrenal and anti-diuretic hormone replacements. As with any pituitary lesion, prompt complete hypothalamic pituitary evaluation is essential to avoid potentially life-threatening consequences.
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- 2011
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11. Incidence, risks, and sequelae of posterior fossa syndrome in pediatric medulloblastoma.
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Korah MP, Esiashvili N, Mazewski CM, Hudgins RJ, Tighiouart M, Janss AJ, Schwaibold FP, Crocker IR, Curran WJ Jr, and Marcus RB Jr
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- Adolescent, Analysis of Variance, Ataxia epidemiology, Ataxia etiology, Cerebellar Neoplasms drug therapy, Cerebellar Neoplasms pathology, Cerebellar Neoplasms surgery, Child, Child, Preschool, Combined Modality Therapy methods, Cranial Irradiation, Disease-Free Survival, Dysarthria epidemiology, Dysarthria etiology, Female, Follow-Up Studies, Humans, Incidence, Male, Medulloblastoma drug therapy, Medulloblastoma pathology, Medulloblastoma surgery, Muscle Hypotonia epidemiology, Muscle Hypotonia etiology, Mutism epidemiology, Mutism etiology, Neoplasm, Residual, Postoperative Complications epidemiology, Radiotherapy Dosage, Retrospective Studies, Risk, Syndrome, Young Adult, Cerebellar Neoplasms radiotherapy, Medulloblastoma radiotherapy
- Abstract
Purpose: To investigate the incidence, risks, severity, and sequelae of posterior fossa syndrome (PFS) in children with medulloblastoma., Methods and Materials: Between 1990 and 2007, 63 children with medulloblastoma at Emory University and Children's Healthcare of Atlanta were treated with craniectomy followed by radiation. Fifty-one patients were assigned to a standard-risk group, and 12 patients were assigned to a high-risk group. Five patients had <1.5-cm(2) residual tumor, 4 had >or=1.5-cm(2) residual tumor, and the remainder had no residual tumor. Eleven patients had disseminated disease. Patients received craniospinal irradiation at a typical dose of 23.4 Gy or 36 Gy for standard- or high-risk disease, respectively. The posterior fossa was given a total dose of 54 or 55.8 Gy. Nearly all patients received chemotherapy following cooperative group protocols., Results: Median follow-up was 7 years. PFS developed in 18 patients (29%). On univariate analysis, brainstem invasion, midline tumor location, younger age, and the absence of radiographic residual tumor were found to be predictors of PFS; the last two variables remained significant on multivariate analysis. From 1990 to 2000 and from 2001 to 2007, the proportions of patients with no radiographic residual tumor were 77% and 94%, respectively. During the same eras, the proportions of patients with PFS were 17% and 39%. Only 4 patients had complete recovery at last follow-up., Conclusions: The incidence of PFS increased in the latter study period and is proportional to more aggressive surgery. Children with midline tumors exhibiting brainstem invasion are at increased risk. With the increased incidence of PFS and the permanent morbidity in many patients, the risks and benefits of complete tumor removal in all patients need to be reexamined.
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- 2010
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12. De novo germline TP53 mutation presenting with synchronous malignancies of the central nervous system.
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Schniederjan MJ, Shehata B, Brat DJ, Esiashvili N, and Janss AJ
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- Adolescent, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Brain Neoplasms radiotherapy, Brain Neoplasms surgery, Carcinoma drug therapy, Carcinoma pathology, Carcinoma radiotherapy, Choroid Plexus Neoplasms drug therapy, Choroid Plexus Neoplasms pathology, Choroid Plexus Neoplasms radiotherapy, Cisplatin administration & dosage, Combined Modality Therapy, Cranial Irradiation, Fatal Outcome, Frontal Lobe pathology, Frontal Lobe surgery, Humans, Lomustine administration & dosage, Male, Neoplasms, Multiple Primary pathology, Neoplasms, Multiple Primary therapy, Neoplasms, Unknown Primary genetics, Neuroectodermal Tumors, Primitive pathology, Neuroectodermal Tumors, Primitive surgery, Radiotherapy, Adjuvant, Spinal Neoplasms drug therapy, Spinal Neoplasms radiotherapy, Spinal Neoplasms secondary, Vincristine administration & dosage, Brain Neoplasms genetics, Carcinoma genetics, Choroid Plexus Neoplasms genetics, Codon, Nonsense, Genes, p53, Germ-Line Mutation, Neoplasms, Multiple Primary genetics, Neuroectodermal Tumors, Primitive genetics, Rhabdomyosarcoma, Alveolar genetics, Rhabdomyosarcoma, Alveolar secondary
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We present a case of a 14-year-old male with a germline TP53 mutation who presented with synchronous primitive neuroectodermal tumor and choroid plexus carcinoma. Identification of synchronous brain tumors prompted genetic testing for predisposition to malignancy. Within 5 months of presentation, the child developed widely metastatic alveolar rhabdomyosarcoma. Patient DNA sequencing showed a TP53 allele with a premature stop codon in the oligomerization/nuclear export signal (NES) domain (R342ter). The child's parents, younger brother, paternal grandparents, and maternal grandmother, are without history of malignancy. The patient's brother tested negative for TP53 mutations. This case identifies a rare, de novo, germline TP53 mutation presenting with synchronous CNS malignancies and exhibiting a more fulminant course than typical cases of Li-Fraumeni syndrome., ((c) 2009 Wiley-Liss, Inc.)
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- 2009
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13. Childhood intracranial ependymoma: twenty-year experience from a single institution.
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Shu HK, Sall WF, Maity A, Tochner ZA, Janss AJ, Belasco JB, Rorke-Adams LB, Phillips PC, Sutton LN, and Fisher MJ
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- Adolescent, Adult, Child, Child, Preschool, Ependymoma drug therapy, Ependymoma radiotherapy, Ependymoma surgery, Female, Humans, Infant, Male, Prognosis, Survival Analysis, Treatment Outcome, Brain Neoplasms pathology, Ependymoma pathology
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Background: Because few large studies of pediatric ependymoma treatment are available, the authors believed that a retrospective review of treatment outcomes from a single institution would yield potentially valuable information regarding potential prognostic factors. In this article, they report their 20-year institutional experience with this disease., Methods: Medical records were reviews of patients with intracranial ependymoma who received their initial treatment at the Children's Hospital of Philadelphia (CHOP)/Hospital of the University of Pennsylvania (HUP) between January 1980 and December 2000. Of the 61 patients who were identified, 49 patients underwent primary therapy at CHOP/HUP and formed the basis for the study. Actuarial overall survival (OS) and progression-free survival (PFS) were determined by the Kaplan-Meier method. Univariate and multivariate analyses were performed using the log-rank test and Cox proportional-hazards models., Results: With median follow-up of 110.2 months, the 5-year OS and PFS rates were 66.2% and 40.7%, respectively. Older age and higher radiation dose significantly predicted for improved OS. Anaplastic histology predicted for decreased PFS. Cervical spinal cord extension resulted in decreased OS primarily caused by failures outside the primary site. Patients who had a favorable prognosis (aged >/=3 years, no dissemination or cord extension, complete resection, and radiation dose >/=54 grays [Gy]) had 5-year OS and PFS rates of 83.1% and 60.6%, respectively., Conclusions: In this study of patients with pediatric intracranial ependymoma, OS and PFS rates were concordant with the rates published in other modern series. The finding of a dose response up to 54 Gy supported the current trend toward dose escalation. Tumor extension to the cervical spine was identified as a predictor for failure outside of the primary site. Although the survival rates were encouraging, there is still significant room for improvement in the management of this disease.
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- 2007
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14. Amifostine for children with medulloblastoma treated with cisplatin-based chemotherapy.
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Fisher MJ, Lange BJ, Needle MN, Janss AJ, Shu HK, Adamson PC, and Phillips PC
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- Child, Child, Preschool, Cisplatin toxicity, Drug Interactions, Ear Diseases chemically induced, Ear Diseases prevention & control, Endpoint Determination, Female, Humans, Hypotension chemically induced, Kidney Diseases chemically induced, Kidney Diseases prevention & control, Male, Medulloblastoma complications, Medulloblastoma radiotherapy, Protective Agents toxicity, Treatment Outcome, Amifostine administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Cisplatin administration & dosage, Medulloblastoma drug therapy, Protective Agents administration & dosage
- Abstract
In adult patients, amifostine appears to ameliorate cisplatin-related nephrotoxicity and ototoxicity. We assessed the safety and efficacy of amifostine in 11 children with newly diagnosed medulloblastoma/primitive neuroectodermal tumor treated with radiotherapy and vincristine, lomustine, and cisplatin. Amifostine was administered immediately prior to and 4 hr into the cisplatin infusion. Amifostine caused assymptomatic hypotension and hypocalcemia in 18 and 82% of patients, respectively. Despite amifostine use, 78% of patients developed significant ototoxicity. Although relatively well tolerated, amifostine does not appear to have a major impact on ameliorating the risk of developing significant nephro- and ototoxicity in children with medulloblastoma. Larger studies will help clarify these findings., (2004 Wiley-Liss, Inc.)
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- 2004
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15. Near complete surgical resection predicts a favorable outcome in pediatric patients with nonbrainstem, malignant gliomas: results from a single center in the magnetic resonance imaging era.
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Bucci MK, Maity A, Janss AJ, Belasco JB, Fisher MJ, Tochner ZA, Rorke L, Sutton LN, Phillips PC, and Shu HK
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- Adolescent, Adult, Age Factors, Child, Child, Preschool, Disease-Free Survival, Female, Humans, Infant, Magnetic Resonance Imaging, Male, Predictive Value of Tests, Prognosis, Retrospective Studies, Treatment Outcome, Brain Neoplasms pathology, Brain Neoplasms surgery, Glioma pathology, Glioma surgery
- Abstract
Background: Because few reports on outcome in patients with pediatric malignant gliomas during the magnetic resonance imaging era were available, the authors studied the outcomes of children with these tumors at their institution., Methods: The medical records of 39 patients with nonbrainstem, malignant gliomas who were treated at the Hospital of the University of Pennsylvania/Children's Hospital of Philadelphia between February 1, 1989 and December 31, 2000 were reviewed retrospectively. Magnetic resonance imaging was used to assess tumors at presentation and at follow-up. Progression-free survival (PFS) and overall survival (OS) were determined using the Kaplan-Meier method. Univariate and multivariate analyses were performed using a Cox proportional hazards model., Results: The median follow-up for the 14 surviving patients was 47.6 months. The median PFS for all patients was 12.2 months, and the median OS for all patients was 21.3 months. The extent of surgery was the strongest prognostic factor for predicting outcomes in these patients, with a median survival of 122.2 months in patients who underwent macroscopic total resection compared with 14.1 months in patients who had significant residual disease after surgery. In univariate analyses, other than the extent of surgery, only the absence of visual symptoms at diagnosis significantly predicted improved OS. Local control was improved for patients who underwent better resection and had smaller tumors. In multivariate analyses, although the extent of surgery continued to predict outcomes significantly, histologic grade, which was not significant in the univariate analysis, also was significant., Conclusions: Children with malignant gliomas appeared to fare better than their adult counterparts. Because the extent of resection was one of the strongest predictors of outcome, the authors concluded that the optimal therapy for these patients would include the maximal possible resection., (Copyright 2004 American Cancer Society.)
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- 2004
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16. Surgery with or without radiation therapy in the management of craniopharyngiomas in children and young adults.
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Stripp DC, Maity A, Janss AJ, Belasco JB, Tochner ZA, Goldwein JW, Moshang T, Rorke LB, Phillips PC, Sutton LN, and Shu HK
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- Adolescent, Adult, Analysis of Variance, Cause of Death, Child, Child, Preschool, Combined Modality Therapy, Craniopharyngioma mortality, Female, Humans, Infant, Male, Pituitary Diseases etiology, Pituitary Neoplasms mortality, Retrospective Studies, Treatment Outcome, Craniopharyngioma radiotherapy, Craniopharyngioma surgery, Pituitary Neoplasms radiotherapy, Pituitary Neoplasms surgery
- Abstract
Purpose: The optimal management of craniopharyngiomas remains controversial, especially in children and young adults. This study reports a single institution's experience with such patients., Methods and Materials: Between 1974 and 2001, 76 patients were treated for craniopharyngioma at the Children's Hospital of Philadelphia and the Hospital of University of Pennsylvania (HUP). Of these, 75 patients (97%) were evaluable with long-term follow-up. Although all patients underwent attempted gross total resection, 27 had documentation of less than total resection with 18 of these patients receiving immediate postoperative radiotherapy (RT). An additional 22 patients received RT at HUP after failing surgery alone., Results: Median follow-up for all patients was 7.6 years. The 10-year actuarial overall survival, relapse-free survival, and local control (LC) rates for all patients were 85%, 48%, and 53%, respectively. When comparing the 57 patients treated with surgery alone to the 18 treated with subtotal resection (STR) followed by RT, a significant difference in LC rates at 10 years (42% vs. 84%, respectively; p = 0.004) was noted. However, no statistically significant difference in overall survival was found between the two groups, because RT was highly effective as salvage therapy. Twenty-two patients at HUP treated with RT after relapse had a 10-year ultimate LC rate comparable to that of patients who received RT immediately after STR., Conclusion: RT given either immediately after STR or at relapse is effective in controlling craniopharyngiomas.
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- 2004
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17. Loss of caspase-8 protein expression correlates with unfavorable survival outcome in childhood medulloblastoma.
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Pingoud-Meier C, Lang D, Janss AJ, Rorke LB, Phillips PC, Shalaby T, and Grotzer MA
- Subjects
- Apoptosis, Blotting, Western, Caspase 8, Caspase 9, Child, Preschool, DNA Methylation, Disease-Free Survival, Dose-Response Relationship, Drug, Female, Humans, Immunohistochemistry, Infant, Interferon-gamma metabolism, Male, Multivariate Analysis, Neoplasm Metastasis, Prognosis, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Treatment Outcome, Caspases biosynthesis, Medulloblastoma enzymology, Medulloblastoma mortality
- Abstract
Purpose: Escaping apoptosis is a hallmark of cancer. In medulloblastoma (MB) cell lines, resistance to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis was recently shown to correlate with loss of caspase-8 mRNA expression, because of aberrant gene methylation (M. A. Grotzer et al., Oncogene, 19: 4604-4610, 2000). Loss of caspase-8 mRNA expression has been demonstrated in a subset of primary MB (T. J. Zuzak et al., Eur. J. Cancer, 38: 83-91, 2002). In this study, we analyzed primary MB samples to test whether loss of caspases correlates with survival outcome., Experimental Design: We used immunohistochemistry to analyze the protein expression of the key initiator caspase-8 and caspase-9 in paraffin-embedded tumor samples from 77 well characterized MB patients and compared the expression levels of caspase-8 and caspase-9 with apoptosis indices, clinical variables, and survival outcomes., Results: Weak expression of caspase-8 and caspase-9 was found in 16 and 24% of the MB samples evaluated, respectively. Weak expression of caspase-8 was an independent significant prognostic factor for unfavorable progression-free survival outcome and was more predictive than standard clinical factors. In contrast, caspase-9 expression was not a prognostic factor. Treatment of caspase-8-deficient MB cells with IFN-gamma resulted in dose-dependent restoration of caspase-8 mRNA and protein expression and restoration of tumor necrosis factor-related apoptosis-inducing ligand sensitivity., Conclusions: Loss of initiator caspase-8 is associated with an unfavorable survival outcome. Restoration of caspase-8 (e.g., by treatment with IFN-gamma) might, therefore, represent a novel experimental therapy in childhood MB.
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- 2003
18. Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop.
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Packer RJ, Biegel JA, Blaney S, Finlay J, Geyer JR, Heideman R, Hilden J, Janss AJ, Kun L, Vezina G, Rorke LB, and Smith M
- Subjects
- Antineoplastic Agents therapeutic use, Brain Neoplasms genetics, Brain Neoplasms therapy, Child, Preschool, Chromosomal Proteins, Non-Histone, Chromosome Deletion, Chromosomes, Human, Pair 22 genetics, DNA-Binding Proteins genetics, General Surgery, Humans, Infant, Monosomy, Neoplasm Proteins genetics, Radiotherapy, Rhabdoid Tumor genetics, Rhabdoid Tumor therapy, SMARCB1 Protein, Teratoma genetics, Teratoma therapy, Transcription Factors, Brain Neoplasms pathology, Rhabdoid Tumor pathology, Teratoma pathology
- Abstract
Childhood atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system (CNS) is a recently described entity. Diagnosis is based on distinctive light microscopy and immunohistochemical findings, coupled with molecular genetic analysis. Most AT/RTs demonstrate monosomy 22 or deletions of chromosome band 22q11 with alterations of the hSNF5/INI1 gene. The tumor's incidence is still undefined, but it may comprise as high as 1 in 4 primitive CNS tumors in infants. Treatment is far from optimal, but there are occasional long-term survivors, especially among older children. Therapeutic approached have included surgery, chemotherapy, and radiotherapy. Prospective clinical trials are needed for children with AT/RTs.
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- 2002
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19. Angiogenic profile of childhood primitive neuroectodermal brain tumours/medulloblastomas.
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Huber H, Eggert A, Janss AJ, Wiewrodt R, Zhao H, Sutton LN, Rorke LB, Phillips PC, and Grotzer MA
- Subjects
- Adolescent, Angiogenesis Inducing Agents genetics, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Brain Neoplasms metabolism, Child, Child, Preschool, Follow-Up Studies, Gene Expression, Glioma metabolism, Humans, Infant, Medulloblastoma blood supply, Medulloblastoma metabolism, Neovascularization, Pathologic pathology, Neuroectodermal Tumors, Primitive metabolism, RNA, Messenger genetics, RNA, Neoplasm genetics, Receptor, trkC genetics, Receptor, trkC metabolism, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Tumor Cells, Cultured, Angiogenesis Inducing Agents metabolism, Brain Neoplasms blood supply, Neovascularization, Pathologic metabolism, Neuroectodermal Tumors, Primitive blood supply
- Abstract
Primitive neuroectodermal brain tumours (PNET) including medulloblastomas (PNET/MB) are the most common malignant brain tumours of childhood. Similar to many other brain tumours, PNET/MB often show marked neovascularisation. To determine which angiogenic factors contribute to PNET/MB angiogenesis, we examined the expression of eight angiogenic factors (vascular endothelial growth factors (VEGF, VEGF-B, VEGF-C), basic fibroblast growth factor (bFGF), angiopoetins (Ang-1, Ang-2), transforming growth factor (TGF-alpha), and platelet-derived endothelial growth factor (PDGF-A)) by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in six PNET cell lines and 28 primary PNET/MB. Expression levels of angiogenic factors were compared with microvessel density, TrkC mRNA expression, clinical variables and survival outcomes. Our results indicate that all PNET/MB tested produce a wide range of angiogenic factors that are, individually or together, likely to play a direct role in PNET/MB tumour growth. This suggests that anti-angiogenesis approaches targeting VEGF alone may be insufficient in PNET/MB.
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- 2001
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20. MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma.
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Grotzer MA, Hogarty MD, Janss AJ, Liu X, Zhao H, Eggert A, Sutton LN, Rorke LB, Brodeur GM, and Phillips PC
- Subjects
- Cerebellar Neoplasms genetics, Child, Child, Preschool, Female, Gene Expression Regulation, Neoplastic, Humans, Infant, Male, Medulloblastoma genetics, Medulloblastoma pathology, Neuroectodermal Tumors, Primitive genetics, Predictive Value of Tests, Prognosis, RNA, Messenger genetics, Receptor, trkC genetics, Reverse Transcriptase Polymerase Chain Reaction, Survival Analysis, Tumor Cells, Cultured, Cerebellar Neoplasms pathology, Genes, myc genetics, Neuroectodermal Tumors, Primitive pathology, RNA, Messenger metabolism
- Abstract
Purpose and Experimental Design: Cerebellar primitive neuroectodermal tumors/medulloblastomas (PNET/MB) are the most common malignant brain tumors in childhood. To identify PNET/MB biological prognostic factors that define a patient group with a sufficiently good prognosis to permit a reduction in treatment intensity, we determined the expression levels of MYC mRNA in fresh frozen tumor samples from 26 PNET/MB patients using semiquantitative reverse transcription-PCR., Results: MYC mRNA expression levels in primary PNET/MB showed a wide range with a 22-fold difference between the highest and lowest values and did not correlate with MYC gene amplification. MYC mRNA expression was an independent significant prognostic factor for progression-free survival outcome and was more predictive than standard clinical factors. The combination of low MYC mRNA expression and high TrkC mRNA expression identified a good outcome group of PNET/MB patients (n = 7) with 100% progression-free survival after a median follow-up time of 55 months (range, 15-91 months). Three of these seven good outcome patients survived without radiotherapy., Conclusions: Low MYC mRNA expression is a powerful independent predictor of favorable clinical outcome in PNET/MB. Assessment of MYC mRNA levels is feasible and may be incorporated in prospective PNET/MB clinical trials to aid in treatment planning for patients with PNET/MB on confirmation of our results in larger studies.
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- 2001
21. Visual loss in children with neurofibromatosis type 1 and optic pathway gliomas: relation to tumor location by magnetic resonance imaging.
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Balcer LJ, Liu GT, Heller G, Bilaniuk L, Volpe NJ, Galetta SL, Molloy PT, Phillips PC, Janss AJ, Vaughn S, and Maguire MG
- Subjects
- Adolescent, Child, Child, Preschool, Cohort Studies, Humans, Magnetic Resonance Imaging, Neurofibromatosis 1 diagnosis, Optic Chiasm pathology, Optic Nerve Glioma diagnosis, Optic Nerve Neoplasms diagnosis, Vision Disorders diagnosis, Visual Acuity
- Abstract
Purpose: To examine the potential for visual acuity loss, and its relation to extent and location of optic pathway gliomas in a cohort of children with neurofibromatosis type 1 studied with magnetic resonance imaging., Methods: We reviewed the neuro-ophthalmologic records and brain/orbital magnetic resonance imaging scans for 43 consecutive pediatric patients with neurofibromatosis type 1 and optic pathway gliomas who were followed at the Children's Hospital of Philadelphia. The presence of visual loss, defined as abnormal visual acuity for age in one or both eyes, was determined. Optic pathway gliomas were classified by tumor extent and location according to involvement of the optic nerves, chiasm, and postchiasmal structures by magnetic resonance imaging., Results: Involvement of the optic tracts and other postchiasmal structures at tumor diagnosis was associated with a significantly higher probability of visual acuity loss (P =.048, chi-square test). Visual loss was noted in 20 of 43 patients (47%) at a median age of 4 years; however, three patients developed visual acuity loss for the first time during adolescence., Conclusions: In pediatric patients with neurofibromatosis type 1 and optic pathway gliomas, the likelihood of visual loss is dependent on the extent and location of the tumor by magnetic resonance imaging and is particularly associated with involvement of postchiasmal structures. Furthermore, older age during childhood (adolescence) does not preclude the occurrence of visual loss. Close follow-up beyond the early childhood years, particularly for those with postchiasmal tumor, is recommended.
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- 2001
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22. High microvessel density in primitive neuroectodermal brain tumors of childhood.
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Grotzer MA, Wiewrodt R, Janss AJ, Zhao H, Cnaan A, Sutton LN, Rorke LB, and Phillips PC
- Subjects
- Adolescent, Adult, Brain Neoplasms mortality, Brain Neoplasms pathology, Cell Division physiology, Cerebellar Neoplasms blood supply, Cerebellar Neoplasms mortality, Cerebellar Neoplasms pathology, Child, Child, Preschool, Female, Follow-Up Studies, Glial Fibrillary Acidic Protein metabolism, Humans, Infant, Male, Medulloblastoma blood supply, Medulloblastoma mortality, Medulloblastoma pathology, Microcirculation pathology, Neovascularization, Pathologic mortality, Neuroectodermal Tumors, Primitive mortality, Neuroectodermal Tumors, Primitive pathology, Survival Rate, Brain Neoplasms blood supply, Neovascularization, Pathologic pathology, Neuroectodermal Tumors, Primitive blood supply
- Abstract
Microvessel density (MVD), a measure of tumor angiogenesis, has been shown to correlate significantly with overall and progression-free survival outcomes in various cancers including astrocytic brain tumors. To assess if the MVD is an independent prognostic factor in primitive neuroectodermal tumors (PNET) of the central nervous system, formalin-fixed paraffin-embedded tumor sections of 78 children with PNET were studied by CD34 immunohistochemistry to highlight endothelial cells. Microvessel density was determined in the most active area of neovascularization according to well-established methods. While it was shown that MVD showed considerable inter-tumor variability (median 75; range 20-345 microvessels per 0.7 mm2 field), no significant associations were found between MVD and metastasis or survival outcomes. We conclude that many PNETs are highly vascular CNS tumors, indicating potent angiogenic activity. Therefore, these tumors would be good candidates for antiangiogenic strategies. However, MVD determined in the most active area of neovascularization is not a predictor of metastatic potential or survival outcomes in childhood PNET.
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- 2001
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23. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy.
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Geoerger B, Kerr K, Tang CB, Fung KM, Powell B, Sutton LN, Phillips PC, and Janss AJ
- Subjects
- Animals, Antibiotics, Antineoplastic administration & dosage, Camptothecin administration & dosage, Cell Division drug effects, Cisplatin administration & dosage, Drug Synergism, Female, Glioma drug therapy, Growth Inhibitors pharmacology, Humans, Mice, Mice, Nude, Sirolimus administration & dosage, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Antibiotics, Antineoplastic pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Brain Neoplasms drug therapy, Medulloblastoma drug therapy, Neuroectodermal Tumors, Primitive drug therapy, Sirolimus analogs & derivatives, Sirolimus pharmacology
- Abstract
We examined the cytotoxicity of the immunosuppressant agent rapamycin and its analogue CCI-779 in human brain tumor cell lines in vitro and in vivo as single agents and in combination with standard chemotherapeutic drugs. In the rapamycin-sensitive PNET/MB cell line DAOY, rapamycin exhibited additive cytotoxicity with cisplatin and with camptothecin. In vivo, CCI-779 delayed DAOY xenograft growth by 160% after 1 week and 240% after 2 weeks of systemic treatment, compared with controls. Single high-dose treatment induced 37% regression of tumor solume. Growth inhibition of DAOY xenografts was 1.3 times greater after simultaneous treatment with CCI-779 and cisplatin than after cisplatin alone. Interestingly, CCI-779 also produced growth inhibition of xenografts derived from U251 malignant glioma cells, a human cell line resistant to rapamycin in vitro. These studies suggest that the rapamycin analogue CCI-779 is an important new agent to investigate in the treatment of human brain tumors, particularly PNET/MB.
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- 2001
24. Reversible posterior leukoencephalopathy during the treatment of acute lymphoblastic leukemia.
- Author
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Shin RK, Stern JW, Janss AJ, Hunter JV, and Liu GT
- Subjects
- Brain pathology, Child, Female, Humans, Magnetic Resonance Imaging, Male, Brain Diseases etiology, Brain Diseases pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications
- Abstract
Three children with acute lymphoblastic leukemia developed altered mental status, headaches, seizures, and visual changes associated with reversible posterior cerebral changes on MRI. These clinical and radiologic findings were consistent with the reversible posterior leukoencephalopathy syndrome, which has not been widely recognized in this setting.
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- 2001
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25. Prognostic significance of Ki-67 (MIB-1) proliferation index in childhood primitive neuroectodermal tumors of the central nervous system.
- Author
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Grotzer MA, Geoerger B, Janss AJ, Zhao H, Rorke LB, and Phillips PC
- Subjects
- Adolescent, Adult, Brain Neoplasms mortality, Cell Division, Child, Child, Preschool, Humans, Immunohistochemistry, Infant, Neuroectodermal Tumors, Primitive mortality, Prognosis, Brain Neoplasms pathology, Ki-67 Antigen analysis, Neuroectodermal Tumors, Primitive pathology
- Abstract
Background: Primitive neuroectodermal tumors (PNET) of the central nervous system, including medulloblastomas, are the most common malignant brain tumors of childhood. Whereas some patients experience prolonged disease control after surgery and adjuvant therapy, others with tumors that appear comparable will relapse and eventually die from progressive disease., Procedure: Because proliferative activity may provide a potential correlate of biologic aggressiveness, PNETs of 78 well-characterized patients were evaluated by Ki-67 (MIB-1) immunohistochemistry. Proliferation indices (PI) were determined by counting Ki-67 (MIB-1) positive tumor cells either in the highest staining region (hot spot PI), or in at least 15 randomly chosen fields (random PI)., Results: Twenty-five of 78 PNETs showed amore than twofold higher value of hot spot PI (median 9.3%; range 0.6-56%), compared to random PI (median 5.6%; range 0.2-41.3%), Univariate Cox regression analysis revealed that PNETs with a high hot spot PI had a significantly greater risk of progression and death than PNETs with a low hot spot PI (hazard ratio 1.58, P = 0.04). The hazard ratio remained significant after adjusting for M-stage in multivariate analysis. In contrast to hot spot PI, random PI proved not to be a significant prognostic predictor., Conclusions: Hot spot PI is a significant and independent prognostic factor in PNETs. Its assessment is uncomplicated, reliable, and may supplement routine histologic examination as a means for improving the accuracy of predicting the biologic behavior of childhood PNETs.
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- 2001
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26. Growth hormone replacement therapy in children with medulloblastoma: use and effect on tumor control.
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Packer RJ, Boyett JM, Janss AJ, Stavrou T, Kun L, Wisoff J, Russo C, Geyer R, Phillips P, Kieran M, Greenberg M, Goldman S, Hyder D, Heideman R, Jones-Wallace D, August GP, Smith SH, and Moshang T
- Subjects
- Adolescent, Cerebellar Neoplasms therapy, Child, Child, Preschool, Hormone Replacement Therapy, Human Growth Hormone deficiency, Humans, Medulloblastoma therapy, Neoplasm Recurrence, Local, Proportional Hazards Models, Retrospective Studies, Survival Analysis, Cerebellar Neoplasms complications, Growth Disorders drug therapy, Growth Disorders etiology, Human Growth Hormone therapeutic use, Medulloblastoma complications
- Abstract
Purpose: Progress has been made in the treatment of medulloblastoma, the most common childhood malignant brain tumor: However, many long-term survivors will have posttherapy growth hormone insufficiency with resultant linear growth retardation. Growth hormone replacement therapy (GHRT) may significantly improve growth, but there is often reluctance to initiate GHRT because of concerns of an increased likelihood of tumor relapse., Patients and Methods: This study retrospectively reviewed the use of GHRT for survivors of medulloblastoma in 11 neuro-oncology centers in North America who received initial treatment for disease between 1980 and 1993 to determine its impact on disease control. A Landmark analysis was used to evaluate the relative risk of relapse in surviving patients., Results: Five hundred forty-five consecutive patients less than 15 years of age at diagnosis were identified. Six-year progression-free survival (mean +/- SD) was 40% +/- 5% in children less than 3 years of age at diagnosis compared with 59% +/- 3% for older patients. Older patients with total or near-total resections (P = .003) and localized disease at diagnosis (P < .0001) had the highest likelihood of survival. One hundred seventy patients (33% +/- 3% of the cohort) received GHRT. GHRT use varied widely among institutions, ranging from 5% to 73%. GHRT was begun a mean of 3.9 years after diagnosis, later in children younger than 3 years at diagnosis (5.4 years). By Landmark analyses, for those surviving 2, 3, and 5 years after diagnosis, there was no evidence that GHRT increased the rate of disease relapse., Conclusion: This large retrospective review demonstrates that GHRT is underutilized in survivors of medulloblastoma and is used relatively late in the course of the illness. GHRT is not associated with an increased likelihood of disease relapse.
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- 2001
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27. Decreased cyclin B1 expression contributes to G2 delay in human brain tumor cells after treatment with camptothecin.
- Author
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Janss AJ, Maity A, Tang CB, Muschel RJ, McKenna WG, Sutton L, and Phillips PC
- Subjects
- Brain Neoplasms pathology, CDC2 Protein Kinase metabolism, Cyclin A biosynthesis, Cyclin A genetics, Cyclin B genetics, Cyclin B1, Glioma pathology, Humans, Medulloblastoma pathology, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, RNA, Messenger biosynthesis, RNA, Messenger genetics, Tumor Cells, Cultured drug effects, Antineoplastic Agents, Phytogenic pharmacology, Brain Neoplasms genetics, Camptothecin pharmacology, Cyclin B biosynthesis, Enzyme Inhibitors pharmacology, G2 Phase drug effects, Gene Expression Regulation, Neoplastic drug effects, Glioma genetics, Medulloblastoma genetics, Neoplasm Proteins biosynthesis, Topoisomerase I Inhibitors
- Abstract
DNA damage produces delayed mitosis (G2/M delay) in proliferating cells, and shortening the delay sensitizes human malignant glioma and medulloblastoma cells to cytotoxic chemotherapy. Although activation of the cyclin-dependent kinase CDC2 mediates G2/M transition in all tumor cells studied to date, regulation of CDC2 varies between tumor types. Persistent hyperphosphorylation of kinase and reduced cyclin expression have been implicated as mediators of treatment-induced G2 delay in different tumor models. To evaluate regulation of G2/M transition in human brain tumors, we studied the expression and/or activity of CDC2 kinase and cyclins A and B1 in U-251 MG and DAOY medulloblastoma cells after their treatment with camptothecin (CPT). Synchronized cells were treated during S phase, then harvested at predetermined intervals for evaluation of cell cycle kinetics, kinase activity mRNA, and protein expression. CPT produced G2 delay associated with decreased CDC2 kinase activity and cyclin B1 expression. Kinase activity was associated with CDC2 bound to cyclin B1, not cyclin A, in both cell lines. Cyclin A mRNA and protein expression were reduced after CPT treatment; however, decreased protein expression was short lived and moderate in the glioma and primitive neuroectodermal tumor/medulloblastoma cells, respectively. We conclude that G2 delay is a common response of brain tumor cells to chemotherapy with topoisomerase I inhibitors and that a mechanism of this delay may be reduced expression of cyclin B1.
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- 2001
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28. Abundance of apoptotic neoplastic cells in diagnostic biopsy samples is not a prognostic factor in childhood primitive neuroectodermal tumors of the central nervous system.
- Author
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Grotzer MA, Janss AJ, Fung KM, Sutton LN, Zhao H, Trojanowski JQ, Rorke LB, and Phillips PC
- Subjects
- Biopsy, Brain Neoplasms mortality, Brain Neoplasms therapy, Cerebellar Neoplasms mortality, Cerebellar Neoplasms pathology, Cerebellar Neoplasms therapy, Child, Child, Preschool, Disease-Free Survival, Female, Humans, In Situ Nick-End Labeling methods, Male, Meningeal Neoplasms pathology, Meningeal Neoplasms secondary, Neoplasm Staging, Neuroectodermal Tumors, Primitive mortality, Neuroectodermal Tumors, Primitive secondary, Neuroectodermal Tumors, Primitive therapy, Prognosis, Retrospective Studies, Supratentorial Neoplasms mortality, Supratentorial Neoplasms pathology, Supratentorial Neoplasms therapy, Survival Rate, Apoptosis, Brain Neoplasms pathology, Neuroectodermal Tumors, Primitive pathology
- Abstract
Purpose: To assess if the abundance of apoptotic tumor cells is an independent prognostic factor in primitive neuroectodermal tumors (PNET) of the central nervous system., Patients and Methods: Formalin-fixed paraffin-embedded tumor tissue sections from 78 clinically well-characterized children with PNET were evaluated by terminal deoxytransferase-mediated deoxyuridinie-5'-triphosphate (dUTP) nick-end labeling (TUNEL). Apoptotic indices (AI) were determined by counting TUNEL-positive tumor cells either in the highest staining region (AI hot spot) or in at least 15 randomly chosen fields (AI random). The AI hot spot and AI random were then correlated with clinical variables and survival outcome., Results: AI hot spot (median 0.56%; range 0%-6.54%) and AI random (median 0.30%; range 0%-3.21%) showed considerable intertumor variability. Moreover, 53% of the evaluated PNET showed a more than two-fold difference between AI hot spot and AI random, showing important intratumoral variability of the abundance of apoptotic cells in a subset of the evaluated PNET. No significant associations were found between AI hot spot and AI random with clinical variables or survival outcome., Conclusion: The apoptotic index does not predict survival outcome and is not specifically associated with clinical variables of prognostic significance in childhood PNET.
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- 2001
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29. Resistance to TRAIL-induced apoptosis in primitive neuroectodermal brain tumor cells correlates with a loss of caspase-8 expression.
- Author
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Grotzer MA, Eggert A, Zuzak TJ, Janss AJ, Marwaha S, Wiewrodt BR, Ikegaki N, Brodeur GM, and Phillips PC
- Subjects
- Adult, Antimetabolites, Antineoplastic pharmacology, Apoptosis Regulatory Proteins, Azacitidine analogs & derivatives, Azacitidine pharmacology, CASP8 and FADD-Like Apoptosis Regulating Protein, Carrier Proteins physiology, Caspase 8, Caspase 9, Caspases biosynthesis, Caspases deficiency, Caspases genetics, Child, Cycloheximide pharmacology, DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors, DNA Methylation drug effects, Decitabine, Drug Resistance, Enzyme Induction, Enzyme Inhibitors pharmacology, Humans, Jurkat Cells drug effects, Jurkat Cells metabolism, Neoplasm Proteins biosynthesis, Neoplasm Proteins deficiency, Neoplasm Proteins genetics, Neuroectodermal Tumors, Primitive enzymology, Protein Synthesis Inhibitors pharmacology, RNA, Messenger biosynthesis, RNA, Neoplasm biosynthesis, Receptors, Tumor Necrosis Factor drug effects, Recombinant Proteins pharmacology, TNF-Related Apoptosis-Inducing Ligand, Transcription, Genetic, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured enzymology, Apoptosis drug effects, Caspases physiology, Gene Expression Regulation, Neoplastic drug effects, Intracellular Signaling Peptides and Proteins, Membrane Glycoproteins pharmacology, Neoplasm Proteins physiology, Neuroectodermal Tumors, Primitive pathology, Tumor Necrosis Factor-alpha pharmacology
- Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in adult malignant glioma and various other human solid tumor models but not in normal tissues. To characterize the TRAIL death pathway in childhood primitive neuroectodermal brain tumor (PNET), 8 human PNET cell lines were tested for TRAIL-induced apoptosis. TRAIL-sensitivity of the PNET cell lines was correlated with mRNA expression levels of TRAIL, its agonistic (TRAIL-R1, TRAIL-R2) and antagonistic (TRAIL-R3, TRAIL-R4) receptors, cellular FLICE-like inhibitory protein (cFLIP), caspase-3 and caspase-8. Three of 8 PNET cell lines tested were susceptible to TRAIL-induced apoptosis. Sensitivity to TRAIL-induced apoptosis did not correlate with mRNA expression of TRAIL receptors or cFLIP. However, all TRAIL-sensitive PNET cell lines expressed caspase-8 mRNA and protein, while none of the five TRAIL-resistant PNET cell lines expressed caspase-8 protein. Treatment with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored mRNA expression of caspase-8 and TRAIL-sensitivity in formerly TRAIL-resistant PNET cells, suggesting that gene methylation inhibits caspase-8 transcription in these cells. We conclude, that loss of caspase-8 mRNA is an important mechanism of TRAIL-resistance in PNET cells. Treatment with recombinant soluble TRAIL, possibly in combination with methyltransferase inhibitors, represents a promising therapeutic approach for PNET that deserves further investigation.
- Published
- 2000
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30. Neurotrophin receptor TrkC predicts good clinical outcome in medulloblastoma and other primitive neuroectodermal brain tumors.
- Author
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Grotzer MA, Janss AJ, Phillips PC, and Trojanowski JQ
- Subjects
- Adolescent, Adult, Brain Neoplasms therapy, Child, Child, Preschool, Disease-Free Survival, Female, Gene Expression Regulation, Neoplastic, Humans, In Situ Hybridization, Fluorescence, Infant, Male, Medulloblastoma therapy, Neuroectodermal Tumors, Primitive therapy, Predictive Value of Tests, Proportional Hazards Models, RNA, Messenger analysis, Receptor, trkC genetics, Retrospective Studies, Survival Analysis, Biomarkers, Tumor analysis, Brain Neoplasms chemistry, Medulloblastoma chemistry, Neuroectodermal Tumors, Primitive chemistry, Receptor, trkC analysis
- Abstract
Background: Neurotrophins and their cognate receptors TrkA, TrkB and TrkC regulate proliferation, differentiation and death of neuronal progenitor cells and may be implicated in the progression of medulloblastoma and other primitive neuroectodermal brain tumors (PNET). These common childhood brain tumors are composed of morphologically undifferentiated cells that have important similarities to neuroectodermal progenitor cells of the developing CNS., Patients and Methods: To identify biologic prognostic factors in childhood PNET we determined expression levels of TrkC mRNA in tumor samples from 87 PNET patients by in situ hybridization. Comparison of TrkC mRNA expression levels with clinical variables was performed using univariate and multivariable Cox regression analysis., Results: Cox regression analysis revealed that children with tumors expressing no or little TrkC mRNA had a 4.8-fold (p < 0.00005) greater risk of death than children with tumors with high TrkC mRNA expression. This hazard ratio remained consistent after adjusting for clinical variables. Five-year survival was 89% for patients with PNETs expressing high levels of TrkC mRNA and 47% for patients with PNETs expressing little or no levels of TrkC mRNA (log rank; p < 0.00005)., Conclusions: The TrkC neurotrophin receptor appears to be a powerful independent prognostic factor in PNET and may have a role in patient assignment to risk-based treatment strategies.
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- 2000
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31. Mutations of the INI1 rhabdoid tumor suppressor gene in medulloblastomas and primitive neuroectodermal tumors of the central nervous system.
- Author
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Biegel JA, Fogelgren B, Zhou JY, James CD, Janss AJ, Allen JC, Zagzag D, Raffel C, and Rorke LB
- Subjects
- Adolescent, Adult, Amino Acid Sequence, Base Sequence, Brain Neoplasms surgery, Child, Child, Preschool, Chromosomal Proteins, Non-Histone, Chromosome Mapping, DNA-Binding Proteins chemistry, Frameshift Mutation, Humans, Infant, Infant, Newborn, Karyotyping, Loss of Heterozygosity, Medulloblastoma surgery, Monosomy, Neuroectodermal Tumors, Primitive surgery, SMARCB1 Protein, Sequence Deletion, Transcription Factors, Brain Neoplasms genetics, Chromosomes, Human, Pair 22, DNA-Binding Proteins genetics, Genes, Tumor Suppressor, Medulloblastoma genetics, Mutation, Neuroectodermal Tumors, Primitive genetics
- Abstract
Germ-line and somatic mutations of the hSNF5/INI1 gene have been reported in atypical teratoid/rhabdoid tumors (AT/RTs) of the brain, consistent with its role as a tumor suppressor gene. In the present study, we determined the frequency of deletions and mutations of INI1 in 52 children whose original diagnosis was medulloblastoma (MB) or primitive neuroectodermal tumor (PNET) of the central nervous system. Mutations were detected in DNA isolated from four tumors, all from children less than 3 years of age at diagnosis. Two of the four were reviewed and reclassified as atypical teratoid tumor, whereas there was insufficient material to establish this diagnosis in the two remaining cases. The relatively low frequency of mutations, even in a large series of infants, suggests that loss of sequences from chromosome 22 and/or mutations of INI1 do not account for the poor prognosis of children with MB or PNET who are less than 3 years of age at diagnosis. Nevertheless, chromosome 22 deletion and INI1-mutation analysis of infants with MB/PNET should be considered for all children who are less than 1 year of age. Detection of these mutations suggests that the child has an AT/RT, rather than a MB/PNET, a finding with important prognostic value.
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- 2000
32. Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy.
- Author
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Reddy AT, Janss AJ, Phillips PC, Weiss HL, and Packer RJ
- Subjects
- Adolescent, Antineoplastic Agents administration & dosage, Antineoplastic Agents, Alkylating administration & dosage, Antineoplastic Agents, Phytogenic administration & dosage, Cerebral Cortex drug effects, Cerebral Cortex radiation effects, Cerebral Cortex surgery, Child, Child, Preschool, Cisplatin administration & dosage, Disease Progression, Disease-Free Survival, Follow-Up Studies, Humans, Linear Models, Lomustine administration & dosage, Neoplasm Staging, Neuroectodermal Tumors, Primitive drug therapy, Neuroectodermal Tumors, Primitive radiotherapy, Pinealoma drug therapy, Pinealoma radiotherapy, Pinealoma surgery, Retrospective Studies, Supratentorial Neoplasms drug therapy, Supratentorial Neoplasms radiotherapy, Survival Rate, Thalamic Diseases drug therapy, Thalamic Diseases radiotherapy, Thalamic Diseases surgery, Treatment Outcome, Vincristine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cranial Irradiation, Neuroectodermal Tumors, Primitive surgery, Supratentorial Neoplasms surgery
- Abstract
Background: The outcome of a child with a primitive neuroectodermal tumors arising supratentorially (SPNET) is not well characterized and may differ from the outcome of a patient with a histologically similar cerebellar tumor (medulloblastoma [MB]). Recently, 5-year progression free survival rates as high as 80% have been reported for children with MB treated with craniospinal radiation (CRT) and chemotherapy including cisplatin, lomustine (CCNU), and vincristine (VCR)., Methods: The authors reviewed the outcome of 22 consecutive patients age 3 years and older (mean age, 10 years; range, 3-18 years) with SPNET who were treated at the study institutions between 1981 and 1996. Tumor location included was 13 pineal, 6 cortical, and 3 thalamic or suprasellar. Five patients had disease dissemination at diagnosis. All patients underwent surgery and staging, followed by CRT and chemotherapy with cisplatin, CCNU, and VCR., Results: Of the 22 patients, 13 had developed disease progression and 10 had died at the time of last follow-up. Overall progression free survival (PFS) was 47% +/- 11% at 3 years and 37% +/- 11% at 5 years. There was a significant difference in PFS between patients with localized disease versus those with disseminated disease (P = 0.04). There was no statistical association between tumor location and survival. Although not significant (P = 0.21), there was a trend toward better survival of those patients with complete or near-complete resection compared with those with partial resection or biopsy., Conclusions: The results of the current study demonstrate that the outcome for children with SPNET treated with radiation and chemotherapy appears worse than for children with MB treated with identical therapy. This suggests that there may be biologic differences between supratentorial and infratentorial primitive neuroectodermal tumors, thus requiring refinements in treatment.
- Published
- 2000
- Full Text
- View/download PDF
33. TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors.
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Grotzer MA, Janss AJ, Fung K, Biegel JA, Sutton LN, Rorke LB, Zhao H, Cnaan A, Phillips PC, Lee VM, and Trojanowski JQ
- Subjects
- Adolescent, Adult, Age Factors, Antigens, Differentiation analysis, Brain Neoplasms diagnosis, Brain Neoplasms genetics, Brain Neoplasms mortality, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 17, Female, Humans, Immunohistochemistry, Infant, Male, Neuroectodermal Tumors, Primitive diagnosis, Neuroectodermal Tumors, Primitive genetics, Neuroectodermal Tumors, Primitive mortality, Prognosis, RNA, Messenger biosynthesis, Sex Factors, Survival Analysis, Biomarkers, Tumor biosynthesis, Brain Neoplasms metabolism, Neuroectodermal Tumors, Primitive metabolism, Receptor, trkC biosynthesis
- Abstract
Purpose: To identify biologic prognostic factors in childhood primitive neuroectodermal tumors (PNET), including medulloblastoma, that accurately define patient groups with sufficiently good prognosis to permit a reduction in treatment intensity., Patients and Methods: We determined expression levels of the neurotrophin receptor TrkC mRNA in formalin-fixed tumor samples from 87 well characterized PNET patients using in situ hybridization. Comparison of TrkC mRNA expression levels with clinical and other laboratory variables was performed using univariate and multivariate Cox regression analysis., Results: High TrkC mRNA expression was found to be associated more with higher 5-year cumulative survival rate than was low TrkC mRNA expression (89% v 46%, respectively). When compared with established clinical prognostic factors and laboratory variables of potential prognostic significance, TrkC mRNA expression, by univariate analysis, was found to be the single most powerful predictor of outcome (hazards ratio, 4.81; P <.00005), exceeding all clinical prognostic factors. In multivariate analysis, the hazards ratio remained significant (P <.00005)., Conclusion: High TrkC mRNA expression in PNET is a powerful independent predictor of favorable clinical outcome. Assessment of TrkC mRNA levels may aid in treatment planning for patients with PNETs and should be incorporated prospectively into PNET clinical trials.
- Published
- 2000
- Full Text
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34. Quality of life of adult survivors of germinomas treated with craniospinal irradiation.
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Sutton LN, Radcliffe J, Goldwein JW, Phillips P, Janss AJ, Packer RJ, and Zhao H
- Subjects
- Achievement, Adolescent, Adult, Biopsy, Body Height radiation effects, Body Weight radiation effects, Brain Neoplasms pathology, Brain Neoplasms psychology, Child, Cranial Irradiation, Disability Evaluation, Female, Follow-Up Studies, Germinoma pathology, Germinoma psychology, Humans, Male, Middle Aged, Spinal Cord Neoplasms pathology, Spinal Cord Neoplasms psychology, Treatment Outcome, Brain Neoplasms radiotherapy, Germinoma radiotherapy, Quality of Life, Spinal Cord Neoplasms radiotherapy, Survivors psychology
- Abstract
Objective: To assess the quality of life (QOL) of a group of patients treated for intracranial germinoma with biopsy followed by prophylactic whole-neuraxis radiation therapy., Methods: The Short-form-36 and Functional Assessment of Cancer Therapy QOL questionnaires were completed by 22 of 27 eligible adults treated with whole-neuraxis irradiation for biopsy-proven, marker-negative intracranial germinomas between 1976 and 1996. In addition, data were obtained regarding height and weight, medications, ability to work, and educational achievement., Results: The patients' QOL was generally good. All of the patients are in or have completed high school; nine are in or have completed college, and five have advanced degrees. Patients rated themselves lower on the physical composite scale of the Short-form-36 (average, 46 versus 54 in a normal population). On the mental composite scale, patients rated themselves more favorably than the normal population (average, 54 versus 49 in a normal population). Patients were normally proportioned for height and weight, but female patients tended to be short. Age at radiation did not correlate with QOL., Conclusion: The QOL of adults treated for marker-negative germinoma with prophylactic whole-neuraxis irradiation is generally good. These data should serve as a benchmark for newer treatment protocols eliminating or reducing radiation.
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- 1999
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35. Neuro-oncology-endocrinology interface: A patient who earned her salt.
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Janss AJ, Heller G, Grimberg A, and Ferry R
- Subjects
- Brain Neoplasms diagnostic imaging, Child, Preschool, Electrolytes blood, Electrolytes urine, Female, Humans, Magnetic Resonance Imaging, Pituitary Neoplasms therapy, Potassium blood, Radiography, Respiratory Tract Infections, Retinoblastoma complications, Retinoblastoma congenital, Retinoblastoma diagnostic imaging, Retinoblastoma genetics, Sodium blood, Arcuate Nucleus of Hypothalamus, Brain Neoplasms therapy, Retinoblastoma therapy, Sella Turcica
- Published
- 1999
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36. Caffeine and staurosporine enhance the cytotoxicity of cisplatin and camptothecin in human brain tumor cell lines.
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Janss AJ, Levow C, Bernhard EJ, Muschel RJ, McKenna WG, Sutton L, and Phillips PC
- Subjects
- Apoptosis, Brain Neoplasms pathology, Drug Screening Assays, Antitumor, Drug Synergism, Drug Therapy, Combination, Flow Cytometry, G2 Phase drug effects, Humans, Tumor Cells, Cultured, Brain Neoplasms metabolism, Caffeine administration & dosage, Camptothecin administration & dosage, Cisplatin administration & dosage, Staurosporine administration & dosage
- Abstract
Caffeine and staurosporine have been shown to attenuate G2 delay produced by DNA-damaging agents and to augment the cytotoxicity of these agents in a number of cell lines in vitro. Studies in rodent brain tumor cell lines suggest that modulation of the G2/M transition may not contribute to the enhanced cytotoxicity produced by caffeine in brain tumor cells. To evaluate the impact of agents that decrease G2 delay on the cytotoxicity of chemotherapy in human brain tumor cells, we examined the ability of caffeine and staurosporine to modulate the G2 delay and cytotoxicity produced by cisplatin (CDDP) and camptothecin (CPT) in U251 glioma and DAOY medulloblastoma cells. Synchronized U251 were incubated with 20 microM CDDP in the presence or absence of 2 mM caffeine. DAOY cells were incubated with 100 nM CPT in the presence or absence of 2 nM staurosporine. Caffeine and staurosporine attenuated G2 delay produced by CDDP and CPT, respectively. Clonogenic assays indicated that continuous exposure to 2 mM caffeine substantially lowered the ID50 and ID90 of CDDP in U251 cells without significantly altering plating efficiency. Twenty-four-hour exposure to 2 nM staurosporine lowered the ID50 and ID90 of CPT in DAOY cells without significantly altering plating efficiency. Evaluation of programmed cell death using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assay indicated that one mechanism for synergistic cytotoxicty of caffeine with CDDP and staurosporine with CPT in U251 and DAOY cells, respectively, is to promote apoptosis. These results underscore the importance of understanding regulation of G2/M transition in brain tumor cells. Such an understanding may lead to novel therapies that target G2 check points to augment the efficacy of currently available treatments for brain tumors., (Copyright 1998 Academic Press.)
- Published
- 1998
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37. Synergistic cytotoxicity of topoisomerase I inhibitors with alkylating agents and etoposide in human brain tumor cell lines.
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Janss AJ, Cnaan A, Zhao H, Shpilsky A, Levow C, Sutton L, and Phillips PC
- Subjects
- Cisplatin pharmacology, Cyclophosphamide analogs & derivatives, Cyclophosphamide pharmacology, Dose-Response Relationship, Drug, Drug Synergism, Humans, In Vitro Techniques, Tumor Cells, Cultured metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents, Alkylating pharmacology, Antineoplastic Agents, Phytogenic pharmacology, Brain Neoplasms drug therapy, Camptothecin pharmacology, Etoposide pharmacology, Topoisomerase I Inhibitors, Topotecan pharmacology
- Abstract
To evaluate potential synergistic interactions between topoisomerase I (Topo I) inhibitors, i.e. camptothecin (CPT) and topotecan (TPT), and chemotherapeutic agents known to be active in treatment of brain tumors, in vitro studies were conducted with human glioma and medulloblastoma cell lines. Tumor cells were exposed to CPT or TPT alone or in combination with cisplatin, 4-hydroperoxycyclophosphamide (4-HC), BCNU or etoposide (VP-16). Cytotoxicity was assessed by colony formation assays. Drug interactions were evaluated by means of a novel analytical model which permits statistical evaluation over a range of dose combination. Experimental results were corroborated by published models of drug interaction. Our findings indicate that in vitro cytotoxic interactions in brain tumor cells between Topo I inhibitors and alkylating agents or etoposide depend on drug dose, dose schedule and tumor cell line. Treatment of DAOY medulloblastoma cells with CPT and either cisplatin, 4-HC or VP-16 produced significant synergistic cytotoxicity over a wide range of dose combinations. When VP-16 was administered after CPT, synergy was reduced to a narrow range of dose combinations. For U251 glioma cells, incubation with CPT and cisplatin or 4HC also produced synergistic cytotoxicity over a broad range of dose combinations. By contrast, antagonistic interactions were observed after administration of CPT with BCNU or VP-16. Treatment of U251 cells with CPT and cisplatin produced synergistic or antagonistic cytotoxicity depending on the dose combination used. These findings support a role for pharmacokinetic analysis in multiagent phase 11 trials involving Topo I inhibitors and have important implications for clinical trial design strategies.
- Published
- 1998
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38. Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system.
- Author
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Biegel JA, Janss AJ, Raffel C, Sutton L, Rorke LB, Harper JM, and Phillips PC
- Subjects
- Age Factors, Brain Neoplasms mortality, Brain Neoplasms pathology, Brain Neoplasms surgery, Cerebellar Neoplasms genetics, Cerebellar Neoplasms mortality, Cerebellar Neoplasms pathology, Cerebellar Neoplasms surgery, Child, Preschool, Chromosome Mapping, Female, Humans, Male, Medulloblastoma mortality, Medulloblastoma pathology, Medulloblastoma surgery, Multivariate Analysis, Neoplasm Staging, Neuroectodermal Tumors, Primitive mortality, Neuroectodermal Tumors, Primitive pathology, Neuroectodermal Tumors, Primitive surgery, Prognosis, Survival Analysis, Brain Neoplasms genetics, Chromosome Deletion, Chromosomes, Human, Pair 17, Medulloblastoma genetics, Neuroectodermal Tumors, Primitive genetics
- Abstract
Deletions in the short arm of chromosome 17 (17p) are the most common genetic abnormality in primitive neuroectodermal tumors of the posterior fossa/medulloblastoma (PNET/Mb). The biological consequences of these deletions are not known for children with PNET/Mb; however, the presence of a tumor suppressor gene located in 17p, distinct from p53, has been implicated in tumorigenesis. Two recent studies suggest that 17p deletions in PNET/Mb are associated with a poor prognosis. To address this question, we identified deletions of chromosome 17p by cytogenetic and/or molecular biology methods in tumor biopsy samples from 56 patients with PNET/Mb. Associations between clinical characteristics or survival outcomes and 17p status were examined by multivariate analysis. Forty-one percent of PNET/Mb cases had a deletion of 17p. No significant association was found between 17p deletion and shorter survival duration or higher metastatic stage. Multivariate analysis did not find independent prognostic significance for 17p deletions after accounting for the effects of significant clinical variables. A larger study of the prognostic value of 17p deletion should be considered; however, clinical use of this factor to distinguish high-risk from standard-risk PNET/Mb populations is not warranted at this time.
- Published
- 1997
39. Glial differentiation predicts poor clinical outcome in primitive neuroectodermal brain tumors.
- Author
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Janss AJ, Yachnis AT, Silber JH, Trojanowski JQ, Lee VM, Sutton LN, Perilongo G, Rorke LB, and Phillips PC
- Subjects
- Adolescent, Adult, Antigens metabolism, Arrestin, Brain Neoplasms metabolism, Cell Differentiation, Child, Child, Preschool, Eye Proteins metabolism, Female, Forecasting, Glial Fibrillary Acidic Protein metabolism, Humans, Infant, Male, Neuroectodermal Tumors, Primitive metabolism, Neurofilament Proteins metabolism, Recurrence, Survival Analysis, Treatment Outcome, Brain Neoplasms pathology, Brain Neoplasms therapy, Neuroectodermal Tumors, Primitive pathology, Neuroectodermal Tumors, Primitive therapy, Neuroglia pathology
- Abstract
Primitive neuroectodermal tumors (PNETs) of the central nervous system, including medulloblastomas (PNET/MB), are the most common malignant brain tumor of childhood. These tumors often express proteins characteristic of glial differentiation (glial fibrillary acidic protein, GFAP), neuronal differentiation (neurofilament proteins, NFPs), and/or photoreceptor differentiation (retinal-S antigen). To identify biological factors of prognostic significance in PNETs, the expression of glial, neuronal, or photoreceptor antigens was evaluated in the tumor specimens of 86 patients with PNETs by immunohistochemistry after microwave antigen enhancement. Patterns of differentiation were then compared with patient relapse-free survival. Multivariate analysis of PNET immunohistochemistry and clinical variables indicated GFAP expression conferred a 6.7-fold greater risk of relapse than tumors that did not express GFAP or NFPs. Increased risk of relapse was directly related to the amount of GFAP expression. Tumors exhibiting clumps or sheets of GFAP-staining cells were associated with a 3.0-fold increased risk of relapse compared with tumors that did not express GFAP, irrespective of immunohistochemical evidence of other differentiation, while scattered GFAP staining was not associated with increased risk of relapse. These findings indicate that expression of GFAP in PNETs has prognostic power comparable with the most significant clinical factors currently used to predict clinical outcome.
- Published
- 1996
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40. Isochromosome 17q demonstrated by interphase fluorescence in situ hybridization in primitive neuroectodermal tumors of the central nervous system.
- Author
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Biegel JA, Rorke LB, Janss AJ, Sutton LN, and Parmiter AH
- Subjects
- Adolescent, Central Nervous System Neoplasms pathology, Child, Chromosome Mapping, Female, Genetic Markers, Humans, In Situ Hybridization, Fluorescence, Interphase, Karyotyping, Male, Neuroectodermal Tumors, Primitive pathology, Sequence Deletion, Central Nervous System Neoplasms genetics, Chromosomes, Human, Pair 17, Isochromosomes, Neuroectodermal Tumors, Primitive genetics
- Abstract
We previously reported an i(17q) as a non-random finding in childhood primitive neuroectodermal tumors (PNETs) of the central nervous system. In the present study, we describe a two-color interphase fluorescence in situ hybridization (FISH) assay for detection of chromosome 17 abnormalities in tumors. Thirty-four PNETs were analyzed by FISH with a series of chromosome 17-specific probes which map to 17p13.3-17q25. The results from the FISH assay were then compared to the karyotypes prepared from the tumors. Ten of the 34 cases demonstrated an i(17q) by FISH and standard cytogenetics. Two PNETs were shown to have an i(17q) by FISH alone, and three additional tumors had deletions of 17p. Thus, a total of 15 of 34 (44%) of the PNETs in this series had a deletion of 17p. This study confirms and extends our previous reports that an i(17q) is the most common cytogenetic abnormality in PNETs. The interphase FISH assay which we employed will have clinical utility for diagnosis of children with malignant brain tumors, and it may be used for identification of tumors with 17p deletions for molecular studies aimed at identifying disease genes.
- Published
- 1995
- Full Text
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41. Optic pathway and hypothalamic/chiasmatic gliomas in children younger than age 5 years with a 6-year follow-up.
- Author
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Janss AJ, Grundy R, Cnaan A, Savino PJ, Packer RJ, Zackai EH, Goldwein JW, Sutton LN, Radcliffe J, and Molloy PT
- Subjects
- Child Behavior Disorders etiology, Child, Preschool, Combined Modality Therapy, Cranial Nerve Neoplasms complications, Cranial Nerve Neoplasms mortality, Disease-Free Survival, Endocrine System Diseases etiology, Female, Follow-Up Studies, Glioma complications, Glioma mortality, Humans, Hypothalamic Neoplasms complications, Hypothalamic Neoplasms mortality, Infant, Intelligence, Male, Optic Nerve Diseases complications, Optic Nerve Diseases mortality, Retrospective Studies, Survival Analysis, Treatment Outcome, Cranial Nerve Neoplasms therapy, Glioma therapy, Hypothalamic Neoplasms therapy, Optic Nerve Diseases therapy, Radiotherapy adverse effects
- Abstract
Background: Gliomas of the hypothalamus and optic pathways (H/OPG) comprise 5% of pediatric intracranial tumors, present most frequently in patients younger than age 5 years, and may have a more aggressive course in younger children. This study examined clinical characteristics and consequences of treatment of young children diagnosed with H/OPG:, Methods: The authors reviewed the course, treatment, and outcomes of 46 children diagnosed with H/OPG younger than age 5 years; the median follow-up was 72 months. The median age at diagnosis was 27 months., Results: Fifteen (33%) of 46 patients had neurofibromatosis-1 (NF-1). Forty children (87%) had tumor progression in the follow-up period, and tumor growth was less common in children with NF-1. Initial therapy was limited to surgical resection in three and radiation in five children. To postpone radiation until after the age of 5 years, initial therapy was limited to chemotherapy in 32 patients. Radiation was not required in 9 of these patients and was postponed for 40 months (mean) in 17. Of the 46 children, 5 died of tumor progression, 4 became blind, and 20 of 34 evaluable patients had endocrine abnormalities. Endocrinopathy did not correlate with therapy. Ten of 17 children evaluated by questionnaire required special education. There was a trend for educational problems to occur in children who were irradiated before the age of 5 years., Conclusions: Gliomas of the hypothalamus and optic pathways and their treatment cause long term morbidity in young children. Chemotherapy postpones radiation effectively, and this delay may reduce neurologic morbidity; however, 60% of children eventually relapse. By contrast, patients with NF-1 have indolent disease.
- Published
- 1995
- Full Text
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42. Superficial siderosis of the central nervous system: magnetic resonance imaging and pathological correlation. Case report.
- Author
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Janss AJ, Galetta SL, Freese A, Raps EC, Curtis MT, Grossman RI, Gomori JM, and Duhaime AC
- Subjects
- Adult, Central Nervous System Diseases pathology, Cerebellum pathology, Cranial Fossa, Posterior, Encephalocele surgery, Female, Humans, Magnetic Resonance Imaging, Postoperative Complications, Siderosis pathology, Central Nervous System Diseases diagnosis, Siderosis diagnosis
- Abstract
The authors report a 32-year-old woman who had undergone repair of an occipital encephalocele in infancy and who experienced a 20-year history of progressive hearing loss and intermittent vertigo. After parturition, she developed a rapidly progressive quadriparesis and brain-stem dysfunction associated with persistent intraventricular and subarachnoid hemorrhage. Serial magnetic resonance (MR) images showed progressive deposition of hemosiderin along the surface of the brain, brain stem, and spinal cord, and enhanced thickened membranes at the site of the original encephalocele repair. Posterior fossa exploration disclosed hemorrhagic membranes, which were resected; despite removal of this tissue, the patient deteriorated and died. Postmortem examination confirmed iron-containing pigment along the meninges, cerebral hemispheres, brain stem, spinal cord, and cranial nerves accompanied by atrophy of the superficial cerebellar cortex. It is concluded that superficial siderosis may accompany encephalocele repair. This is believed to be the first report in the literature of superficial siderosis of the central nervous system to correlate in vivo MR images with autopsy results.
- Published
- 1993
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43. Effect of spinal norepinephrine depletion on descending inhibition of the tail flick reflex from the locus coeruleus and lateral reticular nucleus in the rat.
- Author
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Janss AJ, Jones SL, and Gebhart GF
- Subjects
- Animals, Clonidine pharmacology, Hydroxydopamines pharmacology, Locus Coeruleus physiology, Male, Nociceptors drug effects, Nociceptors physiology, Oxidopamine, Rats, Rats, Inbred Strains, Receptors, Adrenergic drug effects, Receptors, Adrenergic physiology, Reflex drug effects, Reticular Formation physiology, Norepinephrine physiology, Reflex physiology, Spinal Cord physiology
- Abstract
The lateral reticular nucleus (LRN) and locus coeruleus-subcoeruleus (LC/SC), brainstem structures which overlap the A1 and A6 noradrenergic nuclei respectively, have been implicated in descending modulation of spinal nociceptive transmission. The present studies were designed to examine the role of norepinephrine (NE) in the mediation of inhibition of the nociceptive tail flick reflex produced by focal electrical stimulation in the LRN and LC/SC. Spinal NE was depleted by intrathecal administration of 6-hydroxydopamine (6-OHDA; 20 micrograms) and the threshold electrical stimulation in the LRN and the LC/SC necessary to inhibit the tail flick reflex in lightly pentobarbital-anesthetized rats was determined 9 and 14 days later. Despite a significant depletion (greater than 85%) of lumbar spinal cord NE content, there was no significant change in the tail flick inhibitory stimulation thresholds in the LRN or LC/SC. NE depletion did, however, potentiate the elevation in the inhibitory stimulation threshold in the LRN produced by intrathecal administration of the alpha 2-adrenoceptor antagonist, yohimbine, suggesting that upregulation of spinal adrenoceptors had occurred following 6-OHDA treatment. Adrenoceptor up-regulation was examined quantitatively by characterizing the dose-dependent antinociceptive potency of the selective alpha 2-adrenoceptor agonist clonidine 3, 7, 10, and 14 days following 6-OHDA administration, and analysis of [3H]rauwolscine binding to lumbar spinal cord 9 days following administration of the neurotoxin. The development of supersensitivity, defined as the leftward parallel shift of the dose-response curves for clonidine administered intrathecally, corresponded to the time course of NE depletion following 6-OHDA treatment on the days tested. Binding of [3H]rauwolscine to lumbar spinal cord revealed an elevation in the estimated Bmax without a change in the estimated Kd of the high affinity binding component 9 days following 6-OHDA administration. This study demonstrates that spinal adrenoceptor denervation supersensitivity develops rapidly following intrathecal administration of 6-OHDA and compensates for the selective destruction of spinal noradrenergic nerve terminals. Thus, the absence of effect of NE depletion on the tail flick inhibitory stimulation threshold in the LRN and the LC/SC does not argue against the hypothesis that spinopetal NE-containing neurons in these brainstem loci are involved in modulation of spinal nociceptive transmission.
- Published
- 1987
- Full Text
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44. Dissociation of antinociceptive from cardiovascular effects of stimulation in the lateral reticular nucleus in the rat.
- Author
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Janss AJ, Cox BF, Brody MJ, and Gebhart GF
- Subjects
- Animals, Blood Pressure, Brain Mapping, Electric Stimulation, Glutamates pharmacology, Glutamic Acid, Male, Medulla Oblongata drug effects, Rats, Rats, Inbred Strains, Reticular Formation drug effects, Vascular Resistance, Cardiovascular Physiological Phenomena, Medulla Oblongata physiology, Pain physiopathology, Reticular Formation physiology
- Abstract
The lateral reticular nucleus (LRN) in the caudal ventrolateral medulla has been implicated in the regulation of spinal nociceptive transmission and hemodynamics. Experiments were undertaken to examine the relationship between inhibition of the tail flick reflex and cardiovascular effects produced by electrical stimulation in the LRN in rats lightly anesthetized with pentobarbital. Intensity- and frequency-dependent increases in mean arterial pressure and vascular resistance in the hindquarter, mesenteric, renal and caudal arterial beds were observed. Inhibition of the tail flick reflex, however, occurred at intensities of electrical stimulation which produced no significant changes in mean arterial pressure or vascular resistance in any of the arterial beds studied. Selective stimulation of cell bodies in the LRN by microinjection of glutamate similarly inhibited the tail flick reflex but produced significant reductions in mean arterial pressure, without substantially affecting regional vascular resistances. These results suggest that the antinociceptive and depressor effects of stimulation in the LRN are mediated by activation of cell bodies, while pressor effects produced by focal electrical stimulation are mediated by activation of fibers of passage. The descending inhibition produced by stimulation in the LRN is independent of stimulation-produced cardiovascular responses.
- Published
- 1987
- Full Text
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45. Brainstem and spinal pathways mediating descending inhibition from the medullary lateral reticular nucleus in the rat.
- Author
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Janss AJ and Gebhart GF
- Subjects
- Animals, Brain drug effects, Brain Stem physiology, Cerebral Ventricles drug effects, Cerebral Ventricles physiology, Electric Stimulation, Functional Laterality, Glutamates administration & dosage, Glutamates pharmacology, Glutamic Acid, Lidocaine administration & dosage, Lidocaine pharmacology, Male, Medulla Oblongata physiology, Microinjections, Pain Measurement, Rats, Rats, Inbred Strains, Spinal Cord physiology, Brain Stem anatomy & histology, Medulla Oblongata anatomy & histology, Spinal Cord anatomy & histology
- Abstract
The lateral reticular nucleus (LRN) in the caudal ventrolateral medulla has been implicated in descending monoaminergic modulation of spinal nociceptive transmission. Experiments were undertaken to examine the organization of pontine and spinal pathways mediating inhibition of the tail-flick (TF) reflex from the LRN in rats lightly anesthetized with pentobarbital. Microinjections of the local anesthetic lidocaine ipsilaterally or bilaterally into the dorsolateral pons blocked stimulation-produced inhibition of the TF reflex from the nucleus locus coeruleus/subcoeruleus (LC/SC), but had no effect on descending inhibition produced by microinjection of glutamate into the LRN. Thus, adrenergic modulation of the TF reflex from the LRN is not mediated by activation of spinopetal noradrenergic neurons in the LC/SC. The funicular course of descending inhibition produced by focal electrical stimulation in the LRN was studied in separate groups of rats by reversibly (local anesthetic blocks) or irreversibly (surgical transection) compromising conduction in the dorsolateral funiculi (DLFs) at the level of the cervical spinal cord. Bilateral lidocaine blocks in the DLFs significantly shortened control TF latencies and more than doubled the intensity of electrical stimulation in the LRN necessary to inhibit the TF reflex (153 +/- 29% increase from control); changes in these parameters produced by unilateral blocks of the DLFs were not statistically significant. Ipsilateral or bilateral transections of the DLFs significantly increased the intensity of electrical stimulation in the LRN to inhibit the TF reflex (110 +/- 24% and 265 +/- 46% from control, respectively). Neither lidocaine blocks nor transections of the DLFs completely blocked the descending inhibitory effects of electrical stimulation in the LRN. The DLFs appear to carry fibers mediating LRN stimulation-produced inhibition of the TF reflex as well as tonic descending inhibition of spinal reflexes. The results of the present study indicate that (1) adrenergic modulation of the nociceptive TF reflex from the LRN does not depend on a rostral loop through the pontine LC/SC, and (2) descending inhibitory influences from the LRN are contained in, but not confined to, the dorsal quadrants of the spinal cord.
- Published
- 1988
- Full Text
- View/download PDF
46. Quantitative characterization and spinal pathway mediating inhibition of spinal nociceptive transmission from the lateral reticular nucleus in the rat.
- Author
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Janss AJ and Gebhart GF
- Subjects
- Animals, Electric Stimulation, Functional Laterality, Glutamates pharmacology, Glutamic Acid, Male, Neural Inhibition, Neural Pathways physiology, Rats, Rats, Inbred Strains, Reticular Formation drug effects, Sodium Glutamate pharmacology, Spinal Cord drug effects, Nociceptors physiology, Pain physiopathology, Reticular Formation physiology, Spinal Cord physiology
- Abstract
1. The modulation of spinal nociceptive transmission from the lateral reticular nucleus (LRN) was characterized for 47 spinal dorsal horn neurons in pentobarbital-anesthetized, paralyzed rats. All 47 units studied had receptive fields confined to the glabrous skin of the plantar surface of the ipsilateral hind foot and responded to mechanical stimulation as well as noxious heating (50 degrees C). Rostral projections contained in the ventrolateral quadrant of the cervical spinal cord were demonstrated for 15 of the 47 units by antidromic invasion. Glutamate- and stimulation-produced descending inhibition, the spinal pathway, and tonic descending inhibition from the LRN were systematically examined. 2. Inhibition of unit responses to heating of the skin by electrical stimulation in the LRN varied with the intensity, pulse duration (100 or 400 microseconds), and frequency (25-100 Hz) of stimulation. Greater inhibition was produced at lower intensities of stimulation with the 400-microseconds pulse duration and a frequency of 100 Hz. The effects of stimulation on spontaneous activity and responses to heat were compared in 16 experiments; inhibition of spontaneous activity was intensity dependent and did not differ significantly in magnitude from stimulation-produced inhibition of responses to heating of the skin. 3. Tracking experiments established that stimulation in the ipsilateral and contralateral ventrolateral medulla reliably attenuated unit responses to noxious heating of the skin and that stimulation in the LRN produced maximal inhibition at a low intensity of stimulation. Descending inhibition was quantitatively characterized from sites within (n = 32) and outside (n = 30) the LRN. Both the extrapolated mean stimulation threshold for inhibition and mean intensity inhibiting unit responses to heat to 50% of control were significantly lower for sites in the LRN. 4. The responses of seven spinal units to graded noxious heating of the skin were studied; all exhibited linear monotonic stimulus-response functions (SRFs) throughout the temperature range examined (42-50 degrees C). Electrical stimulation in the LRN significantly decreased the slope (42 +/- 4% of control) of the SRFs and increased the neuronal response threshold (2.0 +/- 0.7 degrees C). 5. S-glutamate (50 nmol, 0.5 microliter) was microinjected into stimulation sites within (n = 15) and distant from (n = 6) the LRN. Glutamate produced a transient (less than 7 min) but significant attenuation of neuronal responses to heat to 35 +/- 6% of control only when microinjected into the LRN.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1988
- Full Text
- View/download PDF
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