Paul Graham Fisher, MD
Beirne Family Professor of Pediatric Neuro-Oncology, Professor of Pediatrics and, by courtesy, of Neurosurgery and of Epidemiology and Population Health
Neurology
Bio
Dr. Paul Graham Fisher is Professor of Neurology and Pediatrics, and by courtesy, Neurosurgery and Epidemiology and Population Health; the Beirne Family Professor of Pediatric Neuro-Oncology; and the Dunlevie Family University Fellow in Undergraduate Education.
Following his BA, with Distinction, in Human Biology from Stanford University and then his MD at UCSF, Dr. Fisher completed residencies in pediatrics and neurology at the Johns Hopkins Hospital and then a fellowship in neuro-oncology at Children’s Hospital of Philadelphia and Johns Hopkins. He also obtained a master’s degree in epidemiology at Johns Hopkins University. After starting out on the faculty at Hopkins, in 1997 Dr. Fisher was recruited back to Palo Alto, where he started the pediatric neuro-oncology program at Stanford University. His clinical work and research focus on epidemiology, therapy, and late effects of childhood brain tumors and other childhood cancers. He has authored over 300 scholarly publications on these and other neurology and pediatrics topics.
Dr. Fisher is a longtime faculty member at Stanford. He was Chief of the Division of Child Neurology at Stanford for 15 years and then Interim Chair of the Department of Neurology and Neurological Sciences. Over his time at Stanford, Dr. Fisher has served as a member of the School of Medicine Admissions Committee, IRB member, Neurology Clerkship Director, Child Neurology Residency Program Director, Senior Vice Chair for Academic Affairs in Neurology, and Bing Director of the Program in Human Biology in the School of Humanities and Sciences from 2012 through 2019. He is a past recipient of multiple teaching awards, including the Arthur L. Bloomfield and Henry J. Kaiser Awards in the School of Medicine, as well as the Phi Beta Kappa Northern California Association Award for excellence in undergraduate education. He currently teaches the popular undergraduate classes “Cancer Epidemiology” and “The Human Organism” in Human Biology.
Dr. Fisher is presently the Editor-in-Chief for The Journal of Pediatrics, and past editorial board member for the Journal of Clinical Oncology, Frontiers in Pediatric Oncology, and the Journal of Neuro-Oncology. In 2021, he was elected to the COPE Council of the Committee on Publication Ethics, and he has interests in plagiarism, text-recycling, and the editorial process.
Dr. Fisher’s personal interests are his wife Joy and three grown children, along with downhill skiing, anything baseball, travel with intense picnicking, and his dogs Monkey and Mona.
Clinical Focus
- Cancer > Neuro Oncology
- Neurology - Child Neurology
- Neuro-Oncology
- Neurology
Academic Appointments
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Professor - University Medical Line, Neurology
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Professor - University Medical Line, Pediatrics
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Professor - University Medical Line (By courtesy), Neurosurgery
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Professor - University Medical Line (By courtesy), Epidemiology and Population Health
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Member, Stanford Cancer Institute
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Member, Wu Tsai Neurosciences Institute
Administrative Appointments
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Chief, Division of Child Neurology, Department of Neurology (2008 - 2023)
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The Bing Director, Program in Human Biology, School of Humanities and Sciences (2012 - 2019)
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Vice Chair, Child Neurology, Department of Neurology (2016 - 2023)
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Senior Vice Chair, Academic Affairs, Department of Neurology (2019 - 2023)
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Interim Chair, Department of Neurology (2023 - 2024)
Honors & Awards
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39th Annual Henry J. Kaiser Family Foundation Award for Excellence in Clinical Teaching, Stanford School of Medicine (2007)
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44th Annual Arthur L. Bloomfield Award, Stanford School of Medicine (2007)
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Dunlevie Family University Fellow in Undergraduate Education, Stanford University (2016 - present)
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Undergraduate Teaching Award, Phi Beta Kappa, Beta of California, Stanford University (2020)
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Excellence in Teaching Award, Phi Beta Kappa Northern California Association (2021)
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Medical Staff Distinguished Service Award, Stanford Medicine Children's Health (2023)
Professional Education
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Board Certification: American Board of Pediatrics, Pediatrics (1995)
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B.A., Stanford University, Human Biology (1985)
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Medical Education: University of California at San Francisco School of Medicine (1989) CA
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Internship: Johns Hopkins Hospital Pediatric Residency (1990) MD
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Residency: Johns Hopkins Hospital Pediatric Residency (1991) MD
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Residency: Johns Hopkins Neurology Residency (1994) MD
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Fellowship: Children's Hospital of Philadelphia Child Neurology (1995) PA
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Board Certification, Pediatrics, American Board of Pediatrics (1995)
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Board Certification: American Board of Psychiatry and Neurology, Neurology - Child Neurology (1998)
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Board Certification: United Council for Neurologic Subspecialties, Neuro-Oncology (2017)
Current Research and Scholarly Interests
Clinical neuro-oncology: My research explores the epidemiology, natural history, and disease patterns of brain tumors and other cancers in childhood, as well as prospective clinical trials for treating these neoplasms. Research interests also include neurologic effects of cancer and its therapies.
Clinical Trials
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GD2 CAR T Cells in Diffuse Intrinsic Pontine Gliomas(DIPG) & Spinal Diffuse Midline Glioma(DMG)
Recruiting
The primary purpose of this study is to test whether GD2-CAR T cells can be successfully made from immune cells collected from children and young adults with H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) or spinal H3K27M-mutant diffuse midline glioma (DMG). H3K27Mmutant testing will occur as part of standard of care prior to enrollment.
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Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma
Recruiting
This phase I trial studies the side effects and best dose of pembrolizumab and to see how well it works in treating younger patients with high-grade gliomas (brain tumors that are generally expected to be fast growing and aggressive), diffuse intrinsic pontine gliomas (brain stem tumors), brain tumors with a high number of genetic mutations, ependymoma or medulloblastoma that have come back (recurrent), progressed, or have not responded to previous treatment (refractory). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may induce changes in the body's immune system, and may interfere with the ability of tumor cells to grow and spread.
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An Open-Labeled, Extended-Use of XERECEPT (hCRF) for Patients in Studies NTI 0302, 0303, or Other Designated Studies
Not Recruiting
The purpose of this study is to examine the long-term safety and tolerability of human corticotropin-releasing factor (hCRF), XERECEPT®, in patients requiring dexamethasone (Decadron) to treat peritumoral brain edema. This open-label, extended-use study is open to all patients who participate in either of the blinded studies, NTI 0302, NTI 0303, or other designated studies, including patients who may have discontinued blinded study medication early but completed the protocol-stipulated follow-up periods.
Stanford is currently not accepting patients for this trial. For more information, please contact Lynn Adler, (650) 725 - 8630.
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Arsenic Trioxide and Radiation Therapy in Treating Young Patients With Newly Diagnosed Gliomas
Not Recruiting
RATIONALE: Drugs used in chemotherapy, such as arsenic trioxide, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells and may be an effective treatment for patients with glioma. Drugs such as arsenic trioxide may also make the tumor cells more sensitive to radiation therapy. Combining arsenic trioxide with radiation therapy may kill more tumor cells. PURPOSE: Phase I trial to study the effectiveness of combining arsenic trioxide with radiation therapy in treating patients who have newly diagnosed gliomas.
Stanford is currently not accepting patients for this trial. For more information, please contact Min Wang, (650) 736 - 4281.
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Bevacizumab and Lapatinib in Children With Recurrent or Refractory Ependymoma
Not Recruiting
The goal of this clinical research study is to learn if the combination of Avastin (bevacizumab) and Tykerb (lapatinib) can help to control ependymoma in pediatric patients. The safety of this drug combination will also be studied.
Stanford is currently not accepting patients for this trial. For more information, please contact Carissa Bailey, (650) 725 - 4708.
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Brain Function in Young Patients Receiving Methotrexate for Acute Lymphoblastic Leukemia
Not Recruiting
This clinical trial is looking at brain function in young patients receiving methotrexate for acute lymphoblastic leukemia. Learning about the long-term effects of methotrexate on brain function may help doctors plan cancer treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Lew, (650) 725 - 4318.
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Chemotherapy Combined With Radiation Therapy for Newly Diagnosed CNS AT/RT
Not Recruiting
RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving more than one chemotherapy drug with radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving intrathecal and systemic combination chemotherapy together with radiation therapy works in treating young patients with newly diagnosed central nervous system (CNS) atypical teratoid/rhabdoid tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Paul Fisher, (650) 725 - 8630.
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Chemotherapy Followed by Radiation Therapy in Treating Younger Patients With Newly Diagnosed Localized Central Nervous System Germ Cell Tumors
Not Recruiting
This phase II trial studies how well chemotherapy followed by radiation therapy work in treating younger patients with newly diagnosed central nervous system germ cell tumors that have not spread to other parts of the brain, spinal canal, or body (localized). Drugs used as chemotherapy, such as carboplatin, etoposide, and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x rays to kill tumor cells. Giving chemotherapy followed by radiation therapy may kill more tumor cells.
Stanford is currently not accepting patients for this trial. For more information, please contact Peds Hem/Onc CRAs, 650-497-8953.
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DNA Analysis of Tumor Tissue Samples From Patients With Diffuse Brain Stem Glioma
Not Recruiting
This multi-institutional study will prospectively collect tumor and constitutional tissue samples from patients with diffuse brainstem glioma and other types of brainstem gliomas either during therapy or at autopsy to perform an extensive analysis of genetic and molecular abnormalities in these tumors.
Stanford is currently not accepting patients for this trial.
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Efficacy and Safety of Donepezil Hydrochloride in Preadolescent and Adolescent Children With Attention Impairment Following Cancer Treatment
Not Recruiting
The purpose of this study is to evaluate the efficacy, safety and tolerability of donepezil in children with persistent attention impairment that is present at least 12 months after the completion of cancer treatment.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Lew, (650) 725 - 4318.
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Erlotinib Versus Oral Etoposide in Patients With Recurrent or Refractory Pediatric Ependymoma
Not Recruiting
This is a phase 2 study to evaluate the efficacy of single-agent erlotinib versus oral etoposide in patients with recurrent or refractory pediatric ependymoma.
Stanford is currently not accepting patients for this trial. For more information, please contact Carissa Bailey, (650) 725 - 4708.
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FLT-PET Imaging of Brain Tumors in Children
Not Recruiting
Brain tumors are the leading cause of death from solid tumors in children. Tumor imaging is important in the management of these tumors, but current imaging methods have limitations in providing the necessary information for optimal treatment of these patients. The goal of this study is to evaluate the potential utility of positron emission tomography (PET) with 3'-deoxy-3'-\[F-18\] fluorothymidine (18F-FLT) in the medical management of brain tumors in children. Funding source - FDA Office of Orphan Product Development (OOPD)
Stanford is currently not accepting patients for this trial. For more information, please contact Peds Hem/Onc CRAs, 650-723-5535.
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Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors
Not Recruiting
This molecular biology and phase II trial studies how well imetelstat sodium works in treating younger patients with recurrent or refractory brain tumors. Imetelstat sodium may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial. For more information, please contact Alyson Falwell, 650-736-4281.
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Methylphenidate HCl or Modafinil in Treating Young Patients With Excessive Daytime Sleepiness After Cancer Therapy
Not Recruiting
RATIONALE: Methylphenidate hydrochloride or modafinil may help reduce daytime sleepiness and improve the quality of life of patients with excessive daytime sleepiness after cancer therapy. It is not yet known whether methylphenidate hydrochloride or modafinil are more effective than a placebo in reducing daytime sleepiness in these patients. PURPOSE: This randomized phase II trial is studying methylphenidate hydrochloride or modafinil to see how well they work compared with a placebo in treating young patients with excessive daytime sleepiness after cancer therapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Jennifer Lew, (650) 725 - 4318.
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Optune for Children With High-Grade Glioma or Ependymoma, and Optune With Radiation Therapy for Children With DIPG
Not Recruiting
This is a multicenter trial of the Optune device to examine the feasibility and to describe the device-related toxicity in children with supratentorial high grade glioma (HGG) or ependymoma (Stratum 1) and to examine the feasibility and efficacy of concurrent Optune and standard focal radiation therapy (RT) in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (Stratum 2).
Stanford is currently not accepting patients for this trial. For more information, please contact Paul G. Fisher, MD, MHS, 650-497-8953.
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Palbociclib Isethionate in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors
Not Recruiting
This phase I trial studies the side effects and best dose of palbociclib isethionate in treating younger patients with central nervous system tumors that have grown, come back, or not responded to treatment. Palbociclib isethionate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial. For more information, please contact Prianka Kumar, 650-724-3866.
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Peginterferon Alfa-2b in Younger Patients With Craniopharyngioma That is Recurrent or Cannot Be Removed By Surgery
Not Recruiting
This phase II trial studies how well peginterferon alfa-2b works in treating younger patients with craniopharyngioma that is recurrent or cannot be removed by surgery. Peginterferon alfa-2b may interfere with the growth of tumor cells and slow the growth of craniopharyngioma.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Phase I Rindopepimut After Conventional Radiation in Children w/ Diffuse Intrinsic Pontine Gliomas
Not Recruiting
This is a research study of patients with diffuse intrinsic pontine gliomas. We hope to learn about the safety and efficacy of treating pediatric diffuse intrinsic pontine glioma patients with the EGFRvIII peptide vaccine after conventional radiation.
Stanford is currently not accepting patients for this trial. For more information, please contact Christina Huang, 650-723-0574.
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Phase I Trial of Arsenic Trioxide and Stereotactic Radiotherapy for Recurrent Malignant Glioma
Not Recruiting
To investigate the safety of delivering arsenic trioxide (ATO) in combination with stereotactic radiotherapy in recurrent malignant glioma by performing an open label, Phase I dose escalation trial. Results from this study will provide a basis for further study of ATO combined with radiation therapy as a radiosensitizer for malignant brain tumors in future Phase II studies.
Stanford is currently not accepting patients for this trial. For more information, please contact Laurie Tupper, (650) 498 - 4143.
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Pomalidomide in Treating Younger Patients With Recurrent, Progressive, or Refractory Central Nervous System Tumors
Not Recruiting
This phase I trial studies the side effects and best dose of pomalidomide in treating younger patients with tumors of the brain or spine (central nervous system) that have come back or are continuing to grow. Pomalidomide may interfere with the ability of tumor cells to grow and spread and may also stimulate the immune system to kill tumor cells.
Stanford is currently not accepting patients for this trial.
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Risk-Adapted Therapy for Young Children With Embryonal Brain Tumors, Choroid Plexus Carcinoma, High Grade Glioma or Ependymoma
Not Recruiting
RATIONALE: In this study a combination of anti-cancer drugs (chemotherapy) is used to treat brain tumors in young children. Using chemotherapy gives the brain more time to develop before radiation is given. The chemotherapy in this study includes the drug methotrexate. This drug was an important part of the two clinical trials which resulted in the best survival results for children less than 3 years of age with medulloblastoma. Most patients treated on this trial will also receive radiation which is carefully targeted to the area of the tumor. This type of radiation (focal conformal or proton beam radiotherapy) may result in fewer problems with thinking and learning than radiation to the whole brain and spinal cord. PURPOSE: This clinical trial is studying how well giving combination chemotherapy together with radiation therapy works in treating young patients with newly diagnosed central nervous system tumors.
Stanford is currently not accepting patients for this trial. For more information, please contact Peds Hem Onc CRAs, 650-723-5535.
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Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma
Not Recruiting
This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating or re-treating young patients with low grade glioma that has come back (recurrent) or does not respond to treatment (refractory). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Stanford is currently not accepting patients for this trial. For more information, please contact Prianka Kumar, 650-724-3866.
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Single-agent Erlotinib in Patients Previously Treated With Oral Etoposide in Protocol OSI-774-205
Not Recruiting
Participants that were assigned to the oral etoposide treatment arm in protocol OSI-774-205 and either progressed while on study or discontinued due to unacceptable toxicity related to etoposide were allowed to participate in this study to assess the safety profile of single-agent erlotinib in participants with recurrent or refractory pediatric ependymoma.
Stanford is currently not accepting patients for this trial. For more information, please contact Carissa Bailey, (650) 725 - 4708.
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Trial of Panobinostat in Children With Diffuse Intrinsic Pontine Glioma
Not Recruiting
This phase I trial studies the side effects and best dose of panobinostat in treating younger patients with diffuse intrinsic pontine glioma (DIPG). Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stratum 1 treats patients with DIPG that has returned or gotten worse (progressed). Stratum 2 treats patients with DIPG or H3K27+Thalamic Diffuse Malignant Glioma (DMG) that has not yet gotten worse.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
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Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas
Not Recruiting
This phase I/II trial studies the side effects and the best dose of veliparib when given together with radiation therapy and temozolomide and to see how well they work in treating younger patients newly diagnosed with diffuse pontine gliomas. Veliparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high-energy x rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells either by killing the cells or by stopping them from dividing. Giving veliparib with radiation therapy and temozolomide may kill more tumor cells.
Stanford is currently not accepting patients for this trial. For more information, please contact Alyson Falwell, 650-736-4281.
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Vismodegib in Treating Younger Patients With Recurrent or Refractory Medulloblastoma
Not Recruiting
This phase II trial studies how well vismodegib works in treating younger patients with recurrent or refractory medulloblastoma. Vismodegib may slow the growth of tumor cells.
Stanford is currently not accepting patients for this trial. For more information, please contact Prianka Kumar, 650-724-3866.
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XERECEPT® (hCRF) for Patients Requiring Dexamethasone to Treat Edema Associated With Brain Tumors
Not Recruiting
The purpose of this study is to compare the safety and efficacy of XERECEPT® to dexamethasone (Decadron) a common treatment for symptoms of brain swelling (edema). This study is specifically aimed at patients who require chronic high doses of dexamethasone to manage symptoms.
Stanford is currently not accepting patients for this trial. For more information, please contact Lynn Adler, (650) 725 - 8630.
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XERECEPT® (hCRF) for Primary Glioma Patients Requiring Dexamethasone to Treat Peritumoral Brain Edema
Not Recruiting
The purpose of this study is to examine the safety and efficacy of XERECEPT (human Corticotropin-Releasing Factor, or hCRF) compared to dexamethasone in patients with primary malignant glioma who require increased dexamethasone doses to control symptom of peritumoral brain edema.
Stanford is currently not accepting patients for this trial. For more information, please contact Cathy Recht, (650) 725 - 8630.
2024-25 Courses
- Cancer Epidemiology
HUMBIO 154C (Win) - The Human Organism
HUMBIO 4A (Spr) -
Independent Studies (8)
- Directed Reading in Epidemiology
EPI 299 (Aut, Win, Spr, Sum) - Directed Reading in Neurology and Neurological Science
NENS 299 (Aut, Win, Spr, Sum) - Early Clinical Experience in Neurology and Neurological Sciences
NENS 280 (Aut, Win, Spr, Sum) - Graduate Research
EPI 399 (Aut, Win, Spr, Sum) - Graduate Research
NENS 399 (Aut, Win, Spr, Sum) - Medical Scholars Research
NENS 370 (Aut, Win, Spr, Sum) - Undergraduate Research
EPI 199 (Aut, Win, Spr, Sum) - Undergraduate Research
NENS 199 (Aut, Win, Spr, Sum)
- Directed Reading in Epidemiology
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Prior Year Courses
2023-24 Courses
- Cancer Epidemiology
HUMBIO 154C (Win) - The Human Organism
HUMBIO 4A (Spr)
2022-23 Courses
- Cancer Epidemiology
HUMBIO 154C (Win) - The Human Organism
HUMBIO 4A (Spr)
2021-22 Courses
- Cancer Epidemiology
HUMBIO 154C (Win) - The Human Organism
HUMBIO 4A (Spr)
- Cancer Epidemiology
All Publications
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When Can We Retire 3,600 cGy Craniospinal Irradiation in Medulloblastoma?
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2023: JCO2300008
View details for DOI 10.1200/JCO.23.00008
View details for PubMedID 36753694
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Race, ethnicity, social determinants of health, and The Journal
JOURNAL OF PEDIATRICS
2022; 247: 1
View details for Web of Science ID 000854101300001
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The Journal of Pediatrics Turns 90! A Perspective on Progress, Opportunities, and Challenges.
The Journal of pediatrics
2022; 246: 235-241
View details for DOI 10.1016/j.jpeds.2022.04.034
View details for PubMedID 35750393
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Diversity, Equity, and Inclusion in The Journal of Pediatrics.
The Journal of pediatrics
2021
View details for DOI 10.1016/j.jpeds.2021.07.023
View details for PubMedID 34274308
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Comments and Controversies in Oncology: The Tribulations of Trials Developing ONC201.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2024: JCO2400709
Abstract
Our international team highlights issues with efficacy reports in several studies on DMG with the new drug ONC201.
View details for DOI 10.1200/JCO.24.00709
View details for PubMedID 39110925
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Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.
The Journal of experimental medicine
2024; 221 (8)
Abstract
Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.
View details for DOI 10.1084/jem.20232005
View details for PubMedID 38780621
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The Undiagnosed Diseases Network: Characteristics of solvable applicants and diagnostic suggestions for non-accepted ones.
Genetics in medicine : official journal of the American College of Medical Genetics
2024: 101203
Abstract
Can certain characteristics identify as solvable some undiagnosed patients who seek extensive evaluation and thorough record review, like by the Undiagnosed Diseases Network (UDN)?The UDN is a national research resource to solve medical mysteries through team science. Applicants provide informed consent to access to their medical records. After review, expert panels assess if applicants meet inclusion and exclusion criteria to select participants. When not accepting applicants, UDN experts may offer suggestions for diagnostic efforts. Using minimal information from initial applications, we compare features in applicants not accepted with those accepted and either solved or still not solved by the UDN. The diagnostic suggestions offered to non-accepted applicants and their clinicians were tallied.Non-accepted applicants were more often female, older at first symptoms and application, and longer in review than accepted applicants. The accepted and successfully diagnosed applicants were younger in ages, shorter in review time, more often non-white, of Hispanic ethnicity, and presenting with nervous system features. Half of non-accepted applicants were given suggestions for further local diagnostic evaluation. A few seemed to have two major diagnoses or a provocative environmental exposure history.Comprehensive UDN record review generates possibly helpful advice.
View details for DOI 10.1016/j.gim.2024.101203
View details for PubMedID 38967101
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SEQUENTIAL INTRAVENOUS AND INTRACEREBROVENTRICULAR GD2-CAR T-CELL THERAPY FOR H3K27M-MUTATED DIFFUSE MIDLINE GLIOMAS
OXFORD UNIV PRESS INC. 2024
View details for DOI 10.1093/neuonc/noae064.100
View details for Web of Science ID 001252720000169
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Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder.
Genetics in medicine : official journal of the American College of Medical Genetics
2024: 101166
Abstract
The function of FAM177A1 and its relationship to human disease is largely unknown. Recent studies have demonstrated FAM177A1 to be a critical immune-associated gene. One previous case study has linked FAM177A1 to a neurodevelopmental disorder in four siblings.We identified five individuals from three unrelated families with biallelic variants in FAM177A1. The physiological function of FAM177A1 was studied in a zebrafish model organism and human cell lines with loss-of-function variants similar to the affected cohort.These individuals share a characteristic phenotype defined by macrocephaly, global developmental delay, intellectual disability, seizures, behavioral abnormalities, hypotonia, and gait disturbance. We show that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA-seq and metabolomic datasets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated dysregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation.Our data sheds light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity.
View details for DOI 10.1016/j.gim.2024.101166
View details for PubMedID 38767059
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Immunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant.
American journal of medical genetics. Part A
2024: e63627
Abstract
Casitas B-lineage lymphoma (CBL) encodes an adaptor protein with E3-ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders. Here we report a novel CBL variant (c.1202G>T; p.Cys401Phe) occurring de novo in a subject with café-au-lait macules, feeding difficulties, mild dysmorphic features, psychomotor delay, autism spectrum disorder, thrombocytopenia, hepatosplenomegaly, and recurrent hypertransaminasemia. The identified variant affects an evolutionarily conserved residue located in the RING finger domain, a known mutational hot spot of both germline and somatic mutations. Functional studies documented enhanced EGF-induced ERK phosphorylation in transiently transfected COS1 cells. The present findings further support the association of pathogenic CBL variants with immunological and hematological manifestations in the context of a presentation with only minor findings reminiscent of NS or a clinically related RASopathy.
View details for DOI 10.1002/ajmg.a.63627
View details for PubMedID 38613168
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Exome and genome sequencing in a heterogeneous population of patients with rare disease: Identifying predictors of a diagnosis.
Genetics in medicine : official journal of the American College of Medical Genetics
2024: 101115
Abstract
Exome (ES) and genome sequencing (GS) are increasingly being utilized for individuals with rare and undiagnosed diseases; however, guidelines on their use remain limited. This study aimed to identify factors associated with diagnosis by ES and/or GS in a heterogeneous population of patients with rare and undiagnosed diseases.In this case control study, we reviewed data from 400 diagnosed and 400 undiagnosed randomly selected participants in the Undiagnosed Diseases Network (UDN), all of whom had undergone ES and/or GS. We analyzed factors associated with receiving a diagnosis by ES and/or GS.Factors associated with a decreased odds of being diagnosed included adult symptom onset, singleton sequencing, and having undergone ES and/or GS prior to acceptance to the UDN (48%, 51%, and 32% lower odds, respectively). Factors that increased the odds of being diagnosed by ES and/or GS included having primarily neurological symptoms and having undergone prior chromosomal microarray testing (44% and 59% higher odds, respectively).We identified several factors that were associated with receiving a diagnosis by ES and/or GS. This will ideally inform the utilization of ES and/or GS and help manage expectations of individuals and families undergoing these tests.
View details for DOI 10.1016/j.gim.2024.101115
View details for PubMedID 38436216
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Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.
Annals of clinical and translational neurology
2024
Abstract
ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series.We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant.We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing.This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.
View details for DOI 10.1002/acn3.51983
View details for PubMedID 38311799
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Arrhythmias including Atrial Fibrillation and Congenital Heart Disease in Kleefstra Syndrome: a possible epigenetic link.
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology
2024
Abstract
BACKGROUND: Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder due to haploinsufficiency of EHMT1 and is characterized by neuromuscular and intellectual developmental abnormalities. Although congenital heart disease (CHD) is common, the prevalence of arrhythmias and CHD subtypes in KS is unknown.METHODS: Inspired by a novel case series of KS patients with atrial tachyarrhythmias in the USA, we evaluate the two largest known KS registries for arrhythmias and CHD: Radboudumc (50 patients) based on health record review at Radboud University Medical Center in the Netherlands, and GenIDA (163 patients) based on world-wide surveys of patient families.RESULTS: Three KS patients (aged 17-25 years) presented with atrial tachyarrhythmias without manifest CHD. In the international KS registries, the median(IQR) age was considerably younger; GenIDA/Radboudumc at 10/13.5 (12/13) years respectively. Both registries had a 40% prevalence of cardiovascular abnormalities, the majority being CHD, including septal defects, vascular malformations, and valvular disease. Interestingly, 4 (8%) patients in the Radboudumc registry reported arrhythmias without CHD, including one AF, two with supraventricular tachycardias (SVTs), and one with non-sustained ventricular tachycardia. The GenIDA registry reported one patient with AF and another with chronic ectopic atrial tachycardia. In total, atrial tachyarrhythmias were noted in six young KS patients (6/213 or 3%) with at least four (3 AF and 1 AT) without structural heart disease.CONCLUSION: In addition to a high prevalence of CHD, evolving data reveals early-onset atrial tachyarrhythmias in young KS patients, including AF, even in the absence of structural heart disease.
View details for DOI 10.1093/europace/euae003
View details for PubMedID 38195854
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Physician, patient, and caregiver support for a formal certification in pediatric neuro-oncology: A survey-based report from the SNO pediatrics working group.
Neuro-oncology advances
2023; 5 (1): vdad130
Abstract
Although CNS tumors are the most common pediatric cancer in the United States, most physicians caring for these patients are not formally certified in the subspecialty. To determine support for developing a formal certification process in pediatric neuro-oncology, the Society for Neuro-Oncology's Pediatrics Special Interest Track Training and Credentialing working group performed a cross-sectional survey-based study of physicians and patients/caregivers of children with a CNS tumor history.Surveys were built in Survey Monkey and were available for 3 months. The physician survey had 34 questions and was open to doctors currently caring for pediatric neuro-oncology patients. The patient/caregiver survey had 13 questions. Both surveys were completed anonymously.The physician survey was completed by 193 participants, the majority of whom self-identified as oncologists. Only 5.6% of survey participants had ever been board-certified in neuro-oncology; the majority of participating physicians were either unaware that this certification existed or thought they were not eligible due to training in pediatrics rather than neurology or internal medicine. Almost half of the self-identified pediatric neuro-oncologists had not completed any specific clinical neuro-oncology training. Over 75% of physicians were supportive of the implementation of a formal certification process in pediatric neuro-oncology. A total of 30 participants completed the patient/caregiver survey. Although the majority of survey participants were highly satisfied with their oncologist, 70% would have been more comfortable if their oncologist had been specifically certified in pediatric neuro-oncology.There is support from physicians, patients, and caregivers to establish a formal certification process in pediatric neuro-oncology.
View details for DOI 10.1093/noajnl/vdad130
View details for PubMedID 37964897
View details for PubMedCentralID PMC10642732
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Genomics Research with Undiagnosed Children: Ethical Challenges at the Boundaries of Research and Clinical Care
JOURNAL OF PEDIATRICS
2023; 261
View details for DOI 10.1018/j.jpeds.2023.113537
View details for Web of Science ID 001029333600001
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High-grade glioma in infants and young children is histologically, molecularly, and clinically diverse-Results from the SJYC07 trial and institutional experience.
Neuro-oncology
2023
Abstract
High-grade gliomas (HGG) in young children pose a challenge due to favorable but unpredictable outcomes. While retrospective studies broadened our understanding of tumor biology, prospective data is lacking.A cohort of children with histologically diagnosed HGG from the SJYC07 trial was augmented with non-protocol patients with HGG treated at St. Jude Children's Research Hospital from November 2007 to December 2020. DNA methylome profiling and whole genome, whole exome, and RNA sequencing were performed. These data were integrated with histopathology to yield an integrated diagnosis. Clinical characteristics and pre-operative imaging were analyzed.Fifty-six children (0.0-4.4 years) were identified. Integrated analysis split the cohort into four categories: infant-type hemispheric glioma (IHG), HGG, low-grade glioma (LGG), and other-central nervous system (CNS) tumors. IHG was the most prevalent (n=22), occurred in the youngest patients (median age=0.4 years), and commonly harbored receptor tyrosine kinase gene fusions (7 ALK, 2 ROS1, 3 NTRK1/2/3, 4 MET). The 5-year event-free (EFS) and overall survival (OS) for IHG was 53.13% (95%CI:35.52 -79.47) and 90.91% (95%CI:79.66-100.00) vs. 0.0% and 16.67% (95%CI:2.78-99.74%) for HGG (p=0.0043, p=0.00013). EFS and OS were not different between IHG and LGG (p=0.95, p=0.43). Imaging review showed IHGs are associated with circumscribed margins (p=0.0047), hemispheric location (p=0.0010), and intratumoral hemorrhage (p=0.0149).HGG in young children is heterogeneous and best defined by integrating histopathological and molecular features. Patients with IHG have relatively good outcomes, yet they endure significant deficits, making them good candidates for therapy de-escalation and trials of molecular targeted therapy.
View details for DOI 10.1093/neuonc/noad130
View details for PubMedID 37503880
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Genomics Research with Undiagnosed Children: Ethical Challenges at the Boundaries of Research and Clinical Care.
The Journal of pediatrics
2023: 113537
Abstract
To explore the perspectives of parents of undiagnosed children enrolled in genomic diagnosis research regarding their motivations for enrolling their children, their understanding of the potential burdens and benefits, and the extent to which their experiences ultimately aligned with or diverged from their original expectations.In-depth interviews were conducted with parents, audio-recorded and transcribed. A structured codebook was applied to each transcript, after which iterative memoing was used to identify themes.Fifty-four parents participated, including 17 (31.5%) whose child received a diagnosis through research. Themes describing parents' expectations and experiences of genomic diagnosis research included: 1) the extent to which parents' motivations for participation focused on their hope that it would directly benefit their child; 2) the ways in which parents' frustrations regarding the research process confused the dual clinical and research goals of their participation; and 3) the limited clinical benefits parents ultimately experienced for their children.Our results suggest that parents of undiagnosed children seeking enrollment in genomic diagnosis research are at risk of a form of therapeutic misconception - in this case, diagnostic misconception. These findings indicate the need to examine the processes and procedures associated with this research in order to appropriately communicate and balance the potential burdens and benefits of study participation.
View details for DOI 10.1016/j.jpeds.2023.113537
View details for PubMedID 37271495
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GABAERGIC NEURON-TO-GLIOMA SYNAPSES IN DIFFUSE MIDLINE GLIOMAS
OXFORD UNIV PRESS INC. 2023
View details for DOI 10.1093/neuonc/noad073.044
View details for Web of Science ID 001023504300045
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HIGH-GRADE GLIOMA IN YOUNG CHILDREN IS HISTOLOGICALLY, MOLECULARLY, AND CLINICALLY DIVERSERESULTS FROM THE SJYC07 TRIAL AND INSTITUTIONAL EXPERIENCE
OXFORD UNIV PRESS INC. 2023
View details for Web of Science ID 001023504300153
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Participation in a national diagnostic research study: assessing the patient experience.
Orphanet journal of rare diseases
2023; 18 (1): 73
Abstract
INTRODUCTION: The Undiagnosed Diseases Network (UDN), a clinical research study funded by the National Institutes of Health, aims to provide answers for patients with undiagnosed conditions and generate knowledge about underlying disease mechanisms. UDN evaluations involve collaboration between clinicians and researchers and go beyond what is possible in clinical settings. While medical and research outcomes of UDN evaluations have been explored, this is the first formal assessment of the patient and caregiver experience.METHODS: We invited UDN participants and caregivers to participate in focus groups via email, newsletter, and a private participant Facebook group. We developed focus group questions based on research team expertise, literature focused on patients with rare and undiagnosed conditions, and UDN participant and family member feedback. In March 2021, we conducted, recorded, and transcribed four 60-min focus groups via Zoom. Transcripts were evaluated using a thematic analysis approach.RESULTS: The adult undiagnosed focus group described the UDN evaluation as validating and an avenue for access to medical providers. They also noted that the experience impacted professional choices and helped them rely on others for support. The adult diagnosed focus group described the healthcare system as not set up for rare disease. In the pediatric undiagnosed focus group, caregivers discussed a continued desire for information and gratitude for the UDN evaluation. They also described an ability to rule out information and coming to terms with not having answers. The pediatric diagnosed focus group discussed how the experience helped them focus on management and improved communication. Across focus groups, adults (undiagnosed/diagnosed) noted the comprehensiveness of the evaluation. Undiagnosed focus groups (adult/pediatric) discussed a desire for ongoing communication and care with the UDN. Diagnosed focus groups (adult/pediatric) highlighted the importance of the diagnosis they received in the UDN. The majority of the focus groups noted a positive future orientation after participation.CONCLUSION: Our findings are consistent with prior literature focused on the patient experience of rare and undiagnosed conditions and highlight benefits from comprehensive evaluations, regardless of whether a diagnosis is obtained. Focus group themes also suggest areas for improvement and future research related to the diagnostic odyssey.
View details for DOI 10.1186/s13023-023-02695-5
View details for PubMedID 37032333
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A concurrent dual analysis of genomic data augments diagnoses: experiences of two clinical sites in the Undiagnosed Diseases Network.
Genetics in medicine : official journal of the American College of Medical Genetics
2022
Abstract
Next generation sequencing (NGS) has revolutionized the diagnostic process for rare/ultra-rare conditions. However, diagnosis rates differ between analytical pipelines. In the NIH-Undiagnosed Diseases Network (UDN) study, each individual's NGS data are concurrently analyzed by the UDN sequencing core laboratory and the clinical sites. We examined the outcomes of this practice.A retrospective review was performed at two UDN clinical sites, to compare variants, and diagnoses/candidate genes identified with the dual analyses of the NGS data.Ninety-five individuals had 100 diagnoses/candidate genes. There was 59% concordance between the UDN sequencing core laboratories and the clinical sites in identifying diagnoses/candidate genes. The core laboratory provided more diagnoses, while the clinical sites prioritized more research variants/candidate genes (p <0.001). The clinical sites solely identified 15% of the diagnoses/candidate genes. The differences between the two pipelines were more often due to variant prioritization disparities, than variant detection.The unique dual analysis of NGS data in the UDN synergistically enhances outcomes. The core laboratory provides a clinical analysis with more diagnoses and the clinical sites prioritized more research variants/candidate genes. Implementing such concurrent dual analyses in other genomic research studies and clinical settings can improve both variant detection and prioritization.
View details for DOI 10.1016/j.gim.2022.12.001
View details for PubMedID 36481303
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Stereotactic radiosurgery for recurrent pediatric brain tumors: clinical outcomes and toxicity.
Neurosurgical focus
2022; 53 (5): E2
Abstract
Recurrence of brain tumors in children after the initial course of treatment remains a problem. This study evaluated the efficacy and safety of reirradiation using stereotactic radiosurgery (SRS) in patients with recurrent pediatric primary brain tumors.This IRB-approved retrospective review included pediatric patients with recurrent primary brain tumors treated at Stanford University from 2000 to 2019 using frameless SRS. Time to local failure (LF) and distant intracranial failure (DIF) were measured from the date of SRS and analyzed using competing risk analysis. Overall survival (OS) and progression-free survival (PFS) were analyzed with the Kaplan-Meier method.In total, 37 patients aged 2-24 years (median age 11 years at recurrence) were treated for 48 intracranial tumors. Ependymoma (38%) and medulloblastoma (22%) were the most common tumor types. The median (range) single fraction equivalent dose of SRS was 16.4 (12-24) Gy. The median (range) follow-up time was 22.9 (1.5-190) months. The median OS of all patients was 36.8 months. Eight of 40 (20%) lesions with follow-up imaging locally recurred. The 2-year cumulative incidence of LF after reirradiation with SRS was 12.8% (95% CI 4.6%-25.4%). The 2-year cumulative incidence of DIF was 25.3% (95% CI 12.9%-39.8%). The median PFS was 18 months (95% CI 8.9-44). Five (10.4%) patients developed toxicities potentially attributed to SRS, including cognitive effects and necrosis.Reirradiation using SRS for recurrent pediatric brain tumors appears safe with good local control. Innovations that improve overall disease control should continue because survival outcomes after relapse remain poor.
View details for DOI 10.3171/2022.8.FOCUS22361
View details for PubMedID 36321285
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Differential newborn DNA methylation among individuals with complex congenital heart defects and childhood lymphoma.
Birth defects research
2022
Abstract
BACKGROUND: There is emerging evidence that children with complex congenital heart defects (CHDs) are at increased risk for childhood lymphoma, but the mechanisms underlying this association are unclear. Thus, we sought to evaluate the role of DNA methylation patterns on "CHD-lymphoma" associations.METHODS: From >3 million live births (1988-2004) in California registry linkages, we obtained newborn dried bloodspots from eight children with CHD-lymphoma through the California BioBank. We performed case-control epigenome-wide association analyses (EWAS) using two comparison groups with reciprocal discovery and validation to identify differential methylation associated with CHD-lymphoma.RESULTS: After correction for multiple testing at the discovery and validation stages, individuals with CHD-lymphoma had differential newborn methylation at six sites relative to two comparison groups. Our top finding was significant in both EWAS and indicates PPFIA1 cg25574765 was hypomethylated among individuals with CHD-lymphoma (mean beta=0.04) relative to both unaffected individuals (mean beta=0.93, p=1.5*10-12 ) and individuals with complex CHD (mean beta=0.95, p=3.8*10-8 ). PPFIA1 encodes a ubiquitously expressed liprin protein in one of the most commonly amplified regions in many cancers (11q13). Further, cg25574765 is a proposed marker of pre-eclampsia, a maternal CHD risk factor that has not been fully evaluated for lymphoma risk in offspring, and the tumor microenvironment that may drive immune cell malignancies.CONCLUSIONS: We identified associations between molecular changes present in the genome at birth and risk of childhood lymphoma among those with CHD. Our findings also highlight novel perinatal exposures that may underlie methylation changes in CHD predisposing to lymphoma.
View details for DOI 10.1002/bdr2.2105
View details for PubMedID 36226634
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Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells
AMER ASSOC CANCER RESEARCH. 2022
View details for Web of Science ID 000892509500153
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MAJOR TUMOR REGRESSIONS IN H3K27M-MUTATED DIFFUSE MIDLINE GLIOMA (DMG) FOLLOWING SEQUENTIAL INTRAVENOUS (IV) AND INTRACEREBROVENTRICULAR (ICV) DELIVERY OF GD2-CAR T-CELLS
OXFORD UNIV PRESS INC. 2022: 20-21
View details for Web of Science ID 000840122400074
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A PHASE I TRIAL OF PANOBINOSTAT FOLLOWING RADIATION THERAPY IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) OR H3K27M-MUTATED THALAMIC DIFFUSE MIDLINE GLIOMA (DMG): REPORT FROM THE PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC-047)
OXFORD UNIV PRESS INC. 2022: 19
View details for Web of Science ID 000840122400069
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PATTERNS OF CEREBROSPINAL FLUID DIVERSION AND SURVIVAL IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE INTERNATIONAL DIFFUSE INTRINSIC PONTINE GLIOMA REGISTRY
OXFORD UNIV PRESS INC. 2022: 23-24
View details for Web of Science ID 000840122400084
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Characteristics of Children ≤36 Months of Age with Diffuse Intrinsic Pontine Glioma (DIPG): A Report from the International DIPG Registry.
Neuro-oncology
2022
Abstract
BACKGROUND: Children ≤36 months with Diffuse Intrinsic Pontine Glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes.METHODS: Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed.RESULTS: Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥ 5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3-, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (p=0.018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation.CONCLUSIONS: Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis.
View details for DOI 10.1093/neuonc/noac123
View details for PubMedID 35552452
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MRI Radiogenomics of Pediatric Medulloblastoma: A Multicenter Study.
Radiology
2022: 212137
Abstract
Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient groups suitable for targeted genetic analysis. Purpose To develop machine learning strategies that identify the four clinically significant MB molecular subgroups. Materials and Methods In this retrospective study, consecutive pediatric patients with newly diagnosed MB at MRI at 12 international pediatric sites between July 1997 and May 2020 were identified. There were 1800 features extracted from T2- and contrast-enhanced T1-weighted preoperative MRI scans. A two-stage sequential classifier was designed-one that first identifies non-wingless (WNT) and non-sonic hedgehog (SHH) MB and then differentiates therapeutically relevant WNT from SHH. Further, a classifier that distinguishes high-risk group 3 from group 4 MB was developed. An independent, binary subgroup analysis was conducted to uncover radiomics features unique to infantile versus childhood SHH subgroups. The best-performing models from six candidate classifiers were selected, and performance was measured on holdout test sets. CIs were obtained by bootstrapping the test sets for 2000 random samples. Model accuracy score was compared with the no-information rate using the Wald test. Results The study cohort comprised 263 patients (mean age ± SD at diagnosis, 87 months ± 60; 166 boys). A two-stage classifier outperformed a single-stage multiclass classifier. The combined, sequential classifier achieved a microaveraged F1 score of 88% and a binary F1 score of 95% specifically for WNT. A group 3 versus group 4 classifier achieved an area under the receiver operating characteristic curve of 98%. Of the Image Biomarker Standardization Initiative features, texture and first-order intensity features were most contributory across the molecular subgroups. Conclusion An MRI-based machine learning decision path allowed identification of the four clinically relevant molecular pediatric medulloblastoma subgroups. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Verschakelen in this issue.
View details for DOI 10.1148/radiol.212137
View details for PubMedID 35438562
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Corrigendum to: LTBK-01. Updates On The Phase Ii And Re-treatment Study Of AZD6244 (Selumetinib) For Children With Recurrent Or Refractory Pediatric Low Grade Glioma: A Pediatric Brain Tumor Consortium (PBTC) Study.
Neuro-oncology
2022
View details for DOI 10.1093/neuonc/noac029
View details for PubMedID 35307742
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GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.
Nature
2022
Abstract
Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMG) are universally lethal paediatric central nervous system tumours1. We previously discovered that the disialoganglioside GD2 is highly expressed on H3K27M-mutant glioma cells and demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human Phase 1 clinical trial (NCT04196413). Because CAR T-cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure, and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutant DIPG/DMG treated with GD2-CAR T cells (GD2-CART) at dose level 1 (1e6 GD2-CAR T cells/kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T infusions administered intracerebroventricularly3. Toxicity was largely related to tumor location and reversible with intensive supportive care. On-target, off-tumor toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Proinflammatory cytokines were increased in plasma and cerebrospinal fluid (CSF). Transcriptomic analyses of 65,598 single cells from CAR T cell products and CSF elucidate heterogeneity in response between subjects and administration routes. These early results underscore the promise of this approach for H3K27M+ DIPG/DMG therapy.
View details for DOI 10.1038/s41586-022-04489-4
View details for PubMedID 35130560
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Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.
Neuro-oncology
1800; 24 (1): 141-152
Abstract
BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR).METHODS: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months).RESULTS: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival.CONCLUSION: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.
View details for DOI 10.1093/neuonc/noab140
View details for PubMedID 34114629
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Equity and Inclusion Are Not New Issues
JOURNAL OF PEDIATRICS
2021; 239: 174
View details for Web of Science ID 000719251000031
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50 Years Ago in TheJournalofPediatrics: Equity and Inclusion Are Not New Issues.
The Journal of pediatrics
2021; 239: 174
View details for DOI 10.1016/j.jpeds.2021.09.042
View details for PubMedID 34794642
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Accuracy of Central Neuro-Imaging Review of DIPG Compared with Histopathology in the International DIPG Registry.
Neuro-oncology
2021
Abstract
BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential.METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included non-pontine origin, <50% pontine involvement, focally exophytic morphology, sharply-defined margins, and/or marked diffusion restriction throughout.RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly non-diffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to non-pontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p<0.001), and central neuro-imaging impression was prognostic of overall survival.CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.
View details for DOI 10.1093/neuonc/noab245
View details for PubMedID 34668975
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Genetic counselor roles in the undiagnosed diseases network research study: Clinical care, collaboration, and curation.
Journal of genetic counseling
2021
Abstract
Genetic counselors (GCs) are increasingly filling important positions on research study teams, but there is limited literature describing the roles of GCs in these settings. GCs on the Undiagnosed Diseases Network (UDN) study team serve in a variety of roles across the research network and provide an opportunity to better understand genetic counselor roles in research. To quantitatively characterize the tasks regularly performed and professional fulfillment derived from these tasks, two surveys were administered to UDN GCs in a stepwise fashion. Responses from the first, free-response survey elicited the scope of tasks which informed development of a second structured, multiple-select survey. In survey 2, respondents were asked to select which roles they performed. Across 19 respondents, roles in survey 2 received a total of 947 selections averaging approximately 10 selections per role. When asked to indicate what roles they performed, respondent selected a mean of 50 roles (range 22-70). Survey 2 data were analyzed via thematic coding of responses and hierarchical cluster analysis to identify patterns in responses. From the thematic analysis, 20 non-overlapping codes emerged in seven categories: clinical interaction and care, communication, curation, leadership, participant management, research, and team management. Three themes emerged from the categories that represented the roles of GCs in the UDN: clinical care, collaboration, and curation. Cluster analyses showed that responses were more similar among individuals at the same institution than between institutions. This study highlights the ways GCs apply their unique skill set in the context of a clinical translational research network. Additionally, findings from this study reinforce the wide applicability of core skills that are part of genetic counseling training. Clinical literacy, genomics expertise and analysis, interpersonal, psychosocial and counseling skills, education, professional practice skills, and an understanding of research processes make genetic counselors well suited for such roles and poised to positively impact research experiences and outcomes for participants.
View details for DOI 10.1002/jgc4.1493
View details for PubMedID 34374469
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Radiomic Phenotypes Distinguish Atypical Teratoid/Rhabdoid Tumors from Medulloblastoma.
AJNR. American journal of neuroradiology
2021
Abstract
BACKGROUND AND PURPOSE: Atypical teratoid/rhabdoid tumors and medulloblastomas have similar imaging and histologic features but distinctly different outcomes. We hypothesized that they could be distinguished by MR imaging-based radiomic phenotypes.MATERIALS AND METHODS: We retrospectively assembled T2-weighted and gadolinium-enhanced T1-weighted images of 48 posterior fossa atypical teratoid/rhabdoid tumors and 96 match-paired medulloblastomas from 7 institutions. Using a holdout test set, we measured the performance of 6 candidate classifier models using 6 imaging features derived by sparse regression of 900 T2WI and 900 T1WI Imaging Biomarker Standardization Initiative-based radiomics features.RESULTS: From the originally extracted 1800 total Imaging Biomarker Standardization Initiative-based features, sparse regression consistently reduced the feature set to 1 from T1WI and 5 from T2WI. Among classifier models, logistic regression performed with the highest AUC of 0.86, with sensitivity, specificity, accuracy, and F1 scores of 0.80, 0.82, 0.81, and 0.85, respectively. The top 3 important Imaging Biomarker Standardization Initiative features, by decreasing order of relative contribution, included voxel intensity at the 90th percentile, inverse difference moment normalized, and kurtosis-all from T2WI.CONCLUSIONS: Six quantitative signatures of image intensity, texture, and morphology distinguish atypical teratoid/rhabdoid tumors from medulloblastomas with high prediction performance across different machine learning strategies. Use of this technique for preoperative diagnosis of atypical teratoid/rhabdoid tumors could significantly inform therapeutic strategies and patient care discussions.
View details for DOI 10.3174/ajnr.A7200
View details for PubMedID 34266866
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GD2 CAR T cells mediate clinical activity and manageable toxicity in children and young adults with DIPG and H3K27M-mutated diffuse midline gliomas.
AMER ASSOC CANCER RESEARCH. 2021
View details for Web of Science ID 000680263501014
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SINGLE CELL RNA SEQUENCING FROM THE CSF OF SUBJECTS WITH H3K27M+DIPG/DMG TREATED WITH GD2 CAR T-CELLULAR THERAPY
OXFORD UNIV PRESS INC. 2021: 39
View details for DOI 10.1093/neuonc/noab090.158
View details for Web of Science ID 000671540600159
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GD2 CAR T-CELLS MEDIATE CLINICAL ACTIVITY AND MANAGEABLE TOXICITY IN CHILDREN AND YOUNG ADULTS WITH H3K27M-MUTATED DIPG AND SPINAL CORD DMG
OXFORD UNIV PRESS INC. 2021: 49-50
View details for DOI 10.1093/neuonc/noab090.200
View details for Web of Science ID 000671540600201
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Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy.
Journal of neurogenetics
2021: 1–10
Abstract
KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.
View details for DOI 10.1080/01677063.2021.1892095
View details for PubMedID 33970744
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A resource of lipidomics and metabolomics data from individuals with undiagnosed diseases
SCIENTIFIC DATA
2021; 8 (1): 114
Abstract
Every year individuals experience symptoms that remain undiagnosed by healthcare providers. In the United States, these rare diseases are defined as a condition that affects fewer than 200,000 individuals. However, there are an estimated 7000 rare diseases, and there are an estimated 25-30 million Americans in total (7.6-9.2% of the population as of 2018) affected by such disorders. The NIH Common Fund Undiagnosed Diseases Network (UDN) seeks to provide diagnoses for individuals with undiagnosed disease. Mass spectrometry-based metabolomics and lipidomics analyses could advance the collective understanding of individual symptoms and advance diagnoses for individuals with heretofore undiagnosed disease. Here, we report the mass spectrometry-based metabolomics and lipidomics analyses of blood plasma, urine, and cerebrospinal fluid from 148 patients within the UDN and their families, as well as from a reference population of over 100 individuals with no known metabolic diseases. The raw and processed data are available to the research community so that they might be useful in the diagnoses of current or future patients suffering from undiagnosed disorders.
View details for DOI 10.1038/s41597-021-00894-y
View details for Web of Science ID 000642148100001
View details for PubMedID 33883556
View details for PubMedCentralID PMC8060404
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Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain
GENETICS IN MEDICINE
2021
Abstract
We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA).Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
View details for DOI 10.1038/s41436-021-01152-7
View details for Web of Science ID 000638059400001
View details for PubMedID 33833410
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Functional and structural analysis of cytokine selective IL6ST defects that cause recessive hyper-IgE syndrome.
The Journal of allergy and clinical immunology
2021
Abstract
BACKGROUND: Biallelic variants in IL6ST cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE, eosinophilia, defective acute phase response, susceptibility to bacterial infections and skeletal abnormalities due to cytokine selective loss-of-function in GP130 with defective IL-6 and IL-11, variable OSM and IL-27 but sparing LIF signaling.OBJECTIVE: To understand the functional and structural impact of recessive HIES-associated IL6ST variants.METHODS: We investigated a patient with HIES using exome, genome and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamic simulations and structural modeling of GP130 cytokine receptor complexes were performed.RESULTS: We identify a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro, and exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant results in a more profound IL-6 and IL-11 dominated signaling defect compared to the previously identified recessive IL6ST variants p.Asn404Tyr, and p.Pro498Leu. Molecular dynamics simulations suggest that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilize the hexameric cytokine receptor complexes whereas the trimeric LIF-GP130-LIFR complex remains stable by an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently causes additional defective LIF signaling and Stuve-Wiedemann syndrome.CONCLUSION: Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.
View details for DOI 10.1016/j.jaci.2021.02.044
View details for PubMedID 33771552
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Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-Institutional Trials.
Clinical cancer research : an official journal of the American Association for Cancer Research
2021
Abstract
PURPOSE: Report relevance of molecular groups to clinico-pathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials.PATIENTS AND METHODS: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age<3 years; n=52) and children (SJMB03: age 3-21 years; n=22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiation therapy [focal (infants) and craniospinal (CSI) (children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles.RESULTS: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR (n=21), SHH (n=30), and MYC (n=13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS) (P=0.02). However, outcomes did not differ by molecular groups among infants with non-metastatic (M0) disease. Children with M0 disease and <1.5 cm2 residual tumor had a 5-year progression-free survival (PFS) of 72.7{plus minus}12.7% and OS of 81.8{plus minus}11%. Infants with M0 disease had a 5-year PFS of 39.1{plus minus}11.5% and OS of 51.8{plus minus}12%. Those with metastases fared poorly [5-year OS 25{plus minus}12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS.CONCLUSION: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with non-metastatic ATRT benefit from post-operative CSI and adjuvant chemotherapy.
View details for DOI 10.1158/1078-0432.CCR-20-4731
View details for PubMedID 33737307
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Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases.
Genetics in medicine : official journal of the American College of Medical Genetics
2021
Abstract
PURPOSE: Genomic sequencing has become an increasingly powerful and relevant tool to be leveraged for the discovery of genetic aberrations underlying rare, Mendelian conditions. Although the computational tools incorporated into diagnostic workflows for this task are continually evolving and improving, we nevertheless sought to investigate commonalities across sequencing processing workflows to reveal consensus and standard practice tools and highlight exploratory analyses where technical and theoretical method improvements would be most impactful.METHODS: We collected details regarding the computational approaches used by a genetic testing laboratory and 11 clinical research sites in the United States participating in the Undiagnosed Diseases Network via meetings with bioinformaticians, online survey forms, and analyses of internal protocols.RESULTS: We found that tools for processing genomic sequencing data can be grouped into four distinct categories. Whereas well-established practices exist for initial variant calling and quality control steps, there is substantial divergence across sites in later stages for variant prioritization and multimodal data integration, demonstrating a diversity of approaches for solving the most mysterious undiagnosed cases.CONCLUSION: The largest differences across diagnostic workflows suggest that advances in structural variant detection, noncoding variant interpretation, and integration of additional biomedical data may be especially promising for solving chronically undiagnosed cases.
View details for DOI 10.1038/s41436-020-01084-8
View details for PubMedID 33580225
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A Pilot Study of Low-Dose Craniospinal Irradiation in Patients With Newly Diagnosed Average-Risk Medulloblastoma.
Frontiers in oncology
2021; 11: 744739
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.
View details for DOI 10.3389/fonc.2021.744739
View details for PubMedID 34540703
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Radiomic Signatures of Posterior Fossa Ependymoma: Molecular Subgroups and Risk Profiles.
Neuro-oncology
2021
Abstract
The risk profile for posterior fossa ependymoma (EP) depends on surgical and molecular status [Group A (PFA) versus Group B (PFB)]. While subtotal tumor resection is known to confer worse prognosis, MRI-based EP risk-profiling is unexplored. We aimed to apply machine learning strategies to link MRI-based biomarkers of high-risk EP and also to distinguish PFA from PFB.We extracted 1800 quantitative features from presurgical T2-weighted (T2-MRI) and gadolinium-enhanced T1-weighted (T1-MRI) imaging of 157 EP patients. We implemented nested cross-validation to identify features for risk score calculations and apply a Cox model for survival analysis. We conducted additional feature selection for PFA versus PFB and examined performance across three candidate classifiers.For all EP patients with GTR, we identified four T2-MRI-based features and stratified patients into high- and low-risk groups, with 5-year overall survival rates of 62% and 100%, respectively (p < 0.0001). Among presumed PFA patients with GTR, four T1-MRI and five T2-MRI features predicted divergence of high- and low-risk groups, with 5-year overall survival rates of 62.7% and 96.7%, respectively (p = 0.002). T1-MRI-based features showed the best performance distinguishing PFA from PFB with an AUC of 0.86.We present machine learning strategies to identify MRI phenotypes that distinguish PFA from PFB, as well as high- and low-risk PFA. We also describe quantitative image predictors of aggressive EP tumors that might assist risk-profiling after surgery. Future studies could examine translating radiomics as an adjunct to EP risk assessment when considering therapy strategies or trial candidacy.
View details for DOI 10.1093/neuonc/noab272
View details for PubMedID 34850171
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PATTERNS OF CEREBROSPINAL FLUID DIVERSION AND SURVIVAL IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY
OXFORD UNIV PRESS INC. 2020: 297–98
View details for Web of Science ID 000606080100101
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RE-IRRADIATION OF DIPG: DATA FROM THE INTERNATIONAL DIPG REGISTRY
OXFORD UNIV PRESS INC. 2020: 301–2
View details for Web of Science ID 000606080100117
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NON-DIPG PATIENTS ENROLLED IN THE INTERNATIONAL DIPG REGISTRY: HISTOPATHOLOGIC EVALUATION OF CENTRAL NEURO-IMAGING REVIEW
OXFORD UNIV PRESS INC. 2020: 295–96
View details for Web of Science ID 000606080100093
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MRI-BASED RADIOMICS PROGNOSTIC MARKERS OF POSTERIOR FOSSA EPENDYMOMA
OXFORD UNIV PRESS INC. 2020: 357
View details for Web of Science ID 000606080100349
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A STUDY OF LOW-DOSE CRANIOSPINAL RADIATION THERAPY IN PATIENTS WITH NEWLY DIAGNOSED AVERAGE-RISK MEDULLOBLASTOMA
OXFORD UNIV PRESS INC. 2020: 390–91
View details for Web of Science ID 000606080100491
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NON-DIPG PATIENTS ENROLLED IN THE INTERNATIONAL DIPG REGISTRY: HISTOPATHOLOGIC EVALUATION OF CENTRAL NEURO-IMAGING REVIEW
OXFORD UNIV PRESS INC. 2020: 154
View details for Web of Science ID 000590061300645
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De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.
American journal of human genetics
2020
Abstract
EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.
View details for DOI 10.1016/j.ajhg.2020.02.016
View details for PubMedID 32197074
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Outcome and molecular analysis of young children with choroid plexus carcinoma treated with non-myeloablative therapy: results from the SJYC07 trial.
Neuro-oncology advances
2020; 3 (1): vdaa168
Abstract
Choroid plexus carcinoma (CPC) is a rare and aggressive tumor of infancy without a clear treatment strategy. This study describes the outcomes of children with CPC treated on the multi-institutional phase 2 SJYC07 trial and reports on the significance of clinical and molecular characteristics.Eligible children <3 years-old with CPC were postoperatively stratified to intermediate-risk (IR) stratum if disease was localized or high-risk (HR) stratum, if metastatic. All received high-dose methotrexate-containing induction chemotherapy. IR-stratum patients received focal irradiation as consolidation whereas HR-stratum patients received additional chemotherapy. Consolidation was followed by oral antiangiogenic maintenance regimen. Survival rates and potential prognostic factors were analyzed.Thirteen patients (median age: 1.41 years, range: 0.21-2.93) were enrolled; 5 IR, 8 HR. Gross-total resection or near-total resection was achieved in ten patients and subtotal resection in 3. Seven patients had TP53-mutant tumors, including 4 who were germline carriers. Five patients experienced progression and died of disease; 8 (including 5 HR) are alive without progression. The 5-year progression-free survival (PFS) and overall survival rates were 61.5 ± 13.5% and 68.4 ± 13.1%. Patients with TP53-wild-type tumors had a 5-year PFS of 100% as compared to 28.6 ± 17.1% for TP53-mutant tumors (P = .012). Extent of resection, metastatic status, and use of radiation therapy were not significantly associated with survival.Non-myeloablative high-dose methotrexate-containing therapy with maximal surgical resection resulted in long-term PFS in more than half of patients with CPC. TP53-mutational status was the only significant prognostic variable and should form the basis of risk-stratification in future trials.
View details for DOI 10.1093/noajnl/vdaa168
View details for PubMedID 33506206
View details for PubMedCentralID PMC7813199
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MR Imaging features of Diffuse Intrinsic Pontine Glioma (DIPG) and Relationship to Overall Survival: Report from the International DIPG Registry.
Neuro-oncology
2020
Abstract
This study describes imaging features of diffuse intrinsic pontine glioma (DIPG) and correlates with overall survival (OS) and histone mutation status in the International DIPG registry (IDIPGR).400 cases submitted to the IDIPGR with a local diagnosis of DIPG and baseline MRI were evaluated by consensus review of two neuroradiologists. 43 cases were excluded (inadequate imaging or alternative diagnoses). Agreement between reviewers, association with histone status, and univariable and multivariable analyses relative to OS were assessed.On univariable analysis imaging features significantly associated with worse OS included: extrapontine extension, larger size, enhancement, necrosis, diffusion restriction, and distant disease. 9.5% of patients were considered not to have DIPG on central review. There was moderate mean agreement of MRI features between reviewers. On multivariable analysis chemotherapy, age, and distant disease were predictors of OS. There was no difference in OS between wild-type and H3 mutated cases. The only imaging feature associated with histone status was the presence of ill-defined signal infiltrating pontine fibers.Baseline imaging features are assessed in the IDIPGR. There was a 9.5% discordance in DIPG diagnosis between local and central review demonstrating need for central imaging confirmation for prospective trials. Although several imaging features were significantly associated with OS (univariable) only age and distant disease were significant on multivariable analyses. There was limited association of imaging features with histone mutation status although numbers are small and evaluation exploratory.
View details for DOI 10.1093/neuonc/noaa140
View details for PubMedID 32506137
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Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science.
Genetics in medicine : official journal of the American College of Medical Genetics
2020
Abstract
The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices.We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods.Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling.Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.
View details for DOI 10.1038/s41436-020-00984-z
View details for PubMedID 33093671
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How to evaluate concussion in all children?
The Journal of pediatrics
2019; 214: 1-3
View details for DOI 10.1016/j.jpeds.2019.09.040
View details for PubMedID 31655690
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VarSight: prioritizing clinically reported variants with binary classification algorithms.
BMC bioinformatics
2019; 20 (1): 496
Abstract
When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance.We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network.We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20.We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.
View details for DOI 10.1186/s12859-019-3026-8
View details for PubMedID 31615419
View details for PubMedCentralID PMC6792253
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De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects.
American journal of human genetics
2019; 105 (4): 854-868
Abstract
Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).
View details for DOI 10.1016/j.ajhg.2019.09.005
View details for PubMedID 31585109
View details for PubMedCentralID PMC6817525
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Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial
NEURO-ONCOLOGY
2019; 21 (10): 1319–30
View details for DOI 10.1093/neuonc/noz069
View details for Web of Science ID 000493086800014
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Quality qualitative research for family-centered care.
The Journal of pediatrics
2019; 213: 1-3
View details for DOI 10.1016/j.jpeds.2019.08.006
View details for PubMedID 31561767
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De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.
American journal of human genetics
2019; 105 (3): 672-674
View details for DOI 10.1016/j.ajhg.2019.07.017
View details for PubMedID 31491411
View details for PubMedCentralID PMC6732524
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Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing.
Journal of genetic counseling
2019
Abstract
BACKGROUND: Despite growing evidence of diagnostic yield and clinical utility of whole exome sequencing (WES) in patients with undiagnosed diseases, there remain significant cost and reimbursement barriers limiting access to such testing. The diagnostic yield and resulting clinical actions of WES for patients who previously faced insurance coverage barriers have not yet been explored.METHODS: We performed a retrospective descriptive analysis of clinical WES outcomes for patients facing insurance coverage barriers prior to clinical WES and who subsequently enrolled in the Undiagnosed Diseases Network (UDN). Clinical WES was completed as a result of participation in the UDN. Payer type, molecular diagnostic yield, and resulting clinical actions were evaluated.RESULTS: Sixty-six patients in the UDN faced insurance coverage barriers to WES at the time of enrollment (67% public payer, 26% private payer). Forty-two of 66 (64%) received insurance denial for clinician-ordered WES, 19/66 (29%) had health insurance through a payer known not to cover WES, and 5/66 (8%) had previous payer denial of other genetic tests. Clinical WES results yielded a molecular diagnosis in 23 of 66 patients (35% [78% pediatric, 65% neurologic indication]). Molecular diagnosis resulted in clinical actions in 14 of 23 patients (61%).CONCLUSIONS: These data demonstrate that a substantial proportion of patients who encountered insurance coverage barriers to WES had a clinically actionable molecular diagnosis, supporting the notion that WES has value as a covered benefit for patients who remain undiagnosed despite objective clinical findings.
View details for DOI 10.1002/jgc4.1161
View details for PubMedID 31478310
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Molecular correlates of cerebellar mutism syndrome in medulloblastoma.
Neuro-oncology
2019
Abstract
BACKGROUND: Cerebellar Mutism Syndrome (CMS) is a common complication following resection of posterior fossa tumors, most commonly after surgery for medulloblastoma. Medulloblastoma subgroups have historically been treated as a single entity when assessing CMS risk; however, recent studies highlighting their clinical heterogeneity suggest the need for subgroup-specific analysis. Here, we examine a large international multicenter cohort of molecularly characterized medulloblastoma patients to assess predictors of CMS.METHODS: We assembled a cohort of 370 molecularly characterized medulloblastoma subjects with available neuroimaging from five sites globally including Great Ormond Street Hospital, Christian Medical College and Hospital, Hospital for Sick Children, King Hussein Cancer Center, and Lucile Packard Children's Hospital. Age at diagnosis, sex, tumour volume, and CMS development were assessed in addition to molecular subgroup.RESULTS: Overall, 23.8% of patients developed CMS. CMS patients were younger (mean difference -2.05 years ± 0.50, P=0.0218) and had larger tumours (mean difference 10.25 cm3 ± 4.60, P=0.0010) that were more often midline (OR=5.72, P<0.0001). In a multivariable analysis adjusting for age, sex, midline location, and tumour volume, WNT (Wingless) (adjusted OR=4.91, p=0.0063), Group 3 (adjusted OR=5.56, p=0.0022) and Group 4 (adjusted OR=8.57 p=9.1x10-5) tumours were found to be independently associated with higher risk of CMS compared with SHH (Sonic Hedgehog) tumours.CONCLUSIONS: Medulloblastoma subgroup is a very strong predictor of CMS development, independent of tumour volume and midline location. These findings have significant implications for management of both the tumour and CMS.
View details for DOI 10.1093/neuonc/noz158
View details for PubMedID 31504816
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De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.
American journal of human genetics
2019
Abstract
WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.
View details for DOI 10.1016/j.ajhg.2019.06.014
View details for PubMedID 31327508
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Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.
Biological psychiatry
2019
Abstract
The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.
View details for DOI 10.1016/j.biopsych.2019.05.028
View details for PubMedID 31443933
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Magnetic Resonance Imaging characteristics in case of TOR1AIP1 muscular dystrophy.
Clinical imaging
2019; 58: 108-113
Abstract
Mutations in the torsinA-interacting protein 1 (TOR1AIP1) gene result in a severe muscular dystrophy with minimal literature in the pediatric population. We review a case of TOR1AIP1 gene mutation in a 16-year-old Caucasian female with a long history of muscle weakness. Extensive clinical workup was performed and MRI at time of initial presentation demonstrated no significant muscular atrophy with heterogenous STIR hyperintensity of the lower extremity muscles. MRI findings seven years later included extensive atrophy of the lower extremities, with severe progression, including the gluteal muscles, iliopsoas, rectus femoris, and obturator internus. There was also significant atrophy of the rectus abdominis and internal and external oblique muscles, and iliacus muscles. The MRI findings showed more proximal involvement of lower extremities and no atrophy of the tibialis anterior, making TOR1AIP1 the more likely genetic cause. Muscle biopsy findings supported TOR1AIP1 limb-girdle muscular dystrophy. Though rare, TOR1AIP1 gene mutation occurs in pediatric patients and MRI can aid in diagnosis and help differentiate from other types of muscular dystrophy. Genetic and pathology workup is also crucial to accurate diagnosis and possible treatment of these patients.
View details for DOI 10.1016/j.clinimag.2019.06.010
View details for PubMedID 31299614
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Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification.
American journal of human genetics
2019; 104 (6): 1127-1138
Abstract
Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl-/H+ exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.
View details for DOI 10.1016/j.ajhg.2019.04.008
View details for PubMedID 31155284
View details for PubMedCentralID PMC6562152
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A Patient with Sjogren's Syndrome and Subsequent Diagnosis of Inclusion Body Myositis and Light-Chain Amyloidosis
JOURNAL OF GENERAL INTERNAL MEDICINE
2019; 34 (6): 1058–62
View details for DOI 10.1007/s11606-019-04931-w
View details for Web of Science ID 000469884700059
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Disproving junk science.
The Journal of pediatrics
2019; 209: 1
View details for DOI 10.1016/j.jpeds.2019.04.013
View details for PubMedID 31128721
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Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
2019; 179 (6): 966–77
View details for DOI 10.1002/ajmg.a.61134
View details for Web of Science ID 000468322800015
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Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis.
Human mutation
2019
Abstract
Encoding the slow skeletal muscle isoform of myosin binding protein-C, MYBPC1 is associated with autosomal dominant and recessive forms of arthrogryposis. The authors describe a novel association for MYBPC1 in four patients from three independent families with skeletal muscle weakness, myogenic tremors, and hypotonia with gradual clinical improvement. The patients carried one of two de novo heterozygous variants in MYBPC1, with the p.Leu263Arg variant seen in three individuals and the p.Leu259Pro variant in one individual. Both variants are absent from controls, well conserved across vertebrate species, predicted to be damaging, and located in the M-motif. Protein modeling studies suggested that the p.Leu263Arg variant affects the stability of the M-motif, whereas the p.Leu259Pro variant alters its structure. In vitro biochemical and kinetic studies demonstrated that the p.Leu263Arg variant results in decreased binding of the M-motif to myosin, which likely impairs the formation of actomyosin cross-bridges during muscle contraction. Collectively, our data substantiate that damaging variants in MYBPC1 are associated with a new form of an early-onset myopathy with tremor, which is a defining and consistent characteristic in all affected individuals, with no contractures. Recognition of this expanded myopathic phenotype can enable identification of individuals with MYBPC1 variants without arthrogryposis.
View details for DOI 10.1002/humu.23760
View details for PubMedID 31264822
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IgG4-related disease: Association with a rare gene variant expressed in cytotoxic T cells.
Molecular genetics & genomic medicine
2019: e686
Abstract
Family screening of a 48-year-old male with recently diagnosed IgG4-related disease (IgG4-RD) revealed unanticipated elevations in plasma IgG4 in his two healthy teenaged sons.We performed gene sequencing, immune cell studies, HLA typing, and analyses of circulating cytotoxic CD4+ T lymphocytes and plasmablasts to seek clues to pathogenesis. DNA from a separate cohort of 99 patients with known IgG4-RD was also sequenced for the presence of genetic variants in a specific gene, FGFBP2.The three share a previously unreported heterozygous single base deletion in fibroblast growth factor binding protein type 2 (FGFBP2), which causes a frameshift in the coding sequence. The FGFBP2 protein is secreted by cytotoxic T-lymphocytes and binds fibroblast growth factor. The variant sequence in the FGFBP2 protein is predicted to form a disordered random coil rather than a helical-turn-helix structure, unable to adopt a stable conformation. The proband and the two sons had 5-10-fold higher numbers of circulating cytotoxic CD4 + T cells and plasmablasts compared to matched controls. The three members also share a homozygous missense common variant in FGFBP2 found in heterozygous form in ~40% of the population. This common variant was found in 73% of an independent, well characterized IgG4-RD cohort, showing enrichment in idiopathic IgG4-RD.The presence of a shared deleterious variant and homozygous common variant in FGFBP2 in the proband and sons strongly implicates this cytotoxic T cell product in the pathophysiology of IgG4-RD. The high prevalence of a common FGFBP2 variant in sporadic IgG4-RD supports the likelihood of participation in disease.
View details for DOI 10.1002/mgg3.686
View details for PubMedID 30993913
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Molecular Grouping and Outcomes of Young Children with Newly Diagnosed Ependymoma Treated on the Multi-Institutional SJYC07 Trial.
Neuro-oncology
2019
Abstract
BACKGROUND: This report documents the clinical characteristics, molecular grouping and outcome of young children with ependymoma treated prospectively on a clinical trial.METHODS: Fifty-four children (aged ≤ 3 years) with newly diagnosed ependymoma were treated on the SJYC07 trial with maximal safe surgical resection, 4 cycles of systemic chemotherapy, consolidation therapy using focal conformal radiation therapy (RT) (5-mm clinical target volume), and 6 months of oral maintenance chemotherapy. Molecular groups were determined by tumor DNA methylation using Infinium Methylation EPIC BeadChip and profiled on DKFZ/German molecularneuropathology2.0 classifier.RESULTS: One of the 54 study patients had metastases (CSF+) at diagnosis. Gross- or near-total resection was achieved in 48 (89%) patients prior to RT. At a median follow-up of 4.4 years (range, 0.2-10.3 years), 4-year progression-free survival (PFS) was 75.1% ± 7.2%, and overall survival was 92.6% ± 4.4%. The molecular groups showed no significant difference in PFS [4-year estimates: PF-EPN-A (42/54), 71.2% ± 8.3%; ST-EPN-RELA (8/54), 83.3% ± 17.0%; ST-EPN-YAP (4/54), 100%, p=0.22]. Subtotal resection prior to RT was associated with an inferior PFS compared to gross- or near-total resection (4-year PFS: 41.7% ± 22.5% vs. 79.0% ± 7.1%, p=0.024) as was PF-EPN-A group with 1q gain (p=0.05). Histopathologic grading was not associated with outcomes (classic vs anaplastic; p=0.89).CONCLUSIONS: In this prospectively treated cohort of young children with ependymoma, ST-EPN-RELA tumors had a favorable outcome than reported from retrospective data. Histological grade did not impact outcome. PF-EPN-A with 1q gain, and sub-total resection were associated with inferior outcomes.
View details for PubMedID 30976811
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A PHASE II PROSPECTIVE TRIAL OF SELUMETINIB IN CHILDREN WITH RECURRENT/PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA (PLGG) WITH A FOCUS UPON OPTIC PATHWAY/HYPOTHALAMIC TUMORS AND VISUAL ACUITY OUTCOMES: A PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC) STUDY, PBTC-029B
OXFORD UNIV PRESS INC. 2019: 98–99
View details for DOI 10.1093/neuonc/noz036.145
View details for Web of Science ID 000473243700146
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Point-of-care EEG?
The Journal of pediatrics
2019; 207: 1
View details for DOI 10.1016/j.jpeds.2019.02.010
View details for PubMedID 30922486
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A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing
JOURNAL OF GENETIC COUNSELING
2019; 28 (2): 213–28
View details for DOI 10.1002/jgc4.1119
View details for Web of Science ID 000463993600005
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Developing a genomics rotation: Practical training around variant interpretation for genetic counseling students
JOURNAL OF GENETIC COUNSELING
2019; 28 (2): 466–76
View details for DOI 10.1002/jgc4.1094
View details for Web of Science ID 000463993600030
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Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review.
American journal of medical genetics. Part A
2019
Abstract
Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p=.0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.
View details for PubMedID 30920161
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Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.
American journal of human genetics
2019; 104 (3): 422-438
Abstract
SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.
View details for DOI 10.1016/j.ajhg.2019.01.007
View details for PubMedID 30773277
View details for PubMedCentralID PMC6408318
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Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region.
Epilepsia
2019; 60 (3): 406-418
Abstract
To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype-protein structure-phenotype relationships.We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three-dimensional structural protein model.The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)-binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207-221 had only movement disorder and hypotonia. Patients with variants affecting the C-terminal region had the mildest phenotypes.GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP-binding domain of GNAO1, highlighting the importance of this region for G-protein signaling and neurodevelopment.
View details for DOI 10.1111/epi.14653
View details for PubMedID 30682224
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Have Zackery Lystedt concussion laws made an impact?
The Journal of pediatrics
2019; 206: 2-3
View details for DOI 10.1016/j.jpeds.2019.01.019
View details for PubMedID 30798822
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To sleep and dream without digital screens.
The Journal of pediatrics
2019; 205: 2
View details for DOI 10.1016/j.jpeds.2018.12.017
View details for PubMedID 30684978
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Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.
The Lancet. Oncology
2019
Abstract
Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAFV600E [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported.Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.
View details for DOI 10.1016/S1470-2045(19)30277-3
View details for PubMedID 31151904
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50 Years Ago in The Journal of Pediatrics: The Clinical Spectrum and Early Diagnosis of Dawson's Encephalitis.
The Journal of pediatrics
2019; 213: 102
View details for DOI 10.1016/j.jpeds.2019.03.049
View details for PubMedID 31561773
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50 Years Ago in TheJournal ofPediatrics: The Coincidence of Neuroblastoma and Acute Cerebellar Encephalopathy.
The Journal of pediatrics
2019; 215: 117
View details for DOI 10.1016/j.jpeds.2019.05.059
View details for PubMedID 31761135
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Who is prescribing opioids to children with headaches?
The Journal of pediatrics
2019; 204: 1
View details for DOI 10.1016/j.jpeds.2018.11.010
View details for PubMedID 30579460
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Migrant mothers and risks of developmental disabilities in their children.
The Journal of pediatrics
2019; 204: 2-3
View details for DOI 10.1016/j.jpeds.2018.11.014
View details for PubMedID 30579466
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Genomics in medicine: a novel elective rotation for internal medicine residents.
Postgraduate medical journal
2019
Abstract
It is well recognised that medical training globally and at all levels lacks sufficient incorporation of genetics and genomics education to keep up with the rapid advances and growing application of genomics to clinical care. However, the best strategy to implement these desired changes into postgraduate medical training and engage learners is still unclear. We developed a novel elective rotation in 'Genomic Medicine and Undiagnosed Diseases' for categorical Internal Medicine Residents to address this educational gap and serve as an adaptable model for training that can be applied broadly across different specialties and at other institutions. Key curriculum goals achieved include increased understanding about genetic testing modalities and tools available for diagnosis and risk analysis, the role of genetics-trained allied health professionals, and indications and limitations of genetic and genomic testing in both rare and common conditions.
View details for DOI 10.1136/postgradmedj-2018-136355
View details for PubMedID 31439813
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A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing.
Journal of genetic counseling
2019; 28 (2): 213–28
Abstract
There are approximately 7,000 rare diseases affecting 25-30 million Americans, with 80% estimated to have a genetic basis. This presents a challenge for genetics practitioners to determine appropriate testing, make accurate diagnoses, and conduct up-to-date patient management. Exome sequencing (ES) is a comprehensive diagnostic approach, but only 25%-41% of the patients receive a molecular diagnosis. The remaining three-fifths to three-quarters of patients undergoing ES remain undiagnosed. The Stanford Center for Undiagnosed Diseases (CUD), a clinical site of the Undiagnosed Diseases Network, evaluates patients with undiagnosed and rare diseases using a combination of methods including ES. Frequently these patients have non-diagnostic ES results, but strategic follow-up techniques identify diagnoses in a subset. We present techniques used at the CUD that can be adopted by genetics providers in clinical follow-up of cases where ES is non-diagnostic. Solved case examples illustrate different types of non-diagnostic results and the additional techniques that led to a diagnosis. Frequent approaches include segregation analysis, data reanalysis, genome sequencing, additional variant identification, careful phenotype-disease correlation, confirmatory testing, and case matching. We also discuss prioritization of cases for additional analyses.
View details for PubMedID 30964584
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A Patient with Sjogren's Syndrome and Subsequent Diagnosis of Inclusion Body Myositis and Light-Chain Amyloidosis.
Journal of general internal medicine
2019
Abstract
We discuss a challenging case of a 58-year-old Vietnamese-American woman who presented to her new primary care provider with an 8-year history of slowly progressive dysphagia, hoarseness, muscle weakness with associated frequent falls, and weight loss. She eventually reported dry eyes and dry mouth, and she was diagnosed with Sjogren's syndrome. Subsequently, she was additionally diagnosed with inclusion body myositis and gastric light-chain (AL) amyloidosis. Although inclusion body myositis has been previously associated with Sjogren's syndrome, inclusion body myositis is rare in non-Caucasians, and the trio of Sjogren's syndrome, inclusion body myositis, and AL amyloidosis has not been previously reported. Sjogren's syndrome is a systemic autoimmune condition characterized by ocular and oral dryness. It is one of the most common rheumatologic disorders in the USA and worldwide. Early diagnosis of Sjogren's is particularly important given the frequency and variety of associated autoimmune diseases and extraglandular manifestations. Furthermore, although inclusion body myositis has a low prevalence, it is the most common inflammatory myopathy in older adults and is unfortunately associated with long delays in diagnosis, so knowledge of this disorder is also crucial for practicing internists.
View details for PubMedID 30887439
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts.
Nature medicine
2019
Abstract
It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene1. The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches2-5. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases6-8. This includes muscle biopsies from patients with undiagnosed rare muscle disorders6,9, and cultured fibroblasts from patients with mitochondrial disorders7. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
View details for DOI 10.1038/s41591-019-0457-8
View details for PubMedID 31160820
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Developing a genomics rotation: Practical training around variant interpretation for genetic counseling students.
Journal of genetic counseling
2019
Abstract
With the wide adoption of next-generation sequencing (NGS)-based genetic tests, genetic counselors require increased familiarity with NGS technology, variant interpretation concepts, and variant assessment tools. The use of exome and genome sequencing in clinical care has expanded the reach and diversity of genetic testing. Regardless of the setting where genetic counselors are performing variant interpretation or reporting, most of them have learned these skills from colleagues, while on the job. Though traditional, lecture-based learning around these topics is important, there has been growing need for the inclusion of case-based, experiential training of genomics and variant interpretation for genetic counseling students, with the goal of creating a strong foundation in variant interpretation for new genetic counselors, regardless of what area of practice they enter. To address this need, we established a genomics and variant interpretation rotation for Stanford's genetic counseling training program. In response to changes in the genomics landscape, this has now evolved into three unique rotation experiences, each focused on variant interpretation in the context of various genomic settings, including clinical laboratory, research laboratory, and healthy genomic analysis studies. Here, we describe the goals and learning objectives that we have developed for these variant interpretation rotations, and illustrate how these concepts are applied in practice.
View details for PubMedID 30706981
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MR Imaging-Based Radiomic Signatures of Distinct Molecular Subgroups of Medulloblastoma.
AJNR. American journal of neuroradiology
2018
Abstract
Distinct molecular subgroups of pediatric medulloblastoma confer important differences in prognosis and therapy. Currently, tissue sampling is the only method to obtain information for classification. Our goal was to develop and validate radiomic and machine learning approaches for predicting molecular subgroups of pediatric medulloblastoma.In this multi-institutional retrospective study, we evaluated MR imaging datasets of 109 pediatric patients with medulloblastoma from 3 children's hospitals from January 2001 to January 2014. A computational framework was developed to extract MR imaging-based radiomic features from tumor segmentations, and we tested 2 predictive models: a double 10-fold cross-validation using a combined dataset consisting of all 3 patient cohorts and a 3-dataset cross-validation, in which training was performed on 2 cohorts and testing was performed on the third independent cohort. We used the Wilcoxon rank sum test for feature selection with assessment of area under the receiver operating characteristic curve to evaluate model performance.Of 590 MR imaging-derived radiomic features, including intensity-based histograms, tumor edge-sharpness, Gabor features, and local area integral invariant features, extracted from imaging-derived tumor segmentations, tumor edge-sharpness was most useful for predicting sonic hedgehog and group 4 tumors. Receiver operating characteristic analysis revealed superior performance of the double 10-fold cross-validation model for predicting sonic hedgehog, group 3, and group 4 tumors when using combined T1- and T2-weighted images (area under the curve = 0.79, 0.70, and 0.83, respectively). With the independent 3-dataset cross-validation strategy, select radiomic features were predictive of sonic hedgehog (area under the curve = 0.70-0.73) and group 4 (area under the curve = 0.76-0.80) medulloblastoma.This study provides proof-of-concept results for the application of radiomic and machine learning approaches to a multi-institutional dataset for the prediction of medulloblastoma subgroups.
View details for DOI 10.3174/ajnr.A5899
View details for PubMedID 30523141
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Long-term health and social function in adult survivors of paediatric astrocytoma: A report from the Childhood Cancer Survivor Study.
European journal of cancer (Oxford, England : 1990)
2018; 106: 171–80
Abstract
BACKGROUND: Although paediatric astrocytoma has an excellent 5-year survival rate, survivors remain at risk for morbidity and late mortality. This study aimed to estimate the risk of late mortality, chronic conditions, poor health status and social impairment in ageing paediatric astrocytoma survivors.METHODS: We longitudinally evaluated 1182 5-year astrocytoma survivors diagnosed between 1970 and 1986 and 4023 siblings enrolled in a retrospective cohort study. Kaplan-Meier estimates of late mortality and cumulative incidence of serious chronic conditions were estimated. Cox regression models provided hazard ratios (HRs) with 95% confidence intervals (CIs) for development of chronic conditions, and generalised linear models provided relative risks (RRs) of the poor health status and social outcomes.RESULTS: At 30 years from diagnosis, cumulative late mortality was 22.1% (CI 20.0-24.3%), primarily due to disease progression or recurrence. Compared with siblings, survivors were at increased risk of serious chronic conditions (HR 4.6, CI 3.8-5.5). Survivors reported higher rates of poor general health (RR 3.3, CI 2.8-3.8), poor mental health (RR 1.9, CI 1.7-2.1), functional impairment (RR 9.0, CI 7.7-10.5)and activity limitation (RR 3.6, CI 3.1-4.2) and lower rates of college graduation (RR 0.75, CI 0.69-0.82), marriage (RR 0.62, CI 0.58-0.66), employment (RR 0.75, CI 0.72-0.79)and household income ≥$40,000 (RR 0.68, CI 0.64-0.73). Even survivors without radiation exposure had elevated risk of chronic conditions, poor health statusand social impairment compared with siblings.CONCLUSIONS: Survivors of paediatric astrocytoma are at high risk for long-term complications of their disease and its treatment. They require lifelong monitoring for late effects.
View details for PubMedID 30528801
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Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features.
Cold Spring Harbor molecular case studies
2018; 4 (5)
Abstract
Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent.
View details for DOI 10.1101/mcs.a003046
View details for PubMedID 29970384
View details for PubMedCentralID PMC6169826
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Complementary medicines are not always complimentary in Down syndrome.
The Journal of pediatrics
2018; 201: 2
View details for DOI 10.1016/j.jpeds.2018.07.105
View details for PubMedID 30244727
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Confused about what tests to order for altered mental status?
The Journal of pediatrics
2018; 200: 2-3
View details for DOI 10.1016/j.jpeds.2018.07.052
View details for PubMedID 30144919
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Characteristics of undiagnosed diseases network applicants: implications for referring providers.
BMC health services research
2018; 18 (1): 652
Abstract
The majority of undiagnosed diseases manifest with objective findings that warrant further investigation. The Undiagnosed Diseases Network (UDN) receives applications from patients whose symptoms and signs have been intractable to diagnosis; however, many UDN applicants are affected primarily by subjective symptoms such as pain and fatigue. We sought to characterize presenting symptoms, referral sources, and demographic factors of applicants to the UDN to identify factors that may determine application outcome and potentially differentiate between those with undiagnosed diseases (with more objective findings) and those who are less likely to have an undiagnosed disease (more subjective symptoms).We used a systematic retrospective review of 151 consecutive Not Accepted and 50 randomly selected Accepted UDN applications. The primary outcome was whether an applicant was Accepted, or Not Accepted, and, if accepted, whether or not a diagnosis was made. Objective and subjective symptoms and information on prior specialty consultations were collected from provider referral letters. Demographic data and decision data on network acceptance were gathered from the UDN online portal.Fewer objective findings and more subjective symptoms were found in the Not Accepted applications. Not Accepted referrals also were from older individuals, reported a shorter period of illness, and were referred to the UDN by their primary care physicians. All of these differences reached statistical significance in comparison with Accepted applications. The frequency of subspecialty consults for diagnostic purposes prior to UDN application was similar in both groups.The preponderance of subjective and lack of objective findings in the Not Accepted applications distinguish these from applicants that are accepted for evaluation and diagnostic efforts through the UDN. Not Accepted applicants are referred primarily by their primary care providers after multiple specialist consultations fail to yield answers. Distinguishing between patients with undiagnosed diseases with objective findings and those with primarily subjective findings can delineate patients who would benefit from further diagnostic processes from those who may have functional disorders and need alternative pathways for management of their symptoms.clinicaltrials.gov NCT02450851 , posted May 21st 2015.
View details for DOI 10.1186/s12913-018-3458-2
View details for PubMedID 30134969
View details for PubMedCentralID PMC6106923
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50 Years Ago in The Journal of Pediatrics: Significance of Leukemia Clusters.
The Journal of pediatrics
2018; 198: 130
View details for PubMedID 29936957
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A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative.
Genetics in medicine : official journal of the American College of Medical Genetics
2018
Abstract
Sixty to seventy-five percent of individuals with rare and undiagnosed phenotypes remain undiagnosed after exome sequencing (ES). With standard ES reanalysis resolving 10-15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals.In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing (1) phenotyping; (2) reanalyses of FASTQ files, with innovative bioinformatics; (3) targeted molecular testing; (4) genome sequencing (GS); and (5) conferring of clinical diagnoses when pathognomonic clinical findings occurred.Certain and highly likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping, and targeted testing identifying variants that were undetected or not prioritized on prior ES. GS diagnosed 3/18 individuals with structural variants not amenable to ES. Additionally, tentative diagnoses were made in 3 (8%), and in 5 individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%).Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without GS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.
View details for DOI 10.1038/s41436-018-0044-2
View details for PubMedID 29907797
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CHARACTERISTICS OF PATIENTS >= 10 YEARS OF AGE WITH DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY
OXFORD UNIV PRESS INC. 2018: 63
View details for Web of Science ID 000438339000164
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THE MOLECULAR AND CLINICAL LANDSCAPE OF INFANT MEDULLOBLASTOMA (IMB): RESULTS AND MOLECULAR ANALYSIS FROM A PROSPECTIVE, MULTICENTER PHASE II TRIAL (SJYC07)
OXFORD UNIV PRESS INC. 2018: 126–27
View details for Web of Science ID 000438339000442
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INTRACRANIAL GROWING TERATOMA SYNDROME (IGTS): AN INTERNATIONAL RETROSPECTIVE STUDY
OXFORD UNIV PRESS INC. 2018: 88
View details for Web of Science ID 000438339000272
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RECLASSIFICATION OF CENTRAL NERVOUS SYSTEM PRIMITIVE NEUROECTODERMAL TUMOR (CNS-PNET) INTO ENTITIES REFLECTS OUTCOME: RESULTS FROM THE PROSPECTIVE SJYC07 AND SJMB03 TRIALS
OXFORD UNIV PRESS INC. 2018: 71–72
View details for Web of Science ID 000438339000200
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CLINICAL, RADIOLOGICAL, PATHOLOGICAL AND MOLECULAR CHARACTERISTICS OF CHILDREN < 3 YEARS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): A REPORT FROM THE INTERNATIONAL DIPG REGISTRY
OXFORD UNIV PRESS INC. 2018: 63
View details for Web of Science ID 000438339000165
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Do race and socioeconomic status influence counseling at periviabilty?
The Journal of pediatrics
2018; 197: 2
View details for DOI 10.1016/j.jpeds.2018.04.015
View details for PubMedID 29801538
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Asymmetric tonsils or tonsillar cancer?
The Journal of pediatrics
2018; 197: 3-4
View details for DOI 10.1016/j.jpeds.2018.04.018
View details for PubMedID 29801542
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Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial
LANCET ONCOLOGY
2018; 19 (6): 768–84
Abstract
Young children with medulloblastoma have a poor overall survival compared with older children, due to use of radiation-sparing therapy in young children. Radiotherapy is omitted or reduced in these young patients to spare them from debilitating long-term side-effects. We aimed to estimate event-free survival and define the molecular characteristics associated with progression-free survival in young patients with medulloblastoma using a risk-stratified treatment strategy designed to defer, reduce, or delay radiation exposure.In this multicentre, phase 2 trial, we enrolled children younger than 3 years with newly diagnosed medulloblastoma at six centres in the USA and Australia. Children aged 3-5 years with newly diagnosed, non-metastatic medulloblastoma without any high-risk features were also eligible. Eligible patients were required to start therapy within 31 days from definitive surgery, had a Lansky performance score of at least 30, and did not receive previous radiotherapy or chemotherapy. Patients were stratified postoperatively by clinical and histological criteria into low-risk, intermediate-risk, and high-risk treatment groups. All patients received identical induction chemotherapy (methotrexate, vincristine, cisplatin, and cyclophosphamide), with high-risk patients also receiving an additional five doses of vinblastine. Induction was followed by risk-adapted consolidation therapy: low-risk patients received cyclophosphamide (1500 mg/m2 on day 1), etoposide (100 mg/m2 on days 1 and 2), and carboplatin (area under the curve 5 mg/mL per min on day 2) for two 4-week cycles; intermediate-risk patients received focal radiation therapy (54 Gy with a clinical target volume of 5 mm over 6 weeks) to the tumour bed; and high-risk patients received chemotherapy with targeted intravenous topotecan (area under the curve 120-160 ng-h/mL intravenously on days 1-5) and cyclophosphamide (600 mg/m2 intravenously on days 1-5). After consolidation, all patients received maintenance chemotherapy with cyclophosphamide, topotecan, and erlotinib. The coprimary endpoints were event-free survival and patterns of methylation profiling associated with progression-free survival. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy); biological analyses included all patients with tissue available for methylation profiling. This trial is registered with ClinicalTrials.gov, number NCT00602667, and was closed to accrual on April 19, 2017.Between Nov 27, 2007, and April 19, 2017, we enrolled 81 patients with histologically confirmed medulloblastoma. Accrual to the low-risk group was suspended after an interim analysis on Dec 2, 2015, when the 1-year event-free survival was estimated to be below the stopping rule boundary. After a median follow-up of 5·5 years (IQR 2·7-7·3), 5-year event-free survival was 31·3% (95% CI 19·3-43·3) for the whole cohort, 55·3% (95% CI 33·3-77·3) in the low-risk cohort (n=23) versus 24·6% (3·6-45·6) in the intermediate-risk cohort (n=32; hazard ratio 2·50, 95% CI 1·19-5·27; p=0·016) and 16·7% (3·4-30·0) in the high-risk cohort (n=26; 3·55, 1·66-7·59; p=0·0011; overall p=0·0021). 5-year progression-free survival by methylation subgroup was 51·1% (95% CI 34·6-67·6) in the sonic hedgehog (SHH) subgroup (n=42), 8·3% (95% CI 0·0-24·0%) in the group 3 subgroup (n=24), and 13·3% (95% CI 0·0-37·6%) in the group 4 subgroup (n=10). Within the SHH subgroup, two distinct methylation subtypes were identified and named iSHH-I and iSHH-II. 5-year progression-free survival was 27·8% (95% CI 9·0-46·6; n=21) for iSHH-I and 75·4% (55·0-95·8; n=21) for iSHH-II. The most common adverse events were grade 3-4 febrile neutropenia (48 patients [59%]), neutropenia (21 [26%]), infection with neutropenia (20 [25%]), leucopenia (15 [19%]), vomiting (15 [19%]), and anorexia (13 [16%]). No treatment-related deaths occurred.The risk-adapted approach did not improve event-free survival in young children with medulloblastoma. However, the methylation subgroup analyses showed that the SHH subgroup had improved progression-free survival compared with the group 3 subgroup. Moreover, within the SHH subgroup, the iSHH-II subtype had improved progression-free survival in the absence of radiation, intraventricular chemotherapy, or high-dose chemotherapy compared with the iSHH-I subtype. These findings support the development of a molecularly driven, risk-adapted, treatment approach in future trials in young children with medulloblastoma.American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, NCI Cancer Center, Alexander and Margaret Stewart Trust, Sontag Foundation, and American Association for Cancer Research.
View details for PubMedID 29778738
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Pediatric neuro-oncology survival disparities in California
JOURNAL OF NEURO-ONCOLOGY
2018; 138 (1): 83–97
Abstract
The objective of this study was to investigate racial/ethnic differences in survival for pediatric high-grade glioma (HGG) and medulloblastoma in the state of California. We obtained data from the California Cancer Registry on 552 high-grade glioma patients (110 brainstem, 442 non-brainstem) and 648 medulloblastoma patients ages 0-19 years from 1988 to 2012. Using multivariate Cox proportional hazards regression, we examined the impact of individual and neighborhood characteristics on survival. Socioeconomic quintile and insurance status differed significantly by race for both diagnoses. Hispanic children with non-brainstem HGG had worse survival than non-Hispanic white children: hazard ratio (HR) 1.62; 95% confidence interval (CI) 1.24-2.11, but the difference was mitigated some by accounting for socioeconomic status (HR 1.48, CI 1.10-1.99). Racial/ethnic differences in survival exist for children with high-grade glioma, particularly Hispanic children with non-brainstem high-grade glioma, and are likely related to sociologic factors.
View details for PubMedID 29417400
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Does fat or fat-free body mass drive neurodevelopment?
The Journal of pediatrics
2018; 196: 2
View details for DOI 10.1016/j.jpeds.2018.03.021
View details for PubMedID 29703358
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It's Time for Pediatric Oncology to Grow Up.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
2018; 36 (10): 933–34
View details for PubMedID 29425070
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Cystic periventricular leukomalacia: now you see it, now you don't?
The Journal of pediatrics
2018; 195: 2-3
View details for DOI 10.1016/j.jpeds.2018.02.017
View details for PubMedID 29576177
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Increased prescription drug use immediately after childhood cancer.
The Journal of pediatrics
2018; 195: 4
View details for DOI 10.1016/j.jpeds.2018.02.020
View details for PubMedID 29576181
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Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder
AMERICAN JOURNAL OF HUMAN GENETICS
2018; 102 (3): 494–504
Abstract
ATP synthase, H+ transporting, mitochondrial F1 complex, δ subunit (ATP5F1D; formerly ATP5D) is a subunit of mitochondrial ATP synthase and plays an important role in coupling proton translocation and ATP production. Here, we describe two individuals, each with homozygous missense variants in ATP5F1D, who presented with episodic lethargy, metabolic acidosis, 3-methylglutaconic aciduria, and hyperammonemia. Subject 1, homozygous for c.245C>T (p.Pro82Leu), presented with recurrent metabolic decompensation starting in the neonatal period, and subject 2, homozygous for c.317T>G (p.Val106Gly), presented with acute encephalopathy in childhood. Cultured skin fibroblasts from these individuals exhibited impaired assembly of F1FO ATP synthase and subsequent reduced complex V activity. Cells from subject 1 also exhibited a significant decrease in mitochondrial cristae. Knockdown of Drosophila ATPsynδ, the ATP5F1D homolog, in developing eyes and brains caused a near complete loss of the fly head, a phenotype that was fully rescued by wild-type human ATP5F1D. In contrast, expression of the ATP5F1D c.245C>T and c.317T>G variants rescued the head-size phenotype but recapitulated the eye and antennae defects seen in other genetic models of mitochondrial oxidative phosphorylation deficiency. Our data establish c.245C>T (p.Pro82Leu) and c.317T>G (p.Val106Gly) in ATP5F1D as pathogenic variants leading to a Mendelian mitochondrial disease featuring episodic metabolic decompensation.
View details for PubMedID 29478781
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Fertile ground for education on fertility preservation.
The Journal of pediatrics
2018; 194: 1-2
View details for DOI 10.1016/j.jpeds.2018.01.003
View details for PubMedID 29478489
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In search of biomarkers for HIE.
The Journal of pediatrics
2018; 194: 3
View details for DOI 10.1016/j.jpeds.2018.01.007
View details for PubMedID 29478505
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Born too early for friends?
The Journal of pediatrics
2018; 193: 2-3
View details for DOI 10.1016/j.jpeds.2017.12.005
View details for PubMedID 29389446
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A New Approach to Rare Diseases of Children: The Undiagnosed Diseases Network.
The Journal of pediatrics
2018
View details for PubMedID 29331327
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Congenital heart disease complexity and childhood cancer risk.
Birth defects research
2018; 110 (17): 1314–21
Abstract
Childhood cancer is increased in those with birth defects, including those with congenital heart disease (CHD). Lymphoma risk is increased in children with CHD. This study analyzes the effect of CHD and CHD severity on childhood cancer risk.We analyzed cancer risk in a population-based cohort of children with and without CHD born between 1988 and 2004 by linking data from the California Birth Defects Monitoring Program with data from the California Cancer Registry. We compared cancer risk in children with and without CHD, excluding children with chromosomal anomalies.Of >3 million children in the birth cohort, 65,585 had birth defects (2%), 25,981 with CHD. Cancer occurred in 4,781 (0.15%) children, 43 (0.17%) with CHD. Cancer risk in CHD was increased (hazard ratio [HR]) 2.63, 95% CI: 1.95, 3.55). Leukemia was the most common cancer in those without CHD (1,722/4,738, 36%), central nervous system tumors were second (1,073/4,738, 23%), and lymphoma third (410/4,738, 9%). Among children with CHD, lymphoma and leukemia occurred with the same frequency (12/43, 28% for each). HR for lymphoma was 8.37 (CI: 4.71, 14.86) with CHD versus without. HR for leukemia was 2.05 (CI: 1.16, 3.61) with CHD versus without. CHD complexity was higher in lymphoma (3, interquartile range [IQR]: 2-3) than those with leukemia (1, IQR, 1-2; p < .02).Cancer risk is increased in children with CHD. Lymphoma risk is increased in CHD and is correlated with more complex CHD. These results suggest a shared developmental origin for CHD and lymphoma may be present.
View details for PubMedID 30328285
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Looking beyond the exome: a phenotype-first approach to molecular diagnostic resolution in rare and undiagnosed diseases.
Genetics in medicine : official journal of the American College of Medical Genetics
2018; 20 (4): 464–69
Abstract
PurposeTo describe examples of missed pathogenic variants on whole-exome sequencing (WES) and the importance of deep phenotyping for further diagnostic testing.MethodsGuided by phenotypic information, three children with negative WES underwent targeted single-gene testing.ResultsIndividual 1 had a clinical diagnosis consistent with infantile systemic hyalinosis, although WES and a next-generation sequencing (NGS)-based ANTXR2 test were negative. Sanger sequencing of ANTXR2 revealed a homozygous single base pair insertion, previously missed by the WES variant caller software. Individual 2 had neurodevelopmental regression and cerebellar atrophy, with no diagnosis on WES. New clinical findings prompted Sanger sequencing and copy number testing of PLA2G6. A novel homozygous deletion of the noncoding exon 1 (not included in the WES capture kit) was detected, with extension into the promoter, confirming the clinical suspicion of infantile neuroaxonal dystrophy. Individual 3 had progressive ataxia, spasticity, and magnetic resonance image changes of vanishing white matter leukoencephalopathy. An NGS leukodystrophy gene panel and WES showed a heterozygous pathogenic variant in EIF2B5; no deletions/duplications were detected. Sanger sequencing of EIF2B5 showed a frameshift indel, probably missed owing to failure of alignment.ConclusionThese cases illustrate potential pitfalls of WES/NGS testing and the importance of phenotype-guided molecular testing in yielding diagnoses.
View details for DOI 10.1038/gim.2017.128
View details for PubMedID 28914269
View details for PubMedCentralID PMC5851806
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Surgical outcomes of pediatric spinal cord astrocytomas: systematic review and meta-analysis.
Journal of neurosurgery. Pediatrics
2018: 1–7
Abstract
OBJECTIVE Pediatric spinal astrocytomas are rare spinal lesions that pose unique management challenges. Therapeutic options include gross-total resection (GTR), subtotal resection (STR), and adjuvant chemotherapy or radiation therapy. With no randomized controlled trials, the optimal management approach for children with spinal astrocytomas remains unclear. The aim of this study was to conduct a systematic review and meta-analysis on pediatric spinal astrocytomas. METHODS The authors performed a systematic review of the PubMed/MEDLINE electronic database to investigate the impact of histological grade and extent of resection on overall survival among patients with spinal cord astrocytomas. They retained publications in which the majority of reported cases included astrocytoma histology. RESULTS Twenty-nine previously published studies met the eligibility criteria, totaling 578 patients with spinal cord astrocytomas. The spinal level of intramedullary spinal cord tumors was predominantly cervical (53.8%), followed by thoracic (40.8%). Overall, resection was more common than biopsy, and GTR was slightly more commonly achieved than STR (39.7% vs 37.0%). The reported rates of GTR and STR rose markedly from 1984 to 2015. Patients with high-grade astrocytomas had markedly worse 5-year overall survival than patients with low-grade tumors. Patients receiving GTR may have better 5-year overall survival than those receiving STR. CONCLUSIONS The authors describe trends in the management of pediatric spinal cord astrocytomas and suggest a benefit of GTR over STR for 5-year overall survival.
View details for PubMedID 30028275
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Long-term outcomes of primarily metastatic juvenile pilocytic astrocytoma in children.
Journal of neurosurgery. Pediatrics
2018; 21 (1): 49-53
Abstract
OBJECTIVE Primarily metastatic juvenile pilocytic astrocytoma (JPA) is rare, likely representing 2%-3% of all cases of JPA. Due to the rarity of primarily metastatic JPA, there is currently no standard treatment paradigm and the long-term outcomes are not fully known. The goal of this case series was to add to the current understanding of this disease process. METHODS The authors searched a comprehensive database of pediatric patients with brain and spinal cord tumors treated at Lucile Packard Children's Hospital from 1997 to 2016 and identified 5 patients with primarily metastatic JPA. A retrospective chart review was performed and details of the patients' treatment and clinical course were recorded for further analysis. RESULTS For the 5 patients with primarily metastatic JPA, the mean follow-up period was 12.3 years. All patients in our series had biopsies or subtotal resections and upfront treatment. Three patients were treated with chemotherapy alone, one was treated with chemotherapy and radiotherapy, and one was treated with radiotherapy alone. Four patients had stable disease after initial treatment, and one patient had multiple episodes of progressive disease but underwent successful salvage therapy and has had stable disease for 19 years. One patient died of an intracerebral hemorrhage 10 years following initial radiation treatment believed to be secondary to radiation vasculopathy. CONCLUSIONS Evaluation of the entire neuraxis should be performed in all instances of initial JPA diagnosis to properly assess for primarily metastatic disease. Many patients with primarily metastatic JPA will have stable disease after upfront treatment, although the higher rate of stable disease found in this series relative to other reports is likely secondary to the small sample size.
View details for DOI 10.3171/2017.7.PEDS17168
View details for PubMedID 29125440
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Long-term outcomes of primarily metastatic juvenile pilocytic astrocytoma in children
JOURNAL OF NEUROSURGERY-PEDIATRICS
2018; 21 (1): 49–53
View details for DOI 10.3171/2017.7.PEDS17168
View details for Web of Science ID 000418908800011
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Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease.
The New England journal of medicine
2018
Abstract
Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added.We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care.A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes.The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).
View details for PubMedID 30304647
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Put down that smartphone and read to me!
The Journal of pediatrics
2017; 191: 1-2
View details for DOI 10.1016/j.jpeds.2017.10.020
View details for PubMedID 29173292
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Please diagnose infantile spasm early!
The Journal of pediatrics
2017; 190: 3
View details for DOI 10.1016/j.jpeds.2017.09.033
View details for PubMedID 29144264
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Speak to me in English, Spanish, or both?
The Journal of pediatrics
2017; 190: 1
View details for DOI 10.1016/j.jpeds.2017.09.029
View details for PubMedID 29144235
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Do you know what SUDEP is?
The Journal of pediatrics
2017; 188: 2
View details for DOI 10.1016/j.jpeds.2017.07.022
View details for PubMedID 28843305
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Remember to play and play to remember.
The Journal of pediatrics
2017; 188: 1
View details for DOI 10.1016/j.jpeds.2017.07.019
View details for PubMedID 28843299
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How mild is the outcome of mild neonatal encephalopathy?
The Journal of pediatrics
2017; 187: 2-3
View details for DOI 10.1016/j.jpeds.2017.06.026
View details for PubMedID 28750760
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Getting Published: A Primer on Manuscript Writing and the Editorial Process.
The Journal of pediatrics
2017; 185: 241-244
View details for DOI 10.1016/j.jpeds.2017.02.067
View details for PubMedID 28341526
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MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome.
American journal of human genetics
2017; 100 (6): 843-853
Abstract
One major challenge encountered with interpreting human genetic variants is the limited understanding of the functional impact of genetic alterations on biological processes. Furthermore, there remains an unmet demand for an efficient survey of the wealth of information on human homologs in model organisms across numerous databases. To efficiently assess the large volume of publically available information, it is important to provide a concise summary of the most relevant information in a rapid user-friendly format. To this end, we created MARRVEL (model organism aggregated resources for rare variant exploration). MARRVEL is a publicly available website that integrates information from six human genetic databases and seven model organism databases. For any given variant or gene, MARRVEL displays information from OMIM, ExAC, ClinVar, Geno2MP, DGV, and DECIPHER. Importantly, it curates model organism-specific databases to concurrently display a concise summary regarding the human gene homologs in budding and fission yeast, worm, fly, fish, mouse, and rat on a single webpage. Experiment-based information on tissue expression, protein subcellular localization, biological process, and molecular function for the human gene and homologs in the seven model organisms are arranged into a concise output. Hence, rather than visiting multiple separate databases for variant and gene analysis, users can obtain important information by searching once through MARRVEL. Altogether, MARRVEL dramatically improves efficiency and accessibility to data collection and facilitates analysis of human genes and variants by cross-disciplinary integration of 18 million records available in public databases to facilitate clinical diagnosis and basic research.
View details for DOI 10.1016/j.ajhg.2017.04.010
View details for PubMedID 28502612
View details for PubMedCentralID PMC5670038
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The next generation is here now.
The Journal of pediatrics
2017; 185: 1-2
View details for DOI 10.1016/j.jpeds.2017.04.012
View details for PubMedID 28746034
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R-SCAN: Imaging for Pediatric Simple Febrile Seizures.
Journal of the American College of Radiology
2017
View details for DOI 10.1016/j.jacr.2017.04.007
View details for PubMedID 28551342
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Advancing the ball or holding the line in concussion?
The Journal of pediatrics
2017; 184: 1
View details for DOI 10.1016/j.jpeds.2017.03.010
View details for PubMedID 28434562
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A window into living with an undiagnosed disease: illness narratives from the Undiagnosed Diseases Network.
Orphanet journal of rare diseases
2017; 12 (1): 71
Abstract
Patients' stories of their illnesses help bridge the divide between patients and providers, facilitating more humane medical care. Illness narratives have been classified into three types: restitution (expectation of recovery), chaos (suffering and loss), and quest (unexpected positive effect from illness). Undiagnosed patients have unique illness experiences and obtaining their narratives would provide insights into the medical and emotional impact of living with an undiagnosed illness. Adults and children with undiagnosed diseases apply to be evaluated by the Undiagnosed Diseases Network (UDN). Written illness narratives from 40 UDN applicants, including 20 adult probands who applied for themselves and 20 parents who applied for their children, were analyzed for: 1) narrative content and 2) narrative type.Narrative content: could be grouped into three themes: 1) Expectations of the UDN: the majority felt they had no further healthcare options and hoped the UDN would provide them with a diagnosis, with the adults expecting to return to their previously healthy life and the parents wanting information to manage their child's healthcare. 2) Personal medical information: the narratives reported worsening of symptoms and some offered opinions regarding the cause of their illness. The proband narratives had few objective findings, while parental narratives had detailed objective information. 3) Experiences related to living with their undiagnosed illness: frustration at being undiagnosed was expressed. The adults felt they had to provide validation of their symptoms to providers, given the lack of objective findings. The parents worried that something relevant to their child's management was being overlooked. Narrative type: All the narratives were of the chaos type, but for different reasons, with the probands describing loss and suffering and the parents expressing fear for their child's future. The parental narratives also had elements of restitution and quest, with acceptance of "a new normal", and an emphasis on the positive aspects of their child's illness which was absent from the probands.These narratives illustrate the chaos that coexists with being undiagnosed. The differences between the proband and parental narratives suggest that these two groups have different needs that need to be considered during their evaluation and management.
View details for DOI 10.1186/s13023-017-0623-3
View details for PubMedID 28416019
View details for PubMedCentralID PMC5392939
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Disrupting the CD47-SIRP alpha anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors
SCIENCE TRANSLATIONAL MEDICINE
2017; 9 (381)
Abstract
Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.
View details for DOI 10.1126/scitranslmed.aaf2968
View details for PubMedID 28298418
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Talk with and not around the child.
The Journal of pediatrics
2017; 182: 2
View details for DOI 10.1016/j.jpeds.2017.01.004
View details for PubMedID 28237447
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Does macrocephaly require MRI, CT, ultrasound, or a tape measure?
The Journal of pediatrics
2017; 182: 5
View details for DOI 10.1016/j.jpeds.2017.01.011
View details for PubMedID 28237457
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Brain Perfusion and Diffusion Abnormalities in Children Treated for Posterior Fossa Brain Tumors.
journal of pediatrics
2017
Abstract
To compare cerebral perfusion and diffusion in survivors of childhood posterior fossa brain tumor with neurologically normal controls and correlate differences with cognitive dysfunction.We analyzed retrospectively arterial spin-labeled cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) in 21 patients with medulloblastoma (MB), 18 patients with pilocytic astrocytoma (PA), and 64 neurologically normal children. We generated ANCOVA models to evaluate treatment effects on the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, and cerebral white matter at time points an average of 5.7 years after original diagnosis. A retrospective review of patient charts identified 12 patients with neurocognitive data and in whom the relationship between IQ and magnetic resonance imaging variables was assessed for each brain structure.Patients with MB (all treated with surgery, chemotherapy, and radiation) had significantly lower global CBF relative to controls (10%-23% lower, varying by anatomic region, all adjusted P < .05), whereas patients with PA (all treated with surgery alone) had normal CBF. ADC was decreased specifically in the hippocampus and amygdala of patients with MB and within the amygdala of patients with PA but otherwise remained normal after therapy. In the patients with tumor previously evaluated for IQ, regional ADC, but not CBF, correlated with IQ (R(2) = 0.33-0.75).The treatment for MB, but not PA, was associated with globally reduced CBF. Treatment in both tumor types was associated with diffusion abnormalities of the mesial temporal lobe structures. Despite significant perfusion abnormalities in patients with MB, diffusion, but not perfusion, correlated with cognitive outcomes.
View details for DOI 10.1016/j.jpeds.2017.01.019
View details for PubMedID 28187964
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The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease
AMERICAN JOURNAL OF HUMAN GENETICS
2017; 100 (2): 185-192
Abstract
Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.
View details for DOI 10.1016/j.athg.2017.01.006
View details for PubMedID 28157539
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A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay.
American journal of human genetics
2017; 100 (2): 343-351
Abstract
Whole-exome sequencing (WES) has increasingly enabled new pathogenic gene variant identification for undiagnosed neurodevelopmental disorders and provided insights into both gene function and disease biology. Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy. We observe an identical recurrent de novo heterozygous c.892C>T (p.Arg298Trp) variant in the nucleus accumbens associated 1 (NACC1) gene in seven affected individuals. One of the seven individuals is mosaic for this variant. NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders. The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p = 1.25 × 10-14). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable. Our findings are consistent with a germline recurrent mutational hotspot associated with an allele-specific neurodevelopmental phenotype in NACC1.
View details for DOI 10.1016/j.ajhg.2016.12.013
View details for PubMedID 28132692
View details for PubMedCentralID PMC5294886
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R-SCAN: Imaging for Pediatric Minor Head Trauma.
Journal of the American College of Radiology
2017; 14 (2): 294-297
View details for DOI 10.1016/j.jacr.2016.10.006
View details for PubMedID 28017272
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Child Neurology Residency-Finding the Right Fit.
Pediatric neurology
2017; 67: 3-6
View details for DOI 10.1016/j.pediatrneurol.2016.10.011
View details for PubMedID 27908656
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A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3.
American journal of human genetics
2017; 100 (1): 128-137
Abstract
Early B cell factor 3 (EBF3) is a member of the highly evolutionarily conserved Collier/Olf/EBF (COE) family of transcription factors. Prior studies on invertebrate and vertebrate animals have shown that EBF3 homologs are essential for survival and that loss-of-function mutations are associated with a range of nervous system developmental defects, including perturbation of neuronal development and migration. Interestingly, aristaless-related homeobox (ARX), a homeobox-containing transcription factor critical for the regulation of nervous system development, transcriptionally represses EBF3 expression. However, human neurodevelopmental disorders related to EBF3 have not been reported. Here, we describe three individuals who are affected by global developmental delay, intellectual disability, and expressive speech disorder and carry de novo variants in EBF3. Associated features seen in these individuals include congenital hypotonia, structural CNS malformations, ataxia, and genitourinary abnormalities. The de novo variants affect a single conserved residue in a zinc finger motif crucial for DNA binding and are deleterious in a fly model. Our findings indicate that mutations in EBF3 cause a genetic neurodevelopmental syndrome and suggest that loss of EBF3 function might mediate a subset of neurologic phenotypes shared by ARX-related disorders, including intellectual disability, abnormal genitalia, and structural CNS malformations.
View details for DOI 10.1016/j.ajhg.2016.11.018
View details for PubMedID 28017372
View details for PubMedCentralID PMC5223093
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in a patient with a complex connective tissue phenotype.
Cold Spring Harbor molecular case studies
2017; 3 (1)
Abstract
Here we describe a patient who presented with a history of congenital diaphragmatic hernia, inguinal hernia, and recurrent umbilical hernia. She also has joint laxity, hypotonia, and dysmorphic features. A unifying diagnosis was not identified based on her clinical phenotype. As part of her evaluation through the Undiagnosed Diseases Network, trio whole-exome sequencing was performed. Pathogenic variants in FBN1 and TRPS1 were identified as causing two distinct autosomal dominant conditions, each with de novo inheritance. Fibrillin 1 (FBN1) mutations are associated with Marfan syndrome and a spectrum of similar phenotypes. TRPS1 mutations are associated with trichorhinophalangeal syndrome types I and III. Features of both conditions are evident in the patient reported here. Discrepant features of the conditions (e.g., stature) and the young age of the patient may have made a clinical diagnosis more difficult in the absence of exome-wide genetic testing.
View details for DOI 10.1101/mcs.a001388
View details for PubMedID 28050602
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An Investigation of Connections between Birth Defects and Cancers Arising in Adolescence and Very Young Adulthood.
The Journal of pediatrics
2017; 185: 237–40
Abstract
This study investigated the relationship between birth defects and cancer in adolescents and very young adults using California's population-based registries. Although overall cancer risk was elevated among individuals with chromosomal birth defects, this was not observed in those with nonchromosomal birth defects, as was demonstrated previously in younger children.
View details for PubMedID 28336146
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50 Years Ago in The Journal of Pediatrics: The Normal Achilles Tendon Reflex Time in Children as Measured with the Photomograph.
The Journal of pediatrics
2017; 184: 44
View details for PubMedID 28434578
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Newborns and red reflexes.
The Journal of pediatrics
2016; 179: 3
View details for DOI 10.1016/j.jpeds.2016.10.013
View details for PubMedID 27884271
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Just say no to opioids!
The Journal of pediatrics
2016; 179: 1
View details for DOI 10.1016/j.jpeds.2016.10.008
View details for PubMedID 27884266
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Extending precision to phenoytpes.
The Journal of pediatrics
2016; 178: 3-4
View details for DOI 10.1016/j.jpeds.2016.09.025
View details for PubMedID 27788838
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De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype.
American journal of human genetics
2016; 99 (4): 991-999
Abstract
The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes.
View details for DOI 10.1016/j.ajhg.2016.08.017
View details for PubMedID 27693232
View details for PubMedCentralID PMC5065681
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Shaken baby syndrome and abusive head trauma are real problems.
The Journal of pediatrics
2016; 177: 2
View details for DOI 10.1016/j.jpeds.2016.08.037
View details for PubMedID 27666073
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A molecular biology and phase II study of imetelstat (GRN163L) in children with recurrent or refractory central nervous system malignancies: a pediatric brain tumor consortium study
JOURNAL OF NEURO-ONCOLOGY
2016; 129 (3): 443-451
Abstract
Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted an investigator-sponsored molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-h intravenous infusion at 285 mg/m(2), 12-24 h before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285 mg/m(2). Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of two evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95 % compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5 %), lymphopenia (17.5 %), neutropenia (12.5 %), ALT (7.5 %) and AST (5 %) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.
View details for DOI 10.1007/s11060-016-2189-7
View details for Web of Science ID 000384563800007
View details for PubMedID 27350411
View details for PubMedCentralID PMC5288808
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50 Years Ago in TheJournal ofPediatrics: Brain Scanning in Childhood.
The Journal of pediatrics
2016; 176: 113
View details for DOI 10.1016/j.jpeds.2016.03.049
View details for PubMedID 27568250
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Phase 1 trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study
NEURO-ONCOLOGY
2016; 18 (9): 1319-1325
Abstract
p53 is a promising target in human cancer. p28 is a cell-penetrating peptide that preferentially enters cancer cells and binds to both wild-type and mutant p53 protein, inhibiting COP1-mediated ubiquitination and proteasomal degradation. This results in increased levels of p53, which induces cell cycle arrest at G2/M. We conducted a phase I study to determine the maximum-tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) and pharmacokinetics (PKs) of p28 in children.Children aged 3-21 years with recurrent or progressive central nervous system tumors were eligible. Intravenous p28 was administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult recommended phase II dose) using a rolling-6 study design. Expression status of p53 was characterized by immunohistochemistry, and serum PK parameters were established on the second dose.Of the 18 eligible patients enrolled in the study, 12 completed the DLT monitoring period and were evaluable for toxicity. p28 was well-tolerated; 7 participants received ≥2 courses, and the most common adverse event attributed to the drug was transient grade 1 infusion-related reaction. PK analysis revealed a profile similar to adults; however, an increased area under the curve was observed in pediatric patients. High p53 expression in tumor cell nuclei was observed in 6 of 12 available tissue samples. There were no objective responses; 2 participants remained stable on the study for >4 cycles.This phase I study demonstrated that p28 is well-tolerated in children with recurrent CNS malignancies at the adult recommended phase II dose.
View details for DOI 10.1093/neuonc/now047
View details for PubMedID 27022131
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Do we end life well?
The Journal of pediatrics
2016; 175: 1-4
View details for DOI 10.1016/j.jpeds.2016.06.010
View details for PubMedID 27507307
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Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis
JOURNAL OF CLINICAL ONCOLOGY
2016; 34 (21): 2468-?
Abstract
Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known.Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses.Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation.The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.
View details for DOI 10.1200/JCO.2015.65.7825
View details for Web of Science ID 000381497000006
View details for PubMedID 27269943
View details for PubMedCentralID PMC4962737
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Wandering can be dangerous.
The Journal of pediatrics
2016; 174: 3
View details for DOI 10.1016/j.jpeds.2016.05.046
View details for PubMedID 27346501
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Are neonatal stroke and hypoxic-ischemic encephalopathy related?
The Journal of pediatrics
2016; 173: 1-3
View details for DOI 10.1016/j.jpeds.2016.04.030
View details for PubMedID 27234275
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Remember toxic exposures to antidementia drugs.
The Journal of pediatrics
2016; 172: 1-4
View details for DOI 10.1016/j.jpeds.2016.03.012
View details for PubMedID 27112080
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Pay attention to when children start school!
The Journal of pediatrics
2016; 172: 1-4
View details for DOI 10.1016/j.jpeds.2016.03.007
View details for PubMedID 27112076
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50 Years Ago in The Journal of Pediatrics: Neonatal Myasthenia Gravis.
The Journal of pediatrics
2016; 171: 201
View details for DOI 10.1016/j.jpeds.2015.10.053
View details for PubMedID 27017463
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50 Years Ago in The Journal of Pediatrics: Hydrocephalus.
The Journal of pediatrics
2015; 167 (6): 1286
View details for DOI 10.1016/j.jpeds.2015.06.004
View details for PubMedID 26611456
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Divergent Patterns of Incidence in Peripheral Neuroblastic Tumors.
Journal of pediatric hematology/oncology
2015; 37 (7): 502-506
Abstract
Prior research on trends in neuroblastoma incidence has conflicted. We aimed to compare how ganglioneuroblastoma and neuroblastoma incidence have changed.Using the Surveillance Epidemiology and End Results (SEER) 9 population-based registry, we identified 2081 malignant peripheral neuroblastic tumors in patients 0 to 14 years from 1973 to 2009. Age-adjusted annual incidence rates were calculated using SEER*Stat, and Joinpoint Regression Program was used to calculate annual percent change (APC) and analyze trends. Data were stratified by histology, age, and stage.Overall peripheral neuroblastic tumor incidence increased by an APC of 0.47 (P=0.045). However, ganglioneuroblastoma incidence decreased (APC=-1.48; P=0.003), whereas neuroblastoma incidence increased (APC=0.79; P=0.008). When divided by age and stage, locoregional neuroblastoma incidence increased in infants until a significant inflection point in 1996 (APC=4.19; P<0.001) and then decreased sharply (APC=-6.80; P=0.160).Ganglioneuroblastoma incidence has decreased, whereas neuroblastoma incidence has increased. These changes could be real, or reflect bias from classification changes or increased detection. Neuroblastoma incidence increased most markedly in infants with locoregional disease only until 1996, then declined, which may reflect changes in tumor ascertainment and folate supplementation.
View details for DOI 10.1097/MPH.0000000000000383
View details for PubMedID 26133942
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Phase II Trial Assessing the Ability of Neoadjuvant Chemotherapy With or Without Second-Look Surgery to Eliminate Measurable Disease for Nongerminomatous Germ Cell Tumors: A Children's Oncology Group Study.
Journal of clinical oncology
2015; 33 (22): 2464-2471
Abstract
This phase II trial evaluated the effect of neoadjuvant chemotherapy with or without second-look surgery before craniospinal irradiation on response rates and survival outcomes in children with newly diagnosed nongerminomatous germ cell tumors.Induction chemotherapy consisted of six cycles of carboplatin/etoposide alternating with ifosfamide/etoposide. Patients demonstrating less than complete response after induction chemotherapy were encouraged to undergo second-look surgery. Patients who did not achieve complete response or partial response after chemotherapy with or without second-look surgery proceeded to high-dose chemotherapy with thiotepa and etoposide and autologous peripheral blood stem-cell rescue before craniospinal irradiation.The study included 102 patients treated between January 2004 and July 2008. Median age was 12 years, and 76% were male; 53.9% had pineal region masses, and 23.5% had suprasellar lesions. Sixty-nine percent of patients achieved complete response or partial response with neoadjuvant chemotherapy. At 5 years, event-free survival was 84% ± 4% (SE) and overall survival was 93% ± 3%. During the median follow-up of 5.1 years, 16 patients recurred or progressed, with seven deaths after relapse. No deaths were attributed to therapy-related toxicity. Relapse occurred at the site of primary disease in 10 patients, at a distant site in three patients, or both in one patient. In two patients, progression was detected by marker increase alone. Increased serum α-fetoprotein was a negative prognostic variable. Histologic subtype and increase of beta-human chorionic gonadotropin were not significantly correlated with worse outcomes.Neoadjuvant chemotherapy with or without second-look surgery achieved high response rates contributing to excellent survival outcomes in children with newly diagnosed nongerminomatous germ cell tumors. This regimen should be included as a backbone for further studies.
View details for DOI 10.1200/JCO.2014.59.5132
View details for PubMedID 26101244
View details for PubMedCentralID PMC4507465
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50 Years Ago in The Journal of Pediatrics: Treatment of Hydrocephalus with Acetazolamide: Results in 15 Cases.
The Journal of pediatrics
2015; 166 (6): 1369
View details for DOI 10.1016/j.jpeds.2014.12.043
View details for PubMedID 26008170
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Early detection of cancer: past, present, and future.
American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
2015: 57-65
Abstract
Screening in both healthy and high-risk populations offers the opportunity to detect cancer early and with an increased opportunity for treatment and curative intent. Currently, a defined role for screening exists in some cancer types, but each screening test has limitations, and improved screening methods are urgently needed. Unfortunately, many cancers still lack effective screening recommendations, or in some cases, the benefits from screening are marginal when weighed against the potential for harm. Here we review the current status of cancer screening: we examine the role of traditional tumor biomarkers, describe recommended imaging for early tumor surveillance, and explore the potential of promising novel cancer markers such as circulating tumor cells (CTC) and circulating tumor DNA. Consistent challenges for all of these screening tests include limited sensitivity and specificity. The risk for overdiagnosis remains a particular concern in screening, whereby lesions of no clinical consequence may be detected and thus create difficult management decisions for the clinician and patient. If treatment is pursued following overdiagnosis, patients may be exposed to morbidity from a treatment that may not provide any true benefit. The cost-effectiveness of screening tests also needs to be an ongoing focus. The improvement of genomic and surveillance technologies, which leads to more precise imaging and the ability to characterize blood-based tumor markers of greater specificity, offers opportunities for major progress in cancer screening.
View details for DOI 10.14694/EdBook_AM.2015.35.57
View details for PubMedID 25993143
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Decreased tumor apparent diffusion coefficient correlates with objective response of pediatric low-grade glioma to bevacizumab
JOURNAL OF NEURO-ONCOLOGY
2015; 122 (3): 491-496
Abstract
Recent small, retrospective series suggest bevacizumab may be a therapeutic option for recurrent pediatric low-grade glioma (LGG). Assessment of therapeutic responses is complicated by the unpredictable natural history of these tumors. Because diffusion-weighted imaging quantifies microscopic water motion affected by cellular density and histologic features, we hypothesized that it may be helpful in monitoring therapeutic response of LGG to bevacizumab. We retrospectively reviewed eight consecutive patients, median age 4.8 (range 2.3-12.3) years at initiation of bevacizumab therapy for recurrent or refractory LGG. Patients received 10 mg/kg/dose every 2 weeks (median 16 doses/therapy course). Mean apparent diffusion coefficient (ADC) was measured and analyzed in respect to tumor volume. Following the first treatment course, seven of eight patients had reduced tumor volume (≥25 %) and ADC. The median decrease in tumor volume was 47% (range -6 to 78 %) and the median decrease in ADC was 14 % (range -5 to 30 %). The ADC was significantly decreased during therapy, whereas the decrease in volume was seen only after therapy completion. There was a positive correlation between percent change in tumor volume and ADC (p < 0.05). We report a decrease in tumor ADC during initial bevacizumab therapy that is accompanied by a decrease in volume following therapy. Imaging changes in microscopic water motion associated with histology may be useful in monitoring the therapeutic response of LGG to bevacizumab.
View details for DOI 10.1007/s11060-015-1754-9
View details for Web of Science ID 000354717800008
View details for PubMedID 25758812
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An open-label, two-stage, phase II study of bevacizumab and lapatinib in children with recurrent or refractory ependymoma: a collaborative ependymoma research network study (CERN)
JOURNAL OF NEURO-ONCOLOGY
2015; 123 (1): 85-91
Abstract
Co-expression of ERBB2 and ERBB4, reported in 75% of pediatric ependymomas, correlates with worse overall survival. Lapatinib, a selective ERBB1 and ERBB2 inhibitor has produced prolonged disease stabilization in patients with ependymoma in a phase I study. Bevacizumab exposure in ependymoma xenografts leads to ablation of tumor self-renewing cells, arresting growth. Thus, we conducted an open-label, phase II study of bevacizumab and lapatinib in children with recurrent ependymomas. Patients ≤ 21 years of age with recurrent ependymoma received lapatinib orally twice daily (900 mg/m(2)/dose to the first 10 patients, and then 700 mg/m(2)/dose) and bevacizumab 10 mg/kg intravenously on days 1 and 15 of a 28-day course. Lapatinib serum trough levels were analyzed prior to each course. Total and phosphorylated VEGFR2 expression was measured in peripheral blood mononuclear cells (PBMCs) before doses 1 and 2 of bevacizumab and 24-48 h following dose 2 of bevacizumab. Twenty-four patients with a median age of 10 years (range 2-21 years) were enrolled; 22 were eligible and 20 evaluable for response. Thirteen had anaplastic ependymoma. There were no objective responses; 4 patients had stable disease for ≥ 4 courses (range 4-14). Grade 3 toxicities included rash, elevated ALT, and diarrhea. Grade 4 toxicities included peri-tracheostomy hemorrhage (n = 1) and elevated creatinine phosphokinase (n = 1). The median lapatinib pre-dose trough concentration was 3.72 µM. Although the combination of bevacizumab and lapatinib was well tolerated in children with recurrent ependymoma, it proved ineffective.
View details for DOI 10.1007/s11060-015-1764-7
View details for Web of Science ID 000354893700009
View details for PubMedID 25859842
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Efficacy and patient-reported outcomes with dose-intense temozolomide in patients with newly diagnosed pure and mixed anaplastic oligodendroglioma: a phase II multicenter study.
Journal of neuro-oncology
2015; 122 (1): 111-119
Abstract
Standard initial therapy for patients with pure and mixed anaplastic oligodendrogliomas (AO/MAO) includes chemotherapy and radiation therapy. Anaplastic oligodendrogliomas with 1p/19q co-deletion are more responsive to chemotherapy. There is concern for potential long-term CNS toxicity of radiation. Hence an approach using chemotherapy initially and reserving radiation for progressive disease is attractive. This multicenter phase II trial included patients with newly diagnosed AO/MAO with central pathology review and 1p/19q assay. Temozolomide was given 150 mg/m(2) days 1-7 and 15-21, every 28 days for 8 cycles. The primary endpoint was progression free survival (PFS). Secondary endpoints included response rate, overall survival (OS), treatment toxicity and health-related quality of life (HRQL). Data from 62 patients enrolled between December 2001 and April 2007 at seven centers were analyzed. Among patients with measurable disease, 8 % achieved complete remission, 56 % had stable disease and 36 % had progression. The median PFS and OS were 27.2 months (95 % CI 11.9-36.3) and 105.8 months (95 % CI 51.5-N/A), respectively. Both 1p loss and 1p/19q co-deletion were positive prognostic factors for PFS (p < 0.001) and OS (p < 0.001); and there was some suggestion that 1p/19q co-deletion also predicted better response to chemotherapy (p = 0.007). Grade 3/4 toxicities were mainly hematological. Significantly improved HRQL in the future uncertainty domain of the brain cancer module was seen after cycle 4 (p < 0.001). This trial achieved outcomes similar to those reported previously. Toxicities from dose-intense temozolomide were manageable. Improvement in at least one HRQL domain increased over time. This trial supports the further study of first-line temozolomide monotherapy as an alternative to radiation therapy for patients with newly diagnosed AO/MAO with 1p 19q co-deleted tumors.
View details for DOI 10.1007/s11060-014-1684-y
View details for PubMedID 25534576
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Brain Tumor Epidemiology - A Hub within Multidisciplinary Neuro-oncology. Report on the 15th Brain Tumor Epidemiology Consortium (BTEC) Annual Meeting, Vienna, 2014
CLINICAL NEUROPATHOLOGY
2015; 34 (1): 40-46
View details for DOI 10.5414/NP300846
View details for Web of Science ID 000348244600008
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Brain Tumor Epidemiology - A Hub within Multidisciplinary Neuro-oncology. Report on the 15th Brain Tumor Epidemiology Consortium (BTEC) Annual Meeting, Vienna, 2014.
Clinical neuropathology
2014; 34 (1): 40-6
Abstract
The Brain Tumor Epidemiology Consortium (BTEC) is an open scientific forum, which fosters the development of multi-center, international and inter-disciplinary collaborations. BTEC aims to develop a better understanding of the etiology, outcomes, and prevention of brain tumors (http://epi.grants.cancer.gov/btec/). The 15th annual Brain Tumor Epidemiology Consortium Meeting, hosted by the Austrian Societies of Neuropathology and Neuro-oncology, was held on September 9 - 11, 2014 in Vienna, Austria. The meeting focused on the central role of brain tumor epidemiology within multidisciplinary neuro-oncology. Knowledge of disease incidence, outcomes, as well as risk factors is fundamental to all fields involved in research and treatment of patients with brain tumors; thus, epidemiology constitutes an important link between disciplines, indeed the very hub. This was reflected by the scientific program, which included various sessions linking brain tumor epidemiology with clinical neuro-oncology, tissue-based research, and cancer registration. Renowned experts from Europe and the United States contributed their personal perspectives stimulating further group discussions. Several concrete action plans evolved for the group to move forward until next year's meeting, which will be held at the Mayo Clinic at Rochester, MN, USA.
View details for PubMedID 25518914
View details for PubMedCentralID PMC4317580
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Sports and childhood brain tumors: Can I play?
Neuro-oncology practice
2014; 1 (4): 158-165
Abstract
It is unknown whether children with brain tumors have a higher risk of complications while participating in sports. We sought to estimate the prevalence of such events by conducting a systematic review of the literature, and we surveyed providers involved with pediatric central nervous system (CNS) tumor patients.A systematic review of the literature in the PubMed, Scopus, and Cochrane databases was conducted for original articles addressing sport-related complications in the brain-tumor population. An online questionnaire was created to survey providers involved with pediatric CNS tumor patients about their current recommendations and experience regarding sports and brain tumors.We retrieved 32 subjects, including 19 pediatric cases from the literature. Most lesions associated with sport complications were arachnoid cysts (n = 21), followed by glioma (n = 5). The sports in which symptom onset most commonly occurred were soccer (n = 7), football (n = 5), and running (n = 5). We surveyed 111 pediatric neuro-oncology providers. Sport restriction varied greatly from none to 14 sports. Time to return to play in sports with contact also varied considerably between providers. Rationales for limiting sports activities were partly related to subspecialty. Responders reported 9 sport-related adverse events in patients with brain tumor.Sport-related complications are uncommon in children with brain tumors. Patients might not be at a significantly higher risk and should not need to be excluded from most sports activities.
View details for PubMedID 26034627
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50 Years ago in the Journal of Pediatrics: brain tumors in early infancy--probably congenital in origin.
The Journal of pediatrics
2014; 165 (5): 978
View details for DOI 10.1016/j.jpeds.2014.05.033
View details for PubMedID 25441387
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Quality of life outcomes in proton and photon treated pediatric brain tumor survivors
RADIOTHERAPY AND ONCOLOGY
2014; 113 (1): 89-94
Abstract
Radiotherapy can impair Health Related Quality of Life (HRQoL) in survivors of childhood brain tumors, but proton radiotherapy (PRT) may mitigate this effect. This study compares HRQoL in PRT and photon (XRT) pediatric brain tumor survivors.HRQoL data were prospectively collected on PRT-treated patients aged 2-18 treated at Massachusetts General Hospital (MGH). Cross-sectional PedsQL data from XRT treated Lucile Packard Children's Hospital (LPCH) patients provided the comparison data.Parent proxy HRQoL scores were reported at 3 years for the PRT cohort (PRT-C) and 2.9 years (median) for the XRT cohort (XRT-C). The total core HRQoL score for the PRT-C, XRT-C, and normative population differed from one another and was 75.9, 65.4 and 80.9 respectively (p=0.002; p=0.024; p<0.001). The PRT-C scored 10.3 and 10.5 points higher than the XRT-C in the physical (PhSD) and psychosocial (PsSD) summary domains of the total core score (TCS, p=0.015; p=0.001). The PRT-C showed no difference in PhSD compared with the normative population, but scored 6.1 points less in the PsSD (p=0.003). Compared to healthy controls, the XRT-C scored lower in all domains (p<0.001).The HRQoL of pediatric brain tumor survivors treated with PRT compare favorably to those treated with XRT and similar to healthy controls in the PhSD.
View details for DOI 10.1016/j.radonc.2014.08.017
View details for Web of Science ID 000347604800015
View details for PubMedID 25304720
View details for PubMedCentralID PMC4288853
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50 years ago in the Journal of Pediatrics: cerebrospinal fluid and blood electrolytes in 62 mentally defective infants and children.
The Journal of pediatrics
2014; 165 (3): 515
View details for DOI 10.1016/j.jpeds.2014.03.028
View details for PubMedID 25152154
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50 years ago in the Journal of Pediatrics: an etiologic and diagnostic study of cerebral palsy.
The Journal of pediatrics
2014; 165 (2): 273
View details for DOI 10.1016/j.jpeds.2014.02.059
View details for PubMedID 25060875
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MRI surrogates for molecular subgroups of medulloblastoma.
AJNR. American journal of neuroradiology
2014; 35 (7): 1263-1269
Abstract
Recently identified molecular subgroups of medulloblastoma have shown potential for improved risk stratification. We hypothesized that distinct MR imaging features can predict these subgroups.All patients with a diagnosis of medulloblastoma at one institution, with both pretherapy MR imaging and surgical tissue, served as the discovery cohort (n = 47). MR imaging features were assessed by 3 blinded neuroradiologists. NanoString-based assay of tumor tissues was conducted to classify the tumors into the 4 established molecular subgroups (wingless, sonic hedgehog, group 3, and group 4). A second pediatric medulloblastoma cohort (n = 52) from an independent institution was used for validation of the MR imaging features predictive of the molecular subtypes.Logistic regression analysis within the discovery cohort revealed tumor location (P < .001) and enhancement pattern (P = .001) to be significant predictors of medulloblastoma subgroups. Stereospecific computational analyses confirmed that group 3 and 4 tumors predominated within the midline fourth ventricle (100%, P = .007), wingless tumors were localized to the cerebellar peduncle/cerebellopontine angle cistern with a positive predictive value of 100% (95% CI, 30%-100%), and sonic hedgehog tumors arose in the cerebellar hemispheres with a positive predictive value of 100% (95% CI, 59%-100%). Midline group 4 tumors presented with minimal/no enhancement with a positive predictive value of 91% (95% CI, 59%-98%). When we used the MR imaging feature-based regression model, 66% of medulloblastomas were correctly predicted in the discovery cohort, and 65%, in the validation cohort.Tumor location and enhancement pattern were predictive of molecular subgroups of pediatric medulloblastoma and may potentially serve as a surrogate for genomic testing.
View details for DOI 10.3174/ajnr.A3990
View details for PubMedID 24831600
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Diffusion-weighted MRI derived apparent diffusion coefficient identifies prognostically distinct subgroups of pediatric diffuse intrinsic pontine glioma.
Journal of neuro-oncology
2014; 117 (1): 175-182
Abstract
While pediatric diffuse intrinsic pontine gliomas (DIPG) remain fatal, recent data have shown subgroups with distinct molecular biology and clinical behavior. We hypothesized that diffusion-weighted MRI can be used as a prognostic marker to stratify DIPG subsets with distinct clinical behavior. Apparent diffusion coefficient (ADC) values derived from diffusion-weighted MRI were computed in 20 consecutive children with treatment-naïve DIPG tumors. The median ADC for the cohort was used to stratify the tumors into low and high ADC groups. Survival, gender, therapy, and potential steroid effects were compared between the ADC groups. Median age at diagnosis was 6.6 (range 2.3-13.2) years, with median follow-up seven (range 1-36) months. There were 14 boys and six girls. Seventeen patients received radiotherapy, five received chemotherapy, and six underwent cerebrospinal fluid diversion. The median ADC of 1,295 × 10(-6) mm(2)/s for the cohort partitioned tumors into low or high diffusion groups, which had distinct median survivals of 3 and 13 months, respectively (log-rank p < 0.001). Low ADC tumors were found only in boys, whereas high ADC tumors were found in both boys and girls. Available tissue specimens in three low ADC tumors demonstrated high-grade histology, whereas one high ADC tumor demonstrated low-grade histology with a histone H3.1 K27M mutation and high-grade metastatic lesion at autopsy. ADC derived from diffusion-weighted MRI may identify prognostically distinct subgroups of pediatric DIPG.
View details for DOI 10.1007/s11060-014-1375-8
View details for PubMedID 24522717
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50 Years ago in The Journal of Pediatrics: the hypotonic infant.
The Journal of pediatrics
2014; 164 (3): 565
View details for DOI 10.1016/j.jpeds.2013.09.052
View details for PubMedID 24560317
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Surveillance imaging in children with malignant CNS tumors: low yield of spine MRI.
Journal of neuro-oncology
2014; 116 (3): 617-623
Abstract
Magnetic resonance imaging (MRI) is routinely obtained in patients with central nervous system (CNS) tumors, but few studies have been conducted to evaluate this practice. We assessed the benefits of surveillance MRI and more specifically spine MRI in a contemporary cohort. We evaluated MRI results of children diagnosed with CNS tumors from January 2000 to December 2011. Children with at least one surveillance MRI following the diagnosis of medulloblastoma (MB), atypical teratoid rhabdoid tumor (ATRT), pineoblastoma (PB), supratentorial primitive neuroectodermal tumor, supratentorial high-grade glioma (World Health Organization grade III-IV), CNS germ cell tumors or ependymoma were included. A total of 2,707 brain and 1,280 spine MRI scans were obtained in 258 patients. 97 % of all relapses occurred in the brain and 3 % were isolated to the spine. Relapse was identified in 226 (8 %) brain and 48 (4 %) spine MRI scans. The overall rate of detecting isolated spinal relapse was 9/1,000 and 7/1,000 for MB patients. MRI performed for PB showed the highest rate for detecting isolated spinal recurrence with 49/1,000. No initial isolated spinal relapse was identified in patients with glioma, supratentorial primitive neuroectodermal tumor and ATRT. Isolated spinal recurrences are infrequent in children with malignant CNS tumors and the yield of spine MRI is very low. Tailoring surveillance spine MRI to patients with higher spinal relapse risk such as PB, MB with metastatic disease and within 3 years of diagnosis could improve allocation of resources without compromising patient care.
View details for DOI 10.1007/s11060-013-1347-4
View details for PubMedID 24401959
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Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group
ACTA NEUROPATHOLOGICA
2014; 127 (2): 189-201
Abstract
Medulloblastoma is curable in approximately 70 % of patients. Over the past decade, progress in improving survival using conventional therapies has stalled, resulting in reduced quality of life due to treatment-related side effects, which are a major concern in survivors. The vast amount of genomic and molecular data generated over the last 5-10 years encourages optimism that improved risk stratification and new molecular targets will improve outcomes. It is now clear that medulloblastoma is not a single-disease entity, but instead consists of at least four distinct molecular subgroups: WNT/Wingless, Sonic Hedgehog, Group 3, and Group 4. The Medulloblastoma Down Under 2013 meeting, which convened at Bunker Bay, Australia, brought together 50 leading clinicians and scientists. The 2-day agenda included focused sessions on pathology and molecular stratification, genomics and mouse models, high-throughput drug screening, and clinical trial design. The meeting established a global action plan to translate novel biologic insights and drug targeting into treatment regimens to improve outcomes. A consensus was reached in several key areas, with the most important being that a novel classification scheme for medulloblastoma based on the four molecular subgroups, as well as histopathologic features, should be presented for consideration in the upcoming fifth edition of the World Health Organization's classification of tumours of the central nervous system. Three other notable areas of agreement were as follows: (1) to establish a central repository of annotated mouse models that are readily accessible and freely available to the international research community; (2) to institute common eligibility criteria between the Children's Oncology Group and the International Society of Paediatric Oncology Europe and initiate joint or parallel clinical trials; (3) to share preliminary high-throughput screening data across discovery labs to hasten the development of novel therapeutics. Medulloblastoma Down Under 2013 was an effective forum for meaningful discussion, which resulted in enhancing international collaborative clinical and translational research of this rare disease. This template could be applied to other fields to devise global action plans addressing all aspects of a disease, from improved disease classification, treatment stratification, and drug targeting to superior treatment regimens to be assessed in cooperative international clinical trials.
View details for DOI 10.1007/s00401-013-1213-7
View details for Web of Science ID 000329993100003
View details for PubMedID 24264598
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Arterial spin-labeled perfusion of pediatric brain tumors.
AJNR. American journal of neuroradiology
2014; 35 (2): 395-401
Abstract
Pediatric brain tumors have diverse pathologic features, which poses diagnostic challenges. Although perfusion evaluation of adult tumors is well established, hemodynamic properties are not well characterized in children. Our goal was to apply arterial spin-labeling perfusion for various pathologic types of pediatric brain tumors and evaluate the role of arterial spin-labeling in the prediction of tumor grade.Arterial spin-labeling perfusion of 54 children (mean age, 7.5 years; 33 boys and 21 girls) with treatment-naive brain tumors was retrospectively evaluated. The 3D pseudocontinuous spin-echo arterial spin-labeling technique was acquired at 3T MR imaging. Maximal relative tumor blood flow was obtained by use of the ROI method and was compared with tumor histologic features and grade.Tumors consisted of astrocytic (20), embryonal (11), ependymal (3), mixed neuronal-glial (8), choroid plexus (5), craniopharyngioma (4), and other pathologic types (3). The maximal relative tumor blood flow of high-grade tumors (grades III and IV) was significantly higher than that of low-grade tumors (grades I and II) (P < .001). There was a wider relative tumor blood flow range among high-grade tumors (2.14 ± 1.78) compared with low-grade tumors (0.60 ± 0.29) (P < .001). Across the cohort, relative tumor blood flow did not distinguish individual histology; however, among posterior fossa tumors, relative tumor blood flow was significantly higher for medulloblastoma compared with pilocytic astrocytoma (P = .014).Characteristic arterial spin-labeling perfusion patterns were seen among diverse pathologic types of brain tumors in children. Arterial spin-labeling perfusion can be used to distinguish high-grade and low-grade tumors.
View details for DOI 10.3174/ajnr.A3670
View details for PubMedID 23907239
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Subventricular spread of diffuse intrinsic pontine glioma.
Acta neuropathologica
2014
View details for PubMedID 24929912
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50 years ago in the Journal of Pediatrics: central nervous system complications of children with acute leukemia: an evaluation of treatment methods.
The Journal of pediatrics
2014; 164 (1): 33
View details for DOI 10.1016/j.jpeds.2013.08.003
View details for PubMedID 24359900
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Pilot undergraduate course teaches students about chronic illness in children: An educational intervention study.
Education for health (Abingdon, England)
2014; 27 (1): 34-38
Abstract
Recent data question whether medical education adequately prepares physicians to care for the growing number of children with chronic medical conditions. We describe a 10-week course designed to provide undergraduate students with the knowledge and skills required to understand and care for children with chronic or catastrophic illnesses. The course presented the illness experience from the child's perspective and thus presented information in a manner that was efficient, conducive, and memorable. The curriculum was designed like a graduate-level seminar that included workshops, lectures, readings, writing, and lively discussions.This is an educational intervention study that used survey data to assess changes in attitudes among and between participants completing this course versus students not exposed to this course. We used Somers' D test and Fisher's z-transformation to perform both pre- and post-nonparametric comparisons.Course participants were more likely to change their attitudes and agree that chronically ill children "feel comfortable talking with their peers about their condition" (P=0.003) and less likely to agree that these children "want to be treated differently," "want more sympathy," or "care less about romantic relationships" (P = 0.003, 0.002 and 0.02, respectively). Controls were more likely to continue to agree that chronically ill children "want to be treated differently" (P = 0.009) and "care less about romantic relationships" (P = 0.02), and less likely to agree that these children "talk openly" or "feel comfortable talking with their peers about their condition" (P = 0.04).This classroom-based course serves as a feasible and cost-effective model for universities and medical schools to aid in improving student attitudes toward treating chronically ill children. The course provides the unique opportunity to learn directly from those who care for and those who have lived with chronic illness.
View details for DOI 10.4103/1357-6283.134305
View details for PubMedID 24934941
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Relapse patterns in pediatric embryonal central nervous system tumors
JOURNAL OF NEURO-ONCOLOGY
2013; 115 (2): 209-215
Abstract
Embryonal tumors of the central nervous system (CNS) share histological features and were therefore initially grouped as primitive neuroectodermal tumors (PNET) and treated similarly. We sought to determine the relapse patterns of specific embryonal CNS tumors. We conducted a historical cohort study of children diagnosed with CNS embryonal tumors from January 2000 to December 2011 in two pediatric neuro-oncology centers. Patients of 21 years of age or younger at time of presentation with a diagnosis of medulloblastoma, supratentorial PNET, pineoblastoma or atypical teratoid/rhabdoid tumor (ATRT) and at least one surveillance MRI were included. A total of 133 patients met inclusion criteria and 49 (37 %) patients relapsed during the observation period. The majority (79 %) of sPNET relapses were local, whereas all (100 %) PB relapses were associated with diffuse leptomeningeal disease. Relapse patterns for MB were more diverse with local recurrence in 27 %, distant recurrence in 35 % and diffuse leptomeningeal disease in 38 %. The frequency of relapses involving the spine differed (p < 0.001) between tumor types (MB 28/55 [51 %], sPNET 3/33 [9 %], ATRT 3/7 [43 %] and PB 12/12 [100 %]). No sPNET patients had isolated spinal relapse (0/14). Embryonal tumors were found to have divergent patterns of recurrence. While medulloblastoma has variable relapse presentations, sPNET relapses locally and pineoblastoma recurs with diffuse leptomeningeal disease involving the spine. These results point toward possibly new upfront treatment stratification among embryonal tumors in accordance with relapse pattern.
View details for DOI 10.1007/s11060-013-1213-4
View details for PubMedID 23921420
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50 Years ago in The Journal of Pediatrics: cigarettes, school children, and lung cancer.
The Journal of pediatrics
2013; 163 (5): 1371
View details for DOI 10.1016/j.jpeds.2013.04.064
View details for PubMedID 24160656
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Prognostic role for diffusion-weighted imaging of pediatric optic pathway glioma.
Journal of neuro-oncology
2013; 113 (3): 479-483
Abstract
Optic pathway glioma (OPG) has an unpredictable course, with poor correlation between conventional imaging features and tumor progression. We investigated whether diffusion-weighted MRI (DWI) predicts the clinical behavior of these tumors. Twelve children with OPG (median age 2.7 years; range 0.4-6.2 years) were followed for a median 4.4 years with DWI. Progression-free survival (time to requiring therapy) was compared between tumors stratified by apparent diffusion coefficient (ADC) from initial pre-treatment scans. Tumors with baseline ADC greater than 1,400 × 10(-6) mm(2)/s required treatment earlier than those with lower ADC (log-rank p = 0.002). In some cases, ADC increased leading up to treatment, and declined following treatment with surgery, chemotherapy, or radiation. Baseline ADC was higher in tumors that eventually required treatment (1,562 ± 192 × 10(-6) mm(2)/s), compared with those conservatively managed (1,123 ± 114 × 10(-6) mm(2)/s) (Kruskal-Wallis test p = 0.013). Higher ADC predicted earlier tumor progression in this cohort and in some cases declined after therapy. Evaluation of OPG with DWI may therefore be useful for predicting tumor behavior and assessing treatment response.
View details for DOI 10.1007/s11060-013-1140-4
View details for PubMedID 23673514
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A phase I trial of arsenic trioxide chemoradiotherapy for infiltrating astrocytomas of childhood.
Neuro-oncology
2013; 15 (6): 783-787
Abstract
Background Arsenic trioxide (ATO) has demonstrated preclinical evidence of activity in the treatment of infiltrating astrocytomas. Methods We conducted a phase I trial of ATO given concomitantly with radiation therapy in children with newly diagnosed anaplastic astrocytoma, glioblastoma, or diffuse intrinsic pontine glioma. Eligible patients received a fixed daily dose of 0.15 mg/kg of ATO once a week, with each subsequent cohort of patients receiving an additional dose per week up to a planned frequency of ATO administration 5 days per week as tolerated. Twenty-four children were enrolled and 21 children were evaluable. Results ATO was well tolerated throughout the entire dose escalation, resulting in confirmation of safety when administered 5 days per week during irradiation. Conclusions The recommended dose of ATO during conventional irradiation is 0.15 mg/kg given on a daily basis with each fraction of radiation therapy administered.
View details for DOI 10.1093/neuonc/not021
View details for PubMedID 23460318
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DIVERGENT PATTERNS OF INCIDENCE IN PERIPHERAL NEUROBLASTIC TUMORS
WILEY-BLACKWELL. 2013: S74–S75
View details for Web of Science ID 000317984800253
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PERIPHERAL NEUROBLASTIC TUMORS ARE DEVELOPMENTAL CANCERS THAT SEGREGATE BY AGE, HISTOLOGY, AND LOCATION
WILEY-BLACKWELL. 2013: S73–S73
View details for Web of Science ID 000317984800249
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Changes in health status among aging survivors of pediatric upper and lower extremity sarcoma: a report from the childhood cancer survivor study.
Archives of physical medicine and rehabilitation
2013; 94 (6): 1062-1073
Abstract
To evaluate health status and participation restrictions in survivors of childhood extremity sarcomas.Members of the Childhood Cancer Survivor Study cohort with extremity sarcomas who completed questionnaires in 1995, 2003, or 2007 were included.Cohort study of survivors of extremity sarcomas.Childhood extremity sarcoma survivors (N=1094; median age at diagnosis, 13y (range, 0-20y); current age, 33y (range, 10-53y); 49% male; 87.5% white; 75% had lower extremity tumors) who received their diagnosis and treatment between 1970 and 1986.Not applicable.Prevalence rates for poor health status in 6 domains and 5 suboptimal social participation categories were compared by tumor location and treatment exposure with generalized estimating equations adjusted for demographic/personal factors and time/age.In adjusted models, when compared with upper extremity survivors, lower extremity survivors had an increased risk of activity limitations but a lower risk of not completing college. Compared with those who did not have surgery, those with limb-sparing (LS) and upper extremity amputations (UEAs) were 1.6 times more likely to report functional impairment, while those with an above-the-knee amputation (AKA) were 1.9 times more likely to report functional impairment. Survivors treated with LS were 1.5 times more likely to report activity limitations. Survivors undergoing LS were more likely to report inactivity, incomes <$20,000, unemployment, and no college degree. Those with UEAs more likely reported inactivity, unmarried status, and no college degree. Those with AKA more likely reported no college degree. Treatment with abdominal irradiation was associated with an increased risk of poor mental health, functional impairment, and activity limitation.Treatment of lower extremity sarcomas is associated with a 50% increased risk for activity limitations; upper extremity survivors are at a 10% higher risk for not completing college. The type of local control influences health status and participation restrictions. Both of these outcomes decline with age.
View details for DOI 10.1016/j.apmr.2013.01.013
View details for PubMedID 23380347
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Anti-N-methyl-D-aspartate receptor encephalitis: what's in a name?
journal of pediatrics
2013; 162 (4): 673-675
View details for DOI 10.1016/j.jpeds.2012.11.074
View details for PubMedID 23305956
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Risk of subsequent cancer following a primary CNS tumor
JOURNAL OF NEURO-ONCOLOGY
2013; 112 (2): 285-295
Abstract
Improvements in survival among central nervous system (CNS) tumor patients has made the risk of developing a subsequent cancer an important survivorship issue. Such a risk is likely influenced by histological and treatment differences between CNS tumors. De-identified data for 41,159 patients with a primary CNS tumor diagnosis from 9 Surveillance, Epidemiology and End Results (SEER) registries were used to calculate potential risk for subsequent cancer development. Relative risk (RR) and 95 % confidence interval (CI) of subsequent cancer was calculated using SEER*Stat 7.0.9, comparing observed number of subsequent cancers versus expected in the general United States population. For all CNS tumors studied, there were 830 subsequent cancers with a RR of 1.26 (95 % CI, 1.18-1.35). Subsequent cancers were observed in the CNS, digestive system, bones/joints, soft tissue, thyroid and leukemia. Radiotherapy was associated with an elevated risk, particularly in patients diagnosed with a medulloblastoma/primitive neuroectodermal tumor (MPNET). MPNET patients who received radiotherapy were at a significant risk for development of cancers of the digestive system, leukemia, bone/joint and cranial nerves. Glioblastoma multiforme patients who received radiotherapy were at lower risks for female breast and prostate cancers, though at an elevated risk for cancers of the thyroid and brain. Radiotherapy is associated with subsequent cancer development, particularly for sites within the field of radiation, though host susceptibility and post-treatment status underlie this risk. Variation in subsequent cancer risk among different CNS tumor histological subtypes indicate a complex interplay between risk factors in subsequent cancer development.
View details for DOI 10.1007/s11060-013-1063-0
View details for Web of Science ID 000316755000017
View details for PubMedID 23392847
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AN OPEN-LABEL, TWO-STAGE, PHASE II STUDY OF BEVACIZUMAB AND LAPATINIB IN CHILDREN WITH RECURRENT OR REFRACTORY EPENDYMOMA: A COLLABORATIVE EPENDYMOMA RESEARCH NETWORK STUDY (CERN)
2nd Annual Pediatric Neuro-Oncology Basic and Translational Research Conference
OXFORD UNIV PRESS INC. 2013: 47–47
View details for Web of Science ID 000318570500171
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50 years ago in The Journal of Pediatrics: Sensory neuropathy in a child.
journal of pediatrics
2012; 161 (6): 1034-?
View details for DOI 10.1016/j.jpeds.2012.06.061
View details for PubMedID 23171486
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HEALTH RELATED QUALITY OF LIFE IN PEDIATRIC BRAIN TUMOR PATIENTS: A COMPARISON OF PROTON AND PHOTON TREATED COHORTS
WILEY-BLACKWELL. 2012: 979–79
View details for Web of Science ID 000309754300056
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Trends in the diagnosis and treatment of pediatric primary spinal cord tumors Clinical article
JOURNAL OF NEUROSURGERY-PEDIATRICS
2012; 10 (6): 555-559
View details for DOI 10.3171/2012.9.PEDS1272
View details for Web of Science ID 000311464100017
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Trends in the diagnosis and treatment of pediatric primary spinal cord tumors.
Journal of neurosurgery. Pediatrics
2012; 10 (6): 555-559
Abstract
Pediatric primary spinal cord tumors (PSCTs) are rare, with limited comprehensive data regarding incidence and patterns of diagnosis and treatment. The authors evaluated trends in the diagnosis and treatment of PSCTs using a nationwide database.The Surveillance, Epidemiology, and End Results (SEER) registry was queried for the years 1975-2007, evaluating clinical patterns in 330 patients 19 years of age or younger in whom a pediatric PSCT had been diagnosed. Histological diagnoses were grouped into pilocytic astrocytoma, other low-grade astrocytoma, ependymoma, and high-grade glioma. Patient demographics, tumor pathology, use of external beam radiation (EBR), and overall survival were analyzed.The incidence of pediatric PSCT was 0.09 case per 100,000 person-years and did not change over time. Males were more commonly affected than females (58% vs 42%, respectively; p < 0.006). Over the last 3 decades, the specific diagnoses of pilocytic astrocytoma and ependymoma increased, whereas the use of EBR decreased (60.6% from 1975 to 1989 vs 31.3% from 1990 to 2007; p < 0.0001). The 5- and 10-year survival rates did not differ between these time periods.While the incidence of pediatric PSCT has not changed over time, the pattern of pathological diagnoses has shifted, and pilocytic astrocytoma and ependymoma have been increasingly diagnosed. The use of EBR over time has declined. Relative survival of patients with low-grade PSCT has remained high regardless of the pathological diagnosis.
View details for DOI 10.3171/2012.9.PEDS1272
View details for PubMedID 23061821
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Concurrent cyclophosphamide and craniospinal radiotherapy for pediatric high-risk embryonal brain tumors
JOURNAL OF NEURO-ONCOLOGY
2012; 110 (2): 287-291
Abstract
Embryonal tumors are an aggressive subtype of high-grade, pediatric central nervous system (CNS) tumors often with dismal survival rates. The 5-year survival for highest-risk embryonal tumors may be as low as 10 %. We report feasibility and efficacy from our experience using intravenous (IV) cyclophosphamide concurrently with craniospinal radiation (CSI) in high-risk embryonal CNS tumors of childhood. Ten consecutive children (aged: 3.5-15.5 years, median: 10.2 years, six male) with high-risk embryonal tumors, including: large cell/anaplastic medulloblastoma (6), atypical teratoid rhabdoid tumor (1), and leptomeningeal primitive neuroectodermal tumor (3), were treated with IV cyclophosphamide 1 g/M(2) on days 1 and 2 of CSI. Following a median of 36 Gy CSI plus tumor boosts, adjuvant treatment consisted of 21 doses of oral etoposide (7) and alkylator based chemotherapy from five to eight cycles in all. Of the ten patients thus treated, six remain alive with no evidence of disease and four are deceased. Median survival was 3.3 years, with a 3-year progression-free survival of 50 % (5/10). Median follow-up was: 3.3 years (range: 5 months-12.9 years) in the five patients with progression, median time-to-progression was: 1.3 years (range: 1 month-3 years). Median follow-up in the patients without progression is 8.8 years (range: 3-12.9 years). Complications due to adjuvant chemotherapy were typical and included myelosupression (10), necessitating shortened duration of chemotherapy in three, and hemorrhagic cystitis (1). In high-risk embryonal CNS tumors, cyclophosphamide given concurrently with CSI is well tolerated. Early results suggest that a phase II trial is warranted.
View details for DOI 10.1007/s11060-012-0969-2
View details for Web of Science ID 000311208100017
View details for PubMedID 22941430
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50 years ago in The Journal of Pediatrics: the effect of degree of hypoxia on the electroencephalogram in infants.
journal of pediatrics
2012; 161 (4): 614-?
View details for DOI 10.1016/j.jpeds.2012.05.018
View details for PubMedID 22999578
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In memoriam: Donald W. Lewis, MD (1951-2012 ).
Journal of child neurology
2012; 27 (10): 1355-9
View details for DOI 10.1177/0883073812457464
View details for PubMedID 23007304
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GENDER AND RACIAL RISK FACTORS FOR CHILDHOOD BRAIN TUMORS
17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO)
OXFORD UNIV PRESS INC. 2012: 23–23
View details for Web of Science ID 000310971300097
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50 years ago in The Journal of Pediatrics: the surgical management of meningoceles and meningomyeloceles.
journal of pediatrics
2012; 161 (4): 734-?
View details for DOI 10.1016/j.jpeds.2012.05.019
View details for PubMedID 22999580
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Efficacy and tolerability of rizatriptan in pediatric migraineurs: Results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design
CEPHALALGIA
2012; 32 (10): 750-765
Abstract
Treatment options for children and adolescents with migraine are limited. This study evaluated rizatriptan for the acute treatment of migraine in children and adolescents.Randomized, double-blind, placebo-controlled, parallel-group trial in migraineurs 6-17 years old with unsatisfactory response to nonsteroidal anti-inflammatory drugs or acetaminophen/paracetamol. The trial included a double-blind run-in with weight-based rizatriptan dosing (5 mg for < 40 kg, 10 mg for ≥ 40 kg). In the Stage 1 run-in, patients were randomized in a ratio of 20:1 placebo:rizatriptan and were instructed to treat within 30 minutes of a moderate/severe migraine. Patients with mild/no pain after 15 minutes of treatment (responders) took no further study medication, whereas patients with moderate/severe pain (non-responders) proceeded to take study medication in Stage 2. Non-responders who received placebo in Stage 1 were randomized 1:1 to rizatriptan:placebo, whereas non-responders who received rizatriptan in Stage 1 were allocated to placebo in Stage 2. The primary efficacy endpoint was pain freedom at 2 hours after Stage 2 dose in 12-17-year-olds.A higher proportion of 12-17-year-olds on rizatriptan had pain freedom at 2 hours compared with those on placebo: 87/284 (30.6%) versus 63/286 (22.0%), odds ratio = 1.55 [95% CI: 1.06 to 2.26], p = 0.025. Adverse events within 14 days of dose in 12-17-year-olds were similar for rizatriptan and placebo. The pattern of findings was similar in 6-17-year-olds.Rizatriptan demonstrated a statistically significant improvement over placebo in eliminating pain and was generally well tolerated in migraineurs aged 12-17 and 6-17 years.ClinicalTrials.gov NCT01001234.
View details for DOI 10.1177/0333102412451358
View details for Web of Science ID 000306731800003
View details for PubMedID 22711898
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PSYCHIATRIC SYMPTOMS IN CHILDREN WITH MEDULLOBLASTOMA
15th International Symposium on Pediatric Neuro-Oncology (ISPNO)
OXFORD UNIV PRESS INC. 2012: 128–128
View details for Web of Science ID 000308394400480
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PSYCHIATRIC SYMPTOMS IN SURVIVORS OF CHILDHOOD GERM CELL TUMORS
15th International Symposium on Pediatric Neuro-Oncology (ISPNO)
OXFORD UNIV PRESS INC. 2012: 50–50
View details for Web of Science ID 000308394400184
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HAZARDOUS AIR POLLUTANTS AND RISK OF CHILDHOOD CENTRAL NERVOUS SYSTEM TUMORS IN CALIFORNIA
15th International Symposium on Pediatric Neuro-Oncology (ISPNO)
OXFORD UNIV PRESS INC. 2012: 43–44
View details for Web of Science ID 000308394400159
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Cancer in Children with Nonchromosomal Birth Defects
JOURNAL OF PEDIATRICS
2012; 160 (6): 978-983
Abstract
To examine whether the incidence of childhood cancer is elevated in children with birth defects but no chromosomal anomalies.We examined cancer risk in a population-based cohort of children with and without major birth defects born between 1988 and 2004, by linking data from the California Birth Defects Monitoring Program, the California Cancer Registry, and birth certificates. Cox proportional hazards models generated hazard ratios (HRs) and 95% CIs based on person-years at risk. We compared the risk of childhood cancer in infants born with and without specific types of birth defects, excluding infants with chromosomal anomalies.Of the 4869 children in the birth cohort with cancer, 222 had a major birth defect. Although the expected elevation in cancer risk was observed in children with chromosomal birth defects (HR, 12.44; 95% CI, 10.10-15.32), especially for the leukemias (HR, 28.99; 95% CI, 23.07-36.42), children with nonchromosomal birth defects also had an increased risk of cancer (HR, 1.58; 95% CI, 1.33-1.87), but instead for brain tumors, lymphomas, neuroblastoma, and germ cell tumors.Children with nonchromosomal birth defects are at increased risk for solid tumors, but not leukemias. Dysregulation of early human development likely plays an important role in the etiology of childhood cancer.
View details for DOI 10.1016/j.jpeds.2011.12.006
View details for Web of Science ID 000304377300019
View details for PubMedID 22244463
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The Eyes Have It! The Significance of Unilateral Ptosis
JOURNAL OF PEDIATRICS
2012; 160 (4): 703-?
View details for DOI 10.1016/j.jpeds.2011.11.052
View details for Web of Science ID 000302489800038
View details for PubMedID 22221564
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Complete Ocular Paresis in a Child with Posterior Fossa Syndrome
PEDIATRIC NEUROSURGERY
2012; 48 (1): 51-54
Abstract
Posterior fossa syndrome (PFS), also known as cerebellar affective syndrome, is characterized by emotional lability and decreased speech production following injury or surgery to the cerebellum. Rarely, oculomotor dysfunction has been described in association with PFS. Here, we report a case of complete ocular paresis associated with PFS in an 11-year-old male following medulloblastoma resection.
View details for DOI 10.1159/000339382
View details for Web of Science ID 000309885700010
View details for PubMedID 22906880
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CONCURRENT CYCLOPHOSPHAMIDE AND CRANIOSPINAL RADIATION IN PEDIATRIC EMBRYONAL BRAIN TUMORS
16th Annual Scientific Meeting of the Society-for-Neuro-Oncology (SNO)/AANS/CNS Section on Tumors
OXFORD UNIV PRESS INC. 2011: 100–100
View details for Web of Science ID 000297026600398
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ASL CEREBRAL PERFUSION DIFFERENCES BETWEEN HIGH-GRADE AND LOW-GRADE PEDIATRIC BRAIN TUMORS
16th Annual Scientific Meeting of the Society-for-Neuro-Oncology (SNO)/AANS/CNS Section on Tumors
OXFORD UNIV PRESS INC. 2011: 142–142
View details for Web of Science ID 000297026600558
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Birth Anomalies and Obstetric History as Risks for Childhood Tumors of the Central Nervous System
PEDIATRICS
2011; 128 (3): E652-E657
Abstract
The causes of childhood central nervous system (CNS) tumors are largely unknown. Birth characteristics have been examined as possible risk factors for childhood CNS tumors, although the studies have been underpowered and inconclusive. We hypothesized that birth anomalies and a mother's history of previous pregnancy losses, as a proxy for genetic defects, increase the risk for CNS tumors.From the California Cancer Registry, we identified 3733 patients aged 0 to 14 years with CNS tumors, diagnosed from 1988 through 2006 and linked to a California birth certificate. Four controls were matched to each patient. We calculated odds ratios (ORs) for the reported presence of a birth defect and for history of pregnancy losses by using logistic regression, adjusted for race, Hispanic ethnicity, maternal age, birth weight, and birth order.Offspring from mothers who had ≥ 2 fetal losses after 20 weeks' gestation had a threefold risk for CNS tumors (OR: 3.13 [95% confidence interval (CI): 1.32-7.41]) and a 14-fold risk for high-grade glioma (OR: 14.28 [95% CI: 1.56-130.65]). Birth defects increased risk for the CNS cancers medulloblastoma (OR: 1.70 [95% CI: 1.12-2.57]), primitive neuroectodermal tumor (OR: 3.64 [95% CI: 1.54-8.56]), and germ cell tumors (OR: 6.40 [95% CI: 2.09-19.56]).Multiple pregnancy losses after 20 weeks' gestation and birth defects increase the risk of a childhood CNS tumor. Previous pregnancy losses and birth defects may be surrogate markers for gene defects in developmental pathways that lead to CNS tumorigenesis.
View details for DOI 10.1542/peds.2010-3637
View details for Web of Science ID 000295406100022
View details for PubMedID 21824884
View details for PubMedCentralID PMC3164097
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Liposomal cytarabine for central nervous system embryonal tumors in children and young adults
JOURNAL OF NEURO-ONCOLOGY
2011; 103 (3): 561-566
Abstract
To assess the tolerability and efficacy of liposomal cytarabine (LC), an encapsulated, sustained-release, intrathecal (IT) formulation of cytosine arabinoside, in de novo and relapsed central nervous system (CNS) embryonal tumors in children and young adults. We studied retrospectively all patients less than age 30 at our institution treated consecutively with LC for medulloblastoma (MB), primitive neuroectodermal tumor (PNET), and atypical teratoid rhabdoid tumor (ATRT). Seventeen patients received LC (2 mg/kg up to 50 mg, every 2 weeks to monthly) at diagnosis of high-risk CNS embryonal tumor (2 PNET, 3 ATRT) or relapse of MB (12 MB; 9 had leptomeningeal metastases). Sixteen patients received concurrent systemic chemotherapy. A total of 108 doses were administered (IT 82, intraventricular 26) with a mean of six (range 1-16) treatments per patient. Only three administrations were associated with adverse effects of arachnoiditis or headache. None developed malignant cerebrospinal fluid (CSF) cytology while receiving LC. All the six evaluable patients with malignant CSF cytology and treated with at least two doses cleared their CSF (mean 3 doses, range 1-5). Median overall survival in relapse patients was 9.1 months. Five patients (4 de novo and 1 relapsed) remain alive in complete remission for a median 26.8 months from first LC. Liposomal cytarabine is an easily administered, well-tolerated, and active drug in patients with high-risk embryonal neoplasms. One-third of our cohort remains in remission from otherwise fatal diagnoses. Our findings warrant a phase II trial of LC in newly diagnosed or recurrent CNS embryonal tumors.
View details for DOI 10.1007/s11060-010-0419-y
View details for PubMedID 20859651
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Hedgehogs, Flies, Wnts and MYCs: The Time Has Come for Many Things in Medulloblastoma
JOURNAL OF CLINICAL ONCOLOGY
2011; 29 (11): 1395-1398
View details for DOI 10.1200/JCO.2010.34.0547
View details for Web of Science ID 000289276900016
View details for PubMedID 21357776
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Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2011; 108 (11): 4453-4458
Abstract
Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG self-renewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.
View details for DOI 10.1073/pnas.1101657108
View details for PubMedID 21368213
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Dorsolateral Midbrain MRI Abnormalities and Ocular Motor Deficits Following Cytarabine-Based Chemotherapy for Acute Myelogenous Leukemia
JOURNAL OF NEURO-OPHTHALMOLOGY
2011; 31 (1): 52-53
View details for DOI 10.1097/WNO.0b013e3181e91174
View details for Web of Science ID 000287238700013
View details for PubMedID 20881617
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Clinical Practice Guideline-Neurodiagnostic Evaluation of the Child With a Simple Febrile Seizure
PEDIATRICS
2011; 127 (2): 389-394
View details for DOI 10.1542/peds.2010-3318
View details for Web of Science ID 000286805200058
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A Phase II Study of Metronomic Oral Topotecan for Recurrent Childhood Brain Tumors
PEDIATRIC BLOOD & CANCER
2011; 56 (1): 39-44
Abstract
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.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.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.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.
View details for DOI 10.1002/pbc.22690
View details for Web of Science ID 000284790400008
View details for PubMedID 21108437
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Neurological complications following treatment of children with brain tumors.
Journal of pediatric rehabilitation medicine
2011; 4 (1): 31-36
Abstract
Brain tumors and their treatments in children result in a range of neurological complications that can affect daily function and rehabilitation potential, including neurocognitive sequelae, ototoxicity, seizure disorders, stroke, and peripheral neuropathy. Deficits in cognitive function, particularly learning and memory, attention and speed of information processing, can be debilitating. With new insights to the cellular and molecular etiology of these deficits, new therapies for cognitive decline after therapy are emerging. Management strategies for other neurological complications are also emerging.
View details for DOI 10.3233/PRM-2011-0150
View details for PubMedID 21757808
View details for PubMedCentralID PMC3612581
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Loss of SMARCB1/INI1 expression in poorly differentiated chordomas
ACTA NEUROPATHOLOGICA
2010; 120 (6): 745-753
Abstract
Chordomas are malignant neoplasms that typically arise in the axial spine and primarily affect adults. When chordomas arise in pediatric patients they are more likely to display unusual histological features and aggressive behavior. We noted the absence of SMARCB1/INI1 expression by immunohistochemistry in an index case of poorly differentiated chordoma of the sacrum, leading us to further examine SMARCB1/INI1 expression as well as that of brachyury, a highly specific marker of notochordal differentiation, in 3 additional poorly differentiated chordomas of the clivus, 10 typical chordomas, and 8 atypical teratoid/rhabdoid tumors (AT/RTs). All 4 poorly differentiated chordomas and all AT/RTs lacked nuclear expression of SMARCB1/INI1, while the 10 typical chordomas maintained strong nuclear SMARCB1/INI1 immunoreactivity. All 10 typical and 4 poorly differentiated chordomas expressed brachyury; all 8 AT/RTs were brachyury immunonegative. Cytogenetic evaluation utilizing FISH probes near the SMARCB1/INI1 locus on chromosome 22q was also performed in all of the poorly differentiated chordomas in this series. Three of the four poorly differentiated chordomas had evidence for deletion of this region by FISH. Analysis of the SMARCB1/INI1 gene sequence was performed using formalin-fixed paraffin-embedded tissue in all cases and no point mutations were observed. In summary, all poorly differentiated chordomas in this series showed the absence of SMARCB1/INI1 expression, and were reliably distinguished from AT/RTs, clinically by their characteristic primary sites of origin and pathologically by strong nuclear brachyury expression. Our findings reveal a likely role for SMARCB1/INI1 in a subset of chordomas with aggressive features.
View details for DOI 10.1007/s00401-010-0767-x
View details for PubMedID 21057957
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Birth Weight and Order as Risk Factors for Childhood Central Nervous System Tumors
JOURNAL OF PEDIATRICS
2010; 157 (3): 450-455
Abstract
To determine whether birth characteristics related to maternal-fetal health in utero are associated with the development of childhood central nervous system tumors.We identified, from the California Cancer Registry, 3733 children under age 15 diagnosed with childhood central nervous system tumors between 1988 and 2006 and linked these cases to their California birth certificates. Four controls per case, matched on birth date and sex, were randomly selected from the same birth files. We evaluated associations of multiple childhood CNS tumor subtypes with birth weight and birth order.Low birth weight was associated with a reduced risk of low-grade gliomas (OR=0.67; 95% CI, 0.46 to 0.97) and high birth weight was associated with increased risk of high-grade gliomas (OR=1.57; 95% CI, 1.16 to 2.12). High birth order (fourth or higher) was associated with decreased risk of low-grade gliomas (OR=0.75; 95% CI, 0.56 to 0.99) and increased risk of high-grade gliomas (OR=1.32; 95% CI, 1.01 to 1.72 for second order).Factors that drive growth in utero may increase the risk of low-grade gliomas. There may be a similar relationship in high-grade gliomas, although other factors, such as early infection, may modify this association. Additional investigation is warranted to validate and further define these findings.
View details for DOI 10.1016/j.jpeds.2010.04.006
View details for Web of Science ID 000281116100023
View details for PubMedID 20553692
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Intramedullary papillary ependymoma with choroid plexus differentiation and cerebrospinal fluid dissemination to the brain Case report
JOURNAL OF NEUROSURGERY-PEDIATRICS
2010; 5 (5): 511-517
Abstract
This 8-year-old girl presented with a papillary ependymoma in the thoracic spinal cord. Resection was followed by recurrence at the primary site and later in the lumbosacral thecal sac, followed by cerebrospinal fluid dissemination to the brain approximately 5 years after her initial presentation. The tumor showed cytological and immunohistochemical features overlapping those of classic ependymomas and choroid plexus tumors similar to those seen in uncommon supratentorial papillary ependymomas, also known as papillary tumors of the pineal region. The histopathological and clinical courses of this rare spinal papillary ependymoma exhibiting mixed ependymal and choroid plexus-like differentiation are discussed.
View details for DOI 10.3171/2009.12.PEDS09130
View details for Web of Science ID 000277131500016
View details for PubMedID 20433266
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50 Years Ago in THE JOURNAL OF PEDIATRICS A Critical Evaluation of Therapy of Febrile Seizures
JOURNAL OF PEDIATRICS
2010; 156 (3): 449-449
View details for DOI 10.1016/j.jpeds.2009.10.005
View details for Web of Science ID 000274863800027
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Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas
CANCER RESEARCH
2010; 70 (2): 512-519
Abstract
Malignant astrocytomas are a deadly solid tumor in children. Limited understanding of their underlying genetic basis has contributed to modest progress in developing more effective therapies. In an effort to identify such alterations, we performed a genome-wide search for DNA copy number aberrations (CNA) in a panel of 33 tumors encompassing grade 1 through grade 4 tumors. Genomic amplifications of 10-fold or greater were restricted to grade 3 and 4 astrocytomas and included the MDM4 (1q32), PDGFRA (4q12), MET (7q21), CMYC (8q24), PVT1 (8q24), WNT5B (12p13), and IGF1R (15q26) genes. Homozygous deletions of CDKN2A (9p21), PTEN (10q26), and TP53 (17p3.1) were evident among grade 2 to 4 tumors. BRAF gene rearrangements that were indicated in three tumors prompted the discovery of KIAA1549-BRAF fusion transcripts expressed in 10 of 10 grade 1 astrocytomas and in none of the grade 2 to 4 tumors. In contrast, an oncogenic missense BRAF mutation (BRAF(V600E)) was detected in 7 of 31 grade 2 to 4 tumors but in none of the grade 1 tumors. BRAF(V600E) mutation seems to define a subset of malignant astrocytomas in children, in which there is frequent concomitant homozygous deletion of CDKN2A (five of seven cases). Taken together, these findings highlight BRAF as a frequent mutation target in pediatric astrocytomas, with distinct types of BRAF alteration occurring in grade 1 versus grade 2 to 4 tumors.
View details for DOI 10.1158/0008-5472.CAN-09-1851
View details for Web of Science ID 000278485500011
View details for PubMedID 20068183
View details for PubMedCentralID PMC2851233
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Cerebrovascular disease in childhood cancer survivors A Children's Oncology Group Report
NEUROLOGY
2009; 73 (22): 1906-1913
Abstract
Curative therapy for childhood cancer has dramatically improved over past decades. Therapeutic radiation has been instrumental in this success. Unfortunately, irradiation is associated with untoward effects, including stroke and other cerebrovascular disease (CVD). The Children's Oncology Group (COG) has developed guidelines for screening survivors at risk for persistent or late sequelae of cancer therapy.This review summarizes the pathophysiology and relevant manifestations of radiation-induced CVD and outlines the specific patient groups at risk for early-onset stroke. The reader will be alerted to the availability of the COG recommendations for monitoring, and, when applicable, specific screening and treatment recommendations will be highlighted.A multidisciplinary task force critically reviewed the existing literature and scored the evidence to establish the current COG guidelines for monitoring health of survivors treated with head and neck irradiation.Previous head and neck exposure to therapeutic radiation is associated with latent CVD and increased risk for stroke in some patient groups. Common manifestations of radiation-induced CVD includes steno-occlusive disease, moyamoya, aneurysm, mineralizing microangiopathy, vascular malformations, and strokelike migraines.Risk for stroke is increased in survivors of pediatric CNS tumors, Hodgkin lymphoma, and acute lymphoblastic leukemia who received radiation to the brain and/or neck. As the population of survivors ages, vigilance for stroke and cerebrovascular disease needs to continue based on specific exposures during curative cancer therapy.
View details for DOI 10.1212/WNL.0b013e3181c17ea8
View details for Web of Science ID 000272205200015
View details for PubMedID 19812380
View details for PubMedCentralID PMC2788797
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Medulloblastoma Incidence has not Changed Over Time A CBTRUS Study
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
2009; 31 (12): 970-971
Abstract
Earlier studies have reported changes in the incidence of medulloblastoma (MB) but have conflicted, likely because of small sample size or misclassification of MB with primitive neuroectodermal tumor (PNET). The incidence of MB and PNET from 1985 to 2002 was determined from the Central Brain Tumor Registry of the United States, a large population-based cancer registry, using strict histologic and site codes. No statistically significant change in MB incidence was observed over the last 2 decades, but there was an increase in MB and PNET combined.
View details for Web of Science ID 000272658700019
View details for PubMedID 19887963
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Do children and adults differ in survival from medulloblastoma? A study from the SEER registry
JOURNAL OF NEURO-ONCOLOGY
2009; 95 (1): 81-85
Abstract
Studies investigating whether adults have diminished survival from medulloblastoma (MB) compared with children have yielded conflicting results. We sought to determine in a population-based registry whether adults and children with MB differ in survival, and to examine whether dissimilar use of chemotherapy might contribute to any disparity. 1,226 MB subjects were identified using the Surveillance Epidemiology and End Results (SEER-9) registry (1973-2002) and survival analysis performed. MB was defined strictly to exclude non-cerebellar primitive neuro-ectodermal tumors. Patients were stratified by age at diagnosis: <3 years (infants), 3-17 years (children) and >or=18 years (adults). Because the SEER-9 registry lacks treatment data, a subset of 142 patients were identified using the San Francisco-Oakland SEER registry (1988-2003) and additional analyses performed. There was no significant difference in survival between children and adults with MB in either the SEER-9 (P = 0.17) or SFO (P = 0.89) cohorts but infants fared worse compared to both children (P < 0.01) and adults (P < 0.01). In the SFO sample, children and adults who received chemotherapy plus radiation therapy (XRT) did not differ in survival. Among patients treated with XRT alone, children showed increased survival (P = 0.04) compared with adults. Children and adults with MB do not differ with respect to overall survival, yet infants fare significantly worse. For children and adults with MB treated with both XRT and chemotherapy, we could not demonstrate a survival difference. Similar outcomes between adult and childhood MB may justify inclusion of adults in pediatric cooperative trials for MB.
View details for DOI 10.1007/s11060-009-9894-4
View details for Web of Science ID 000269884600010
View details for PubMedID 19396401
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Incidence Patterns of Central Nervous System Germ Cell Tumors A SEER Study
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
2009; 31 (8): 541-544
Abstract
Incidence patterns of central nervous system (CNS) germ cell tumors (GCTs) have been reported, but the influence of underlying host risk factors has not been rigorously explored. We aimed to determine in a large, population-based cancer registry how age, sex, and race, influence the occurrence of CNS GCTs in the pediatric population.Using the Surveillance, Epidemiology, and End Results registry, we identified cases of histologically confirmed GCTs in children, adolescents, and young adults (age 0 to 29 y), diagnosed between 1973 and 2004. The cases were limited to only those with the International Classification of Childhood Cancer Xa: intracranial and intraspinal germ-cell tumors. Incidence rates (per 10,000) for each sex and race were plotted for single-age groups, and then stratified by tumor location and pathology subtype.The sample included a total of 638 cases (490 males). Males had significantly higher rates of CNS GCTs than females. Male and female rates diverged significantly starting at the age of 11 years and remained widely discrepant until the age of 30 years. There were more germinomas than nongerminomas in both sexes. Germinomas peaked in incidence during adolescence, whereas nongerminoma incidence remained relatively constant in children and young adults. Tumor location differed strikingly by sex (P<0.0001) with pineal location more common in males (61.0% vs. 15.5%). Asian race was associated with a higher rate of CNS GCTs than other races.Males have higher incidence of CNS GCTs, primarily germinomas, than females, starting in the second decade. Pineal location is strongly associated with male sex, with pineal germinomas representing over half of all CNS GCTs in males. Asian-Americans have higher rates than other races. These findings suggest a robust but poorly understood influence of sex, either genetic or hormonal, and race on the occurrence of CNS GCTs.
View details for Web of Science ID 000268815000003
View details for PubMedID 19636276
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Incidence patterns for ependymoma: a Surveillance, Epidemiology, and End Results study Clinical article
JOURNAL OF NEUROSURGERY
2009; 110 (4): 725-729
Abstract
Previous small studies disagree about which clinical risk factors influence ependymoma incidence. The authors analyzed a large, population-based cancer registry to examine the relationship of incidence to patient age, sex, race, and tumor location, and to determine incidence trends over the past 3 decades.Data were obtained from the Surveillance, Epidemiology, and End Results (SEER-9) study, which was conducted from 1973 to 2003. Histological codes were used to define ependymomas. Age-adjusted incidence rates were compared by confidence intervals in the SEER*Stat 6.2 program. Multiplicative Poisson regression and Joinpoint analysis were used to determine annual percentage change and to look for sharp changes in incidence, respectively.From the SEER database, 1402 patients were identified. The incidence rate per 100,000 person-years was significantly higher in male than in female patients (males 0.227 +/- 0.029, females 0.166 +/- 0.03). For children, the age at diagnosis differed significantly by tumor location, with the mean age for patients with infratentorial tumors calculated as 5 +/- 0.4 years; for supratentorial tumors it was 7.77 +/- 0.6 years, and for spinal lesions it was 12.16 +/- 0.8 years. (Values are expressed as the mean +/- standard error [SE].) Adults showed no difference in the mean age of incidence by location, although most tumors in this age group were spinal. Between 1973 and 2003, the incidence increased significantly among adults but not among children, and there were no sharp changes at any single year, both before and after age adjustment.Males have a higher incidence of ependymoma than do females. A biological explanation remains elusive. Ependymoma occurs within the CNS at distinct locations at different ages, consistent with hypotheses postulating distinct populations of radial glial stem cells within the CNS. Ependymoma incidence appears to have increased over the past 3 decades, but only in adults.
View details for DOI 10.3171/2008.9.JNS08117
View details for Web of Science ID 000264594300017
View details for PubMedID 19061350
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Levetiracetam For Seizures in Children With Brain Tumors and Other Cancers
PEDIATRIC BLOOD & CANCER
2009; 52 (2): 288-289
Abstract
Children with brain tumors and other cancers can suffer from seizures. Unfortunately, most antiepileptic therapies are metabolized by the hepatic cytochrome P450 (CYP) system. Levetiracetam, a newer anticonvulsant, does not undergo CYP metabolism and does not alter the pharmacokinetics of chemotherapy, antiemetics, and corticosteroids, which are metabolized by the liver. We studied 23 patients with cancer and seizures treated with levetiracetam. Over 95% of patients had fewer seizures, with 65.2% becoming seizure free; only one patient experienced an adverse reaction. Levetiracetam is effective and well tolerated in children with brain tumors and other cancers, who are often on multiple enzyme-inducing drugs.
View details for DOI 10.1002/pbc.21772
View details for Web of Science ID 000261796000032
View details for PubMedID 18831033
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Both Location and Age Predict Survival in Ependymoma: A SEER Study
PEDIATRIC BLOOD & CANCER
2009; 52 (1): 65-69
Abstract
Studies have suggested that supratentorial ependymomas have better survival than infratentorial tumors, with spinal tumors having the best prognosis, but these data have been based on small samples. Using a population-based registry of ependymomas, we analyzed how age, gender, location, race and radiotherapy influence survival in children.We queried the Surveillance Epidemiology End Results database (SEER-17) from 1973 to 2003, strictly defining ependymomas by histology. Site codes were used to distinguish between supratentorial, infratentorial, and spinal tumors when available. Outcomes were compared by location, age, gender, race and radiotherapy, using Kaplan-Meier analysis and logrank tests. Cox regression was completed, incorporating all significant covariates from univariate analysis.Six hundred thirty-five children were identified with an overall 5-year survival of 57.1 +/- standard error (SE) 2.3%. Increasing age was associated with improved survival (P < 0.0001). Five-year survival by location was 59.5 +/- SE 5.5% supratentorial, 57.1 +/- SE 4.1% infratentorial and 86.7 +/- SE 5.2% spinal. Radiotherapy of the infratentorial tumors resulted in significantly improved survival in both univariate analysis (logrank P < 0.018) and multivariate analysis restricted to this tumor location (P = 0.033). Using multivariate analysis that incorporated all tumor locations, age (P < 0.001) and location (P = 0.020) were significant predictors for survival.Age and location independently influence survival in ependymoma. Spinal tumors are associated with a significantly better prognosis than both supratentorial and infratentorial tumors, and may represent a distinct biological entity. Radiotherapy appears beneficial for survival in patients with infratentorial ependymoma.
View details for DOI 10.1002/pbc.21806
View details for Web of Science ID 000261300000016
View details for PubMedID 19006249
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Reproductive health issues in survivors of childhood and adult brain tumors.
Cancer treatment and research
2009; 150: 215-222
View details for DOI 10.1007/b109924_14
View details for PubMedID 19834671
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Neurological complications in children.
Cancer treatment and research
2009; 150: 133-143
View details for DOI 10.1007/b109924_9
View details for PubMedID 19834666
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Gender Affects Survival for Medulloblastoma Only in Older Children and Adults: A Study From the Surveillance Epidemiology and End Results Registry
PEDIATRIC BLOOD & CANCER
2009; 52 (1): 60-64
Abstract
Males have a higher incidence of medulloblastoma (MB) than females, but the effect of gender on survival is unclear. Studies have yielded conflicting results, possibly due to small sample sizes or differences in how researchers defined MB. We aimed to determine the effect of gender on survival in MB using a large data set and strict criteria for defining MB.A sample of 1,226 subjects (763 males and 463 females) was identified from 1973 to 2002, using the Surveillance Epidemiology and End Results (SEER-9) registry. MB was strictly defined to exclude non-cerebellar embryonal tumors (primitive neuro-ectodermal tumors). Because children <3 years of age are known to have worse survival, patients were stratified by age <3 years at diagnosis (95 males, 82 females) and >3 years (668 males, 381 females).Overall, there was no significant difference in survival between males and females (log rank P = 0.22). However, among subjects >3 years, females had significantly greater survival than males (log rank P = 0.02). In children <3 years, there was a non-significant trend toward poorer survival in females (median survival: males 27 months, females 13 months; log rank P = 0.24). This interaction between age group and gender was statistically significant (P = 0.03).Females with MB have a survival advantage only in subjects >3 years. In children <3 years, females may even have poorer outcome. The effect of gender on survival and incidence in MB warrants additional biologic investigation, and may differ in very young children with MB.
View details for DOI 10.1002/pbc.21832
View details for Web of Science ID 000261300000015
View details for PubMedID 19006250
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Outcome analysis of childhood low-grade astrocytomas
PEDIATRIC BLOOD & CANCER
2008; 51 (2): 245-250
Abstract
We aimed to determine the long-term natural history of low-grade astrocytomas (LGA) in children, with respect to pathology, and to evaluate influence of treatment on survival.A consecutive cohort of patients < or =21 years with surgically confirmed LGA from 1965 to 1996 was assembled. All available pathology specimens were reviewed, masked to original diagnosis, patient data, and neuroimaging.Two hundred seventy-eight children (160 males; mean age 9.1 years; tumor location: 77 cerebrum, 62 cerebellum, 51 hypothalamic, 30 thalamus, 9 ventricle, 40 brainstem, and 9 spine) were assessed. Among 246 specimens reviewed, diagnoses were 135 pilocytic astrocytoma (PA), 27 diffuse astrocytoma (DA), 75 unclassifiable well-differentiated astrocytoma (NOS), and 9 subependymal giant cell astrocytoma. At 5 and 10 years from initial surgery, for all LGA overall survival (OS) was 87% and 83%, while progression-free survival (PFS) was 55% and 42%, respectively. Original pathology diagnoses did not predict PFS (P = 0.47), but reviewed diagnoses were significantly associated with PFS (P = 0.007). Reviewed diagnoses were highly associated with OS (P < 0.0001), with 5-year OS for PA 96%, DA 48%, and NOS 86%; these differences remained significant when stratified by location or extent of resection. Among patients with residual tumor after surgery, 5-year PFS was 48% with observation alone (n = 114), no different (P = 0.32) from that achieved with immediate irradiation (n = 86).LGA, particularly PA, have excellent long-term OS. While tumor location and resection extent affect outcome, pathologic diagnosis when carefully interpreted significantly influences long-term survival. Immediate postoperative irradiation does not confer an advantage in delaying first progression in children with residual PA.
View details for DOI 10.1002/pbc.21563
View details for Web of Science ID 000256871800018
View details for PubMedID 18386785
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Identification of a novel p53 in-frame deletion in a Li-Fraumeni-like family
PEDIATRIC BLOOD & CANCER
2008; 50 (4): 914-916
Abstract
We describe a 2-year-old female with a completely resected cerebral pilocytic astrocytoma who subsequently developed B-progenitor acute lymphoblastic leukemia (ALL). Her father and paternal uncle were previously diagnosed with glioblastoma multiforme. Sequence analysis of the patient's p53 gene revealed a novel germline three base-pair deletion (339_341delCTT) in exon 4, resulting in removal of an evolutionarily conserved phenylalanine amino acid residue at codon 113. The same mutation was found in the patient's two clinically unaffected siblings. The in-frame deletion we describe has not previously been reported and adds to our understanding of the biologic effects of p53 gene mutation in Li-Fraumeni syndrome (LFS).
View details for DOI 10.1002/pbc.21247
View details for PubMedID 17554785
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Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas
CANCER
2008; 112 (5): 1139-1146
Abstract
The prognosis for patients with recurrent high-grade gliomas is poor and treatment options are limited. Current chemotherapeutic regimens can improve clinical outcomes, but extend survival by only a few months. Temozolomide is a methylating agent that is typically administered once daily. Because preclinical studies suggested that a twice-daily dosing schedule might be more effective, the safety and efficacy of twice-daily dosing of temozolomide were studied in patients with recurrent gliomas at their first, second, or third recurrence.This multi-institutional trial enrolled 120 patients with recurrent glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or anaplastic oligodendroglioma (AO). An initial oral dose of 200 mg/m(2) of temozolomide was followed by 9 consecutive doses of 90-mg/m(2) every 12 hours. Treatment cycles were repeated every 28 days. Doses were escalated to 100 mg/m(2) twice daily in the absence of unacceptable toxicity or were reduced if unacceptable toxicity occurred.For GBM, AA, and AO patients, respectively, the median progression-free survival (PFS) was 4.2 months, 5.8 months, and 7.7 months, whereas the median overall survival (OS) was 8.8 months, 14.6 months, and 18 months. The overall response rate (partial and complete) for the GBM, AA, and AO patients was 31%, 46%, and 46%, respectively. Grade 3/4 toxicities included neutropenia (1.1%), thrombocytopenia (3.6%), and anemia (0.3%) (graded according to the World Health Organization grading system).Twice-daily dosing may enhance the efficacy of temozolomide in the treatment of recurrent gliomas without increasing toxicity. This regimen compares favorably with other dosing schedules of temozolomide reported in the literature.
View details for DOI 10.1002/cncr.23167
View details for Web of Science ID 000253569100025
View details for PubMedID 18246536
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In cyclosporine-induced neurotoxicity, is tacrolimus an appropriate substitute or is it out of the frying pan and into the fire? Response
PEDIATRIC BLOOD & CANCER
2008; 50 (2): 427-427
View details for DOI 10.1002/pbc.21210
View details for Web of Science ID 000252006000062
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Treatment of children with diffuse intrinsic brain stem glioma with radiotherapy, vincristine and oral VP-16: A children's oncology group phase II study
PEDIATRIC BLOOD & CANCER
2008; 50 (2): 227-230
Abstract
The prognosis for children with brain stem glioma remains grim. Based on studies suggesting efficacy of vincristine and oral VP-16, The Pediatric Oncology Group (POG, now part of the Children's Oncology Group) conducted a study using these agents in combination with standard external beam radiation for children with newly diagnosed brain stem glioma.Children were eligible for the study if they 3-21 years of age, had MRI-evidence of a diffuse intrinsic pontine glioma, and had neurologic deficits of <6 months duration. Patients received local radiotherapy to a dosage of 54 Gy. Chemotherapy consisted of two 28-day cycles of vincristine, 1.5 mg/m(2), days 1, 8, and 15 and oral VP-16, 50 mg/m(2), days 1-21, starting concurrent with radiation, and continuing for ten cycles following radiation.Of the 31 children enrolled, 30 were eligible and evaluable for survival and toxicity. Their median age was 8 years (range 3-14 years). Seven patients (23%) had a partial response following radiation, 18 (60%) had stable disease, 2 (7%) had progressive disease, and response in 3 patients (10%) was not measured. All 30 children have died. Overall survival at 1 year was 27 +/- 7% and at 2 years, 3 +/- 2%. The median survival was 9 months (range 3-36 months). Hematologic toxicity was significant; other toxicities included constipation, mucositis, emesis, and infection.The addition of vincristine and oral VP-16 to standard external beam radiation causes moderate toxicity and does not improve survival of children with diffuse intrinsic brain stem glioma.
View details for DOI 10.1002/pbc.21154
View details for Web of Science ID 000252006000009
View details for PubMedID 17278121
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Congenital glioblastoma multiforme: Case report and review of the literature
PEDIATRIC NEUROSURGERY
2008; 44 (4): 304-312
Abstract
Congenital glioblastoma multiforme is a rare primary brain tumor that has a unique biology distinct from pediatric and adult variants. In this report, we present a case of congenital glioblastoma with complicated management course. A literature review of previously reported cases is included to illustrate the epidemiology and natural history of this disease. A 9-month-old male infant developed acute lethargy, hemiparesis and unilaterally dilated pupil. Imaging studies revealed a large hemispheric tumor, resulting in significant midline shift suggestive of impending herniation. Emergent tumor cystic fluid drainage was performed at initial presentation. A frontotemporoparietal craniotomy was performed on the following day to attempt a gross total resection. Adjuvant chemotherapy consisting of oral temozolomide was administered. The patient eventually succumbed 4 months later due to aggressive tumor progression. Congenital glioblastoma should be included in the differential diagnosis of infants with large intracranial tumors. Although surgical intervention may increase survival, the overall outcome remains poor despite maximal multimodal treatment.
View details for DOI 10.1159/000134922
View details for PubMedID 18504417
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Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium.
Cancer
2008; 113 (7 Suppl): 1953–68
Abstract
Epidemiologists in the Brain Tumor Epidemiology Consortium (BTEC) have prioritized areas for further research. Although many risk factors have been examined over the past several decades, there are few consistent findings, possibly because of small sample sizes in individual studies and differences between studies in patients, tumor types, and methods of classification. Individual studies generally have lacked samples of sufficient size to examine interactions. A major priority based on available evidence and technologies includes expanding research in genetics and molecular epidemiology of brain tumors. BTEC has taken an active role in promoting understudied groups, such as pediatric brain tumors; the etiology of rare glioma subtypes, such as oligodendroglioma; and meningioma, which, although it is not uncommon, has only recently been registered systematically in the United States. There also is a pressing need for more researchers, especially junior investigators, to study brain tumor epidemiology. However, relatively poor funding for brain tumor research has made it difficult to encourage careers in this area. In this report, BTEC epidemiologists reviewed the group's consensus on the current state of scientific findings, and they present a consensus on research priorities to identify which important areas the science should move to address.
View details for DOI 10.1002/cncr.23741
View details for PubMedID 18798534
View details for PubMedCentralID PMC2861559
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Verbal memory impairments in children after cerebellar tumor resection
BEHAVIOURAL NEUROLOGY
2008; 20 (1-2): 39-53
Abstract
This study was designed to investigate cerebellar lobular contributions to specific cognitive deficits observed after cerebellar tumor resection. Verbal working memory (VWM) tasks were administered to children following surgical resection of cerebellar pilocytic astrocytomas and age-matched controls. Anatomical MRI scans were used to quantify the extent of cerebellar lobular damage from each patient's resection. Patients exhibited significantly reduced digit span for auditory but not visual stimuli, relative to controls, and damage to left hemispheral lobule VIII was significantly correlated with this deficit. Patients also showed reduced effects of articulatory suppression and this was correlated with damage to the vermis and hemispheral lobule IV/V bilaterally. Phonological similarity and recency effects did not differ overall between patients and controls, but outlier patients with abnormal phonological similarity effects to either auditory or visual stimuli were found to have damage to hemispheral lobule VIII/VIIB on the left and right, respectively. We postulate that damage to left hemispheral lobule VIII may interfere with encoding of auditory stimuli into the phonological store. These data corroborate neuroimaging studies showing focal cerebellar activation during VWM paradigms, and thereby allow us to predict with greater accuracy which specific neurocognitive processes will be affected by a cerebellar tumor resection.
View details for DOI 10.3233/BEN-2008-0216
View details for PubMedID 19491473
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Family history of cancer among children with brain tumors - A critical review
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
2008; 30 (1): 8-14
Abstract
The occurrence of brain tumors in children has been anecdotally associated with an increased cancer incidence among relatives. This study rigorously reviewed the epidemiologic literature regarding family history of cancer in children with brain tumors. Six case-control and 10 cohort studies remained after applying stringent inclusion criteria. Most studies found no significant increase in cancer risk among relatives of childhood brain tumor patients. Those associations that were detected were often of borderline significance or demonstrated wide confidence intervals. There is limited evidence that a family history of cancer is more common among families of childhood brain tumor patients.
View details for Web of Science ID 000252486900003
View details for PubMedID 18176173
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Update on new treatments and developments in childhood brain tumors
CURRENT OPINION IN PEDIATRICS
2007; 19 (6): 670-674
Abstract
Childhood primary central nervous system tumors remain a therapeutic conundrum. As the second most common pediatric cancer, brain tumors lead to significantly worse survival and long-term effects compared with those seen with hematologic malignancies and other solid tumors. This review discusses current management strategies in three pediatric brain tumors, the long-term effects of therapy, as well as novel laboratory findings that may alter future treatment strategies.The current literature focuses on tactics to predict those at risk of treatment failure and long-term effects. By analyzing tumors at a molecular genetics level rather than traditional histology, new data have begun to emerge on methods to begin to consider targeted therapies, tailored to the individual child. Furthermore, as survivorship has improved with current radiation and chemotherapy regimens, long-term effects have been identified and merit clinical attention.Even though long-term survival for children with a brain tumor approaches 70%, the need for improved treatment regimens is striking. Secondary malignancies, neurocognitive deficits and treatment failure continue to afflict these children and young adults. The current review will inform clinicians of the challenges faced by basic scientists and clinicians when treating brain tumors, and point to future research directions.
View details for Web of Science ID 000251347800010
View details for PubMedID 18025934
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Impaired human hippocampal neurogenesis after treatment for central nervous system
ANNALS OF NEUROLOGY
2007; 62 (5): 515-520
Abstract
The effects of cancer treatments such as cranial radiation and chemotherapy on human hippocampal neurogenesis remain unknown. In this study, we examine neuropathological markers of neurogenesis and inflammation in the human hippocampus after treatment for acute myelogenous leukemia or medulloblastoma. We demonstrate a persistent radiation-induced microglial inflammation that is accompanied by nearly complete inhibition of neurogenesis after cancer treatment. These findings are consistent with preclinical animal studies and suggest potential therapeutic strategies.
View details for DOI 10.1002/ana.21214
View details for Web of Science ID 000251383300012
View details for PubMedID 17786983
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A syndrome of irreversible leukoencephalopathy following pediatric allogeneic bone marrow transplantation
PEDIATRIC BLOOD & CANCER
2007; 48 (2): 213-217
Abstract
Despite decreases in overall mortality following bone marrow transplantation (BMT), a number of complications such as neurotoxicity have been described and often associated with immunosuppressive agents. The syndrome of reversible posterior leukoencephalopathy has been described in patients receiving cyclosporin and FK-506. We report here a subset of children who developed a syndrome of previously undescribed irreversible leukoencephalopathy following allogeneic BMT.Between 1996 and 2002, 138 pediatric patients received an allogeneic BMT at Lucile Salter Packard Children's Hospital at Stanford. Six cases of irreversible leukoencephalopathy were observed. Cases were defined as children who exhibited progressive and continued, severe neurologic deterioration lasting greater than 2 weeks and consistent with non-localizing, central nervous system abnormalities. Medical records and magnetic resonance images (MRIs) were reviewed.Median age of the affected patients at BMT was 7.8 years. All six received cyclosporine, and [corrected] one had elevated drug levels. Encephalopathy occurred at a median of 53 days (range 14-77) following BMT. Symptoms at onset of leukoenceophalopathy included confusion and altered mental status, sluggish pupillary responses, abnormal movements, and seizures. Two patients died during their neurologic decline. Four patients remain alive with persistent encephalopathy. MRI showed abnormalities in all patients including periventricular or subcortical white matter involvement in all, and basal ganglia lesions in three.We report a syndrome of irreversible neurologic deficits and cerebral white matter abnormalities following allogeneic BMT, yet not associated with elevated cyclosporin levels. A precise mechanism for this syndrome is lacking and warrants further consideration.
View details for DOI 10.1002/pbc.20731
View details for Web of Science ID 000242875800016
View details for PubMedID 16365853
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Advances toward an understanding of brainstem gliomas
JOURNAL OF CLINICAL ONCOLOGY
2006; 24 (8): 1266-1272
Abstract
The diagnosis of brainstem glioma was long considered a single entity. However, since the advent of magnetic resonance imaging in the late 1980s, neoplasms within this anatomic region are now recognized to include several tumors of varying behavior and natural history. More recent reports of brainstem tumors include diverse sites such as the cervicomedullary junction, pons, midbrain, or the tectum. Today, these tumors are broadly categorized as either diffuse intrinsic gliomas, most often in the pons, or the nondiffuse brainstem tumors originating at the tectum, focally in the midbrain, dorsal and exophytic to the brainstem, or within the cervicomedullary junction. Although we briefly discuss the nondiffuse tumors, we focus specifically on those diffuse brainstem tumors that regrettably still carry a bleak prognosis.
View details for DOI 10.1200/JCO.2005.04.6599
View details for Web of Science ID 000236235700006
View details for PubMedID 16525181
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Etoposide, vincristine, and cyclosporin a with standard-dose radiation therapy in newly diagnosed diffuse intrinsic brainstem gliomas: A pediatric oncology group Phase I study
PEDIATRIC BLOOD & CANCER
2005; 45 (5): 644-648
Abstract
Brainstem gliomas (BSGs) are resistant to all therapy. Based on their imaging characteristics, we postulated that inhibition of P-glycoprotein (P-gp) associated with endothelial cells of the blood-brain barrier might enhance penetration of xenobiotic antineoplastics.Seven patients were enrolled in a Phase I study of etoposide, continuous infusion cyclosporine A given with and escalating doses of vincristine and concomitant standard-dose irradiation.Six patients were entered at the first level and one at the second. Closure of the study was mandated by dose-limiting neurotoxicity, consisting of seizures associated with white-matter changes, and alteration of consciousness with bulbar signs. One patient had tumor necrosis at 6 weeks, suggesting some tumor effect. Median survival for the group was 11 months, and for the patients who completed more than 1 month of therapy it was 11 months.This regimen proved excessively toxic.
View details for DOI 10.1002/pbc.20382
View details for Web of Science ID 000231623800004
View details for PubMedID 16110498
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Profile of daily life in children with brain tumors: An assessment of health-related quality of life
39th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO)
AMER SOC CLINICAL ONCOLOGY. 2005: 5493–5500
Abstract
The survival of children with CNS tumors approaches 70%, yet health-related quality of life (HRQOL) has not been investigated rigorously in this population. We aimed to show that universal assessment of HRQOL could be obtained easily by using the PedsQL 4.0 and to provide a composite profile of their daily lives.The PedsQL was administered to all patients seen in the neuro-oncology clinic at Lucile Packard Children's Hospital (Palo Alto, CA) from December 2001, to September 2002. Patients were compared with healthy controls by using two-sided t tests to evaluate statistically significant differences.One hundred thirty-four patients (73 male; mean age +/- standard deviation, 11.8 +/- 5.4 years; 55 had low-grade glioma, 32 had medulloblastoma/primitive neuroectodermal tumor/embryonal tumor, 17 had malignant astrocytoma, nine had germ-cell tumor, and 21 had other types of tumors) were assessed, each in less than 20 minutes. Scores on both child and parent-proxy reports for the total HRQOL, psychosocial, physical, emotional, social, and school-functioning scales were all significantly lower than controls (P < .01). Patients with low-grade glioma were reported to have the highest total HRQOL. Children receiving radiation therapy (XRT) but no chemotherapy had significantly lower total, psychosocial, emotional, and social functioning than those receiving other treatments, including XRT plus chemotherapy.The PedsQL can be used to assess HRQOL rapidly and easily in children with CNS tumors, who have significantly worse HRQOL than healthy children. Children receiving XRT fare worse overall; chemotherapy added to XRT does not seem to worsen HRQOL. Assessment of HRQOL should be included as an outcome in future clinical trials.
View details for DOI 10.1200/JCO.2005.10.190
View details for Web of Science ID 000231371700020
View details for PubMedID 16110009
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Malignant gliomas in 2005 - Where to GO from here?
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION
2005; 293 (5): 615-617
View details for Web of Science ID 000226694200026
View details for PubMedID 15687318
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Biologic risk stratification of medulloblastoma: The real time is now
JOURNAL OF CLINICAL ONCOLOGY
2004; 22 (6): 971-974
View details for DOI 10.1200/JCO.2004.12.939
View details for Web of Science ID 000220287900001
View details for PubMedID 14970187
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Cortical ependymoma - A case report and review
PEDIATRIC NEUROSURGERY
2003; 39 (1): 50-54
Abstract
The authors report a rare case of a cortical ependymoma in a 10-year-old boy. The patient presented with complex partial seizures and a well-circumscribed, right frontal cortical mass. Routine microscopy showed a glial tumor with diverse histologic features. Immunohistochemistry and electron microscopy were required to establish the definitive diagnosis of cortical ependymoma. Cortical-based pediatric brain tumors range from World Health Organization grade I to III lesions and require significantly different treatment and follow-up. This case illustrates the importance of establishing an accurate neuropathologic tissue diagnosis of all pediatric cortical tumors.
View details for DOI 10.1159/000070881
View details for Web of Science ID 000183529400012
View details for PubMedID 12784079
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Radiation therapy for intracranial germ cell tumors
43rd Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology
ELSEVIER SCIENCE INC. 2003: 511–18
Abstract
To review the combined experiences of University of California, San Francisco, and Stanford University Medical Center in the treatment of intracranial germ cell tumors (GCT) and to assess the impact of craniospinal radiation (CSI) on patterns of relapse, progression-free survival (PFS), and overall survival (OS).Ninety-three patients received radiation for newly diagnosed intracranial GCTs, including 49 germinomas, 16 nongerminomatous GCTs (NGGCT), and 28 with no biopsy. Median follow-up for surviving patients was 4.5 years (range 0.25-34). Tests for variables correlating with OS and PFS were conducted using Cox proportional hazards model.Five-year PFS and OS rates were 60% +/- 15% and 68% +/- 14% for patients with NGGCT and 88% +/- 5% and 93% +/- 4% for those with germinoma. Of 6 patients with localized NGGCT who did not receive CSI, 1 experienced an isolated spinal recurrence but was salvaged. Of 41 patients with localized germinoma, 6 who received CSI and 35 who did not, no isolated spinal cord relapses occurred. Twenty-one patients with localized germinoma received neither CSI nor whole brain radiation. Of these, none of 18 with ventricular radiation relapsed. One of 3 patients with primary tumor radiation relapsed intracranially but had only received 11 Gy at initial treatment. On multivariate analysis, germinoma histology but not CSI correlated with improved PFS and OS.CSI is not indicated in the treatment of localized germinomas. For patients with localized germinomas treated with radiation alone, we recommend ventricular irradiation followed by primary tumor boost to a total of 45-50 Gy.
View details for DOI 10.1016/S0360-3016(02)04611-4
View details for Web of Science ID 000182861500026
View details for PubMedID 12738328
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Intrathecal thiotepa: Reappraisal of an established therapy
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
2002; 24 (4): 274-278
Abstract
Intrathecal thiotepa is recommended as a treatment of leptomeningeal metastases (LM) in children, although published data to support this approach are limited. The authors sought to determine the efficacy of intrathecal thiotepa for pediatric LM.The authors reviewed all children treated with intrathecal thiotepa for LM at two tertiary children's hospitals, assessing outcome by cerebrospinal fluid cytology, neuroimaging, neurologic examination, and overall survival rate.Fifteen children with LM evidenced by malignant cells in the cerebrospinal fluid (mean age 7.3 years; five medulloblastoma, one anaplastic astrocytoma, one glioblastoma, one retinoblastoma, one neuroblastoma, two rhabdomyosarcoma, one non-Hodgkin lymphoma, two acute lymphoblastic leukemia, and one acute myelogenous leukemia) were treated with intrathecal thiotepa at 5 to 11.5 mg/m2 per dose for two to seven doses. Five children received concomitant craniospinal irradiation; 12 received simultaneous systemic or other intrathecal chemotherapy, or both. Four children experienced clearance of malignant cells from the spinal fluid, but this response was sustained in only two. All four children with cytologic response received concurrent radiotherapy, chemotherapy, or both. No patients showed partial or complete response on neuroimaging. Only one child had improvement on the neurologic examination; six were unchanged and eight had worsening neurologic signs. Median survival was 15.1 weeks, with a 1-year overall survival rate of 26.7% (standard error 11.4%).The unfavorable outcomes observed suggest that intrathecal thiotepa adds little to combination therapy for pediatric LM.
View details for Web of Science ID 000175481200009
View details for PubMedID 11972095
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Childhood cerebellar hemangioblastoma does not predict germline or somatic mutations in the von Hippel-Landau tumor suppressor gene
37th Annual Meeting of the American-Society-of-Clinical-Oncology
WILEY-LISS. 2002: 257–60
Abstract
Tumor suppressor gene "knockout" models would predict that children who present with hemangioblastoma are likely to harbor germline mutation of the von Hippel-Lindau gene. We screened 6 pediatric patients with cerebellar hemangioblastoma for germline or somatic mutations of the von Hippel-Lindau gene. Two had prior clinical manifestations of von Hippel-Lindau disease and, as expected, had germline von Hippel-Lindau gene mutations. Four children with solitary hemangioblastoma did not have a detectable germline deletion, rearrangement, or point mutation in their von Hippel-Lindau gene, and tumor specimens in 3 of these 4 showed no somatic von Hippel-Lindau allelic loss. Solitary cerebellar hemangioblastoma in children does not predict a germline or somatic mutation in the von Hippel-Lindau tumor suppressor gene. The tumorigenesis of hemangioblastoma in younger patients may differ from that in adults, and may involve a molecular process unrelated to the von Hippel-Lindau tumor suppressor pathway.
View details for DOI 10.1002/ana.10107
View details for Web of Science ID 000173636200017
View details for PubMedID 11835384
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Surveillance neuroimaging to detect relapse in childhood brain tumors: A pediatric oncology group study
JOURNAL OF CLINICAL ONCOLOGY
2001; 19 (21): 4135-4140
Abstract
To investigate the prognostic significance of surveillance neuroimaging for detection of relapse among children with malignant brain tumors.A historical cohort study examined all children who experienced relapse from 1985 to 1999 on one of 10 Pediatric Oncology Group trials for malignant glioma, medulloblastoma, or ependymoma.For all 291 patients (median age at diagnosis, 8.2 years), median time to first relapse was 8.8 months (range, 0.6 to 115.6 months). Ninety-nine relapses were radiographic, and 192, clinical; median time to relapse was 15.7 versus 6.6 months, respectively (P = .0001). When stratified by pathology, radiographic and clinical groups showed differences in median time to relapse for malignant glioma (7.8 v 4.3 months, respectively; P = .041) and medulloblastoma (23.6 v 8.9 months, respectively; P = .0006) but not ependymoma (19.5 v 13.3 months, respectively; P = .19). When stratified by early (< 8.8 months) or late (> or = 8.8 months) time to relapse, 115 early relapses were clinical, and 32, radiographic; for late relapses, 77 were clinical, and 67, radiographic (P = .001). Overall survival (OS) from relapse was significantly longer for radiographic compared with clinical detection (median, 10.8 months; 1-year OS, 46% v median, 5.5 months; 1-year OS, 33%; P = .002), but this trend did not retain significance when analyzed by pathology subgroups.Surveillance neuroimaging detects a proportion of asymptomatic relapses, particularly late relapses, and may provide lead time for other therapies on investigational trials. During the first year after diagnosis, radiographic detection of asymptomatic relapse was infrequent. A prospective study is needed to formulate a rational surveillance schedule based on the biologic behavior of these tumors.
View details for Web of Science ID 000171901100006
View details for PubMedID 11689581
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A guide to children with acute and chronic headaches.
Journal of pediatric health care
2001; 15 (5): 229-235
Abstract
Children with acute and chronic headaches are often seen by primary care providers. A complete, elaborate history, obtained from both the parents and child, is key in diagnosing and managing the child who presents with a headache. A thorough social and educational history may reveal significant school or family stresses. Historic features of concern must be explored immediately. A thorough physical examination with a focused neurologic examination must be done Focal neurologic findings may indicate serious organic problems. A comprehensive approach to the management of headaches in children consisting of reassurance, education, pharmacologic interventions, and nonpharmacologic interventions is presented. A two-tiered management plan is used in conjunction with medications. The aim of this article is to provide the novice or experienced practitioner with a comprehensive review of acute and chronic headache pathogenesis, assessment, and management. This review includes migraines and other nonmigraine types of headaches.
View details for PubMedID 11562640
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Weekly dosing of carboplatin increases risk of allergy in children
36th Annual Meeting of the American-Society-of-Clinical-Oncology
LIPPINCOTT WILLIAMS & WILKINS. 2001: 349–52
Abstract
Carboplatin (CBDCA) has been used increasingly to treat pediatric low-grade gliomas. Allergic reactions to CBDCA have been reported in 2% to 30% of children. The reason for this high incidence of allergy is unclear.To determine the risk factors for CBDCA allergy, an historic cohort study was conducted for all children who received the drug during a 6-year period at the Lucile Salter Packard Children's Hospital at Stanford. The patients' medical records were reviewed for data on age, tumor type, CBDCA dose schedule, total number of doses, cumulative dosage, dose per treatment, other chemotherapy administered, and allergic reaction.Fifty-four children (mean age 7.2 years, 35 boys) were identified. Six children (11.1%) had an allergic reaction to CBDCA. All reactors had low-grade gliomas treated with weekly CBDCA and vincristine, with a dosage per treatment <500 mg/m2. Overall, six (75%) of eight children administered weekly CBDCA, 6 (46.2%) of 13 children with brain tumors, and 6 (40%) of 15 administered CBDCA dosage <500 mg/m2 manifested allergic reactions. Patients receiving more than five doses had significant risk for CBDCA allergy (relative risk [RR] = 11.8; 95% confidence interval [CI]: 1.5-94.1). Using logistic regression with multiple variables, weekly dose schedule was the most predictive covariate for allergic reaction (P < 0.000 1), and other factors were unrelated or redundant.Children with low-grade gliomas receiving CBDCA weekly are at significantly increased risk for CBDCA allergy. The repetitive, weekly dosing schedule of CBDCA appears to be a key risk factor for allergic reaction in brain tumor patients. The high frequency of allergy with weekly CBDCA warrants further consideration when planning future trials.
View details for Web of Science ID 000170884300006
View details for PubMedID 11563768
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Rapid deterioration of a newborn with congenital spinal cord astrocytoma
MEDICAL AND PEDIATRIC ONCOLOGY
2001; 36 (4): 500-502
View details for Web of Science ID 000167593000013
View details for PubMedID 11260577
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Visual loss caused by pseudotumor cerebri in an infant on peritoneal dialysis
PEDIATRIC NEPHROLOGY
2001; 16 (3): 216-218
Abstract
Infants with chronic renal insufficiency have multiple risk factors for developing pseudotumor cerebri (PTC) and are at particular risk for being diagnosed with PTC late, because of their inability to express symptoms. We describe a 13-month-old infant dependent on peritoneal dialysis, without evidence of central nervous system infection or inflammation, who developed acute vision loss secondary to PTC. Signs of PTC in infants include torticollis, inattentiveness, inability to track, facial paresis, or new-onset strabismus. Physicians responsible for the care of children with renal failure should be aware of the potential for PTC, as the diagnosis should be made as early as possible to prevent permanent visual loss.
View details for Web of Science ID 000167661800003
View details for PubMedID 11322367
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Prognostic implications for gadolinium enhancement of the meninges in low-grade astrocytomas of childhood
PEDIATRIC NEUROSURGERY
2001; 34 (2): 88-93
Abstract
Persistent gadolinium enhancement on MRI of the meninges in some children with low-grade astrocytomas (LGA) is a widely recognized phenomenon. The relationship of this finding with the clinical course is unclear.From a consecutive cohort of 282 children with pathologically confirmed LGA we identified all patients with asymptomatic gadolinium enhancement of the meninges found on surveillance MRI. A nested case-control study was performed, comparing patients with meningeal enhancement to controls without enhancement.Twenty-one children were identified with meningeal enhancement. The median follow-up was 5.2 years with enhancement noted for a median of 2.2 years. The 5-year overall survival for this cohort was 91.2% (Greenwood SE 8.0%), and the 5-year progression-free survival was 20.9% (SE 11.9%). Five patients are now free of disease, while 15 continue to have stable disease. The overall and progression-free survival was not significantly different compared to controls.Gadolinium enhancement of the meninges on MRI may occur in a significant number of children with LGA, particularly juvenile pilocytic astrocytoma, but does not appear to affect progression-free or overall survival. Change in management based on this finding alone is unwarranted.
View details for Web of Science ID 000167991100005
View details for PubMedID 11287808
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Daily low-dose carboplatin as a radiation sensitizer for newly diagnosed malignant glioma
JOURNAL OF NEURO-ONCOLOGY
2001; 53 (1): 27-32
Abstract
Surgical resection followed by local field radiotherapy is currently our most effective approach to treatment for most patients with malignant glioma. Carboplatin chemotherapy has direct cytotoxic effects on glioma cells and acts as a radiation sensitizer to enhance cell killing. Its demonstrated efficacy as a sensitizer in other solid tumors led to this clinical trial of carboplatin as a radiation sensitizer in the treatment of newly diagnosed glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). Fourteen patients (nine GBM and five AA) were treated with daily low-dose carboplatin 25 mg/m2 intravenously within 2 h of their fractionated radiotherapy to a total dose of 600 mg/m2. No significant toxicities attributable to this combined therapy were observed. All patients have progressed, with median time to progression of 16 weeks. Eleven patients have died, with median survival of 38 weeks for the entire cohort. Although this regimen appeared safe, there was no benefit in survival time compared to historical patients treated with radiotherapy. The limitations and future potential for the strategy of radiation sensitization are discussed.
View details for Web of Science ID 000170979800004
View details for PubMedID 11678427
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A clinicopathologic reappraisal of brain stem tumor classification - Identification of pilocytic astrocytoma and fibrillary astrocytoma as distinct entities
CANCER
2000; 89 (7): 1569-1576
Abstract
Brain stem tumors in children have been classified pathologically as low grade or high grade gliomas and descriptively as diffuse gliomas, intrinsic gliomas, midbrain tumors, tectal gliomas, pencil gliomas, dorsal exophytic brain stem tumors, pontine gliomas, focal medullary tumors, cervicomedullary tumors, focal gliomas, or cystic gliomas.To search for a simplified and prognostic clinicopathologic scheme for brain stem tumors, the authors reviewed a consecutive cohort of patients younger than age 21 years with tumors diagnosed from 1980 through 1997. Pathology specimens and neuroimaging were classified by masked review. Statistical and survival analysis along with Cox proportional hazards regression was performed.Seventy-six patients were identified, with initial diagnostic magnetic resonance imaging available for 51 and pathology specimens for 48 patients. Twenty cases were classified histologically as pilocytic astrocytoma (PA), 14 as fibrillary astrocytoma (FA), and 14 as other tumors or indeterminate pathology. For all tumors, characteristics significantly associated with a worse survival rate were: symptom duration less than 6 months before diagnosis (P = 0.004); abducens palsy at presentation (P < 0.0001); pontine location (P = 0.0002); and engulfment of the basilar artery (P = 0.006). Pilocytic astrocytoma was associated with location outside the ventral pons (P = 0.001) and dorsal exophytic growth (P = 0.013); Fibrillary astrocytoma was associated with symptoms less than 6 months (P = 0. 006), abducens palsy (P < 0.001), and engulfment of the basilar artery (P = 0.002). Pilocytic astrocytoma showed 5-year overall survival (OS) of 95% (standard error [SE], 5%) compared with FA 1-year OS of 23% (SE, 11%;P < 0.0001).Brain stem tumors can be succinctly and better biologically classified as diffusely infiltrative brain stem gliomas-generally FA located in the ventral pons that present with abducens palsy, often engulf the basilar artery, and carry a grim prognosis-and focal brain stem gliomas-frequently PA arising outside the ventral pons, often with dorsal exophytic growth, a long clinical prodrome, and outstanding prognosis for survival. Our findings emphasize the individuality of PA as a distinct clinicopathologic entity with an exceptional prognosis.
View details for Web of Science ID 000089411300022
View details for PubMedID 11013373
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Management of children with metastatic spinal myxopapillary ependymoma using craniospinal irradiation
MEDICAL AND PEDIATRIC ONCOLOGY
2000; 35 (4): 443-445
View details for Web of Science ID 000089577700013
View details for PubMedID 11025481
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No responses to oral etoposide in 15 patients with recurrent brain tumors
35th Annual Meeting of the American-Society-of-Clinical-Oncology
WILEY-LISS. 2000: 80–82
View details for Web of Science ID 000087946900015
View details for PubMedID 10881014
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Meningeal leukemia with cerebrospinal fluid block
MEDICAL AND PEDIATRIC ONCOLOGY
2000; 34 (4): 281-283
View details for Web of Science ID 000086052800015
View details for PubMedID 10742072
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Case study: Suprasellar germinoma presenting with psychotic and obsessive-compulsive symptoms
JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY
2000; 39 (1): 116-119
Abstract
This case describes a 13-year-old boy who had a suprasellar germinoma involving the bilateral basal ganglia. His presenting symptoms included left-sided weakness, diabetes insipidus, a decline in academic functioning as well as psychotic and obsessive-compulsive symptoms. His neuroradiological findings and clinical symptoms lend support to the potential role of the basal ganglia in psychotic and obsessive-compulsive symptomatology.
View details for Web of Science ID 000084518400024
View details for PubMedID 10638075
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Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
1999; 58 (10): 1061-1068
Abstract
Among tumors classified as pilocytic astrocytoma (PA) in the Johns Hopkins Hospital Department of Pathology files, we identified 18 cases with a distinctive monomorphous pilomyxoid histological pattern and a higher recurrence rate than that of PA with classical histological features (classical PA). The majority of the tumors occurred in infants and young children and involved the hypothalamic/chiasmatic region. The tumors were histologically similar to PA, but they were more monomorphous and more myxoid. Rosenthal fibers were not seen and only 1 of 18 tumors had eosinophilic granular bodies. At the end of the follow-up period, 6 patients were dead and 12 were alive with evidence of disease. Progression free survival (PFS) at 1 year was 38.7%. In comparison, we identified a control group of 13 classical PAs in the same age range and location as the study group. In this group, PFS at 1 year was 69.2%, which was significantly better than that for pilomyxoid tumors (p = 0.04). There was no CSF dissemination or death due to tumor progression among patients with classical PA. Eight of these patients are alive with recurrent disease, and 4 have no evidence of disease. While the monomorphous pilomyxoid tumors have some resemblance to classical PA, our results suggest that the former is a more aggressive variant or a separate entity that needs to be recognized for prognostic purposes.
View details for Web of Science ID 000083076100004
View details for PubMedID 10515229
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Hyperfractionated radiotherapy in the management of diffuse intrinsic brainstem tumors: When is enough enough?
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS
1999; 43 (5): 947-949
View details for Web of Science ID 000079279100001
View details for PubMedID 10192338
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Outcomes and failure patterns in childhood craniopharyngiomas
8th International Symposium on Pediatric Neuro-oncology
SPRINGER. 1998: 558–63
Abstract
Past studies of craniopharyngiomas in children have shown overall survival (OS) up to 95% at 5 years and 80% progression-free survival (PFS) at 5 years, although many of these series predate modern neuroimaging and current therapeutic management. Moreover, little mention has been made of failure patterns for craniopharyngioma in children. To obtain a contemporary assessment of outcome among pediatric craniopharyngioma patients, and also to determine the failure patterns for this tumor, we completed a retrospective study of a consecutive cohort of all children with craniopharyngioma diagnosed at the Johns Hopkins Hospital from 1980 to 1996. Resection was performed in 30 children, in 8 of whom gross total resection (GTR) was achieved. Initial treatment took the form of GTR followed by observation for 8, subtotal resection (STR) plus observation in 11, and STR followed immediately by radiotherapy in 8. The timing of radiotherapy following STR was unclear for 3. OS was 95.2% (SE= 4.7%) at 5 years, with only 2 children dying after 4 years from diagnosis. Five-year PFS was 59.4% (SE=10.2%). Before surgery, 19 children had visual loss and 15, endocrine deficits; after surgery, 21 children had visual loss and 29, endocrine deficits. Median time to relapse was 0.98 years (SD=2.5 years). Radiographic (n=4) and clinical (n=7) relapses did not differ in time to progression (P=0.32), but radiographic relapses were significantly associated with age at diagnosis less than 5 years (P=0.02). Degree of resection was not significantly associated with PFS (P=0.32) or with postoperative visual or endocrine deficits. Absence of calcification on diagnostic neuroimaging (n=8) was significantly associated with improved PFS [5-year PFS 100% vs. 42.9% (SE=14.7%), P=0.02], even when adjusted for extent of resection (P=0.03). Preoperative visual loss was predictive of postoperative visual loss (P=0.03). Survival for children diagnosed with craniopharyngioma in the current era is outstanding, even with relapse, although postoperative visual and endocrinological morbidities are high. Failures occurred both radiographically and clinically, typically in the first 3-4 years after surgery, suggesting a need for close surveillance initially with neuroimaging, particularly in younger children, and also clinical examination. The short times to relapse observed here may stem from a tendency to delay radiotherapy until recurrence. Lack of calcification at diagnosis is associated with a tendency to remain free of relapse.
View details for Web of Science ID 000076744200006
View details for PubMedID 9840379
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Rethinking brain tumors in babies and more
ANNALS OF NEUROLOGY
1998; 44 (3): 300-302
View details for Web of Science ID 000075744700002
View details for PubMedID 9749594
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Lessons learned from the clinical cooperative trials groups for childhood brain tumors
NEUROSURGERY QUARTERLY
1998; 8 (3): 216-231
View details for Web of Science ID 000081492800006
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Salvage therapy after postoperative chemotherapy for primary brain tumors in infants and very young children
24th Annual Meeting of the Child-Neurology-Society
JOHN WILEY & SONS INC. 1998: 566–74
Abstract
A trend toward the use of prolonged postoperative chemotherapy, with radiotherapy deferred until relapse, has emerged for very young children with malignant brain tumors. This study was undertaken to determine the failure patterns among infants who receive such treatment and to evaluate their responses to first salvage therapy, particularly radiotherapy, after postoperative chemotherapy.A retrospective cohort was assembled, which comprised all children younger than 36 months with biopsy-proven malignant brain tumors diagnosed during the years 1987-1993 at 3 pediatric oncology referral centers. Fifty-eight children were treated with postoperative chemotherapy without irradiation, 40 of whom experienced relapse of their malignancy. These patients' charts were reviewed for failure patterns. Thirty-five of these children received salvage therapy. Statistical and survival analysis with the Cox proportional hazards regression model was performed.Among the 40 children who experienced relapse, 30 of 31 (97%) with solitary disease at initial diagnosis relapsed at the primary site of disease. Thirty-seven of 39 infants (95%) developed relapse that included their primary site of disease. Sixty percent of relapses were asymptomatic and were detected by magnetic resonance imaging (MRI) surveillance rather than by clinical examination. Two-year progression free survival (PFS) after relapse for infants who received salvage therapy was 29% (standard error [SE] = 8%). For infants who received radiotherapy alone, the 2-year PFS was 21% (SE = 9%). PFS did not differ according to whether relapses were detected clinically or radiographically or treated by radiotherapy, chemotherapy, surgery, or multimodal therapy.Relapse of brain tumors in infants after prolonged postoperative chemotherapy is largely a problem of local disease control. Salvage is possible after prolonged postoperative chemotherapy, but it yields few instances of long term, progression free survival. No therapeutic modality is superior for salvage at relapse. A strategy of reserving radiotherapy for the salvage of infants whose brain tumors relapse during postoperative chemotherapy demonstrated only limited effectiveness.
View details for Web of Science ID 000074982100027
View details for PubMedID 9690551
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Third ventricular choroid plexus papilloma with psychosis - Case report
JOURNAL OF NEUROSURGERY
1997; 87 (1): 103-105
Abstract
This 9-year-old boy with a history of behavioral problems and worsening psychosis responded initially to treatment with haloperidol. However, a magnetic resonance image obtained as part of his psychiatric evaluation revealed an anterior third ventricle tumor and mild-to-moderate hydrocephalus. The resected tumor was found on pathological examination to be a choroid plexus papilloma. The patient had an uneventful postoperative course and remained free of psychosis or mood disorder at 1-year follow-up examination.
View details for Web of Science ID A1997XF33100017
View details for PubMedID 9202274
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PARANEOPLASTIC OPSOCLONUS
NEUROLOGY
1995; 45 (7): 1421-1421
View details for Web of Science ID A1995RJ27900043
View details for PubMedID 7677891
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ANTI-HU ANTIBODY IN A NEUROBLASTOMA-ASSOCIATED PARANEOPLASTIC-SYNDROME
PEDIATRIC NEUROLOGY
1994; 10 (4): 309-312
Abstract
A 20-month-old infant with Turner syndrome presented with opsoclonus-myoclonus and tonic pupils in association with an abdominal neuroblastoma. Despite complete removal of the tumor, the child developed progressive hearing loss, areflexia, and seizures. Immunohistochemical and Western blot studies of serum and cerebrospinal fluid revealed the presence of anti-Hu antineuronal antibody, which cross-reacted with areas of the patient's tumor. Treatment with intravenous immunoglobulin coincided with the resolution of opsoclonus-myoclonus and the cessation of new neurologic symptoms. This case provides direct support for the autoimmune basis of paraneoplastic symptoms associated with neuroblastoma and suggests that treatment with intravenous immunoglobulin may be of value.
View details for Web of Science ID A1994NU41300007
View details for PubMedID 8068157