Paul Graham Fisher, MD

All Publications

• Molecular Grouping and Outcomes of Young Children with Newly Diagnosed Ependymoma Treated on the Multi-Institutional SJYC07 Trial. Neuro-oncology Upadhyaya, S. A., Robinson, G. W., Onar-Thomas, A., Orr, B. A., Billups, C. A., Bowers, D. C., Bendel, A. E., Hassall, T., Crawford, J. R., Partap, S., Fisher, P. G., Tatevossian, R. G., Seah, T., Qaddoumi, I. A., Vinitsky, A., Armstrong, G. T., Sabin, N. D., Tinkle, C. L., Klimo, P., Indelicato, D. J., Boop, F. A., Merchant, T. E., Ellison, D. W., Gajjar, A. 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 DOI 10.1093/neuonc/noz069

  View details for PubMedID 30976811

• Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review. American journal of medical genetics. Part A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. R., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Undiagnosed Diseases Network, Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. 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

• Developing a genomics rotation: Practical training around variant interpretation for genetic counseling students. Journal of genetic counseling Grove, M. E., White, S., Fisk, D. G., Rego, S., Dagan-Rosenfeld, O., Kohler, J. N., Reuter, C. M., Bonner, D., Wheeler, M. T., Bernstein, J. A., Ormond, K. E., Hanson-Kahn, A. K. 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 DOI 10.1002/jgc4.1094

  View details for PubMedID 30706981

• Who is prescribing opioids to children with headaches? The Journal of pediatrics Fisher, P. G. 2019; 204: 1

  View details for DOI 10.1016/j.jpeds.2018.11.010

  View details for PubMedID 30579460

• Migrant mothers and risks of developmental disabilities in their children. The Journal of pediatrics Fisher, P. G. 2019; 204: 2–3

  View details for DOI 10.1016/j.jpeds.2018.11.014

  View details for PubMedID 30579466

• Point-of-care EEG? The Journal of pediatrics Fisher, P. G. 2019; 207: 1

  View details for DOI 10.1016/j.jpeds.2019.02.010

  View details for PubMedID 30922486

• To sleep and dream without digital screens. The Journal of pediatrics Fisher, P. G. 2019; 205: 2

  View details for DOI 10.1016/j.jpeds.2018.12.017

  View details for PubMedID 30684978

• A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing. Journal of genetic counseling Zastrow, D. B., Kohler, J. N., Bonner, D., Reuter, C. M., Fernandez, L., Grove, M. E., Fisk, D. G., Yang, Y., Eng, C. M., Ward, P. A., Bick, D., Worthey, E. A., Fisher, P. G., Ashley, E. A., Bernstein, J. A., Wheeler, M. T. 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

• A Patient with Sjogren's Syndrome and Subsequent Diagnosis of Inclusion Body Myositis and Light-Chain Amyloidosis. Journal of general internal medicine Hom, J., Marwaha, S., Postolova, A., Kittle, J., Vasquez, R., Davidson, J., Kohler, J., Dries, A., Fernandez-Betancourt, L., Majcherska, M., Dearlove, J., Raghavan, S., Vogel, H., Bernstein, J. A., Fisher, P., Ashley, E., Sampson, J., Wheeler, M. 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

• Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes. American journal of human genetics Burrage, L. C., Reynolds, J. J., Baratang, N. V., Phillips, J. B., Wegner, J., McFarquhar, A., Higgs, M. R., Christiansen, A. E., Lanza, D. G., Seavitt, J. R., Jain, M., Li, X., Parry, D. A., Raman, V., Chitayat, D., Chinn, I. K., Bertuch, A. A., Karaviti, L., Schlesinger, A. E., Earl, D., Bamshad, M., Savarirayan, R., Doddapaneni, H., Muzny, D., Jhangiani, S. N., Eng, C. M., Gibbs, R. A., Bi, W., Emrick, L., Rosenfeld, J. A., Postlethwait, J., Westerfield, M., Dickinson, M. E., Beaudet, A. L., Ranza, E., Huber, C., Cormier-Daire, V., Shen, W., Mao, R., Heaney, J. D., Orange, J. S., Bertola, D., Yamamoto, G. L., Baratela, W. A., Butler, M. G., Ali, A., Adeli, M., Cohn, D. H., Krakow, D., Jackson, A. P., Lees, M., Offiah, A. C., Carlston, C. M., Carey, J. C., Stewart, G. S., Bacino, C. A., Campeau, P. M., Lee, B. 2019; 104 (3): 422–38

  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 PubMedID 30773277

• Have Zackery Lystedt concussion laws made an impact? The Journal of pediatrics Fisher, P. G. 2019; 206: 2–3

  View details for DOI 10.1016/j.jpeds.2019.01.019

  View details for PubMedID 30798822

• Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate-binding region. Epilepsia Kelly, M., Park, M., Mihalek, I., Rochtus, A., Gramm, M., Pérez-Palma, E., Axeen, E. T., Hung, C. Y., Olson, H., Swanson, L., Anselm, I., Briere, L. C., High, F. A., Sweetser, D. A., Kayani, S., Snyder, M., Calvert, S., Scheffer, I. E., Yang, E., Waugh, J. L., Lal, D., Bodamer, O., Poduri, A. 2019; 60 (3): 406–18

  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 PubMedID 30682224

• Brain Tumor Epidemiology - A Hub within Multidisciplinary Neuro-oncology. Report on the 15th Brain Tumor Epidemiology Consortium (BTEC) Annual Meeting, Vienna, 2014. Clinical neuropathology Woehrer, A., Lau, C. C., Prayer, D., Bauchet, L., Rosenfeld, M., Capper, D., Fisher, P. G., Kool, M., Müller, M., Kros, J. M., Kruchko, C., Wiemels, J., Wrensch, M., Danysh, H. E., Zouaoui, S., Heck, J. E., Johnson, K. J., Qi, X., O'Neill, B. P., Afzal, S., Scheurer, M. E., Bainbridge, M. N., Nousome, D., Bahassi, E. M., Hainfellner, J. A., Barnholtz-Sloan, J. S. ; 34 (1): 40–46

  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

• 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) Effinger, K. E., Stratton, K. L., Fisher, P. G., Ness, K. K., Krull, K. R., Oeffinger, K. C., Armstrong, G. T., Robison, L. L., Hudson, M. M., Leisenring, W. M., Nathan, P. C. 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

• 50 Years Ago in The Journal of Pediatrics: Significance of Leukemia Clusters. The Journal of pediatrics Fisher, P. G. 2018; 198: 130

  View details for DOI 10.1016/j.jpeds.2018.01.021

  View details for PubMedID 29936957

• Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial LANCET ONCOLOGY Robinson, G. W., Rudneva, V. A., Buchhalter, I., Billups, C. A., Waszak, S. M., Smith, K. S., Bowers, D. C., Bendel, A., Fisher, P. G., Partap, S., Crawford, J. R., Hassall, T., Indelicato, D. J., Boop, F., Klimo, P., Sabin, N. D., Patay, Z., Merchant, T. E., Stewart, C. F., Orr, B. A., Korbel, J. O., Jones, D. W., Sharma, T., Lichter, P., Kool, M., Korshunov, A., Pfister, S. M., Gilbertson, R. J., Sanders, R. P., Onar-Thomas, A., Ellison, D. W., Gajjar, A., Northcott, P. A. 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

• THE MOLECULAR AND CLINICAL LANDSCAPE OF INFANT MEDULLOBLASTOMA (IMB): RESULTS AND MOLECULAR ANALYSIS FROM A PROSPECTIVE, MULTICENTER PHASE II TRIAL (SJYC07) Robinson, G. W., Rudneva, V. A., Buchhalter, I., Billups, C. A., Waszak, S. M., Smith, K., Bowers, D. C., Bendel, A., Fisher, P., Partap, S., Crawford, J., Hassall, T., Indelicato, D. J., Boop, F., Klimo, P., Sabin, N. D., Patay, Z., Merchant, T. E., Stewart, C. F., Orr, B. A., Korbel, J. O., Jones, D. W., Sharma, T., Lichter, P., Kool, M., Korshunov, A., Pfister, S. M., Gilbertson, R. J., Sanders, R. P., Onar-Thomas, A., Ellison, D. W., Gajjar, A., Northcott, P. A. OXFORD UNIV PRESS INC. 2018: 126–27

  View details for Web of Science ID 000438339000442

• CHARACTERISTICS OF PATIENTS >= 10 YEARS OF AGE WITH DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY Erker, C., Lane, A., Chaney, B., Escorza, N., Fuller, C., Saab, R., Kieran, M., Packer, R., Nazarian, J., Minturn, J., Dodgshun, A., Parkin, S., Foreman, N., Broxson, E., Lombardi, M., Goldman, S., Sandler, E., Warren, K., Greiner, R., Gottardo, N., Dholaria, H., Shih, C., Hassall, T., Hansford, J. R., Wang, S., Samson, Y., Leary, S., Ma, J., Bartels, U., Broniscer, A., Monje, M., Fisher, P., Ziegler, D., Wagner, L., Koschmann, C., Doughman, R., Drissi, R., Jones, B., Leach, J., White, P., Dexheimer, P., Hendershot, J., Hawkins, C., Bandopadhayay, P., Fouladi, M. OXFORD UNIV PRESS INC. 2018: 63

  View details for Web of Science ID 000438339000164

• INTRACRANIAL GROWING TERATOMA SYNDROME (IGTS): AN INTERNATIONAL RETROSPECTIVE STUDY Michaiel, G., Strother, D., Gottardo, N., Bartels, U., Coltin, H., Eisenstat, D. D., Hukin, J., Johnston, D. L., Wilson, B., Zelcer, S., Hansford, J. R., Wells, O., Abdelbaki, M. S., Abu-Arja, M. H., Cole, K. A., Dhall, G., Fisher, P. G., Hoffman, L., Leary, S. S., Pickle, E., Smiley, N. P., Smith, A., Vinitsky, A., Vitanza, N. A., Wright, A., Yeo, K. K., Chow, L. L., Kirby, M., Valvi, S., Vanan, M. I., Wong, G., Ziegler, D., Bouffet, E., Lafay-Cousin, L. OXFORD UNIV PRESS INC. 2018: 88

  View details for Web of Science ID 000438339000272

• RECLASSIFICATION OF CENTRAL NERVOUS SYSTEM PRIMITIVE NEUROECTODERMAL TUMOR (CNS-PNET) INTO ENTITIES REFLECTS OUTCOME: RESULTS FROM THE PROSPECTIVE SJYC07 AND SJMB03 TRIALS Liu, A., Orr, B., Lin, T., Hassall, T., Bowers, D. C., Bouffet, E., Gururangan, S., Fisher, P., Crawford, J., Kellie, S. J., Chintagumpala, M., Fisher, M., Bendel, A., Ellison, D., Robinson, G., Gajjar, A. OXFORD UNIV PRESS INC. 2018: 71–72

  View details for Web of Science ID 000438339000200

• CLINICAL, RADIOLOGICAL, PATHOLOGICAL AND MOLECULAR CHARACTERISTICS OF CHILDREN < 3 YEARS WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG): A REPORT FROM THE INTERNATIONAL DIPG REGISTRY Bartlett, A., Cochrane, A., Lane, A., Yanez-Escorza, N., Chaney, B., Doughman, R., DeWire-Schottmiller, M., Goldman, S., Warren, K., Bandopadhayay, P., Foreman, N., Shih, C., Minturn, J., Bartels, U., Packer, R., Nazarian, J., Hassall, T., Samson, Y., Monje-Deisseroth, M., Fisher, P., Wagner, L., Koschmann, C., Ziegler, D., Kieran, M., Hawkins, C., White, P., Dexheimer, P., Hendershot, J., Drissi, R., Fuller, C., Leach, J., Jones, B., Fouladi, M. OXFORD UNIV PRESS INC. 2018: 63

  View details for Web of Science ID 000438339000165

• Pediatric neuro-oncology survival disparities in California JOURNAL OF NEURO-ONCOLOGY Cooney, T., Fisher, P. G., Tao, L., Clarke, C. A., Partap, S. 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 DOI 10.1007/s11060-018-2773-0

  View details for Web of Science ID 000431211800009

  View details for PubMedID 29417400

• It's Time for Pediatric Oncology to Grow Up. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Fisher, P. G. 2018; 36 (10): 933–34

  View details for DOI 10.1200/JCO.2017.77.4307

  View details for PubMedID 29425070

• Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder AMERICAN JOURNAL OF HUMAN GENETICS Olahova, M., Yoon, W., Thompson, K., Jangam, S., Fernandez, L., Davidson, J. M., Kyle, J. E., Grove, M. E., Fisk, D. G., Kohler, J. N., Holmes, M., Dries, A. M., Huang, Y., Zhao, C., Contrepois, K., Zappala, Z., Fresard, L., Waggott, D., Zink, E. M., Kim, Y., Heyman, H. M., Stratton, K. G., Webb-Robertson, B. M., Snyder, M., Merker, J. D., Montgomery, S. B., Fisher, P. G., Feichtinger, R. G., Mayr, J. A., Hall, J., Barbosa, I. A., Simpson, M. A., Deshpande, C., Waters, K. M., Koeller, D. M., Metz, T. O., Morris, A. A., Schelley, S., Cowan, T., Friederich, M. W., McFarland, R., Van Hove, J. K., Enns, G. M., Yamamoto, S., Ashley, E. A., Wangler, M. F., Taylor, R. W., Bellen, H. J., Bernstein, J. A., Wheeler, M. T., Undiagnosed Diseases Network 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

• A New Approach to Rare Diseases of Children: The Undiagnosed Diseases Network. The Journal of pediatrics Reuter, C. M., Brimble, E., DeFilippo, C., Dries, A. M., Enns, G. M., Ashley, E. A., Bernstein, J. A., Fisher, P. G., Wheeler, M. T. 2018

  View details for PubMedID 29331327

• 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 Pena, L. D., Jiang, Y. H., Schoch, K., Spillmann, R. C., Walley, N., Stong, N., Rapisardo Horn, S., Sullivan, J. A., McConkie-Rosell, A., Kansagra, S., Smith, E. C., El-Dairi, M., Bellet, J., Keels, M. A., Jasien, J., Kranz, P. G., Noel, R., Nagaraj, S. K., Lark, R. K., Wechsler, D. S., Del Gaudio, D., Leung, M. L., Hendon, L. G., Parker, C. C., Jones, K. L., Goldstein, D. B., Shashi, V. 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

• Surgical outcomes of pediatric spinal cord astrocytomas: systematic review and meta-analysis. Journal of neurosurgery. Pediatrics Azad, T. D., Pendharkar, A. V., Pan, J., Huang, Y., Li, A., Esparza, R., Mehta, S., Connolly, I. D., Veeravagu, A., Campen, C. J., Cheshier, S. H., Edwards, M. S., Fisher, P. G., Grant, G. A. 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 DOI 10.3171/2018.4.PEDS17587

  View details for PubMedID 30028275

• Congenital heart disease complexity and childhood cancer risk. Birth defects research Collins, R. T., Von Behren, J., Yang, W., Carmichael, S. L., Reynolds, P., Fisher, P. G., Shaw, G. M. 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 DOI 10.1002/bdr2.1390

  View details for PubMedID 30328285

• Characteristics of undiagnosed diseases network applicants: implications for referring providers. BMC health services research Walley, N. M., Pena, L. D., Hooper, S. R., Cope, H., Jiang, Y. H., McConkie-Rosell, A., Sanders, C., Schoch, K., Spillmann, R. C., Strong, K., McCray, A. T., Mazur, P., Esteves, C., LeBlanc, K., Wise, A. L., Shashi, V. 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

• Born too early for friends? The Journal of pediatrics Fisher, P. G. 2018; 193: 2–3

  View details for DOI 10.1016/j.jpeds.2017.12.005

  View details for PubMedID 29389446

• Fertile ground for education on fertility preservation. The Journal of pediatrics Fisher, P. G. 2018; 194: 1–2

  View details for DOI 10.1016/j.jpeds.2018.01.003

  View details for PubMedID 29478489

• In search of biomarkers for HIE. The Journal of pediatrics Fisher, P. G. 2018; 194: 3

  View details for DOI 10.1016/j.jpeds.2018.01.007

  View details for PubMedID 29478505

• Cystic periventricular leukomalacia: now you see it, now you don't? The Journal of pediatrics Fisher, P. G. 2018; 195: 2–3

  View details for DOI 10.1016/j.jpeds.2018.02.017

  View details for PubMedID 29576177

• Increased prescription drug use immediately after childhood cancer. The Journal of pediatrics Fisher, P. G. 2018; 195: 4

  View details for DOI 10.1016/j.jpeds.2018.02.020

  View details for PubMedID 29576181

• Does fat or fat-free body mass drive neurodevelopment? The Journal of pediatrics Fisher, P. G. 2018; 196: 2

  View details for DOI 10.1016/j.jpeds.2018.03.021

  View details for PubMedID 29703358

• Do race and socioeconomic status influence counseling at periviabilty? The Journal of pediatrics Fisher, P. G. 2018; 197: 2

  View details for DOI 10.1016/j.jpeds.2018.04.015

  View details for PubMedID 29801538

• Asymmetric tonsils or tonsillar cancer? The Journal of pediatrics Fisher, P. G. 2018; 197: 3–4

  View details for DOI 10.1016/j.jpeds.2018.04.018

  View details for PubMedID 29801542

• 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 Shashi, V., Schoch, K., Spillmann, R., Cope, H., Tan, Q. K., Walley, N., Pena, L., McConkie-Rosell, A., Jiang, Y. H., Stong, N., Need, A. C., Goldstein, D. B. 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

• 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 Tan, Q. K., Cope, H., Spillmann, R. C., Stong, N., Jiang, Y. H., McDonald, M. T., Rothman, J. A., Butler, M. W., Frush, D. P., Lachman, R. S., Lee, B., Bacino, C. A., Bonner, M. J., McCall, C. M., Pendse, A. A., Walley, N., Shashi, V., Pena, L. D. 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 PubMedID 29970384

• Confused about what tests to order for altered mental status? The Journal of pediatrics Fisher, P. G. 2018; 200: 2–3

  View details for DOI 10.1016/j.jpeds.2018.07.052

  View details for PubMedID 30144919

• Complementary medicines are not always complimentary in Down syndrome. The Journal of pediatrics Fisher, P. G. 2018; 201: 2

  View details for DOI 10.1016/j.jpeds.2018.07.105

  View details for PubMedID 30244727

• Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. The New England journal of medicine Splinter, K., Adams, D. R., Bacino, C. A., Bellen, H. J., Bernstein, J. A., Cheatle-Jarvela, A. M., Eng, C. M., Esteves, C., Gahl, W. A., Hamid, R., Jacob, H. J., Kikani, B., Koeller, D. M., Kohane, I. S., Lee, B. H., Loscalzo, J., Luo, X., McCray, A. T., Metz, T. O., Mulvihill, J. J., Nelson, S. F., Palmer, C. G., Phillips, J. A., Pick, L., Postlethwait, J. H., Reuter, C., Shashi, V., Sweetser, D. A., Tifft, C. J., Walley, N. M., Wangler, M. F., Westerfield, M., Wheeler, M. T., Wise, A. L., Worthey, E. A., Yamamoto, S., Ashley, E. A. 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

• Long-term outcomes of primarily metastatic juvenile pilocytic astrocytoma in children JOURNAL OF NEUROSURGERY-PEDIATRICS Yecies, D., Fisher, P., Cheshier, S., Edwards, M., Grant, G. 2018; 21 (1): 49–53

  View details for DOI 10.3171/2017.7.PEDS17168

  View details for Web of Science ID 000418908800011

• MR Imaging-Based Radiomic Signatures of Distinct Molecular Subgroups of Medulloblastoma. AJNR. American journal of neuroradiology Iv, M., Zhou, M., Shpanskaya, K., Perreault, S., Wang, Z., Tranvinh, E., Lanzman, B., Vajapeyam, S., Vitanza, N. A., Fisher, P. G., Cho, Y. J., Laughlin, S., Ramaswamy, V., Taylor, M. D., Cheshier, S. H., Grant, G. A., Young Poussaint, T., Gevaert, O., Yeom, K. W. 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 PubMedID 30523141

• 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 Gholamin, S., Mitra, S. S., Feroze, A. H., Liu, J., Kahn, S. A., Zhang, M., Esparza, R., Richard, C., Ramaswamy, V., Remke, M., Volkmer, A. K., Willingham, S., Ponnuswami, A., McCarty, A., Lovelace, P., Storm, T. A., Schubert, S., Hutter, G., Narayanan, C., Chu, P., Raabe, E. H., Harsh, G., Taylor, M. D., Monje, M., Cho, Y., Majeti, R., Volkmer, J. P., Fisher, P. G., Grant, G., Steinberg, G. K., Vogel, H., Edwards, M., Weissman, I. L., Cheshier, S. H. 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

• Brain Perfusion and Diffusion Abnormalities in Children Treated for Posterior Fossa Brain Tumors. journal of pediatrics Li, M. D., Forkert, N. D., Kundu, P., Ambler, C., Lober, R. M., Burns, T. C., Barnes, P. D., Gibbs, I. C., Grant, G. A., Fisher, P. G., Cheshier, S. H., Campen, C. J., Monje, M., Yeom, K. W. 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

• The Undiagnosed Diseases Network: Accelerating Discovery about Health and Disease AMERICAN JOURNAL OF HUMAN GENETICS Ramoni, R. B., Mulvihill, J. J., Adams, D. R., Allard, P., Ashley, E. A., Bernstein, J. A., Gahl, W. A., Hamid, R., Loscalzo, J., McCray, A. T., Shashi, V., Tifft, C. J., Wise, A. L. 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

• R-SCAN: Imaging for Pediatric Minor Head Trauma. Journal of the American College of Radiology Lee, S., Grant, G. A., Fisher, P. G., Imler, D., Padrez, R., Avery, C., Sharp, A. L., Wintermark, M. 2017; 14 (2): 294-297

  View details for DOI 10.1016/j.jacr.2016.10.006

  View details for PubMedID 28017272

• Child Neurology Residency-Finding the Right Fit. Pediatric neurology Santoro, J. D., Fisher, P. G. 2017; 67: 3-6

  View details for DOI 10.1016/j.pediatrneurol.2016.10.011

  View details for PubMedID 27908656

• Advancing the ball or holding the line in concussion? The Journal of pediatrics Fisher, P. G. 2017; 184: 1

  View details for DOI 10.1016/j.jpeds.2017.03.010

  View details for PubMedID 28434562

• Does macrocephaly require MRI, CT, ultrasound, or a tape measure? The Journal of pediatrics Fisher, P. G. 2017; 182: 5

  View details for DOI 10.1016/j.jpeds.2017.01.011

  View details for PubMedID 28237457

• in a patient with a complex connective tissue phenotype. Cold Spring Harbor molecular case studies Zastrow, D. B., Zornio, P. A., Dries, A., Kohler, J., Fernandez, L., Waggott, D., Walkiewicz, M., Eng, C. M., Manning, M. A., Farrelly, E., Fisher, P. G., Ashley, E. A., Bernstein, J. A., Wheeler, M. T. 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

• A Recurrent De Novo Variant in NACC1 Causes a Syndrome Characterized by Infantile Epilepsy, Cataracts, and Profound Developmental Delay. American journal of human genetics Schoch, K., Meng, L., Szelinger, S., Bearden, D. R., Stray-Pedersen, A., Busk, O. L., Stong, N., Liston, E., Cohn, R. D., Scaglia, F., Rosenfeld, J. A., Tarpinian, J., Skraban, C. M., Deardorff, M. A., Friedman, J. N., Akdemir, Z. C., Walley, N., Mikati, M. A., Kranz, P. G., Jasien, J., McConkie-Rosell, A., McDonald, M., Wechsler, S. B., Freemark, M., Kansagra, S., Freedman, S., Bali, D., Millan, F., Bale, S., Nelson, S. F., Lee, H., Dorrani, N., Goldstein, D. B., Xiao, R., Yang, Y., Posey, J. E., Martinez-Agosto, J. A., Lupski, J. R., Wangler, M. F., Shashi, V. 2017; 100 (2): 343–51

  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 PubMedID 28132692

• Talk with and not around the child. The Journal of pediatrics Fisher, P. G. 2017; 182: 2

  View details for DOI 10.1016/j.jpeds.2017.01.004

  View details for PubMedID 28237447

• An Investigation of Connections between Birth Defects and Cancers Arising in Adolescence and Very Young Adulthood. The Journal of pediatrics Von Behren, J., Fisher, P. G., Carmichael, S. L., Shaw, G. M., Reynolds, P. 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

• Getting Published: A Primer on Manuscript Writing and the Editorial Process. The Journal of pediatrics Fisher, P. G., Goodman, D. M., Long, S. S. 2017; 185: 241–44

  View details for PubMedID 28341526

• 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 Fisher, P. G. 2017; 184: 44

  View details for DOI 10.1016/j.jpeds.2016.12.004

  View details for PubMedID 28434578

• MARRVEL: Integration of Human and Model Organism Genetic Resources to Facilitate Functional Annotation of the Human Genome. American journal of human genetics Wang, J., Al-Ouran, R., Hu, Y., Kim, S. Y., Wan, Y. W., Wangler, M. F., Yamamoto, S., Chao, H. T., Comjean, A., Mohr, S. E., Perrimon, N., Liu, Z., Bellen, H. J. 2017; 100 (6): 843–53

  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 PubMedID 28502612

• The next generation is here now. The Journal of pediatrics Fisher, P. G. 2017; 185: 1–2

  View details for DOI 10.1016/j.jpeds.2017.04.012

  View details for PubMedID 28746034

• How mild is the outcome of mild neonatal encephalopathy? The Journal of pediatrics Fisher, P. G. 2017; 187: 2–3

  View details for DOI 10.1016/j.jpeds.2017.06.026

  View details for PubMedID 28750760

• Remember to play and play to remember. The Journal of pediatrics Fisher, P. G. 2017; 188: 1

  View details for DOI 10.1016/j.jpeds.2017.07.019

  View details for PubMedID 28843299

• Do you know what SUDEP is? The Journal of pediatrics Fisher, P. G. 2017; 188: 2

  View details for DOI 10.1016/j.jpeds.2017.07.022

  View details for PubMedID 28843305

• Speak to me in English, Spanish, or both? The Journal of pediatrics Fisher, P. G. 2017; 190: 1

  View details for DOI 10.1016/j.jpeds.2017.09.029

  View details for PubMedID 29144235

• Please diagnose infantile spasm early! The Journal of pediatrics Fisher, P. G. 2017; 190: 3

  View details for DOI 10.1016/j.jpeds.2017.09.033

  View details for PubMedID 29144264

• Put down that smartphone and read to me! The Journal of pediatrics Fisher, P. G. 2017; 191: 1–2

  View details for DOI 10.1016/j.jpeds.2017.10.020

  View details for PubMedID 29173292

• A Syndromic Neurodevelopmental Disorder Caused by De Novo Variants in EBF3. American journal of human genetics Chao, H. T., Davids, M., Burke, E., Pappas, J. G., Rosenfeld, J. A., McCarty, A. J., Davis, T., Wolfe, L., Toro, C., Tifft, C., Xia, F., Stong, N., Johnson, T. K., Warr, C. G., Yamamoto, S., Adams, D. R., Markello, T. C., Gahl, W. A., Bellen, H. J., Wangler, M. F., Malicdan, M. C. 2017; 100 (1): 128–37

  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 PubMedID 28017372

• A window into living with an undiagnosed disease: illness narratives from the Undiagnosed Diseases Network. Orphanet journal of rare diseases Spillmann, R. C., McConkie-Rosell, A., Pena, L., Jiang, Y. H., Schoch, K., Walley, N., Sanders, C., Sullivan, J., Hooper, S. R., Shashi, V. 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

• 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 Salloum, R., Hummel, T. R., Kumar, S. S., Dorris, K., Li, S., Lin, T., Daryani, V. M., Stewart, C. F., Miles, L., Poussaint, T. Y., Stevenson, C., Goldman, S., Dhall, G., Packer, R., Fisher, P., Pollack, I. F., Fouladi, M., Boyett, J., Drissi, R. 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

• 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 Lulla, R. R., Goldman, S., Yamada, T., Beattie, C. W., Bressler, L., Pacini, M., Pollack, I. F., Fisher, P. G., Packer, R. J., Dunkel, I. J., Dhall, G., Wu, S., Onar, A., Boyett, J. M., Fouladi, M. 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

• Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis JOURNAL OF CLINICAL ONCOLOGY Ramaswamy, V., Hielscher, T., Mack, S. C., Lassaletta, A., Lin, T., Pajtler, K. W., Jones, D. T., Luu, B., Cavalli, F. M., Aldape, K., Remke, M., Mynarek, M., Rutkowski, S., Gururangan, S., McLendon, R. E., Lipp, E. S., Dunham, C., Hukin, J., Eisenstat, D. D., Fulton, D., van Landeghem, F. K., Santi, M., van Veelen, M. C., Van Meir, E. G., Osuka, S., Fan, X., Muraszko, K. M., Tirapelli, D. P., Oba-Shinjo, S. M., Marie, S. K., Carlotti, C. G., Lee, J. Y., Rao, A. A., Giannini, C., Faria, C. C., Nunes, S., Mora, J., Hamilton, R. L., Hauser, P., Jabado, N., Petrecca, K., Jung, S., Massimi, L., Zollo, M., Cinalli, G., Bognar, L., Klekner, A., Hortobagyi, T., Leary, S., Ermoian, R. P., Olson, J. M., Leonard, J. R., Gardner, C., Grajkowska, W. A., Chambless, L. B., Cain, J., Eberhart, C. G., Ahsan, S., Massimino, M., Giangaspero, F., Buttarelli, F. R., Packer, R. J., Emery, L., Yong, W. H., Soto, H., Liau, L. M., Everson, R., Grossbach, A., Shalaby, T., Grotzer, M., Karajannis, M. A., Zagzag, D., Wheeler, H., von Hoff, K., Alonso, M. M., Tuon, T., Schueller, U., Zitterbart, K., Sterba, J., Chan, J. A., Guzman, M., Elbabaa, S. K., Colman, H., Dhall, G., Fisher, P. G., Fouladi, M., Gajjar, A., Goldman, S., Hwang, E., Kool, M., Ladha, H., Vera-Bolanos, E., Wani, K., Lieberman, F., Mikkelsen, T., Omuro, A. M., Pollack, I. F., Prados, M., Robins, H. I., Soffietti, R., Wu, J., Metellus, P., Tabori, U., Bartels, U., Bouffet, E., Hawkins, C. E., Rutka, J. T., Dirks, P., Pfister, S. M., Merchant, T. E., Gilbert, M. R., Armstrong, T. S., Korshunov, A., Ellison, D. W., Taylor, M. D. 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

• Newborns and red reflexes. The Journal of pediatrics Fisher, P. G. 2016; 179: 3

  View details for DOI 10.1016/j.jpeds.2016.10.013

  View details for PubMedID 27884271

• Are neonatal stroke and hypoxic-ischemic encephalopathy related? The Journal of pediatrics Fisher, P. G. 2016; 173: 1–3

  View details for DOI 10.1016/j.jpeds.2016.04.030

  View details for PubMedID 27234275

• 50 Years Ago in The Journal of Pediatrics: Neonatal Myasthenia Gravis. The Journal of pediatrics Fisher, P. G. 2016; 171: 201

  View details for DOI 10.1016/j.jpeds.2015.10.053

  View details for PubMedID 27017463

• Pay attention to when children start school! The Journal of pediatrics Fisher, P. G. 2016; 172: 1–4

  View details for DOI 10.1016/j.jpeds.2016.03.007

  View details for PubMedID 27112076

• Remember toxic exposures to antidementia drugs. The Journal of pediatrics Fisher, P. G. 2016; 172: 1–4

  View details for DOI 10.1016/j.jpeds.2016.03.012

  View details for PubMedID 27112080

• Wandering can be dangerous. The Journal of pediatrics Fisher, P. G. 2016; 174: 3

  View details for DOI 10.1016/j.jpeds.2016.05.046

  View details for PubMedID 27346501

• Do we end life well? The Journal of pediatrics Fisher, P. G. 2016; 175: 1–4

  View details for DOI 10.1016/j.jpeds.2016.06.010

  View details for PubMedID 27507307

• 50 Years Ago in TheJournal ofPediatrics: Brain Scanning in Childhood. The Journal of pediatrics Fisher, P. G. 2016; 176: 113

  View details for DOI 10.1016/j.jpeds.2016.03.049

  View details for PubMedID 27568250

• Shaken baby syndrome and abusive head trauma are real problems. The Journal of pediatrics Fisher, P. G. 2016; 177: 2

  View details for DOI 10.1016/j.jpeds.2016.08.037

  View details for PubMedID 27666073

• De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype. American journal of human genetics Shashi, V., Pena, L. D., Kim, K., Burton, B., Hempel, M., Schoch, K., Walkiewicz, M., McLaughlin, H. M., Cho, M., Stong, N., Hickey, S. E., Shuss, C. M., Freemark, M. S., Bellet, J. S., Keels, M. A., Bonner, M. J., El-Dairi, M., Butler, M., Kranz, P. G., Stumpel, C. T., Klinkenberg, S., Oberndorff, K., Alawi, M., Santer, R., Petrovski, S., Kuismin, O., Korpi-Heikkilä, S., Pietilainen, O., Aarno, P., Kurki, M. I., Hoischen, A., Need, A. C., Goldstein, D. B., Kortüm, F. 2016; 99 (4): 991–99

  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

• Extending precision to phenoytpes. The Journal of pediatrics Fisher, P. G. 2016; 178: 3–4

  View details for DOI 10.1016/j.jpeds.2016.09.025

  View details for PubMedID 27788838

• Just say no to opioids! The Journal of pediatrics Fisher, P. G. 2016; 179: 1

  View details for DOI 10.1016/j.jpeds.2016.10.008

  View details for PubMedID 27884266

• Divergent Patterns of Incidence in Peripheral Neuroblastic Tumors. Journal of pediatric hematology/oncology Merrihew, L. E., Fisher, P. G., Effinger, K. E. 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

• 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 Goldman, S., Bouffet, E., Fisher, P. G., Allen, J. C., Robertson, P. L., Chuba, P. J., Donahue, B., Kretschmar, C. S., Zhou, T., Buxton, A. B., Pollack, I. F. 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

• Decreased tumor apparent diffusion coefficient correlates with objective response of pediatric low-grade glioma to bevacizumab JOURNAL OF NEURO-ONCOLOGY Hsu, C. H., Lober, R. M., Li, M. D., Partap, S., Murphy, P. A., Barnes, P. D., Fisher, P. G., Yeom, K. W. 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

• 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 DeWire, M., Fouladi, M., Turner, D. C., Wetmore, C., Hawkins, C., Jacobs, C., Yuan, Y., Liu, D., Goldman, S., Fisher, P., Rytting, M., Bouffet, E., Khakoo, Y., Hwang, E. I., Foreman, N., Stewart, C. F., Gilbert, M. R., Gilbertson, R., Gajjar, A. 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

• 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 Ahluwalia, M. S., Xie, H., Dahiya, S., Hashemi-Sadraei, N., Schiff, D., Fisher, P. G., Chamberlain, M. C., Pannullo, S., Newton, H. B., Brewer, C., Wood, L., Prayson, R., Elson, P., Peereboom, D. M. 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

• Brain Tumor Epidemiology - A Hub within Multidisciplinary Neuro-oncology. Report on the 15th Brain Tumor Epidemiology Consortium (BTEC) Annual Meeting, Vienna, 2014 CLINICAL NEUROPATHOLOGY Woehrer, A., Lau, C. C., Prayer, D., Bauchet, L., Rosenfeld, M., Capper, D., Fisher, P. G., Kooi, M., Mueller, M., Kros, J. M., Kruchkow, C., Wiemels, J., Wrensch, M., Danysh, H. E., Zouaoui, S., Heck, J. E., Johnson, K. J., Qi, X., O'Neill, B. P., Afza, S., Scheurer, M. E., Bainbridge, M. N., Nousome, D., Bahassi, E. M., Hainfellner, J. A., Barnholtz-Sloan, J. S. 2015; 34 (1): 40-46

  View details for DOI 10.5414/NP300846

  View details for Web of Science ID 000348244600008

• Early detection of cancer: past, present, and future. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting Schiffman, J. D., Fisher, P. G., Gibbs, P. 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

• 50 Years Ago in The Journal of Pediatrics: Hydrocephalus. The Journal of pediatrics Fisher, P. G. 2015; 167 (6): 1286

  View details for DOI 10.1016/j.jpeds.2015.06.004

  View details for PubMedID 26611456

• 50 Years Ago in The Journal of Pediatrics: Treatment of Hydrocephalus with Acetazolamide: Results in 15 Cases. The Journal of pediatrics Fisher, P. G. 2015; 166 (6): 1369

  View details for DOI 10.1016/j.jpeds.2014.12.043

  View details for PubMedID 26008170

• Sports and childhood brain tumors: Can I play? Neuro-oncology practice Perreault, S., Lober, R. M., Davis, C., Stave, C., Partap, S., Fisher, P. G. 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

  View details for PubMedCentralID PMC4369718

• Quality of life outcomes in proton and photon treated pediatric brain tumor survivors RADIOTHERAPY AND ONCOLOGY Yock, T. I., Bhat, S., Szymonifka, J., Yeap, B. Y., Delahaye, J., Donaldson, S. S., MacDonald, S. M., Pulsifer, M. B., Hill, K. S., DeLaney, T. F., Ebb, D., Huang, M., Tarbell, N. J., Fisher, P. G., Kuhlthau, K. A. 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

• MRI surrogates for molecular subgroups of medulloblastoma. AJNR. American journal of neuroradiology Perreault, S., Ramaswamy, V., Achrol, A. S., Chao, K., Liu, T. T., Shih, D., Remke, M., Schubert, S., Bouffet, E., Fisher, P. G., Partap, S., Vogel, H., Taylor, M. D., Cho, Y. J., Yeom, K. W. 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

• Diffusion-weighted MRI derived apparent diffusion coefficient identifies prognostically distinct subgroups of pediatric diffuse intrinsic pontine glioma. Journal of neuro-oncology Lober, R. M., Cho, Y., Tang, Y., Barnes, P. D., Edwards, M. S., Vogel, H., Fisher, P. G., Monje, M., Yeom, K. W. 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

• Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group ACTA NEUROPATHOLOGICA Gottardo, N. G., Hansford, J. R., McGlade, J. P., Alvaro, F., Ashley, D. M., Bailey, S., Baker, D. L., Bourdeaut, F., Cho, Y., Clay, M., Clifford, S. C., Cohn, R. J., Cole, C. H., Dallas, P. B., Downie, P., Doz, F., Ellison, D. W., Endersby, R., Fisher, P. G., Hassall, T., Heath, J. A., Hii, H. L., Jones, D. T., Junckerstorff, R., Kellie, S., Kool, M., Kotecha, R. S., Lichter, P., Laughton, S. J., Lee, S., McCowage, G., Northcott, P. A., Olson, J. M., Packer, R. J., Pfister, S. M., Pietsch, T., Pizer, B., Pomeroy, S. L., Remke, M., Robinson, G. W., Rutkowski, S., Schoep, T., Shelat, A. A., Stewart, C. F., Sullivan, M., Taylor, M. D., Wainwright, B., Walwyn, T., Weiss, W. A., Williamson, D., Gajjar, A. 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

• Arterial spin-labeled perfusion of pediatric brain tumors. AJNR. American journal of neuroradiology Yeom, K. W., MITCHELL, L. A., Lober, R. M., Barnes, P. D., Vogel, H., Fisher, P. G., Edwards, M. S. 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

• Surveillance imaging in children with malignant CNS tumors: low yield of spine MRI. Journal of neuro-oncology Perreault, S., Lober, R. M., Carret, A., Zhang, G., Hershon, L., Décarie, J., Vogel, H., Yeom, K. W., Fisher, P. G., Partap, S. 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

• Pilot undergraduate course teaches students about chronic illness in children: An educational intervention study. Education for health (Abingdon, England) Montenegro, R. E., Birnie, K. D., Fisher, P. G., Dahl, G. V., Binkley, J., Schiffman, J. D. 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

• 50 Years ago in The Journal of Pediatrics: the hypotonic infant. The Journal of pediatrics Fisher, P. G. 2014; 164 (3): 565

  View details for DOI 10.1016/j.jpeds.2013.09.052

  View details for PubMedID 24560317

• 50 years ago in the Journal of Pediatrics: an etiologic and diagnostic study of cerebral palsy. The Journal of pediatrics Fisher, P. G. 2014; 165 (2): 273

  View details for DOI 10.1016/j.jpeds.2014.02.059

  View details for PubMedID 25060875

• 50 years ago in the Journal of Pediatrics: cerebrospinal fluid and blood electrolytes in 62 mentally defective infants and children. The Journal of pediatrics Fisher, P. G. 2014; 165 (3): 515

  View details for DOI 10.1016/j.jpeds.2014.03.028

  View details for PubMedID 25152154

• 50 Years ago in the Journal of Pediatrics: brain tumors in early infancy--probably congenital in origin. The Journal of pediatrics Fisher, P. G. 2014; 165 (5): 978

  View details for DOI 10.1016/j.jpeds.2014.05.033

  View details for PubMedID 25441387

• 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 Fisher, P. G. 2014; 164 (1): 33

  View details for DOI 10.1016/j.jpeds.2013.08.003

  View details for PubMedID 24359900

• Subventricular spread of diffuse intrinsic pontine glioma. Acta neuropathologica Caretti, V., Bugiani, M., Freret, M., Schellen, P., Jansen, M., van Vuurden, D., Kaspers, G., Fisher, P. G., Hulleman, E., Wesseling, P., Vogel, H., Monje, M. 2014

  View details for DOI 10.1007/s00401-014-1307-x

  View details for PubMedID 24929912

• Relapse patterns in pediatric embryonal central nervous system tumors JOURNAL OF NEURO-ONCOLOGY Perreault, S., Lober, R. M., Carret, A., Zhang, G., Hershon, L., Decarie, J., Yeom, K., Vogel, H., Fisher, P. G., Partap, S. 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 Web of Science ID 000325821900009

  View details for PubMedID 23921420

• Prognostic role for diffusion-weighted imaging of pediatric optic pathway glioma. Journal of neuro-oncology Yeom, K. W., Lober, R. M., Andre, J. B., Fisher, P. G., Barnes, P. D., Edwards, M. S., Partap, S. 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

• 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 Marina, N., Hudson, M. M., Jones, K. E., Mulrooney, D. A., Avedian, R., Donaldson, S. S., Popat, R., West, D. W., Fisher, P., Leisenring, W., Stovall, M., Robison, L. L., Ness, K. K. 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

• DIVERGENT PATTERNS OF INCIDENCE IN PERIPHERAL NEUROBLASTIC TUMORS Merrihew, L., Fisher, P., Effinger, K. WILEY-BLACKWELL. 2013: S74–S75

  View details for Web of Science ID 000317984800253

• PERIPHERAL NEUROBLASTIC TUMORS ARE DEVELOPMENTAL CANCERS THAT SEGREGATE BY AGE, HISTOLOGY, AND LOCATION Effinger, K., Merrihew, L., Fisher, P. WILEY-BLACKWELL. 2013: S73–S73

  View details for Web of Science ID 000317984800249

• A phase I trial of arsenic trioxide chemoradiotherapy for infiltrating astrocytomas of childhood. Neuro-oncology Cohen, K. J., Gibbs, I. C., Fisher, P. G., Hayashi, R. J., Macy, M. E., Gore, L. 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

• Anti-N-methyl-D-aspartate receptor encephalitis: what's in a name? journal of pediatrics Campen, C. J., Fisher, P. G. 2013; 162 (4): 673-675

  View details for DOI 10.1016/j.jpeds.2012.11.074

  View details for PubMedID 23305956

• Risk of subsequent cancer following a primary CNS tumor JOURNAL OF NEURO-ONCOLOGY Strodtbeck, K., Sloan, A., Rogers, L., Fisher, P. G., Stearns, D., Campbell, L., Barnholtz-Sloan, J. 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

• 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 Dewire, M., Fouladi, M., Stewart, C., Wetmore, C., Hawkins, C., Jacobs, C., Yuan, Y., Goldman, S., Fisher, P., Rytting, M., Bouffet, E., Khakoo, Y., Hwang, E., Foreman, N., Gilbert, M., Gilbertson, R., Gajjar, A. OXFORD UNIV PRESS INC. 2013: 47–47

  View details for Web of Science ID 000318570500171

• 50 Years ago in The Journal of Pediatrics: cigarettes, school children, and lung cancer. The Journal of pediatrics Fisher, P. G. 2013; 163 (5): 1371

  View details for DOI 10.1016/j.jpeds.2013.04.064

  View details for PubMedID 24160656

• 50 years ago in The Journal of Pediatrics: Sensory neuropathy in a child. journal of pediatrics Fisher, P. G. 2012; 161 (6): 1034-?

  View details for DOI 10.1016/j.jpeds.2012.06.061

  View details for PubMedID 23171486

• HEALTH RELATED QUALITY OF LIFE IN PEDIATRIC BRAIN TUMOR PATIENTS: A COMPARISON OF PROTON AND PHOTON TREATED COHORTS Kuhlthau, K., Bhat, S., Yeap, B. Y., Delahaye, J., Hill, K. S., Pulsifer, M., DeLaney, T. F., MacDonald, S. M., Ebb, D., Tarbell, N. J., Fisher, P. G., Yock, T. I. WILEY-BLACKWELL. 2012: 979–79

  View details for Web of Science ID 000309754300056

• Trends in the diagnosis and treatment of pediatric primary spinal cord tumors Clinical article JOURNAL OF NEUROSURGERY-PEDIATRICS Gephart, M. G., Lober, R. M., Arrigo, R. T., Zygourakis, C. C., Guzman, R., Boakye, M., Edwards, M. S., Fisher, P. G. 2012; 10 (6): 555-559

  View details for DOI 10.3171/2012.9.PEDS1272

  View details for Web of Science ID 000311464100017

• Trends in the diagnosis and treatment of pediatric primary spinal cord tumors. Journal of neurosurgery. Pediatrics Hayden Gephart, M. G., Lober, R. M., Arrigo, R. T., Zygourakis, C. C., Guzman, R., Boakye, M., Edwards, M. S., Fisher, P. G. 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

• Concurrent cyclophosphamide and craniospinal radiotherapy for pediatric high-risk embryonal brain tumors JOURNAL OF NEURO-ONCOLOGY Campen, C. J., Dearlove, J., Partap, S., Murphy, P., Gibbs, I. C., Dahl, G. V., Fisher, P. G. 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

• 50 years ago in The Journal of Pediatrics: the effect of degree of hypoxia on the electroencephalogram in infants. journal of pediatrics Fisher, P. G. 2012; 161 (4): 614-?

  View details for DOI 10.1016/j.jpeds.2012.05.018

  View details for PubMedID 22999578

• GENDER AND RACIAL RISK FACTORS FOR CHILDHOOD BRAIN TUMORS 17th Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology (SNO) Campen, C. J., Von Behren, J., Reynolds, P., Fisher, P. G. OXFORD UNIV PRESS INC. 2012: 23–23

  View details for Web of Science ID 000310971300097

• 50 years ago in The Journal of Pediatrics: the surgical management of meningoceles and meningomyeloceles. journal of pediatrics Lober, R. M., Fisher, P. G. 2012; 161 (4): 734-?

  View details for DOI 10.1016/j.jpeds.2012.05.019

  View details for PubMedID 22999580

• Efficacy and tolerability of rizatriptan in pediatric migraineurs: Results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design CEPHALALGIA Ho, T. W., Pearlman, E., Lewis, D., Hamalainen, M., Connor, K., Michelson, D., Zhang, Y., Assaid, C., Mozley, L. H., Strickler, N., Bachman, R., Mahoney, E., Lines, C., Hewitt, D. J. 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

• Cancer in Children with Nonchromosomal Birth Defects JOURNAL OF PEDIATRICS Fisher, P. G., Reynolds, P., Von Behren, J., Carmichael, S. L., Rasmussen, S. A., Shaw, G. M. 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

• PSYCHIATRIC SYMPTOMS IN SURVIVORS OF CHILDHOOD GERM CELL TUMORS 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) Campen, C. J., Ashby, D., Fisher, P. G., Monje, M. OXFORD UNIV PRESS INC. 2012: 50–50

  View details for Web of Science ID 000308394400184

• HAZARDOUS AIR POLLUTANTS AND RISK OF CHILDHOOD CENTRAL NERVOUS SYSTEM TUMORS IN CALIFORNIA 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) Fisher, P. G., Von Behren, J., Nelson, D. O., Reynolds, P. OXFORD UNIV PRESS INC. 2012: 43–44

  View details for Web of Science ID 000308394400159

• PSYCHIATRIC SYMPTOMS IN CHILDREN WITH MEDULLOBLASTOMA 15th International Symposium on Pediatric Neuro-Oncology (ISPNO) Campen, C. J., Ashby, D., Fisher, P. G., Monje, M. OXFORD UNIV PRESS INC. 2012: 128–128

  View details for Web of Science ID 000308394400480

• The Eyes Have It! The Significance of Unilateral Ptosis JOURNAL OF PEDIATRICS Lopez, J., Fisher, P. G. 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

• Complete Ocular Paresis in a Child with Posterior Fossa Syndrome PEDIATRIC NEUROSURGERY Afshar, M., Link, M., Edwards, M. S., Fisher, P. G., Fredrick, D., Monje, M. 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

• In memoriam: Donald W. Lewis, MD (1951-2012 ). Journal of child neurology Toor, S. S., Fisher, P. G. 2012; 27 (10): 1355–59

  View details for DOI 10.1177/0883073812457464

  View details for PubMedID 23007304

• 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 Campen, C. J., Fisher, P. G. OXFORD UNIV PRESS INC. 2011: 100–100

  View details for Web of Science ID 000297026600398

• 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 Campen, C. J., Soman, S., Fisher, P. G., Edwards, M. S., Yeom, K. W. OXFORD UNIV PRESS INC. 2011: 142–142

  View details for Web of Science ID 000297026600558

• Birth Anomalies and Obstetric History as Risks for Childhood Tumors of the Central Nervous System PEDIATRICS Partap, S., Maclean, J., Von Behren, J., Reynolds, P., Fisher, P. G. 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

• Liposomal cytarabine for central nervous system embryonal tumors in children and young adults JOURNAL OF NEURO-ONCOLOGY Partap, S., Murphy, P. A., Vogel, H., Barnes, P. D., Edwards, M. S., Fisher, P. G. 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 Web of Science ID 000291703000018

  View details for PubMedID 20859651

• Hedgehogs, Flies, Wnts and MYCs: The Time Has Come for Many Things in Medulloblastoma JOURNAL OF CLINICAL ONCOLOGY Monje, M., Beachy, P. A., Fisher, P. G. 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

• Hedgehog-responsive candidate cell of origin for diffuse intrinsic pontine glioma PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Monje, M., Mitra, S. S., Freret, M. E., Raveh, T. B., Kim, J., Masek, M., Attema, J. L., Li, G., Haddix, T., Edwards, M. S., Fisher, P. G., Weissman, I. L., Rowitch, D. H., Vogel, H., Wong, A. J., Beachy, P. A. 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

• Dorsolateral Midbrain MRI Abnormalities and Ocular Motor Deficits Following Cytarabine-Based Chemotherapy for Acute Myelogenous Leukemia JOURNAL OF NEURO-OPHTHALMOLOGY Doan, T., Lacayo, N., Fisher, P. G., Liao, Y. J. 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

• Clinical Practice Guideline-Neurodiagnostic Evaluation of the Child With a Simple Febrile Seizure PEDIATRICS Duffner, P. K., Berman, P. H., Baumann, R. J., Fisher, P. G., Green, J. L., Schneider, S. 2011; 127 (2): 389-394

  View details for DOI 10.1542/peds.2010-3318

  View details for Web of Science ID 000286805200058

• A Phase II Study of Metronomic Oral Topotecan for Recurrent Childhood Brain Tumors PEDIATRIC BLOOD & CANCER Minturn, J. E., Janss, A. J., Fisher, P. G., Allen, J. C., Patti, R., Phillips, P. C., Belasco, J. B. 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

• Neurological complications following treatment of children with brain tumors. Journal of pediatric rehabilitation medicine Monje, M., Fisher, P. G. 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

• Loss of SMARCB1/INI1 expression in poorly differentiated chordomas ACTA NEUROPATHOLOGICA Mobley, B. C., McKenney, J. K., Bangs, C. D., Callahan, K., Yeom, K. W., Schneppenheim, R., Hayden, M. G., Cherry, A. M., Gokden, M., Edwards, M. S., Fisher, P. G., Vogel, H. 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 Web of Science ID 000284593200005

  View details for PubMedID 21057957

• Birth Weight and Order as Risk Factors for Childhood Central Nervous System Tumors JOURNAL OF PEDIATRICS Maclean, J., Partap, S., Reynolds, P., Von Behren, J., Fisher, P. G. 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

• Intramedullary papillary ependymoma with choroid plexus differentiation and cerebrospinal fluid dissemination to the brain Case report JOURNAL OF NEUROSURGERY-PEDIATRICS Dulai, M. S., Caccamo, D. V., Briley, A. L., Edwards, M. S., Fisher, P. C., Lehman, N. L. 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

• 50 Years Ago in THE JOURNAL OF PEDIATRICS A Critical Evaluation of Therapy of Febrile Seizures JOURNAL OF PEDIATRICS Campen, C. J., Fisher, P. G. 2010; 156 (3): 449-449

  View details for DOI 10.1016/j.jpeds.2009.10.005

  View details for Web of Science ID 000274863800027

• Oncogenic BRAF Mutation with CDKN2A Inactivation Is Characteristic of a Subset of Pediatric Malignant Astrocytomas CANCER RESEARCH Schiffman, J. D., Hodgson, J. G., VandenBerg, S. R., Flaherty, P., Polley, M. C., Yu, M., Fisher, P. G., Rowitch, D. H., Ford, J. M., Berger, M. S., Ji, H., Gutmann, D. H., James, C. D. 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

• Cerebrovascular disease in childhood cancer survivors A Children's Oncology Group Report NEUROLOGY Morris, B., Partap, S., Yeom, K., Gibbs, I. C., Fisher, P. G., King, A. A. 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

• Medulloblastoma Incidence has not Changed Over Time A CBTRUS Study JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Partap, S., Curran, E. K., Propp, J. M., Le, G. M., Sainani, K. L., Fisher, P. G. 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

• Do children and adults differ in survival from medulloblastoma? A study from the SEER registry JOURNAL OF NEURO-ONCOLOGY Curran, E. K., Le, G. M., Sainani, K. L., Propp, J. M., Fisher, P. G. 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

• Incidence Patterns of Central Nervous System Germ Cell Tumors A SEER Study JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Goodwin, T. L., Sainani, K., Fisher, P. G. 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

• Incidence patterns for ependymoma: a Surveillance, Epidemiology, and End Results study Clinical article JOURNAL OF NEUROSURGERY McGuire, C. S., Sainani, K. L., Fisher, P. G. 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

• Levetiracetam For Seizures in Children With Brain Tumors and Other Cancers PEDIATRIC BLOOD & CANCER Partap, S., Fisher, P. G. 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

• Reproductive health issues in survivors of childhood and adult brain tumors. Cancer treatment and research Goodwin, T., Delasobera, B. E., Fisher, P. G. 2009; 150: 215-222

  View details for DOI 10.1007/b109924_14

  View details for PubMedID 19834671

• Gender Affects Survival for Medulloblastoma Only in Older Children and Adults: A Study From the Surveillance Epidemiology and End Results Registry PEDIATRIC BLOOD & CANCER Curran, E. K., Sainani, K. L., Le, G. M., Propp, J. A., Fisher, P. G. 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

• Both Location and Age Predict Survival in Ependymoma: A SEER Study PEDIATRIC BLOOD & CANCER McGuire, C. S., Sainani, K. L., Fisher, P. G. 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

• Neurological complications in children. Cancer treatment and research Partap, S., Fisher, P. G. 2009; 150: 133-143

  View details for DOI 10.1007/b109924_9

  View details for PubMedID 19834666

• Outcome analysis of childhood low-grade astrocytomas PEDIATRIC BLOOD & CANCER Fisher, P. G., Tihan, T., Goldthwaite, P. T., Wharam, M. D., Carson, B. S., Weingart, J. D., Repka, M. X., Cohen, K. J., Burger, P. C. 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

• Identification of a novel p53 in-frame deletion in a Li-Fraumeni-like family PEDIATRIC BLOOD & CANCER Schiffman, J. D., Chun, N., Fisher, P. G., Dahl, G. V., Ford, J. M., Eggerding, F. A. 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 Web of Science ID 000253661200049

  View details for PubMedID 17554785

• Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas CANCER Balmaceda, C., Peereboom, D., Pannullo, S., Cheung, Y. K., Fisher, P. G., Alavi, J., Sisti, M., Chen, J., Fine, R. L. 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

• 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 Korones, D. N., Fisher, P. G., Kretschmar, C., Zhou, T., Chen, Z., Kepner, J., Freeman, C. 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

• 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 Minn, A. Y., Fisher, P. G., Barnes, P. D., Dahl, G. V. 2008; 50 (2): 427-427

  View details for DOI 10.1002/pbc.21210

  View details for Web of Science ID 000252006000062

• Family history of cancer among children with brain tumors - A critical review JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Dearlove, J. V., Fisher, P. G., Buffler, P. A. 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

• Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer Bondy, M. L., Scheurer, M. E., Malmer, B., Barnholtz-Sloan, J. S., Davis, F. G., Il'yasova, D., Kruchko, C., McCarthy, B. J., Rajaraman, P., Schwartzbaum, J. A., Sadetzki, S., Schlehofer, B., Tihan, T., Wiemels, J. L., Wrensch, M., Buffler, P. A. 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

• Verbal memory impairments in children after cerebellar tumor resection BEHAVIOURAL NEUROLOGY Kirschen, M. P., Davis-Ratner, M. S., Milner, M. W., Chen, S. H., Schraedley-Desmond, P., Fisher, P. G., Desmond, J. E. 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

• Congenital glioblastoma multiforme: Case report and review of the literature PEDIATRIC NEUROSURGERY Hou, L. C., Bababeygy, S. R., Sarkissian, V., Fisher, P. G., Vogel, H., Barnes, P., Huhn, S. L. 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 Web of Science ID 000258318800008

  View details for PubMedID 18504417

• Update on new treatments and developments in childhood brain tumors CURRENT OPINION IN PEDIATRICS Partap, S., Fisher, P. G. 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

• Impaired human hippocampal neurogenesis after treatment for central nervous system ANNALS OF NEUROLOGY Monje, M. L., Vogel, H., Masek, M., Ligon, K. L., Fisher, P. G., Palmer, T. D. 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

• A syndrome of irreversible leukoencephalopathy following pediatric allogeneic bone marrow transplantation PEDIATRIC BLOOD & CANCER Minn, A. Y., Fisher, P. G., Barnes, P. D., Dahl, G. V. 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

• Advances toward an understanding of brainstem gliomas JOURNAL OF CLINICAL ONCOLOGY Donaldson, S. S., Laningham, F., Fisher, P. G. 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

• 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 Greenberg, M. L., Fisher, P. G., Freeman, C., Korones, D. N., Bernstein, M., Friedman, H., Blaney, S., Hershon, L., Zhou, T. N., Chen, Z. J., Kretschmar, C. 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

• 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) Bhat, S. R., Goodwin, T. L., Burwinkle, T. M., Lansdale, M. F., Dahl, G. V., Huhn, S. L., Gibbs, I. C., Donaldson, S. S., Rosenblum, R. K., Varni, J. W., Fisher, P. G. 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

• Malignant gliomas in 2005 - Where to GO from here? JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Fisher, P. G., Buffler, P. A. 2005; 293 (5): 615-617

  View details for Web of Science ID 000226694200026

  View details for PubMedID 15687318

• Biologic risk stratification of medulloblastoma: The real time is now JOURNAL OF CLINICAL ONCOLOGY Fisher, P. G., Burger, P. C., Eberhart, C. G. 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

• Cortical ependymoma - A case report and review PEDIATRIC NEUROSURGERY Lehman, N. L., Jorden, M. A., Huhn, S. L., Barnes, P. D., Nelson, G. B., Fisher, P. G., Horoupian, D. S. 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 PubMedID 12784079

• Radiation therapy for intracranial germ cell tumors 43rd Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology Haas-Kogan, D. A., Missett, B. T., Wara, W. M., Donaldson, S. S., Lamborn, K. R., Prados, M. D., Fisher, P. G., Huhn, S. L., Fisch, B. M., Berger, M. S., Le, Q. T. 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

• Intrathecal thiotepa: Reappraisal of an established therapy JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Fisher, P. G., Kadan-Lottick, N. S., Korones, D. N. 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

• 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 Fisher, P. G., Tontiplaphol, A., Pearlman, E. M., Duffner, P. K., Hyder, D. J., Stolle, C. A., Vortmeyer, A. O., Zhuang, Z. P. 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

• Surveillance neuroimaging to detect relapse in childhood brain tumors: A pediatric oncology group study JOURNAL OF CLINICAL ONCOLOGY Minn, A. Y., Pollock, B. H., Garzarella, L., Dahl, G. V., Kun, L. E., Ducore, J. M., Shibata, A., Kepner, J., Fisher, P. G. 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

• A guide to children with acute and chronic headaches. Journal of pediatric health care Rosenblum, R. K., Fisher, P. G. 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

• Weekly dosing of carboplatin increases risk of allergy in children 36th Annual Meeting of the American-Society-of-Clinical-Oncology Yu, D. Y., Dahl, G. V., Shames, R. S., Fisher, P. G. 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

• Rapid deterioration of a newborn with congenital spinal cord astrocytoma MEDICAL AND PEDIATRIC ONCOLOGY Colby, C., Rozance, P., Goodwin, T. L., Fisher, P. G. 2001; 36 (4): 500-502

  View details for Web of Science ID 000167593000013

  View details for PubMedID 11260577

• Visual loss caused by pseudotumor cerebri in an infant on peritoneal dialysis PEDIATRIC NEPHROLOGY Belson, A., Alcorn, D. M., Yorgin, P. D., Fisher, P. G., Sarwal, M. 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

• Prognostic implications for gadolinium enhancement of the meninges in low-grade astrocytomas of childhood PEDIATRIC NEUROSURGERY Hurwitz, M. D., Burger, P. C., Goldthwaite, P. T., Tihan, T., Wharam, M. D., Fisher, P. G. 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

• Daily low-dose carboplatin as a radiation sensitizer for newly diagnosed malignant glioma JOURNAL OF NEURO-ONCOLOGY Peterson, K., Harsh, G., Fisher, P. G., Adler, J., Le, Q. 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

• A clinicopathologic reappraisal of brain stem tumor classification - Identification of pilocytic astrocytoma and fibrillary astrocytoma as distinct entities CANCER Fisher, P. G., Breiter, S. N., Carson, B. S., Wharam, M. D., Williams, J. A., Weingart, J. D., Foer, D. R., Goldthwaite, P. T., Tihan, T., Burger, P. C. 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

• Management of children with metastatic spinal myxopapillary ependymoma using craniospinal irradiation MEDICAL AND PEDIATRIC ONCOLOGY Chinn, D. M., Donaldson, S. S., Dahl, G. V., Wilson, J. D., Huhn, S. L., Fisher, P. C. 2000; 35 (4): 443-445

  View details for Web of Science ID 000089577700013

  View details for PubMedID 11025481

• No responses to oral etoposide in 15 patients with recurrent brain tumors 35th Annual Meeting of the American-Society-of-Clinical-Oncology Korones, D. N., Fisher, P. G., Cohen, K. J., Dubowy, R. L. WILEY-LISS. 2000: 80–82

  View details for Web of Science ID 000087946900015

  View details for PubMedID 10881014

• Meningeal leukemia with cerebrospinal fluid block MEDICAL AND PEDIATRIC ONCOLOGY Fisher, P. G., Chiello, C. 2000; 34 (4): 281-283

  View details for Web of Science ID 000086052800015

  View details for PubMedID 10742072

• Case study: Suprasellar germinoma presenting with psychotic and obsessive-compulsive symptoms JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY Mordecai, D., Shaw, R. J., Fisher, P. G., Mittelstadt, P. A., Guterman, T., Donaldson, S. S. 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

• Pediatric astrocytomas with monomorphous pilomyxoid features and a less favorable outcome JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY Tihan, T., Fisher, P. G., Kepner, J. L., Godfraind, C., McComb, R. D., Goldthwaite, P. T., Burger, P. C. 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

• Hyperfractionated radiotherapy in the management of diffuse intrinsic brainstem tumors: When is enough enough? INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Fisher, P. G., Donaldson, S. S. 1999; 43 (5): 947-949

  View details for Web of Science ID 000079279100001

  View details for PubMedID 10192338

• Outcomes and failure patterns in childhood craniopharyngiomas 8th International Symposium on Pediatric Neuro-oncology Fisher, P. G., Jenab, J., Goldthwaite, P. T., Tihan, T., Wharam, M. D., Foer, D. R., Burger, P. C. 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

• Rethinking brain tumors in babies and more ANNALS OF NEUROLOGY Fisher, P. G. 1998; 44 (3): 300-302

  View details for Web of Science ID 000075744700002

  View details for PubMedID 9749594

• Lessons learned from the clinical cooperative trials groups for childhood brain tumors NEUROSURGERY QUARTERLY Fisher, P. G., Fry, T. J., Wharam, M. D. 1998; 8 (3): 216-231

  View details for Web of Science ID 000081492800006

• Salvage therapy after postoperative chemotherapy for primary brain tumors in infants and very young children 24th Annual Meeting of the Child-Neurology-Society Fisher, P. G., Needle, M. N., Cnaan, A., Zhao, H. Q., Geyer, J. R., Molloy, P. T., Goldwein, J. W., Herman-Liu, A. B., Phillips, P. C. 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

• Third ventricular choroid plexus papilloma with psychosis - Case report JOURNAL OF NEUROSURGERY Carson, B. S., Weingart, J. D., Guarnieri, M., Fisher, P. G. 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

• PARANEOPLASTIC OPSOCLONUS NEUROLOGY Fisher, P. G., Singer, H. S. 1995; 45 (7): 1421-1421

  View details for Web of Science ID A1995RJ27900043

  View details for PubMedID 7677891

• ANTI-HU ANTIBODY IN A NEUROBLASTOMA-ASSOCIATED PARANEOPLASTIC-SYNDROME PEDIATRIC NEUROLOGY Fisher, P. G., Wechsler, D. S., Singer, H. S. 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