Publications by authors named "Paul G Fisher"

103 Publications

Functional and structural analysis of cytokine selective IL6ST defects that cause recessive hyper-IgE syndrome.

J Allergy Clin Immunol 2021 Mar 23. Epub 2021 Mar 23.

Translational Gastroenterology Unit, University of Oxford, Oxford, UK;; Department of Paediatrics, University of Oxford, Oxford, UK;; Oxford NIHR Biomedical Research Centre, Oxford, UK.

Background: Biallelic variants in IL6ST cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE, eosinophilia, defective acute phase response, susceptibility to bacterial infections and skeletal abnormalities due to cytokine selective loss-of-function in GP130 with defective IL-6 and IL-11, variable OSM and IL-27 but sparing LIF signaling.

Objective: To understand the functional and structural impact of recessive HIES-associated IL6ST variants.

Methods: We investigated a patient with HIES using exome, genome and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamic simulations and structural modeling of GP130 cytokine receptor complexes were performed.

Results: We identify a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro, and exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant results in a more profound IL-6 and IL-11 dominated signaling defect compared to the previously identified recessive IL6ST variants p.Asn404Tyr, and p.Pro498Leu. Molecular dynamics simulations suggest that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilize the hexameric cytokine receptor complexes whereas the trimeric LIF-GP130-LIFR complex remains stable by an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently causes additional defective LIF signaling and Stüve-Wiedemann syndrome.

Conclusion: Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.
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http://dx.doi.org/10.1016/j.jaci.2021.02.044DOI Listing
March 2021

Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-institutional Trials.

Clin Cancer Res 2021 Mar 18. Epub 2021 Mar 18.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: Report relevance of molecular groups to clinicopathologic features, germline alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials.

Materials And Methods: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; = 52) and children (SJMB03: age 3-21 years; = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles.

Results: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR ( = 21), SHH ( = 30), and MYC ( = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. GLAs were not associated with PFS.

Conclusions: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4731DOI Listing
March 2021

Outcome and molecular analysis of young children with choroid plexus carcinoma treated with non-myeloablative therapy: results from the SJYC07 trial.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa168. Epub 2020 Dec 15.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Background: Choroid plexus carcinoma (CPC) is a rare and aggressive tumor of infancy without a clear treatment strategy. This study describes the outcomes of children with CPC treated on the multi-institutional phase 2 SJYC07 trial and reports on the significance of clinical and molecular characteristics.

Methods: Eligible children <3 years-old with CPC were postoperatively stratified to intermediate-risk (IR) stratum if disease was localized or high-risk (HR) stratum, if metastatic. All received high-dose methotrexate-containing induction chemotherapy. IR-stratum patients received focal irradiation as consolidation whereas HR-stratum patients received additional chemotherapy. Consolidation was followed by oral antiangiogenic maintenance regimen. Survival rates and potential prognostic factors were analyzed.

Results: Thirteen patients (median age: 1.41 years, range: 0.21-2.93) were enrolled; 5 IR, 8 HR. Gross-total resection or near-total resection was achieved in ten patients and subtotal resection in 3. Seven patients had -mutant tumors, including 4 who were germline carriers. Five patients experienced progression and died of disease; 8 (including 5 HR) are alive without progression. The 5-year progression-free survival (PFS) and overall survival rates were 61.5 ± 13.5% and 68.4 ± 13.1%. Patients with -wild-type tumors had a 5-year PFS of 100% as compared to 28.6 ± 17.1% for -mutant tumors ( = .012). Extent of resection, metastatic status, and use of radiation therapy were not significantly associated with survival.

Conclusions: Non-myeloablative high-dose methotrexate-containing therapy with maximal surgical resection resulted in long-term PFS in more than half of patients with CPC. mutational status was the only significant prognostic variable and should form the basis of risk-stratification in future trials.
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http://dx.doi.org/10.1093/noajnl/vdaa168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813199PMC
December 2020

MR imaging features of diffuse intrinsic pontine glioma and relationship to overall survival: report from the International DIPG Registry.

Neuro Oncol 2020 11;22(11):1647-1657

Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Background: This study describes imaging features of diffuse intrinsic pontine glioma (DIPG) and correlates with overall survival (OS) and histone mutation status in the International DIPG Registry (IDIPGR).

Methods: Four hundred cases submitted to the IDIPGR with a local diagnosis of DIPG and baseline MRI were evaluated by consensus review of 2 neuroradiologists; 43 cases were excluded (inadequate imaging or alternative diagnoses). Agreement between reviewers, association with histone status, and univariable and multivariable analyses relative to OS were assessed.

Results: On univariable analysis imaging features significantly associated with worse OS included: extrapontine extension, larger size, enhancement, necrosis, diffusion restriction, and distant disease. On central review, 9.5% of patients were considered not to have DIPG. There was moderate mean agreement of MRI features between reviewers. On multivariable analysis, chemotherapy, age, and distant disease were predictors of OS. There was no difference in OS between wild-type and H3 mutated cases. The only imaging feature associated with histone status was the presence of ill-defined signal infiltrating pontine fibers.

Conclusions: Baseline imaging features are assessed in the IDIPGR. There was a 9.5% discordance in DIPG diagnosis between local and central review, demonstrating need for central imaging confirmation for prospective trials. Although several imaging features were significantly associated with OS (univariable), only age and distant disease were significant on multivariable analyses. There was limited association of imaging features with histone mutation status, although numbers are small and evaluation exploratory.
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http://dx.doi.org/10.1093/neuonc/noaa140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690352PMC
November 2020

Do gastrostomies prevent hospitalizations?

Authors:
Paul G Fisher

J Pediatr 2020 Feb;217:1-3

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http://dx.doi.org/10.1016/j.jpeds.2019.11.042DOI Listing
February 2020

It's time to detect kids' brain attacks early.

Authors:
Paul G Fisher

J Pediatr 2020 01;216:1-3

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http://dx.doi.org/10.1016/j.jpeds.2019.10.087DOI Listing
January 2020

How to evaluate concussion in all children?

Authors:
Paul G Fisher

J Pediatr 2019 Nov;214:1-3

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http://dx.doi.org/10.1016/j.jpeds.2019.09.040DOI Listing
November 2019

Molecular correlates of cerebellar mutism syndrome in medulloblastoma.

Neuro Oncol 2020 02;22(2):290-297

Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Cerebellar mutism syndrome (CMS) is a common complication following resection of posterior fossa tumors, most commonly after surgery for medulloblastoma. Medulloblastoma subgroups have historically been treated as a single entity when assessing CMS risk; however, recent studies highlighting their clinical heterogeneity suggest the need for subgroup-specific analysis. Here, we examine a large international multicenter cohort of molecularly characterized medulloblastoma patients to assess predictors of CMS.

Methods: We assembled a cohort of 370 molecularly characterized medulloblastoma subjects with available neuroimaging from 5 sites globally, including Great Ormond Street Hospital, Christian Medical College and Hospital, the Hospital for Sick Children, King Hussein Cancer Center, and Lucile Packard Children's Hospital. Age at diagnosis, sex, tumor volume, and CMS development were assessed in addition to molecular subgroup.

Results: Overall, 23.8% of patients developed CMS. CMS patients were younger (mean difference -2.05 years ± 0.50, P = 0.0218) and had larger tumors (mean difference 10.25 cm3 ± 4.60, P = 0.0010) that were more often midline (odds ratio [OR] = 5.72, P < 0.0001). In a multivariable analysis adjusting for age, sex, midline location, and tumor volume, Wingless (adjusted OR = 4.91, P = 0.0063), Group 3 (adjusted OR = 5.56, P = 0.0022), and Group 4 (adjusted OR = 8.57 P = 9.1 × 10-5) tumors were found to be independently associated with higher risk of CMS compared with sonic hedgehog tumors.

Conclusions: Medulloblastoma subgroup is a very strong predictor of CMS development, independent of tumor volume and midline location. These findings have significant implications for management of both the tumor and CMS.
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http://dx.doi.org/10.1093/neuonc/noz158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442348PMC
February 2020

Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing.

J Genet Couns 2019 12 3;28(6):1107-1118. Epub 2019 Sep 3.

Center for Undiagnosed Diseases, Stanford University School of Medicine, Stanford, CA.

Background: Despite growing evidence of diagnostic yield and clinical utility of whole exome sequencing (WES) in patients with undiagnosed diseases, there remain significant cost and reimbursement barriers limiting access to such testing. The diagnostic yield and resulting clinical actions of WES for patients who previously faced insurance coverage barriers have not yet been explored.

Methods: We performed a retrospective descriptive analysis of clinical WES outcomes for patients facing insurance coverage barriers prior to clinical WES and who subsequently enrolled in the Undiagnosed Diseases Network (UDN). Clinical WES was completed as a result of participation in the UDN. Payer type, molecular diagnostic yield, and resulting clinical actions were evaluated.

Results: Sixty-six patients in the UDN faced insurance coverage barriers to WES at the time of enrollment (67% public payer, 26% private payer). Forty-two of 66 (64%) received insurance denial for clinician-ordered WES, 19/66 (29%) had health insurance through a payer known not to cover WES, and 5/66 (8%) had previous payer denial of other genetic tests. Clinical WES results yielded a molecular diagnosis in 23 of 66 patients (35% [78% pediatric, 65% neurologic indication]). Molecular diagnosis resulted in clinical actions in 14 of 23 patients (61%).

Conclusions: These data demonstrate that a substantial proportion of patients who encountered insurance coverage barriers to WES had a clinically actionable molecular diagnosis, supporting the notion that WES has value as a covered benefit for patients who remain undiagnosed despite objective clinical findings.
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http://dx.doi.org/10.1002/jgc4.1161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901723PMC
December 2019

Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial.

Lancet Oncol 2019 07 28;20(7):1011-1022. Epub 2019 May 28.

Department of Haematology and Oncology, Cincinnati Children's Hospital, Cincinnati, OH, USA.

Background: Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.

Methods: The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3-21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549-BRAF fusion or the BRAF [Val600Glu] mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.

Findings: Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% [95% CI 18-57]) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72-45·59). In stratum 3, ten (40% [21-61]) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14-51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five [10%]) and maculopapular rash (five [10%]). No treatment-realted deaths were reported.

Interpretation: Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.

Funding: National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(19)30277-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628202PMC
July 2019

Disproving junk science.

Authors:
Paul G Fisher

J Pediatr 2019 Jun;209

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http://dx.doi.org/10.1016/j.jpeds.2019.04.013DOI Listing
June 2019

Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial.

Neuro Oncol 2019 10;21(10):1319-1330

Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee, USA.

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 y) with newly diagnosed ependymoma were treated on the St Jude Young Children 07 (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 the German Cancer Research Center/Molecular Neuropathology 2.0 classifier.

Results: One of the 54 study patients had metastases (cerebrospinal fluid positive) 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 y), 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: posterior fossa ependymoma group A [PF-EPN-A; 42/54], 71.2% ± 8.3%; supratentorial ependymoma positive for v-rel avian reticuloendotheliosis viral oncogene homolog A [ST-EPN-RELA; 8/54], 83.3% ± 17.0%; and supratentorial ependymoma positive for Yes-associated protein [4/54], 100%, P = 0.22). Subtotal resection prior to RT was associated with an inferior PFS compared with 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 more favorable outcome than reported from retrospective data. Histologic grade did not impact outcome. PF-EPN-A with 1q gain and subtotal resection were associated with inferior outcomes.
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http://dx.doi.org/10.1093/neuonc/noz069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784269PMC
October 2019

A toolkit for genetics providers in follow-up of patients with non-diagnostic exome sequencing.

J Genet Couns 2019 04;28(2):213-228

Center for Undiagnosed Diseases, Stanford University, Stanford, California.

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.
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http://dx.doi.org/10.1002/jgc4.1119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385984PMC
April 2019

Point-of-care EEG?

Authors:
Paul G Fisher

J Pediatr 2019 Apr;207

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http://dx.doi.org/10.1016/j.jpeds.2019.02.010DOI Listing
April 2019

Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review.

Am J Med Genet A 2019 06 28;179(6):966-977. Epub 2019 Mar 28.

Department of Pediatrics, Stanford School of Medicine, Stanford, California.

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.
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http://dx.doi.org/10.1002/ajmg.a.61134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488410PMC
June 2019

To sleep and dream without digital screens.

Authors:
Paul G Fisher

J Pediatr 2019 Feb;205

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http://dx.doi.org/10.1016/j.jpeds.2018.12.017DOI Listing
February 2019

Congenital heart disease complexity and childhood cancer risk.

Birth Defects Res 2018 10 16;110(17):1314-1321. Epub 2018 Oct 16.

Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, California.

Background: 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.

Methods: 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.

Results: 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).

Conclusion: 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.
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http://dx.doi.org/10.1002/bdr2.1390DOI Listing
October 2018

Surgical outcomes of pediatric spinal cord astrocytomas: systematic review and meta-analysis.

J Neurosurg Pediatr 2018 Oct 20;22(4):404-410. Epub 2018 Jul 20.

Departments of1Neurosurgery and.

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.
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http://dx.doi.org/10.3171/2018.4.PEDS17587DOI Listing
October 2018

Asymmetric tonsils or tonsillar cancer?

Authors:
Paul G Fisher

J Pediatr 2018 06;197:3-4

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http://dx.doi.org/10.1016/j.jpeds.2018.04.018DOI Listing
June 2018

Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial.

Lancet Oncol 2018 06 16;19(6):768-784. Epub 2018 May 16.

Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.

Background: 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.

Methods: 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/m on day 1), etoposide (100 mg/m 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/m 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.

Findings: 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.

Interpretation: 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.

Funding: 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.
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http://dx.doi.org/10.1016/S1470-2045(18)30204-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078206PMC
June 2018