Pediatric Subcutaneous Panniculitis-like T-cell Lymphoma of the Orbit.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare and distinct subtype of peripheral T-cell lymphoma, representing <1% of all non-Hodgkin lymphomas. SPTCL usually arises in the fourth decade of life with multifocal involvement of the limbs and trunk. Orbital disease is uncommon. We present the youngest known case of orbital SPTCL in a 3-year-old child, where the diagnosis was initially confounded by a lower eyelid mass masquerading as preseptal cellulitis. MRI revealed a poorly defined anterior orbital mass. Immunophenotyping and histological analysis of an orbital biopsy specimen confirmed SPTCL, which was managed by the pediatric oncology team with multiagent chemotherapy. This case is unique due to the young age of presentation and primary orbital involvement. Nonresolving or atypical periorbital cellulitis needs to be investigated, as malignancy can mimic such conditions.

Parents' experiences of postmortem tumor donation for high-grade gliomas: benefits and suggested improvements.

BACKGROUND: Pediatric high-grade glioma is a devastating diagnosis. There has been no improvement in outcomes for several decades, with few children surviving 2 years postdiagnosis. Research progress has been hampered by a lack of tumor samples, which can be used to develop and test novel therapies. Postmortem tumor donations are therefore a valuable opportunity to collect tissue. In this study, we explored Australian parents' experiences of donating their child's tumor for research after their child had died. METHODS: We collected qualitative data from 11 bereaved parents who consented to donate samples of their child's high-grade glioma for research postmortem. We asked parents about their perceived benefits/burdens of the autopsy, recommendations for improving consent discussions, and decision regret. RESULTS: Parents hoped that their donation would help to find a cure for future children with high-grade glioma. They described feeling comforted knowing that their child's suffering may help others. Some parents also felt that the donation would help them better understand their child's tumor. Although some parents described discomfort about procedures leading up to the autopsy, parents reported minimal regret regarding their decision to donate their child's tumor. Parents provided recommendations to improve consent discussions, such as providing more information about the autopsy logistics and why the donation was needed. CONCLUSION: Parents consented to autopsy for altruistic reasons, although donation may also assist parents in their grieving. There is a strong need to improve access to tumor donations for any family who wishes to donate.

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03).

PURPOSE: SJMB03 (ClinicalTrials.gov identifier: NCT00085202) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS: Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS: Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort (P = .74) or when patients were stratified by clinical risk (P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION: These results establish a new risk stratification for future medulloblastoma trials.

Correction to: Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials.

The original version of this article unfortunately contained a typesetting error in Fig 3c. The corrected Fig. 3 is given in the following page.

Risk-adapted therapy and biological heterogeneity in pineoblastoma: integrated clinico-pathological analysis from the prospective, multi-center SJMB03 and SJYC07 trials.

Pineoblastoma is a rare embryonal tumor of childhood that is conventionally treated with high-dose craniospinal irradiation (CSI). Multi-dimensional molecular evaluation of pineoblastoma and associated intertumoral heterogeneity is lacking. Herein, we report outcomes and molecular features of children with pineoblastoma from two multi-center, risk-adapted trials (SJMB03 for patients ≥ 3 years; SJYC07 for patients < 3 years) complemented by a non-protocol institutional cohort. The clinical cohort consisted of 58 patients with histologically diagnosed pineoblastoma (SJMB03 = 30, SJYC07 = 12, non-protocol = 16, including 12 managed with SJMB03-like therapy). The SJMB03 protocol comprised risk-adapted CSI (average-risk = 23.4 Gy, high-risk = 36 Gy) with radiation boost to the primary site and adjuvant chemotherapy. The SJYC07 protocol consisted of induction chemotherapy, consolidation with focal radiation (intermediate-risk) or chemotherapy (high-risk), and metronomic maintenance therapy. The molecular cohort comprised 43 pineal parenchymal tumors profiled by DNA methylation array (n = 43), whole-exome sequencing (n = 26), and RNA-sequencing (n = 16). Respective 5-year progression-free survival rates for patients with average-risk or high-risk disease on SJMB03 or SJMB03-like therapy were 100% and 56.5 ± 10.3% (P = 0.007); respective 2-year progression-free survival rates for those with intermediate-risk or high-risk disease on SJYC07 were 14.3 ± 13.2% and 0% (P = 0.375). Of patients with average-risk disease treated with SJMB03/SJMB03-like therapy, 17/18 survived without progression. DNA-methylation analysis revealed four clinically relevant pineoblastoma subgroups: PB-A, PB-B, PB-B-like, and PB-FOXR2. Pineoblastoma subgroups differed in age at diagnosis, propensity for metastasis, cytogenetics, and clinical outcomes. Alterations in the miRNA-processing pathway genes DICER1, DROSHA, and DGCR8 were recurrent and mutually exclusive in PB-B and PB-B-like subgroups; PB-FOXR2 samples universally overexpressed the FOXR2 proto-oncogene. Our findings suggest superior outcome amongst older children with average-risk pineoblastoma treated with reduced-dose CSI. The identification of biologically and clinically distinct pineoblastoma subgroups warrants consideration of future molecularly-driven treatment protocols for this rare pediatric brain tumor entity.

Elevated Preoperative Neutrophil-Lymphocyte Ratio is Predictive of a Poorer Prognosis for Pediatric Patients with Solid Tumors.

BACKGROUND: An elevated neutrophil-lymphocyte ratio (NLR) has been shown to indicate poorer prognosis for adults with solid tumors and potentially represents an independent, universal adjunct prognostic factor. The value of NLR in a pediatric setting has not been evaluated. This study sought to determine the prognostic value of NLR for pediatric patients with solid tumors. METHODS: Pediatric patients with solid tumors undergoing neoadjuvant chemotherapy followed by surgery with curative intent between 2000 and 2014 were eligible for this study. A preoperative peripheral blood count within 1 month of surgery taken after recovery from recent chemotherapy was analyzed in relation to overall survival (OS) and event-free survival (EFS). RESULTS: This retrospective study enrolled 293 patients. The median age at diagnosis was 46.5 months (range 0.1-206.1 months). Males accounted for 58% of the patients. The median OS was 49 months. An NLR cutoff of 2.5 was used in the analysis. In the univariate analysis, a high NLR was associated with low OS (p = 0.001) and low EFS (p = 0.020). Other factors identified in the univariate analysis that affected survival included metastatic disease at diagnosis (p < 0.001) and tumor type (p = 0.012). The multivariate analyses showed that a high NLR was associated with low OS (p = 0.014) but not with EFS (p = 0.270). The multivariate analysis of neuroblastoma patients found that a high NLR was associated with low OS (p = 0.013). CONCLUSIONS: An elevated NLR is prognostic of a poorer outcome for pediatric patients with solid tumors and potentially represents an independent, universal adjunct prognosticator in such cases.

A Paediatric Acute Promyelocytic Leukaemia Patient Harbouring a Cryptic PML-RARA Insertion due to a Complex Structural Chromosome 17 Rearrangement.

Acute promyelocytic leukaemia with PML-RARA fusion is usually associated with the t(15;17)(q24.1;q21.1) translocation but may also arise from complex or cryptic rearrangements. The fusion usually resides on chromosome 15 but occasionally on others. We describe a cryptic PML-RARA fusion within a novel chromosome 17 rearrangement. We performed interphase fluorescence in situ hybridisation (FISH) using a dual-fusion PML-RARA probe, followed by reverse transcriptase-polymerase chain reaction (RT-PCR) for PML-RARA, karyotyping, and metaphase FISH using RARA break-apart, locus-specific, and subtelomere probes for chromosome 17. An 850K SNP microarray was also employed. Interphase and metaphase FISH showed atypical results involving a single PML-RARA fusion, no second fusion, but instead separate diminished PML and RARA signals. RT-PCR confirmed PML-RARA fusion; however, karyotyping detected only an altered chromosome 17. Metaphase FISH showed the single fusion and diminished 5' RARA signals located unexpectedly in the subtelomeric short-arm and long-arm regions of the rearranged chromosome 17, respectively. SNP microarray revealed no copy number abnormality. This paediatric patient with PML-RARA fusion reflects a cryptic insertion that resides within a complex and novel chromosome 17 rearrangement. This rearrangement likely arose via 7 chromosome breaks with the insertion occurring first followed by sequential paracentric and then pericentric inversions.

Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy: Overlapping Genetic Features With Clear Cell Sarcoma of Kidney.

Soft tissue undifferentiated round cell sarcoma (URCS) occurring in infants is a heterogenous group of tumors, often lacking known genetic abnormalities. On the basis of a t(10;17;14) karyotype in a pelvic URCS of a 4-month-old boy showing similar breakpoints with clear cell sarcoma of kidney (CCSK), we have investigated the possibility of shared genetic abnormalities in CCSK and soft tissue URCS. Most CCSKs are characterized by BCOR exon 16 internal tandem duplications (ITDs), whereas a smaller subset shows YWHAE-NUTM2B/E fusions. Because of overlapping clinicopathologic features, we have also investigated these genetic alterations in the so-called primitive myxoid mesenchymal tumor of infancy (PMMTI). Among the 22 infantile URCSs and 7 PMMTIs selected, RNA sequencing was performed in 5 and 2 cases, with frozen tissue, respectively. The remaining cases with archival material were tested for YWHAE-NUTM2B/E by fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR), and BCOR ITD by PCR. A control group of 4 CCSKs and 14 URCSs in older children or adults without known gene fusion and 20 other sarcomas with similar histomorphology or age at presentation were also tested. A YWHAE-NUTM2B fusion was confirmed in the index case by FISH and RT-PCR, whereas BCOR ITD was lacking. An identical YWHAE-NUTM2B fusion was found in another URCS case of a 5-month-old girl with a back lesion. The remaining cases and control group lacked YWHAE gene rearrangements; instead, consistent BCOR ITDs, similar to CCSK, were found in 15/29 (52%) infantile sarcoma cases (9/22 infantile URCS and 6/7 PMMTI). In the control cohort, BCOR ITD was found only in 3 CCSK cases but not in the other sarcomas. Histologically, URCS with both genotypes and PMMTI shared significant histologic overlap, with uniform small blue round cells with fine chromatin and indistinct nucleoli. A prominent capillary network similar to CCSK, rosette structures, and varying degree of myxoid change were occasionally seen. BCOR ITD-positive tumors occurred preferentially in the somatic soft tissue of the trunk, abdomen, and head and neck, sparing the extremities. RNAseq showed high BCOR mRNA levels in BCOR ITD-positive cases, compared with other URCSs. In summary, we report recurrent BCOR exon 16 ITD and YWHAE-NUTM2B fusions in half of infantile soft tissue URCS and most PMMTI cases, but not in other pediatric sarcomas. These findings suggest a significant overlap between infantile URCS and CCSK, such as age at presentation, histologic features, and genetic signature, thus raising the possibility of a soft tissue counterpart to CCSK.

ß-HCG Elevation in Wilms Tumor: An Uncommon Presentation.

Wilms tumor (nephroblastoma) is a readily diagnosed common abdominal tumor in children. Rarely, it may present with factors that may confound the diagnosis. We report a 6-year-old female child who presented with a rapidly growing and invasive abdominal mass with the histopathologic features of Wilms tumor associated with an elevated serum beta human chorionic gonadotropin, which has not been previously reported in this condition.

Confirmation of Bevacizumab Activity, and Maintenance of Efficacy in Retreatment After Subsequent Relapse, in Pediatric Low-grade Glioma.

BACKGROUND: Management of low-grade gliomas (LGG) can be a challenge, particularly when not resectable and refractory or recurrent following standard treatments. We undertook a retrospective analysis of 2 institutions' experiences treating children for refractory or progressive LGG with bevacizumab-based therapy (BBT). PROCEDURE: Inclusion criteria were patients younger than 18 years of age who had previously failed one or more lines of therapy. Treatment was intravenous bevacizumab 10 mg/kg and intravenous irinotecan 125 to 150 mg/m2 every 2 weeks. RESULTS: Sixteen children (median age of 8.6 y), 5 with neurofibromatosis type 1 and 8 with disseminated disease were treated between 2009 and 2013. Median duration of treatment was 12 months (range, 3 to 45 mo). Seven patients (44%) showed clinical improvement (3 patients within a month) and 8 patients (50%) remained clinically stable during BBT. Imaging studies showed 3 (19%) had a partial response, 11 (69%) stable disease, and 2 (12%) had progressive disease. Four patients had progressive disease after stopping BBT (median duration of 5 mo). Three of these 4 were able to be retreated with BBT and all achieved an objective response. Treatment was well tolerated with no grade 3 or 4 toxicities related to bevacizumab. Irinotecan was discontinued in 4 patients because of grade 2-3 toxicities. CONCLUSIONS: We conclude that BBT is well tolerated and led to disease control in patients with refractory or recurrent cases of LGG. Retreatment with BBT led to disease control in most of these cases. Larger, prospective studies are warranted to confirm these results.

Childhood folate, B6, B12, and food group intake and the risk of childhood brain tumors: results from an Australian case-control study.

PURPOSE: The etiology of childhood brain tumors (CBT) is poorly understood, but dietary factors could be involved. In this case-control study of CBT, the possible associations of childhood intake of dietary and supplemental folate, vitamin B6, and vitamin B12 with the risk of CBT were investigated, along with various food groups. METHODS: Cases diagnosed between 2005 and 2010 were identified from 10 pediatric oncology centers in Australia and controls by nationwide random-digit dialling. For study children of ages 3-14 years, diet in the year before diagnosis (or recruitment) was assessed using food frequency questionnaires. Folate intake was adjusted for bioavailability, and dietary micronutrient intake was energy-adjusted. Micronutrients and food groups were analyzed using logistic regression adjusting for relevant confounders. Principal components analysis was conducted to assess food group intake patterns for analysis. RESULTS: Food and micronutrient data were available for 216 cases and 523 controls. Folate intake was associated with a reduced risk of CBT overall (odds ratio for highest tertile vs. lowest: 0.63, 95% confidence interval 0.41, 0.97) and particularly low-grade gliomas (odds ratio for highest tertile vs. lowest: 0.52, 95% confidence interval 0.29, 0.92). Vitamin B6 and B12 intake was not associated with CBT risk, nor was processed meat. CONCLUSIONS: High folate intake during childhood may reduce the risk of CBT. This potentially important finding needs to be corroborated in other studies. If replicated, these results could have important implications for public health recommendations regarding diet during childhood.

Barriers to cure for children with cancer in India and strategies to improve outcomes: a report by the Indian Pediatric Hematology Oncology Group.

The survival of children with cancer in India is inferior to that of children in high-income countries. The Indian Pediatric Hematology Oncology Group (IPHOG) held a series of online meetings via www.Cure4kids.org to identify barriers to cure and develop strategies to improve outcomes. Five major hurdles were identified: delayed diagnosis, abandonment, sepsis, lack of co-operative groups, and relapse. Development of regional networks like IPHOG has allowed rapid identification of local causes of treatment failure for children with cancer in India and identification of strategies likely to improve care and outcomes in the participating centers. Next steps will include interventions to raise community awareness of childhood cancer, promote early diagnosis and referral, and reduce abandonment and toxic death at each center. Starting of fellowship programs in pediatric hemato-oncology, short training programs for pediatricians, publishing outcome data, formation of parent and patient support groups, choosing the right and effective treatment protocol, and setting up of bone marrow transplant services are some of the effective steps taken in the last decade, which needs to be supported further.

Mesenchymal migration as a therapeutic target in glioblastoma.

Extensive infiltration of the surrounding healthy brain tissue is a cardinal feature of glioblastomas, highly lethal brain tumors. Deep infiltration by the glioblastoma cells renders complete surgical excision difficult and contemporary adjuvant therapies have had little impact on long-term survival. Thus, deep infiltration and resistance to irradiation and chemotherapy remain a major cause of patient mortality. Modern therapies specifically targeted to this unique aspect of glioblastoma cell biology hold significant promise to substantially improve survival rates for glioblastoma patients. In the present paper, we focus on the role of adhesion signaling molecules and the actin cytoskeleton in the mesenchymal mode of motility that characterizes invading glioblastoma cells. We then review current approaches to targeting these elements of the glioblastoma cell migration machinery and discuss other aspects of cell migration that may improve the treatment of infiltrating glioblastoma.

Global child health priorities: what role for paediatric oncologists?

Despite increasing globalisation, international mobility and economic interdependence, 9.7 million children aged less than 5 years in low income countries will die this year, almost all from preventable or treatable diseases. Diarrhoea, pneumonia and malaria account for 5 million of these deaths each year, compared to about 150,000 deaths from childhood cancer in low- and middle-income countries. In high-income countries, 80% of the 50,000 children diagnosed with cancer each year survive, yet cancer remains the leading disease-related cause of childhood death. In low- and middle-income countries, where 80% of children live, the 200,000 children diagnosed with cancer each year have limited access to curative treatment, and only about 25% survive. Some might argue that death from paediatric cancer in poor countries is insignificant compared to death from other causes, and that scarce health resources may be better used in other areas of public health. Is there a role for the treatment of children with cancer in these regions? Do international partnerships or 'twinning' programmes enhance local health care or detract from other public health priorities? What is ethical and what is possible? This review examines the health challenges faced by infants and children in low-income countries, and assesses the role and impact of international paediatric oncology collaboration to improve childhood cancer care worldwide.

The prognostic value of tumor markers in newly diagnosed patients with primary central nervous system germ cell tumors.

BACKGROUND: To determine the impact of diagnostic serum and/or cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (b-HCG) elevations on survival in newly diagnosed patients with central nervous system germ cell tumors (CNS GCT) treated with chemotherapy with the intent to avoid irradiation. PROCEDURE: Seventy-five patients with newly diagnosed CNS GCT enrolled in two sequential internationally conducted clinical trials with serum and CSF AFP and b-HCG levels available from initial diagnosis were retrospectively analyzed. Subjects received platinum based chemotherapy and were followed with serial imaging and tumor marker evaluations. RESULTS: The 5-year overall survival (OS) and event free survival (EFS) for patients with normal tumor markers compared with those with elevated markers at diagnosis was 78% (95% CI 51-91%) versus 60% (95% CI 46-72%) (P = 0.08) and 22% (95% CI 7-43%) versus 28% (95% CI 16-40%) (P = 0.68). The hazard ratio of death for patients with elevated markers was 1.9 times as high as that for those with normal markers (95% CI 0.58-6.5) after adjusting for other baseline characteristics. There was no observed difference in survival among patients with histologically confirmed germinomas, irrespective of level of b-HCG. CONCLUSIONS: Patients with elevated tumor markers appear to have poorer OS independent of tumor histology, although these differences do not reach statistical significance (P < or = 0.05). No differences were observed in EFS between groups likely due to the poor response of chemotherapy only approach to patients with normal markers. b-HCG elevations in biopsy proven germinomas do not seem to alter a patient's prognosis.

Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine.

PURPOSE: To assess the activity and tolerability of 2-chlorodeoxyadenosine (2-CDA) in treating mass lesions of the central nervous system (CNS) due to Langerhans cell histiocytosis (LCH). PATIENTS AND METHODS: The records of eight children and four adults with CNS LCH who were treated with 2-CDA were reviewed. The pattern of CNS disease included involvement of the hypothalamic-pituitary axis, gadolinium enhancing parenchymal as well as dural and choroid plexus based mass lesions, and atrophy. 2-CDA (5-13 mg/m(2)/day) was given on 3-5 consecutive days and repeated every 2-8 weeks for a period ranging from 3 to 12 months. RESULTS: Eight patients demonstrated a complete radiographic response to 2-CDA with resolution of all enhancing mass lesions and four patients showed a sustained, partial radiographic response. One patient died from a non-treatment related cause without evidence of LCH on autopsy. With a follow-up ranging from 2 to 10 years after completion of therapy, the 11 surviving patients remain in continuous remission or are progression free. Prolonged bone marrow suppression was the most common toxicity (four patients). Permanent sequelae of CNS LCH, such as panhypopituitarism, diabetes insipidus (DI) and neurocognitive dysfunction, were not found to be reversible with 2-CDA therapy. CONCLUSIONS: 2-CDA is an active agent in patients with CNS LCH, with the possible exception of neurodegenerative disease, and should be further evaluated in a prospective multi-center clinical trial for LCH patients with enhancing mass lesions of the CNS.