Rhabdoid tumors in patients conceived following ART: is there an association?

STUDY QUESTION: In children affected by rhabdoid tumors (RT), are there clinical, therapeutic, and/or (epi-)genetic differences between those conceived following ART compared to those conceived without ART? SUMMARY ANSWER: We detected a significantly elevated female predominance, and a lower median age at diagnosis, of children with RT conceived following ART (RT_ART) as compared to other children with RT. WHAT IS KNOWN ALREADY: Anecdotal evidence suggests an association of ART with RT. STUDY DESIGN, SIZE, DURATION: This was a multi-institutional retrospective survey. Children with RT conceived by ART were identified in our EU-RHAB database (n = 11/311 children diagnosed between January 2010 and January 2018) and outside the EU-RHAB database (n = 3) from nine different countries. A population-representative German EU-RHAB control cohort of children with RTs conceived without ART (n = 211) (EU-RHAB control cohort) during the same time period was used as a control cohort for clinical, therapeutic, and survival analyses. The median follow-up time was 11.5 months (range 0-120 months) for children with RT_ART and 18.5 months (range 0-153 months) for the EU-RHAB control cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed 14 children with RT_ART diagnosed from January 2010 to January 2018. We examined tumors and matching blood samples for SMARCB1 mutations and copy number alterations using FISH, multiplex ligation-dependent probe amplification, and DNA sequencing. DNA methylation profiling of tumor and/or blood samples was performed using DNA methylation arrays and compared to respective control cohorts of similar age (n = 53 tumors of children with RT conceived without ART, and n = 38 blood samples of children with no tumor born small for gestational age). MAIN RESULTS AND THE ROLE OF CHANCE: The median age at diagnosis of 14 individuals with RT_ART was 9 months (range 0-66 months), significantly lower than the median age of patients with RT (n = 211) in the EU-RHAB control cohort (16 months (range 0-253), P = 0.03). A significant female predominance was observed in the RT_ART cohort (M:F ratio: 2:12 versus 116:95 in EU-RHAB control cohort, P = 0.004). Eight of 14 RT_ART patients were diagnosed with atypical teratoid rhabdoid tumor, three with extracranial, extrarenal malignant rhabdoid tumor, one with rhabdoid tumor of the kidney and two with synchronous tumors. The location of primary tumors did not differ significantly in the EU-RHAB control cohort (P = 0.27). Six of 14 RT_ART patients presented with metastases at diagnosis. Metastatic stage was not significantly different from that within the EU-RHAB control cohort (6/14 vs 88/211, P = 1). The incidence of pathogenic germline variants was five of the 12 tested RT_ART patients and, thus, not significantly different from the EU-RHAB control cohort (5/12 versus 36/183 tested, P = 0.35). The 5-year overall survival (OS) and event free survival (EFS) rates of RT_ART patients were 42.9 ± 13.2% and 21.4 ± 11%, respectively, and thus comparable to the EU-RHAB control cohort (OS 41.1 ± 3.5% and EFS 32.1 ± 3.3). We did not find other clinical, therapeutic, outcome factors distinguishing patients with RT_ART from children with RTs conceived without ART (EU-RHAB control cohort). DNA methylation analyses of 10 tumors (atypical teratoid RT = 6, extracranial, extrarenal malignant RT = 4) and six blood samples from RT_ART patients showed neither evidence of a general DNA methylation difference nor underlying imprinting defects, respectively, when compared to a control group (n = 53 RT samples of patients without ART, P = 0.51, n = 38 blood samples of patients born small for gestational age, P = 0.1205). LIMITATIONS, REASONS FOR CAUTION: RTs are very rare malignancies and our results are based on a small number of children with RT_ART. WIDER IMPLICATIONS OF THE FINDINGS: This cohort of patients with RT_ART demonstrated a marked female predominance, and a rather low median age at diagnosis even for RTs. Other clinical, treatment, outcome, and molecular factors did not differ from those conceived without ART (EU-RHAB control cohort) or reported in other series, and there was no evidence for imprinting defects. Long-term survival is achievable even in cases with pathogenic germline variants, metastatic disease at diagnosis, or relapse. The female preponderance among RT_ART patients is not yet understood and needs to be evaluated, ideally in larger international series. STUDY FUNDING/COMPETING INTEREST(S): M.C.F. is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.10, by the 'Deutsche Forschungsgemeinschaft' DFG FR 1516/4-1 and by the Deutsche Krebshilfe 70113981. R.S. received grant support by Deutsche Krebshilfe 70114040 and for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. P.D.J. is supported by the Else-Kroener-Fresenius Stiftung and receives a Max-Eder scholarship from the Deutsche Krebshilfe. M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). BB is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.05. We declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Response-adapted omission of radiotherapy in children and adolescents with early-stage classical Hodgkin lymphoma and an adequate response to vincristine, etoposide, prednisone, and doxorubicin (EuroNet-PHL-C1): a titration study.

BACKGROUND: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. METHODS: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1-5; prednisone 60 mg/m2 orally on days 1-15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006-000995-33) and is completed. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1-69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3-89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8-92·5), for which the 95% CI included the 90% target rate. The most common grade 3-4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. INTERPRETATION: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

Lineage switching of the cellular distribution of BRAFV600E in multisystem Langerhans cell histiocytosis.

Most children with high-risk Langerhans cell histiocytosis (LCH) have BRAFV600E mutation. BRAFV600E alleles are detectable in myeloid mononuclear cells at diagnosis but it is not known if the cellular distribution of mutation evolves over time. Here, the profiles of 16 patients with high-risk disease were analyzed. Two received conventional salvage chemotherapy, 4 patients on inhibitors were tracked at intervals of 3 to 6 years, and 10 patients, also given inhibitors, were analyzed more than 2 years after diagnosis. In contrast to the patients responding to salvage chemotherapy who completely cleared BRAFV600E within 6 months, children who received inhibitors maintained high BRAFV600E alleles in their blood. At diagnosis, mutation was detected predominantly in monocytes and myeloid dendritic cells. With time, mutation switched to the T-cell compartment, which accounted for most of the mutational burden in peripheral blood mononuclear cells, more than 2 years from diagnosis (median, 85.4%; range, 44.5%-100%). The highest level of mutation occurred in naïve CD4+ T cells (median, 51.2%; range, 3.8%-93.5%). This study reveals an unexpected lineage switch of BRAFV600E mutation in high-risk LCH, which may influence monitoring strategies for the potential withdrawal of inhibitor treatment and has new implications for the pathogenesis of neurodegeneration, which occurred in 4 patients.

Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population.

Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

Endoscopic extended transsphenoidal surgery for newly diagnosed paediatric craniopharyngiomas.

PURPOSE: Endoscopic extended transsphenoidal surgery (EETSS) has gained popularity for treatment of craniopharyngiomas. The aim of this study is to assess the outcome of endoscopic extended transsphenoidal surgery (EETSS) for newly diagnosed paediatric craniopharyngiomas. METHODS: Patient details were obtained from a prospective database of all endoscopic transnasal operations performed by a single surgeon. Outcomes including visual function, pituitary function, body mass index (BMI), postoperative neurological deficit, extent of resection and recurrence on follow-up were obtained. Obesity was defined as BMI percentile of equal to or greater than 95%. RESULTS: Between January 2011 and January 2020, 15 of 16 children (5-18 years old) with newly diagnosed craniopharyngiomas underwent EETSS. Four patients had a conchal-type sphenoid sinus. Gross total resection (GTR) was achieved in 4 patients and near total resection (NTR) in 5 patients. The remaining 6 had subtotal resection (STR). Postoperative radiotherapy was used in 6 patients (4 with STR, 2 with NTR). There were no postoperative deaths, strokes or CSF leaks. Normalisation of visual fields (VF) occurred in 9/13 patients with preoperative VF defects. One patient developed a new visual field defect. During a median follow-up period of 74 (8-104) months, 2 patients have required further surgery for tumour progression following initial STR, where a tumour remnant was left in situ to preserve the pituitary stalk. 6/11 patients developed new anterior pituitary dysfunction as a result of surgery and 9/12 developed new diabetes insipidus (DI). At the time of last follow-up, 14/15 children had anterior panhypopituitarism, 13/15 had DI and 1 patient developed new onset obesity. Two patients, who were obese preoperatively, were no longer obese at last follow-up. CONCLUSIONS: EETSS can be performed as the first option in the majority of children with newly diagnosed craniopharyngioma, despite factors such as small nose, non-pneumatised sphenoid sinus, small sella or purely suprasellar tumour location. Preservation of the pituitary stalk at the expense of leaving residual tumour may not be in the best interests of the patient.

Assessment of Waldeyer's ring in pediatric and adolescent Hodgkin lymphoma patients-Importance of multimodality imaging: Results from the EuroNet-PHL-C1 trial.

BACKGROUND: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging. PATIENTS, MATERIALS, AND METHODS: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from 18 F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment. RESULTS: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient. CONCLUSIONS: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.

A Novel Approach to Extensive Chest Wall Reconstruction in a Child.

Reconstruction of extensive chest wall defects is challenging in young children. Rigid prosthetic plates, designed to prevent paradoxic respiration, do not grow with the child and may result in progressive chest and spinal deformity. Also because of the greater proportionate size of the thorax relative to the limbs in young children, extrathoracic soft tissue flaps may be too small for an adequate reconstruction. Here we report reconstruction of a large chest wall defect after resection of a Ewing's sarcoma in a 2-year-old boy using Permacol membrane (Medtronic, Minneapolis, MN) supported by a diagonally translocated seventh rib and covered by a latissimus dorsi flap.

Comparison of Interim PET Response to Second-Line Versus First-Line Treatment in Classic Hodgkin Lymphoma: Contribution to the Development of Response Criteria for Relapsed or Progressive Disease.

In first-line treatment of Hodgkin lymphoma (HL), Deauville scores 1-3 define complete metabolic remission. Interim 18F-FDG PET is also used for relapse-treatment adaptation; however, PET response criteria are not validated for relapse treatment. Methods: We performed a pairwise comparative analysis of early response to first- and second-line treatments in 127 patients with classic HL who experienced relapse. The patients participated in the prospective, multicenter EuroNet-PHL-C1 study. Residual uptake was measured retrospectively using the qPET method, a validated semiautomatic quantitative extension of the Deauville score. Empiric cumulative distribution functions of the qPET values were used to systematically analyze the response to first- and second-line treatments. Results: Individual patients responded variably to first- and second-line treatments. However, the empiric cumulative distribution functions of the qPET values from all patients were nearly superimposable. Conclusion: The findings support that first- and second-line treatments in HL do not require different response criteria.

Survival of childhood and adolescent/young adult (AYA) cancer patients in Ireland during 1994-2013: comparisons by age.

BACKGROUND: Some studies indicate that survival of adolescents and young adults (AYA) with cancer may be inferior to that of younger children with similar cancers, possibly related (in part) to differences in access to centralized or standardized treatment. AIMS: This study aims to evaluate differences in survival for AYA patients when compared with paediatric patients treated in Ireland over a 20-year time period. METHODS: This study compares relative survival for patients diagnosed in Ireland at ages 0-15 (paediatric group) and 16-24 (AYA group) during 1994-2013, followed to the end of 2014, for cancers defined by the International Classification of Childhood Cancer (ICCC) (Third Edition) group or subgroup. Five-year relative survival estimates, and excess hazard ratios (EHR) comparing excess mortality associated with a cancer diagnosis among AYA with that in the paediatric group, are presented. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. RESULTS: Significantly higher excess mortality was found for AYA with leukaemias, lymphomas, astrocytomas, malignant bone tumours, and Ewing and related bone sarcomas, soft tissue sarcomas and 'other/unspecified' epithelial cancers, rhabdomyosarcomas, and 'other and unspecified' carcinomas. In contrast, lower excess mortality was found in the AYA group for all cancers and intracranial/intraspinal tumours, and for gliomas other than astrocytomas or ependymomas. Comparing 1994-2003 and 2004-2013 cohorts, age-related survival differences narrowed for lymphoid leukaemias, but widened for all cancers combined and intracranial/intraspinal tumours combined. Centralization of services varied depending upon cancer subtype, with leukaemias, CNS tumours and bone sarcomas most centralized. Within these, improvements in survival for leukaemias and CNS tumours have been seen for the AYA population. CONCLUSIONS: Reasons for age-related survival differences, and differences in time-trend by age group, are not clear. The significant narrowing of survival differences by age in more recent years for lymphoid leukaemias reflects a more marked recent increase in survival among AYA. More work is required to explain and improve other age-related survival differences.

Age and DNA methylation subgroup as potential independent risk factors for treatment stratification in children with atypical teratoid/rhabdoid tumors.

BACKGROUND: Controversy exists as to what may be defined as standard of care (including markers for stratification) for patients with atypical teratoid/rhabdoid tumors (ATRTs). The European Rhabdoid Registry (EU-RHAB) recruits uniformly treated patients and offers standardized genetic and DNA methylation analyses. METHODS: Clinical, genetic, and treatment data of 143 patients from 13 European countries were analyzed (2009-2017). Therapy consisted of surgery, anthracycline-based induction, and either radiotherapy or high dose chemotherapy following a consensus among European experts. Fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, and sequencing were employed for assessment of somatic and germline mutations in SWItch/sucrose nonfermentable related, matrix associated, actin dependent regulator of chromatin, subfamily B (SMARCB1). Molecular subgroups (ATRT-SHH, ATRT-TYR, and ATRT-MYC) were determined using DNA methylation arrays, resulting in profiles of 84 tumors. RESULTS: Median age at diagnosis of 67 girls and 76 boys was 29.5 months. Five-year overall survival (OS) and event-free survival (EFS) were 34.7 ±â€…4.5% and 30.5 ±â€…4.2%, respectively. Tumors displayed allelic partial/whole gene deletions (66%; 122/186 alleles) or single nucleotide variants (34%; 64/186 alleles) of SMARCB1. Germline mutations were detected in 26% of ATRTs (30/117). The patient cohort consisted of 47% ATRT-SHH (39/84), 33% ATRT-TYR (28/84), and 20% ATRT-MYC (17/84). Age <1 year, non-TYR signature (ATRT-SHH or -MYC), metastatic or synchronous tumors, germline mutation, incomplete remission, and omission of radiotherapy were negative prognostic factors in univariate analyses (P < 0.05). An adjusted multivariate model identified age <1 year and a non-TYR signature as independent negative predictors of OS: high risk (<1 y + non-TYR; 5-y OS = 0%), intermediate risk (<1 y + ATRT-TYR or ≥1 y + non-TYR; 5-y OS = 32.5 ±â€…8.7%), and standard risk (≥1 y + ATRT-TYR, 5-y OS = 71.5 ±â€…12.2%). CONCLUSIONS: Age and molecular subgroup status are independent risk factors for survival in children with ATRT. Our model warrants validation within future clinical trials.

Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand?

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

Correction to: International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma.

There are two errors and one omission in the original article. Author Gottardo's correct name is Nicholas G. Gottardo, author Hulleman's correct affiliation is no. 3 (VUMC, Amsterdam), and the Acknowledgements should include the following sentence: "We would like to thank Dr Angel Montero Carcaboso (Hospital Sant Joan de Deu, Barcelona, Spain) for generously supplying the HSJD-DIPG007 cells."

International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma.

PURPOSE: Diffuse intrinsic pontine glioma is the most aggressive form of high grade glioma in children with no effective therapies. There have been no improvements in survival in part due poor understanding of underlying biology, and lack of representative in vitro and in vivo models. Recently, it has been found feasible to use both biopsy and autopsy tumors to generate cultures and xenograft models. METHODS: To further model development, we evaluated the collective international experience from 8 collaborating centers to develop DIPG pre-clinical models from patient-derived autopsies and biopsies. Univariate and multivariate analysis was performed to determine key factors associated with the success of in vitro and in vivo PDX development. RESULTS: In vitro cultures were successfully established from 57% of samples (84.2% of biopsies and 38.2% of autopsies). Samples transferred in DMEM media were more likely to establish successful culture than those transported in Hibernate A. In vitro cultures were more successful from biopsies (84.2%) compared with autopsies (38.2%) and as monolayer on laminin-coated plates than as neurospheres. Primary cultures successfully established from autopsy samples were more likely to engraft in animal models than cultures established from biopsies (86.7% vs. 47.4%). Collectively, tumor engraftment was more successful when DIPG samples were directly implanted in mice (68%), rather than after culturing (40.7%). CONCLUSION: This multi-center study provides valuable information on the success rate of establishing patient-derived pre-clinical models of DIPG. The results can lead to further optimization of DIPG model development and ultimately assist in the investigation of new therapies for this aggressive pediatric brain tumor.

Revised antiemetics guidelines and the impact on nutritional status during induction chemotherapy in children with high-risk neuroblastoma.

BACKGROUND: High-risk neuroblastoma (HR NBL) treatment requires intensive induction chemotherapy. The profoundly emetogenic agents used can compromise nutritional status. Our institution introduced a new antiemetic guideline in 2010 incorporating regular dexamethasone, in addition to ondansetron, for all highly emetogenic protocols. PROCEDURE: A retrospective comparative review of pediatric patients diagnosed with HR NBL who received rapid COJEC induction chemotherapy as per HR-SIOPEN NBL trial. Prophylactic antiemetics were prescribed regardless of chemotherapy emetogenicity in group A (2004-2010) but for defined time periods considering chemotherapy emetogenicity in group B (2010-2017). RESULTS: Sixty-three children were eligible for inclusion (median age, 31 months; range, 1-88 months). Group A had more episodes of emesis than group B (189 vs. 116, P < 0.0001). There was a significant difference in weight-for-age Z score change between the groups by induction end (P = 0.0027). Four children (13%) in group A lost >10% body weight versus none in group B. Nutrition support (NS) was utilized by 29 children (94%) in group A and 22 children (69%) in group B. Group A had a median of 3 (range, 1-7) admissions for febrile neutropenia (FN) versus a median of 1.5 (range, 0-4) for group B (P = 0.003) during induction. CONCLUSION: The review of our guidelines led to reduced emesis frequency for group B. They also required less NS, followed expected growth trajectories more closely and had fewer FN admissions. We propose that this may have occurred due to better emesis control resulting in improved nutritional status and associated enhanced immune function.

18F-FDG PET Response of Skeletal (Bone Marrow and Bone) Involvement After Induction Chemotherapy in Pediatric Hodgkin Lymphoma: Are Specific Response Criteria Required?

To determine whether the current 18F-FDG PET response criterion for skeletal involvement in Hodgkin lymphoma (HL) is suitable, we performed a systematic evaluation of the different types of skeletal involvement and their response on PET after 2 cycles of chemotherapy (PET-2). A secondary objective was to observe the influence of the initial uptake intensity (measured as qPET) and initial metabolic tumor volume (MTV) of skeletal lesions on the PET-2 response. Methods: The initial PET scans of 1,068 pediatric HL patients from the EuroNet-PHL-C1 trial were evaluated for skeletal involvement by central review. Three types of skeletal lesions were distinguished: PET-only lesions (those detected on PET only), bone marrow (BM) lesions (as confirmed by MRI or BM biopsy), and bone lesions. qPET and MTV were calculated for each skeletal lesion. All PET-2 scans were assessed for residual tumor activity. The rates of complete metabolic response for skeletal and nodal involvement on PET-2 were compared. Results: Of the 1,068 patients, 139 (13%) showed skeletal involvement (44 PET-only, 32 BM, and 63 bone). Of the 139 patients with skeletal involvement, 101 (73%) became PET-2-negative in the skeleton and 94 (68%) became PET-2-negative in the lymph nodes. The highest number of PET-2-negative scans in the skeleton was 42 (95%) in the 44 PET-only patients, followed by 22 skeletal lesions (69%) in the 32 BM patients and 37 (59%) in the 63 bone patients. Lesions that became PET-2-negative showed a lower initial median qPET (2.74) and MTV (2 cm3) than lesions that remained PET-2-positive (3.84 and 7 cm3, respectively). Conclusion: In this study with pediatric HL patients, the complete response rate for skeletal involvement on PET-2 was similar to that for nodal involvement. Bone flare seemed to be irrelevant. Overall, the current skeletal PET response criterion-comparison with the local skeletal background-is well suited. The initial qPET and MTV of skeletal lesions were predictive of the PET-2 result. Higher values for both parameters were associated with a worse PET-2 response.

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.

We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

Development of the SIOPE DIPG network, registry and imaging repository: a collaborative effort to optimize research into a rare and lethal disease.

Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.

Tumor progression in DICER1-mutated cystic nephroma-witnessing the genesis of anaplastic sarcoma of the kidney.

We report a 7-month-old female infant with a multicystic left renal tumor having histologic features predominantly of a cystic nephroma, but with microscopic cellular foci which contained atypical mitotic figures and anaplastic nuclei. Immunohistochemistry showed strong p53 reactivity in the anaplastic region. DICER1 sequencing confirmed 2 mutations: germ line mutation c.2450delC and c.5438A>G somatic within the tumor. Despite an initial consideration of cystic partially differentiated nephroblastoma, the presence of anaplasia ruled that possibility out, as this is not an acceptable feature for that diagnosis. Moreover, the germ line DICER1 mutation prompted consideration that this case represents a unique "nascent" anaplastic sarcoma of kidney, and further immunohistochemical workup demonstrated cytoplasmic, but no nuclear WT-1 reactivity in the cellular foci. The importance of meticulous sampling of cystic lesions is highlighted by this unprecedented case, which lends support to the recent recognition of anaplastic sarcoma of kidney as a DICER1-associated cancer.

Rapid regression of left ventricular outflow tract rhabdomyoma after sirolimus therapy.

The neonatal presentation of cardiac rhabdomyomas varies in severity from severe outflow tract obstruction to minimal cardiac dysfunction. The natural history for these lesions is spontaneous regression in the majority of cases. We describe a newborn boy with severe left ventricular outflow tract obstruction secondary to a large rhabdomyoma. The tumor infiltrated the paraaortic area and extended around the origin of the right coronary artery, making surgical resection challenging. Oral sirolimus therapy resulted in a rapid regression of the tumor and alleviation of outflow tract obstruction within 1 month of treatment. This is the first report of sirolimus therapy in alleviating critical left ventricular outflow tract obstruction in this condition.