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Inherited heterozygous mutations in the MMR genes result in Lynch syndrome (LS). Individuals with biallelic mutation of one of the MMR genes developed malignancies in childhood. This recessively inherited condition is named CMMRD for constitutional mismatch repair deficiency. The spectrum of tumours is distinct from LS. Malignant brain tumours are at least as frequent as gastrointestinal tumours, and in more than a third of cases, haematological malignancies were also reported. Patients also displayed clinical features of neurofibromatosis type 1. The most commonly involved genes in CMMRD are PMS2 and MSH6, while biallelic MLH1 and MSH2 mutations are rare.

Background: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40–69) and 5-year overall survival was 65% (95% CI 52–81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. Funding: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

The role of percutaneous thermal ablation as a minimally-invasive treatment has not been evaluated in children under 18 years of age with pulmonary osteosarcoma metastases. This was a retrospective review of children treated with percutaneous thermal ablation for pulmonary osteosarcoma metastasis after prior surgical metastasectomy and chemotherapy. Selection criteria included number of pulmonary nodules

Background Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. Methods Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. Results 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2–33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26–213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations ( MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). Conclusions In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance.

Over 14 000 patients aged 15-24 are estimated to be diagnosed with cancer in the European Union (EU) each year. Teenagers and young adults (TYA) often fall down gaps between children's and adults cancer services. The specific challenges of providing optimal care to them are described, but we present a summary of recent progress. Progress to overcome these challenges is happening at different rates across Europe. We summarise the European national projects in this field but more recently we have seen the beginnings of European coordination. Within the EU 7th Funding Programme (FP7) European Network for Cancer Research in Children and Adolescents programme (ENCCA), a specific European Network for Teenagers and Young Adults with Cancer has held a series of scientific meetings, including professionals, patients and caregivers. This group has proposed unanswered research questions and agreed key features of a high-quality service that can improve outcomes for TYA with cancer, including the primacy of collaboration between adult and paediatric services to eliminate the gap in the management of TYA with cancer.

Resume Propos Faire un etat des lieux des difficultes d’insertion scolaire et professionnelle rencontrees par les adolescents et jeunes adultes (AJA, 15–25 ans) atteints de cancer et des moyens d’aides existant en France. Methodes Revue de la litterature nationale et internationale des difficultes d’insertion. Analyse des aides existantes sur les sites officiels et enquetes par questionnaire en ligne aupres des centres avec des programmes dedies aux AJA atteints de cancer, membres de l’association Go-AJA (Groupe onco-hematologie adolescents et jeunes adultes). Resultats Le fait d’etre ou d’avoir ete malade du cancer affecte sensiblement les parcours de vie, tant au niveau scolaire que professionnel, mais peu d’etudes specifiques a cette population existent en France. Les moyens d’aide a l’insertion des AJA sont plus importants, structures et anciens au niveau du secondaire que dans le superieur. Ils reposent sur des structures nationales et associatives. Mais les mesures d’accompagnement au niveau de la scolarite dans le secondaire et le superieur, ainsi que de l’insertion professionnelle sont insuffisantes. L’aide a l’insertion professionnelle repose principalement sur des assistantes sociales et rarement sur des professionnels dedies a cette activite, encore moins dedies a cette tranche d’âge. Des initiatives plus recentes dediees aux AJA ont vu le jour depuis 2012. Toutes ces aides sont inegalement reparties sur le territoire national. Conclusion Une enquete nationale sur les parcours scolaire et professionnel des AJA atteints de cancer est necessaire en France et va prochainement debuter. Un referentiel sur l’accompagnement de l’insertion des AJA atteints de cancer est en cours de preparation par GO-AJA en collaboration avec l’AFSOS (Association francophone des soins oncologiques de support).

Preserving fertility is a requisite for any child undergoing gonadotoxic treatment for cancer. Techniques vary depending on the age, sex of the patient and nature of the treatment. Boys undergoing irradiation have testicular protection or transposition. Post-pubertal boys undergoing chemotherapy can have semen cryopreservation like adults. However, fertility preservation for pre-pubertal boys undergoing chemotherapy implies testicular tissue cryopreservation. Research concentrates on germ cell transplantation, autotransplantation of testicular tissue or in vitro spermatogonial maturation in order to later restore spermatogenesis. Ovarian transposition can be undergone in case of brachytherapy or external beam radiotherapy in girls and has published success rates of 80%. Ovarian cryopreservation has been developed since 1995 for pre-pubertal and post-pubertal girls undergoing chemotherapy. The ovary is retrieved surgically and ovarian cortical segments are frozen. Thawing and transplantation of gonadal tissue are the next steps to restoring fertility. However, immature oocytes will have to be matured either in vivo or in vitro in order to restore fertility. Fertility preservation must be offered to children with cancer even if maturation of immature germ cells is uncertain for research 20 to 30 years from now will probably enable fertility restoration.

Background Rhabdomyosarcoma (RMS) occasionally occurs in a context of a predisposition syndrome. The most common predisposition syndromes include germline TP53 mutations and constitutive alterations in RAS pathway activation, such as Costello syndrome, Noonan syndrome and neurofibromatosis type 1. We report a national retrospective series of 16 RMS occurring in neurofibromatosis type 1 (NF1) patients during childhood, within a 20-year period. Results The mean age at diagnosis of the cancer was 2.5 years. All were embryonal subtype. Most tumours developed in the pelvis. One was metastatic. Chemotherapy and radiotherapy were normally scheduled without any specific toxicity. The 5-year event-free survival and overall survival were 67% and 87%, respectively. Long-term sequel related to chemotherapy consisted in two chronic tubulopathies, hence not obviously different from non-NF1 patients. No second cancer was reported so far with a median follow-up of 9.7 years. The genomic analysis performed on six samples revealed the abnormalities commonly observed in sporadic RMS: gain of chromosome 2 (5/6), 8 (6/6) and chromosome 11p loss of heterozygosity (5/6). Interestingly, we identified small deletions in tumour suppressor genes that may synergize with NF1 inactivation. Conclusions Patients with neurofibromatosis are prone to develop embryonal-type RMS that require the same treatment as sporadic cases. Pediatr Blood Cancer 2015;62:1733–1738. © 2015 Wiley Periodicals, Inc.

In the European Union, the pediatric medicines regulation in 2007 modified significantly the access to new agents in pediatric oncology. Early oncology trials are still thought to be associated with limited benefit and substantial risk. We report the characteristics and outcome of patients below 21 years enrolled in investigational trials in the Pediatric and Adolescent Department at Gustave Roussy between January 2000 and December 2012. A total of 235 patients (median age, 10.4 [0.8 to 20.7] y) were included in 26 trials (16 cytotoxic and 10 targeted agents) for a total of 260 inclusions. A total of 117 patients (50%) had brain tumors and 68 (29%) had various soft tissue and bone sarcoma. Thirteen of the 106 patients in a phase I trial experienced dose-limiting toxicity. Main severe toxicity was hematologic; none had toxic death. Grade 3 to 4 toxicities were associated with combination trials, cytotoxic agent, and at least 1 previous line of therapy. Thirty patients (12%) had objective response and 42 (16%) had stable disease for4 months. Median overall survival was 9.0 months (95% CI, 7.5-10.5) and 73% of patients received further anticancer treatment. Phase I to II pediatric oncology trials are safe, associated with clinical benefit, and can be successfully integrated in current relapse strategies.

High-dose irradiation is the cornerstone treatment of bone cancers of the pelvic rim. To protect the small bowel from irradiation and following consequences, we described the laparoscopic use of the sigmoid to perform a hammock.Three patients were diagnosed with metastatic Ewing's sarcoma, localized malignant peripheral nerve sheath tumor, and localized BCOR-CCNB3 (Ewing-like) sarcoma of the pelvic rim at 13.1, 5.7, and 12.9 years, respectively. After neoadjuvant chemotherapy, the 2 female patients underwent a hemisacrectomy under S2 only by the posterior approach, whereas no orthopedic surgery was required for the male patient because of excellent local response to chemotherapy. A 54-Gy intensity-modulated radiotherapy of the posterior part of the pelvis was intended for all patients.The laparoscopic procedure consisted in the fixation of the sigmoid loop to the anterior parietal wall on a transverse line just below the umbilicus, associated with a colostomy in the right iliac fossa. The anterior transposition of the two ovaries, uterus, and rectum and the dissection of left iliac vessels to move them anteriorly were added in female patients. Stomas were closed around 6 months after completion of the radiotherapy course, associated with the repositioning of the uterus, ovaries, and colon. With a mean follow-up of 22 months, all patients are alive without any recurrences or radiation-related symptoms.The laparoscopic "hammock technique" both protects the small bowel from irradiation and secures the orthopedic procedure by displacing the abdominal organs forward.

Background In most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014. Methods Treatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate. Results 409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7–24.5), with 55 patients aged 18–25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51–62%) and overall survival 71% (66–76%). Conclusion M-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen.

Background Efficacy and role of cytoreductive surgery (CRS) and hyperthermic peritoneal perfusion with chemotherapy (HIPEC) remain poorly documented in pediatric tumors. Methods This retrospective national study analyzed all pediatric patients with peritoneal tumor spread treated by CRS and HIPEC as part of a multimodal therapy in France from 2001 to 2015. Results Twenty-two patients (nine males and 13 females) were selected. The median age at diagnosis was 14.8 years (4.2-17.6). Seven had peritoneal mesotheliomas; seven, desmoplastic small round cells tumors (DSRCT); and eight, other histologic types. A complete macroscopic resection (CC-0, where CC is completeness of cytoreduction) was achieved in 16 (73%) cases. Incomplete resections were classified as CC-1 in four (18%) cases and CC-2 in two (9%) cases. Fourteen (64%) patients had complications within 30 days from HIPEC, requiring an urgent laparotomy in eight (36%) cases. Thirteen (59%) patients received adjuvant chemotherapy and four (18%) received total abdominal radiotherapy after surgery. Sixteen (72%) patients had relapse after a median time of 9.6 months (1.4-86.4) and nine (41%) eventually died after a median time of 5.3 months (0.1-36.1) from relapse. Six (27%) patients (four mesotheliomas, one pseudopapillary pancreatic tumor, and one DSRCT) were alive and in complete remission after a median follow-up of 25.0 months (5.3-78.2). The mean overall survival (OS) and disease-free survival (DFS) were 57.5 months (95% CI [38.59-76.32]) and 30.9 months (95% CI [14.96-46.77]). Patients with a peritoneal mesothelioma had a significantly better OS (p = 0.015) and DFS (p = 0.028) than other histologic type. Conclusions In this national series, outcomes of HIPEC are encouraging for the treatment of peritoneal mesothelioma in children.

About one third of patients with rhabdoid tumors (RT) harbor a heterozygous germline variant in SMARCB1. Molecular diagnosis therefore keeps a crucial place in the diagnosis of RT, and genetic counseling should be systematically recommended. However, immunohistochemistry has progressively replaced molecular tools to assess the status of SMARCB1 in tumors; the necessity of analyzing SMARCB1 status in the tumor may thus be less considered by neuropathologists and pediatric neuro-oncologists. In the present manuscript as aforementioned, we report on two patients with bifocal RT in the first month of life and in whom no germline variant was initially found in the SMARCB1 coding sequence. Careful analysis of SMARCB1 status in the tumors revealed that only one of the two inactivating hits was found in the coding sequence. By sequencing the tumor cells RNA, we were able to detect an insertion with an abnormal sequence, due to the same intronic variant of SMARCB1, which led to the exonisation of the first intron. This cryptic variant was absent in the germline DNA of both patients. Of note, we previously reported one patient with the same deep intronic variant in the germline in a soft tissue RT. To our mind, this additional report on two patients clearly demonstrates that this intronic variant is a new hotspot that should now be systematically added to the germline screening of SMARCB1. We therefore recommend searching for and cautiously interpreting germline analysis if SMARCB1 has not been extensively studied in the tumor.

Development of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germlineAmong 328 unrelated patients harbouring a germlineThis study performed on a large series of

This interim analysis of an ongoing randomized clinical trial presents preliminary findings regarding use of whole-body magnetic resonance imaging for cancer surveillance of TP53 mutation carriers.

Non-Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies with high incidence in adolescents and young adults (AYAs). The most common diseases include diffuse large B-cell lymphoma, anaplastic large cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, and primary mediastinal large B-cell lymphoma. In comparison to younger children and adults, AYAs (15-39 years) with NHL present a specific set of challenges including variations in tumor biology, inconsistent treatment, pharmacodynamics, and psychosocial barriers. While survival of AYAs with NHL has improved, cure rates remain suboptimal. Incorporation of novel agents into pediatric-inspired treatment regimens specifically designed for NHL in AYAs has led to improved outcomes. Consideration of AYAs as a distinct population in the diagnosis and treatment of NHL is encouraged.

Hereditary gastrointestinal cancer predisposition syndromes have been well characterized, but management strategies and surveillance remain a major challenge, especially in childhood. In October 2016, the American Association for Cancer Research organized the AACR Childhood Cancer Predisposition Workshop in which international experts in care of children with a hereditary risk of cancer met to define surveillance strategies and management of children with cancer predisposition syndromes. In this article, we review the current literature in polyposis syndromes that can be diagnosed in childhood and may be associated with an increased incidence of gastrointestinal neoplasms and other cancer types. These disorders include adenomatous polyposis syndromes (APC and MUTYH), juvenile polyposis coli (BMPR1A and SMAD4), Peutz–Jeghers Syndrome (STK11/LKB1), and PTEN hamartoma tumor syndrome (PHTS; PTEN), which can present with a more limited juvenile polyposis phenotype. Herein, the panel of experts provides recommendations for clinical diagnosis, approach to genetic testing, and focus on cancer surveillance recommendations when appropriate during the pediatric period. We also review current controversies on genetic evaluation of patients with hepatoblastoma and indications for surveillance for this tumor. Childhood cancer risks and surveillance associated with disorders involving the mismatch repair genes, including Lynch syndrome and constitutional mismatch repair deficiency (CMMRD), are discussed elsewhere in this series. Clin Cancer Res; 23(13); e107–e14. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Background Angiogenesis is essential for the progression and metastatic spread of solid tumours. Expression of vascular endothelial growth factor (VEGF) has been linked to poor survival among osteosarcoma patients but the clinical relevance of monitoring blood and urine angiogenic factors is uncertain. The aim of this study was to determine the prognostic significance of blood VEGF and blood and urinary basic fibroblast growth factor (bFGF) levels in osteosarcoma patients, both at diagnosis and during treatment. Methods Patients with localised or metastatic osteosarcoma enrolled in OS2005 and OS2006 studies between 2005 and 2011 were prospectively included in this study. VEGF and bFGF levels in serum and plasma and bFGF levels in urine were measured by ELISA at diagnosis, before surgery, and at the end of treatment. Endpoints considered for the prognostic analysis were histological response, progression-free and overall survival. Kruskal-Wallis tests were used to compare the distribution of baseline biomarker values across the different subgroups, and paired sample Wilcoxon rank tests were used to analyze changes over time. Association between biomarker levels and outcomes were assessed in multivariable models (logistic regression for histologic response, and Cox models for survival). Results Samples were available at diagnosis for 269 patients (54% males; age ≤ 18 years: 73%; localised disease in 68%, doubtful lung lesions in 17%, and metastases in 15%). High serum VEGF and bFGF levels were observed in respectively 61% and 51% of patients. Serum and plasma VEGF values were not strongly correlated with one another (r = 0.53). High serum and plasma VEGF levels were significantly more frequent in patients with large tumours (≥10 cm; p = 0.003 and p = 0.02, respectively). VEGF levels fell significantly during pre-operative chemotherapy (p

Replication proofreading is crucial to avoid mutation accumulation in dividing cells. In humans, proofreading and replication repair is maintained by the exonuclease domains of DNA polymerases and the mismatch repair system. Individuals harboring germline mutations in genes involved in this process are at increased risk of early cancers from multiple organs. Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1, and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency or constitutional mismatch repair deficiency syndrome (CMMRD). Data gathered in the last decade allow us to better define the clinical manifestations, tumor spectrum, and diagnostic algorithms for CMMRD. In this article, we summarize this information and present a comprehensive consensus surveillance protocol for these individuals. Ongoing research will allow for further definition of replication repair–deficient cancer syndromes, assessing the cost-effectiveness of such surveillance protocols and potential therapeutic interventions for these children and families. Clin Cancer Res; 23(11); e32–e37. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

Purpose: This single-institutional feasibility study prospectively characterized genomic alterations in recurrent or refractory solid tumors of pediatric patients to select a targeted therapy. Experimental Design: Following treatment failure, patients with signed consent and ages above 6 months, underwent tumor biopsy or surgical resection of primary or metastatic tumor site. These newly acquired samples were analyzed by comparative genomic hybridization array, next-generation sequencing for 75 target genes, whole-exome and RNA sequencing. Biological significance of the alterations and suggestion of most relevant targeted therapies available were discussed in a multidisciplinary tumor board. Results: From December 2012 to January 2016, 75 patients were included, 73 patients underwent 79 interventions, 56 of which were research biopsies with a low complication rate. All patients were pretreated, 37.0% had a brain tumor, and 63.0% had an extra-cranial solid tumor. Median tumor cell content was 70% (range, 0%–100%). Successful molecular analysis in 69 patients detected in 60.9% of patients an actionable alteration in various oncogenic pathways (42.4% with copy-number change, 33.3% with mutation, 2.1% with fusion), and change in diagnosis in three patients. Fourteen patients received 17 targeted therapies; two had received a matched treatment before inclusion. Conclusions: Research biopsies are feasible in advanced pediatric malignancies that exhibit a considerable amount of potentially actionable alterations. Genetic events affecting different cancer hallmarks and limited access to targeted agents within pediatric clinical trials remain the main obstacles that are addressed in our two subsequent precision medicine studies MAPPYACTS and AcSé-ESMART. Clin Cancer Res; 23(20); 6101–12. ©2017 AACR.

Resume Des progres recents dans les traitements ont permis l’augmentation des taux de survie des enfants et des adolescents souffrant de cancer. Les traitements gonadotoxiques pris pendant l’enfance peuvent alterer la fertilite future de ces patients. La preservation de la fertilite doit etre evoquee avant la mise en route de ces traitements. La cryoconservation de cortex ovarien est la seule technique existante de preservation de la fertilite pour les petites filles prepuberes et doit etre proposee si le risque d’insuffisance ovarienne prematuree est important. Cette approche ne differe pas les traitements pour le cancer et permet le stockage de follicules, qui pourront etre utilises, dans l’avenir, soit in vivo (autogreffe de cortex ovarien), soit in vitro (cultures de follicules ovariens) pour obtenir des ovocytes matures. A ce jour, au moins 26 enfants sont nes apres une autogreffe de cortex ovarien congele/decongele. Une grossesse vient d’etre rapportee apres greffe de cortex ovarien preleve alors que la patiente etait prepubere. Cette possibilite d’utilisation du cortex ovarien n’est pas possible pour toutes les patientes a cause du risque de reintroduction de la maladie car le tissu ovarien est retire avant les traitements gonadotoxiques. La restauration de la fertilite pourrait alors se faire par le developpement et la maturation in vitro de l’ovocyte au sein du follicule. Actuellement, dans l’espece humaine, aucun ovocyte mature n’a ete obtenu apres maturation ovo-folliculaire in vitro. Concernant la fonctionnalite du tissu ovarien preleve avant la puberte, il a ete montre par deux fois que la greffe de cortex ovarien preleve chez des enfants prepuberes a permis d’induire une puberte spontanee confirmant la capacite fonctionnelle du tissu ovarien congele avant la puberte.

Pheochromocytomas and paragangliomas (PHEO/PGL) are neuroendocrine tumors that arise from sympathetic and parasympathetic paraganglia. Although well described in the adult population, diagnosis and treatment of these exceptionally rare neoplasms remains poorly characterized in children. This article reviews recent advances in clinical presentation, genetics, biochemistry, imaging and treatment of children with benign or malignant PHEO/PGL. Compared to adults, pediatric PHEO/PGL are more frequently familial, bilateral, multifocal and malignant. Approximately 50% of pediatric PHEO/PGL are associated with a mutation of one of the 12 known susceptibility genes. Von Hippel-Lindau disease, type 1 neurofibromatosis, type 2 multiple endocrine neoplasia and familial PGL syndrome are hereditary tumor syndromes associated with an increased risk of developing such diseases. Clinical presentation includes symptoms related to catecholamine hypersecretion and/or tumor mass effect. Plasma and/or urine metanephrine dosages are recommended as first-line diagnostic biochemical tests. Magnetic resonance imaging is useful as initial radiological approach. Most pediatric PHEO/PGLs are benign. Surgical resection, with appropriate perioperative management of catecholamine-related symptoms, remains the treatment of choice. In case of metastatic disease, surgical removal of metastases when possible and I-131-MIBG radiotherapy provide limited results whereas chemotherapy is reserved for more advanced stages.

Resume Objectif Le retour en classe des collegiens et lyceens traites pour un cancer est essentiel, mais complexe. Un dispositif experimental d’intervention en classe et/ou en equipe educative a ete mis en place pour faciliter le retour en classe de ces adolescents. Cette etude a pour objet d’evaluer les quatre annees scolaires d’existence de ce dispositif. Methode Des questionnaires (2) et un entretien semi-directif ont ete proposes aux patients ayant beneficie du dispositif, juste apres et a distance de l’intervention. A titre comparatif, un questionnaire et un entretien semi-directif a ete propose a des adolescents n’ayant pas beneficie du programme. Des questionnaires d’evaluation ont ete proposes aux eleves des classes concernees et aux equipes educatives. Resultats Sur 23 interventions preparees, 15 interventions ont pu etre realisees. Les 11 patients ayant ete accompagnes en classe ont repondu aux premiers questionnaires, sept ont repondu aux deuxiemes et/ou ont realise un entretien et 142 questionnaires ont ete remplis par des eleves de college et lycee. Dans l’etude comparative, 21 patients ont pu etre inclus. Ce dispositif legitime la parole des familles et permet une meilleure sensibilisation des equipes aux « handicaps invisibles ». En repondant aux interrogations des camarades de classes, le dispositif evite questions indiscretes et moqueries pour le patient-eleve.

Background This retrospective multicenter study assessed the clinical, radiological and pathological presentation, treatment and outcome of 26 patients with Ewing-like sarcoma harboring BCOR-CCNB3 gene fusion transcript. Tumor samples had been collected between 1994 and April 2012. Procedure Eligibility criteria included assessment of a BCOR-CCNB3 transcript-positive tumor after molecular analysis and availability of minimal clinical and pathological data. Radiological data were also retrieved when possible. Data were analyzed by descriptive statistics and methods for survival analysis. Results Median age at diagnosis was 13.1 years (5.9 to 25.6 years). Most patients (24/26) had localized tumors. All tumors but five were localized to bone. CCNB3 immunochemistry showed strong nuclear staining on all samples. No specific radiological features were found. Most patients received chemotherapy (15 according to protocols designed for Ewing tumors), before and/or after local treatment (surgery and/or radiotherapy, with 46.2% receiving both). Local and metastatic relapses were of poor prognosis. Induction chemotherapy and treatment according to an Ewing protocol might influence survival for patients with localized tumors. Sixteen patients are alive in complete remission with a median follow-up of 86 months. Five year overall survival and disease-free survival were respectively 76.5% (95% CI, 58%–95%) and 67.9% (95% CI, 48%–88%). Conclusions BCOR-CCNB3 transcript-positive Ewing-like sarcoma diagnosis should be discussed for a transcript-negative small round cell sarcoma in a child, adolescent or young adult patient. Diagnosis needs to be stated through CCNB3 immunochemistry or transcript identification. The exquisite chemosensitivity of these tumors should encourage the use of polychemotherapy for appropriate care, associated with best local tumor control. Pediatr Blood Cancer 2014;61:2191–2198. © 2014 Wiley Periodicals, Inc.

Fibrolamellar hepatocellular carcinoma (FLC) is a rare subtype of liver cancer occurring mostly in children and young adults. We have shown that FLC comprises two separate entities: pure (p-FLC) and mixed-FLC (m-FLC), differing in clinical presentation and course. We show that p-FLCs have a distinct gene expression signature different from that of m-FLCs, which have a signature similar to that of classical hepatocellular carcinomas. We found p-FLC profiles to be unique among 263 profiles related to diverse tumoral and nontumoral liver samples. We identified two distinct molecular subgroups of p-FLCs with different outcomes. Pathway analysis of p-FLCs revealed ERBB2 overexpression and an up-regulation of glycolysis, possibly leading to compensatory mitochondrial hyperplasia and oncocytic differentiation. Four of the sixteen genes most significantly overexpressed in p-FLCs were neuroendocrine genes: prohormone convertase 1 (PCSK1); neurotensin; delta/notch-like EGF repeat containing; and calcitonin. PCSK1 overexpression was validated by immunohistochemistry, yielding specific, diffuse staining of the protein throughout the cytoplasm, possibly corresponding to a functional form of this convertase. Conclusion: p-FLCs have a unique transcriptomic signature characterized by the strong expression of specific neuroendocrine genes, suggesting that these tumors may have a cellular origin different from that of HCC. Our data have implications for the use of genomic profiling for diagnosis and selection of targeted therapies in patients with p-FLC. (Hepatology 2014;59:2228–2237)

Constitutional mismatch repair deficiency (CMMRD) syndrome is a distinct childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four MMR genes, MLH1, MSH2, MSH6 or PMS2. The tumour spectrum is very broad, including mainly haematological, brain and intestinal tract tumours. Patients show a variety of non-malignant features that are indicative of CMMRD. However, currently no criteria that should entail diagnostic evaluation of CMMRD exist. We present a three-point scoring system for the suspected diagnosis CMMRD in a paediatric/young adult cancer patient. Tumours highly specific for CMMRD syndrome are assigned three points, malignancies overrepresented in CMMRD two points and all other malignancies one point. According to their specificity for CMMRD and their frequency in the general population, additional features are weighted with 1-2 points. They include multiple hyperpigmented and hypopigmented skin areas, brain malformations, pilomatricomas, a second childhood malignancy, a Lynch syndrome (LS)-associated tumour in a relative and parental consanguinity. According to the scoring system, CMMRD should be suspected in any cancer patient who reaches a minimum of three points by adding the points of the malignancy and the additional features. The diagnostic steps to confirm or refute the suspected diagnosis are outlined. We expect that application of the suggested strategy for CMMRD diagnosis will increase the number of patients being identified at the time when they develop their first tumour. This will allow adjustment of the treatment modalities, offering surveillance strategies for second malignancies and appropriate counselling of the entire family.

The study's purpose was to assess whether individuals who developed a second malignant neoplasm (SMN) after treatment for a first malignant neoplasm (FMN) had a lower ability to repair DNA double-strand breaks (DSBs) using a bioassay with γH2AX intensity as a surrogate endpoint. In a case-control study nested in a cohort of childhood cancer survivors, lymphoblastoid cell lines (LCLs) were established from blood samples collected from 94 cases (SMN) and 94 matched controls (FMN). LCLs were irradiated with ionizing radiation (2 and 5 Gy) and γH2AX intensities measured 1, 3, 5 and 24h post-irradiation. Differences in mean γH2AX intensity between cases and controls were compared using Kruskal-Wallis tests. Generalized linear models for repeated measures and conditional logistic regressions for SMN risk estimates were performed. The mean baseline γH2AX intensity measured without irradiation was 9.1 [95% confidence interval (95% CI): 8.5-9.7] in the LCLs from cases and 6.4 (95% CI: 6.0-6.8) from controls (P < 0.001). Markedly higher γH2AX intensity, particularly at 1 h post-irradiation, was also found in the LCLs from the cases compared with the controls for all FMNs and for different types of FMN. Chemotherapy and radiation doses received by bone marrow and thymus for FMN treatment showed a non-significant effect on γH2AX intensity. This case-control study shows that higher baseline and post-irradiation levels of DNA DSBs, as measured by γH2AX intensity, are associated with the risk of SMN in childhood cancer survivors. Further investigations in a prospective setting are warranted to confirm this association.

Resume Objectif L’objectif de cette etude etait d’evaluer l’action de la relaxation sur les differents symptomes rencontres par les adolescents et les jeunes adultes en cours de traitement pour une tumeur. Methodes Une seance de relaxation etait systematiquement proposee a tous les patients de plus de 12 ans pris en charge dans le departement de pediatrie de l’institut Gustave-Roussy. L’impact de la relaxation sur la fatigue, la tristesse, les tensions, le mal-etre corporel, les douleurs, les nausees et le stress, a ete evalue par une echelle numerique (de 0 a 10 pour chaque item) donnee avant et apres chaque seance. Resultats Nous avons etudie 284 seances chez 71 patients, realisees entre mars et decembre 2007. Avant la relaxation, le pourcentage de seances pour lesquelles le score est superieur a 0 est de 84 % pour la fatigue, 78 % pour la tension, 54 % pour la douleur, 50 % pour le stress, 48 % pour le mal-etre corporel, 42 % pour la tristesse et 38 % pour les nausees. Pour chaque item, il existe une diminution du score moyen apres la seance de relaxation (−1,2 a −2,8 points). Elle est superieure a 2 points pour les items de la tension, du mal-etre corporel et du stress. Conclusion La relaxation a une action positive sur les 7 symptomes evalues et souvent rencontres par les enfants et les adolescents traites pour un cancer. Elle est bien acceptee par les patients, participe a l’amelioration de leur qualite de vie et apporte un soutien complementaire de la prise en charge medicale et psychologique classique.

Introduction. Osteosarcoma relapse has a poor prognosis, with less than 25% survival at 5 years. We describe the experience of the French Society of Paediatric Oncology (SFCE) with high dose (HD) thiotepa and autologous stem cell transplantation (ASCT) in 45 children with relapsed osteosarcoma.Patients and Methods. Between 1992 and 2004, 53 patients received HD thiotepa (900 mg/m2) followed by ASCT in 6 centres. Eight patients were excluded from analysis, and we retrospectively reviewed the clinical radiological and anatomopathological patterns of the 45 remaining patients.Results. Sixteen girls and 29 boys (median age, 15.9 years) received HD thiotepa after initial progression of metastatic disease (2), first relapse (26), and second or third relapse (17). We report 12 radiological partial responses and 9 of 31 histological complete responses. Thirty-two patients experienced further relapses, and 13 continued in complete remission after surgical resection of the residual disease. Three-year overall survival was 40%, and 3-year progression-free survival was 24%. Delay of relapse (+/− 2 years from diagnosis) was a prognostic factor (P=0.011). No acute toxic serious adverse event occurred.Conclusion. The use of HD thiotepa and ASCT is feasible in patients with relapsed osteosarcoma. A randomized study for recurrent osteosarcoma between standard salvage chemotherapy and high dose thiotepa with stem cell rescue is ongoing.

Identification of new treatments for relapsing pediatric cancer is an unmet clinical need and a societal challenge. Hepatoblastoma (HB) is a rare tumor that constitutes the most frequent form of childhood liver cancer. Current improvement in medical care allows 80% of children to survive this disease, but no second line treatment is available at relapse, so that 20% will not survive. Patient population small size and very low mutation rate besides beta-catenin activating mutation, which is at present undruggable, make HB an orphan disease. Very few anti-cancer drugs evaluated for adult diseases are investigated in the pediatric population, with 12 drugs approved for adult cancers every year against 6 drugs approved in childhood cancer since 1978. The need of incentives to encourage pharmaceutical industry to invest in this field has been well received by the European and US medicine agencies, and recent modification to regulations on adult and pediatric oncology drug development are expected to induce pharmaceutical companies to test their new compounds in the pediatric setting. Parallel to this initiative, it is imperative that the scientific community develops research tools and scientific rational to assist drug development as well as repositioning of drugs already approved in adult cancers. To this aim, in collaboration with the International Childhood Liver Tumour Strategy Group (SIOPEL) and the network of hospitals in the Paris area (AP-HP), XenTech has launched in 2010 the development of a panel of HB patient-derived xenografts (HB-PDXs). To date, 26 HB-PDXs have been established from 80 engraftments from patients at surgery after chemotherapy or at relapse. As these models were established from tumor cells that either evaded chemotherapy or promoted local and distant metastases, they present a biological surrogate of the recurrent disease. From these PDXs, 9 cellular models have been established to allow the exploration of the functional mechanisms of tumor growth and resistance to treatment, as well as to facilitate drug screening. This project is receiving worldwide participation from the HB scientific community including clinicians, academic researchers and parents associations. Thanks to this joint effort all the models are now fully characterized at the molecular level, PDXs pharmacological profiling has been done and is currently ongoing for many of these models, and PDXs and cellular models are being used from a growing number of collaborators to perform 3D culture, to improve our knowledge on the HB biology and to identify new drugs. The ambition of this project is to generate a reference preclinical platform that will be used for research purposes by the academic community and as a testing site for biotechs and pharmaceutical companies to accelerate the identification of anti-cancer therapies for children with aggressive HB. Citation Format: Carolina Armengol, Roland Kappler, Liqin Zhu, Nikolai Timchenko, Dina Kats, Charles Keller, Lisa Howard, Christophe Grosset, Delphine Nicolle, Olivier Déas, Martina Pigazzi, Laurence Brugières, Charlotte Mussini, Louise Galmiche-Rolland, Christophe Chardot, Sophie Brancereau, Jean-Gabriel Judde, Stefano Cairo. A scientific task force to generate proof-of-concept data packages for clinical trials in pediatric cancers: The hepatoblastoma example [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3107.

Purpose: Li-Fraumeni syndrome (LFS), due to TP53 germline mutations, is characterized by high incidence of multiple cancers. Dysregulation of the TP53 pathway is associated with changes in chemokine production and reduced tumor immune infiltration in some cancer types. Recent works also suggested that TP53 negatively regulates PDL1 expression through the non-coding RNA miR-34. To better understand immune evasion of LFS spectrum cancers and to explore the feasibility of PD1/PDL1 targeted therapies as an alternative to genotoxic treatments in LFS patients, we investigated a range of LFS-related tumor types for PDL1 expression and tumor-infiltrating immune cells. Methods: We retrospectively collected a total of 72 tumor samples (osteosarcoma=32, rhabdomyosarcoma=11, adrenocortical carcinoma=11 and breast carcinoma=18) from 60 pediatric and adult patients identified through the LFS French database and direct contact with oncologic centers. Immunochemistry analyses were performed on whole slide sections. PDL1 staining was performed using the clone E1L3N (Cell Signaling Technology) according to the standard automated protocols. Immune infiltrate was characterized by the following antibody panel: CD8, FOXP3 and CD68. For CD8+ and FoxP3+ T cells, cell density per surface unit was determined by cell counting; for CD68+ macrophages, a semi-quantitative scoring (from 0 to 4) was performed. Results: Median age of patients was 13 years (range: 6-23) for osteosarcoma, 1.7 years (range: 0.8-5) for rhabdomyosarcoma, 2.3 years (range: 0.4-6) for adrenocortical carcinoma and 27.5 years (range: 22-54) for breast carcinoma. Seven patients presented ≥2 metachronous tumors. Biopsy was performed at diagnosis for 68 patients, at relapse for 3 patients and at early progression for one patient. None of the samples presented any detectable PDL1 expression neither on tumor cells nor on tumor microenvironment. Low/very low amount of CD8+ cytotoxic T-cells was displayed, regardless of the histology. FoxP3+ regulatory T-cell infiltration varied among tumor types. Thirty-five/72 tumors (49%) did not contain regulatory T cells. Breast carcinomas presented significant amounts of regulatory T cells (16/18, 89%), but at low density for 10 out of 16 samples (62%). Sixty-two/72 tumors (86%) presented CD68+ macrophage infiltrates, with high density in 37/62 (60%) of them (score ≥ 2+). Conclusion: The absence of PDL1 expression on tumor cells and microenvironment as well as the low amount of regulatory T cells do not support the hypothesis of PDL1 induction through p53 inactivation in LFS. The role of innate immunity needs to be explored to identify alternative immunological targets. Citation Format: Emilie Saucier, Claudia Pasqualini, Louise Galmiche, Frédérique Larousserie, Marie Karanian, Véronique Minard-Colin, Birgit Geoerger, Dominique Valteau-Couanet, Laurence Brugières, Jean-Yves Scoazec. Programmed death-ligand 1 expression and tumor-infiltrating immune cells in cancers associated with Li-Fraumeni syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 979.

10061 Background: Platinum chemotherapy (CT) and cranial radiotherapy (RT) are risk factors of ototoxicity. Effects of RT dose at inner ear and of other CT were investigated. Methods: Of 7670 5-year childhood cancer survivors from the FCCSS treated before 20 years of age in 1942-2000 for solid cancer or lymphoma, 5243 with ototoxicity long-term follow-up data were included. Severe ototoxicity, defined as the need of hearing aids or Brock grade 3-4 hearing loss, was identified from self-administrated questionnaires, clinical visits and cohort linkage with the French Hospital Database and health insurance information system (SNIIRAM). The mean RT dose at inner ear was estimated using home-made software. Multivariable Cox models adjusted for gender, age at diagnosis, time period and social deprivation index was used to identify risk factors for severe ototoxicity. Results: After a mean follow-up of 30 years, 199 cases of severe ototoxicity were identified. Cumulative incidences at 30 and 50 years of age (30,50y-CumInc) were, 2.8% (95%CI = 2.4-3.3) and 5.5% (4.6-6.5), respectively. Mean RT dose at inner ear (Hazard Ratio HR = 1.6 (95%CI = 1.0-2.5), 4.5 (2.7-7.2), 5.7 (3.0-10.8) and 14.0 (9.2-21.2) for 0- < 5, 5- < 30, 30- < 40 and ≥40 Gy), as well as cisplatin (HR = 2.8, 95%CI = 1.9-4.0), melphalan (HR = 3.3, 95%CI = 1.9-5.7) and busulfan exposure (HR = 2.6, 95%CI = 1.6-4.4) were significantly associated with severe ototoxicity. Concerning melphalan (n = 199/5243 exposed), almost all cases were identified in neuroblostma patients (NBL), who also received cisplatin 200mg/m²/cycle (26/92 NBL, 30y-CumInc = 36.4% (95%CI = 25.9-48.4), vs. 3/107 non-NBL, 30y-CumInc = 1.6% (0.4-5.6)). Concerning busulfan (n = 131/5243 exposed), all cases were identified in NBL (n = 16/63, all treated with melphalan and cisplatin) and brain tumors (n = 13/28, all with RT at inner ear ≥5Gy). The 30y-CumInc in patients with RT at inner ear ≥5Gy was 7.4% (95%CI = 5.7-9.6) and 39.8% (22.5-60.0) respectively with and without busulfan. Conclusions: RT at inner ear has significant deleterious impact on audition, with cumulative incidence still worsening > 30years after RT, and with likely potentiation by busulfan. The deleterious effect of melphalan was related to previous treatment with cisplatin, either by interaction between these drugs, or by the high cisplatin dose by cycle used in NBL.

11014 Background: The survival of pediatric OS is stable worldwide since two decades. The management of OS is lacking new approaches to classify closely the patients and adapt thereafter the treatments. The objectives of our molecular study, using allelotyping, quantitative PCR (qPCR) and droplet digital PCR (ddPCR), were to determine the survival impact of tumor molecular profiling in the initial tumor biopsy, in the tumor resection after neoadjuvant chemotherapy and on circulating DNA at different treatment steps. The gene panel based on biomarkers of bone dedifferentiation was already identified in the large tumor cohort of the French national protocol OS94 and demonstrated a significant prognostic impact of 3 genes MET, TWIST and APC. To go further and understand its significance throughout protocols, the same study was performed in OS2006 tumors. Methods: We applied retrospectively in the cohort of OS2006 protocol (135 patients) the same molecular assessment comprising the targeting of those 3 genes with 3 techniques evaluating their rearrangement by allelotyping, their copy number variations by qPCR and ddPCR. A preliminary cohort of 20 patients with liquid biopsies at diagnosis, before tumor surgery and at the end of chemotherapy was screened by ddPCR. Results: We were able to determine frequent rearrangements in the regions containing these 3 genes and a statistically significant correlation was made between the presence of a gene rearrangement and a worst outcome. The 3-gene signature was significantly predicting the outcome of more than 85% of patients diagnosed for an OS. Furthermore, the persistence of those genes’ rearrangements in the primitive tumor after neoadjuvant chemotherapy comparatively to the initial biopsy was correlated to a higher risk of relapse. This 3-gene signature was also used for assessment of residual disease (RD) in liquid biopsies and was able to determine before tumor surgery the level of RD. Conclusions: This molecular signature seems to be clearly associated with patient outcome and was able to provide evidence that this approach is a powerful tool to be used in pediatric OS follow up to determine early relapse or progression.

Resume L’hepatoblastome est la tumeur maligne hepatique la plus frequente, dont l’incidence est en voie d’augmentation. Elle atteint surtout l’enfant de moins de 3 ans, indemne de pathologie hepatique sous-jacente. Meme si l’etiologie reste largement inconnue, il existe des facteurs de predisposition genetique. L’hepatoblastome apparait comme une tumeur bien circonscrite avec le plus souvent une augmentation importante de l’alfa-fœtoproteine serique. La semiologie radiologique est le reflet de la composante histologique (forme epitheliale ou mixte). La realisation d’une biopsie est neanmoins necessaire non seulement pour confirmer le diagnostic mais aussi pour rechercher des facteurs histo-pronostiques et permettre une classification de la tumeur puis une stratification du traitement. Celui-ci repose sur une chimiotherapie a base de cisplatine associee a une exerese de la tumeur, pouvant parfois conduire a une transplantation hepatique en premiere remission. L’intensification de la chimiotherapie facilite la chirurgie d’exerese complete et permet d’obtenir une survie globale d’environ 80 % a 3 ans.

Medulloblastomas (MB) are classified in four subgroups: the well defined WNT and Sonic Hedgehog (SHH) subgroups, and the less defined groups 3 and 4. They occasionally occur in the context of a cancer predisposition syndrome. While germline APC mutations predispose to WNT MB, germline mutations in SUFU, PTCH1, and TP53 predispose to SHH tumors. We report on a child with a Rubinstein-Taybi syndrome (RTS) due to a germline deletion in CREBBP, who developed a MB. Biological profilings demonstrate that this tumor belongs to the group 3. RTS may therefore be the first predisposition syndrome identified for non-WNT/non-SHH MB.

In an international study of systemic childhood ALCL, 12/463 patients had CNS involvement, three of which had isolated CNS disease. Comparative analysis of CNS positive and negative patients showed no difference in ALK positivity, immunophenotype, presence of B symptoms or other sites of disease. The lymphohistiocytic variant was over represented in the CNS positive group (36% vs. 5%). With multi-agent chemotherapy, including high dose methotrexate, Ara-C and intrathecal treatment, the event free and overall survival of the CNS positive group at 5 years were 50% (95%CI, 25-75%) and 74% (45-91%), respectively with a median follow up of 4.1 years.

RESUME Les petites filles traitees pour un cancer sont a risque de developper une dysfonction hormonale ovarienne ou une infertilite du fait de la gonadotoxicite de certaines molecules de chimiotherapie et/ou de la radiotherapie. En consequence, la preservation de la fertilite doit etre evoquee avant la mise en route de traitements gonadotoxiques. La cryoconservation de cortex ovarien est la seule technique existante de preservation de la fertilite pour les petites filles prepuberes et doit etre proposee si le risque d’insuffisance ovarienne prematuree est important. Cette approche prometteuse permet le stockage d’un grand nombre de follicules, qui pourront etre, dans l’avenir, soit transplantes soit cultives pour obtenir des ovocytes matures. Les resultats de la cryoconservation de cortex ovarien chez l’adulte sont encourageants car au moins une vingtaine d’enfants sont nes apres autogreffe orthotopique de cortex ovarien prealablement congele. Il a ete aussi montre par deux fois que la greffe de cortex ovarien preleve chez des enfants prepuberes a permis d’induire une puberte spontanee confirmant la capacite fonctionnelle du tissu ovarien congele avant la puberte.

La preservation de la fertilite des jeunes patients traites par chimiotherapie, chirurgie ou radiotherapie est une preoccupation constante des oncologues. La congelation de sperme est une technique validee, facilement realisable et accessible en theorie a tout jeune homme pubere physiquement capable d’ejaculer. Pourtant, les oncologues et en particulier les pediatres rencontrent des difficultes a aborder cette question avec les adolescents et leur famille. Devant ce constat, un livret d’information intitule « Le CECOS c’est quoi ? » a ete realise avec l’aide d’adolescents. Grâce a un financement de la Ligue contre le cancer, dans le cadre des appels d’offres « adolescents et cancer », ce livret a pu etre distribue dans les services d’oncologie pediatrique francais (centres SFCE pour Societe francaise du cancer de l’enfant). Dans quatre d’entre eux, un questionnaire de satisfaction a ete donne avec le livret. Nous rapportons ici les resultats de l’analyse des questionnaires de satisfaction distribues, ainsi que les resultats d’une enquete nationale realisee aupres des centres d’oncologie pediatrique de la SFCE afin d’apprehender le niveau d’information des praticiens concernant l’existence de ce livret et leur satisfaction depuis sa mise a disposition. Les resultats de ces deux enquetes sont tres positifs et les adolescents comme les medecins reconnaissent la pertinence et l’utilite de cet outil.

Background The most appropriate design of Phase-II trials evaluating new therapies in osteosarcoma remains poorly defined. Objective To study consistency in phase-II clinical trials evaluating new therapies for osteosarcoma recurrences with respect to eligibility criteria, response assessment, end-points, statistical design and reported results. Methods Systematic review of clinical trials registered on clinicaltrials.gov, clinicaltrialsregister.eu and French National Cancer Institute website or referenced in PubMed and American Society of Clinical Oncology websites, between 2003 and 2016, using the following criteria: (osteosarcoma OR bone sarcoma) AND (Phase-II). Results Among the 99 trials identified, 80 were Phase-II, 17 I/II and 2 II/III, evaluating mostly targeted therapy (n = 40), and chemotherapy alone (n = 26). Results were fully (n = 28) or partially (abstract, n = 6) published. Twenty-four trials were dedicated to osteosarcoma, 22 had an osteosarcoma stratum. Twenty-eight out of 99 trials refer to the age range observed at recurrence (28%). Overall, 65 trials were run in multicentre settings, including 17 international trials. Only 9 trials were randomised. The primary end-point was tumour response in 71 trials (response rate, n = 40 or best response, n = 31), with various definitions (complete + partial ± minor response and stable disease), mainly evaluated with RECIST criteria (n = 69); it was progression-free survival in 24 trials and OS in 3. In single-arm trials evaluating response rate, the null hypothesis tested (when available, n = 12) varied from 5% to 25%. Conclusion No robust historical data can currently be derived from past efficacy Phase-II trials. There is an urgent need to develop international randomised Phase-II trials across all age ranges with standardised primary end-point.

Lymphomas are one of the commonest malignancies in adolescents and young adults (AYA) accounting respectively for 22% of all cancers in patients aged 15-24 years (16% for Hodgkin lymphoma (HL) and 6% for non-HL (NHL)). The distribution of NHL subtypes in this age group differs strikingly from the distribution in children and in older adults with 4 main subtypes accounting for the majority of the cases: diffuse large B-cell lymphoma (DLBCL) including primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma or anaplastic large cell lymphoma. Age-related differences in tumor biology have been demonstrated mainly in DLBCL but there is still a need for biological studies to better understand age-related differences in this age group. AYA patients currently diagnosed with HL and NHL have 5-year survival expectations exceeding 90 and 75%, respectively. Different therapeutic strategies are often used in children and adult lymphoma and the dispersion of lymphoma care between adult and pediatric hematologist-oncologists results in heterogeneous strategies for each subgroup according to age. The impact of these different strategies on outcomes is not easy to evaluate given the paucity of population-based data focused on this age group, taking into account tumor biology and the lack of a uniform staging system. Given the excellent results obtained with current therapies, the challenge now is to develop strategies aimed at reducing acute and long-term toxicity in most patients while maintaining high cure rates and to identify patients at high risk of failure requiring new strategies including more selective targeted therapies.

Purpose Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations and outcomes in children. The somatic BRAFV600E mutation occurs frequently, but clinical significance remains to be determined. Patients and Methods BRAFV600E mutation was investigated in a French LCH cohort. We analyzed associations between mutation status and clinical presentation, extent of disease, reactivation rate, response to therapy, and long-term permanent sequelae. Results Among 315 patients with successfully determined BRAF status, 173 (54.6%) carried a BRAFV600E mutation. Patients with BRAFV600E manifested more severe disease than did those with wild-type BRAF. Patients with BRAFV600E comprised 87.8% of patients (43 of 49) with multisystem LCH with risk organ involvement (liver, spleen, hematology), 68.6% of patients (35 of 51) with multisystem LCH without risk organ involvement, 43.9% of patients (86 of 196) with single-system LCH, and 42.1% of patients (8 of 19) with lung-involved LCH (P < .001). BRAFV600E mutation was also associated with organ involvement that could lead to permanent, irreversible damage, such as neurologic (75%) and pituitary (72.9%) injuries. Compared with patients with wild-type BRAF, patients with BRAFV600E more commonly displayed resistance to combined vinblastine and corticosteroid therapy (21.9% v 3.3%; P = .001), showed a higher reactivation rate (5-year reactivation rate, 42.8% v 28.1%; P = .006), and had more permanent, long-term consequences from disease or treatment (27.9% v 12.6%; P = .001). Conclusion In children with LCH, BRAFV600E mutation was associated with high-risk features, permanent injury, and poor short-term response to chemotherapy. Further population-based studies should be undertaken to confirm our observations and to assess the impact of BRAF inhibitors for this subgroup of patients who may benefit from targeted therapy.

Objectives The aim of this retrospective international analysis was to evaluate the role of risk factors in pediatric patients with adrenocortical carcinoma (ACC) observed in European countries (2000–2013) in an attempt to identify factors associated with poor prognosis. Procedures Data were retrieved from databases of Germany, France, Poland, and Italy, which form the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT). Patients were less than 18 years old, with at least one of the following tumor-related risk factors: metastases, volume more than 200 cm3, Cushing syndrome, vascular or regional lymph node invasion, initial biopsy, or incomplete excision. Role of patients’ age was also evaluated. Results Eighty-two patients were evaluated: 62 with localized disease and 20 with metastases. The 3-year progression-free survival (PFS) and overall survival (OS) were 39% and 55% for the whole population, respectively, and 51% and 73% for localized diseases, respectively. Concerning the whole population, PFS and OS were influenced by distant metastases, tumor volume, lymph node involvement, age, and presence of two or more risk factors. Factors significant only at OS were vascular involvement and incomplete surgery. At multivariable analysis, the main factors at PFS were volume more than 200 cm3 (hazard ratio [HR]: 2.6, 95% confidence interval [CI]: 1.18–5.70) and presence of distant metastases (HR: 8.26, 95% CI: 3.49–19.51). The OS was significantly influenced by the presence of metastases (P < 0.0001). Concerning patients with localized tumors, the only significant prognostic factor was volume more than 200 cm3 with a HR of 4.38 (95% CI: 1.60–12.00) for PFS and of 3.68 (95% CI: 1.02–13.30) for OS. Conclusions Distant metastases and large tumor volume were the main unfavorable prognostic factors. Presence of two or more factors related to ACC was associated with an aggressive behavior of disease.

Contains fulltext : 167540.pdf (Publisher’s version ) (Open Access) This report summarizes the results of the 3rd Joint ENCCA-WP7, EuroSarc, EEC, PROVABES, and EURAMOS European Bone Sarcoma Network Meeting, which was held at the Children's Cancer Research Institute in Vienna, Austria on September 24-25, 2015. The joint bone sarcoma network meetings bring together European bone sarcoma researchers to present and discuss current knowledge on bone sarcoma biology, genetics, immunology, as well as results from preclinical investigations and clinical trials, to generate novel hypotheses for collaborative biological and clinical investigations. The ultimate goal is to further improve therapy and outcome in patients with bone sarcomas.

Nature 480, 94–98 (2011); doi:10.1038/nature10539 In this Letter, one image was mistakenly duplicated during preparation of the artwork. In the original Fig. 3d, the left image illustrating migration of RCC4 cells transduced with empty adenovirus (EV) at 24 h is a duplicate of the middle image showing migration of RCC4 cells transduced with an adenovirus encoding Mi-WT.

ALK-directed therapy is effective in ALK-positive lymphomas, but the appropriate duration of therapy is unclear. In two patients in whom crizotinib was discontinued, recurrence was rapid (within days). Further ALK-directed therapy induced responses.

Children and adolescents with pre-existing conditions such as DNA repair defects or other primary immunodeficiencies have an increased risk of non-Hodgkin lymphoma. However, large-scale data on patients with non-Hodgkin lymphoma and their entire spectrum of pre-existing conditions are scarce. A retrospective multinational study was conducted by means of questionnaires sent out to the national study groups or centers, by the two largest consortia in childhood non-Hodgkin lymphoma, the European Intergroup for Childhood non-Hodgkin Lymphoma, and the international Berlin-Frankfurt-Munster Study Group. The study identified 213 patients with non-Hodgkin lymphoma and a pre-existing condition. Four subcategories were established: a) cancer predisposition syndromes (n=124, 58%); b) primary immunodeficiencies not further specified (n=27, 13%); c) genetic diseases with no increased cancer risk (n=40, 19%); and d) non-classifiable conditions (n=22, 10%). Seventy-nine of 124 (64%) cancer predispositions were reported in groups with more than 20 patients: ataxia telangiectasia (n=32), Nijmegen breakage syndrome (n=26), constitutional mismatch repair deficiency (n=21). For the 151 patients with a known cancer risk, 5-year event-free survival and overall survival rates were 40%±4% and 51%±4%, respectively. Five-year cumulative incidences of progression/relapse and treatment-related death as a first event were 22%±4% and 24%±4%, respectively. Ten-year incidence of second malignancy was 24%±5% and 7-year overall survival of the 21 patients with a second malignancy was 41%±11%. Patients with non-Hodgkin lymphoma and pre-existing conditions have an inferior survival rate with a large proportion of therapy-related deaths compared to patients with non-Hodgkin lymphoma and no pre-existing conditions. They may require special vigilance when receiving standard or modified/reduced-intensity chemotherapy or when undergoing allogeneic stem cell transplantation.