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Solid tumors or predisposition syndromes are increasingly suspected before birth. However optimal management and outcomes remain unclear. We have performed a ten-year retrospective study of oncologic indications of prenatal diagnosis in public hospitals in Marseille. Data were obtained from prenatal diagnosis center and hospital imaging databases and pediatric oncology department files. Fifty-one cases were identified, 40 with mass: adrenal 17, sacrococcygeal 9, cardiac 7, abdominal 4, ovarian 1, cervical 2; 8 with developmental abnormalities (omphalocele 4, macroglossia 4), 3 WITH familial predisposition syndromes (familial rhabdoid 2, Li-Fraumeni 1). Median detection time was 30 week. Termination of pregnancy was decided for 9 fetuses (4 cardiac lesions and suspected tuberous sclerosis, 2 sacrococcygeal tumors, 1 Beckwith–Wiedemann Syndrome, 2 SMARCB1 mutations. Preterm birth occurred in 8 cases. Eleven newborns (26,1%) required intensive care (8 for mechanical complications). Of of 17 adrenal mass ES, 4 disappeared before birth and 5 before one year. Seventeen newborns underwent surgery: 13 masses (teratoma 7, myelomeningocele 2, cystic nephroma 1, neuroblastoma 2), 4 omphaloceles, one biopsy. Surgery performed after one year for incomplete regression identified 1 neuroblastoma, 2 bronchogenic cysts and 2 nonmalignant masses. Three newborns received chemotherapy. Except one patient with BWS who died of obstructive apnea, all children are alive disease free with a median follow-up of 60 months [9–131 months]. Twelve have sequelae. Various solid tumors and cancer predisposition syndromes can be detected before birth. A multidisciplinary collaboration is strongly recommended for optimal management before and after birth. [ABSTRACT FROM AUTHOR]

Prognosis of high-risk neuroblastoma (HRNB) remains poor despite multimodal therapies. Better prediction of survival could help to refine patient stratification and better tailor treatments. We established a mechanistic model of metastasis in HRNB relying on two processes: growth and dissemination relying on two patient-specific parameters: the dissemination rate μ and the minimal visible lesion size Svis. This model was calibrated using diagnosis values of primary tumor size, lactate dehydrogenase circulating levels, and the meta-iodobenzylguanidine International Society for Paediatric Oncology European (SIOPEN) score from nuclear imaging, using data from 49 metastatic patients. It was able to describe the data of total tumor mass (lactate dehydrogenase, R2 > 0.99) and number of visible metastases (SIOPEN, R2 = 0.96). A prediction model of overall survival (OS) was then developed using Cox regression. Clinical variables alone were not able to generate a model with sufficient OS prognosis ability (P =.507). The parameter μ was found to be independent of the clinical variables and positively associated with OS (P =.0739 in multivariable analysis). Critically, addition of this computational biomarker significantly improved prediction of OS with a concordance index increasing from 0.675 (95% CI, 0.663 to 0.688) to 0.733 (95% CI, 0.722 to 0.744, P <.0001), resulting in significant OS prognosis ability (P =.0422). [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about transfusion-associated Hepatitis E in France.

Hepatoblastoma is the most frequent pediatric liver cancer. The current treatments lead to 80% of survival rate at 5 years. In this study, we evaluated the clinical relevance of molecular features to identify patients at risk of chemoresistance, relapse and death of disease. All the clinical data of 86 children with hepatoblastoma were retrospectively collected. Pathological slides were reviewed, tumor DNA sequencing (by whole exome, whole genome or target) and transcriptomic profiling with RNAseq or 300-genes panel were performed. Associations between the clinical, pathological, mutational and transcriptomic data were investigated. High-risk patients represented 44% of our series and the median age at diagnosis was 21.9 months (range: 0–208). Alterations of the WNT/ß-catenin pathway and of the 11p15.5 imprinted locus were identified in 98% and 74% of the tumors, respectively. Other cancer driver genes mutations were only found in less than 11% of tumors. After neoadjuvant chemotherapy, disease-specific survival and poor response to neoadjuvant chemotherapy were associated with 'Liver Progenitor' (p = 0.00049, p < 0.0001) and 'Immune Cold' (p = 0.0011, p < 0.0001) transcriptomic tumor subtypes, SBS35 cisplatin mutational signature (p = 0.018, p = 0.001), mutations in rare cancer driver genes (p = 0.0039, p = 0.0017) and embryonal predominant histological type (p = 0.0013, p = 0.0077), respectively. Integration of the clinical and molecular features revealed a cluster of molecular markers associated with resistance to chemotherapy and survival, enlightening transcriptomic 'Immune Cold' and Liver Progenitor' as a predictor of survival independent of the clinical features. Response to neoadjuvant chemotherapy and survival in children treated for hepatoblastoma are associated with genomic and pathological features independently of the clinical features. [Display omitted] • Identification of molecular features of chemoresistance and poor survival in HB. • These features are observed at the time of surgery, after neoadjuvant chemotherapy. • They are independent of the current risk stratification performed at diagnosis. • Includes 'Progenitor' and 'Immune cold' classifications, rare driver alterations. • SBS35 mutational signature shows specific resistance to platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Metronomic chemotherapy (MC) is the administration of chemotherapy at doses below the maximal tolerated dose on a frequent schedule of administration, with no prolonged drug-free breaks. Objective: The aim of this research was to assess the effectiveness and tolerance of a metronomic etoposide/ cyclophosphamide/celecoxib regimen in children and adolescents with refractory cancer. Methods: This retrospective, single-center study evaluated the use of MC with etoposide 25 mg/m2.d-1 (days 1-14), cyclophosphamide 25 mg/m2 d-1 (days 15-28), and celecoxib 100 to 400 mg/d (days 1-28), in children with refractory, or high-risk relapsing, cancer. Adverse events were determined through laboratory analyses and investigator observations. Results: From January 2005 to December 2007, 17 children and adolescents were treated. The best responses observed were stabilizations of the disease that lasted over 20 weeks in 7 patients (41%). Most importantly, in 4 patients (24%) antalgic treatment could be transiently diminished or stopped, and in 1 patient (6%) oxygen support could be stopped for several weeks. Four grade IV platelet toxicities were noted in 3 patients; 2 grade IV anemia occurred in 2 patients (who had platelet and red blood cell transfusions before initiation of treatment); and 1 patient had grade III neutropenia. No other grade III or IV toxicities were noted. Grade II alopecia and stomatitis were observed in 1 patient and grade II vomiting was observed in 2 patients. One patient with meningeal carcinomatosis developed bilateral subdural hematoma for which the role of MC could not be ruled out. Circulating endothelial cells were elevated in 3 out of 3 patients in whom they were quantified and who were progressing while under MC. Conclusion: The MC regimen we report here was associated with disease stabilization without major toxicities. This assessment of MC in children and adolescents warrants further studies. [Copyright &y& Elsevier]

COVID-19 infection in paediatric patients with cancer is severe or critical in 20% of the patients. It can therefore directly affect paediatric patients with cancer and/or their care. We aimed at evaluating the safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine in adolescents and young adults (AYA) with solid tumour. This study includes a retrospective analysis of safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine administered to patients, ≥16 years old, under treatment for a solid tumour or within 6 months after treatment from 15th February 2021 to 15th April 2021. Two administrations of the vaccine 3 weeks apart were given. Sera were tested for anti-SARS-Cov-2 immunoglobulin G (IgG) antibodies directed against the S1 domain of the spike protein. In case of positive serology, neutralisation of SARS-Cov-2 was tested. Twenty-three patients with solid tumours were identified and proposed to get vaccinated. Nine patients refused, and 1 previously developed COVID-19 infection with positive serology. At the time of writing, 13 patients (10 M/2 F; median age: 17) started vaccination. All patients received 2 injections except 2 patients who stopped vaccination because of tumour progression. Ten patients were under treatment (alone or in combination: chemotherapy: 7 patients [pts], immunotherapy: 2 pts, targeted therapy: 3 pts, follow-up: 3 patients). Overall, vaccines were well tolerated. Five patients did not report any side-effects after the first injection and 4 after the second injection. The main local reactivity symptom was mild pain at the site of injection (6 and 2 pts). Fatigue (2 pts and 5 pts) was the most frequent systemic symptom. One patient refused serology testing. All patients but 1 had pre-vaccination negative serology; 7 of 10 patients tested had positive serology before second vaccine injection, and 9 of 10 patients had positive serology one month after the second injection. All patients with seroconversion had positive COVID-19 neutralisation test. No patient developed COVID infections. We report the good safety profile and good efficacy of the BNT162B2 vaccine in AYA with solid tumours. Larger series and monitoring of the kinetics of anti-Sars-Cov-2 IgG antibodies for several months are mandatory to confirm these preliminary results and to determine long-term vaccination. • The mRNA COVID-19 vaccineFaces a high refusal rate in AYA. • The mRNA COVID-19 vaccine displays high efficacy especially in AYA when compared to adult with cancer. • The mRNA COVID-19 vaccine has a good safety profile in AYA. [ABSTRACT FROM AUTHOR]

PURPOSE: In 2012, the French African Pediatric Oncology Group established the African School of Pediatric Oncology (EAOP), a training program supported by the Sanofi Espoir Foundation's My Child Matters program. As part of the EAOP, the pediatric oncology training diploma is a 1-year intensive training program. We present this training and certification program as a model for subspecialty training for low- and middle-income countries. METHODS: A 14-member committee of multidisciplinary experts finalized a curriculum patterned on the French model Diplôme Inter-Universitaire d'Oncologie Pédiatrique. The program trained per year 15 to 25 physician participants committed to returning to their home country to work at their parent institutions. Training included didactic lectures, both in person and online; an onsite practicum; and a research project. Evaluation included participant evaluation and feedback on the effectiveness and quality of training. RESULTS: The first cohort began in October 2014, and by January 2019, 72 participants from three cohorts had been trained. Of the first 72 trainees from 19 French-speaking African countries, 55 (76%) graduated and returned to their countries of origin. Four new pediatric oncology units have been established in Niger, Benin, Central African Republic, and Gabon by the graduates. Sixty-six participants registered on the e-learning platform and continue their education through the EAOP Web site. CONCLUSION: This training model rapidly increased the pool of qualified pediatric oncology professionals in French-speaking countries of Africa. It is feasible and scalable but requires sustained funding and ongoing mentoring of graduates to maximize its impact. [ABSTRACT FROM AUTHOR]

PURPOSE: In 2012, the French African Pediatric Oncology Group established the African School of Pediatric Oncology (EAOP), a training program supported by the Sanofi Espoir Foundation's My Child Matters program. As part of the EAOP, the pediatric oncology training diploma is a 1-year intensive training program. We present this training and certification program as a model for subspecialty training for low- and middle-income countries. METHODS: A 14-member committee of multidisciplinary experts finalized a curriculum patterned on the French model Diplôme Inter-Universitaire d'Oncologie Pédiatrique. The program trained per year 15 to 25 physician participants committed to returning to their home country to work at their parent institutions. Training included didactic lectures, both in person and online; an onsite practicum; and a research project. Evaluation included participant evaluation and feedback on the effectiveness and quality of training. RESULTS: The first cohort began in October 2014, and by January 2019, 72 participants from three cohorts had been trained. Of the first 72 trainees from 19 French-speaking African countries, 55 (76%) graduated and returned to their countries of origin. Four new pediatric oncology units have been established in Niger, Benin, Central African Republic, and Gabon by the graduates. Sixty-six participants registered on the e-learning platform and continue their education through the EAOP Web site. CONCLUSION: This training model rapidly increased the pool of qualified pediatric oncology professionals in French-speaking countries of Africa. It is feasible and scalable but requires sustained funding and ongoing mentoring of graduates to maximize its impact. [ABSTRACT FROM AUTHOR]

Background: In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues.Methods: The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH.Results: Patients <18 months (18 m) showed a better outcome in all stages as compared to older patients (5-year OS in localised stages: <18 m: 0.95 ± 0.04, >18 m: 0.67 ± 0.14, p = 0.011; metastatic: <18 m: 0.76 ± 0.15, >18 m: 0.28 ± 0.09, p = 0.084). The genomic 'background', but not MNA clone sizes, correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. Infiltrated bone marrows and relapse tumour cells mostly displayed no MNA. However, one stage 4s tumour with segmental chromosomal aberrations showed a homogeneous MNA in the relapse.Conclusions: This study provides a rationale for the necessary distinction between heterogeneous and homogeneous MNA. HetMNA tumours have to be evaluated individually, taking age, stage and, most importantly, genomic background into account to avoid unnecessary upgrading of risk/overtreatment, especially in infants, as well as in order to identify tumours prone to developing homogeneous MNA. [ABSTRACT FROM AUTHOR]

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways. [ABSTRACT FROM AUTHOR]

New protocols based on ALK-targeted therapy by crizotinib or other ALK-targeting molecules have opened for the treatment of patients with neuroblastoma ( NB) if their tumors showed mutation and/or amplification of the ALK gene. However, tumor samples are not always available for analysis of ALK mutational status in particular at relapse. Here, we evaluated the ALK mutational status of NB samples by analysis of circulating DNA, using the droplet digital PCR (dd PCR) system. dd PCR assays was developed for the detection of ALK mutations at F1174 and R1275 hotspots found in NB tumors and was applied for the analysis of circulating DNA obtained from 200 μL of serum or plasma samples collected from 114 patients with NB. The mutations F1174L (exon 23 position 3520, T>C and position 3522, C>A) and the mutation R1275Q (exon 25 position 3824, G>A) were detected in circulating DNA. The sensitivity of our test was 100%, 85%, and 92%, respectively, and the specificity was 100%, 91%, and 98%, respectively. In conclusion, the assay that we have developed offers a reliable, noninvasive blood test to assess ALK mutational status at F1174 and R1275 hotspots and should help clinicians to identify patients showing an ALK mutation in particular when no tumor tissue is available. [ABSTRACT FROM AUTHOR]

Background: Somatically acquired genomic alterations with MYCN amplification (MNA) are key features of neuroblastoma (NB), the most common extra-cranial malignant tumour of childhood. Little is known about the frequency, clinical characteristics and outcome of NBs harbouring genomic amplification(s) distinct from MYCN. Methods: Genomic profiles of 1100 NBs from French centres studied by array-CGH were re-examined specifically to identify regional amplifications. Patients were included if amplifications distinct from the MYCN locus were seen. A subset of NBs treated at Institut Curie and harbouring MNA as determined by array-CGH without other amplification was also studied. Clinical and histology data were retrospectively collected. Results: In total, 56 patients were included and categorised into 3 groups. Group 1 (n = 8) presented regional amplification(s) without MNA. Locus 12q13-14 was a recurrent amplified region (4/8 cases). This group was heterogeneous in terms of INSS stages, primary localisations and histology, with atypical clinical features. Group 2 (n = 26) had MNA as well as other regional amplifications. These patients shared clinical features of those of a group of NBs MYCN amplified (Group 3, n = 22). Overall survival for group 1 was better than that of groups 2 and 3 (5 year OS: 87.5%±11% vs 34.9%±7%, log-rank p<0.05). Conclusion: NBs harbouring regional amplification(s) without MNA are rare and seem to show atypical features in clinical presentation and genomic profile. Further high resolution genetic explorations are justified in this heterogeneous group, especially when considering these alterations as predictive markers for targeted therapy. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To investigate variability of clinical target volume (CTV) delineation and deviations according to doses delivered in normal tissue for abdominal tumor irradiation in children. Material and methods: For a case of nephroblastoma six French pediatric radiation oncologists outlined post-operative CTV, on the same dosimetric CT scan according to the International Society for Pediatric Oncology 2001 protocol. On a reference CTV and organs at risk (OAR), we performed dosimetric planning with the constraints as 25.2Gy for CTV, V 20 max to 50% for liver, V 12 <15% for kidney. Data were analyzed with Aquilab© software. Results: Final CTVs showed inter-clinician variability: 44.85–120.78cm3. The recommended liver doses were not respected in four cases: V 20 from 74% to 88% of the volume; for kidney, in two cases: V 12 of 17.6% and 25%, respectively. For vertebral bodies, no deviations were noted. Conclusion: Variability not only affected CTV delineation but also dose distribution to OAR with different compromises. This practice training demonstrates the hudge lack of data about correlation between dose, volume and risk of late effects in pediatric radiotherapy. We intend to record prospectively the dose/volume histogram of each OAR in a national database in order to characterize late effects occurring in relation to treatment modalities. [Copyright &y& Elsevier]

Background: Filgrastim is an effective granulocyte colony-stimulating factor (G-CSF) used to reduce periods of neutropenia and the risk of infection after chemotherapy courses. Pegfilgrastim is a pegylated filgrastim with a longer plasma half-life that is administered once per cycle. Objective: The aim of this study was to compare the efficacy of pegfilgrastim and filgrastim administered after chemotherapy in children with Ewing sarcoma. Methods: We performed a retrospective chart review of pediatric patients with Ewing sarcoma. Every patient received both types of G-CSF in different treatment courses of chemotherapy, which consisted of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE); vincristine, actinomycin D, and ifosfamide (VAI); or vincristine, actinomycin D, and cyclophosphamide (VAC). A single injection of pegfilgrastim 100 μg/kg SC or a daily injection of filgrastim 5 to 10 μg/kg SC was administered 48 to 72 hours after the completion of chemotherapy. The following data were collected from the medical charts: proportion of chemotherapy courses with grade 4 neutropenia, duration of grade 4 neutropenia, proportion with severe neutropenia, duration of severe neutropenia, proportion with febrile neutropenia, duration of antibiotic treatment, duration of hospitalization, and percentage of patients receiving transfusion. Grade 4 neutropenia was defined as an absolute neutrophil count of <500 × 109/L; severe neutropenia was defined as a count of <200 × 109/L. Adverse events were collected from the medical charts. Results: Twenty children were included (13 girls and 7 boys). The patients'' median age was 12.8 years (range, 9–17 years) and median weight was 45.2 kg (range, 28–90 kg). A total of 178 chemotherapy courses (108 VIDE; 70 VAI or VAC) were administered and evaluated, including 134 courses with pegfilgrastim and 44 courses with filgrastim. Considering all types of chemotherapy combined, those courses in which pegfilgrastim was used were associated with a significantly lower incidence of severe neutropenia (0.21 vs 0.85; P = 0.03), a shorter duration of severe neutropenia (0.49 vs 2.36 days; P = 0.01), and a shorter duration of antibiotic treatment (1.07 vs 4.22 days; P = 0.03) compared with courses treated with filgrastim. No statistically significant differences were observed for the proportion and duration of grade 4 neutropenia, proportion of febrile neutropenia, duration of hospitalization, or red blood cell and platelet transfusions. Adverse effects were few and comparable between pegfilgrastim and filgrastim. Conclusions: In this retrospective chart review of children with Ewing sarcoma, using pegfilgrastim after chemotherapy courses was associated with significantly reduced frequency and shorter duration of severe neutropenia compared with those courses followed by filgrastim. Randomized controlled trials are needed to confirm these preliminary observations. [Copyright &y& Elsevier]

Purpose: To determine the contribution of total body irradiation (TBI) to late sequelae in children treated with high-dose chemotherapy and autologous bone marrow transplantation for Stage IV neuroblastoma. Patients and Methods: We compared two populations that were similar with regard to age, stage, pre–autologous bone marrow transplantation chemotherapy (CT) regimen, period of treatment, and follow-up (12 years). The TBI group (n = 32) received TBI as part of the megatherapy procedure (1982–1993), whereas the CT group (n = 30) received conditioning without TBI (1985–1992). Analysis 12 years later focused on growth, weight and corpulence (body mass index) delay; hormonal deficiencies; liver, kidney, heart, ear, eye, and dental sequelae; school performance; and the incidence of secondary tumors. Results: Impact of TBI was most marked in relation to growth and weight delay, although the mean delay was not severe, probably because of treatment with growth hormones. Other consequences of TBI were thyroid insufficiency, cataracts, and a high incidence of secondary tumors. Hearing loss and dental agenesis were more prominent in the group treated with CT alone. No differences were observed in school performance. Conclusion: The most frequent side effects of TBI were cataracts, thyroid insufficiency, and growth delay, but more worrying is the risk of secondary tumors. Because of the young mean age of patients and the toxicity of TBI regimens without any survival advantage, regimens without TBI are preferable in the management of Stage IV neuroblastoma. [Copyright &y& Elsevier]

Background: Pleuropulmonary blastoma (PPB) is a rare childhood dysontogenetic intrathoracic neoplasm associated with an unfavourable clinical behaviour. Cases presentation: We report pathological and cytogenetic findings in two cases of PPB at initial diagnosis and recurrence. Both tumors were classified as type III pneumoblastoma and histological findings were similar at diagnosis and relapse. In both cases, conventional cytogenetic techniques revealed complex numerical and structural chromosomal abnormalities. Molecular cytogenetic analysis (interphase/metaphase FISH and multicolor FISH) identified accurately chromosomal aberrations. In one case, TP53 gene deletion was detected on metaphase FISH. To date, only few cytogenetic data have been published about PPB. Conclusion: The PPB genetic profile remains to be established and compared to others embryonal neoplasia. Our cytogenetic data are discussed reviewing cytogenetics PPBs published cases, illustrating the contribution of multicolor FISH in order to identify pathogenetically important recurrent aberrations in PPB. [ABSTRACT FROM AUTHOR]

Neuroblastoma (NB) is a frequent pediatric tumor for which recurrent somatic rearrangements are known. Germline mutations of predisposing gene(s) are suspected on the basis of rare familial cases and the association of NB with other genetically determined congenital malformations of neural crest-derived cells--namely, Hirschsprung disease (HSCR) and/or congenital central hypoventilation syndrome (CCHS).We recently identified the paired-like homeobox 2B (PHOX2B) gene as the major disease-causing gene in isolated and syndromic CCHS, which prompted us to regard it as a candidate gene in NB. Here, we report on germline mutations of PHOX2B in both a familial case of NB and a patient with the HSCR-NB association. PHOX2B, therefore, stands as the first gene for which germline mutations predispose to NB. [ABSTRACT FROM AUTHOR]