Childhood pancreatic neuroendocrine neoplasms: A national experience.

Pancreatic neuroendocrine neoplasms (pNENs) diagnosed in childhood are very rare, with few data available. The aim was to describe the clinical presentation and behavior of children with pNENs at a national level. METHODS: National multicenter retrospective study of all patients, aged from 0 to 17 years at diagnosis, treated from 2011 to 2020 for a pNEN and registered in the French National Registry of Childhood Cancers or FRACTURE database. RESULTS: Fifteen patients, 13 well-differentiated pancreatic neuroendocrine tumors (pNETs) and two neuroendocrine carcinomas (pNECs), were selected. Median age at diagnosis was 14 years (range, 7-17). Eight patients, all with localized disease, had a cancer predisposition syndrome (CPS), including five cases diagnosed during systematic screening. Five (31%) had metastatic disease at diagnosis: three grade 2 pNETs and two pNECs. First line therapy included exclusive pancreatectomy (seven cases, all M0), active surveillance (three cases, all M0), medical therapies (somatostatin analogues, chemotherapy; four cases, all M1), and surgery with medical therapy (one M1 case). Three-year progression-free survival was 57% (confidence interval [CI] 95%: 27-78) and was significantly better for patients with low-grade well differentiated (73 vs. 0%; p < 10-4) and localized (76 vs. 20%; p = .02) tumors. The two patients with pNECs died. Three-year overall survival was 92% (CI95%: 59-99) and was significantly better in patients with low-grade tumor (100 vs. 50%; p = 10-4). CONCLUSION: Childhood pNENs occur more frequently in adolescents with CPS. Localized low-grade pNETs in children have a very good prognosis, whereas the treatment of high-grade and metastatic pNETs/pNECs should be better defined.

Molecular and clinicopathologic characterization of pediatric histiocytoses.

The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E . Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E -mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.

The French FRACTURE database: A way to improve knowledge on management of children with very rare tumors.

INTRODUCTION: Very rare pediatric tumors (VRTs), defined by an annual incidence ≤2 per million inhabitants, represent a heterogeneous group of cancers. Due to their extremely low incidence, knowledge on these tumors is scant. Since 2012, the French Very Rare Tumors Committee (FRACTURE) database has recorded clinical data about VRTs in France. This study aims: (a) to describe the tumors registered in the FRACTURE database; and (b) to compare these data with those registered in the French National Registry of Childhood Cancer (RNCE). METHODS: Data recorded in the FRACTURE database between January 1, 2012 and December 31, 2018 were analyzed. In addition, these data were compared with those of the RNCE database between 2012 and 2015 to evaluate the completeness of the documentation and understand any discrepancies. RESULTS: A total of 477 patients with VRTs were registered in the FRACTURE database, representing 97 histological types. Of the 14 most common tumors registered in the RNCE (772 patients), only 19% were also registered in the FRACTURE database. Total 39% of children and adolescent VRTs registered in the RNCE and/or FRACTURE database (323 of a total of 828 patients) were not treated in or linked to a specialized pediatric oncology unit. CONCLUSION: VRTs represent many different heterogenous entities, which nevertheless account for 10% of all pediatric cancers diagnosed each year. Sustainability in the collection of these rare tumor cases is therefore important, and a regular systematic collaboration between the FRACTURE database and the RNCE register helps to provide a more exhaustive picture of these VRTs and allow research completeness for some peculiar groups of patients.

First Case of Acute Myocarditis Caused by Metapneumovirus in an Immunocompromised 14-year-old Girl.

Background: Human metapneumovirus (hMPV) is a paramyxovirus, well known as a causative agent of respiratory tract infections. Non-respiratory manifestations, including cardiac impairments, remain rare. Only two cases of myocarditis caused by hMPV have been described in adults. Case description: We present the case of a 14-year-old female suffering from Burkitt leukemia and diagnosed with severe myocarditis caused by hMPV, based on results from real-time polymerase chain reaction (RT-PCR) and magnetic resonance imaging (MRI). She was successfully treated by venoarterial extracorporeal membrane oxygenation and intravenous immunoglobulins. She was discharged from pediatric intensive care unit (PICU) 3 weeks later. Conclusion: This is the first pediatric case of hMPV myocarditis requiring venoarterial extracorporeal membrane oxygenation. How to cite this article: Makhlouf A, Peipoch L, Duport P, Darrieux E, Reguerre Y, Ramful D, et al. First Case of Acute Myocarditis Caused by Metapneumovirus in an Immunocompromised 14-year-old Girl. Indian J Crit Care Med 2022;26(6):745-747.

Thymoma and thymic carcinoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Thymic tumors are epithelial tumors arising from the anterior mediastinum and constitute 0.2-1.5% of all adult malignancies but are exceptional in pediatric population. Thymic epithelial tumors (TETs) encompass a variety of histologic subtypes associated with different clinical outcomes. Due to its rarity in children, TETs' management requires a multidisciplinary approach. However, prognosis remains still poor, especially among patients with thymic carcinoma. This study presents the internationally recognized recommendations for the diagnosis and treatment of thymic tumors in children and adolescents, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) group within the EU-funded project Paediatric Rare Tumours Network - European Registry (PARTNER).

Pancreatoblastoma in children: EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Pancreatoblastoma (PBL) is a rare malignant epithelial neoplasm that affects typically young children. Signs related to advanced upper-abdominal tumor accompanied by elevated serum α-fetoprotein levels in a young child suggest PBL, however histopathological confirmation is mandatory. The mainstay of the treatment is a complete surgical resection. Unresectable and/or metastatic PBL may become amenable to complete delayed surgery after neoadjuvant chemotherapy. This manuscript presents the international consensus recommendations for the diagnosis and treatment of children with PBL, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded PARTNER (Paediatric Rare Tumors Network - European Registry) project.

Facing the challenges of very rare tumors of pediatric age: The European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) background, goals, and achievements.

It has become increasingly clear in recent years that we need to develop ad hoc strategies to combat very rare tumors (VRT) of pediatric age. In 2008, several schemes being run in different countries were pooled together to create the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) project: a cooperative study group that aimed to promote research in the relatively uncharted territory of rare tumors of pediatric age. EXPeRT members were able to activate different levels of cooperation to achieve their goals, and to obtain dedicated funding by participating in EU-financed projects. Their experiences emphasize the merits of networking, seeking new partnerships, joining forces, and pooling resources to extend the reach of research efforts, and ultimately improve the quality of patient care. Between 2018 and 2021, the EXPeRT has been active in establishing the Pediatric Rare Tumors Network - European Registry (PARTNER). This project had the main purposes of building a European common registry of pediatric VRT, but also the major task of developing diagnostic and treatment guidelines for VRT (or at least part of them). These clinical recommendations are the subject of a series of papers on Pediatric Blood and Cancer.

Cutaneous melanoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Cutaneous melanoma is rare in children and, like other very rare pediatric tumors, it suffers from a shortage of knowledge and clinical expertise. The clinical management of pediatric melanoma is often challenging. Its clinical and pathological diagnosis may be difficult, and there is no standard treatment. In the absence of specific treatment guidelines, young patients are generally treated following the same principle as for adults, but concern remains about their access to clinical trials and new drugs, which have been shown to dramatically change the natural history of advanced melanoma. This paper presents the internationally recognized recommendations for the diagnosis and treatment of children and adolescents with cutaneous melanoma, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the EU-funded project called PARTNER (Paediatric Rare Tumours Network - European Registry). Main recommendations for melanoma are to discuss pediatric patients in multidisciplinary teams that include both pediatric oncologists and specialists in adult melanoma; to enroll patients in prospective trials, if available; to collect data in national-international databases; and to develop an effective international collaboration between pediatric and adult melanoma groups in order to facilitate the transfer of potentially effective new agents from the adult to the pediatric setting.

The European Paediatric Rare Tumours Network - European Registry (PARTNER) project for very rare tumors in children.

The PARTNER project (Paediatric Rare Tumours Network - European Registry) was launched in 2016. PARTNER aims to create a European Registry dedicated to children and adolescents with very rare tumors (VRT). It links existing national registries and provides a registry for those countries in which a VRT registry has not yet been created. This consortium is composed of the various national cooperative groups and their respective member institutions. The strategic value of this project is based on the Europe-wide data collection concerning the treatment of VRTs. These data are provided to experts and constitute the basis for new clinical practice guidelines for use by ERN (European Reference Network) and non-ERN institutions. The proposed tasks and milestones will increase collaboration in the field of pediatric oncology among member states and will also facilitate the inclusion of low health expenditure average rate (LHEAR) countries in this process. In addition, this project creates a platform for VRTs that may represent a model on how to elaborate a comprehensive approach (case registration, international case consultation and treatment recommendations, and website to provide information for parents/patients) for rare diseases.

Nasopharyngeal carcinoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Nasopharyngeal carcinoma (NPC) is a rare pediatric tumor. Collaborative studies performed over the last decades showed improved results compared to historical data, but standardized guidelines for diagnosis and management of pediatric NPC are still unavailable. This study presents a European consensus guideline for the diagnosis and treatment of pediatric NPC developed by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT). Main recommendations include induction chemotherapy with cisplatin and 5-flurouracil, concomitant chemoradiotherapy in advanced disease, and to consider maintenance treatment with interferon beta (IFN-ß) for selected high-risk patients. Dose adjustments of radiotherapy based on response to induction chemotherapy may decrease the rates of long-term treatment-related complications that affect most of the survivors.

Pleuropulmonary blastoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Pleuropulmonary blastoma (PPB) is a rare cancer occurring mainly during early childhood and often associated with germline DICER1 mutations. It is classified by the macroscopic appearance into three interrelated clinico-pathologic entities on a developmental continuum. Complete tumor resection is a main prognostic factor and can be performed at diagnosis or after neoadjuvant treatment that includes chemotherapy and in some cases radiotherapy. Optimal modalities of neo- or adjuvant treatments can be challenging taking into account potential long-term toxicities in this young population. This paper presents the recommendations for diagnosis and treatment of children and adolescents with PPB elaborated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) within the European Union-funded project PARTNER (Paediatric Rare Tumours Network - European Registry).

Long-term follow-up of children with risk organ-negative Langerhans cell histiocytosis after 2-chlorodeoxyadenosine treatment.

The nucleoside analogue, 2-chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO-) involvement. However, we lack data on long-term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long-term tolerance. This study included 44 children from the French LCH registry, treated for a RO- LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3-19·7 years) and the median follow-up after was 5·4 years (range, 0·6-15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five-year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases [72% below absolute lymphocyte count (ALC) of 0·5 G/l], was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five-year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long-term therapy for treating patients with RO- LCH. Appropriate management of induced immune deficiency is mandatory.

Exploring heterogeneity of adrenal cortical tumors in children: The French pediatric rare tumor group (Fracture) experience.

INTRODUCTION: Pediatric adrenal cortical tumors are characterized by a wide spectrum of behavior. Questions remain regarding intermediate disease stages with isolated tumor rupture or relapse. OBJECTIVES: To describe clinical characteristics, treatment strategy, and outcome of patients depending on disease stage, tumor rupture, or in case of a refractory tumor, to discuss optimal management. MATERIAL AND METHODS: Pediatric patients with histological material reviewed and treated between 2000 and 2018 in 23 French oncology centers were included. RESULTS: Among 95 cases, 59% of patients had stage I tumors (n = 55), 16% had stage II tumors (n = 16), 19% had stage III tumors (n = 17), and 5% had stage IV tumors (n = 5) (missing data: 2). Overall, 27% of patients (n = 25) had an unfavorable histology. Initial tumor resection was performed for 90% of patients (n = 86). Systemic therapies included mitotane in 20 cases and chemotherapy in 13 cases. Among 17 stage III patients, 12 had microscopic residual tumor due to an initial biopsy (n = 5), intraoperative rupture (n = 8), or surgical resection with microscopic residue or tumor spillage surgery (n = 1) (two patients with two modalities). After a median follow-up of 96 months (25-119), four early progressions and two relapses occurred. A total of seven patients died, including five of disease. Stage III diseases due to microscopic residual disease correlated with a worse prognosis: 5-year progression-free survival 44% (95% CI, 22-87%) versus 82% (95% CI, 73-91%) for the whole cohort (P < .0001). Among the 14 patients with refractory disease, only 3 were alive and free of disease after multimodal second-line therapy. CONCLUSIONS: Stage III diseases due to a microscopic residual tumor have a dismal prognosis, arguing for the systematic use of adjuvant therapy. Patients with a relapsed disease should be included in experimental studies.

Dramatic response to nivolumab in xeroderma pigmentosum skin tumor.

We report the case of a 6-year-old female with xeroderma pigmentosum (XP) who developed a nonoperable scalp tumor, treated with anti-programmed cell death protein 1 (anti-PD-1) therapy (nivolumab). She presented with a sarcomatoid carcinoma of the scalp with bone lysis as well as vascular and meningeal contact. Nivolumab was initiated because it has emerged as a promising immunotherapy. We observed a dramatic tumor response with excellent tolerance. However, while on nivolumab therapy she developed two large skin melanomas and several squamous cell carcinomas, which have been resected. These results demonstrate that cancer immunotherapy in patients with XP can be impressive but complex and warrants further investigation.

Pediatric patients with cutaneous melanoma: A European study.

INTRODUCTION: Cutaneous melanoma is rare in childhood and published studies have mainly been retrospective single-institution series or small case series. Given the absence of clinical protocols dedicated to pediatric melanoma, the treatment approach is generally extrapolated from the ones applied to adults. METHODS: Coordinated by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT), this study collected patients prospectively registered between 2002 and 2012 under national cooperative projects dedicated to rare pediatric tumors in Italy, Poland, Germany, and France. Additional cases were collected from dermatology registries in Germany and Israel. RESULTS: A total of 219 patients aged 0-18 years (median 14.4) were included in the analysis. Sentinel lymph node biopsy was performed in 112 patients (76% of those with Breslow thickness > 0.75 mm) and was positive in 37.5%. Systemic therapy was used in 33 cases. In stage III cases, survival rates were similar for patients who received (23 cases) or not (21 cases) adjuvant therapy. For the whole series, 3-year overall and disease-free survival rates were 91.4% and 84.0%, respectively (median follow-up 41.8 months). Tumor site, tumor stage, and ulceration influenced survival rates. Patients treated by pediatric oncologists (n = 140) were more likely to have advanced disease than those treated by dermatologists (n = 79). DISCUSSION: This study would suggest that the clinical history of melanoma in children and adolescents might resemble that of adult counterpart. Cooperative efforts are needed to make new drugs more readily available to pediatric patients to increase the outcome of patient with advanced disease.

Childhood Nasopharyngeal Carcinoma: State-of-the-Art, and Questions for the Future.

In children, nasopharyngeal carcinoma (NPC) is a very rare tumor, mostly Epstein-Barr Virus related and quite always diagnosed at a locally advanced stage. With current protocols associating induction cisplatin-based chemotherapy and concomitant chemoradiotherapy, prognosis is excellent with overall survival higher than 85%. However, long-term toxicities are frequent. Improvement in radiation therapy modalities like intensity-modulated radiation therapy and new strategies with radiation dose adaptation to chemotherapy response have been introduced to reduce acute and long-term toxicities. Actually, 2 main questions remain: is it possible to pursue a therapeutic deescalation in children with low-risk NPC or very good response to induction chemotherapy in order to reduce the risk of late effects? Could an immunologic maintenance treatment improve prognosis of children with high-risk NPC? International collaborative groups and prospective trials including biological studies are necessary to answer these questions to improve childhood NPC treatment and knowledge.

Outcome and prognostic factors in high-risk childhood adrenocortical carcinomas: A report from the European Cooperative Study Group on Pediatric Rare Tumors (EXPeRT).

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.

Langerhans cell histiocytosis: therapeutic strategy and outcome in a 30-year nationwide cohort of 1478 patients under 18 years of age.

The French national cohort of children with Langerhans cell histiocytosis (LCH) has included 1478 patients since it was established in 1983. LCH therapeutic strategies substantially changed in 1998, so we have divided the cohort into two 15-year periods. Starting in 1998, therapy duration increased from 6 to 12 months, repeated induction therapy was performed in cases showing a poor response to the first induction with vinblastine and steroids, and refractory disease in a risk organ (RO+) was treated with cladribine and cytarabine. A total of 483 (33%) patients were enrolled before 1998, and 995 (67%) after 1998. Five-year survival was 96·6% (95% confidence interval: 95·4-97·5%) overall, improving from 92% pre-1998 to 99% post-1998 (P < 0·001 adjusted to disease extent). This change was supported by an increase in 5-year survival from 60% to 92% in the RO+ group. Survival was particularly associated with cladribine and cytarabine among refractory RO+ patients. Disease reactivation was slightly less frequent after 1998, due to better enrolment of single-system patients, extended therapy duration, and more efficient second-line therapy. The crude rates of endocrine and neurological sequelae (the most frequent sequelae) appeared to improve over time, but this difference was not observed when the analysis was stratified by disease extent.

Impact of early molecular response in children with chronic myeloid leukemia treated in the French Glivec phase 4 study.

Studies in adults have shown that an early molecular response to imatinib predicts clinical outcome in chronic myeloid leukemia (CML). We investigated the impact of the BCR-ABL1 transcript level measured 3 months after starting imatinib in a cohort of 40 children with CML. Children with a BCR-ABL1/ABL ratio higher than 10% at 3 months after the start of imatinib had a larger spleen size and a higher white blood cell count compared with those with BCR-ABL1/ABL ≤10%. Children with BCR-ABL1/ABL ≤10% 3 months after starting imatinib had higher rates of complete cytogenetic response and major molecular response at 12 months compared with those with BCR-ABL1/ABL >10%. With a median follow-up of 71 months (range, 22-96 months), BCR-ABL1/ABL ≤10% correlated with better progression-free survival. Thus, early molecular response at 3 months predicts outcome in children treated with imatinib for CML. This trial was registered at www.clinicaltrials.gov as #NCT00845221.