Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic ...profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS and PRC2 pathways. Finally, the association between JMML outcome and mutational profile suggests a dose-dependent effect for RAS pathway activation, distinguishing very aggressive JMML rapidly progressing to acute myeloid leukemia.
Although all tumours are rare in childhood, there are some particularly rare paediatric cancers which have not benefited from advances made by the international paediatric oncology network. To ...establish a shared definition and produce a list of these entities, the European Union Joint Action on Rare Cancers (JARC) promoted a consensus effort. The definition was based on the incidence rates estimated using the information network on rare cancers (RARECAREnet) database, pooling data from 94 population-based cancer registries and 27 countries. The RARECAREnet list of cancers was used to estimate the incidence rates. This list groups cancers by combining the International Classification of Diseases for Oncology, third edition, morphology and topography codes. According to the consensus, very rare paediatric cancers were identified as those with an annual incidence <2/1000000 and corresponded to 11% of all cancers in patients aged 0–14 years. Two subgroups were identified: tumour types typical of childhood (i.e. hepatoblastoma, pleuropulmonary blastoma, pancreatoblastoma) and those typical of adult age (i.e. carcinomas, melanoma). The threshold of 2/1000000 could also be adopted in populations aged 0–19 years: in this case, three tumour types had an incidence rate which was >2/1000000 (i.e. thyroid and testicular cancers and skin melanoma), but the consensus experts considered them as ‘very rare’ according to their clinical needs (e.g. shortage of knowledge and clinical expertise as the other rare paediatric cancers). The JARC consensus produced a definition and a list of very rare paediatric cancers which may represent a starting point for prioritising research on these tumours, based on data and patients' clinical needs.
•Very rare paediatric cancers are 11% of all cancers in children and in adolescents.•This consensus provides a definition and a list of very rare paediatric cancers.•By consensus, very rare paediatric cancers are those with an incidence <2/1000000.
Abstract Purpose The aim is to study statural growth in a large cohort of children with chronic myeloid leukaemia (CML) treated with front-line imatinib. Methods Retrospective data from 81 children ...less than 18 years of age with CML identified in the French pediatric registry were analysed. Height was expressed as standard deviation score (SDS). Results A gradual decrease in height SDS was observed over time since starting imatinib. The height SDS was significantly lower 12 months and 24 months after the start of imatinib overall ( p < 10−4 ) irrespective of gender and pubertal age. The height SDS was significantly ( p < 10−4 ) lower 12 months after the start of imatinib in boys and girls, and in the prepubertal age group as well as in the postpubertal age group, respectively. A similar finding was observed in the subgroups of boys and girls starting imatinib at a prepubertal or postpubertal age. Loss in height SDS 12 months after the start of imatinib was of the same range in boys when compared to girls and in patients who started imatinib at a prepubertal age compared to those who started at a postpubertal age. Conclusion Growth velocity was altered during the first years of imatinib treatment in boys as well as in girls and in prepubertal age patients as well as in adolescents.
The French phase II AcSé-crizotinib trial aimed to evaluate the safety and efficacy of crizotinib in patients with ALK, ROS1 and MET-driven malignancies including ALK-positive, anaplastic large cell ...lymphoma (ALK+ALCL).
ALK+ALCL patients 12 months or older with measurable disease and no standard care options available received crizotinib twice daily at 165 mg/m2 in children and adolescents and 250 mg in adults. The primary endpoint was the response rate at 8 weeks.
Twenty-eight patients were enrolled between 02/2014 and 03/2018. Three patients, not treated, were excluded from analysis. Median age was 19 years. Median previous line of chemotherapy was two. In the 24 patients with evaluable response, the response rate at 8 weeks was 67% (95%CI:47-82%). All patients discontinued crizotinib after a median treatment duration of 3.7 months: 8 for progression, 2 for adverse events related to prior treatments, and 15 by choice including 6 for allogenic stem-cell transplantation. The median follow-up was 45 months. Nine patients experienced an event: eight relapses (seven after crizotinib discontinuation and one after dose reduction) and one died in complete remission. The median duration of response was 43.3 months (95%CI:8.3-not reached). The 3-year-progression-free and overall survival rates were 40%(95%CI:23-59%) and 63%(95%CI:43-79). Grade 3 or 4 treatment-related adverse events occurred in 32% of patients.
Crizotinib shows efficacy and an acceptable safety profile in ALK+ALCL relapsed/refractory patients. However, a large proportion of patients experience a relapse after crizotinib discontinuation. Future studies will assess if prolonged ALK inhibitor exposure has curative potential without consolidation.
•High response rate is obtained with crizotinib in relapsed/resistant ALK+ ALCL.•Drug level monitoring should be an inherent part of crizotinib standard of care.•Relapse after discontinuing crizotinib or after a dose reduction are not rare.•Optimal dose and duration of crizotinib as well as the need for a consolidation have to be determined.
Abstract Objective To analyse ovarian Sertoli-Leydig cell tumours (SLCTs) for potential prognostic markers and their use for treatment stratification. Patients Forty-four patients were included. ...Patients were prospectively reported to the German MAKEI (Maligne Keimzelltumoren) studies ( n = 23), French TGM protocols ( n = 10), Italian Rare Tumour Project (TREP) registry ( n = 6), and the Polish Pediatric Rare Tumour Study group ( n = 5). Tumours were classified according to World Health Organisation (WHO) and staged according to International Federation of Gynecological Oncology (FIGO). Results Median age was 13.9 (0.5–17.4) years. All patients underwent resection by tumour enucleation ( n = 8), ovariectomy ( n = 17), adenectomy isolated ( n = 18) or with hysterectomy ( n = 1). FIGO-stage: Ia 24 pts., Ic 17 pts., II/III 3 pts. One patient had bilateral tumours. Four patients (stage Ia: 3, stage Ic: 1) developed a metachronous contralateral tumour. Otherwise, all stage Ia patients remained in complete remission. Among 20 patients with incomplete resection or tumour spread (stage Ic–III), eight relapsed, and five patients died. Eleven patients were initially treated with two to six cycles of cisplatin-based chemotherapy. Of these, seven patients are in continuous remission. Poor histological differentiation was associated with higher relapse rate (5/13) compared to intermediate (3/18) and high differentiation (0/4). Tumours with retiform pattern or heterologous elements showed a high relapse rate, too (5/11). After a median follow-up of 62 months, event-free survival is 0.70 ± 0.07, relapse-free survival 0.81 ± 0.06 and overall survival 0.87 ± 0.05. Conclusions Prognosis of SLCTs is determined by stage and histopathologic differentiation. Complete resection with careful avoidance of spillage is a prerequisite of cure. The impact of chemotherapy in incompletely resected and advanced stage tumours remains to be evaluated.
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.
Primary lung carcinoma is an exceptionally rare childhood tumour, as per definition of the European Cooperative Study Group on Paediatric Rare Tumours (EXPeRT), with an incidence of 0.1–0.2/1,000,000 ...per year. Little is known about the clinical characteristics of children with primary lung carcinoma, a gap which this joint analysis of the EXPeRT group aimed to fill.
We performed a retrospective case series of children (aged 0–18 years) with primary lung carcinoma, as collected through the EXPeRT databases between 2000 and 2021. We recorded relevant clinical characteristics including treatment and outcome.
Thirty-eight patients were identified with a median age of 12.8 years at diagnosis (range: 0–17). Mucoepidermoid carcinoma (MEC) was the most frequent entity (n = 20), followed by adenocarcinoma (n = 12), squamous cell carcinoma (n = 4), adenosquamous carcinoma (n = 1) and small-cell lung cancer (n = 1). Patients with MEC presented rarely with lymph node metastases (2/20 cases). Overall, 19/20 patients achieved long-lasting remission by surgical resection only. Patients with other histologies often presented in advanced stages (14/18 TNM stage IV). With multimodal treatment, 3-year overall survival was 52% ± 13%. While all patients with squamous cell carcinoma died, the 12 patients with adenocarcinoma had a 3-year overall survival of 64% ± 15%.
Primary lung carcinomas rarely occur in children. While the outcome of children with MEC is favourable with surgery alone, patients with other histotypes have a poor prognosis, despite aggressive treatment, highlighting the need to develop new strategies for these children, such as mutation-guided treatment.
•Primary lung carcinomas are very rare tumours during childhood.•Patients with mucoepidermoid carcinoma have a favourable outcome after resection.•Patients with other histotypes need new multimodal therapeutic strategies.•ALK inhibition in ALK-altered adenocarcinomas may improve the outcome.•Molecular tumour profiling should be systematically performed at an early stage.
Summary
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.
Background: The French phase II AcSé-crizotinib trial aimed to evaluate the safety and efficacy of crizotinib in patients with ALK, ROS1, and MET-driven malignancies, including ...ALK-positive anaplastic large-cell lymphoma (ALK ALCL). Methods - ALK ALCL patients 12 months or older with measurable disease and no standard care options available received crizotinib twice daily at 165 mg/m in children and adolescents and 250 mg in adults. The primary end-point was the response rate at 8 weeks.Results: Twenty-eight patients were enroled between February 2014 and March 2018. Three patients who were not treated were excluded from the analysis. The median age was 19 years. The median previous line of chemotherapy was two. In the 24 patients with an evaluable response, the response rate at 8 weeks was 67% (95% CI: 47-82%). All patients discontinued crizotinib after a median treatment duration of 3.7 months: eight for progression, two for adverse events (AEs) related to prior treatments, and 15 by choice, including six for allogeneic stem-cell transplantation. The median follow-up was 45 months. Nine patients experienced an event: eight relapses (seven after crizotinib discontinuation and one after dose reduction), and one died in complete remission. The median duration of response was 43.3 months (95% CI: 8.3-not reached). The 3-year progression-free and overall survival rates were 40% (95% CI: 23-59%) and 63% (95% CI: 43-79%). Grade 3 or 4 treatment-related AEs occurred in 32% of patients.Conclusion: Crizotinib shows efficacy and an acceptable safety profile in ALK ALCL relapsed/refractory patients. However, a large proportion of patients experience a relapse after crizotinib discontinuation. Future studies will assess if prolonged ALK inhibitor exposure has curative potential without consolidation.
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