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.

Invasive Fungal Infections in Immunocompromised Children: Novel Insight Following a National Study.

OBJECTIVE: To obtain a national overview of the epidemiology and management of invasive fungal infections (IFIs) in France for severely immunocompromised children who were treated for acute leukemia or had undergone allogeneic hematopoietic stem cell transplantation (a-HSCT). STUDY DESIGN: We performed a national multicenter retrospective study to collect epidemiologic data for proven and probable IFIs in children with acute leukemia under first- line or relapse treatment or who had undergone a-HSCT. We also conducted a prospective practice survey to provide a national overview of IFI management in pediatric hematology units. RESULTS: From January 2014 to December 2017, 144 cases of IFI were diagnosed (5.3%) in 2721 patients, including 61 cases of candidiasis, 60 cases of aspergillosis, and 23 cases of infection with "emergent" fungi, including 10 cases of mucormycosis and 6 cases of fusariosis. The IFI rate was higher in patients with acute myelogenous leukemia (12.9%) (OR, 3.24; 95% CI, 2.15-4.81; P < .0001) compared with the rest of the cohort. Patients undergoing a-HSCT had an IFI rate of only 4.3%. In these patients, the use of primary antifungal prophylaxis (principally fluconazole) was associated with a lower IFI rate (OR, 0.28; 95% CI, 0.14-0.60; P = 4.90 ×10-4) compared with a-HSCT recipients who did not receive antifungal prophylaxis. The main cause of IFI in children receiving prophylaxis was emergent pathogens (41%), such as mucormycosis and fusariosis, which were resistant to the prophylactic agents. CONCLUSIONS: The emerging fungi and new antifungal resistance profiles uncovered in this study should be considered in IFI management in immunocompromised children.

A French national breast and thyroid cancer screening programme for survivors of childhood, adolescent and young adult (CAYA) cancers - DeNaCaPST programme.

BACKGROUND: Survival of childhood, adolescent and young adult (CAYA) cancers has increased with progress in the management of the treatments and has reached more than 80% at 5 years. Nevertheless, these survivors are at great risk of second cancers and non-malignant co-morbidities in later life. DeNaCaPST is a non-interventional study whose aim is to organize a national screening for thyroid cancer and breast cancer in survivors of CAYA cancers. It will study the compliance with international recommendations, with the aim, regarding a breast screening programme, of offering for every woman living in France, at equal risk, an equal screening. METHOD: DeNaCaPST trial is coordinated by the INSERM 1018 unit in cooperation with the LEA (French Childhood Cancer Survivor Study for Leukaemia) study's coordinators, the long term follow up committee and the paediatric radiation committee of the SFCE (French Society of Childhood Cancers). A total of 35 centres spread across metropolitan France and la Reunion will participate. FCCSS (French Childhood Cancer Survivor Study), LEA and central registry will be interrogated to identify eligible patients. To participate, centers agreed to perform a complete "long-term follow-up consultations" according to good clinical practice and the guidelines of the SFCE (French Society of Children Cancers). DISCUSSION: As survival has greatly improved in childhood cancers, detection of therapy-related malignancies has become a priority even if new radiation techniques will lead to better protection for organs at risk. International guidelines have been put in place because of the evidence for increased lifetime risk of breast and thyroid cancer. DeNaCaPST is based on these international recommendations but it is important to recognize that they are based on expert consensus opinion and are supported by neither nonrandomized observational studies nor prospective randomized trials in this specific population. Over-diagnosis is a phenomenon inherent in any screening program and therefore such programs must be evaluated.

Feasibility and clinical integration of molecular profiling for target identification in pediatric solid tumors.

BACKGROUND: The role of tumor molecular profiling in directing targeted therapy utilization remains to be defined for pediatric tumors. We aimed to evaluate the feasibility of a sequencing and molecular biology tumor board (MBB) program, and its clinical impact on children with solid tumors. PROCEDURE: We report on a single-center MBB experience of 60 pediatric patients with a poor prognosis or relapsed/refractory solid tumors screened between October 2014 and November 2015. Tumor molecular profiling was performed with panel-based next-generation sequencing and array comparative genomic hybridization. RESULTS: Mean age was 12 ± 5.7 years (range 0.1-21.5); main tumor types were high-grade gliomas (n = 14), rare sarcomas (n = 9), and neuroblastomas (n = 8). The indication was a poor prognosis tumor at diagnosis for 16 patients and relapsed (n = 26) or refractory disease (n = 18) for the remaining 44 patients. Molecular profiling was feasible in 58 patients. Twenty-three patients (40%) had a potentially actionable finding. Patients with high-grade gliomas had the highest number of targetable alterations (57%). Six of the 23 patients subsequently received a matched targeted therapy for a period ranging from 16 days to 11 months. The main reasons for not receiving targeted therapy were poor general condition (n = 5), pursuit of conventional therapy (n = 6), or lack of pediatric trial (n = 4). CONCLUSIONS: Pediatric molecular profiling is feasible, with more than a third of patients being eligible to receive targeted therapy, yet only a small proportion were treated with these therapies. Analysis at diagnosis may be useful for children with very poor prognosis tumsors.

[Desmoid tumors in children: current strategy]. / Les tumeurs desmoïdes en pédiatrie : état des connaissances actuelles.

Desmoid tumor (DT) or aggressive fibromatosis is a histologically benign-appearing neoplasms of the soft tissues, arising from connective tissues, the fascial sheaths and musculoaponevrotic structures of muscles. DT is a non-metastasizing tumor but has a potential for local invasion and local recurrence. DT can be seen in all age groups including young children. The overall incidence is reported as 2-4 cases per million per year. The etiology of DT is unknown. However, a genetic predisposition, familial adenomatous polyposis and Gardner's syndrome, has been implicated in 2% of the cases. The histological diagnosis has to be confirmed by biopsy in order to eliminate other sarcomas. The clinical behavior of DT seems unpredictable with a high rate of local recurrence. Treatment depends on the aggressiveness of the disease. A "wait-and-see" strategy is, at the present time, preferred in case of asymptomatic or non-progressive disease. Complete resection after surgery is rare, that is why first-line surgery should be seriously questioned and only considered when a complete resection can be feasible without functional or cosmetic damage. If not, medical treatments (cytotoxic or not) are rather discussed. Radiation therapy is rarely an option in children in this benign tumor. Authors present accurate knowledge of this disease in children.

Desmoid fibromatosis in pediatric patients: management based on a retrospective analysis of 59 patients and a review of the literature.

Background. Only limited data are available concerning desmoid tumor in children. Methods. Fifty-nine children and adolescents with desmoid tumor treated in 2 French cancer centers with a very long followup were retrospectively reviewed. Results. Median age was 6 years (range, 0-15). Tumors mainly involved the limbs (42%). Five cases occurred in a context of genetic disorder. Surgery was first-line treatment in 80% of cases. Resection was microscopically complete in 3 patients (pts), with a microscopic residue in 19 pts and a macroscopic residue in 35 cases. Various adjuvant therapies were used. Overall response to all systemic therapies was 33%. Thirty-eight patients developed one or more recurrences or progressions. After a median followup of 8.5 years, 34 patients were alive in complete remission (CR), including 16 first CR. Seven patients died, 6 from refractory disease and 1 from colorectal carcinoma in a genetic context. Ten-year progression-free survival (PFS) and overall survival were 31% and 88%, respectively. In univariate analysis, age less than 10 years and head-neck site were favorable prognostic factors for PFS. Conclusions. When surgery is required, surgical margins must be negative. Low-dose chemotherapy can be proposed as adjuvant therapy. Prospective trials must be developed to evaluate long-term response and side effects.

PCA analgesia for children with chemotherapy-related mucositis: a double-blind randomized comparison of morphine and pethidine.

AIMS: This study aimed to compare pethidine and morphine on efficacy and toxicity in children with severe mucositis following chemotherapies. PATIENTS AND METHODS: From March 2000 to November 2003, 35 hospitalized children with chemotherapy-related mucositis were randomly assigned to receive double blindly "patient-controlled analgesia" (PCA) bolus doses of morphine or pethidine. The mucositis pain score was the mean of pain measured four times a day with a Visual Analogue Scale from day 2 to 5 of PCA. RESULTS: Study stops before total accrual for difficulties of recruitment. Out of the 29 patients with more than one day of PCA, the median (range) of the Mean Pain Score was 44 (13-72) and 33 (3-89) in the morphine (n = 14) and pethidine (n = 15) groups, respectively (P = 0.32). PCA was stopped for failure in 10 cases (five in each group). Constipation requiring specific treatment was higher in the morphine group (43% versus 0%). CONCLUSIONS: PCA with pethidine appears not inferior to morphine, with less constipation requiring specific treatment, but a larger study is warranted to confirm this.

Efficacy of fractionated gemtuzumab ozogamicin combined with cytarabine in advanced childhood myeloid leukaemia.

Gemtuzumab ozogamicin (GO) monotherapy is reported to yield a 20-30% response rate in advanced acute myeloid leukaemia (AML). This study examined the efficacy and tolerability of GO combined with cytarabine (GOCYT) in children with refractory/relapsed CD33(+) AML. Seventeen children received GO 3 mg/m(2) on days 1, 4 and 7 plus cytarabine 100 mg/m(2)/d for 7 d on a compassionate-use basis. Seven patients then received GO-based consolidation. At the outset of GOCYT, two patients were refractory; eight patients were in refractory first relapse; six patients had relapsed after stem cell transplantation (SCT); and one patient [del(5q) therapy-related AML (t-AML)] had not yet been treated. Mean follow-up was 17 months (8-33 months). Ten responses were obtained after GOCYT induction, including complete remission (CR) or CR without complete recovery of platelets (CRp) in six patients (35%). The responses improved in three children who received GOCYT consolidation, increasing the CR + CRp rate to 53%. SCT was subsequently performed in eight responders. Grade 3-4 adverse events consisted of haematological disorders (n = 17, 100%) and documented infections (n = 5, 29%). No cases of sinusoidal obstructive syndrome occurred. Three patients were alive at the cut-off date for this analysis, all of whom had responded to GOCYT. GOCYT combination therapy yielded a high response rate (53%) and showed acceptable toxicity in heavily pretreated children with refractory/relapsed AML. These results warrant a larger prospective study.

Prognostic factors for leukemic induction failure in children with acute lymphoblastic leukemia and outcome after salvage therapy: the FRALLE 93 study.

PURPOSE: To identify prognostic factors and to evaluate the outcome of children with acute lymphoblastic leukemia (ALL) failure after induction therapy. PATIENTS AND METHODS: Between June 1993 and December 1999, 1,395 leukemic children were included in the French Acute Lymphoblastic Leukemia 93 study. RESULTS: Fifty-three patients (3.8%) had a leukemic induction failure (LIF) after three- or four-drug induction therapy. In univariate analysis, high WBC count (P = .001), mediastinal mass (P = .017), T-cell phenotype (T-ALL; P = .001), t(9;22) translocation (P = .001), and a slow early response (at day 8 and/or on day 21, P = .001) were predictive of LIF. The following three prognostic groups for LIF were identified by multivariate analysis: a low-risk group with B-cell progenitor (BCP) ALL without t(9;22) (odds ratio [OR] = 1), an intermediate-risk group with T-ALL and a mediastinal mass (OR = 7.4, P < .0001), and a high-risk group with BCP-ALL and t(9;22) or T-ALL without a mediastinal mass (OR = 28.4, P < .0001). Complete remission (CR) was subsequently obtained in 43 patients (81%). The 5-year overall survival (OS) rate of the 53 patients was 30% +/- 6%. The 5-year OS rate among allogeneic graft recipients, autologous graft recipients, and after chemotherapy were 30.4% +/- 9.6% (50% +/- 26% after genoidentical transplantation), 50% +/- 17.7%, and 41.7% +/- 14.2%, respectively (P = .18). Fourteen patients (26%) were still in first CR after a median of 83 months (range, 53 to 117 months). CONCLUSION: Three risk categories for LIF in children with ALL were identified. Approximately one third of patients with LIF can be successfully treated with salvage therapy overall. Subsequent CR after LIF is mandatory for cure.