ctDNA quantification improves estimation of outcomes in patients with high-grade osteosarcoma: a translational study from the OS2006 trial.

BACKGROUND: Osteosarcoma stratification relies on clinical parameters and histological response. We developed a new personalized stratification using less invasive circulating tumor DNA (ctDNA) quantification. PATIENTS AND METHODS: Plasma from patients homogeneously treated in the prospective protocol OS2006, at diagnosis, before surgery and end of treatment, were sequenced using low-passage whole-genome sequencing (lpWGS) for copy number alteration detection. We developed a prediction tool including ctDNA quantification and known clinical parameters to estimate patients' individual risk of event. RESULTS: ctDNA quantification at diagnosis (diagCPA) was evaluated for 183 patients of the protocol OS2006. diagCPA as a continuous variable was a major prognostic factor, independent of other clinical parameters, including metastatic status [diagCPA hazard ratio (HR) = 3.5, P = 0.002 and 3.51, P = 0.012, for progression-free survival (PFS) and overall survival (OS)]. At the time of surgery and until the end of treatment, diagCPA was also a major prognostic factor independent of histological response (diagCPA HR = 9.2, P < 0.001 and 11.6, P < 0.001, for PFS and OS). Therefore, the addition of diagCPA to metastatic status at diagnosis or poor histological response after surgery improved the prognostic stratification of patients with osteosarcoma. We developed the prediction tool PRONOS to generate individual risk estimations, showing great performance ctDNA quantification at the time of surgery and the end of treatment still required improvement to overcome the low sensitivity of lpWGS and to enable the follow-up of disease progression. CONCLUSIONS: The addition of ctDNA quantification to known risk factors improves the estimation of prognosis calculated by our prediction tool PRONOS. To confirm its value, an external validation in the Sarcoma 13 trial is underway.

Functional analysis of young patients with desmoid-type fibromatosis: Initial surveillance does not jeopardize long term quality of life.

BACKGROUND: With recent conservative strategies, prognosis of patients with desmoid-type fibromatosis (DTF) is about function preservation. We analyzed the long-term quality of life (QoL) of pediatric patients with DTF. METHODS: All French young patients (<21years) treated between 2005 and 2016 for a DTF in the EpSSG NRSTS-05 study were analyzed. A first wait-and-see strategy was recommended. Patients' QoL was analyzed with the internationally validated Child Health Questionnaire (CHQ). We focused on the relevant subscales scores: physical functioning (PF), role social limitations physical (RP), bodily pain (BP), general health perception (GH) and physical (PhS) and psychosocial (PsS) summary measures. RESULTS: Among the 81 patients, 52 families answered the CHQ (median delay since diagnosis = 6.2years; min2.2-max13.3 years). Median age at diagnosis was 11.5 years. Primary site: limbs (52%), head/neck (27%), or trunk (21%). Five year-Progression Free Survival was 39.1% (95%CI: 27.7-50.5%). As initial management for these 52 patients, 30 patients were first observed (57%), 13 had surgery (25%) and 9 received chemotherapy (18%). Total burden of therapy was exclusive surgery (9pts/18%), exclusive chemotherapy (18pts/35%), surgery + chemotherapy (13pts/25%), chemotherapy + radiotherapy (1 pt), surgery + chemotherapy + radiotherapy (1 pt), wait and see (10 pt). Regarding the parent forms, patients have significant lower PF (86.0vs.96.1; p = 0.03), RP (82.0vs.93.6; p = 0.04), GH (60vs.73; p < 0.005) and PhS (46.2 vs.53; p = 0.02) scores compared to healthy population. Comparison of QoL subscales scores according to initial strategy (wait-and-see vs.surgery/chemotherapy) did not reveal any difference (PF = 87.3vs.84.9; p = 0.80/RP = 83.4vs.78.7; p = 0.72/BP = 78.9vs.78.2; p = 0.95/GH = 59.7vs60; p = 0.97). Similar results were found using the children or adult forms. CONCLUSIONS: Initial wait-and-see strategy does not affect long term functional impairment.

Photobiomodulation with a combination of two wavelengths in the treatment of oral mucositis in children: The PEDIALASE feasibility study.

Photobiomodulation is recommended in adults for the prevention of mucositis induced by cervicofacial irradiation or pre-transplant chemotherapy. The results of pediatric studies are promising but this support treatment is still underused. The objective was to conduct a feasibility study in the pediatric hematology-oncology unit at X Children's Hospital. Extra- and intraoral scans were performed a minimum of three times every 2 days for grade 2 or higher mucositis in children (median age, 8.6 years) using the Oncolase laser (Biophoton, Saint Alban, France), with a combination of two wavelengths (635 and 815nm). The effect of the laser on mucositis grade, pain, the child's tolerance, and the time dedicated to this care were also evaluated. The success of the procedure was 77% in 1 year, with the inclusion of 84% of the patients (n=22) and 146 laser treatment sessions (median of four per episode of mucositis). We observed excellent tolerance and pain relief with a gain of two points on the VAS and the HEDEN mucositis scale. This study shows that photobiomodulation that incorporates two application modes (intra- and extraoral) through the combination of two wavelengths is feasible when integrated into the care of a pediatric hematology-oncology department and is perfectly tolerated, even by young children. Along with oral hygiene and analgesic management, it alleviates pain associated with oral mucositis.

Whole-exome sequencing in osteosarcoma reveals important heterogeneity of genetic alterations.

BACKGROUND: Whole-genome sequencing studies have recently shown that osteosarcomas (OSs) display high rates of structural variation, i.e. they contain many somatic mutations and copy number alterations. TP53 and RB1 show recurrent somatic alterations in concordant studies, suggesting that they could be key players in bone oncogenesis. PATIENTS AND METHODS: we carried out whole-genome sequencing of DNA from seven high-grade OS samples matched with normal tissue from the same patients. RESULTS: We confirmed the presence of genetic alterations of the TP53 (including novel unreported mutations) and RB1 genes. Most interestingly, we identified a total of 84 point mutations and 4 deletions related to 82 different genes in OS samples, of which only 15 have been previously reported. Interestingly, the number of mutated genes (ranging from 4 to 8) was lower in TP53mut cases compared with TP53wt cases (ranging from 14 to 45). This was also true for the mutated RB1 case. We also observed that a dedifferentiated OS harboring MDM2 amplification did not carry any other mutations. CONCLUSION: This study suggests that bone oncogenesis driven by TP53 or RB1 mutations occurs on a background of relative genetic stability and that the dedifferentiated OS subtype represents a clinico-pathological entity with distinct oncogenic mechanisms and thus requires different therapeutic management.

[Thymoma in children: a rare and difficult diagnosis]. / Thymome de l'enfant : un diagnostic parfois difficile.

Thymoma is extremely rare within the pediatric age range, which could lead to delayed diagnosis. Based on the clinical case of a mediastinal tumor in an 8-year-old patient, we detail the key points in the management of this disease highlighted by our recent experience.

[Clear-cell sarcoma of the kidney: about a paediatric case]. / Sarcome à cellules claires du rein : à propos d'un cas pédiatrique.

Clear-cell sarcoma of the kidney (CCSK) is a rare malignant tumor of childhood, known for its aggressiveness, its tendency to recurrence and to metastasis to bone. We report an observation of a child of 48 months carrying a large abdominal mass. The diagnosis of the SCCR was made on biopsy, since imaging remained uncertain as to the renal origin of the mass. Indeed, our observation underlines the difficulty of its diagnosis. Excepting the morphological aspect, there is no criterion for its recognition. Its prognosis has been improved by the new treatments.

[Central venous totally implantable access for high dose chemotherapy in children]. / Utilisation des sites veineux implantables dans les chimiothérapies massives en pédiatrie.

BACKGROUND: The feasibility and complication rate of central venous totally implantable access ports (TIAP), used for delivering high-dose chemotherapy (HDC) with autologous stem cell transplantation, have not been fully investigated to date, due to the almost exclusive use of external catheters (EC) in this clinical setting. PATIENTS AND METHODS: We retrospectively studied infectious and mechanical complications of 45 TIAP and 19 EC, in 64 children receiving HDC and autologous stem cell transplantation at the Centre Leon-Berard (Lyon) or at the oncology unit of Toulouse children hospital between January 1999 and December 2003. RESULTS: From the beginning of intensification to 60 days after bone marrow transplantation, 7 catheter-related bloodstream infections (3/19 EC or 15.8% corresponding to 2.69 infections for 1000 days of observation; 4/45 TIAP or 8.9% corresponding to 1.38 infections for 1000 days of observation) and 2 local infections (1/45 TIAP; 1/19 EC) were reported. Seven cases of reversible obstruction (6/7 with TIAP) and no deep venous thrombosis were detected. In 7 cases, another venous access was required either for accidental removal (2 EC), catheter infection (2 TIAP), or admission to intensive care (2 TIAP, 1 EC). TIAP complication rate does not seem to be influenced by factors such as low weight, massive blood product transfusion or prolonged parenteral nutrition. In 8 children, TIAP were used for collection of hematopoietic progenitor cells. CONCLUSIONS: The use of TIAPs appears as a safe and effective option for HDC. We found more mechanical complications but less infectious complications with TIAP than with EC. Nevertheless, results need to be validated prospectively in a larger study cohort.

[Congenital galactosaemia: an unusual presentation]. / La galactosémie congénitale: une révélation singulière.

Congenital galactosaemia reveals usually in the second and third weeks of life with a severe liver dysfunction. We report on a case of congenital galactosaemia with, on the one hand, an early onset liver failure, without any free interval, and on the other hand, an hemophagocytic syndrome as a severe secondary outbreak with pulmonary haemorrhage. Appropriate diet led to normalisation of liver function. Hemophagocytosis, probably linked to an associated Klebsiella Pneumoniae sepsis, had a favourable outcome after antibiotic and corticosteroid therapy.

[Testicular feminization, germinal tumor, NK lymphoma: what is the relationship?]. / Testicule féminisant, tumeur germinale, lymphome NK, quel lien?

CASE REPORT: The authors report the case of a ten-year-old girl, who had been treated for a malignant germinal tumour five years before, presenting with a leukaemia-like syndrome associating bone pain, liver and spleen nodules and bone marrow involvement. The cyto-pathological analysis showed undifferentiated cells and CD56 and protein S100 were found as the only positive markers. The child received several subsequent lines of chemotherapy and ultimately died of the disease. COMMENTS: Particular cytogenetic abnormalities were observed (iso1q10, iso6p10) and were in favor of an unusual NK cell lymphoma. CONCLUSION: This analysis revealed a XY genotype (testicular feminization syndrome).