Sclerosing Epithelioid Fibrosarcoma (SEF) versus Low Grade Fibromyxoid Sarcoma (LGFMS): Presentation and outcome in the nationwide NETSARC+ series of 330 patients over 13 years.

Sclerosing Epithelioid Fibrosarcoma (SEF) and Low Grade Fibromyxoid Sarcoma (LGFMS) are ultrarare sarcomas sharing common translocations whose natural history are not well known. We report on the nationwide exhaustive series of 330 patients with SEF or LGFMS in NETSARC+ since 2010. PATIENTS AND METHODS: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTB). Since 2010, (i) pathological review has been mandatory for sarcoma,and (ii) tumour/patients' characteristics have been collected in the NETSARC+ nationwide database. The characteristics of patients with SEF and LGFMS and their outcome are compared. RESULTS: 35/73 (48%) and 125/257(49%) of patients with SEF and LGFMS were female. More visceral, bone and trunk primary sites were observed in SEF (p < 0.001). 30% of SEF vs 4% of LGFMS patients had metastasis at diagnosis (p < 0.0001). Median size of the primary tumor was 51 mm (range 10-90) for LGFMS vs 80 (20-320) for SEF (p < 0.001). Median age for LGFMS patients was 12 years younger than that of SEF patients (43 [range 4-98] vs 55 [range 10-91], p < 0.001). Neoadjuvant treatment was more often given to SEF (16% vs 9%, p = 0.05). More patients with LGFMS were operated first in reference centers (51% vs 26%, p < 0.001). The R0 rate on the operative specimen was 41% in LGFMS vs 16% in SEF (p < 0.001). Median event-free survival (EFS) of patients with SEF and LGFMS were 32 vs 136 months (p < 0.0001). The median overall survival (OS) was not reached. Fifty-months OS was 93% vs 81% for LGFMS vs SEF (p = 0.05). Median OS was 77 months after first relapse, similar for SEF and LGFMS. In multivariate analysis, age, tumor size, metastasis at diagnosis were independent prognostic factors for OS in LGFMS. CONCLUSIONS: Although sharing close molecular alterations, SEF and LGFMS have a different natural history, clinical presentation and outcome, with a higher risk of metastatic relapse in SEF. Survival after relapse is longer than with other sarcomas, and similar for SEF and LGFMS.

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.

Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid malignancies and young adults with osteosarcoma (ITCC-050)☆.

BACKGROUND: We report results from the phase I dose-finding and phase II expansion part of a multicenter, open-label study of single-agent lenvatinib in pediatric and young adult patients with relapsed/refractory solid tumors, including osteosarcoma and radioiodine-refractory differentiated thyroid cancer (RR-DTC) (NCT02432274). PATIENTS AND METHODS: The primary endpoint of phase I was to determine the recommended phase II dose (RP2D) of lenvatinib in children with relapsed/refractory solid malignant tumors. Phase II primary endpoints were progression-free survival rate at 4 months (PFS-4) for patients with relapsed/refractory osteosarcoma; and objective response rate/best overall response for patients with RR-DTC at the RP2D. RESULTS: In phase I, 23 patients (median age, 12 years) were enrolled. With lenvatinib 14 mg/m2, three dose-limiting toxicities (hypertension, n = 2; increased alanine aminotransferase, n = 1) were reported, establishing 14 mg/m2 as the RP2D. In phase II, 31 patients with osteosarcoma (median age, 15 years) and 1 patient with RR-DTC (age 17 years) were enrolled. For the osteosarcoma cohort, PFS-4 (binomial estimate) was 29.0% [95% confidence interval (CI) 14.2% to 48.0%; full analysis set: n = 31], PFS-4 by Kaplan-Meier estimate was 37.8% (95% CI 20.0% to 55.4%; full analysis set) and median PFS was 3.0 months (95% CI 1.8-5.4 months). The objective response rate was 6.7% (95% CI 0.8% to 22.1%). The patient with RR-DTC had a best overall response of partial response. Some 60.8% of patients in phase I and 22.6% of patients in phase II (with osteosarcoma) had treatment-related treatment-emergent adverse events of grade ≥3. CONCLUSIONS: The lenvatinib RP2D was 14 mg/m2. Single-agent lenvatinib showed activity in osteosarcoma; however, the null hypothesis could not be rejected. The safety profile was consistent with previous tyrosine kinase inhibitor studies. Lenvatinib is currently being investigated in osteosarcoma in combination with chemotherapy as part of a randomized, controlled trial (NCT04154189), in pediatric solid tumors in combination with everolimus (NCT03245151), and as a single agent in a basket study with enrollment ongoing (NCT04447755).

Clinical management of adolescents and young adults suffering from sarcoma in the French Rhône-Alpes region: A prospective exhaustive cohort with 10 years follow up.

INTRODUCTION: Survival of adolescents and young adults (AYA) with sarcoma is lower than in younger patients. The objective of this study was to describe the regional healthcare circuits, the differences in the management between adult, paediatric and mixed units and to assess the prognostic impact of compliance with clinical practice guidelines (CPGs) on overall survival (OS) and on relapse free survival (RFS). MATERIALS AND METHODS: Retrospective analysis of the management and long term follow-up of all 13-25 year old patients with a sarcoma diagnosed in the Rhône-Alpes area between 2000 and 2005. RESULTS: 140 patients satisfied inclusion criteria and were selected. The majority of 13-25 year old patients were treated in paediatric units. Joint management resulted in a higher rate of discussion in multidisciplinary tumour board, inclusion in clinical trials, and fertility preservation. Non-compliance with guidelines was observed in 65% of cases. Overall compliance was not reported to correlate to survival. Compliance of radiotherapy with CPG's seemed associated with a better prognosis for OS (HR = 0.20, 95% CI = [0.10-0.40]; p < 0.0001) and RFS (HR = 0.18, 95% CI = [0.09-0.37; p < 0.0001) as well as compliance of surgery for OS (HR = 0.43, 95% CI = [0.23-0.81]; p = 0.01). Multivariate Cox regression analysis revealed other independent predictors of OS like age at diagnosis, stage and histological subtype. CONCLUSIONS: Management of AYA in joint units seems to improve the quality of care. Compliance of surgery and radiotherapy with CGP's seems to improve survival.

Programmed cell death 1 (PD-1) targeting in patients with advanced osteosarcomas: results from the PEMBROSARC study.

PURPOSE: There are some lines of evidence suggesting a potential role of immunotherapy for treating patients with osteosarcomas. PATIENTS AND METHODS: This was an open-label, multicentre, phase 2 study of pembrolizumab in combination with metronomic cyclophosphamide in patients with advanced osteosarcomas. All patients received 50 mg b.i.d. of cyclophosphamide one week on and one week off and 200 mg of intravenous pembrolizumab (every 3 weeks). There was a dual primary end-point, encompassing both the non-progression and objective responses at 6 months per Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1. An objective response rate of 20% and/or a 6-month non-progression rate of 60% were determined as reasonable objectives for treatment with meaningful effect. Correlative studies of immune biomarkers were planned from the patients' tumour samples. RESULTS: Between October 13 2015 and July 3 2017, 17 patients were included. Fifty were assessable for the efficacy end-point. Four patients experienced tumour shrinkage, resulting in a partial response (PR) in one patient (6.7%). The 6-month non-progression rate was 13.3% (95% confidence interval [CI]: 1.7-40.5). The most frequent adverse events were grade I or II nausea, anaemia, anorexia and fatigue. programmed death-ligand 1 (PD-L1) expression rate was low, observed in only 2 cases of 14 with available tumour material. The only patient who experienced PR had a PD-L1-negative tumour. CONCLUSION: Programmed cell death 1 (PD-1) inhibition has limited activity in osteosarcomas. Further studies investigating PD-1 inhibitor in combination with agents modulating the microenvironment are warranted. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT02406781.

[Does consumption of tobacco, alcohol, and cannabis in adolescents and young adults with cancer affect the use of analgesics during hospitalizations?]. / La consommation de tabac, alcool et cannabis chez les adolescents et jeunes adultes atteints de cancer a-t-elle un impact sur l'utilisation hospitalière des traitements antalgiques pendant la période de traitement ?

INTRODUCTION: The specificities of adolescents and young adults (AYAs) aged 15-25 years with cancer are now well recognized. Dedicated care was initiated in 2012 in France under the leadership of the INCa (National Cancer Institute). Research on supportive care and particularly pain management are still rare. This study aimed to evaluate the consumption of toxic substances (tobacco, cannabis, alcohol) in AYAs with cancer as well as its progression during the month following the diagnosis and to analyze its influence on opioid analgesic prescriptions during treatment. METHODS: This is a prospective study including all new patients aged 15-25 years in two centers between January and June 2013. Data on consumption of psychoactive substances were obtained during an individual interview with a questionnaire. National surveys were used to compare this cohort with the general population. Data on opioid treatments were collected from the computerized prescription software and computerized patient record. RESULTS: Thirty-seven AYAs were eligible and 30 were included; 67% of them were male and the median age was 18.7 years. The questionnaire on tobacco, alcohol, and cannabis consumption at diagnosis was well accepted. Consumption profiles were comparable to the general population. Changes in behavior were observed during the 1st month after diagnosis, with a decrease or cessation of consumption, particularly among young people. This study showed differences in the use and requirements for opioid analgesics during hospitalization according to these consumption data. CONCLUSION: Prevention and support for AYAs who are regular consumers of toxic substances must be organized during initial care in oncology.

Radiofrequency ablation of metastases from osteosarcoma in patients under 25 years: the SCFE experience.

BACKGROUND: Radiofrequency ablation (RFA) has demonstrated its effectiveness in controlling metastases measuring less than 3 cm in several adult malignancies but not yet in osteosarcoma. We report our experience of RFA in the treatment of metastases in adolescents and young adults (AYA) with osteosarcoma. PROCEDURE: Sixteen patients treated for osteosarcoma in French Society of Childhood Cancer centers had undergone an RFA procedure between 2006 and 2012. RESULTS: Thirteen sessions were performed in 10 patients to treat 22 lung metastases. Seven patients were in complete remission at last follow up (range 19-51 months; median, 24 months after RFA). None had a recurrence at RFA sites. We report three cases each of hemoptysis and pneumothorax. Eight sessions were performed in seven patients to treat bone lesions. PROCEDURE was intended as: curative for a small metastatic lesion (n = 3, all in remission more than 3 years after); local control of small bone lesions in multi-metastatic diseases (n = 3); analgesia (n = 1). Complications included one first-degree burn, one fracture, and one soft tissue infection. CONCLUSIONS: RFA is feasible in AYA with osteosarcoma. It efficiently achieved local control of small peripheral lung metastases. Its role in the curative care of small secondary bone lesions remains to be confirmed.

[Analgesic efficacy of topical lidocaine for vaso-occlusive crisis in children with sickle cell disease]. / Efficacité des emplâtres de lidocaïne 5 % sur les douleurs des crises vaso-occlusives chez l'enfant drépanocytaire.

Pain associated with vaso-occlusive crisis is the main cause of hospitalization in children with sickle cell disease. Recent studies have suggested that pain might have a neuropathic component. Lidocaine patches are commonly prescribed as a topical analgesic in adult neuropathic pain. This study reports the efficacy and safety of such treatment in 6 patients with sickle cell disease, aged 6-18 years, who had been hospitalized for vaso-occlusive crisis after failure of the standard analgesic treatment. These data have led to setting up a confirmatory phase II trial, which is currently underway.

Atypical granular cell tumor occurring in an individual with Noonan syndrome treated with growth hormone.

We report a large infiltrating atypical granular cell tumor in a child with Noonan syndrome. Even though granular cell tumors are rare in childhood, five cases have been reported in children with Noonan syndrome. This study compares these different cases and explores the possibility of activation of the granular cell by the Ras pathway.

Deep sedation in pediatric imaging: efficacy and safety of intravenous chlorpromazine.

BACKGROUND: The quality of MRI and CT depends largely on immobility of the patient during the procedure, which is often difficult to achieve without sedation in children below the age of 6 years. OBJECTIVE: To assess the efficacy and safety of intravenous chlorpromazine sedation for repeated imaging in young children treated for cancer. MATERIALS AND METHODS: From July 2003 to January 2007, information on children younger than 6 years of age having MRI or CT was prospectively collected. Forty-five minutes before the scan, a 10-min infusion of chlorpromazine 0.5 mg/kg was administered and managed by non-anesthetic staff. Patient monitoring included continuous measurement of pulse, respiration, oxygen saturation and arterial blood pressure. Procedure-related parameters and adverse events were documented. Sedation was considered successful when the procedure was completed and at least 95% of images were usable. RESULTS: One-hundred-one procedures (82 MRI, 19 CT) were evaluated in 62 children, 3-74 months old. Adequate sedation was achieved in 96% of cases, with mean induction time, 22 min; mean duration of sleep, 72 min, and mean duration of procedure, 33 min. Mean time spent in the radiology unit was 104 min. Ninety-six percent of imaging procedures were successfully completed. No cardiac, respiratory, neurological or allergic complication occurred. CONCLUSION: Intravenous chlorpromazine is safe and effective for procedural sedation in young children with cancer undergoing MRI and CT.

Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG).

BACKGROUND: Data regarding the role of chemotherapy (CT) in patients with recurrent and/or unresectable desmoid tumors (DTs) are scarce. PATIENTS AND METHODS: Records of patients with DT who were treated with CT in centers from the French Sarcoma Group were reviewed. RESULTS: Sixty-two patients entered the study. The two most common locations were extremities (35.5%) and internal trunk (32.5%). Twelve patients (19.5%) were diagnosed with Gardner syndrome. Thirty-seven patients (54.7%) received previously one or more lines of systemic therapies (nonsteroidal anti-inflammatory drugs: 43.5%, antiestrogens: 43.5% and imatinib: 30.5%). Combination CT was delivered in 44 cases (71%) and single agent in 18 patients (29%), respectively. Thirteen patients (21%) received an anthracycline-containing regimen. The most frequent nonanthracycline regimen was the methotrexate-vinblastine combination (n=27). Complete response, partial response, stable disease and progressive disease were observed in 1 (1.6%), 12 (19.4%), 37 (59.6%) and 12 (19.4%) patients, respectively. The response rate was higher with anthracycline-containing regimens: 54% versus 12%, P=0.0011. Median progression-free survival (PFS) was 40.8 months. The sole factor associated with improved PFS was the nonlimb location: 12.1 months (95% confidence interval 5.6-18.7) versus not reached, P=0.03. CONCLUSIONS: CT has significant activity in DT. Anthracycline-containing regimens appear to be associated with a higher response rate.

[Management of neuropathic pain in children: guidelines for good clinical practice]. / Prise en charge des douleurs neuropathiques chez l'enfant: recommandations de bonne pratique clinique.

Neuropathic pain exists in children and its incidence is often underestimated due to the lack of knowledge on the existence and the diagnosis of this pain. Although the semiological characteristics can be compared to those of the adult (allodynia, hypoesthesia, burning and stabbing sensations), their etiology often differs, and pain treatments are more limited because of a lack of pharmacological data and the absence of clinical studies. Therapeutic management is sometimes insufficient and requires better knowledge of this entity. Based on the June 2009 recommendations of the French Agency for Food and Drug Safety (Afssaps) (drug therapy in acute and chronic pain in children), this article presents a review of the data available in the literature on the subject, taking into account expert opinion and proposing clinical recommendations of good practice for the recognition and the treatment of neuropathic pain in children.

[PNET/Ewing tumours: current treatments and future perspectives]. / Tumeurs PNET/Ewing : prise en charge actuelle et perspectives.

Ewing tumours are characterised as tumours consisting of small, blue, round malignant cells that may exhibit varying degrees of neural differentiation. Most of them arise in bony sites, and they represent the second commonest primary osseous malignancy in and adolescence and young adults. During the past 30 years, chemotherapy has increased survival from less than 5% to 65-70% in localized tumours and to 25-30% in primary metastatic tumours. Surgery is a major tool, whereas advances in imaging techniques have improved treatment indication and optimization. Radiotherapy remains useful, either alone or in addition to surgery, and new techniques (conformational RT and IMRT) will reduce short-term toxic effects. However, long-term toxic effects are also of major concern. Clinical and biological prognostic factors has been clearly identified and should guide the therapeutic choice for these patients. The metastatic Ewing tumours are of extremely poor prognosis, and impose the development of new therapeutic agents. This article is a review of the data available in 2009 concerning Ewing's sarcoma either as biologic aspects or as therapeutic aspects.

[A positioning pillow to improve lumbar puncture in paediatric haematology-oncology patients: a randomized controlled trial.]. / Coussin de positionnement pour ponctions lombaires en oncohématologie pédiatrique : résultats d'un essai randomisé

ObjectivesLumbar punctures (LPs) are common in children with cancer. Although pain management during the LP has been well standardised, dealing with stress and anxiety is not well addressed yet. Our objective was to evaluate the potential improvement of the LPs success rate using a positioning pillow, to ensure maximum lumbar flexion, and allow paravertebral muscles to relax, in children who are awake, with either conscious sedation or no sedation.Patients and methodsChildren aged 2-18 years undergoing LPs were randomly assigned to a positioning pillow or no intervention. The primary outcome was the rate of success, i.e. achieving the LPs (sampling or injection) at the first attempt, without bleeding (RBC < 50/mm3). The secondary outcomes included: the child's pain, assessed by a self-administered visual analogical scales (VAS) for children over 6 years of age; the parents' and caregivers' perception of the child's pain; the satisfaction of the children, the parents, the caregivers and the physician. The child's cooperation and the occurrence of post-LP syndrome were also evaluated.ResultsOne hundred twenty-four children (62 in each group) were included. The LP pillow tended to increase the success rate of LPs (67 vs 57%; P = 0.23), and decreased the post-LP syndromes (15 vs 24%; P = 0.17) but the differences were not statistically significant. In children over 6-year of age (N = 72), the rate of success was significantly higher in the pillow group (58.5 vs 41.5%; P = 0.031), with a tendency to feel less pain (for less pain and better satisfaction) [median VAS: 25 vs 15 mm; P = 0.39] and being more satisfied (84.4 vs 75.0%; P = 0.34).ConclusionEven if the results presented here are not as optimistic as we might have wished, we can confirm that there is a benefit in using this pillow for LPs. It is especially promising in children over 6-year of age.

Use of totally implantable catheters for peripheral blood stem cell apheresis.

Collection of PBSC by leukapheresis requires one venous access (VA) for inflow and one for outflow. The use of implantable venous access devices (IVAD) has never been reported in this setting. We retrospectively analyzed the use of IVAD for performing apheresis. The study was conducted between January 2000 and June 2005 on 64 patients (41 children) requiring intensification for treatment of a solid tumor. Mean body weight was 26 kg (range 8-91 kg) for a median age of 8.5 years (range 0.7-66 years). A total of 121 aphereses were performed (mean 1.89 apheresis/patient). The second VA was in a cubital vein in 84 procedures and was a temporary central VA in 31. Mean duration of apheresis was 3 h (range 30-274 min). Mean flow rate was 41.3 ml/min (range 12-85 ml/min). Mean collection rate was 59.2% for CD34+ cells and 70% for mononuclear cells. The total number of CD34+ cells collected was 2.5 x 10(6)/kg per apheresis, and 5.9 x 10(6)/kg per patient. Several complications occurred: one catheter-related sepsis (0.86%), four catheter occlusions (3.47%) and eight hemodynamic instabilities related to extracorporeal volume. Weight <10 kg is a risk factor for complication (P=0.0006). IVAD are effective and safe for PBSC collection. Placement of a second central VA (requiring general anesthesia for children) could be avoided.