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.

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.

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.

Self-inflicted crossbow injury in the head: A case report.

Injuries and deaths from crossbows are uncommon, especially when self-inflicted. We present here the case of a 45 years old patient with history of mental illness, who attempted suicide with a crossbow. The bolt penetrated the chin, crossed the oral floor, the oral cavity, the bony palate, the left nasal cavity and exited at the level of the nasal bones. The main concern was the management of the airways, before proceeding to the removal of the bolt. A nasotracheal intubation through the right nasal cavity while the patient was conscious was performed, but the instruments needed for an emergency tracheotomy were in the operating room in case of failure. The intubation was successful, he underwent general anesthesia, and the bolt was removed from the face.

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.

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.

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.

Internal dosimetry: towards harmonisation and coordination of research.

The CONRAD Project is a Coordinated Network for Radiation Dosimetry funded by the European Commission 6th Framework Programme. The activities developed within CONRAD Work Package 5 ('Coordination of Research on Internal Dosimetry') have contributed to improve the harmonisation and reliability in the assessment of internal doses. The tasks carried out included a study of uncertainties and the refinement of the IDEAS Guidelines associated with the evaluation of doses after intakes of radionuclides. The implementation and quality assurance of new biokinetic models for dose assessment and the first attempt to develop a generic dosimetric model for DTPA therapy are important WP5 achievements. Applications of voxel phantoms and Monte Carlo simulations for the assessment of intakes from in vivo measurements were also considered. A Nuclear Emergency Monitoring Network (EUREMON) has been established for the interpretation of monitoring data after accidental or deliberate releases of radionuclides. Finally, WP5 group has worked on the update of the existing IDEAS bibliographic, internal contamination and case evaluation databases. A summary of CONRAD WP5 objectives and results is presented here.

[Functional outcome and quality of life after pancreaticoduodenectomy]. / Séquelles fonctionnelles et qualité de vie après duodénopancréatectomie céphalique.

AIM OF STUDY: Pancreaticoduodenectomy is a major surgical procedure whose physiological effects may weigh heavily on quality of life. The goal of this retrospective unicentric pilot study was to assess the the functional outcome after pancreaticoduodenectomy and its effect on the patient's quality of life. PATIENTS AND METHOD: Thirty patients free from tumor recurrence more than one year after pancreaticoduodenectomy responded to the GIQLI questionnaire (Gastro Intestinal Quality of Life Index) and to a specific questionnaire evaluating long-term functional outcome. RESULTS: The acceptability rate was 100%. The internal coherence of the GIQLI questionnaire was good (a Cronbach rate=0.85). The average total score of the GIQLI was 94 (IC-95%=[86-101]) compared to an ideal rate of 144. The quality of life was significantly impaired by steatorrhea, need for treatment of diarrhea, or need for enzymatic substitutive treatment. CONCLUSION: Compared to the reference for the normal population, patients post-pancreaticoduodenectomy have an average 25% decrease of quality of life scores (although more than 25% of patients experience a normal quality of life). The impairment of quality of life after pancreaticoduodenectomy appears to be related to the functional digestive consequences of the procedure. The GIQLI score could be used to assess the technical surgical variants.

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.

Hair dosimetry following neutron irradiation.

Use of hair as a biological dosimeter of neutron exposure was proposed a few years ago. To date, the (32)S(n,p)(32)P reaction in hair with a threshold of 2.5 MeV is the best choice to determine the fast neutron dose using body activation. This information is essential with regards to the heterogeneity of the neutron transfer to the organism. This is a very important parameter for individual dose reconstruction from the surface to the deeper tissues. This evaluation is essential to the adapted management of irradiated victims by specialized medical staff. Comparison exercises between clinical biochemistry laboratories from French sites (the CEA and COGEMA) and from the IRSN were carried out to validate the measurement of (32)P activity in hair and to improve the techniques used to perform this examination. Hair was placed on a phantom and was irradiated at different doses in the SILENE reactor (Valduc, France). Different parameters were tested: variation of hair type, minimum weight of hair sample, hair wash before measurement, delivery period of results, and different irradiation configurations. The results obtained in these comparison exercises by the different laboratories showed an excellent correlation. This allowed the assessment of a dose-activity relationship and confirmed the feasibility and the interest of (32)P measurement in hair following fast neutron irradiation.

Review of standards of protection for pregnant workers and their offspring.

The recommendations of the International Commission on Radiological Protection and the IAEA Basic Safety Standards (BSS) make clear that the embryo and fetus should be regarded as a member of the public when considering the protection of female workers who are or may be pregnant. The BSS note that the embryo and fetus should be 'afforded the same broad level of protection as required for members of the public'. Similar guidance is included in national legislation in a number of countries. On the basis of a review of such guidance, it was concluded that although the recommendations provided in the BSS are in general agreement with the international consensus on approaches to the protection of pregnant workers and their offspring, more specific supporting guidance is needed. The IAEA is preparing a technical document that extends and clarifies previous advice and considers the practical application of the advice for workers in different types of workplace, for which important potential routes of exposure for the pregnant worker have been identified. This action is being carried out under the framework of the International Action Plan for Occupational Radiation Protection.

MEDOR, a didactic tool to support interpretation of bioassay data after internal contamination by actinides.

A didactic software, MEthodes DOsimètriques de REférence (MEDOR), is being developed to provide help in the interpretation of biological data. Its main purpose is to evaluate the pertinence of the application of different models. This paper describes its first version that is focused on inhalation exposure to actinide aerosols. With this tool, sensitivity analysis on different parameters of the ICRP models can be easily done for aerosol deposition, in terms of activity and particle number, actinide biokinetics and doses. The user can analyse different inhalation cases showing either that dose per unit intake cannot be applied if the aerosol contains a low number of particles or that an inhibition of the late pulmonary clearance by particle transport can occur which contributes to a 3-4 fold increase in effective dose as compared with application of default parameters. This underlines the need to estimate systematically the number of deposited particles, as well as to do chest monitoring as long as possible.

Coordination of research on internal dosimetry in Europe: the CONRAD project.

The EUropean RAdiation DOSimetry Group (EURADOS) initiated in 2005 the CONRAD Project, a Coordinated Network for Radiation Dosimetry funded by the European Commission (EC), within the 6th Framework Programme (FP). The main purpose of CONRAD is to generate a European Network in the field of Radiation Dosimetry and to promote both research activities and dissemination of knowledge. The objective of CONRAD Work Package 5 (WP5) is the coordination of research on assessment and evaluation of internal exposures. Nineteen institutes from 14 countries participate in this action. Some of the activities to be developed are continuations of former European projects supported by the EC in the 5th FP (OMINEX and IDEAS). Other tasks are linked with ICRP activities, and there are new actions never considered before. A collaboration is established with CONRAD Work Package 4, dealing with Computational Dosimetry, to organise an intercomparison on Monte Carlo modelling for in vivo measurements of (241)Am deposited in a knee phantom. Preliminary results associated with CONRAD WP5 tasks are presented here.

[Results of resection of locally recurrent rectal cancer]. / Résultats de l'exérèse des récidives locorégionales des cancers du rectum.

AIMS OF THE STUDY: The treatment of locally recurrent rectal cancer (LRRC) remains a difficult and controversial issue. The aim of this study was to retrospectively assess the results of an univocal attitude associating resection of a priori resectable lesions using visceral excisions as required, without sacral excision, but including intra-operative radiotherapy (IORT). PATIENTS AND METHODS: Between 1989 and 1999, 32 patients underwent resection for LRRC. Twelve had previously undergone abdomino-perineal excision and 22 had received radiotherapy. Twenty-three patients underwent pelvic exenteration (total in 17, with rectus myocutaneous flap in 18). Twenty-five patients underwent IORT. RESULTS: Three patients (9.3%) died in the early postoperative period and 11 experienced complications (37%). Resections were considered R0 in 6 patients, R1 in 21 patients and R2 in 5 patients. Five-year survival rates, overall and without disability, were respectively 12%, 12% and 5%. Median survivals, overall and without disability, were respectively 22 and 12 months. CONCLUSION: Resection of LRRC remains a surgical challenge. It may achieve an average of one-year survival without disability, and hope for a few cures. Improvement of oncologic results might come from a more accurate patient selection.