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.

Pilomatrix Carcinoma of the scalp. A case report and review of the literature.

INTRODUCTION: Pilomatrix Carcinoma (PC) is a rare and malignant dermo-hypodermic tumor. Only 11 cases were reported in patients younger than 18 years old and only 13 cases were reported on the scalp. CASE REPORT: We report the case of a 15-year-old woman who underwent cyst excision on the vertex. Anatomopathology shed light trichilemmal cyst. Five months later, she presented a first local recurrence. The tumor was removed with wide margin. Anatomopathology shed light PC. No adjuvant therapy was performed. The patient presented a second recurrence 3 months later with a parietal bone and superior sagittal sinus invasion and a lung metastasis. She underwent a craniotomy and radiochemotherapy. A third local recurrence was detected 4 months later. Three more lines of chemotherapy were performed without success. DISCUSSION: PC is a locally aggressive tumour, with a high rate of local recurrences and metastases. PC arises de novo or through malignant transformation of a pilomatrixoma. PC were observed frequently in the white male over 50 years old. The histological diagnosis is difficult to prove. Treatment consists of a wide surgical excision. Peritumoral margins are not codified. Because of most cases are on the face and neck, Mohs Micrographic Surgery seems to be a good modality to limit margins. Radiation therapy is an adjuvant treatment. Chemotherapy can be used in metastasis case. CONCLUSION: PC is a rare malignant tumor with high rate of disease relapse. Histological diagnosis is difficult and treatment is not standardized. Surgical procedure with wide margins is recommended to avoid the large recurrence when the staging shows no metastasis.

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.

[Persistent thrombocytopenia in a child: morphological examination of blood platelets established the diagnosis of Wiskott-Aldrich syndrome]. / Thrombopénie persistante chez un enfant: l'examen morphologique des plaquettes a conduit au diagnostic de syndrome de Wiskott-Aldrich.

Thrombocytopenia frequently occurs in laboratory practice. The present work illustrates, through the presentation of a case report of Wiskott-Aldrich syndrome, the difficulties encountered to identify and characterize thrombocytopenia. The clinicobiological validation of a low platelet count involves both the biologist, who must assume the validation of numeration while mentioning the morphological characteristics of the platelets and other blood cells, as well as the physician who has to interpret these data according to the clinical context.

Effectiveness of antibacterial prophylaxis in children with acute leukemia: A report from a single institution over a 20-year period.

BACKGROUND: Infection is the major cause of treatment-related mortality in childhood acute leukemia, mainly due to bacterial translocation across the intestinal mucosa. Only a few studies have reported the impact of different antibacterial prophylaxis treatments on digestive tract flora and infection-related mortality. PROCEDURES: We performed a retrospective analysis of two different digestive tract decontamination modalities (selective or total digestive decontamination) in a large single-center series of 323 children during the induction treatment of acute leukemia between January 1995 and December 2014. We examined the impact of antibiotic prophylaxis and food regimen (sterile or selected) on the digestive tract flora during the period of antibacterial prophylaxis, on the frequency of bacteremia, and on antibiotic sensitivity. RESULTS: Only one Gram-negative (Klebsiella pneumonia) translocation occurred in the SDD group. No infection-related death occurred. Extended-spectrum beta-lactamase (ESBL) bacteria were observed in seven of 170 (4%) patients in the SDD group. The faecal-flora total suppression and faecal-flora Gram-negative bacilli suppression was 67 and 77%, respectively, in the TDD group with sterile food, 0 and 58%, respectively, in the SDD group with sterile food, and 6 and 63%, respectively, in the SDD group with selective food. CONCLUSIONS: This study gives a rationale not to use antibacterial prophylaxis systematically in children who receive induction treatment for acute leukemia; additionally, antibiotics should only be used in case of stool contamination by highly pathogenic bacteria with a high potential of translocation.

[Thrombotic thrombocytopenic purpura in a newborn]. / Purpura thrombotique thrombocytopénique chez un nouveau-né.

A newborn presented with haemolytic anemia, thrombocytopenia, hyperbilirubinemia and renal failure as early as the first hours of life. An early plasmatherapy was undertaken, followed by good outcome. The specific von Willebrand factor-cleaving protease (ADAMTS 13) was found at less than 5%. This is the specific biologic diagnostic element of congenital thrombotic thrombocytopenic purpura or Upshaw-Schulman syndrome. This disease of constitutional thrombotic microangiopathy was well identified and understood only few years ago. It's a rare disease which early diagnosis and treatment are crucial in order to preserve functional and vital capacities of the patient.

[Thrombocytopenia: clinicobiologic validation and classification]. / Validation et classification clinicobiologique d'une thrombopénie.

Thrombocytopenia occurs frequently. We will illustrate, through the presentation of a clinical case, the difficulties encountered to identify and characterize thrombocytopenia. The clinicobiological validation of a low platelet count implies, at the same time, the biologist, who must assume the validation of numeration while mentioning the morphological characteristics of the platelets and other blood cells, as well as the clinician who must interpret these data according to the clinical context. Firstly, we will detail the basic rules to correctly ensure this validation. Secondly, we will see which are the arguments which that make it possible to direct the diagnosis towards an acquired or inherited thrombocytopenia. Lastly, we will approach the classification of inherited thrombocytopenias.

[Treatment of febrile neutropenia episodes in children, with a piperacillin-tazobactam and netilmicin combination]. / Traitement des épisodes de neutropénie fébrile chimio-induite de l'enfant par l'association pipéracilline-tazobactam et nétilmicine.

OBJECTIVES: The authors had for aim to assess the effectiveness and toxicity of a piperacillin-tazobactam-netilmicin combination, and the possibility of avoiding using glycopeptide, in children with febrile neutropenic episodes induced by chemotherapy. METHODS: A retrospective study was made, including children treated for a febrile neutropenic episode (absolute neutrophile count < 0.5 x 10(9)/l) by a piperacillin-tazobactam-netilmicin combination. If fever persisted 48 hours after the beginning of antibiotic therapy, a glycopeptide could be added. The responses to the treatment were defined as follows: 1) total success (no fever or documented infection) at 48 hours and at 72 hours following the beginning of treatment; 2) partial success (apyrexia beyond 72 hours without any therapeutic change); 3) failure (persistent infectious signs 48 hours after the introduction of glycopeptide). RESULTS: Sixty-nine episodes were assessable, corresponding to 41 patients, treated for a solid tumour (29), an acute leukaemia in remission (11), or a metabolic disease (1). The febrile episodes were divided into fever of unknown origin (71%), microbiologically documented fever (12%), and clinically documented fever (17%). No death occurred, no toxicity was reported. With this antibiotic therapy, total success at 72 hours was observed in 72% in case of fever of unknown origin and 45% in case of documented infections. The success rate reached 84% when a glycopeptide was added (30% of the cases). CONCLUSION: The piperacillin-tazobactam-netilmicin combination is very effective and well tolerated in probabilistic treatment of febrile neutropenia induced by chemotherapy, but does not allow to decreasing the frequency of glycopeptide administration.

[Ewing sarcoma located in the mandible: A case report]. / Tumeur d'Ewing de localisation mandibulaire. À propos d'un cas.

Ewing sarcoma is the second most common primary malignant bone cancer in children and adolescents. Clinical presentation is usually dominated by local pain and a palpable mass. These symptoms justify imaging investigations: the first one, when an osseous lesion is suspected, is usually a conventional radiograph in two planes. Ewing sarcoma appears as a poorly defined osteolytic lesion that may frequently be associated with cortical erosion or laminar periosteal response ("onion skin"). However, this aspect is not pathognomonic and the definitive diagnosis is made by biopsy. Absence of pain or an unusual localization can lead to misdiagnosis. We report the case of a 7-year-old boy with Ewing sarcoma located in the mandible with a clinical picture including progressive mandibular swelling but no pain.

Total removal of intramedullary ependymomas: follow-up study of 16 cases.

With microsurgical techniques, most intramedullary ependymomas may be totally removed. Such a complete surgical removal has been performed in 16 patients with intramedullary ependymomas. Of the 14 patients with benign tumors, 3 have no sequelae, 7 are able to walk, and 4 with preoperative paraplegia remain unchanged. The two other patients had malignant ependymomas and died within three years following surgery, in spite of chemotherapy and radiotherapy. Besides the histological and clinical factors, the prognosis depends largely on the surgical technique. The technical points that are important for locating the medullary posterior sulcus, for opening of the spinal cord, and for removal of the tumor are described.

[Acute myeloblastic leukemia without maturation (AML-M1) with basophilic elements and associated with translocation t(6;9)]. / Leucémie aiguë myéloblastique sans maturation (LAM1) avec éléments basophiles associée à la translocation t(6;9).

The clinical, hematological, and cytogenetic data from a 4 year-old child with acute myeloid (AML-M1) and basophilia is reported. Interestingly, cytogenetic investigations revealed the presence of the translocation t(6;9) (p23;q34). This abnormality is rare and associated with myelodysplastic syndromes or with subtypes of acute myeloid leukemia (M1, M2, M4, M7), usually with preceding or underlying myelodysplasia. The prognosis is poor, without response to chemotherapy regimen alone. Allogeneic bone marrow transplantation appears likely to be a more appropriate treatment.

[Traumatic atlanto-axial dislocation. (About two cases with late clinical manifestations) (author's transl)]. / Les luxations atloido-axoidiennes traumatiques à propos de deux observations à révélation tardive.

Two cases of atlanto axial dislocation with late neurological manifestations are reported and the very few cases of the literature are reviewed. The clinical signs are non specific. Excellent lateral tomography must demonstrate the abnormal space between atlas and axis. Surgical treatment includes bone fusion after reduction of the dislocation by cautious skull-traction. The results are excellent if the operation is performed before the onset of severe neurological deficits.

[Spino-thalamic cordotomy in cancerous pain. Results of a series of 124 patients operated on by the direct posterior approach]. / La cordotomie spino-thalamique dans les douleurs cancéreuses. Résultats d'une série de 124 malades opérés par abord direct postérieur

The authors -- about a series of 124 cancerous patients treated during the 12 last years with open spino-thalamic cordotomy for intractable pain -- have tried to evaluate effectiveness of the operation with regard to its levels in relation to the site of pain. Patients suffering median or bilateral perineo-pelvic pain, isolated or associated with algias in one or both legs (group I: 50%) underwent a bilateral C8-C6 cordotomy in one stage. Patients with the same perineo-pelvic cancers but suffering only unilateral pain (group II : 31,8%) and patients with painful cancers in the leg (group III : 3,2%), were operated on with a C7 controlateral cordotomy. Patients suffering widespread unilateral pain in the chest, isolated or associated with algias in the arm, for instance from lung or breast cancers (group IV : 15%) underwent a controlateral C2 cordotomy. There was 3,2% mortality and one paraplegia. A useful early effect(i.e. complete or partial relief) was obtained : in 85% cases (60% and 25%) for the 1st group, in only 51% (36% and 15%) for the 2nd, and in 87% (56% and 31%) for the 4th. Relief was complete in each of the 4 cases of the 3rd group. In the 2nd group 39% of patients were completely relieved of their initial unilateral pain, but complained of an early post-operative pain on the other side. This secondary pain was supposed existing prior to the operation, but masked because of its lesser intensity. The useful results at the time of death, after a 6 month mean survival (from 1 month to 4 years), were 63,75% in the 1st group, 33% in the 2nd, 100% in the 3rd and 72% in the 4th. The high rate of poor results with unilateral cervical cordotomy in the perineo-pelvic cancers with apparently unilateral pain, led us since then to systematically perform for them a bilateral cordotomy. Thus, our general management for pain of malignant origin is now as follows: C8-C6 bilateral cordotomy for all the perineo-pelvic cancers whatever uni- or bilateral the site of pain may be; C7 controlateral cordotomy for the painful cancers of the leg; and C2 controlateral cordotomy for hemithoracic and/or arm pain, when related to very extended lung or breast cancers. We prefer complete posterior rhizotomy for limited cancers of the thoracic wall, and selective posterior rhizotomy through the scope, from -- the brachial plexus roots down to T4 -- for pain as from the PANCOAST-TOBIAS syndromes, or in case of painful involvements of the upper limb roots. For cervico-facial cancers we generally use combined sections of the sensory cranial nerves in the posterior fossa and of the cervical posterior roots.

[Repair of recurrent osteo-meningeal lesions at the base of the skull]. / Réparation des brèches ostéo-méningées récidivantes de la base du crâne

Treatment of cerebro-spinal fluid rhinorrhea from traumatic or tumoral origin, by simple dural patching, is not always sufficient because of the possible necrosis of the patch, mainly in case of severe osteo-meningeal defects. After having pointed out the frequency of such recurrences (5 to 30%, according to the data of literature), the authors report 6 personal cases successfully reoperated in order to repair the osteo-dural lesions with autogenous aponeurosis and bone grafts. 4 were after traumatism and 2 after removal of a tumor, in fronto-ethmoido-sphenoidal base of the skull. The authors suggest to combine bone reconstruction by autograft to the dural repair, even in case of primary fistula, when there is a severe traumatic or tumoral bone defect, or when we are dealing with a spontaneous rhinorrhea which is known to be generally due to local C.S.F. hyperpressure.

[Experimental intracranial venous microsurgery. Bypass of the sagittal sinus for arterial or venous repair and preoperative measurement of the cerebral impedance in the dog]. / Microchirurgie veineuse intracranienne expérimentale. Pontage du sinus sagittal par autogreffe artérielle ou veineuse et mesures peropératoires de l'impédance cérébrale, chez le chien

By-passes of the sagittal sinus-which is 2,5 mm in diameter-were carried out with autogenous arterial or venous grafts, in 34 dogs, using the classical microtechniques (operative microscope, micro-instruments, micro-sutures...). Controls were done both 1 degree by angiography (direct sinography was the only convenient procedure to visualize the sinus and the by-pass) during survival, and 2 degrees by anatomical and histological examination after sacrifying the animals, on an average the 40th post-operative day (from the 10th to the 75th day). The early patency rate (within the first post-operative month) was 76 p. 100. All cases of early thromboses, which affected especially venous autografts, were related to technical insufficiencies. The late patency rate (after a one month follow-up) was only 64 p. 100, because of the secondary occlusion of some arterial autografts. All these late thromboses were related to an extensive fibrosis of the arterial wall.

[Ewing's sarcoma of the mandible in children: reconstruction by induced membrane]. / Sarcome d'Ewing mandibulaire chez l'enfant : reconstruction par membrane induite.

INTRODUCTION: Ewing's sarcoma (ES) is a malignant bone neoplasm that develops during the first two decades of life, and affects male more than female patients (sex ratio 1.6/1). ES head and neck bone localization is extremely uncommon (2 to 4%). We report a rapid induced membrane reconstruction without primary bone autograft. OBSERVATION: A 7-year-old boy presented with a 50mm mandibular ES centered on the horizontal branch of the right mandible. This patient was treated by a combination of neo-adjuvant chemotherapy, surgery, and adjuvant radio-chemotherapy, according to the Euro-Ewing 99 protocol. The right horizontal mandibular branch was resected, following induction chemotherapy. A macroplate and a cement spacer were used for the reconstruction, while expecting anatomopathological results. Seventeen days later, we removed the spacer because of scar disunion. The radiographic controls revealed a spontaneous osteogenesis along the macroplate despite the early cement spacer removal. This spontaneously bone growth allowed avoiding a free vascularized bone transfer for the reconstruction. The tissue regeneration potential of this young boy and the cement spacer induced membrane could explain this spontaneous osteogenesis phenomenon. DISCUSSION: Induced membrane can be added to the therapeutic options for pediatric oncologic mandibular bone loss. It avoids using of a free vascularized bone transfer.

How to design nutritional intervention trials to slow cognitive decline in apparently healthy populations and apply for efficacy claims: a statement from the International Academy on Nutrition and Aging Task Force.

Interventions are crucial as they offer simple and inexpensive public health solutions that will be useful over the long term use. A Task Force on designing trials of nutritional interventions to slow cognitive decline in older adults was held in Toulouse in September 2012. The aim of the Task Force was to bring together leading experts from academia, the food industry and regulatory agencies to determine the best trial designs that would enable us to reach our goal of maintaining or improving cognitive function in apparently healthy aging people. An associated challenge for this Task Force was to determine the type of trials required by the Public Food Agencies for assessing the impact of nutritional compounds in comparison to well established requirements for drug trials. Although the required quality of the study design, rationale and statistical analysis remains the same, the studies designed to show reduction of cognitive decline require a long duration and the objectives of this task force was to determine best design for these trials. Two specific needs were identified to support trials of nutritional interventions: 1- Risk- reduction strategies are needed to tackle the growing burden of cognitive decline that may lead to dementia, 2- Innovative study designs are needed to improve the quality of these studies.

[Hodgkin disease and autoimmunity in children: 11 case reports]. / Maladie de Hodgkin et auto-immunité chez l'enfant : à propos de 11 observations.

The association of lymphoma and autoimmune manifestations has been predominantly studied in adults affected by non-Hodgkin lymphoma. Few publications exist in the literature concerning Hodgkin lymphoma, particularly in children and adolescents. The objectives of this study were to define the characteristics of the link between Hodgkin disease and autoimmunity in childhood. The present 25-year retrospective study was conducted in all centers affiliated with the French Society of Paediatric Oncology (SFCE). Eleven children with Hodgkin disease presented manifestations of disimmunity preceding or following their diagnosis. Four patients had thrombocytopenic purpura, the remaining 7 each had a different autoimmune pathology: lupus syndrome, antiphospholipid syndrome with transient ischemic attack, Evans syndrome, leukocytoclastic vasculitis, autoimmune hemolytic anemia, autoimmune thyroiditis, and juvenile idiopathic arthritis. Lymphoma relapse occurred in 3 patients. Two children died, death being directly attributed to the autoimmune disease in 1 case. Our data suggest that development of autoimmunity is related to significant morbidity. Possible pathophysiological mechanisms include lymphocyte proliferation secondary to chronic inflammation, cell-mediated immune deficiency in Hodgkin disease, molecular mimetics, and antineoplastic phenomena are discussed. A study with a larger patient population is needed to identify the group of children at high risk of autoimmunity for whom additional investigations and modified therapy may be indicated.