Innovative treatments for meningiomas.

Multi-recurrent high-grade meningiomas remain an unmet medical need in neuro-oncology when iterative surgeries and radiation therapy sessions fail to control tumor growth. Nevertheless, the last 10years have been marked by multiple advances in the comprehension of meningioma tumorigenesis via the discovery of new driver mutations, the identification of activated intracellular signaling pathways, and DNA methylation analyses, providing multiple potential therapeutic targets. Today, Anti-VEGF and mTOR inhibitors are the most used and probably the most active drugs in aggressive meningiomas. Peptide radioactive radiation therapy aims to target SSTR2A receptors, which are strongly expressed in meningiomas, but have an insufficient effect in most aggressive meningiomas, requiring the development of new techniques to increase the dose applied to the tumor. Based on the multiple potential intracellular targets, multiple targeted therapy clinical trials targeting Pi3K-Akt-mTOR and MAP kinase pathways as well as cell cycle and particularly, cyclin D4-6 are ongoing. Recently discovered driver mutations, SMO, Akt, and PI3KCA, offer new targets but are mostly observed in benign meningiomas, limiting their clinical relevance mainly to rare aggressive skull base meningiomas. Therefore, NF2 mutation remains the most frequent mutation and main challenging target in high-grade meningioma. Recently, inhibitors of focal adhesion kinase (FAK), which is involved in tumor cell adhesion, were tested in a phase 2 clinical trial with interesting but insufficient activity. The Hippo pathway was demonstrated to interact with NF2/Merlin and could be a promising target in NF2-mutated meningiomas with ongoing multiple preclinical studies and a phase 1 clinical trial. Recent advances in immune landscape comprehension led to the proposal of the use of immunotherapy in meningiomas. Except in rare cases of MSH2/6 mutation or high tumor mass burden, the activity of PD-1 inhibitors remains limited; however, its combination with various radiation therapy modalities is particularly promising. On the whole, therapeutic management of high-grade meningiomas is still challenging even with multiple promising therapeutic targets and innovations.

Radiotherapy management of paediatric cancers with synchronous metastasis.

Cancer in childhood represent 1% of all the new diagnosed cancers. About 30% of children with cancer receive radiation therapy, representing about 600 to 700 patients per year in France. As a consequence, paediatric cancers with synchronous metastasis is a very rare situation in oncology, with usually poor standard of care. However, considerable efforts are made by paediatric oncology scientific societies to offer trials or treatment consensus despite these rare situations. The article proposes to synthesize the radiotherapy management of both primary tumour and synchronous metastasis in the most "common" childhood or adolescent cancers.

Outcome analysis of childhood pilocytic astrocytomas: a retrospective study of 148 cases at a single institution.

BACKGROUND: Pilocytic astrocytomas (PAs) are characterized by an excellent prognosis although several factors of adverse outcome have been reported. The mitogen-activated protein kinase pathway plays a major role in their tumorigenesis. AIM: To report a series of 148 PAs in children to define clinicopathological and biological prognostic factors. METHODS: Clinical data were collected from patient files and mail inquiry. Pathological specimens were centrally reviewed. The three major KIAA1549:BRAF fusion subtypes were analysed by reverse transcription - polymerase chain reaction (RT-PCR) in a subset of 47 frozen cases and by fluorescence in situ hybridization on formalin-fixed paraffin-embedded tissue in 23 cases. Tumour location, age at surgery, extent of surgical removal, histological subtype and KIAA1549:BRAF fusion by RT-PCR were searched for prognostic significance. RESULTS: Pilomyxoid astrocytoma (PMA) and the hypothalamo-chiasmatic (H/C) location were associated with a worse prognosis [P < 0.001 for overall survival (OS) and P = 0.001 for progression-free survival (PFS)]. Patients who underwent complete surgical excision had a better OS (P = 0.004) and a longer PFS (P < 0.001) than the others. Age was also a strong prognostic factor for OS but not for PFS. Infants (<1 year) and young children (<3 years) had a much worse outcome than the others (P < 0.001 and P = 0.004 respectively). KIAA1549:BRAF fusion status was not predictive of outcome. CONCLUSION: This study highlights the good prognostic factors of PAs but H/C PA remains a subgroup with dismal prognosis associated with young age, PMA variant and incomplete surgery. Search for KIAA1549:BRAF fusion in tumours with PA pattern is recommended even though the prognostic impact is still unclear.

Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage lung cancer with interstitial lung disease (ILD): An observational and exploratory case series of non-asian patients.

Interstitial lung disease (ILD) can coexist with early-stage lung cancer (LC) and may compromise surgery and worsen patients' outcomes. Stereotactic body radiation therapy (SBRT) is the gold standard treatment for medically inoperable early-stage lung cancer, but radiation therapy is contra-indicated for patients with ILD because of the higher risk of severe radiation-induced pneumonitis. SBRT may spare healthy lung tissue, but data are scarce in this rare population. Our exploratory case series aimed to retrospectively identify patients treated with SBRT in this setting: 19 patients were diagnosed with early-stage LC-ILD over the past 6 years and 9 received SBRT. Most of them were smokers with a median age of 71, 4 had no pathological documentation. After SBRT, 5 patients had grade I-II respiratory adverse events (AEs), but none had treatment-related grade III-IV respiratory AEs. Two patients died within 6 months of SBRT, and for both, death was related to metastatic relapse. In this case series, the radiological evolution of ILD before radiotherapy and the evolution of the radiotherapy scar on CT-Scan were also explored with different evolutionary models. This exploratory study shows available data that could be studied in a larger retrospective cohort to identify risk factors for SBRT in the LC-ILD population. The use of dosimetric data as a risk factor for SBRT should be done with cautiousness due to heterogeneous and complex dose delivery and different fractionation schedule.

[Characteristics of radiotherapy for adolescents and young adults]. / Caractéristiques de la radiothérapie chez les adolescents et les jeunes adultes.

Radiotherapy for adolescents and young adults is complex in several aspects. The population is very heterogeneous and has characteristics derived from both paediatric and adult populations both in terms of pathology (anatomical pathology, response to treatment) and the patient's physical, biological and psychological characteristics. This article reviews the characteristics to be taken into account in adolescent and young adult patients radiotherapy and more particularly in some of the most common diseases.

Locomotion performance for oscillatory swimming in free mode.

Oscillatory swimming of a fishlike body, whose motion is essentially promoted by the flapping tail, has been studied almost exclusively in axial mode under an incoming uniform stream or, more recently, self-propelled under a virtual body resistance. Obviously, both approaches do not consider the unavoidable recoil motions of the real body which have to be necessarily accounted for in a design procedure for technological means. Actually, once combined with the prescribed kinematics of the tail, the recoil motions lead to a remarkable improvement on the resulting swimming performance. An inviscid impulse model, linear in both potential and vortical contributions, is a proper tool to obtain a deeper comprehension of the physical events with respect to more elaborated flow interaction models. In fact, at a first look, the numerical results seem to be quite entangled, since their trends in terms of the main flapping parameters are not easy to be identified and a fair interpretation is obtained by means of the model capability to separate the effects of added mass and vortex shedding. Specifically, a prevailing dependence of the potential contribution on the heave amplitude and of the vortical contribution on the pitch amplitude is instrumental to unravel their combined action. A further aid for a proper interpretation of the data is provided by accounting separately for a geometrical component of the recoil which is expected to follow from the annihilation of any spurious rigid motion in case no fluid interactions occur. The above detailed decomposition of the recoil motions shows, through the numerical results, how the single components are going to influence the main flapping parameters and the locomotion performance as a guide for the design of biomimetic swimmers.

Guide for paediatric radiotherapy procedures.

A third of children with cancer receive radiotherapy as part of their initial treatment, which represents 800 paediatric irradiations per year in France carried out in 15 specialized centres approved on the recommendations of the French national cancer institute in decreasing order of frequency, the types of cancer that require irradiation are: brain tumours, neuroblastomas, Ewing's sarcomas, Hodgkin's lymphomas, soft tissue sarcomas including rhabdomyosarcomas, and nephroblastomas. The treatment guidelines follow the recommendations of the French society for childhood cancers (SFCE) or the French and European prospective protocols. The therapeutic indications, the technical and/and ballistic choices of complex cases are frequently discussed during bimonthly paediatric radiotherapy technical web-conferences. All cancers combined, overall survival being 80%, long-term toxicity logically becomes an important concern, making the preparation of treatments complex. The irradiation methods include all the techniques currently available: 3D conformational irradiation, intensity modulation radiation therapy, irradiation under normal or hypofractionated stereotaxic conditions, brachytherapy and proton therapy. We present the update of the recommendations of the French society for radiation oncology on the indications, the technical methods of realization and the organisation and the specificities of paediatric radiation oncology.

[Medulloblastomas: review]. / Les médulloblastomes: revue générale.

INTRODUCTION: The term of "medulloblastoma" refers to cerebellar tumors belonging to the family of primitive neuro-ectodermic tumors (PNET). Medulloblastomas represent 40% of cerebellar tumors, 15 to 20% of brain tumors and the first cause of malignant brain tumors in childhood. Seventy to 80% of cases are diagnosed in children versus 20 to 30% in adults. UPDATED KNOWLEDGE: Diagnosis is based on clinical and radiological exams, and proved on pathological analysis in association with molecular biology. Treatment comprises surgery, craniospinal radiotherapy except for children under five years of age and chemotherapy according to age and high-risk criteria. Medulloblastoma is a rare case of a central nervous system tumor which is radio- and chemo-sensitive. Treatment goals are, on one hand, to improve the survival rates and, on the other hand, to avoid late neurocognitive, neuroendocrine and orthopedic side effects related to radiation therapy, notably in children. The prognosis is relatively good, with a five year survival rate over 75% after complete resection of a localized tumor although sequelae may still compromise outcome. PERSPECTIVES AND CONCLUSION: Management of patients with medulloblastoma implies a multidisciplinary approach combining the contributions of neurosurgery, neuroradiology, pediatric oncology, neuro-oncology and radiotherapy teams.

Radio-induced esophageal motility disorders: An unrecognized diagnosis.

PURPOSE: Esophageal motility disorders (EMD) after cervical or thoracic radiation therapy (RT) may represent a late impairment and appear under-diagnosed. This study aimed to assess the prevalence of EMD, diagnosed by high-resolution esophageal manometry (HREM) after cervical or thoracic RT. In this retrospective, single-centre study, all patients whom received cervical or thoracic RT and underwent HREM were eligible. MATERIAL AND METHODS: Oncologic data were collected: site of neoplasia, type of cancer, oncologic management (surgery and chemotherapy). EMD were classified according to the new Chicago Classification. RESULTS: Twenty patients (14 females), of mean age 62.33±11.14 years were included. Breast cancer was the most represented indication for RT (40%). Other cancers were lung tumor, head and neck tumors and Hogdkin's lymphoma. Dysphagia was the most frequent symptom justifying HREM (70%). Patients received a mean of 51±19.27 Gy, 70% of them (14/20) had radiation therapy concomitantly with chemotherapy. The delay between last radiation therapy session and HERM was 10.68±12.42 years. Twelve (60%) patients had an abnormal pattern at on HERM. Among them, 3 patients (15%) presented with a major motility disorder. The most frequent motility disorder was ineffective esophageal motility in 8 (40%) patients, 1 (5%) patient presented with type II achalasia. CONCLUSION: EMD should be suspected in patients with a history of cervical or thoracic RT in case of upper GI symptoms with normal endoscopy. In these particular patients, a manometric diagnosis that can explain their symptoms is of particular importance to limit anxiety linked to unexplained troubles.

Radiotherapy Advances in Paediatric Medulloblastoma Treatment.

Radiotherapy is an essential element in the multidisciplinary management of children with medulloblastoma and postoperative craniospinal axis radiotherapy is considered to be the cornerstone of curative treatment. With modern multidisciplinary management, more than 80% of children with standard-risk medulloblastoma and up to 70% of children with high-risk medulloblastoma are long-term survivors. Current clinical trials are evaluating risk-adapted radiotherapy in standard-risk medulloblastoma to reduce long-term sequelae, whereas the research approach in high-risk medulloblastoma is to improve clinical outcome with dose-intensification of chemotherapy and the use of hyperfractionated radiotherapy regimens. Technological advances, such as tomotherapy, volumetric modulated arc therapy and proton therapy, may further improve the therapeutic ratio by reducing radiotherapy toxicities. A selected group of children with recurrent disease after treatment for standard-risk medulloblastoma may be considered for re-irradiation.

Predictive factors of the response to chemoradiotherapy in esophageal cancer.

BACKGROUND: The aim of this study was to identify factors predictive of a complete endoscopic/histopathological response to chemoradiotherapy in patients with esophageal cancer. PATIENTS: Clinical and histopathological factors (Ki67, p53 and EGFR expression) were studied in 56 patients presenting with esophageal cancer between September 2000 and March 2006 (35 squamous cell carcinomas, 20 adenocarcinomas, one undifferentiated carcinoma). The response to chemoradiotherapy was evaluated endoscopically and by histological examination in 16 patients who underwent surgical resection. RESULTS: Independent factors predictive of a complete endoscopic response were good performance status (RR=15.75; CI: 1.74-142.58; P=0.01) and overexpression of Ki67 (RR=4.46; CI: 1.08-18.31; P=0.04). In patients who underwent surgery, a major histopathological response was associated with complete endoscopic response (P<0.01), complete CT-scan response (P=0.04) and good performance status (WHO=0) (P=0.04). The mean survival was 40 months. Adenocarcinoma histology (RR=3.18, CI: 1.13-8.54; P=0.02) and an impaired performance status (RR=4.79; CI: 1.07-21.41; P=0.04) were independently associated with poor survival. CONCLUSION: In the present study, good performance status and overexpression of Ki67 were two independent factors for complete endoscopic response after chemoradiotherapy for esophageal cancer. Independent risk factors for poor survival were adenocarcinoma histological type and impaired performance status. Further prospective studies are necessary to complete the present results.

[Interest of image-guided radiotherapy for brain tumors and positioning control]. / Apport du guidage par l'image pour le repositionnement au cours de la radiothérapie des tumeurs encéphaliques.

A narrow therapeutic index and more and more patients with long survival characterize primary and second brain tumors. Image-guided radiotherapy can increase accuracy of the patient's position during a course of intracranial irradiation thanks to a direct or indirect visualization of targets volumes. Treatment reproducibility and organ at risk-sparing are the primary issues, particularly with the development of stereotactic radiotherapy and protontherapy. Regarding intracranial treatments, image-guided radiotherapy seems to be a repetitive task based on skeletal structures registration. And yet, this innovation makes possible to assess the dosimetric impact of daily positioning variations avoiding invasive immobilizations. Image-guided radiotherapy offers automated tools to limit time consumption and furthers adaptive radiotherapy opportunities. Nevertheless, medical evaluation is still necessary and image processing should be strictly defined (frequency, use, performance). The purpose of this article is to describe image-guidance in brain irradiation, as repositioning tool and to focus on its recent prospects.

Mini-open incision for distal biceps repair by suture anchors: follow-up of eighteen patients.

BACKGROUND: This clinical trial was done to describe a mini approach for distal biceps repair using two or three suture anchors. PATIENTS AND METHODS: Twenty patients have undergone surgical repair over the last 10 years. All patients were males with mean age 46.8 (range 35-72), and dominant arm was involved in 70 %. Eighteen patients were evaluated with subjective and objective criteria including patient's satisfaction, active range of motion (ROM), and maximum isometric strength (in supination and flexion) using Cybex dynamometer. Functional scoring included Mayo Elbow Performance Score, Disabilities of the Arm, Shoulder and Hand score and Oxford Elbow Score. RESULTS: Eighty percent of patients were highly satisfied, with excellent results as defined by Mayo and Oxford Elbow score. Compared to contralateral, the active ROM was not affected in flexion and extension, but pronation and supination were decreased by 5°-10° in two cases. One of eighteen showed hypoesthesia of first and second fingers, and one of eighteen showed a symptomatic heterotopic ossification. There were no reruptures. CONCLUSIONS: Surgical repair of distal biceps tendon with a mini-single-incision as we described provides patient's satisfaction and very good results with respect to ROM and functional scoring, with a low complication rate.

[Radiotherapy for paediatric cancers]. / Radiothérapie des cancers de l'enfant.

The purpose of this article is to describe the specificities of paediatric radiation oncology: cancer types, radiotherapy indications, techniques, organisation and reglementary framework.

[French organization of paediatric radiation treatment: Results of a survey conducted by the radiotherapy Committee of the French Society of Paediatric Cancers (SFCE)]. / Organisation française de la radiothérapie pédiatrique : résultats d'une enquête du comité radiothérapie de la Société française des cancers de l'enfant (SFCE).

PURPOSE: Radiotherapy is a rare indication in paediatric oncology, with 800 to 900 children in treatment per year in France. Child cancers represent approximately 1% of cancers in France and half occur before the age of 5 years. Paediatric radiation requires appropriate tools, local, time and specific training. In France, in 2015, 18 centres are accredited by the French National Cancer Institute (INCa) for this activity. MATERIAL AND METHODS: Survey conducted in February 2015 on the care of children (0 to 18 years) in radiotherapy departments in France. The survey was sent to the radiation oncologists involved in the 18 centres. The questions concerned the qualitative and quantitative aspect, medical and organizational aspects, and the involvement of assistant practitioners in the management of this activity. RESULTS: Seventeen centres responded. In 2014, 889 children under 18 were treated in radiotherapy departments. These departments are working together with one to four paediatric oncology departments. Regarding access to general anaesthesia: three centres perform one to seven treatment(s) under anaesthesia per year, three centres eight to ten treatments under anaesthesia per year, three centres ten to 24 treatments under anaesthesia per year and nine centres out of 17 use hypnosis techniques. In terms of human resources, in 2015, 29 radiation therapists have a paediatric radiotherapy activity. Involvement of assistant practitioners is growing and specific training are desired. Regarding treatment preparation and delivery, 13 centres have specific paediatric contentions, 14 of 16 centres employ radiation intensity modulated if dosimetry is more satisfying with 11 regularly to the craniospinal irradiation. Radiotherapy on moving areas with respiratory gating or hypofractionation is under developed. CONCLUSION: Paediatric radiation therapy is a specific activity requiring a dedicated management, both in human, organizational, medical and scientific aspects.

[French experience in paediatric total body irradiation: A study from the radiotherapy committee of the Société française des cancers de l'enfant (SFCE)]. / Expérience française de l'irradiation corporelle totale en pédiatrie : étude du comité de radiothérapie de la Société française des cancers de l'enfant (SFCE).

A survey was conducted in 2015 in France on the care of children in radiotherapy services. We present the results for total body irradiation in children, a specific technique of radiation treatment, which needs dedicated controls for this particular population. Of the 17 centres interviewed, 16 responded, and 13 practiced total body irradiation. Patients are positioned in lateral decubitus in 11 centres and supine/prone in two centres. Doses used for total body irradiation in myeloablative bone marrow transplantation are the same in all centres (12Gy); treatments are always fractionated. Lung shielding is positioned to limit the dose at an average of 8Gy with extremes ranging from 6 to 10Gy. The shape of the shieldings varies depending on departments' protocol, with a smaller size in case of mediastinal mass. Four centres have experience of total body irradiation under general anaesthesia, despite twice-daily fractions. In total, practice is relatively homogeneous throughout France and is inspired by the knowledge obtained in adults.

Do human lymphocytes exposed to the fallout of the Chernobyl accident exhibit an adaptive response? III. Challenge with bleomycin in lymphocytes from children hit by the initial acute dose of ionizing radiation.

In the present paper, we report data on the possible adaptive response, induced in vivo by exposure to ionizing radiation to a challenge treatment with the radiomimetic glycopeptide bleomycin (BLM). Lymphocytes from children living in Pripjat at the time of the Chernobyl accident, and thus hit by the initial acute dose of ionizing radiation, were treated for the last 5 h of culture with 0.004 U/ml BLM. Significantly lower chromosome damage was found only in lymphocytes from children who, independently of the initial acute exposure to ionizing radiation, still showed a 137Cs internal contamination, due to persistent continuous exposure to low doses of radiation. The present results indicate that past exposure to acute high dose of ionizing radiation does not interfere with resistance to BLM which is related to internal contamination.

Cytogenetic study in lymphocytes from children exposed to ionizing radiation after the Chernobyl accident.

The present study concerns the monitoring of children from the Byelorussian, Ukrainian and Russian republics exposed to the fall-out of the Chernobyl accident. Cytogenetic analyses have been performed on 41 children coming from different areas and exhibiting varying amounts of 137Cs internal contamination, as evaluated by whole-body counter (WBC) analysis. On a total of 28,670 metaphases scored, radiation-induced chromosome damage is still present, although at a very low frequency. Due to the very low fraction of dicentrics, because of the time elapsed from the accident and the relatively low doses of exposure, radiobiological dosimetry is not possible for these children. However, considering that the WBC data indicate that the children are still exposed to 137Cs contamination, the observed occurrence of stable chromosome rearrangements and breaks may represent the persisting effect of continuous low doses of radiation. The present study also indicates that the parallel use of internal contamination dosimetry and cytogenetics could be usefully employed to monitor individual exposure to radiation and to define further management measures.

Do human lymphocytes exposed to the fallout of the Chernobyl accident exhibit an adaptive response? 1. Challenge with ionizing radiation.

Several studies suggest that cells appear to become less susceptible to the induction of radiation damage, and in particular of chromosome and chromatid aberrations in short-term cultures of human lymphocytes, when a challenge exposure to ionizing radiation is preceded by a low 'adaptive' dose. Contradictory results have been reported on the conditions under which the phenomenon can be evidenced. In the present work, circulating lymphocytes of 13 children contaminated from the fallout after the Chernobyl accident were tested for their capability to exhibit an adaptive response in experiments in which the challenge dose was administered to stimulated lymphocytes in the S-G2 phase. Furthermore, the possible influence of 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase, was also investigated. Our results indicate that, at least in the instance of the end-point here used (chromosome and chromatid aberrations, the former resulting possibly from the Cs burden), human lymphocytes, chronically exposed to low doses from fallout, do not exhibit any decreased susceptibility to ionizing radiation. However, as reported in the accompanying paper, the same samples appear to show an 'adaptive' response when exposed to a challenge treatment with bleomycin (B. Tedeschi et al., 1995, this issue).

Do human lymphocytes exposed to the fallout of the Chernobyl accident exhibit an adaptive response? 2. Challenge with bleomycin.

The present study concerns the possible adaptive response, induced in vivo by a continuous exposure to ionizing radiations, to a challenge treatment with the radiomimetic glycopeptide bleomycin (BLM). Lymphocytes from children contaminated as a consequence of Chernobyl accident were treated for the last 5 h of culture with 2.5 micrograms/ml BLM. The induced chromosome damage was significantly lower than that found with the same treatment in lymphocytes from control children. This hyposensitivity to BLM was still present if, 1 h after the addition of the drug, inhibitors of the enzymes involved in DNA repair, such as 3-aminobenzamide (2 mM), or aphidicolin (0.4 microM) or 3-dideoxythymidine (5 mM) were added to the cultures. The resistance to BLM in lymphocytes from contaminated children seems to be related to a mechanism upstream in respect to the activities of enzymes involved in the DNA repair and specifically linked to the action of this drug. This is consistent with the different response found when the cells were challenged with ionizing radiation in vitro, as reported in the accompanying paper (L. Padovani, L. et al. (1995) Mutation Res., this issue).