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The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have simultaneously developed with success treatment strategies with specific attention paid to long-term sequelae. Neurological sequelae may be reduced by establishing a diagnosis with an endoscopic biopsy and/or cerebrospinal fluid (CSF) and/or serum analysis, deferring the need to perform a radical surgery. Depending on markers and/or histological characteristics, patients are treated as either germinoma or non-germinomatous germ cell tumors (NGGCT). Metastatic disease is defined by a positive CSF cytology and/or distant drops in craniospinal MRI. The combination of surgery and/or chemotherapy and radiation therapy is tailored according to grouping and staging. With more than 90% 5-year event-free survival (EFS), localized germinomas can be managed without aggressive surgery, and benefit from chemotherapy followed by whole ventricular irradiation with local boost. Bifocal germinomas are treated as non-metastatic entities. Metastatic germinomas may be cured with craniospinal irradiation. With a 5-year EFS over 70%, NGGCT benefit from chemotherapy followed by delayed surgery in case of residual disease, and some form of radiotherapy. Future strategies will aim at decreasing long-term side effects while preserving high cure rates.

Inclusion of brain tumour patients in oncological protocols may be hampered by their neurological impairment. The goal of this study was to assess the reliability of Karnofsky Performance Scale (KPS) and WHO Performance Scale (WHO-PS) scores in this population. A cross-sectional survey was conducted through the Association des Neuro-Oncologues d‘Expression Francaise (ANOCEF) and European Neuro-Oncology Association (EANO) networks. Clinicians were asked to write a text defining their operative definition of a patient with ≥ 70 KPS and to assess KPS and WHO-PS in six different clinical case vignettes. Two hundred seventy-six clinicians sent a response. The operative definition mentioned a normal life (89%), what patients were able (26%) or unable (29%) to do, normal cognitive processing (8%) and caregivers (6%). Older physicians mentioned more often what patients were unable to do (p = 0.005). The two scales were homogeneous in less severely handicapped patients only. More patients were excluded for hemiplegia than for expressive aphasia. Older physicians significantly excluded more patients for KPS and WHO-PS. Speciality of the physician significantly influenced scoring. On multivariable analysis, age and speciality of the physicians were correlated with KPS and WHO-PS rating even if adjusted on cases. Discordant scoring increased with severity of the deficit: in nearly all cases, the KPS would have denied, while WHO-PS would have allowed, access to a trial. Performance scores assigned to brain tumour patients are clinician and score dependant. WHO-PS would allow more access to a trial. Specific criteria should be developed for patients with neurological deficits to facilitate their access to trials.

This chapter discusses a number of central nervous system (CNS) tumours of childhood. It details the diagnosis, radiology, molecular pathology, biology, and current treatment strategies for germ-cell tumours (both intracranial and extracranial) and craniopharyngiomas (WHO grade I tumours of the intra/suprasellar region). It also outlines the histopathology, molecular classification, risk stratification, surgery, and outlook for ependymomas. Ependymomas are the third most common paediatric tumour of the CNS, accounting for 10% of brain tumours in children. The chapter also covers choroid plexus tumours (CPT). These rare intraventricular neoplasms derive from the choroid plexus epithelium and represent 0.2% of all CNS neoplasms.

Inclusion of brain tumour patients in oncological protocols may be hampered by their neurological impairment. The goal of this study was to assess the reliability of Karnofsky Performance Scale (KPS) and WHO Performance Scale (WHO-PS) scores in this population.A cross-sectional survey was conducted through the Association des Neuro-Oncologues d'Expression Française (ANOCEF) and European Neuro-Oncology Association (EANO) networks. Clinicians were asked to write a text defining their operative definition of a patient with ≥ 70 KPS and to assess KPS and WHO-PS in six different clinical case vignettes.Two hundred seventy-six clinicians sent a response. The operative definition mentioned a normal life (89%), what patients were able (26%) or unable (29%) to do, normal cognitive processing (8%) and caregivers (6%). Older physicians mentioned more often what patients were unable to do (p = 0.005). The two scales were homogeneous in less severely handicapped patients only. More patients were excluded for hemiplegia than for expressive aphasia. Older physicians significantly excluded more patients for KPS and WHO-PS. Speciality of the physician significantly influenced scoring. On multivariable analysis, age and speciality of the physicians were correlated with KPS and WHO-PS rating even if adjusted on cases. Discordant scoring increased with severity of the deficit: in nearly all cases, the KPS would have denied, while WHO-PS would have allowed, access to a trial.Performance scores assigned to brain tumour patients are clinician and score dependant. WHO-PS would allow more access to a trial. Specific criteria should be developed for patients with neurological deficits to facilitate their access to trials.

BACKGROUND MBL is the most common malignant pediatric brain tumor but represents 1% of adult brain tumors. Recent molecular classification suggests that MBL is not the same disease in children and adults. For standard risk pediatric medulloblastomas current therapy includes CSI at reduced doses (23.4Gy) associated with chemotherapy. Most adult patients with similar risk factors still receive CSI at 36 Gy±chemotherapy (CT): in the adult series treated according to the HIT protocol (CSI 35.2 Gy + boost to 55.2 Gy to posterior fossa followed in most patients by maintenance CT with lomustine, vincristine and cisplatin) a 73% 5-year PFS was reported {Friedrich, Eur J Cancer 2013}, so far the best published data. Hence retrospective experience of 23.4 Gy together with CT for adult patients in some institutions is worthwhile reporting. MATERIAL AND METHODS We gathered M0 patients, aged over 18 years with medulloblastomas and no/minimal post-surgical residues/no biological negative factor, between 1996–2018 in Centre Léon Bérard of-Lyon and Fondazione IRCCS Istituto Nazionale dei Tumori-Milan. RESULTS Forty-four patients were included, median age 26 (18–48) years,20 females. Median follow-up 90 months(10–227). Thirty-six and 8 received 23.4Gy and 30Gy CSI, respectively, + posterior fossa/tumor bed boost and CT in all: pre-RT (carbo/VPx2 courses or 8 drugs-in-one day x 2 courses (13 patients)) and/or post-RT (carbo/VPx2 courses in 11 and 8 drugs-in-one day x 2 courses in 10; CDDP/VCR/CCNU x 8courses in other 22). The 5/10 year PFS and OS were respectively 80.9±6.5%/76.8±7.4% and 88.4±5.5%/73.1±8.5%. Median progression time was 44 months. Relapses (8) were local (4), local+CSF or spine or bone in one instance each and bone only in one. Among variable considered, higher CSI dose than 23.4 Gy, pre-RT CT did not influence PFS, while females had a trend to better PFES and OS (P=0.07). CONCLUSION These combined series present results comparable to - or even better than- those obtained after high CSI doses highlighting the need for treatment redefinition in adults.

BACKGROUND The skills of adult versus pediatric neuro-oncologists are not completely similar though additive. Because the tumors and their protocols are different and the tolerance and expected sequelae are specific. Multidisciplinary meetings including adult and pediatric neuro oncologists are warranted to share expertise. MATERIAL AND METHODS Since 2008, on behalf of ANOCEF, GO-AJA and SFCE societies, a weekly national web based conference was held in France. Any patient with the following criteria could be discussed: Adolescent and Young Adults aged between 15 and 25 years, and any adult with a pediatric type pathology, including medulloblastoma, germ cell tumors, embryonic tumors, ependymoma, pilocytic astrocytoma. RESULTS Number of cases discussed increased from 8 to 202/year, with a mean number of 3 cases (1 to 7) discussed at each meeting. In 2018, 36 meetings were held, with a mean of 8 participants (2 to 14) issued from various French centers. 168 cases were discussed in 2018. Mean age was 30 years old (7 to 67). 45% were discussed at diagnosis; The patients had mostly medulloblastomas (n=47), ependymomas (n=24), low (n=21) or high grade gliomas (n=11), pineal tumors (n=20), germ cell tumors (n=9) and embryonal tumors (n=6). The rate of inclusion in protocols was increased since the opening of this web conference, especially for the germ cell tumor GCT SIOP protocol that is opened without age restriction, and in RSMA standard risk or MEVITEM relapse adult medulloblastoma protocols. CONCLUSION Multidisciplinary Web conference for AYAs is feasible and fruitful. It shares knowledge and increases the inclusion rate in protocols. It should be developped further.

BACKGROUND Even if medulloblastoma is considered as a curable disease, recurrent medulloblastoma has a poor prognosis, independently of therapy used. Medulloblastoma is very rare in adults, unlike children, and therapeutic strategies at recurrence are lacking. Nevertheless, adult teams sometimes use as “compassionate” chemotherapy some regimens published in children, such as the MEMMAT metronomic combination. However, this treatment, targeting both endothelial and proliferating tumor cells, has to date not been studied in the adult population. MATERIAL AND METHODS We present the case of a 40-year-old man, suffering from a right cerebellar SHH mutated medulloblastoma initially diagnosed and treated in 2014 by craniospinal radiotherapy associated with 4 cycles of carboplatine-VP16 following complete resection. Since April 2016, date of first relapse, numerous successive recurrences occurred, initially focal, treated by several surgeries (April and November 2016, January 2017), chemotherapy (rechallenge by carboplatine-VP16) then stereotactic radiotherapy. He then developed in October 2017 a new relapse in the posterior fossa, also associated with a meningeal dissemination on lumbar MRI. IK was 90%. He was then treated by TOTEM regimen (Temozolomide-Topotecan) followed by “Packer” regimen (Cisplatin-Belustine-Vincristin), without tumor control. However, because patient was non symptomatic with a KPS of 80%, we decided, according to the AJA French group, to propose what we presumed to be a “compassionate” chemotherapy, by metronomic pediatric regimen “MEMMAT”. For “supportive care” reasons, we decided not to realize the “Intrathecal part” of this regimen and administered to the patient intravenous bevacizumab (10 mg/kg d1-d14-d21), thalidomide (100 mg/d), celecoxib (300 mg bid), fenofibrate (160 mg/d) and etoposide (100 mg/d d1-21), alternating with cyclophosphamide (100 mg/d d22-42). RESULTS Clinical tolerance was very good, except grade 1 heel pain and fatigue; hematological toxicity was mild (transient grade 3 neutropenia, grade 4 lymphopenia); renal impairment, already present at the beginning, was increasing, and justified dose adjustment after 5 cycles and nephrologic explorations, ongoing. Radiological evaluation showed a complete radiological response with complete disappearance of enhancing lesions on first MRIs realized after 3 months (2 cycles); this response was confirmed after 6 months (4 cycles) and 9 months (6 cycles) on both cerebral and spinal MRI. Patient is now receiving the 7th cycle. CONCLUSION We report here the first case of a complete and sustaining response of an adult multi-recurrent metastatic medulloblastoma treated by a pediatric antiangiogenic metronomic regimen “MEMMAT”. This promising result incites to develop a dedicated prospective trial in adults in view to confirm the interest of this strategy.

BACKGROUND Optimal strategy for treatment of relapsing intracranial malignant germ cell tumors remains ill-defined. Authors describe the French experience over a 25-year period. MATERIAL AND METHODS Relapsing patients were retrieved by their participation in the SFOP-TGM 90-92 or GCT 96 protocols or from National Childhood Solid Tumour Registry. RESULTS The cohort included Group A: documented germinomas (n=14), Group B: patients treated as germinomas without histopathological proof (n=5) and Group C: secreting germ cell tumours (n=25). Patients all received standard dose chemotherapy, and some high dose chemotherapy (VP16 Thiotepa with stem cell rescue) and/or various type of radiation. The 5 year EFS and OS post relapse are: 79%[47 to 93%] and 86% [54 to 96%] respectively in group A, 20% [1 to 58%] and 80% [20 to 97%] respectively in group B, 56% [35 to 73%] and 60% [38 to 76%] respectively in group C. Among 14 Group A patients, 7/12 receiving high dose versus 3/3 receiving standard dose chemotherapy, and 9/11 re-irradiated versus 1/3 not re-irradiated are CR2. Among 21 Group C patients. who had received radiation in first line, 10/15 receiving high dose versus 1/6 receiving standard dose chemotherapy, and 7/11 re-irradiated versus 4/10 not re-irradiated are CR2. CONCLUSION The outcome of relapsing germinoma is favourable and intensity of second line remains matter of debate. High dose chemotherapy with radiotherapy, when feasible, should remain the reference for treatment of a relapsed non germinoma, though more active treatments are warranted.

Resume Le cancer reste la premiere cause de deces par maladie chez l’enfant et l’adolescent. Donner un large acces aux innovations therapeutiques est un objectif strategique majeur de l’onco-hematologie pediatrique en Europe. Objectif Analyser la participation des enfants et adolescents aux essais precoces de nouveaux medicaments anticancereux en France. Methode Les donnees saisies des essais precoces ouverts aux inclusions dans les centres de la SFCE de 2010 a 2013 ont ete exploitees. Resultats Trente-sept essais precoces ont inclus 607 patients (487 porteurs d’une tumeur solide [80 %], 120 d’une leucemie ou d’un lymphome [20 %]). Il s’agissait de 15 essais de phase 1, 5 de phase 1/2 et 17 de phase 2 evaluant 33 nouveaux medicaments (66 % de therapies ciblees) et une nouvelle formulation. Soixante-huit pour cent etaient des essais internationaux du reseau europeen ITCC. Soixante-deux pour cent etaient promus par un industriel du medicament. En 2013, il y a eu 195 inclusions, soit +77 % par rapport a 2010, dans 30 essais ouverts. Les inclusions en France representent 50 % des inclusions dans le reseau europeen ITCC sur les 10 dernieres annees. Conclusion La France est attractive et leader en Europe. Il existe une dynamique de reseau qui est claire et efficace avec un nombre d’essais ouverts par an qui a triple en 4 ans et un nombre d’inclusions qui a presque double. Mais ceci reste insuffisant par rapport aux besoins medicaux et aux attentes des parents et des patients. L’objectif est de doubler les inclusions dans un essai precoce a l’issue du Plan Cancer 3.

The management of pineal tumors is a model for multidisciplinarity. Apart from an emergency situation that requires immediate shunting of cerebrospinal fluid (CSF), the initial discussion should involve at least a radiologist, a surgeon, a neurologist and an oncologist. The initial decision is whether obtaining a histological proof is obligatory. It depends on age and ethnicity, site (mono- or bifocality), presence of markers in serum as well as CSF, and/or of malignant cells in the CSF. In cases of marker elevation indicating a germ cell tumor, front line chemotherapy can avoid dangerous immediate surgery. When histological proof is required, the extent of surgery should be discussed, aiming either only at obtaining tissue or removal. If a germ cell tumor is detected, treatment will include a cisplatin-containing chemotherapy followed by focal or ventricular irradiation. Tumors of the pineal parenchyma will be treated according to grade, either by surgery alone (pinealocytoma) or chemo-radiotherapy (pinealoblastomas). Similarly, gliomas will be treated depending on their grade with several different possible lines in low grade, and usually radio-chemotherapy in high grade. A careful balance between improved survival rates and decreased long-term side effects will guide the decisions of all these specialists.

Adult medulloblastomas are orphan diseases that differ from their pediatric counterpart. Most are classified as classic or desmoplastic and fall in the SHH subgroup, mainly with loss-of-function mutations in PTCH1 and some by TP53-mutation due to underlying germline mutation. Activation of the WNT pathway is sporadic, although underlying Turcot syndrome may be present. One-third of tumors are issued from group 4. Most adult studies are small non-randomized retrospective heterogeneous studies performed at a single center with short follow-up. Standard craniospinal irradiation followed by maintenance chemotherapy (CCNU, cisplatin-vincristine) results in a 4-year event-free survival (EFS) and overall survival (OS) of 68% and 89% respectively in standard-risk adults, and in a 4-year EFS and OS of 50% and 90%, respectively in high-risk adults. Several pooled analyses point out the potential role of chemotherapy in adults. The feasibility of pediatric protocols in adults is sometimes hampered because of blood and peripheral nerve toxicity. In the near future, subgroups of medulloblastomas may be treated by personalized therapies. With prolonged follow-up, adults fare worse. Long-term sequelae and second line treatment are not well defined in adults. Prospective studies are ongoing to define optimal first-line and relapse treatments.

Blurred vision is common among patients with brain tumor. It may result from increased intracranial pressure and/or compression and/or invasion of the optic pathway. We assessed the incidence and etiology of visual impairment in patients with intracranial germinoma tumors (ICGT). METHODS AND MATERIALS: We performed a blinded retrospective review of the charts and initial imaging of 28 patients with ICGT. Thirteen tumors were pineal; 5 were supraoptic, 7 bifocal; and one each involved the optic nerve, corpus callosum, and brainstem. RESULTS: Twelve patients reported decreased visual acuity. Six of them demonstrated no clinical or radiological signs of raised intracranial pressure; five showed invasion and/or compression of the anterior optic pathway. Two of those were initially managed as “retrobulbar neuritis” when endocrinological symptoms prompted magnetic resonance imaging. The involvement of the optic pathway was underestimated and both relapsed. Three further patients had supraoptic mass with contiguous involvement and/or compression of the chiasm. None of the patients with loss of visual acuity and headache and none of those with no loss of visual acuity had invasion/compression of the anterior optic pathway and none relapsed. CONCLUSIONS: Compression and/or invasion of the optic pathway by germinoma is not rare and should not be overlooked when thickening and/or contrast enhancement is detected. Radiotherapy fields should be extended accordingly.

Introduction Les tumeurs chiasmato-hypothalamiques representent 7 % des tumeurs cerebrales de l’enfant. Leur prise en charge reste difficile et le role de la chirurgie est mis en question. Nous rapportons une serie de patients qui ont ete traites a Lyon avec une chirurgie large. Materiel et methodes Vingt-trois patients ont ete traites depuis 2000 a 2017 pour une tumeur chiasmato-hypothalamique : 12 filles et 10 garcons. L’âge est compris entre deux mois et 17 ans. Du point de vue clinique, 5 patients presentaient des troubles visuelles dont 1 patient completement aveugle ; 6 patients une hypertension intracrânienne ; 6 patients presentaient un nystagmus pluridirectionnel, 1 patient une puberte precoce ; 4 patients un strabisme d’apparition brutale. Deux patients presentaient une neurofibromatose. Tous les patients ont ete etudies avec un IRM craniomedullaire. Du point de vue chirurgical, 8 patients ont ete traites avec une exerese complete, 10 patients avec une exerese partielle et 4 patients ont eu une simple biopsie. Chez 8 patients un traitement avec chimiotherapie a ete instaure, 8 patients ont ete traites avec de la radiotherapie, 3 patients avec de la protontherapie. Resultats Quarante-sept pour cent des patients ont une vie de bonne qualite avec une bonne scolarite, 25 % des patients des sequelles moderee avec une scolarite adapte ; 20 % des patients ont une vie avec des sequelles severes. Trois patients ont presente une aggravation visuelle. Conclusion La chirurgie d’exerese des tumeurs chiasmato-hypothalamiques doit respecter la qualite de vie des patients et elle est possible lorsque le traitement par chimiotherapie ne permet pas le controle de la maladie. L’abord chirurgical pour une resection large trouve encore sa place dans les cas avec evolution clinique et volumetrique et apres echec de la chimiotherapie.

BACKGROUND Personalized anti-tumoral therapies may currently be proposed on the basis of immuno-histochemistry, but also next-generation sequencing and comparative genomic hybridization. ProfiLER trial explored the feasibility, efficacy and the impact of molecular profiling for patients with solid or hematological advanced cancers including brain tumors. MATERIAL AND METHODS Patients with primary brain tumors, pre-treated with at least one line of anti-cancer treatment, could be included in this multicentric prospective trial. A molecular profile (next-generation sequencing and comparative genomic hydridization) was established on fresh or archived sample. Weekly molecular tumor board analysed results to propose as far as possible a molecular targeted therapy. RESULTS between February 2013 and December 2015, 141 patients with primary brain tumor were enrolled. One hundred five samples were further analyzed as 30 samples were excluded, and 6 are on-going. The rate of screen failure was 16/33 for stereotactic biopsy (49%) versus 11/104 (11%) for removal. The main representative histologic type of tumors were glioblastoma (n=46, 43,8%), low grade glioma (n=26, 24,8%), high grade glioma (n=12, 11,4%) and atypical and anaplastic meningioma (n=8, 7,6%). Median delay between the diagnostic of the primitive tumor and the inclusion in ProfiLER study was 2.7 years (0.2 - 29 years). Median delay between the consent and the results of the multidisciplinary meeting was 2.8 months (1–7.1 months). Forty-three patients (41%) presented at least one “druggable molecular alteration”. The most frequently altered genes were CDKN2A (n=18, 29%), EGFR (n=12, 20%), PDGFRa (n=8, 13%), PTEN (n=8, 13%), CDK4 (n=7, 11%), KIT (n=6, 10%), PIK3CA (n=5, 8%), MDM2 (n=3, 5%). Sixteen patients could not have a proposition of specific treatment due to death before MBT (n=5, 31.3%), lack of available clinical trials (n=9, 56%), or ambiguous results (n=2, 12.5%). Among the 27 patients (26%) for whom a specific therapy has been proposed, only six patients ultimately received a medical targeted therapy (everolimus n=3, erlotinib n=1, ruloxitinib n=1, sorafenib n=1). Four patients discontinued the treatment for toxicity, the 2 others for clinical progression. CONCLUSION routine high-throughput sequencing is feasible for brain tumors but delays should be reduced to be able to propose targeted therapies to patients fit enough to benefit from experimental treatment. Macroscopic surgery is the best way to obtain workable samples. Specific panel genes for neurologic tumors should be developed, as well as change of practices concerning exclusion criteria in clinical trials.

BACKGROUND Inclusion criteria for oncological protocols often use the Karnofsky performance score (KPS) >=70 or the WHO performance score (PS) 0–2 as a cut-off value. Inclusion of neuro-oncology patients may be hampered, when general condition is preserved, while performance is decreased due to physical handicap. The goal of this study is to compare the KPS and PS assessments according to the status of the clinician. MATERIAL AND METHODS A cross-sectional survey was conducted through ANOCEF and EANO networks. Clinicians evaluated KPS and PS in 6 clinical situations concerning neuro oncology patients (from youngest and fittest to oldest, crippled with comorbidities). RESULTS The rate of PS 2 increased significantly from case 1 to 6. Sex or nationality of the clinicians had no impact when adjusting on clinician characteristics. Conversely, speciality (residents/general practitioner vs neurosurgeons vs neurologists vs oncologists), impacted KPS or PS evaluations (p In a multivariate analysis, age and speciality were correlated with KPS and PS rating even if adjusted on cases. Discordant decision for protocol inclusion (i:e: (KPS) >=70 vs PS 0–2) showed little discrepancy in case 1 (2.3%), while discrepancy increased to respectively 16, 46, 39, 33 and 43% for cases 2 to 6: in nearly all cases, the KPS would have denied access to a trial, while WHO Ps would have allowed CONCLUSION Rating of KP and PS is subjective in neuro oncology patients: influenced by speciality, age and inclusion habit (for KPS) of clinicians, PS 0–2 allows usually more inclusion than KPS>=70 in more severely disabled patients. A Neuro oncology specific KPS and/or PS definition is warranted to allow more widely inclusion of patients with exclusive neurologic handicap.

BACKGROUND Choroid plexus tumours represent less than 1% of brain tumours. Low-grade papilloma may be treated with gross total surgical resection, while in disseminated progressive atypical choroid plexus papilloma (APP), there is no standard treatment: various chemotherapy regimens have been reported. Since this tumour is characterized by a rich vascular component, antiangiogenic therapy is an attractive treatment. The use of Bevacizumab has already been reported in three patients. Authors expand this experience with 5 further patients diagnosed with progressive APP treated with bevacizumab. MATERIAL AND METHODS Patients were recruited through the weekly Adolescent Young Adult French web conference. They have been treated with bevacizumab 10 mg/kg by intravenous injection each 2 to 3 weeks. Their clinical status and radiological response are reported: Karnofsky Index (KI), Pain Scale (PS) and RANO criteria were used. RESULTS All our patients had a progressive disease prior to bevacizumab. Pt 1: 41 years old; APP with cranio-spinal dissemination; Previous treatments: local and cranio-spinal irradiation in 2012 and in 2014; surgery: complete and partial resection in 2010, 2014, and VP shunt in 2018; Bevacizumab: total of 33 cures in 18 months. Result: radiological and clinical stabilization. Pt 2: 58 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: VP shunt and gross total resection, in 2006; VP shunt, in 2011. Bevacizumab: total of 4 cures, in 2 months. Result: radiological and clinical stabilization. Pt 3: 34 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: gross total resection, in 1992, and shunt in 2008. Bevacizumab: total of 21 cures, in 21 months. Result: radiological and clinical stabilization. Pt 4: 63 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: surgical resection and VP shunt in 2013; chemotherapy: temozolomide. Bevacizumab: 29 months (still treated). Result: radiological and clinical stabilization. Pt 5: 62 years old; APP with cranio-spinal dissemination; Previous treatments: surgery: gross total resection in 1999 and VP shunt in 2009; chemotherapy: Carboplatin Vespesid. Bevacizumab: 23 cures, in 14 months. Result: radiological stabilization and clinical amelioration. CONCLUSION Despite their previous worsening disease, all patients obtained a stabilization or amelioration of their IK and PS under bevacizumab. Bevacizumab should be evaluated in a multicentric trial as standard therapy for disseminated metastasized progressive choroid plexus tumours.

BACKGROUND The brainstem is the second location of brain tumors after optic pathways in NF1. In NF1 children, brainstem gliomas are usually indolent and have a better prognosis than their counterparts in non NF1 children. In contrast, the natural history and prognosis of adult brainstem gliomas in NF1 are nearly unknown. MATERIAL AND METHODS We conducted a retrospective analysis of medical records and MRI of adult NF1 patients followed for a brainstem glioma in 8 centers over a 17 years period (2000–2017). Clinical and imaging characteristics, management and outcome were analyzed. RESULTS Twenty five patients were included in the study (13 males and 12 females) with a median age of 32 (range 17–58). The epicenter of the tumor was located into the pons n=13 (52%), the mesencephalon n=7 (28%), the medulla oblongata n=5 (20%). On MRI, contrast enhancement was seen in 19 tumors (76%). Pathological examination was available in 13 tumors (52%) and showed a high grade astrocytoma (III or IV) in 9 tumors. Five patients were asymptomatic, 3 remained asymptomatic during the follow-up (median follow-up: 86 months, range 22–124). Twenty patients were symptomatic with a median duration of symptom of 2.5 months (range 1–10) before diagnosis. Among these symptomatic patients, 15 died from tumor progression despite treatment with radiation therapy and or chemotherapy. The median overall survival of symptomatic patients was 36 months. CONCLUSION Brainstem gliomas are rare tumors in adults with NF1. Unlike children, adult brainstem gliomas seem to have an unexpected poor prognosis, suggesting the disease may be different in adulthood.

Introduction L’ependymome est la tumeur spinale la plus frequente chez l’adulte mais il est plutot rare chez l’enfant. L’objectif de cette etude est de resumer l’experience clinique et therapeutique retrospective des ependymomes rachidiens pediatriques dans plusieurs grands centres en France. Materiel et methodes Des donnees epidemiologiques, liees a la tumeur et au traitement de patients âges de moins de 18 ans, traites entre 2000 et 2010 pour ependymomes spinaux ont ete collectees et analysees. Les facteurs pronostiques de la survie sans progression ont ete evalues. Resultats Vingt-huit patients (22 M, 6 F) ont ete identifies. L’âge median a la chirurgie etait de 13,67 (0,7 a 17,6 ans). Une exerese totale (ET) a ete realisee chez 22 enfants et une exerese subtotale (EST) chez 6 enfants. Sur le plan histologique, 15 etaient des ependymomes myxopapillaires, 11 ependymomes de grade II et 2 de grade III. Une radiotherapie initiale adjuvante (RT) a ete realisee chez 6 patients. Le suivi median etait de 40 mois (2,3 a 127,5 mois). La survie sans progression SSP a 5 ans est de 51 % (IC95 % = 26,3 ; 71,2) et la survie globale est de 100 %. En analyse univariee, seule l’exerese totale avait une influence significative sur la SSP (p = 0,0013). Une analyse de sous-groupe a montre un benefice de la RT chez les patients ayant beneficie d’une ET, mais elle n’a pas reussi a prevenir les rechutes dans le groupe avec une EST. Conclusion Ces donnees suggerent que la radiotherapie adjuvante initiale chez les patients ayant eu une exerese complete peut ameliorer la SSP mais n’empeche pas la rechute chez les patients avec une exerese subtotale. D’autres etudes sont necessaires pour definir des traitements plus specifiques dans ce dernier groupe.

Central nervous system (CNS) germ cell tumors (GCTs) are separated into germinomas and nongerminomatous germ cell tumors (NGGCTs). The latter group includes teratoma (mature and immature), teratoma with malignant transformation, yolk sac tumor, embryonal carcinoma, choriocarcinoma, and mixed GCTs. CNS GCTs can be classified based on their histologic appearance and immunohistochemical profiles with histologic subtype being the best predictor of outcome. Germinomas respond exceptionally well to chemotherapy and irradiation and have been shown to have survival rates in excess of 90 %. In contrast, NGGCTs are more resistant to therapy and require more intensive chemotherapy, as well as higher doses of irradiation. There is little information on the histogenesis and molecular genetics of CNS GCTs. Fluorescent in situ hybridization (FISH) studies have shown a gain of X chromosome in a majority of GCTs. Other studies have shown that 12p abnormalities (gains and isochromosome 12p) are common, especially in germinomas. Gene expression analysis studies show overexpression of self-renewing pluripotency genes and genes responsible for tumor growth and differentiation in various tumors with no significant differences in gene expression between CNS GCTs of similar histology arising at different sites and different ages within the pediatric age group. Differences in microRNA expression have been demonstrated between histologic subtypes of CNS GCTs, and their potential use as a biomarker in the serum and cerebrospinal fluid is being explored. KIT mutations are the most commonly found abnormality on whole genome sequencing, predominantly in germinomas, followed by genes involved in the MAPK signaling pathway, suggesting a role for KIT inhibitors in the management of these tumors.

M. Fevre-Montange, A. Vasiljevic, D. Frappaz, J. Champier, A. Szathmari, M.-H. Aubriot Lorton, F. Chapon, A. Coulon, I. Quintin Roue, M.-B. Delisle, D. Figarella-Branger, A. Laquerriere, C. Miquel, J.-F. Michiels, M. Peoch, M. Polivka, F. Fauchon and A. Jouvet (2012) Neuropathology and Applied Neurobiology38, 87–94 Utility of Ki67 immunostaining in the grading of pineal parenchymal tumours: a multicentre study Aims: Pineal parenchymal tumours (PPTs) are rare neoplasms that are divided into pineocytoma (PC), pineoblastoma (PB) and PPT of intermediate differentiation (PPTID). Factors affecting the survival of patients with PPTs are morphological subtype and histological grading according to mitotic index and neurofilament immunostaining. Grading criteria to distinguish PPTIDs are difficult to define, particularly when using small specimens. The Ki67 labelling index (LI) might be helpful in distinguishing between grade II and III PPTIDs. Our study was performed to assess the predictive value of the Ki67 LI in a large cooperative series of PPTs and to evaluate whether inclusion of this data would improve and refine the World Health Organization classification. Methods: A retrospective analysis of 33 PPTs was performed. The histological features of the tumours were reviewed and Ki67 LI scoring was evaluated by immunohistochemistry. Data were correlated with the patients' survival. Results: The mean Ki67 LI was significantly different for tumour grades (0 in PC, 5.2 ± 0.4 in PPTID grade II, 11.2 ± 2.0 in PPTID grade III, 36.4 ± 6.2 in PB; P

Introduction Le medulloblastome (Mb) est la tumeur maligne la plus frequente chez l’enfant. Le traitement standard repose sur une exerese totale ou subtotale, une irradiation cranio-spinale et/ou une chimiotherapie. La strategie therapeutique est orientee en fonction des donnees de genetiques qui permettent de definir 4 sous-groupes de Mb avec un pronostic different. Nous avons repris les cas de medulloblastomes traites a Lyon entre 2000 et 2015 afin d’etudier l’evolution clinique en fonction de la strategie therapeutique. Patients et methode De 2000 a 2015, 52 patients ont eu un diagnostic de Mb. Ils ont beneficie d’une chirurgie d’exerese et d’un traitement complementaire adapte selon les criteres de gravite et le statut moleculaire. Au total, 62 % d’enfants souffraient d’hypertension intracrânienne. Vingt-neuf pour cent etaient metastatiques au moment du diagnostic. L’exerese chirurgicale a ete macroscopiquement complete dans 70 % des cas. Nous avons etudie la survie globale et sans progression pour l’ensemble des patients, puis dans le cadre d’analyse uni et multivariee, l’effet de differents criteres : le type histologique, le risque pronostique, le statut metastatique, la qualite d’exerese. Resultats L’âge moyen au diagnostic etait de 7,9 ans. Le sex-ratio etait de 2,7. Au total, 26 presentaient un risque eleve, 23 un risque standard et trois un risque faible. Dix-sept patients ont presente une recidive et 14 sont decedes. Les taux de survie globale est de 76 % a 5 ans et de 73 % a 10 ans, mais il est de 60 % dans le groupe a haut risque. En analyse multivariee, seul le niveau de risque modifie significativement le taux de survie. Conclusion La prise en charge du medulloblastome ainsi que son pronostic ont enormement evolue ces dernieres annees grâce aux decouvertes en genetique. Cette revue retrospective unicentrique retrouve des taux de survie variables en fonction du niveau de risque. Ceci confirme la necessite des etudes pour preciser les criteres evolutifs de ces tumeurs et mieux adapter les traitements complementaires et ameliorer le pronostic de certains groupes.

Background The population of survivors of childhood cancer is currently growing. Studies from other countries have shown an increased risk of late mortality. In order to measure this risk within a French cohort, the mortality of children who had survived five years from a cancer diagnosis were compared to the mortality of the general population, according to follow-up interval and cancer and treatment characteristics. Methods The study population consisted of 635 children diagnosed with cancer before the age of 15 who had survived at least five years, and were registered in the Rhone-Alpes region cancer registry from 1987 to 1992. Mortality was compared with general population rates of the Rhone-Alpes region to assess age and sex standardized mortality ratio (SMR) and absolute excess risk of death. Results The median follow-up of children was 14.0 years. Among the 42 observed deaths, 71.4% were attributed to a recurrence of the original cancer, 9.5% to a second cancer. The 15-year cumulative risk of death, all causes, was 7.1%. The overall mortality of the cohort was 20.7 fold greater than the general population (95% CI: 14.9–27.9), and the absolute excess risk of 6.9 per 1000 persons-years. The long term excess-mortality was higher in case of recurrence of original cancer (SMR = 99.9, 95% CI: 67.9–141.9, absolute excess risk 35.4 per 1000 persons-years); it was raised during the five to nine years follow-up interval after diagnosis (SMR = 33.8, 95% CI: 23.2–47.3) mainly due to the primary malignancy, and decreased after (10–14 years follow-up interval SMR = 6.5, 95% IC 2.4–14.2). Conclusion The late mortality of childhood cancer is significantly increased during the five to nine years following diagnosis and decreases after, but the cohort follow-up has to be extended in order to assess outcome beyond 15 years after diagnosis.

Background To evaluate the efficacy of BCNU, cisplatin, and vincristine (BCV regimen) in a prospective nonrandomized study among newly diagnosed children with high-grade glioma. Procedure Following surgery, patients received a combination of BCNU + cisplatin + VP16 (BCV), over 3 consecutive days. Patients with residual tumor continued this regimen unless no further improvement was observed on MRI, for a maximum of six courses. Patients who underwent complete surgical resection received six courses of adjuvant BCV. Results Seventy-three patients were enrolled. Out of 66 eligible patients with central pathology review, the diagnosis of high-grade glioma was confirmed in 53 cases. The response rate was 20%. With a median follow-up of 128 months, 5- and 10-year event free survival rates are 16 ± 9 and 13.3 ± 9.4%. In univariate analysis, two prognostic factors were statistically significant: extent of resection and tumor location, while macroscopic total resection was the only significant prognostic factor in the multivariate analysis. The response to BCV did not translate into improved event free survival. Interstitial pneumonitis occurred in seven patients, leading to six deaths. Conclusion This BCV regimen could not be recommended in the treatment of high-grade gliomas in children, according to its lack of efficacy and its unacceptable pulmonary toxicity. Pediatr Blood Cancer 2007;49:803–807. © 2006 Wiley-Liss, Inc.

Aim Improvement of EFS of children older than 3 years with high risk medulloblastoma. Methods Between 1993 and 1999, 115 patients (3–18 years, mean 8 years) with high risk medulloblastoma were included. After surgery treatment consisted of chemotherapy (‘8in1’ and etoposide/carboplatin) before and after craniospinal radiotherapy. Results Patients were staged using Chang-criteria (PF residue only, M1 and M2/M3) by local investigator as well as by central review panel (82.4% concordance). Chemotherapy was well tolerated without major delays in radiotherapy. With a mean follow up of 81 months (9–119), 5-year EFS was 49.8% and OS 60.1%. In detail according to subgroups EFS was 68.8% for PF residue only, 58.8% for M1 disease and 43.1% for M2/M3. Conclusion M1 patients are legitimate high risk patients. Survival rates are still very low for high risk medulloblastoma patients and future trials should therefore focus on more intensive (chemotherapy/radiotherapy) treatment.

The aim of this study was to evaluate a chemotherapy strategy that avoids radiotherapy in first-line treatment of young children with high-grade glioma. A total of 21 children under 5 years of age received the BBSFOP protocol, comprising seven cycles of three drug pairs (carboplatin/procarbazine, cisplatin/etoposide and vincristine/cyclophosphamide) administered over a 16 month period. Radiotherapy was performed in case of recurrence/progression. Median age at diagnosis was 23 months. Histology was classified as World Health Organisation (WHO) grade III in 13 and grade IV in 8. Of the 13 children with a residual tumour, chemotherapy induced 2 partial responses (PR), 1 minor response (MR) and 1 stable disease (SD) with no recurrent disease. Five-year progression-free survival was 35% and 5-year overall survival was 59%, with a median follow-up of 5.2 years. At the last update, 12 children were alive (10 without radiotherapy). In conclusion, this study shows that an adjuvant chemotherapy first approach is safe and allows radiotherapy to be avoided in selected children.

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, 'DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m(-2) for Group A and 100 mg m(-2) for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.

La prise en charge des tumeurs cerebrales pediatriques vise a ameliorer les taux de survie, sans accepter des sequelles incompatibles avec une bonne qualite ulterieure de vie. Le modele du medulloblastome est exemplaire: apres exerese locale, la radiotherapie crâniospinale (± chimiotherapie) reste le standard chez l’enfant de plus de cinq ans au diagnostic. Elle est cependant pourvoyeuse de sequelles neuropsychologiques d’autant plus importantes que l’âge au diagnostic est faible. Aussi la chimiotherapie exclusive est-elle proposee en cas d’exerese complete avant l’âge de cinq ans avec des taux eleves de guerison. La prise en charge multidisciplinaire est abordee.

Resume Les cancers de l'enfant sont rares puisqu'ils ne constituent que 1 % de l'ensemble des cancers. Objectif. – Le taux eleve de guerison, en progression constante, justifie le recueil regulier du suivi de ces patients. Materiel et methodes. – Nous presentons les donnees d'incidence et de survie des enfants de 0 a 15 ans atteints de cancer dans la region Rhone-Alpes de 1987 a 1999. Resultats. – Durant cette periode, 1945 nouveaux cas de cancers de l'enfant ont ete recenses, soit une moyenne stable dans le temps de 149,6 nouveaux cas par an. L'incidence brute sur cette periode est de 134,1/106 par an et l'incidence standardisee selon l'âge est de 139,2/106 par an. Respectivement, la repartition histologique et la survie globale a cinq ans sont de 30,2 et de 73 % pour les leucemies, 12,3 et 91,6 % pour les lymphomes, 24,7 et 60,1 % pour les tumeurs du systeme nerveux central, 9,1 et 71,1 % pour les tumeurs du systeme nerveux sympathique, 2,5 et 94,1 % pour les retinoblastomes, 5,8 et 89,9 % pour les tumeurs du rein, 1 et 75 % pour les tumeurs du foie, 6,1 et 60,9 % pour les tumeurs osseuses, 4,1 et 58,6 % pour les tumeurs des tissus mous, 1,1 et 71 % pour les tumeurs germinales, 2,4 et 85,1 % pour les carcinomes. Conclusion. – Globalement, la survie atteint 75 %. Il est maintenant important d'evaluer les complications a long terme, et dans le cadre du plan national de lutte contre le cancer, redefinir les moyens socioeconomiques a mettre en œuvre pour la surveillance de ces enfants gueris et devenus adultes.

Cisplatin may have additive activity with temozolomide due to ablation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (MGMT). This phase I/II study determined recommended combination doses using the Continual Reassessment Method, toxicities and antitumour activity in paediatric patients, and evaluated MGMT in peripheral blood mononuclear cells (PBMCs) in order to correlate with haematological toxicity. In total, 39 patients with refractory or recurrent solid tumours (median age approximately 13 years; 14 pretreated with high-dose chemotherapy, craniospinal irradiation, or having bone marrow involvement) were treated with cisplatin, followed the next day by oral temozolomide for 5 days every 4 weeks at dose levels 80 mg m(-2)/150 mg m(-2) day(-1), 80/200, and 100/200, respectively. A total of 38 patients receiving 113 cycles (median 2, range 1-7) were evaluable for toxicity. Dose-limiting toxicity was haematological in all but one case. Treatment-related toxicities were thrombocytopenia, neutropenia, nausea-vomiting, asthenia. Hearing loss was experienced in five patients with prior irradiation to the brain stem or posterior fossa. Partial responses were observed in two malignant glioma, one brain stem glioma, and two neuroblastoma. Median MGMT activity in PBMCs decreased after 5 days of temozolomide treatment: low MGMT activity correlated with increased severity of thrombocytopenia. Cisplatin-temozolomide combinations are well tolerated without additional toxicity to single-agent treatments; the recommended phase II dosage is 80 mg m(-2) cisplatin and 150 mg m(-2) x 5 temozolomide in heavily treated, and 200 mg m(-2) x 5 temozolomide in less-heavily pretreated children.

Retinoblastoma is the most common primary cancer of the eye in children. The prognosis for survival is excellent. The current therapy includes an improved survival rate and decreased iatrogenic sequelae. The relative risk of a second tumor in survivors of retinoblastoma is documented, especially in those who carry a germline RB mutation. It is strongly increased in case of radiation therapy. The most common types of second primary tumor are sarcoma of soft tissues and osteosarcoma. We present here a rare case of a retinoblastoma patient who received radiation therapy as a part of his treatment and developed a papillar thyroid cancer as a second malignancy. Papillar thyroid cancer has a good prognosis. Systematic screening for thyroid carcinoma should be undertaken in patients irradiated for congenital retinoblastoma.

There is no agreement on immunization of children treated with chemotherapy (CT) for solid tumors. Based on a review of the literature, we have attempted to establish guidelines on this subject. Except for hepatitis B vaccine, there is no argument to support the use of vaccine during CT. After a standard CT, a 3-month washout period appears to be necessary before starting an immunization program for a child not previously vaccinated, or to proceed with the recommended booster injections for diphteria anatoxin, tetanus vaccine, poliomyelitis inactivated vaccine, pertussis vaccine, and haemophilus influenza type b vaccine if the child is less than 5 years old. For mumps, measles, and rubella live vaccines, a longer post-CT washout of 6 months is suggested for the initial immunization, or for a revaccination of a child proved to be negative for all three serologies. Following high-dose CT a minimal 12-months term and a normalization of the blood lymphocytes count is necessary before planning booster injections once having checked for antidiphteria, tetanic, polio, measles, mumps, rubella and +/- haemophilus antibody titles. We don't find any reason to recommend a systematic varicella immunization in pediatric oncology. Pneumococcal vaccine is recommended in case of asplenia. Any other vaccination (BCG, influenza, yellow fever) must be evaluated individually.

The maximum tolerated dose of paclitaxel administered by 24-hour continuous infusion in children is known. Short infusion might offer equivalent antitumour efficacy and reduced haematological toxicity, without increasing the allergic risk. Our aims were to determine the maximum tolerated dose and the pharmacokinetics of paclitaxel in children when administered in 3-h infusion every 3 weeks. Patients older than 6 months, younger than 20 years with refractory malignant solid tumours were eligible when they satisfied standard haematological, renal, hepatic and cardiologic inclusion criteria with life expectancy exceeding 8 weeks. Paclitaxel was administered as a 3-hour infusion after premedication (dexamethasone, dexchlorpheniramine). Pharmacokinetic analysis and solvent assays (ethanol, cremophor) were performed during the first course. 20 courses were studied in 17 patients; 4 dosage levels were investigated (240 to 420 mg/m2). No dose-limiting haematological toxicity was observed. Severe acute neurological and allergic toxicity was encountered. One treatment-related death occurred just after the infusion at the highest dosage. Delayed peripheral neurotoxicity and moderate allergic reactions were also encountered. Pharmacokinetic analysis showed dose-dependent clearance of paclitaxel and elevated blood ethanol and Cremophor EL levels. Although no limiting haematological toxicity was reached, we do not recommend this paclitaxel schedule in children because of its acute neurological toxicity. © 2001 Cancer Research Campaign http://www.bjcancer.com

Background In children over 1 year of age with metastatic neuroblastoma, clearance of metaiodobenzylguanidine (MIBG) skeletal uptake after four courses of induction chemotherapy is one of the most powerful prognostic factors. How subjective is quantification of MIBG uptake, and can earlier MIBG scintigraphy separate good and bad responders? Procedure The data from 47 patients who received uniform induction therapy were reviewed. A novel scoring system of MIBG update intensity was proposed. Initial, intermediate (after two courses), and final (after four courses) intensities were scored (0 to 21 points) independently by six different observers. The initial global score and the relative score (calculated by dividing the global score after two courses by the initial score) were compared to the final score. Good responders were those who scored 0 at final MIBG. Results Between two observers, the correlation coefficient for the global score was superior to 0.80, in nine of ten comparisons established between observers 1–5. The initial score did not predict the final score insofar as only nine of fourteen patients with low initial scores were good responders. The relative score also failed to predict outcome; only six of ten patients with favorable relative score (i.e.

Our objective was to adapt and validate the Health Utilities Index Mark 2 (HUI 2) and HUI 3 health status classification systems self-report questionnaire in a population of children with cancer, a group of 42 children already included in a multi-centre database designed by the Group on Brain Tumors in Children of the French Society for Pediatric Oncology. Children were recruited during a routine consultation. Most of them had completed treatment. The version of the questionnaire for French adults was adapted linguistically for children. Open-ended queries by children about the comprehensiveness of the questions and very low non-response rates showed a good acceptability of the questionnaire. The main psychometric properties of the HUI 2 and HUI 3 classification systems were assessed in 3 groups of raters (child, parent, physician): construct validity was tested against the rating of the child's health state on a Likert scale and through comparison with clinical data, and internal consistency was determined through multi-trait analysis. Weighted and unweighted kappa values were used to measure the inter-rater agreement between the child's, parent's and physician's assessment of the child's health state. The convergent validity was satisfactory, with better results when the physician's assessment was used. The most affected attributes were the expected ones (i.e., cognition, pain and emotion). Disagreement was observed between the 3 raters, more often in the same direction: taking the child's assessment as the reference, the parents tended to under-estimate the health status while physicians tended to over-estimate it.

PURPOSE The three-drug combination of melphalan (M), etoposide (E), and carboplatin (C) followed by autologous stem-cell (ASC) rescue has been evaluated prospectively by the French Society of Pediatric Oncology (SFOP) in pediatric high-risk recurrent (HRR) Wilms' tumor (WT) patients with chemotherapy-responsive disease. PATIENTS AND METHODS From October 1988 to October 1994, 29 patients with HRR WT were treated in nine SFOP centers. Two additional patients with stage IV anaplastic WT were consolidated in first complete response (CR) with the same regimen and have been studied separately. The regimen consisted of M 180 mg/m2 for 1 day, E 200 mg/m2/d for 5 days, and C at a daily targeted area under the concentration-time curve (AUC) of 4 mg x min/mL for 5 days. ASCs were reinfused 48 hours after M. RESULTS Twelve of 28 assessable patients with HRR WT are still in continuous CR at a median of 48.5 months (range, 36 to 96) after consolidation. Disease-free survival (DFS) and overall survival (OS) estimated by the Kaplan-Meier method at 3 years were 50%+/-17% and 60%+/-18%, respectively. Sixteen patients relapsed at a median of 8.5 months (range, 3 to 53) after consolidation. Toxicity data are available in 31 grafted patients. Grade III and IV toxicities included hematologic side effects (n=31), hemorrhage (n=8), mucositis (n=24), diarrhea (n=12), renal disorders (n=8), and pneumonitis (n=3). CONCLUSION The adverse prognostic factors (APF) used to select patients for this dose-intensive chemotherapy define children with very-poor-risk recurrent WT. Despite high treatment-related toxicity, about half of these patients remain disease-free at 3 years. Patient outcome is statistically better when high-dose chemotherapy (HDCT) is performed as early as the second CR or partial response (PR). Novel therapeutic approaches with innovative preparative regimens are warranted for the remaining high-risk patients.

PURPOSE The European Bone Marrow Transplantation (EBMT) Solid Tumor Registry (STR) contains detailed information on children with advanced neuroblastoma who, after standard-dose induction chemotherapy and surgery, received myeloablative megatherapy (MGT) followed by stem-cell transplantation (SCT). This data base was analyzed to identify factors that predict event-free survival (EFS). PATIENTS AND METHODS Eligibility criteria were stage IV neuroblastoma, age over 1 year at diagnosis, and no relapse before MGT/SCT. Between February 1978 and July 1992, 549 patients were registered by 36 European transplant centers. The median age at diagnosis was 36 months (range, 13 to 216 months) and the male-female ratio was 1:45. Before MGT, 157 patients were in complete remission (CR), 156 in very good partial remission (VGPR), and 208 in partial remission (PR), whereas 24 had had only a minor response (MR). One hundred ten of 546 patients had undergone two successive MGT procedures. The median observation time was 60 months (range, 12 to 187 months). RESULTS Actuarial EFS is 26% at 5 years. Multivariate analysis by the Cox proportional hazards regression model included 529 patients with complete data sets. After adjustment for treatment duration before MGT and double MGT procedures, two adverse, independent risk factors that influenced EFS were identified: (1) persisting skeletal lesions before MGT as defined by technetium (99TC) scans and/or meta-iodobenzylguanidine (mIBG) scans (P = .004) and (2) persisting bone marrow involvement before MGT (P = .03). CONCLUSION After induction treatment, persisting skeletal disease as defined above and persisting bone marrow involvement may be predictive of a particularly poor outcome. Physicians may consider this an additional important tool to decide the patient's management.

The fortuitous discovery of a left posterior cervico-mediastinal mass during hospitalization for hemolytic anemia in an 18 month old baby is reported. Metaiodobenzylguanidine (MIBG) uptake suggested a sympathetic tissue origin of the mass despite negative catecholamines excretion, but histopathologic examination revealed a juvenile capillary angioma within a normal sympathic ganglion.

Between March 1990 and December 1994, 316 consecutive children with localised neuroblastoma were registered in the French NBL 90 study. In addition to the assessment of a new chemotherapy regimen in unresectable neuroblastoma, we evaluated the prognostic significance of MYC N amplification and loss of the short arm of chromosome 1 (LOH1p). MYC N was found in 22/225 children (10%) and associated with unfavourable clinical features such as age at diagnosis > 1 year and large and unresectable tumours. LOH1p was observed in 9/91 patients (10%), of whom some had favourable prognostic factors such as age at diagnosis n = 4), INSS stage 1 or 2 ( n = 3) and no MYC N amplification ( n = 4). Overall survival (OS) and event-free survival (EFS) were, respectively, 56% and 22% (median follow-up: 36 months) for children with LOH1p compared with 97% and 94% for those without (log-rank = 10 −8 ). All except 1 of the 5 children with MYC N amplification and LOH1p relapsed and ultimately died of the disease. Among the 4 with LOH1p and no MYC N amplification, recurrence occurred in 3 (2 local, 1 metastatic), all alive in second remission after salvage therapy (12–19 months after the relapse). In multivariate analysis, LOH1p was the strongest prognostic indicator for subsequent relapse. LOH1p appears more discriminant than MYC N amplification for predicting the risk of recurrence in children with localised neuroblastoma. However, its analysis was possible in only 30% of our patients and its final impact on survival should be confirmed in larger, prospective studies in order to stratify subsequent treatment.

The aim of this study was to evaluate the feasibility, toxicity and efficacy of escalating doses of subcutaneous recombinant interleukin-6 (IL-6) in children with solid tumours in relapse. Recombinant IL-6 was administered subcutaneously once daily for 14 consecutive days, with a 14 day follow-up period. The starting dose for IL-6 was 1 microgram/kg/day and was escalated in subsequent patients groups until 10 micrograms/kg. Doses were escalated every 3 patients, provided that grade III or IV organ toxicity did not occur at the preceding dose level. Twelve patients were treated, three at each dose level. No grade 3-4 major organ toxicity was observed. Flu-like symptoms and fatigue were the most common side effects. All these symptoms resolved after the end of IL-6 administration. Significant increases in acute-phase proteins (CRP [C reactive protein], fibrinogen) and ESR (Erthrocyte sedimentation rate) were observed in all patients. Stimulatory effects on thrombocytopoiesis were observed at every dose level, and were maximal at 5 micrograms/kg and 10 microgram/kg. There was no tumour response observed during IL-6 administration. Pharmacokinetic profiles performed in 3 patients are consistent with previous reports in adults. IL-6 is a promising new cytokine for paediatric oncology, in particular to increase thrombocyte counts. We recommend that further studies in children proceed at a dose of 5-10 micrograms/kg/day in a once or, better, twice daily administration.

A pilot study of neuroblastoma mass screening was initiated in January 1990 in the Rhone French district. The expected number of births per year is 26,000. The study is designed for a 5-year period with three major goals: 1) measurement of the compliance rate of a voluntary test at 4 months of age; 2) evaluation of the technical value of high-pressure liquid chromatography (HPLC) as a screening method; and 3) detailed biological characterization of all detected tumors. 61,551 children were screened between May 1, 1990 and December 31, 1993. Participation was 69% in 1990, 81.5% in 1991, and over 83% in 1992. HPLC was a satisfactory assay method. The number of clinical examinations required for positive tests as defined in the protocol is 1 per 3,621 tests. The false positive rate is 1 per 3,583 tests. Eight neuroblastomas were discovered by-screening (one stage I, three stage II, one stage III, three stage IVs). All are alive and well but were good prognosis cases according to the main prognostic factors. Five patients were discovered before screening (so called Halo effect): one stage I, one stage III, three stage IVs. One died of disease and four are alive in complete remission after treatment. Two patients were false negative (one stage III with N-myc amplification, one stage IV with bad prognosis features) and three cases of neuroblastoma were missed because of noncompliance with the screening program. This pilot study concludes on the feasibility of a mass screening program in France. The estimated cumulative incidence of neuroblastoma at 3 years is 1 per 4,375 living births and overdiagnosis is probable. All the detected cases were of good prognosis and the false negative ones were poor prognosis cases.

Introduction Exophytic tectal plate tumours are a particular kind of brain stem tumour that can be treated with microsurgical resection. This paper reports our surgical experience with a paediatric series stressing and underlines the fact that this surgery can be possible because the rate of surgical mortality is low in experienced hands with acceptable morbidity. Material and methods From 1997 to 2010, 27 patients were treated for exophytic tectal plate tumours. The clinical symptomatology was characterized by an intracranial hypertensive syndrome in 77% of cases, visual disorders in 36% of cases and a Parinaud's syndrome in 12% of cases. All patients were studied using a pre-operative cranio-spinal MRI with and without gadolinium. Hydrocephalus was present in 20 cases treated with a VP shunt in 6 cases and an ETV in the other cases. The surgical removal was total in 60% of cases, partial in 28% of cases and only a large biopsy in 12% of cases. From an histological point of view benign gliomas were diagnosed in 84% of cases and in 16% of cases were classified as WHO grade II and III. Eight patients needed complementary treatment, four with chemotherapy and four with chemotherapy associated to radiotherapy. As a surgical complication two patients had hydrocephalus, one patient had a sub-dural acute haematoma, two patients had an infectious complication requiring surgical treatment and antibiotic therapy, and 5 patients a mechanical shunt dysfunction. No post-surgical mortality was observed. Results The most recent results after a median survival of 4.3 years show that 22 patients are still alive while 5 patients died of a progressive disease. Twenty patients in school age continue to follow a normal school programme but 10 patients need assistance. Conclusion Exophytic tectal plate tumours can be treated based on a microsurgical approach in paediatric patients. In experienced hands surgery can be performed with an acceptable morbidity and with zero percent mortality. In our experience, the sub-occipital transtentorial approach permits a wide view of the region and safe surgical removal.

Background. - Outcone of patients with retinoblastoma is strongly related to the extent of the disease at diagnosis. Thus, prognosis of extra-ocular retinoblastoma is poor and metastases to central nervous system are usually fatal. Case report. - An 8-year-old child presented with a lose recurrence of bilateral retinoblastoma. Initial treatment had associated enuclation of the left eye and radiation therapy on the right. At time of tumour recurrence, clinical examination showed cervical lymph nodes. There was a large frontal metastasis on the CT scan and bone marrow examination showed a minimal involvement by malignant cells. The patient achieved complete remission with high dose etopiside and carboplatin; he subsequently underwent massive chemotherapy followed by bone marrow rescue, and received additional radiation therapy on the frontal and cervical areas. He is well, five years after relapse. Conclusion. - This case highlights efficacy of chemotherapy in advanced retinoblastomas, intensive chemotherapy is a promising and potentially curative approach in the management of advanced or metastatic retiboblastomas.