Danielle Bours

Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics†

Medulloblastoma is the most frequent malignant paediatric brain tumour. The activation of the Wnt/β‐catenin pathway occurs in 10‐15% of medulloblastomas and has been recently described as a marker for favourable patient outcome. We report a series of 72 paediatric medulloblastomas evaluated for β‐catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of β‐catenin showed extensive nuclear staining (>50% of the tumour cells) in six cases and focal nuclear staining (<10% of cells) in three cases. The other cases either exhibited a signal strictly limited to the cytoplasm (58 cases) or were negative (five cases). CTNNB1 mutations were detected in all β‐catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/β‐catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear β‐catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/β‐catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow‐up of 75.7 months (range 27.5–121.2 months) from diagnosis. All three patients with focal nuclear staining of β‐catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1‐mutated tumours represent a distinct molecular subgroup of medulloblastomas with favourable outcome, indicating that therapy de‐escalation should be considered. International consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved. Copyright

Analysis of ototoxicity in young children receiving carboplatin in the context of conservative management of unilateral or bilateral retinoblastoma

Carboplatin plays an important role in the conservative management of retinoblastoma, but is associated with risk of ototoxicity in these young children whose sensory prognosis may be also compromised by their loss of vision. This retrospective study analyzed the impact of carboplatin on hearing in the context of conservative management of children with retinoblastoma.

Chemothermotherapy in the management of retinoblastoma

OBJECTIVE To evaluate the results of chemothermotherapy for the treatment of retinoblastoma. DESIGN Non-comparative interventional case series. PATIENTS Fifty-one children (65 eyes and 103 tumors) were treated with chemothermotherapy in a single institution from January 1995 to May 1998. METHODS Chemothermotherapy consists of a combination of transpupillary thermotherapy delivered shortly after intravenous (IV) injection of carboplatin (560 mg/m(2)). Each tumor is treated separately with a diode laser using a microscope. Laser intensity, spot size, and duration are adapted to the size of each tumor and to the clinical response. After 8 days, thermotherapy alone is repeated. This cycle is performed from one to six times, every 28 days. The treatment data and outcome are analyzed separately. MAIN OUTCOME MEASURES Assessment of local tumor control. RESULTS One hundred three tumors were treated in 65 eyes of 51 children. Age at diagnosis was 0 to 60 months (median, 7 months). Median tumor diameter at the time of treatment was 3.5 mm (range, 1.5-12 mm). Laser modalities were as follows: median intensity, 450 mW (range, 150-1000 mW); median spot size, 1.2 mm (range, 0.3-2.0 mm); and median number of cycles required to obtain tumor control, three. Tumor regression was obtained for 99 tumors (96.1%) after a median follow-up of 30 months (17-61 months). Seven tumors relapsed after initial control (6.8%). Salvage treatment (external beam radiation, iodine plaques, or enucleation) was necessary for a total of 11 tumors (10.7%). The only risk factor for relapse was the initial diameter of the lesion greater than 3.5 mm, whereas the other tumor characteristics or treatment variables were not significantly correlated with relapse. Ninety-seven percent of treated eyes were able to be preserved, and 92% of cases were treated without external beam radiation. CONCLUSIONS Chemothermotherapy is an effective technique to treat small- to medium-sized retinoblastomas in children, avoiding external beam irradiation.

Conservative Treatments of Intraocular Retinoblastoma

OBJECTIVE To describe the efficacy of conservative management of retinoblastoma by an association of conservative ocular therapies and chemothermotherapy. DESIGN Phase II prospective nonrandomized trial. PARTICIPANTS Eighty-three children were included (115 eyes). METHODS Conservative ocular therapies and chemothermotherapy (intravenous carboplatin followed by transpupillary thermotherapy to the tumor) after chemoreduction by 2 cycles of carboplatin and etoposide. MAIN OUTCOME MEASURES Use of external beam therapy and ocular tumor control. RESULTS One hundred fifteen of the 147 affected eyes were eligible for conservative management. Nineteen children had unilateral lesions (22.8%), and 64 (77.1%) had bilateral lesions. Sixty-six children received neoadjuvant chemotherapy before ocular therapy, which consisted of one or a combination of several techniques: chemothermotherapy (65 children [86 eyes]) with a mean of 3 cycles per child, thermotherapy alone (22 children [24 eyes]), cryoapplication (49 children [58 eyes]), and iodine 125 brachytherapy (26 children [29 eyes]). Tumor control was achieved for 97 eyes (84%). At the end of the study, external beam radiotherapy (EBR) was necessary for a total of 9 children (11%) and 13 eyes (12%). Enucleation was necessary for a total of 23 eyes (20%), because of complications in 5 cases. CONCLUSIONS Neoadjuvant chemotherapy with 2 cycles of carboplatin and etoposide followed by ocular therapy and chemothermotherapy achieves satisfactory tumor control and permits a low need for EBR.

Radiation and chemotherapy combination for nasopharyngeal carcinoma in children: Radiotherapy dose adaptation after chemotherapy response to minimize late effects†

To retrospectively report the clinical and therapeutic features of children with nasopharyngeal carcinoma (NPC) treated by chemotherapy and doses adapted of radiotherapy.

Familial retinoblastoma: fundus screening schedule impact and guideline proposal. A retrospective study

AimsTo assess if systematic fundus screening according to an ‘intensive’ schedule alters ocular outcome and to propose fundus screening schedule guidelines for children related to a retinoblastoma patient.MethodsFor children with a positive family history of retinoblastoma, we perform fundus exams shortly after birth under general anaesthesia and then at regular intervals according to schedules based on the risk. Familial retinoblastoma cases seen at our institution from January 1995 to December 2004 were retrospectively classified as ‘screened’ or ‘non-screened’ (NS) and, among the ‘screened’ patients, as ‘intensively screened’ (IS) if screening matched our recommendations or ‘non-intensively screened’ (S). Groups were compared by Fisher exact test for categorical variables and Kruskal–Wallis test for continuous variables.ResultsAmong the 547 retinoblastoma patients managed at our institution during this period, 59 were familial cases. In all, 20 were in the NS group, 23 in the S group, and 16 in the IS group. The number of children enucleated was, respectively, 13, 2, and 0 (P<10−4); external beam radiation (EBRT) was required for, respectively, 6, 0, and 2 children (P<0.009). Chemotherapy burden and visual acuity were not significantly different between groups.ConclusionAn ‘intensive’ fundus screening schedule decreased the need for enucleation and EBRT. Therefore, despite the heavy burden of the screening schedule, we recommend physicians and health-care professionals to better inform and refer children with a family history of retinoblastoma for genetic counselling and proper fundus screening in specialized centres.

338 Traitements conservateurs du rétinoblastome

Objectif Evaluer l’efficacite du traitement conservateur du retinoblastome par des traitements locaux ou la thermo-chimiotherapie (carboplatine intraveineux suivi de thermotherapie sur les tumeurs) precedee d’une phase de chimiotherapie premiere de deux cycles de l’association carboplatine et etoposide. Materiels et Methodes Etude prospective non randomisee concernant des enfants pris en charge a l’Institut Curie entre decembre 1998 et mars 2002 pour un retinoblastome accessible a un traitement conservateur. L’objectif principal est la reduction du recours a l’irradiation externe en raison de ses risques. Resultats 83 enfants ont ete inclus 19 ayant une atteinte unilaterale (22.8 %) et 64 enfants (77.1 %) ayant une atteinte bilaterale soit 147 yeux atteints dont seuls 115 yeux pouvaient beneficier d’une approche conservatrice. 66 enfants ont recu une chimiotherapie neo adjuvante avant les traitements oculaires. Ceux-ci ont consiste en l’association d’un ou plusieurs techniques : thermo-chimiotherapie (65 enfants 86 yeux) avec une moyenne de 3 cycles recus par enfant, thermotherapie seule : 22 enfants (24 yeux), cryo-application : 49 enfants (58 yeux), pose de disque d’iode 125 : 26 enfants (29 yeux). Discussion Au terme de ces traitements un controle tumoral a ete obtenu pour 97 yeux (84 %). Le recours a la radiotherapie externe a ete necessaire pour un total de 9 enfants (11 %) et 13 yeux (12 %) dont 7 enfants (10 yeux) en tant que traitement initial. Une enucleation secondaire a ete necessaire pour 23 yeux (20 %) dont 5 pour complications. Ces resultats, comparables en termes d’efficacite a d’autres series, ont ete obtenus avec des doses cumulatives de chimiotherapie moins importantes laissant esperer une moindre toxicite a moyen et long terme. Conclusion L’association d’une chimiotherapie premiere par deux cycles de carboplatine et etoposide suivie des traitements oculaires dont la thermochimiotherapie permet un controle tumoral satisfaisant et diminue le recours a l’irradiation externe.