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/beta-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 beta-catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of beta-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 beta-catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/beta-catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear beta-catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/beta-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 beta-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.

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

BACKGROUND: 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. METHODS: Data for 175 children treated at the Institut Curie between 1994 and 2002 were analyzed. RESULTS: Median age at diagnosis was 8 months (0-60). Carboplatin was administered on 3 days (200 mg/m(2)/day) or 5 days (160 mg/m(2)/day) with etoposide and with diode-laser therapy at the dose of 560 mg/m(2) (chemothermotherapy). Median cumulative dose of carboplatin was 2,880 mg/m(2) (560-6,160). Ototoxicity was investigated by pure-tone audiometry and scored by Brock's grading scale before and after treatment. The median follow-up of hearing assessment was 5 years (1.8-11). Ototoxicity was detected in 8 children: 3 grade 1, 1 grade 2, and 2 grade 4. The two patients with grade 4 hearing-loss required a hearing aid. Two children developed bilateral high frequency hearing-loss, considered to be secondary to carboplatin but with less than Brock grade 1. Ototoxicity was observed for a median cumulative dose of carboplatin of 3,120 mg/m(2) (1,200-5,830). Only one child developed ototoxicity during treatment. All other cases were discovered after the last dose of carboplatin with a median interval of 3.7 years (0-7.6). No other risk factor for ototoxicity was able to account for these lesions. CONCLUSION: Children receiving carboplatin require long-term audiometric follow-up.

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.

OBJECTIVES: To retrospectively report the clinical and therapeutic features of children with nasopharyngeal carcinoma (NPC) treated by chemotherapy and doses adapted of radiotherapy. PATIENTS AND METHODS: From 1978 to 2005, 34 children were treated for NPC. All histologic and/or cytologic samples and CT scans were reviewed. Cervical nodal irradiation was reduced (<50 Gy) in the case of a good response to chemotherapy (>/=90% of initial tumor volume). RESULTS: Thirty-two children had metastatic cervical nodes and one child had systemic metastases at diagnosis. All children had AJJC-TNM Stage IV. Thirty-one children received neoadjuvant chemotherapy with various regimens. The overall chemotherapy response rate was 78%. Fifteen patients had cervical nodal irradiation dose reduced: Median 47 Gy (range: 45-50). Nasopharyngeal radiotherapy was delivered at a dose of 59.4 Gy (range: 45-66). Local and distant failure rates were 10% and 18%, respectively. The 5-year overall survival was 73 +/- 8% and the event-free survival (EFS) was 75 +/- 8%. CONCLUSIONS: The overall prognosis was not influenced by TNM status, dose of local radiotherapy delivered or response to initial chemotherapy, but EFS was better in patients with a good response to chemotherapy. The cervical local failure rate was low despite radiotherapy dose reduction in the case of a good response to neoadjuvant chemotherapy. We also propose a reduction of nasopharyngeal radiation (

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.