Research highlights ►Medulloblastoma originating out of ovarian teratomas is extremely rare. ►Malignancy with extra-ovarian dissemination has an extremely poor prognosis. ►Primary surgery and a ...regimen of high dose cis-platinum can result in a cure.
We have recently described the enzymatic subunit of telomerase (hTERT) as an important prognostic marker for paediatric ependymoma. Because of the lack of good, representative pre-clinical models for ...ependymoma, we took advantage of our large cohort of ependymoma patients, some with multiple recurrences, to investigate telomere biology in these tumours. Our cohort consisted of 133 ependymomas from 83 paediatric patients and included 31 patients with recurrences. Clinical outcome was measured as overall survival, progression-free survival and response to therapy. In all 133 tumours, hTERT expression correlated with proliferative markers, including MIB-1 index (P<0.0001) and mitotic index (P=0.005), as well as overall tumour grade (P=0.001), but not with other markers of anaplasia. There was no correlation between telomere length and hTERT expression or survival. Surprisingly, prior radiation or chemotherapy neither induced sustained DNA damage nor affected telomere maintenance in recurrent tumours. There was an inverse correlation between hTERT expression and telomere dysfunction as measured by gamma H2AX expression (P=0.016). Combining gamma H2AX and hTERT expressions could segregate tumours into three different survival groups (log rank, P<0.0001) such that those patients whose tumours expressed hTERT and showed no evidence of DNA damage had the worst outcome. This study emphasises the importance of telomere biology as a prognostic tool and telomerase inhibition as a therapeutic target for paediatric ependymoma. Furthermore, we have demonstrated that analysing tumours as they progress in vivo is a viable approach to studying tumour biology in humans.
Background
The quality of MRI and CT depends largely on immobility of the patient during the procedure, which is often difficult to achieve without sedation in children below the age of 6 years.
...Objective
To assess the efficacy and safety of intravenous chlorpromazine sedation for repeated imaging in young children treated for cancer.
Materials and methods
From July 2003 to January 2007, information on children younger than 6 years of age having MRI or CT was prospectively collected. Forty-five minutes before the scan, a 10-min infusion of chlorpromazine 0.5 mg/kg was administered and managed by non-anesthetic staff. Patient monitoring included continuous measurement of pulse, respiration, oxygen saturation and arterial blood pressure. Procedure-related parameters and adverse events were documented. Sedation was considered successful when the procedure was completed and at least 95% of images were usable.
Results
One-hundred-one procedures (82 MRI, 19 CT) were evaluated in 62 children, 3–74 months old. Adequate sedation was achieved in 96% of cases, with mean induction time, 22 min; mean duration of sleep, 72 min, and mean duration of procedure, 33 min. Mean time spent in the radiology unit was 104 min. Ninety-six percent of imaging procedures were successfully completed. No cardiac, respiratory, neurological or allergic complication occurred.
Conclusion
Intravenous chlorpromazine is safe and effective for procedural sedation in young children with cancer undergoing MRI and CT.
To determine the incidence and characteristics of pediatric patients with central nervous system (CNS) germ cell tumors (GCT) in Canada.
A national retrospective review of hospital charts was done on ...all patients with CNS GCT diagnosed between 1990 and 2004. Patients had to be under age 18 years at the time of diagnosis of a CNS germ cell tumor and be a resident of Canada. Information extracted included age and year of diagnosis, pathological diagnosis, location of tumor, evidence of disseminated disease at time of diagnosis and biological markers.
One hundred and twenty-one cases were identified (83 germinoma; 38 non-germinoma germ cell tumor). The mean annual incidence of CNS GCT was 1.06 per million children (0.7 per million for germinoma; 0.3 per million for NGGCT). Though yearly incidences varied, there was no clear trend to increased incidence. Male predominance was noted (2.4:1 for germinoma; 11:1 for NGGCT). The primary locations were the pineal and suprasellar regions. At the time of diagnosis, disseminated disease was not uncommon (22% germinoma; 32% NGGCT). Beta human gonadotrophin was elevated in the serum, cerebrospinal fluid (CSF) or both in 7% of patients with germinoma and 36% of patients with NGGCT. Elevation of alpha-fetoprotein in serum, CSF or both was seen in 34% of patients with NGGCT.
The incidence of CNS germ cell tumors in Canadian children is similar to that observed in other Western countries.
Concerns about radiotherapy-related neurocognitive sequelae in young children have led to deferral or avoidance of radiation in contemporary treatment for this fragile group of patients. We compared ...survival and neurocognitive outcome in two groups of infants with medulloblastoma who received adjuvant conventional craniospinal irradiation (CSI) or reduced or no radiotherapy during an era of change in the philosophy of infant medulloblastoma treatment.
From 1985 to 2007, 29 patients 3 years of age or younger were diagnosed and treated with curative intent in our institution. Children treated before 1994 received adjuvant radiation with chemotherapy; subsequently, radiation was prescribed essentially for disease progression or relapse.
Median age at diagnosis was 24 months (range: 1-36 months); 15 patients (52%) presented with metastatic disease at diagnosis. As part of initial treatment, 8 children received adjuvant radiotherapy with chemotherapy, and 21 children received postoperative chemotherapy only. Five children treated with chemotherapy alone are in prolonged remission. The 5-year event-free and overall survivals were 35.9% +/- 9.8% and 50.2% +/- 9.6% respectively. Extent of resection, metastatic status, and desmoplastic histology were not found to be significant prognostic factors. On serial neurocognitive evaluations, patients treated with chemotherapy with or without reduced radiotherapy demonstrated improvement of intellectual function over time. Patients treated with conventional csi exhibited significantly lower intelligence quotient scores and academic performance, with the exception of receptive vocabulary.
Avoidance of conventional CSI in treatment of very young children with medulloblastoma appears to be associated with a preserved neurocognitive profile. Neurocognitive evaluation should be integrated into the primary objectives of future infant protocols.
Prognostic factors were studied in children older than 1 year who were treated with chemotherapy for extracranial localized malignant non seminomatous germ cell tumors.
Data from two consecutive ...protocols were pooled. The TGM 85 (1985-1989) protocol consisted of alternating courses of cyclophosphamide, dactinomycin and vinblastine, bleomycin, and cisplatin at a dose of 100 mg/m(2) per course. The TGM 90 (1990-1994) protocol was initiated with carboplatin 400 mg/m(2) substituted for cisplatin as the only modification to the previous protocol.
We examined alpha-fetoprotein (AFP) levels, disease stage, and primary site and identified three prognostic groups. Patients with a poor prognosis had either an AFP level >/= 10,000 ng/mL or stage III disease and a sacrococcygeal or mediastinal primary site; such patients represented 46% of the patient population and experienced a 43% 3-year failure-free survival rate and a 77% overall survival rate. Patients with a good prognosis had an AFP level less than 10,000 ng/mL, stage I or II disease, and a testicular, ovarian, perineal, or retroperitoneal primary site; such patients represented 22% of the patient population and experienced no treatment failures. The other patients were classified in the intermediate prognosis group and represented 37% of the patient population, with an 81% 3-year failure-free survival rate and a 92% overall survival rate.
Initial AFP level, disease stage, and primary site are the most important prognostic factors in this analysis. Prognostic models for pediatric germ cell tumors should allow the stratification of patients for a risk-adapted approach to treatment.
Chemotherapy has been used extensively in the management of children with intracranial ependymoma. In this review, we discuss the results of phase II studies and clinical trials conducted in newly ...diagnosed and recurrent ependymomas. There is little evidence that chemotherapy is effective in this tumour. The response rate to single agents is 11%, with less than 5% complete responses, cisplatin being the most active agent in phase II studies. Combinations may be more effective, although the response rate with high-dose regimens is disappointing. Early results of protocols conducted in infants and young children do not suggest that chemotherapy is beneficial. A more rigorous assessment of chemotherapy is required in order to define its role in patients with intracranial ependymomas. Indeed, it is difficult to justify the use of chemotherapy outside such studies. More large studies, perhaps intergroup, limited to children with ependymomas would be of particular value.
Background
High‐dose chemotherapy (HDC) strategies were developed to avoid unacceptable neurotoxicity associated with craniospinal irradiation in infants with embryonal brain tumors. However, the ...impact of molecular and pathological characterizations in such approaches and long‐term outcome have not been widely described in young children.
Methods
We retrospectively collected information from seven North American institutions, on young children with medulloblastoma (MB) treated with sequential HDC, as per the CCG 99703 protocol. Data collection included clinical presentation, histology, molecular subgroup, irradiation, ototoxicity, and neurocognitive evaluations.
Results
The cohort included 53 patients diagnosed at a median age of 24 months (2.9–63.2). Seventeen patients (32.1%) had nodular desmoplatic MB, all belonging to the sonic Hedgehog (SHH) subgroup, as did 30% of classic MB. The 5‐year progression‐free survival (PFS) and overall survival (OS) was 69.6% (±6·9%) and 76.1% (±6.5%), respectively. Seventeen (32.1%) patients received irradiation (nine adjuvant radiotherapy RT). Patients with SHH and group 3 MB had a 5‐year PFS of 86·2% (±7.4%) and 49·1% (±14%), respectively (P = 0.03). The 5‐year PFS radiation free for group 3 MB was 46.4%. Patients with macroscopic metastasis (M2 and M3) had a worst survival. Fifteen (45.5%) patients had significant ototoxicity. Mean Full Scale Intellectual Quotient (FSIQ) for 24 survivors was 91.6 (range 52–119).
Conclusions
This HDC strategy led to an encouraging OS while only 20% of the patients received adjuvant RT. SHH MB, irrespective of histological subgroup, had an excellent outcome. Such intensive therapy may not be needed for this subgroup. Patients with classic histology or group 3 had an encouraging PFS of 58% and 46.4%, respectively, in the absence of adjuvant RT. The neurocognitive profile of the survivors appears to be within the normal range.
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