Maria Luisa Garrè

Survival and Prognostic Factors of Early Childhood Medulloblastoma: An International Meta-Analysis

PURPOSE To assess the prognostic role of clinical parameters and histology in early childhood medulloblastoma. PATIENTS AND METHODS Clinical and histologic data from 270 children younger than age 5 years diagnosed with medulloblastoma between March 1987 and July 2004 and treated within prospective trials of five national study groups were centrally analyzed. RESULTS Two hundred sixty children with medulloblastoma and specified histologic subtype were eligible for analysis (median age, 1.89 years; median follow-up, 8.0 years). Rates for 8-year event-free survival (EFS) and overall survival (OS) were 55% and 76%, respectively, in 108 children with desmoplastic/nodular medulloblastoma (DNMB) or medulloblastoma with extensive nodularity (MBEN); 27% and 42%, respectively, in 145 children with classic medulloblastoma (CMB); and 14% and 14%, respectively, in seven children with large-cell/anaplastic (LC/A) medulloblastoma (P < .001). Histology (DNMB/MBEN: hazard ratio [HR], 0.44; 95% CI, 0.31 to 0.64; LC/A medulloblastoma: HR, 2.27; 95% CI, 0.95 to 5.54; P < .001 compared with CMB), incomplete resection and metastases (M0R1: HR, 1.86; 95% CI, 1.29 to 2.80; M+: HR, 2.28; 95% CI, 1.50 to 3.46; P < .001 compared with M0R0), and national group were independent prognostic factors for EFS, and OS. The HRs for OS ranged from 0.14 for localized M0 and DNMB/MBEN to 13.67 for metastatic LC/A medulloblastoma in different national groups. CONCLUSION Our results confirm the high frequency of desmoplastic variants of medulloblastomas in early childhood and histopathology as a strong independent prognostic factor. A controlled de-escalation of treatment may be appropriate for young children with DNMB and MBEN in future clinical trials.

A Prospective Study on the Epidemiology of Febrile Episodes during Chemotherapy-Induced Neutropenia in Children with Cancer or after Hemopoietic Stem Cell Transplantation

BACKGROUND The purpose of our study was to evaluate the incidence and clinical characteristics of febrile episodes during neutropenia following chemotherapy in children with cancer. PATIENTS AND METHODS A prospective, 3-year single-center observational study of periods of neutropenia was performed. Epidemiology and clinical diagnoses of febrile episodes occurring during the neutropenic periods were evaluated, taking into consideration different categories of anticancer treatment based on the type of tumor and phase of therapy. RESULTS A total of 703 febrile episodes were observed during 614 (34%) of 1792 neutropenic periods (34%), for a total of 28,001 days at risk, accounting for a rate of 0.76 episodes per 30 days at risk. The highest proportions of neutropenic periods with primary febrile episodes were observed after autologous hemopoietic stem cell transplantation (58%), aggressive treatment for acute leukemia or non-Hodgkin lymphoma (48%), and allogeneic hemopoietic stem cell transplantation (44%); the lowest proportion (9%) was observed during maintenance chemotherapy for acute leukemia (P<.001). The most frequent clinical diagnosis was fever of unknown origin (in 79% of cases), followed by bacteremia (10%); invasive mycosis was diagnosed in only 2% of cases. CONCLUSIONS The overall incidence of febrile neutropenia and severe infectious complications in children with cancer is low, with differences according to the aggressiveness of chemotherapy. This fact must be considered when designing clinical trials on the management of infectious complications in children with cancer.

Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas

To investigate the molecular mechanisms of tuberous sclerosis (TSC) histopathologic lesions, we have tested for loss of heterozygosity the two TSC loci (TSC1 and TSC2) and seven tumor suppressor gene‐containing regions (TP53, NF1, NF2, BRCA1, APC, VHL, and MLM) in 20 hamartomas from 18 TSC patients. Overall, eight angiomyolipomas, eight giant cell astrocytomas, one cortical tuber, and three rhabdomyomas were analyzed. Loss of heterozygosity at either TSC locus was found in a large fraction of the informative patients, both sporadic (7/14) and familial (1/4). Interestingly, a statistically significant preponderance of loss of heterozygosity at TSC2 was observed in the sporadic group (P < 0.01). Among the possible explanations considered, the bias in the selection for TSC patients with the most severe organ impairment seems particularly appealing. According to this view, a TSC2 defect might confer a greater risk for early kidney failure or, possibly, a more rapid growth of a giant cell astrocytoma. None of the seven antioncogenes tested showed loss of heterozygosity, indicating that the loss of either TSC gene product may be sufficient to promote hamartomatous cell growth. Finally, the observation of loss of heterozygosity at different markers in an astrocytoma and in an angiomyolipoma from the same patient might suggest the multifocal origin of the second‐hit mutation. Genes Chromosom Cancer 15:18–25 (1996).

SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease

BACKGROUND We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s). METHODS Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy. RESULTS Patients with localized germinoma (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 ± 0.02 vs 0.88 ± 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 ± 0.023 event-free and overall survival. CONCLUSIONS Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease.

Craniopharyngioma : modern concepts in pathogenesis and treatment

Purpose of review Craniopharyngioma is a benign tumour. Its tendency to recur after excision and the high surgical risk due to involvement of the most vital structures of the brain mean that alternatives to radical surgery should be considered, namely limited surgical procedures followed by radiotherapy. Since both options present inherent risks, optimal craniopharyngioma treatment remains controversial. This paper aims to critically review the recent literature on craniopharyngioma. Recent findings The management of children with craniopharyngioma has benefited from concerted efforts by national and international groups to improve outcome and reduce morbidity. From the current literature it is evident that there is a trend to better integrate all treatment modalities available, tailoring therapies to specific risk factors. Modern imaging and new surgical and radiotherapy techniques are increasing the possibility of cure. Biological markers are under investigation and this will increase our knowledge on craniopharyngioma. Summary Studies on treatment, biology and pathogenesis of craniopharyngioma, available in the current literature, grew considerably in the last year. Although a consensus has not been reached on all aspects of this complex disease, there is a trend in the field to move quickly towards a better understanding of the disease to improve treatment strategies and to produce clinical cooperative trials.

Medulloblastoma Variants: Age-Dependent Occurrence and Relation to Gorlin Syndrome—A New Clinical Perspective

Purpose: We aimed to test the hypothesis that medulloblastoma (MB) variants show a different age distribution and clinical behavior reflecting their specific biology, and that MB occurring at very young age is associated with cancer predisposition syndromes such as Gorlin syndrome (GS). Experimental Design: We investigated the frequency, age distribution, location, response to treatment, outcome, and association with familial cancer predisposition syndromes in a series of 82 cases of MB in patients ages <14 years diagnosed at the Giannina Gaslini Childrens Hospital, Genoa, between 1987 and 2004. Results: Desmoplastic MB and MB with extensive nodularity (MBEN), were present in 22 of 82 cases (27%) and were more frequent in children ages ≤3 years (13 of 25; 52%). In this age group, MBEN was significantly more frequent than desmoplastic MB and classic MB (P < 0.001) and had a good prognosis. MBEN was associated with GS in 5 of 12 cases. Overall, 8 cases occurred in the context of familial tumor predisposition syndromes (5 GS, 1 each NF1, Li-Fraumeni, and Fragile X) and 7 of these patients were ages ≤3 years at diagnosis. Desmoplastic histology and a more intensive treatment represented independent favorable prognostic factors in multivariate analysis (P = 0.003 and P = 0.0139, respectively). Metastasis was a predictor of bad outcome (P = 0.0001). Conclusions: Our data indicate that biologically different MB entities warrant risk-adapted treatment and that MBEN is strongly associated with GS. Patients, ages ≤3 years, with MB and their families should be investigated for tumor predisposition syndromes such as GS.

Stereotactically guided conformal radiotherapy for progressive low-grade gliomas of childhood.

PURPOSE To describe the rationale, technique, and early results of stereotactically guided conformal radiotherapy (SCRT) in the treatment of progressive or inoperable low-grade gliomas (LGGs) of childhood. METHODS AND MATERIALS Between September 1994 and May 1999, 14 children (median age 6 years, range 5-16) with LGG were treated with SCRT at the Royal Marsden NHS Trust. Tumors were located at the optic chiasm (n = 9), third ventricle (n = 2), hypothalamus, craniocervical junction, and pineal region (each n = 1). Four patients received chemotherapy before SCRT. Immobilization was in a Gill-Thomas-Cosman frame (n = 12) and subsequently in a specially designed pediatric version of the frame (n = 2). Stereotactic coordinates and the tumor were defined by CT scanning with a fiducial system and MRI fusion. The median tumor volume was 19.5 cm(3) (range 7.5-180). The planning target volume was defined as the area of enhancing tumor plus a 5-10-mm margin. The treatment technique consisted of 4 isocentric, noncoplanar, conformal, fixed fields. Treatment was delivered in 30-33 daily fractions to a total dose of 50-55 Gy. RESULTS SCRT was well tolerated, with transient hair loss the only acute toxicity. The median follow-up was 33 months (range 2-53). At 6 months after SCRT, 4 of 12 children with neurologic deficits improved and 5 remained stable. Twelve children were available for MRI evaluation. Two had a complete response, 6 a partial response, and 4 stable disease. One child with optic chiasm glioma had local progression at 25 months, and 1 developed diffuse leptomeningeal disease without local progression at 27 months. The 3-year local progression-free survival and overall survival rate after SCRT was 87% and 100%, respectively, compared with 89% and 98% for an historic control treated with conventional RT. New endocrine deficiencies were noted in 2 children after a follow-up of 20 and 23 months. CONCLUSION SCRT is a feasible, high-precision technique of RT for children with LGGs for whom RT is considered appropriate. The local control and acute toxicity of SCRT are comparable to a historic control of patients with conventionally delivered RT. The frequency of delayed hypothalamic-pituitary axis dysfunction reflects tumor location adjacent to the hypothalamus and pituitary. Additional follow-up is required to demonstrate that SCRT contributes to a reduction in treatment-related late toxicity, while maintaining the local control achieved with conventionally delivered RT in children with progressive LGGs.

Medulloblastoma in children : CT and MRI findings

Our purpose was to determine whether medulloblastoma (MB) shows specific neuroradiological features which may be employed in differential diagnosis from other common posterior cranial fossa tumours in childhood. Preoperative MRI was performed on 20 children with MB, and preoperative CT in 17 of them. All underwent surgery and histopathological diagnosis. There was a constant relationship between high density on CT and low signal on T1-weighted images. Signal behaviour on T2-weighted images and the degree of contrast enhancement were more variable. Most tumours arose in the midline, from the cerebellar vermis, involving the fourth ventricle, but hemisphere and extra-axial neoplasms were also seen. The combination of high density on CT and low signal on T1-weighted images is highly suggestive of MB and may assist preoperative differential diagnosis from other posterior cranial fossa tumours.

Subtype-specific expression and genetic alterations of the chemokinereceptor gene CXCR4 in medulloblastomas

Recent findings indicate that the chemokine receptor Cxcr4 is essential for normal development of the cerebellar cortex. As medulloblastomas (MBs), the most common malignant brain tumors of childhood, are believed to arise from neuronal cerebellar precursors, we asked whether there is a potential role for Cxcr4 in the pathogenesis of MB. RT‐PCR and immunohistochemistry revealed expression of Cxcr4 in different variants of MBs. Whereas 18/20 classic MBs showed very low levels of CXCR4 mRNA, high amounts were expressed in 17/18 desmoplastic and 6/7 extensively nodular MBs. In addition, a significant correlation of high CXCR4 mRNA levels and presence of the neurotrophin receptor p75NTR or expression of ATOH1 and GLI1 suggests that CXCR4 is a reliable marker for tumors derived from the cerebellar external granular layer. Because Cxcr4 is important for migration and cell cycle control of granular precursors, we screened for mutations in the coding region by SSCP and gene sequencing. In a series of 90 MBs and 8 MB cell lines, we found one germline and one somatic mutation resulting in amino acid substitutions in the first (Ile53Leu) and second (Asp97Asn) transmembrane regions, respectively. These data suggest that Cxcr4 may be involved in the pathogenesis of MBs.

New MR sequences (diffusion, perfusion, spectroscopy) in brain tumours

While MRI has been instrumental in significantly improving care in children harbouring brain tumours, conventional sequences lack information regarding functional parameters including cellularity, haemodynamics and metabolism. Advanced MR imaging modalities, such as diffusion (including diffusion tensor imaging and fibre tractography), perfusion and spectroscopy have significantly improved our understanding of the physiopathology of brain tumours and have provided invaluable additional information for treatment planning and monitoring of treatment results. The contribution of these methods to the characterization of brain neoplasms in children is the focus of the present manuscript.