Nasjla Saba da Silva

Genome-Wide Analyses Identify Recurrent Amplifications of Receptor Tyrosine Kinases and Cell-Cycle Regulatory Genes in Diffuse Intrinsic Pontine Glioma

PURPOSE Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. PATIENTS AND METHODS Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas. RESULTS Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar. CONCLUSION DIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.

Primary chemotherapy for intracranial germ cell tumors: results of the third international CNS germ cell tumor study.

The treatment of central nervous system (CNS) germ cell tumors (GCT) remains controversial. The purpose of this study was to demonstrate efficacy of a chemotherapy only strategy, with less morbidity, when compared to regimens with irradiation.

The management of patients with primary central nervous system (CNS) germinoma: Current controversies requiring resolution

The management of patients with primary central nervous system (CNS) germinomas provides a rare opportunity in neurooncology to pose the question as to how little therapy is required to achieve cure, while at the same time maximally preserving quality of life. Radiation therapy alone can cure in excess of 90% of patients with CNS germinomas. The standard target volume for irradiation was at one time the entire craniospinal axis. While effective, craniospinal irradiation (CSI) was associated with significant endocrine and neurocognitive toxicities. Several institutions have reported equivalent control rates with the irradiation target limited to either the whole brain (WBI) or the intracranial ventricular system [1–11]. Ventricular field irradiation (VFI) has now become the most widely accepted standard of treatment. In recent years, induction chemotherapy has been utilized to permit reduction in both the radiation therapy volume and dose. Protocols have also tailored the radiation therapy to the radiographic response to pre-irradiation chemotherapy. Published studies already indicate that these strategies result in preserved high cure rates, not different from those achieved with irradiation alone (albeit at higher doses) [12–25]. All the national and international cooperative groups presented updates of their combined chemo-radiation studies at the 2nd International CNS Germ Cell Tumor Symposium. Matsutani [18] delivered a final report for the Japanese Study Group on 123 patients with germinoma treated with chemotherapy followed by 24 Gy loco-regional irradiation. The total tumor-free survival rate was 89% and 5-year survival was 98%. The recurrence rate differed significantly according to irradiation volume: 0% for WBI (given only to patients with widely disseminated tumor), 6% for extended field irradiation, but 28% for those treated with focal irradiation with less than 2 cm margins. Calaminus et al. [22] and Frappaz et al. [23] presented an update on the Societé Internationale d’Oncologie Pediatrique (SIOP) CNS GCT 96 Trial at the 2nd International CNS GCT Symposium; of 113 patient treated with initial chemotherapy followed by focal irradiation to 40 Gy, the 3-year EFS was 93%; this outcome was identical with that for patients treated with a concomitant treatment option on the Trial of CSI to 24 Gy and primary site boost to 40 Gy. Alapetite et al. [19] presented long term follow up data from the Societé Francaise d’Oncologie Pediatrique (SFOP-90) Trial, in which 60 patients with localized germinoma received chemotherapy followed by 40 Gy focal irradiation. They reported an 8-year event free survival of 83% and overall survival of 98%. Eight of 10 recurring patients failed at the margin or outside of the focal irradiation field. The North American experiences from New York University [16,24], M.D. Anderson Cancer Center [21] and Seattle [20] echo these larger European and Japanese experiences. It remains to be determined whether induction chemotherapy with reduced dose and volume irradiation results in less adverse impact on neurocognitive functioning and quality of life than irradiation alone. The attempts at radiation therapy reduction have engendered intense international debate within the neuro-oncology community, largely centered on the following hypotheses: (1) that pre-irradiation chemotherapy can successfully be followed (in patients achieving complete or near complete radiographic responses) by focal field irradiation rather than VFI, WBI or CSI, (2) that sub-sets of patients with primary CNS germinoma still require CSI even following pre-irradiation chemotherapy, irrespective of attainment of complete radiographic response. An additional, all encompassing debate, relates to the precise definition of a pure germinoma. It is accepted that a pathological diagnosis is required, but often only tiny tumor biopsies are obtained because of the mid-line location of these tumors, and such biopsies may not be representative of the entire tumor. Therefore, the absence of both serum and cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) is essential to affirm the diagnosis of pure germinoma, since AFP elevations are absolutely inconsistent with the diagnosis of pure germinoma. Far more controversial is the level of beta-human chorionic gonadotropin (HCGb) that is considered consistent with a pure germinoma. It is well recognized that pure germinomas can include

Pediatric central nervous system tumors: a single-center experience from 1989 to 2009.

The objective of this study was to determine the epidemiology of primary tumors of the central nervous system (CNS) in pediatric patients from a Brazilian oncology institute. We retrospectively analyzed 741 charts (415 males and 326 females) of patients under 21 years of age who were diagnosed with a CNS tumor. The analysis included patients from 1989 to 2009 and was performed using the World Health Organization criteria. We evaluated the distribution of age, sex, topography, clinical symptoms, symptom intervals, and classification of the tumors. Patients with clinical/radiologic diagnoses were included. Seven hundred forty-one patients with tumors in the CNS were reviewed, and 83% of the patients presented a histologic diagnosis. Males (56%) were more prevalent than females. In children under the age of 1 year, the supratentorial compartment was the predominant region involved (62.0%). Astrocytoma was the most frequent tumor type (37.0%), followed by medulloblastoma (13.6%), craniopharyngioma (10.5%), and ependymoma (6.8%). Headaches were the most common symptom, and the symptom intervals varied from 1 to 5010 days. Approximately 4% of the patients had associated genetic syndromes. Although it was not a population study and selection bias may have occurred, this study supplies important epidemiologic data from an emerging country in which population studies are rare.

Cystic craniopharyngioma: intratumoral chemotherapy with alpha interferon

OBJECTIVE To assess whether the cystic craniopharyngiomas can be controlled with the use of intratumoral applications of interferon alpha. METHOD Nineteen patients with the diagnosis of cystic craniopharyngioma were treated with intratumoral chemotherapy with interferon alpha from January 2002 to April 2006. All patients underwent placement of an intracystic catheter connected to an Ommaya reservoir. Through this reservoir were made applications during chemotherapy cycles. Each cycle corresponded to application of 3,000,000 units of interferon alpha three times per week on alternate days totalizing 36,000,000 units. Response to treatment was evaluated by calculating the tumor volume on MRI control after one, three and six months after the end of each cycle. Patients who developed worsening of symptoms or who had insignificant reduction in tumor volume during follow-up underwent repeat cycle chemotherapy. RESULTS Four patients received four cycles of chemotherapy, three patients received three cycles, six patients received two cycles and six patients received one. The lower percentage of reduction in tumor volume was 60% and the bigger reduction was 98.37%. Eleven patients had a reduction greater than 90%. Five patients had a tumor reduction between 75 and 90% and in three patients the tumors were reduced by less than 75%. No deaths occurred during treatment and side effects of interferon alpha were well tolerated. No treatment was discontinued. Follow-up after the last application ranged from one year and five months to three years and nine months. CONCLUSION The intratumoral chemotherapy with interferon alpha decreases the volume of cystic craniopharyngiomas and so far can be considered a new therapeutic alternative.

Cavectomy for the Treatment of Wilms Tumor With Vascular Extension

PURPOSE Vascular extension to the vena cava occurs in 4% of Wilms tumor cases and can reach the right atrium in up to 1%. When this happens the thrombus is usually not adherent to the vessel wall, and there is blood flow around it. Preoperative chemotherapy can cause thrombus regression and even resolution. If the thrombus persists after chemotherapy, surgery will be a challenge. On the other hand, if the thrombus invades the vessel wall, its removal may not be feasible. In this situation cavectomy is a good surgical strategy because it provides complete resection. The prerequisite for cavectomy is the absence of blood flow in the vena cava on preoperative Doppler ultrasonography. We report 3 cases of Wilms tumor with vena caval invasion in which cavectomy was performed, and discuss the principles, indications and operative technique. MATERIALS AND METHODS A total of 171 patients with Wilms tumor were treated at our institution between 1984 and 2004. Of these patients 6 with intravascular extension of thrombus within the right atrium were treated with extracorporeal circulation, cardiac arrest and profound hypothermia, and 3 were treated with cavectomy. RESULTS There were no instances of surgical complications or postoperative renal failure in our patients who underwent cavectomy. All remain well and free of disease. CONCLUSIONS Cavectomy is a safe procedure for treating pediatric patients with Wilms tumor when there is extension and invasion of the vena cava wall without blood flow.

Speech-language and hearing complaints of children and adolescents with brain tumors.

Central nervous system (CNS) tumors generally leave sequelae that may compromise speech, language, swallowing, hearing, and voice functions. This report describes the incidence of speech‐language and hearing complaints and disorders in children and adolescents with CNS tumor under treatment at one of the most important Brazilian reference center for pediatric cancer. One‐hundred ninety patients were examined for speech‐pathology screening and analysis: forty‐two percent presented with complaints and symptoms. From the remaining patients, 68% presented clinical symptoms and 32% were actually free from any speech‐language and hearing‐related symptoms. The high incidence of complaints and symptoms indicate that these patients might benefit from specific rehabilitation interventions. Pediatr Blood Cancer 2008;50:706–708.

Prevalência de desnutrição em crianças com tumores sólidos

OBJETIVE: To evaluate the malnutrition prevalence in children and adolescents with solid tumors, who received treatment in a Brazilian oncology center. METHODS: 44 patients were evaluated during the first month of the oncology therapy, using anthropometric measures and, according to the World Health Organization criteria, the Z-scores of weight/age, height/age, and weight/height. RESULTS: The Z-scores of weight/age, height/age, and weight/height showed 16%, 7% e 16% of malnutrition, respectively. Prevalence of malnutrition was observed in 27% of patients with cerebral tumors, 25% of those with neuroblastomas, and 11% of those with Wilms tumor. CONCLUSION: The high prevalence of malnutrition in this population, may be associated with the disease, its treatment, and the social and economic factors. Nonetheless, failure to identify nutritional risk, due to the lack of a nutritional protocol, may be another cause of malnutrition in patients with solid tumors.

Diffuse intrinsic brainstem tumor in an infant: a case of therapeutic efficacy with vinorelbine.

Brainstem gliomas constitute 10% to 20% of all pediatric tumors of the central nervous system, and diffusely infiltrative brainstem gliomas are the most common brainstem tumors associated with a poor prognosis. A small subset of these tumors is benign, showing low-grade features on histology. The role of chemotherapy in the management of these tumors is ill defined, especially in the neonates. There are anecdotal reports of spontaneous remission, but the natural history of these tumors does not support a wait-and-see approach. Thus, we report a successful experience of chemotherapy in a 4-month-old girl with a diffuse brainstem fibrillary astrocytoma, treated with vinorelbine (30 mg/m2/d on days 0, 8, and 22), a vinca alkaloid that has shown activity against glioma. Our experience suggests that vinorelbine may be effective in pediatric low-grade gliomas as this patient showed significant clinical improvement over a short period of time.

Early traits of metabolic syndrome in pediatric post-cancer survivors: outcomes in adolescents and young adults treated for childhood medulloblastoma

OBJECTIVE To analyze traits of metabolic syndrome (MetS) in medulloblastoma survivors. SUBJECTS AND METHODS Sixteen childhood medulloblastoma survivors aged 18.0 (4.4) years, with history of craniospinal radiation therapy (RT) were compared with nine control subjects matched by age, gender, and body mass index, according to fat distribution, metabolic and cardiovascular variables. RESULTS Medulloblastoma patients showed increases in waist circumference and its relationships (all p < 0.05), and HOMA1-IR (p = 0.006), which were modified by growth hormone (GH) secretion status. However, these increases were within normal range. CONCLUSIONS Adolescent and young adult survivors of medulloblastoma showed centripetal fat deposition and decreased insulin sensitivity, associated with GH status. Pediatric brain tumor survivors following RT should be monitored for the diagnosis of MetS traits predisposing to cardiovascular disease.