Characteristics of children ≤36 months of age with DIPG: A report from the international DIPG registry.

BACKGROUND: Children ≤36 months with diffuse intrinsic pontine glioma (DIPG) have increased long-term survival (LTS, overall survival (OS) ≥24 months). Understanding distinguishing characteristics in this population is critical to improving outcomes. METHODS: Patients ≤36 months at diagnosis enrolled on the International DIPG Registry (IDIPGR) with central imaging confirmation were included. Presentation, clinical course, imaging, pathology and molecular findings were analyzed. RESULTS: Among 1183 patients in IDIPGR, 40 were eligible (median age: 29 months). Median OS was 15 months. Twelve patients (30%) were LTS, 3 (7.5%) very long-term survivors ≥5 years. Among 8 untreated patients, median OS was 2 months. Patients enrolled in the registry but excluded from our study by central radiology review or tissue diagnosis had median OS of 7 months. All but 1 LTS received radiation. Among 32 treated patients, 1-, 2-, 3-, and 5-year OS rates were 68.8%, 31.2%, 15.6% and 12.5%, respectively. LTS had longer duration of presenting symptoms (P = .018). No imaging features were predictive of outcome. Tissue and genomic data were available in 18 (45%) and 10 patients, respectively. Among 9 with known H3K27M status, 6 had a mutation. CONCLUSIONS: Children ≤36 months demonstrated significantly more LTS, with an improved median OS of 15 months; 92% of LTS received radiation. Median OS in untreated children was 2 months, compared to 17 months for treated children. LTS had longer duration of symptoms. Excluded patients demonstrated a lower OS, contradicting the hypothesis that children ≤36 months with DIPG show improved outcomes due to misdiagnosis.

Final results of the Choroid Plexus Tumor study CPT-SIOP-2000.

INTRODUCTION: Standards for chemotherapy against choroid plexus tumors (CPT) have not yet been established. METHODS: CPT-SIOP-2000 (NCT00500890) was an international registry for all CPT nesting a chemotherapy randomization for high-risk CPT with Carboplatin/Etoposide/Vincristine (CarbEV) versus Cyclophosphamide/Etoposide/Vincristine (CycEV). Patients older than three years were recommended to receive irradiation: focal fields for non-metastatic CPC, incompletely resected atypical choroid plexus papilloma (APP) or metastatic choroid plexus papilloma (CPP); craniospinal fields for metastatic CPC/APP and non-responsive CPC. High risk was defined as choroid plexus carcinoma (CPC), incompletely resected APP, and all metastatic CPT. From 2000 until 2010, 158 CPT patients from 23 countries were enrolled. RESULTS: For randomized CPC, the 5/10 year progression free survival (PFS) of patients on CarbEV (n = 20) were 62%/47%, respectively, compared to 27%/18%, on CycEV (n = 15), (intention-to-treat, HR 2.6, p = 0.032). Within the registry, histological grading was the most influential prognostic factor: for CPP (n = 55) the 5/10 year overall survival (OS) and the event free survival (EFS) probabilities were 100%/97% and 92%/92%, respectively; for APP (n = 49) 96%/96% and 76%/76%, respectively; and for CPC (n = 54) 65%/51% and 41%/39%, respectively. Without irradiation, 12 out of 33 patients with CPC younger than three years were alive for a median of 8.52 years. Extent of surgery and metastases were not independent prognosticators. CONCLUSIONS: Chemotherapy for Choroid Plexus Carcinoma is feasible and effective. CarbEV is superior to CycEV. A subset of CPC can be cured without irradiation.

Accuracy of central neuro-imaging review of DIPG compared with histopathology in the International DIPG Registry.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, <50% pontine involvement, focally exophytic morphology, sharply defined margins, and/or marked diffusion restriction throughout. RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

Glioma del nervio óptico en paciente adulto con presentación hemorrágica tratado mediante abordaje endoscópico transesfenoidal extendido / Optic nerve glioma in an adult patient with hemorrhagic presentation treated by an extended transsphenoidal endoscopic approach

El glioma del nervio óptico es una entidad de muy baja incidencia en pacientes adultos, lo cual impide tener suficiente información sobre historia natural y conducta terapéutica en este grupo etario. En el presente artículo comunicamos el caso de un paciente de 27 años de edad con compromiso agudo del nervio óptico izquierdo debido a hemorragia intra tumoral, forma de presentación muy poco común en este tipo de tumores. Se realizó la resección mediante un abordaje endoscópico transesfenoidal extendido, con preservación funcional de la vía óptica contralateral. La anatomía patológica confirmó astrocitoma pilocítico positivo para el rearreglo KIAA 1549-BRAF. y negativo para la mutación BRAF V600E. Teniendo en cuenta la histopatología y biología molecular en este caso, la estabilidad visual contralateral y la resección quirúrgica amplia, se decidió no realizar tratamiento adyuvante con radioterapia o quimioterapia. El objetivo de esta conducta fue evitar lesiones adicionales sobre el quiasma, nervio óptico contralateral y/o hipotálamo. Dada la escasa información existente en la literatura médica, el reporte de este caso podría contribuir con información adicional en el manejo y conducta terapéutica de este tipo de lesiones.

The optic nerve glioma is a very uncommon entity in adult patients, with little information about its natural history and therapeutical management. We report the case of a 27-year-old patient with acute involvement of the left optic nerve due to intratumoral hemorrhage, a very uncommon form of presentation in this type of tumor. Resection was performed using an extended transsphenoidal endoscopic approach, with functional preservation of the contralateral optic pathway. The histopathology confirmed positive pilocytic astrocytoma with KIAA 1549-BRAF rearrangement and without BRAF V600E mutation. Considering the histopathology and molecular biology, the contralateral visual stability and the wide surgical resection, it was decided not to perform further treatment. The purpose of this decision was to avoid additional damage to the chiasm, contralateral optic nerve and/or hypothalamus. Given the limited data available in medical literature, the report of this case could contribute with additional information on the management and therapeutic approach of this type of tumors

VHL Germline Mutations in Argentinian Patients with Clinical Diagnoses or Single Typical Manifestations of Type 1 von Hippel-Lindau Disease.

AIMS: von Hippel-Lindau (VHL) disease is caused by mutations in the VHL tumor suppressor gene. As tumors that develop in the context of VHL also occur in a sporadic context, the frequency of this syndrome may be underestimated. Our aim was to identify VHL gene mutations in Argentinian patients who fulfilled the clinical criteria for type 1 VHL disease and in patients with VHL-associated manifestations that did not meet these criteria. METHODS: We performed a retrospective cohort study, including patients who met current diagnostic criteria for type 1 VHL (Group 1, n = 19) and patients with VHL-associated manifestations that did not meet these criteria (Group 2, n = 21). Genomic DNA was extracted from peripheral blood leukocytes. Mutation analysis involved DNA sequencing, while large deletions were determined by universal primer quantitative fluorescent multiplex polymerase chain reaction (UPQFM-PCR) and multiplex ligation-dependent probe amplification (MLPA) analysis. RESULTS: VHL mutations were detected in 16/19 (84.2%) patients in Group 1 and included: gross deletions (4/16); nonsense mutations (6/16); frameshift mutations (4/16); missense mutations (1/16); and splicing mutations (1/16). Three of these mutations were novel. No alterations were found in 3 of 19 VHL patients. In Group 2, one nonsense VHL mutation was detected in a young patient with a solitary central nervous system hemangioblastoma without familial history. A study of 30 first-degree relatives revealed four carriers with VHL mutations. CONCLUSIONS: We found three novel mutations in the VHL gene in our population. Our results emphasize the importance of a complete genetic study of VHL to confirm type 1 VHL disease, not only in patients with clinical diagnostic criteria but also in those presenting a single typical manifestation.

Trastornos vasculares por antiangiogénicos / Vascular disorders due to antiangiogenic

Los eventos tromboembólicos cerebrales están asociados con secuelas permanentes y con deterioro de la calidad de vida. Sangrados, trastornos venosos y arteriales han sido descriptos con el uso de agentes antiangiogénicos. Presentamos un caso con sarcoma mixoide que desarrolló un accidente cerebrovascular isquémico mientras estaba siendo tratado con sorafenib. Repasamos también las drogas usadas en oncología que podrían estar asociadas con eventos tromboembólicos arteriales o venosos. Los médicos tratantes deberían monitorear a los pacientes que reciben agentes antiangiogénicos en relación a síntomas neurológicos y, en ausencia de otras etiologías, la pronta suspensión de la droga debería ser considerada (AU)

The cerebral thromboembolic events are linked with permanent sequelae and deterioration in quality of life. Bleeding, venous and arterial thromboembolic events have been described with antiangiogenics agents. We report a case with myxoid sarcoma that developed a cerebrovascular accident while on sorafenib treatment. We also reviewed drugs used in oncology that could be associated with arterial and venous thromboembolic events. Physicians should monitor patients receiving antiangiogenics agents for neurologic symptoms and in the absences of other etiology, prompt discontinuation of these drugs should be considered (AU)

Relapse and outcome patterns of patients with central nervous system mixed malignant germ cell tumors treated without irradiation: Findings from the third international central nervous system (CNS) germ cell tumor (GCT) study.

OBJECTIVES: To evaluate patterns of relapse and outcome in patients newly diagnosed with CNS Mixed Malignant GCT (MMGCT) treated initially with chemotherapy alone. METHODS: A retrospective chart review was conducted using all 25 patients enrolled on the International CNS GCT Study III, with at least 7 years follow-up for all surviving patients. RESULTS: Thirteen patients at diagnosis had CNS MMGCT by pathology and tumor markers (n = 11), or tumor markers alone (n = 2). Twelve received chemotherapy alone, one additionally receiving focal irradiation prior to relapse. Six patients (46%) relapsed (mean of 30.5 months; range 6-59 months), two beyond and four within the primary site alone. Three patients relapsed early (6-23 months from diagnosis), two with alpha-fetoprotein elevations and one without tumor markers assessed; all three expired of progressive disease at 2-10 months following initial relapse. Three patients relapsed late (37-59 months) without AFP elevations, one with pathologically pure germinoma, two with mild beta-human chorionic gonadotropin elevations; these patients survive disease-free at 86+, 94+, and 126+ months following additional treatment. CONCLUSIONS: Patients with CNS MMGCT relapsing following chemotherapy alone display two distinct patterns of recurrence and outcome; patients relapsing early possess MMGCT elements and have a dismal prognosis, while patients relapsing late do so with pure germinomatous elements and have an excellent outcome. Current cooperative group studies utilizing more localized fields of irradiation should monitor closely the patterns of relapse and outcome; late recurrences with germinomatous elements might be avoided by initial use of low-dose larger field irradiation in select patients.

Web-based survey of resources for treatment and long-term follow-up for children with brain tumors in developing countries.

INTRODUCTION: Information about pediatric survivors of brain tumors in developing countries is scant. PURPOSE: In this study, we aimed to investigate the availability of resources for treatment and long-term follow-up of children with central nervous system tumors in developing countries. MATERIALS AND METHODS: A web-based questionnaire on available services and follow-up of brain tumor survivors was posted at www.cure4kids.org , and registered users were invited to participate. RESULTS: A total of 140 evaluable responses from developing countries (n = 103) and high-income countries (n = 37) were obtained. There was a significant correlation between gross national income and the availability of services for treatment and follow-up and between patient load and the availability of some services. CONCLUSION: The resources for treatment and long-term follow-up of children with brain tumors need to be improved in developing countries.

Tumores oligodendrogliales: correlación entre el genotipo tumoral e imágenes de perfusión por RM / Oligodendroglial tumors: correlation between tumor genotype and perfusion magnetic resonance imaging

Objetivo: realizar una evaluación retrospectiva respecto de la correlación entre la técnica de perfusión (PWI) por resonancia magnética (RM), el volumen sanguíneo cerebral relativo (VSCr) y el genotipo tumoral, en pacientes con neoplasias oligodendrogliales grado II. Materiales y métodos: once pacientes (7 hombres y 4 mujeres), con un rango de edad entre los 28 y 64 años, con tumores oligodendrogliales (OD) grado II, fueron estudiados con RM convencional y PWI, con la finalidad de obtener un valor de VSCr. Se realizó el análisis genético en todos los pacientes para evaluar el estado de los cromosomas 1p/19q. Resultados: cinco pacientes con tumores ODs grado II (45%) presentaron un VSCr < 1,75 y ausencia de alteraciones en 1p/19q. Tres pacientes tenían oligoastrocitomas (OA), 2 de ellos con alteraciones en 1p/19q y el restante con 1p/19q intacto. Dos de los pacientes con gliomas mixtos, uno con alteración en 1p/19q y el otro con 1p/19q intacto, presentaron un VSCr> 1,75, mientras que en el paciente restante con glioma mixto y deleción en 1p/19q, el VSCr fue de < 1,75. Dos pacientes con ODs grado II presentaron un VSCr> 1,75, uno con 1p/19q intacto y el restante con deleción en 1p/19q. El último paciente presentó un OD grado II con un VSCr< 1,75 y pérdida de 1p/19q. Conclusiones: aproximadamente el 45% de los pacientes con los cromosomas 1p/19q intactos mostró un VSCr< 1,75, lo que sugiere una neoangiogénesis tumoral limitada. Estos hallazgos podrían ser de utilidad para monitorear respuesta a agentes antiangiogénicos. Los estudios realizados en series mayores podrían proporcionar información valiosa antes de la cirugía y contribuir a un mejor manejo de estos pacientes.

Objective: To perform a retrospective assessment of the correlation between perfusion MR imaging, relative cerebral blood volume (rCBV) and genotype in patients with grade II oligodendroglial neoplasms. Materials and methods: Eleven patients (7 men and 4 women), age range: 28-64 years, with grade II oligodendroglial tumors (OD) were studied using conventional MR and perfusion MR imaging (rCBV). Genetic analysis was carried out in all patients to assess -1p/-19q genotype status. Results: Five patients with grade II oligodendroglial tumors (45%) presented rCBV < 1.75 and intact 1p/19q. Three patients had mixed gliomas, two of them had deletion in 1p/19q, and the other presented intact 1p/19 q. rCBV was > 1.75 in two patients and < 1.75 in the other patient. Two patients with grade II oligodendroglioma had an rCBV > 1.75, one with intact 1p/19q, and the other with deletion. The last patient presented a grade II oligodendroglial tumor with rCBV < 1.75 and 1p/19q loss. Conclusions: Approximately 45% of patients with intact 1p/19q showed rCBV < 1.75, suggesting limited tumor neoangiogenesis. These findings could be important for the antiangiogenic therapy follow-up. Studies in larger series could provide valuable information prior to surgery and contribute to a better management of these patients.

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

BACKGROUND: 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. METHODS: Between January 2001 and December 2004 newly diagnosed patients with CNS GCT were treated with one of two risk-tailored chemotherapy regimens. Twenty-five patients aged 4 months to 24.5 years were stratified: Regimen A consisted of 4-6 cycles of carboplatin/etoposide alternating with cyclophosphamide/etoposide for low risk (LR) localized germinoma with normal cerebrospinal fluid (CSF) and serum tumor markers. Regimen B consisted of 4-6 cycles of carboplatin/cyclophosphamide/etoposide for intermediate-risk (IR) germinoma with positive human chorionic gonadotrophin-beta (HCGbeta) and/or CSF HCGbeta <50 mIU/ml and high-risk (HR) biopsy-proven non-germinomatous malignant elements (MMGCT) or elevated serum/CSF alpha-fetoprotein and/or HCGbeta serum/CSF >50 mIU/ml. RESULTS: Eleven patients were classified as LR, 2 IR, and 12 HR. Seventeen (68%) patients achieved complete radiographic and marker responses after two courses and 19 (76%) after four courses of chemotherapy. Eleven patients relapsed at a mean of 30.8 months; eight of them subsequently received irradiation. The 6-year event free and overall survival for the 25 patients was 45.6% and 75.3%, respectively. CONCLUSION: These intensive chemotherapy regimens proved less effective than irradiation containing regimens. Our results indicate that, at the present time, standard treatment for CNS GCT continues to include irradiation either alone or combined with chemotherapy for pure germinomas and with chemotherapy for those with MMGCT.

Evaluation of the exposure equivalence of oral versus intravenous temozolomide.

PURPOSE: Oral temozolomide is approved in many countries for malignant glioma and for melanoma in some countries outside the USA. This study evaluated the exposure equivalence and safety of temozolomide by intravenous infusion and oral administration. METHODS: Subjects with primary central nervous system malignancies (excluding central nervous system lymphoma) received 200 mg/m(2) of oral temozolomide on days 1, 2 and 5. On days 3 and 4, subjects received 150 mg/m(2) temozolomide either as a 90-min intravenous infusion on one day or by oral administration on an alternate day. RESULTS: Ratio of log-transformed means (intravenous:oral) of area under the concentration-time curve and maximum concentration of drug after dosing for temozolomide and 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) met exposure equivalence criteria (90% confidence interval = 0.8-1.25). Treatment-emergent adverse events were consistent with those reported previously in subjects with recurrent glioma treated with oral temozolomide, except for mostly mild and transient injection site reactions with intravenous administration. CONCLUSIONS: This study demonstrated an exposure equivalence of a 90-min intravenous infusion of temozolomide and an equivalent oral dose.

Atypical choroid plexus papilloma: clinical experience in the CPT-SIOP-2000 study.

Atypical choroid plexus papilloma (APP) represents a novel intermediate-grade subtype of choroid plexus tumor (CPT), the clinical outcome of which has not been described yet. We present the first analysis of a group of APP patients enrolled in the ongoing CPT-SIOP-2000 study of CPTs. A worldwide registration and a randomized trial for those patients who require chemotherapy started in 2000. For APP, maximal surgical resection was recommended. After surgery, patients who had undergone complete resection were observed, whereas patients with incompletely resected or metastasized APP were treated with six chemotherapy courses (etoposide and vincristine, combined with either carboplatin or cyclophosphamide). Risk-adapted radiotherapy was given only to patients older than 3 years of age. Of the 106 patients with a centrally confirmed CPT histology, 30 had APP, 42 CPP and 34 CPC. APP patients were significantly younger (median = 0.7 years) than patients with CPP or CPC (both medians = 2.3 years). Complete resection was achieved in 68 (64%) patients (79% in CPP, 63% in APP, and 47% in CPC). Metastases were present at diagnosis in 17% of APP patients, 5% of CPP patients, and 21% of CPC patients. All nine APP patients who received postoperative chemotherapy showed an early response after two cycles: two had complete remission, four had partial response, and three had stable disease. In the observation group of 15 patients, one event was seen, and all patients were alive. In the treatment group, one patient with a metastasized tumor and incompletely resected APP died. While APP was defined histologically, median percentages of both the Ki-67/MIB-1 proliferation marker and the p53 tumor suppressor protein increased across the three histological subtypes (from CPP to APP and then CPC), suggesting that the subtypes comprise an ordinal categorization of increasingly severe CPT tumors. This ordering was reiterated by clinical outcome in the 92 patients treated per the study protocol, with 5-year EFS rates of 92% in 39 CPP patients, 83% in 24 APP patients, and 28% in 29 CPC patients. A similar ordering was seen when all 106 patients were evaluated for EFS. APP responded favorably to chemotherapy. The intermediate position of APP between CPP and CPC was supported by the clinical data.

The prognostic value of tumor markers in newly diagnosed patients with primary central nervous system germ cell tumors.

BACKGROUND: To determine the impact of diagnostic serum and/or cerebrospinal fluid (CSF) alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (b-HCG) elevations on survival in newly diagnosed patients with central nervous system germ cell tumors (CNS GCT) treated with chemotherapy with the intent to avoid irradiation. PROCEDURE: Seventy-five patients with newly diagnosed CNS GCT enrolled in two sequential internationally conducted clinical trials with serum and CSF AFP and b-HCG levels available from initial diagnosis were retrospectively analyzed. Subjects received platinum based chemotherapy and were followed with serial imaging and tumor marker evaluations. RESULTS: The 5-year overall survival (OS) and event free survival (EFS) for patients with normal tumor markers compared with those with elevated markers at diagnosis was 78% (95% CI 51-91%) versus 60% (95% CI 46-72%) (P = 0.08) and 22% (95% CI 7-43%) versus 28% (95% CI 16-40%) (P = 0.68). The hazard ratio of death for patients with elevated markers was 1.9 times as high as that for those with normal markers (95% CI 0.58-6.5) after adjusting for other baseline characteristics. There was no observed difference in survival among patients with histologically confirmed germinomas, irrespective of level of b-HCG. CONCLUSIONS: Patients with elevated tumor markers appear to have poorer OS independent of tumor histology, although these differences do not reach statistical significance (P < or = 0.05). No differences were observed in EFS between groups likely due to the poor response of chemotherapy only approach to patients with normal markers. b-HCG elevations in biopsy proven germinomas do not seem to alter a patient's prognosis.

Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the "Head Start" I and II protocols.

PURPOSE: To determine the survival of infants and young children with non-metastatic medulloblastoma using intensive myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). METHODS: Twenty-one children less than 3 years old at diagnosis with non-metastatic medulloblastoma were enrolled on two identical serial studies, "Head Start" I and "Head Start" II. After surgery, patients received five cycles of induction chemotherapy consisting of vincristine, cisplatin, cyclophosphamide and etoposide. Following induction, all patients underwent myeloablative chemotherapy using carboplatin, thiotepa and etoposide with AuHCR. Irradiation was used only at relapse. RESULTS: The 5-year event-free (EFS) and overall survival (OS) rates (+/-SE) for all patients, patients with gross total resection, and patients with residual tumor were 52 +/- 11% and 70 +/- 10%, 64 +/- 13% and 79 +/- 11%, and 29 +/- 17% and 57 +/- 19%, respectively. The 5-year EFS and OS ( +/- SE) for patients with desmoplastic and classical medulloblastoma were 67 +/- 16% and 78 +/- 14%, and 42 +/- 14 and 67 +/- 14%, respectively. There were four treatment related deaths. The majority of survivors (71%) avoided irradiation completely. Mean intellectual functioning and quality of life (QoL) for children surviving without irradiation was within average range for a majority of survivors tested. CONCLUSION: This strategy of brief intensive chemotherapy for young children with non-metastatic medulloblastoma eliminated the need for craniospinal irradiation 52% of the patients, and may preserve QoL and intellectual functioning. The excellent survival rates are somewhat dampened by high toxic mortality.

Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and II experience.

BACKGROUND: Children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNET) have poor outcomes compared to medulloblastoma patients, despite similar treatments. In an effort to improve overall survival (OS) and event-free survival (EFS) and to decrease radiation exposure, the Head Start (HS) protocols treated children with newly diagnosed sPNET utilizing intensified induction chemotherapy (ICHT) followed by consolidation with myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR). PROCEDURES: Between 1991 and 2002, 43 children with sPNET were prospectively treated on two serial studies (HS I and II). After maximal safe surgical resection, patients on HS I and patients with localized disease on HS II were treated with five cycles of ICHT (vincristine, cisplatin, cyclophosphamide, and etoposide). Patients on HS II with disseminated disease received high-dose methotrexate during ICHT. If the disease remained stable or in response, patients received a single cycle of high-dose myeloablative chemotherapy followed by AuHCR. RESULTS: Five-year EFS and OS were 39% (95%CI: 24%, 53%) and 49 (95%CI: 33%, 62%), respectively. Non-pineal sPNET patients faired significantly better than those patients with pineal sPNETs. Metastasis at diagnosis, age, and extent of resection were not significant prognostic factors. Sixty percent of survivors (12 of 20) are alive without exposure to radiation therapy. CONCLUSIONS: ICHT followed by AuHCR in young patients with newly diagnosed sPNET appears to not only provide an improved EFS and OS for patients who typically have a poor prognosis, but also it successfully permitted deferral and elimination of radiation therapy in a significant proportion of patients.

El desarrollo e implementación de la resonancia magnética intraoperatoria en neurocirugía (remain) y su aplicación en 83 intervenciones en la Argentina / Development of REMAIN for neurosurgery and application in 83 operative intervention in Argentina

Objective: To show implementation and development of an operating room in which we operated 83 patients using intraoperative MRI (REMAIN). Method: We used a side-opening-magnet, 0.23 Tesla, installed in a surgical area specially designed with all the advances of the modern operating rooms. Results: A great variety of neuro-surgical procedures can be made with REMAIN controls. The obtained images are clear, without devices and with an excellent definition of the anatomical structures and the pathology, that allows the neurosurgeon to make more precise and safer interventions. Conclusions: The images of REMAIN in a surgical scope, make possible that injuries can be identified and located with absolute precision. It is particularly useful in determining with exactitude the tumor-like limits, optimizing the surgical approaches, obtaining complete extirpations of brain injuries and controlling the possible intraoperative complications.

Outcome for young children newly diagnosed with ependymoma, treated with intensive induction chemotherapy followed by myeloablative chemotherapy and autologous stem cell rescue.

BACKGROUND: The purpose of this study is to investigate the efficacy of an intensive chemotherapy induction regimen followed by myeloablative chemotherapy and autologous hematopoietic stem cell rescue (AHSCR) in children with newly diagnosed ependymoma. PATIENTS AND METHODS: Twenty-nine children less than 10 years of age at diagnosis of ependymoma were enrolled on the "Head Start" studies. Twenty-four patients with localized disease received an induction regimen including five cycles of chemotherapy (cisplatin, vincristine, etoposide cyclophosphamide, and high dose methotrexate for patients with metastatic disease). Following induction, individuals without evidence of disease proceeded to marrow-ablative chemotherapy (thiotepa, carboplatin, and etoposide) with AHSCR. RESULTS: The estimated 5-year event free survival (EFS) and overall survival (OS) from diagnosis were 12% (+/-6%) and 38% (+/-10%), respectively. The toxic mortality amongst this group of 29 patients was 10.3%. Younger age (less than 18 months at diagnosis) was the only statistically significant prognostic factor. The estimated 5-year OS rate for the five patients with metastatic disease at presentation was 80% (+/-18%). Overall, radiation-free survival at 5 years from diagnosis was 8% (+/-5%). CONCLUSIONS: The use of an intensive induction chemotherapy regimen including myeloablative chemotherapy followed by AHSCR in newly diagnosed young children with ependymoma is not superior to other previously reported chemotherapeutic strategies.

Consenso para el tratamiento de las metástasis cerebrales / Consensus about cerebral metastases treatment

El avance en la terapia oncológica ha hecho del tratamiento de las metástasis cerebrales un factor primordial en el tiempo de sobrevida y la calidad de vida de los pacientes con cáncer. A pesar de que existen numerosas publicaciones sobre el tema, no existe todavía un consenso sobre la mejor estrategia terapéutica, problablemente por la heterogeneidad de la población en términos de estado funcional, tipo de neoplasia, control sistémico de la enfermedad y número y localización de las lesiones en el sisteman nervioso central. Nuestro objetivo es presentar recomendaciones generales basadas en un análisis racional para guiar el manejo práctico de las metástasis cerebrales. Con este propósito, un equipo multidisciplinario integrado por neurocirujanos, neurooncólogos, neuropatólogos, radioterapeutas y neurólogos fue convocado para conducir una búsqueda minuciosa en las publicaciones en inglés y español a través de PubMed (1980-2006) coincidiendo con el comienzo del empleo de la resonancia magnética en la práctica médica. Se seleccionaron revisiones y artículos originales con un n=o>a 20. También se incluyeron capítulos de libros escritos por expertos conocidos. La evaluación de la literatura así como la experiencia de los autores permitió el desarrollo del "Consenso para el Tratamiento de las Metástasis Cerebrales". Finalmente los autores esperan que elpresente trabajo contribuya a un abordaje multidisciplinario para el manejo de las metástasis cerebrales con recomendaciones simples y prácticas y probablemente estimule nuevos desarrollos en este campo. Palabras clave: cirugía, metástasis cerebrales, quimioterapia, radioterapia

The advances in oncological therapies has made brain metastases treatment a major factor influencing the survival time and the quality of life patients with cancer. Although there are numerous publications on the issue, there is no consensus about the best treatment strategy. This is probably due to population heterogeneity in terms of functional status, type of neoplasia, control of the systemic disease, and the number and localization of the lesions in the cetral nervous system. Our objective is to present general recommendations based on a rational analysis in order to guide the practical management of brain metastases. With this purpose, a multidisciplinary team composed by neurosurgeons, neurooncologists, neuropathologist, radiotherapist and neurologists were brought together to conduct athrough search in english and spanish publications through PubMed (1980-2006). The starting period was set at the beginning of the use of magnetic resonance in medical practice. Reviews and original articles with n=or>20 were selected. Also, book chapters of renowned authors in the different consulted areas were included. The assessment of the literature, in addition to the experience of the authors allowed the development of "Consensus for the treatment of Brain Metastases". Finally, the authors expect that the present work will contribute to the multidisciplinary approach in the management of brain metastases with simple and practical recommendations, and probably stimulating future developments in this field. Key words: cerebral metastasis, chemotherapy, radiotherapy, surgery.

Sonic hedgehog is produced by follicular dendritic cells and protects germinal center B cells from apoptosis.

The Hedgehog (Hh) signaling pathway is involved in the development of many tissues during embryogenesis, but has also been described to function in adult self-renewing tissues. In the immune system, Sonic Hedgehog (Shh) regulates intrathymic T cell development and modulates the effector functions of peripheral CD4(+) T cells. In this study we investigate whether Shh signaling is involved in peripheral B cell differentiation in mice. Shh is produced by follicular dendritic cells, mainly in germinal centers (GCs), and GC B cells express both components of the Hh receptor, Patched and Smoothened. Blockade of the Hh signaling pathway reduces the survival, and consequently the proliferation and Ab secretion, of GC B cells. Furthermore, Shh rescues GC B cells from apoptosis induced by Fas ligation. Taken together, our data suggest that Shh is one of the survival signals provided by follicular dendritic cells to prevent apoptosis in GC B cells.

Intensive cisplatin and cyclophosphamide-based chemotherapy without radiotherapy for intracranial germinomas: failure of a primary chemotherapy approach.

PURPOSE: High rates of overall and event-free survival have been reported in patients with intracranial germinomas treated with craniospinal radiotherapy. More recently, similar results have been reported with chemotherapy combined with radiotherapy to more localized treatment volumes. Our interest in exploring chemotherapy without radiotherapy in patients with CNS germinomas was based on concerns about the late sequelae of radiotherapy to the brain or neuraxis and also the well documented success of chemotherapy alone in patients with disseminated extracranial germinomas. The primary objective of this study was to determine whether intensive cisplatin and cyclophosphamide-based combination chemotherapy, without radiotherapy, was effective in patients with CNS germinomas. PATIENTS AND METHODS: Nineteen patients were enrolled, ranging in age from 1 to 24 years (median, 14 years). Thirteen were male. Nine had diabetes insipidus. Therapy comprised two courses of Regimen 'A' (cisplatin, etoposide, cyclophosphamide, and bleomycin) followed by MRI evaluation. Patients achieving a complete remission (CR) completed all planned therapy with two courses of regimen 'B' (carboplatin, etoposide, and bleomycin). Patients achieving less than a CR received two courses of Regimen 'B' followed by another evaluation. Those in CR after four courses of treatment received one additional course of Regimen 'A' and Regimen 'B', while those not in CR after four treatment courses underwent second look surgery and/or radiation therapy. RESULTS: Eleven of 11 patients with residual postoperative disease assessable for response achieved a CR. With a median follow-up of 6.5 years, eight out of 19 (0.42) patients remain in CR 1 without radiotherapy and another three patients are in stable second or subsequent remissions. Three patients died from treatment-related toxicity and another died in CR 1 from an uncharacterized leukoencephalopathy. The 5-year event-free survival (EFS) was 0.47 +/- 0.23 and 5-year overall survival (OS) was 0.68 +/- 0.22. CONCLUSIONS: Intensive cisplatin and cyclophosphamide-based chemotherapy was effective in achieving remissions, however, the long-term outcome using this treatment program was unsatisfactory and associated with unacceptable morbidity and mortality, particularly in patients with diabetes insipidus.