Lígia Castro

Frequency of TERT promoter mutations in human cancers

Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase.

Adult-onset leukodystrophy with axonal spheroids

We report two cases of adult-onset leukodystrophy with axonal spheroids in a brother and sister, one with an autopsy, the other with a cerebral biopsy. Symptoms developed at 24 and 33years. The sister died within four years, her brother in 2 and a half. Her brain showed a large lesion in the frontal centrum semiovale extending through the corpus callosum and shading off into the normal appearing U-fibers. With routine stains axonal spheroids were most easily detected in the mildly affected regions, although stains for neurofilaments showed that they were actually more numerous, though more irregular in shape, where the lesions were more severe. Axons and myelin appeared equally affected. Pigmented cells were absent. Electron microscopy on the cerebral biopsy showed that the spheroids contained neurofilaments and neurotubules, mitochondria and degenerate mitochondria, with a suggestion of polarity such that neurofilaments were more common in the proximal part of spheroids. Many other axons were found whose size was only slightly increased although they were filled with sacs of abnormal granular material which were probably derived from mitochondria. The anterior commissure and the corticospinal tracts in the spinal cord of the sister showed fiber loss and large vacuoles within which occasional intact axons could be identified. This was considered to represent intramyelin edema. In the cerebral biopsy one vacuole arising from myelin splitting was found in confirmation of this hypothesis. We conclude that both myelin and axons are damaged, although the lesions of myelin are conditioned by axonal abnormalies in this genetic disease.

The prognostic impact of TERT promoter mutations in glioblastomas is modified by the rs2853669 single nucleotide polymorphism

Human hotspot TERT promoter (TERTp) mutations have been reported in a wide range of tumours. Several studies have shown that TERTp mutations are associated with clinicopathological features; in some instances, TERTp mutations were considered as biomarkers of poor prognosis. The rs2853669 SNP, located in the TERT promoter region, was reported to modulate the increased TERT expression levels induced by the recurrent somatic mutations. In this study we aimed to determine the frequency and prognostic value of TERTp mutations and TERT rs2853669 SNP in 504 gliomas from Portuguese and Brazilian patients. TERTp mutations were detected in 47.8% of gliomas (216/452). Glioblastomas (GBM) exhibited the highest frequency of TERTp mutations (66.9%); in this glioma subtype, we found a significant association between TERTp mutations and poor prognosis, regardless of the population. Moreover, in a multivariate analysis, TERTp mutations were the only independent prognostic factor. Our data also showed that the poor prognosis conferred by TERTp mutations was restricted to GBM patients carrying the rs2853669 A allele and not in those carrying the G allele. In conclusion, the presence of TERTp mutations was associated with worse prognosis in GBM patients, although such association depended on the status of the rs2853669 SNP. The status of the rs2853669 SNP should be taken in consideration when assessing the prognostic value of TERTp mutations in GBM patients. TERTp mutations and the rs2853669 SNP can be used in the future as biomarkers of glioma prognosis.

Lung cancer: atypical brain metastases mimicking neurocysticercosis.

The authors describe a case of a 47-year-old male smoker with a 3-month history of hearing loss, tinnitus and dizziness. Physical examination revealed neurosensory hearing loss. Small rounded hypodensities without mass effect were evident in a computed tomography scan of the head, confirmed by brain magnetic resonance imaging as multiple cystic lesions in both cerebral and cerebellar hemispheres, without perilesional edema or gadolinium enhancement, suggestive of neurocysticercosis. Extraparenchymal involvement was also noted. Albendazole and dexamethasone were started. As a chest radiograph showed a bilateral reticulonodular pattern, a bronchoscopy was performed showing normal results. However, transbronchial biopsy revealed lung adenocarcinoma. Thoracoabdominopelvic computed tomography scan showed secondary lung and bone lesions. Since brain lesions were not suggestive of secondary tumor lesions, a brain biopsy was performed confirming metastatic disease. This case illustrates some peculiar imagiological features of brain metastases in lung cancer, indicating that sometimes invasive procedures are required to establish a definitive diagnosis.

Voluminoso hamartoma hipotalámico en un niño de 5 meses: Epilepsia y cirugía

Resumen Los autores presentan el caso clinico de un nino de 5 meses de edad con un hamartoma hipotalamico, con crisis gelasticas persistentes y refractarias a una amplia combinacion de diferentes antiepilepticos. Se decidio realizar una remocion parcial de la lesion tumoral para descompresion y disminucion del estimulo epileptogenico, en un intento de control quirurgico de las crisis. La terapeutica quirurgica se revelo como una opcion valida en el tratamiento de las crisis gelasticas incontrolables con la terapeutica medica.

Biopsias estereotáxicas: Revisión de una serie de 80 casos. ¿Está justificada la realización de una tomografía computarizada (TC) en las primeras horas tras el procedimiento?

Resumen Objetivo Evaluar la sensibilidad diagnostica de las biopsias estereotaxicas (BE) realizadas en el Servicio de Neurocirugia del Hospital de Sao Joao para el diagnostico de lesiones intracerebrales y determinar la incidencia de hemorragia postoperatoria. Material y metodos Los autores revisaron 80 casos consecutivos de pacientes sometidos a una biopsia estereotaxica, en 63 de los cuales se realizo TC cerebral de control entre 4 y 6 horas despues del procedimiento. Resultados La BE fue diagnostica en 75 de los 80 pacientes lo que corresponde al 93,7% de los casos. En 5 pacientes (6,25%) los resultados fueron inconcluyentes. Se observo una morbilidad significativa en 4 casos (5,8%) y no hubo mortalidad. En 25 pacientes las TC de control no mostro alteraciones significativas y en 27 solo mostro una hemorragia residual. En los restantes 11 pacientes la hemorragia fue considerada significativa. Conclusiones La BE es un metodo diagnostico sensible y seguro para las lesiones cerebrales. La realizacion de una TC cerebral precoz despues del procedimiento permite identificar un subgrupo de pacientes sin hemorragia intracerebral que podrian ser dados de alta en el mismo dia.

Second-Line Chemotherapy in Recurrent Glioblastoma: A 2-Cohort Study

Background: Glioblastoma (GB) is the most common malignant primary central nervous system tumor in adults. Standard-of-care therapy includes surgical resection, radiotherapy and temozolomide, but nearly all patients experience disease progression. The purpose of this study was to describe 2 cohorts of patients with recurrent GB submitted to second-line treatment with procarbazine/lomustine/vincristine (PCV) or bevacizumab/irinotecan (BI). Material and Methods: Retrospective analysis of GB patients treated in our center with PCV or BI, after progression with temozolomide, between 2004 and 2012. Results: Among 60 patients, 41 were treated with BI and 19 with PCV. According to the Macdonald criteria, the overall response rate in the BI group was 66% (n = 27) while it was 11% (n = 2) in the PCV group. The median progression-free survival was 5 and 3 months in the BI and PCV group, respectively. The median overall survival (OS) since second-line chemotherapy was 9 months in the BI group and 5 months in the PCV group. The latter group had a worse toxicity profile (grade 3-4: 52.6% vs. 22.0%; grade 1-2: 89.5% vs. 68.3%). Conclusions: The BI cohort had higher response rates, almost twice the OS and a lower degree of toxicity in contrast to the PCV group. The small number of patients and historical cohorts limits these comparisons.

Epithelioid sarcoma of the spine: Case report and literature review

Epithelioid sarcomas are rare mesenchymal neoplasms mainly arising in the limbs of young adults. We report the case of a 24-year-old male presenting low back pain radiating to both lower limbs, constipation and urinary retention. The MRI scan showed an intraspinal lesion extending from L4 to S2. Surgery resulted in gross total removal of the extradural lesion and partial removal of the intradural component. The immunohistological study of the lesion was consistent with an epithelioid sarcoma. The patient was submitted to radiotherapy and chemotherapy, but a local recurrence of the lesion and dissemination along the neuraxis were observed 3 months after surgery. Despite treatment, the patient died 4 months after the surgical procedure due to multiorgan failure. Despite there being isolated reports of epithelioid sarcomas appearing in the spine, this is, to our knowledge, the first case with intradural extension.

Spinal intramedullary ependymal cyst - Current concepts for diagnosis and surgical management

Abstract We describe a case of a 48-year-old woman who presented with neck pain and progressive left arm weakness. Magnetic Resonance Imaging showed a cervical intramedullary cystic lesion. The lesion was removed and neuropathological analysis revealed an ependymal cyst.

Analysis of a synchronous gliosarcoma and meningioma with long survival: A case report and review of the literature

Background: The simultaneous occurrence of multiple intracranial neoplasms has been reported, especially in genetic familial syndromes and after cranial irradiation. In the absence of these etiologic factors, some reports showed simultaneous occurrence of glioblastoma and meningioma but the association between gliosarcoma and meningioma is unknown. Case Description: We report a case of a 51-year-old woman with synchronous gliosarcoma and meningioma in whom extensive immunohistochemical characterization and molecular profile was performed. The gliosarcoma recurred 21 months after the first resection, reaching 3 years of overall survival. A molecular characterization of all three lesions was performed. None of the lesions showed the presence of mutations in TP53 and BRAF genes. MGMT analysis showed the presence of loss of expression associated with promoter hypermethylation in both gliosarcoma lesions. EGFR overexpression and gene amplification was found only in the recurrent gliosarcoma. Conclusion: The immunohistochemistry and molecular data of this unique case, suggest the distinct clonal origin of meningioma and gliosarcoma lesions, and the association of MGMT methylation with the presumable favorable prognosis observed.