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- A Rare Case of Spontaneous Remission and Relapse of a Primary Central Nervous System LymphomaPublication . Ramos, R; Fernandes, JS; Almeida, M; Almeida, RPrimary central nervous system lymphoma remission after steroid treatment is a well-known phenomenon, but remission without any type of treatment is extremely rare. We present a rare case of spontaneous remission of a diffuse large B-cell lymphoma of the central nervous system as well as its subsequent reappearance in another location. The atypical presentation misled the neurosurgeons and neurologists, delaying diagnosis and treatment. The patient underwent brain biopsy after the relapse and started radiotherapy and chemotherapy with cytarabine + methotrexate + rituximab. As of 32 months after the diagnosis, the patient remained asymptomatic, with no focal neurological deficits and the disease in complete remission. A PubMed search of the literature up to June 2017 regarding spontaneous remission central nervous system lymphoma was also carried out.
- WNT6 is a novel oncogenic prognostic biomarker in human glioblastomaPublication . Gonçalves, CS; Vieira de Castro, J; Pojo, M; Martins, EP; Queirós, S; Chautard, E; Taipa, R; Pires, MM; Pinto, AA; Pardal, F; Custódia, C; Faria, CC; Clara, C; Reis, RM; Sousa, N; Costa, BMGlioblastoma (GBM) is a universally fatal brain cancer, for which novel therapies targeting specific underlying oncogenic events are urgently needed. While the WNT pathway has been shown to be frequently activated in GBM, constituting a potential therapeutic target, the relevance of WNT6, an activator of this pathway, remains unknown. Methods: WNT6 protein and mRNA levels were evaluated in GBM. WNT6 levels were silenced or overexpressed in GBM cells to assess functional effects in vitro and in vivo. Phospho-kinase arrays and TCF/LEF reporter assays were used to identify WNT6-signaling pathways, and significant associations with stem cell features and cancer-related pathways were validated in patients. Survival analyses were performed with Cox regression and Log-rank tests. Meta-analyses were used to calculate the estimated pooled effect. Results: We show that WNT6 is significantly overexpressed in GBMs, as compared to lower-grade gliomas and normal brain, at mRNA and protein levels. Functionally, WNT6 increases typical oncogenic activities in GBM cells, including viability, proliferation, glioma stem cell capacity, invasion, migration, and resistance to temozolomide chemotherapy. Concordantly, in in vivo orthotopic GBM mice models, using both overexpressing and silencing models, WNT6 expression was associated with shorter overall survival, and increased features of tumor aggressiveness. Mechanistically, WNT6 contributes to activate typical oncogenic pathways, including Src and STAT, which intertwined with the WNT pathway may be critical effectors of WNT6-associated aggressiveness in GBM. Clinically, we establish WNT6 as an independent prognostic biomarker of shorter survival in GBM patients from several independent cohorts. Conclusion: Our findings establish WNT6 as a novel oncogene in GBM, opening opportunities to develop more rational therapies to treat this highly aggressive tumor.
- Effects of the functional HOTAIR rs920778 and rs12826786 genetic variants in glioma susceptibility and patient prognosisPublication . Xavier-Magalhães, A; Oliveira, AI; Vieira de Castro, J; Pojo, M; Gonçalves, CS; Lourenço, T; Viana-Pereira, M; Costa, S; Linhares, P; Vaz, R; Nabiço, R; Amorim, J; Pinto, AA; Reis, RM; Costa, BMAbnormal expression of the long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) is oncogenic in several human cancers, including gliomas. The HOTAIR single nucleotide polymorphisms (SNPs) rs920778 (C > T) and rs12826786 (C > T) present in the intronic enhancer and promoter regions of HOTAIR, respectively, are associated with expression, cancer susceptibility, and patient prognosis in some tumor types. However, the relevance of these HOTAIR SNPs has not been studied in glioma. Here, we report a case-control study comprising 177 Portuguese glioma patients and 199 cancer-free controls. All subjects were genotyped by PCR and restriction fragment length polymorphism (RFLP). No statistically significant differences were found in the genotype or allele distributions of either rs920778 or rs12826786 between glioma patients and controls, suggesting these SNPs are not associated with glioma risk. No significant associations were found between rs920778 variants and HOTAIR expression levels, while rs12826786 CT genotype was associated with increased intratumoral HOTAIR RNA levels when compared to TT genotype (p-value = 0.04). Univariate (Log-rank) and multivariate (Cox proportional) analyses showed both rs920778 CT and rs12826786 CT genotypes were significantly associated with longer overall survival of WHO grade III anaplastic oligodendroglioma patients. Our results suggest that HOTAIR SNPs rs920778 and rs12826786 do not play a significant role in glioma susceptibility, but may be important prognostic factors in anaplastic oligodendroglioma patients. Future studies are warranted to validate and expand these findings, and to further dissect the importance of these SNPs in glioma.
- Herniação Meningoencefálica do Osso TemporalPublication . Miranda, D; Pereira, S; Ramos, R; Pinto, A; Vilarinho, S; Dias, LIntrodução: As herniações meningoencefálicas do osso temporal correspondem à presença de parênquima encefálico e/ou meninges prolapsados através de um defeito ósseo temporal. Trata-se de uma condição rara, podendo ter consequências catastróficas para o paciente. Descrição de Caso: Doente de 69 anos, sexo feminino, com antecedentes pessoais de otite média crónica, submetida a cirurgia otológica, hipertensão arterial e neoplasia da mama. Admitida no serviço de urgência por convulsões tónico-clónico generalizadas secundárias a meningoencefalite com ponto de partida em foco infecioso otológico. A investigação imagiológica revelou a presença de uma herniação meningoencefálica, que foi corrigida cirurgicamente por equipa multidisciplinar de Otorrinolaringologia e Neurocirurgia. Discussão/Conclusões: O tratamento cirúrgico tem por objetivo a remoção de tecidos meningoencefálicos herniados, reparação do defeito ósseo e recuperação da audição. O tamanho e localização do defeito ósseo e da herniação meningoencefálica são fatores decisivos na escolha da via de abordagem cirúrgica.
- Herniação Meningoencefálica do Osso TemporalPublication . Miranda, D; Pereira, S; Ramos, R; Pinto, A; Vilarinho, S; Dias, LBackground: Temporal bone meningoencephalic herniations correspond to the presence of brain parenchyma and/or prolapsed meninges through a bone defect. It is a rare condition with potentially catastrophic consequences for the patient. Case Description: Sixty-nine year-old female patient with past medical history of chronic otitis media submitted to otologic surgery, arterial hypertension and breast cancer. Admitted to emergency department with tonic-clonic seizures secondary to meningoencephalitis triggered by otologic infection. The imaging investigation revealed the presence of a meningoencephalic herniation that was surgically treated by a multidisciplinary ENT and neurosurgery team. Discussion/Conclusions: Surgical treatment aims to remove meningoencephalic herniated tissue, bone defect repair and hearing recovery. Size and location of bone defect and meningoencephalic herniation are decisive factors in surgical approaches choice.
- Incisão sublabial versus columelar no acesso trans-septal para cirurgia trans-esfenoidal microscópica da hipófise. Estudo retrospectivoPublication . Guimarães, J; Santos, J; Miranda, D; Carvalho Moreira, F; Marçal, N; Pereira, G; Marques, O; Almeida, R; Vilarinho, S; Frias, A; Alegria, C; Pratas, RObjectivos: Comparar a incisão sublabial com a incisão columelar no acesso trans-septal para cirurgia trans- -esfenoidal microscópica da hipófise, quanto às complicações perioperatórias e sequelas observadas. Desenho do estudo: Estudo retrospectivo. Material e métodos: Revisão dos registos clínicos de 50 doentes submetidos a cirurgia trans-esfenoidal microscópica para ressecção de adenoma da hipófise, no Hospital de Braga, entre Julho de 2007 e Novembro de 2010. Foram colhidos e avaliados dados demográficos, co-morbilidades pré-operatórias, classificações histológica e imagiológica do adenoma, duração da cirurgia, duração do internamento e complicações per(pré)- e pós-operatórias. O seguimento dos doentes foi entre um e seis meses. Na análise estatística foi utilizado o programa SPSS® Statistics 17.0. Resultados: 50 doentes, 32 (64%) do sexo feminino e 18 (36%) do sexo masculino, com idades compreendidas entre os 16 e 87 anos, média de 50 anos. 40 (80%) casos tratavam-se de macroadenomas e 10 (20%) de microadenomas. 15/47 (31.9%) doentes foram submetidos a cirurgia trans-esfenoidal transseptal através de incisão columelar e 32/47 (68.1%) doentes através de incisão sublabial. Verificaram-se complicações oronasais num total de 5/14 (35.7%) doentes no grupo em que foi utilizada incisão columelar e 14/29 (48.3%) doentes no grupo em que foi utilizada incisão sublabial (p>0.05). Verificou-se que doentes com excesso de peso tiveram mais frequentemente complicações (p<0.01). Não se verificaram diferenças estatisticamente significativas na taxa de doentes com complicações de acordo com a idade, género, incisão cirúrgica utilizada, tipo de adenoma, ou em doentes com outras co-morbilidades pré-operatórias. A duração da cirurgia e do internamento não tiveram diferenças estatisticamente significativas relativamente à incisão cirúrgica utilizada. Conclusões: As incisões sublabial e columelar na cirurgia trans-esfenoidal mostraram, neste estudo, não afectar as taxas de complicações per(pré)- e pós-operatórias. Título abreviado: Cirurgia trans-esfenoidal da hipófise Palavras-chave: cirurgia trans-esfenoidal, cirurgia da hipófise, complicações da cirurgia da hipófise, adenoma da hipófise.
- Gliosarcoma with neuroaxis metastases.Publication . Ramos, R; Morais, N; Silva, AI; Almeida, RGliosarcomas are rare tumours of the central nervous system, with a well-known capacity for metastasis. When they metastasise, the dissemination occurs more frequently via the haematogenous route to extraneural sites. Metastasis-spread through the cerebrospinal fluid is extremely rare. We present the case of a 58-year-old man who underwent a gross total resection of a lesion in the left temporal lobe. The histological findings revealed a gliosarcoma and the patient received radiotherapy followed by chemotherapy. Seven months after surgery, while the patient remained neurologically intact, brain and spinal cord MRI revealed tumour recurrence and neuroaxis metastases through the traffic routes of the cerebrospinal fluid. The patient died 8 months after the diagnosis. A PubMed search regarding metastatic gliosarcoma up to June 2015 was also carried out. To the best of our knowledge, this is the first case report of gliosarcoma metastases to the brain and spinal cord leptomeninges.
- Ten-year follow-up of a giant prolactinomaPublication . Fernandes, V; Santos, MJ; Almeida, R; Marques, OGiant prolactinomas are rare pituitary tumours of which management can be a challenge. A 28-year-old man presented with headaches, visual impairment and behavioural changes. Clinically, the patient was found to have hypogonadism and bitemporal hemianopsia. A MRI demonstrated a pituitary tumour 76 mm in diameter and blood tests revealed a serum prolactin of 158 700 µU/mL (reference range 58-254). Initially, a craniotomy was performed. Immunohistochemistry of the tumour identified a prolactinoma with a high proliferative index and the patient was started on treatment with a dopamine agonist. A year later, neurological symptoms worsened due to regrowth of the lesion's cystic component, and so further surgery was performed. After 10 years of treatment with dopamine agonists, the prolactin levels decreased by 96.8%, there was an effective reduction in tumour size, and the neurological signs and symptoms resolved.
- A transcriptomic signature mediated by HOXA9 promotes human glioblastoma initiation, aggressiveness and resistance to temozolomidePublication . Pojo, M; Gonçalves, CS; Xavier-Magalhães, A; Oliveira, AI; Gonçalves, T; Correia, S; Rodrigues, AJ; Costa, S; Pinto, L; Pinto, AA; Lopes, JM; Reis, RM; Rocha, M; Sousa, N; Costa, BMGlioblastoma is the most malignant brain tumor, exhibiting remarkable resistance to treatment. Here we investigated the oncogenic potential of HOXA9 in gliomagenesis, the molecular and cellular mechanisms by which HOXA9 renders glioblastoma more aggressive, and how HOXA9 affects response to chemotherapy and survival. The prognostic value of HOXA9 in glioblastoma patients was validated in two large datasets from TCGA and Rembrandt, where high HOXA9 levels were associated with shorter survival. Transcriptomic analyses identified novel HOXA9-target genes with key roles in cancer-related processes, including cell proliferation, DNA repair, and stem cell maintenance. Functional studies with HOXA9-overexpressing and HOXA9-silenced glioblastoma cell models revealed that HOXA9 promotes cell viability, stemness and invasion, and inhibits apoptosis. Additionally, HOXA9 promoted the malignant transformation of human immortalized astrocytes in an orthotopic in vivo model, and caused tumor-associated death. HOXA9 also mediated resistance to temozolomide treatment in vitro and in vivo via upregulation of BCL2. Importantly, the pharmacological inhibition of BCL2 with the BH3 mimetic ABT-737 reverted temozolomide resistance in HOXA9-positive cells. These data establish HOXA9 as a driver of glioma initiation, aggressiveness and resistance to therapy. In the future, the combination of BH3 mimetics with temozolomide should be further explored as an alternative treatment for glioblastoma.
- Macroprolactinomas: avaliação da resposta aos agonistas dopaminérgicosPublication . Santos, MJ; Almeida, R; Marques, O
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