Oncogene-induced senescence in meningiomas-an immunohistochemical study.

PURPOSE: Meningiomas are tumours originating from meningothelial cells, the majority belonging to grade 1 according to the World Health Organization classification of the tumours of the Central Nervous System. Factors contributing to the progression to the higher grades (grades 2 and 3) have not been elucidated yet. Senescence has been proposed as a potential mechanism constraining the malignant transformation of tumours. Senescence-associated beta-galactosidase (SA-ß-GAL) and inhibitors of cyclin-dependent kinases p16 and p21 have been suggested as senescence markers. METHODS: We analysed 318 meningiomas of total 343 (178 grade 1, 133 grade 2 and 7 grade 3). Tissue microarrays were constructed and stained immunohistochemically, using antibodies for SA-ß-GAL, p16 and p21. RESULTS: The positive correlation of the tumour grade with the expression of p16 (p = 0.016) and SA-ß-GAL (p = 0.002) was observed. The expression of p16 and SA-ß-GAL was significantly higher in meningiomas grade 2 compared to meningiomas grade 1 (p = 0.006 and p = 0.004, respectively). SA-ß-GAL positivity positively correlated with p16 and p21 in the whole cohort. In grade 2 meningiomas, a positive correlation was only between SA-ß-GAL and p16. Correlations of senescence markers in meningiomas grade 2 were not present. CONCLUSION: Our findings suggest the senescence activation in meningiomas grade 2 as a potential mechanism for the restraining of tumour growth and give hope for applying of promising senolytic therapy.

A potential role of mechano-gated potassium channels in meningioma-related seizures.

Every third patient with intracranial meningioma develops seizures of poorly understood etiology. Tumor and peritumoral edema may exert mechanical pressure on the cortex that may affect mechano-gated potassium channels - KCNK2 and KCNK4. These channels regulate neuron excitability and have been related to seizures in some other conditions. The objective of the present study was to explore a potential relation between the levels of these proteins in tumor tissue and adjacent cortex and seizures development. The study included 19 meningioma patients that presented one or more preoperative seizures and 24 patients with no seizures. Tissue samples were collected in the course of surgical removal of the meningioma. Postoperative seizure freedom was achieved in 11 out of 19 patients. The relative level of KCNK2 in the cortical tissue was lower in patients with preoperative seizures. On the other hand, cortical tissue level of KCNK4 was higher in patients that became seizure-free after the surgery. In addition, relative levels of KCNK4 in the cortical and tumor tissue appear to be lowered by the treatment with anti-seizure medication levetiracetam. These results imply that KCNK2 and KCNK4 may be involved in the development of meningioma-related seizures and may represent promising therapeutic targets.

Proapoptotic and proautophagy effect of H1-receptor antagonist desloratadine in human glioblastoma cell lines.

Glioblastomas are aggressive and usually incurable high-grade gliomas without adequate treatment. In this study, we aimed to investigate the potential of desloratadine to induce apoptosis/autophagy as genetically regulated processes that can seal cancer cell fates. All experiments were performed on U251 human glioblastoma cell line and primary human glioblastoma cell culture. Cytotoxic effect of desloratadine was investigated using MTT and CV assays, while oxidative stress, apoptosis, and autophagy were detected by flow cytometry and immunoblot. Desloratadine treatment decreased cell viability of U251 human glioblastoma cell line and primary human glioblastoma cell culture (IC50 value 50 µM) by an increase of intracellular reactive oxygen species and caspase activity. Also, desloratadine decreased the expression of main autophagy repressor mTOR and its upstream activator Akt and increased the expression of AMPK. Desloratadine exerted dual cytotoxic effect inducing both apoptosis- and mTOR/AMPK-dependent cytotoxic autophagy in glioblastoma cells and primary glioblastoma cell culture.

A unique case of intracranial collision tumor composed of ganglioglioma WHO gr I and supratentorial ependymoma WHO gr III: case-based literature review.

PURPOSE: Intracranial collision tumor is a rare entity that represents the coexistence of two histopathological different tumor types in the same area without histological admixture or an intermediate cell population zone. So far, several cases of collision tumors with ganglioglioma as its component have been reported in the literature, while supratentorial ependymoma has never been reported as a collision tumor component. We are presenting a unique case of collision tumor in patient without previous history of head trauma, neurological surgery, radiotherapy, or phakomatosis. METHODS AND RESULTS: A 17-year-old male with no previous history of head trauma, neurological surgery, radiotherapy, or phakomatosis was presented to our clinic with grand mal seizure. Brain magnetic resonance imaging with gadolinium contrast was done revealing a contrast-enhancing lesion of right frontal lobe closely related to dura, surrounded by perifocal edema. The patient underwent a gross total tumor resection. Histological examination revealed collision tumor with two distinct components: ganglioglioma and supratentorial ependymoma. CONCLUSION: To our best knowledge, no previous reports of collision tumor composed of ganglioglioma and supratentorial ependymoma in a single patient have been reported. We believe that this report could significantly contribute to further surgical practice as well as to treatment decision for these types of collision tumors.

Case report: Nocardial brain abscess in a persistently SARS-CoV-2 PCR positive patient with systemic lupus erythematosus.

Coronavirus disease (COVID-19) in immunocompromised patients represents a major challenge for diagnostics, surveillance, and treatment. Some individuals remain SARS-CoV-2 PCR-positive for a prolonged period. The clinical and epidemiological significance of this phenomenon is not well understood. We report a case of a patient with a history of systemic lupus erythematosus (SLE) who has been persistently SARS-CoV-2 PCR positive for 9 months, with multiple thromboembolic complications, and development of nocardial brain abscess successfully treated with surgery and antibiotics.

Case Report: Atypical Solitary Brain Metastasis: The Role of MR Spectroscopy In Differential Diagnosis.

Background: Metastatic brain tumors are typically located at the cerebral hemispheres or the cerebellum and most frequently originate from primary breast or lung tumors. Metastatic lesions are usually associated with blood-brain barrier disruption, solid or ring-like contrast enhancement, and perilesional vasogenic edema on brain imaging. Even in cases where metastases are predominantly cystic, enhancement of the minor solid component can be detected. In contrast, non-enhancing secondary brain tumors were only reported in a patient after antiangiogenic treatment with bevacizumab. Case report: We report a case of a 54-year-old male who presented with left-sided weakness and multiple seizures. Brain magnetic resonance imaging revealed a T2-weighted heterogeneous solid tumor in the right frontoparietal parasagittal region, with no apparent enhancement on T1-weighted post-contrast images and no evident perilesional edema. Further MRS analysis revealed markedly increased choline and lipid peaks. The patient underwent craniotomy for tumor removal. Histopathology revealed findings consistent with metastatic non-microcellular neuroendocrine lung cancer. positron emission tomography/computed tomography (PET/CT) revealed a stellate lesion within the right upper lung lobe, compatible with primary lung cancer. Conclusion: Non-enhancing brain metastatic tumors are rarely reported in the literature, usually following antiangiogenic treatment. Here, we report the first ever case of a non-enhancing metastatic brain tumor with no prior history of antiangiogenic treatment, with particular emphasis on the importance of MRS analysis in atypical brain lesions.

Clinical profile, treatment and outcome of pediatric brain tumors in Serbia in a 10-year period: A national referral institution experience.

OBJECTIVE: This study aimed to evaluate the characteristics of children with primary brain tumors, the effectiveness of treatment modalities, and to detect factors related to the outcome. METHODS: A detailed analysis was performed on a series of 173 pediatric patients treated in a Serbian referral oncology institution between 2007 and 2016, based on their clinical, histological, treatment, and follow-up data. RESULTS: Mean survival time of all children was 94.5months. 2-, 5- and 10-year overall survival probabilities were 68.8%, 59.4%, and 52.8%, respectively. Patients with supratentorial tumors had longer survival than patients with infratentorial tumors and patients with tumors in both compartments (p = 0.011). Children with the unknown histopathology (brainstem glioma) and high-grade glioma had a shorter life than embryonal tumors, ependymoma, and low-grade glioma (p<0.001). Survival of the children who underwent gross total resection was longer than the children in whom lesser degrees of resection were achieved (p = 0.015). The extent of the disease is a very important parameter found to be associated with survival. Patients with no evidence of disease after surgery had a mean survival of 123 months, compared with 82 months in patients with local residual disease and 55 months in patients with disseminated disease (p<0.001). By the univariate analysis, factors predicting poor outcome in our series were the presentation of disease with hormonal abnormalities, tumor location, and the extent of the disease, while the factors predicting a better outcome were age at the time of diagnosis, presentation of the disease with neurological deficit, and type of resection. By the multivariate analysis, the extent of the disease remained as the only strong adverse risk factor for survival (HR 2.06; 95% CI = 1.38-3.07; p<0.001). CONCLUSIONS: With an organized and dedicated multidisciplinary team, the adequate outcomes can be achieved in a middle-income country setting. The presence of local residual disease after surgery and disseminated disease has a strong negative effect on survival.

Expression of kisspeptin and KISS1 receptor in pituitary neuroendocrine tumours - an immunohistochemical study.

INTRODUCTION: Pituitary neuroendocrine tumours (PitNETs), traditionally designated as pituitary adenomas, show elatively frequent invasive growth with exceptional metastatic potential, the causes of which are not entirely elucidated. Kisspeptins, which perform their activity through KISS1 receptor (KISS1R), are recognised as metastatic suppressors in many malignant tumours. This study aimed to investigate the immunohistochemical expression of kisspeptin and KISS1R in different types of PitNETs and to compare it with the expression in the normal anterior pituitary, using tissue microarray. MATERIAL AND METHODS: The experimental group consisted of 101 patients with PitNETs, with 45 (37.3%) being of gonadotroph, 40 (33.9%) somatotroph, 4 (3.4%) corticotroph, 4 (3.4%) thyrotroph, 3 (2.5%) lactotroph, and 6 (5.1%) null-cell type. The control group consisted of anterior pituitary tissue accidentally removed during the surgery for PitNETs in 17 patients. RESULTS: Kisspeptin expression was observed in both experimental and control groups, without statistically significant differences in the staining intensity. Negative kisspeptin staining was detected in 10 (9.9%), weak in 79 (78.2%), and moderate in 12 tumours (11.9%); none of the tumours had strong staining intensity. The weak staining intensity was predominant in all PitNET types except thyrotroph tumours. Significant statistical difference in terms of kisspeptin expression between types of PitNET and the control group was not observed. Immunohistochemical expression of KISS1R was not observed in the control group or in the experimental group. CONCLUSIONS: We conclude that immunohistochemistry, as a method, cannot confirm the involvement of kisspeptin in tumourigenesis and aggressiveness of PitNETs, but potentially supports its antimetastatic role. The absence of KISS1R immunohistochemical expression in all anterior pituitaries and PitNETs in our cohort needs verification through the use of different procedures designed for the detection of the presence and localisation of proteins in the cell.

Low-grade epilepsy-associated tumour management with or without presurgical evaluation: a multicentre, retrospective, observational study of postsurgical epilepsy outcome.

Low-grade epilepsy-associated neuroepithelial tumours (LEATs) encompass the broad spectrum of tumours associated with epilepsy. Since the postsurgical seizure outcome in LEATs is favourable, it is speculated that epileptological presurgical evaluation (EPE) might not be required for patients with LEATs. A multicentre study involving referring epilepsy and neurosurgery centres was performed, aimed at evaluating postsurgical epilepsy outcome in patients with LEATs, with and without EPE, including long-term video-EEG monitoring (vEEGM). In total, 149 surgically treated patients were enrolled (age: 31±14 years; age at surgery: 26.4±13.1 years; males; 55.7%) with histopathological confirmation of LEATs and follow-up of more than six months. All patients had undergone standard assessment: clinical, routine EEG and brain MRI. In addition to vEEGM, EPE included other additional investigations. Epileptologists did not assess patients treated in neurosurgical centres. The EPE was performed in 51% of patients. Histopathological diagnosis revealed ganglioglioma in 43.6%, DNET in 32.9%, pilocytic astrocytoma in 17.4%, and others in 6.1% of patients. The majority of patients were seizure-free (ILAE epilepsy surgery outcome Class 1; 71.1%). The median follow-up period was 36 months. Patients who were rendered seizure-free were younger (mean age: 24.2±12.2) than those who were not seizure-free (31.8±14.0) (p=0.001). No difference was identified between evaluated and non-evaluated patients with respect to seizure freedom (p=0.45). EPE patients had a longer epilepsy duration (median: 10 years) and a higher proportion of drug resistance (73.6%) compared to non-evaluated patients (median: two years; 26.4%) (p<0.001). Based on a significant difference in major clinical variables, that may well affect postoperative results, the similar postsurgical seizure outcome in groups with and without EPE observed in our study should be considered with caution, and conclusions as to whether there is value in formal presurgical evaluation in LEAT patients cannot be drawn. Our data strongly encourage the clear need for continued discussion around such patients at epilepsy management conferences.

Multinodular and vacuolating neuronal tumour of the cerebrum: a rare neuroimaging incidentaloma or a potentially treatable cause of focal epilepsy?

Multinodular and vacuolating neuronal tumour (MVNT) of the cerebrum is a relatively new, well defined histopathological and neuroradiological entity, in many cases associated with an early adult-onset epilepsy. These lesions have an indolent course and resemble both malformative and neoplastic processes, combining a focal developmental anomaly and a low-grade tumour. Herein, we report a case of a 48-year-old female patient with left temporal lobe epilepsy associated with MVNT. In addition, a comprehensive review of all the previously published cases is provided with a focus on seizure-related cases, surgical treatment, and postoperative outcome.

SOX3 can promote the malignant behavior of glioblastoma cells.

PURPOSE: Glioblastoma is the most common and lethal adult brain tumor. Despite current therapeutic strategies, including surgery, radiation and chemotherapy, the median survival of glioblastoma patients is 15 months. The development of this tumor depends on a sub-population of glioblastoma stem cells governing tumor propagation and therapy resistance. SOX3 plays a role in both normal neural development and carcinogenesis. However, little is known about its role in glioblastoma. Thus, the aim of this work was to elucidate the role of SOX3 in glioblastoma. METHODS: SOX3 expression was assessed using real-time quantitative PCR (RT-qPCR), Western blotting and immunohistochemistry. MTT, immunocytochemistry and Transwell assays were used to evaluate the effects of exogenous SOX3 overexpression on the viability, proliferation, migration and invasion of glioblastoma cells, respectively. The expression of Hedgehog signaling pathway components and autophagy markers was assessed using RT-qPCR and Western blot analyses, respectively. RESULTS: Higher levels of SOX3 expression were detected in a subset of primary glioblastoma samples compared to those in non-tumoral brain tissues. Exogenous overexpression of this gene was found to increase the proliferation, viability, migration and invasion of glioblastoma cells. We also found that SOX3 up-regulation was accompanied by an enhanced activity of the Hedgehog signaling pathway and by suppression of autophagy in glioblastoma cells. Additionally, we found that SOX3 expression was elevated in patient-derived glioblastoma stem cells, as well as in oncospheres derived from glioblastoma cell lines, compared to their differentiated counterparts, implying that SOX3 expression is associated with the undifferentiated state of glioblastoma cells. CONCLUSION: From our data we conclude that SOX3 can promote the malignant behavior of glioblastoma cells.

Management and treatment of children with medulloblastoma in Serbia, a middle-income country.

PURPOSE: The aim of this study was to present the management and treatment of children with medulloblastoma in Serbia, a middle-income country (MIC). METHODS: The data of 87 children diagnosed with medulloblastoma and treated at the Institute for Oncology and Radiology of Serbia from 2000 to 2013 were analyzed. RESULTS: The children's median age was 8.3 years (range 2.5-17.3). Eighty-two (94.2%) were 3 years or older. Sixtytwo (71.3%) patients had stage M0 medulloblastoma, 12 (13.8%) had stage M1 and 13 (14.9%) had stage M2 or M3. As of October 2015, 51 (58.6%) patients were alive and 31 (35.6%) had died. Five patients (5.7%) were lost to followup. Twenty-six patients relapsed. The median follow-up time was 58 months (range 4-187). Mean overall survival (OS) was 76.4% at 3 years, 66.2% at 5 years and 59.2% at 10 years. Mean disease-free survival (DFS) was 75.8% at 3 years, 62.8% at 5 years and 56.6% at 10 years. Mean OS of stage M0 patients was 86.4% at 3 years, 74% at 5 years and 63.1% at 10 years. The OS of stage M1, M2 and M3 patients combined was 48.9% at 3 years, 44.0% at 5 years and 37.7% at 10 years. CONCLUSION: In Serbia, a MIC, it is possible to achieve good treatment results in children with medulloblastoma using international treatment guidelines and recommendations, available resources and an experienced team of professionals dedicated to pediatric neurooncology.

A Survival Analysis with Identification of Prognostic Factors in a Series of 110 Patients with Newly Diagnosed Glioblastoma Before and After Introduction of the Stupp Regimen: A Single-Center Observational Study.

BACKGROUND: Current treatment protocol for glioblastoma multiforme (GBM) is based on maximal safe resection followed by the Stupp protocol. In Serbia, temozolomide was introduced as adjuvant therapy in 2011. The aims of this study were to confirm the safety and efficacy on overall and progression-free survival of the Stupp protocol and evaluate the influence of prognostic factors in one of the largest series of patients with GBM treated over a 2-year period. METHODS: Between January 2010 and December 2012, 110 patients with newly diagnosed GBM underwent surgical removal at the Neurooncology Department of the Clinic Center of Serbia. Patients were divided into 2 groups according to postoperative treatment. Group A (n = 24 patients), treated before January 2011, received adjuvant standard radiation therapy and carmustine (bis-chloroethyl-nitrosourea), and group B (n = 86 patients), treated after January 2011, received postoperative treatment according to the Stupp protocol. RESULTS: The Stupp protocol had a significant favorable impact on overall survival at 1-year follow-up (79.1% in group B vs. 62.5% in group A; P = 0.016); no differences were noted in regard to progression-free survival. Multivariate analysis identified younger age and gross total resection of tumor as positive prognostic factors. CONCLUSIONS: Adoption of the Stupp protocol had a favorable impact on overall, but not on progression-free, survival rate. Wider surgical resection involving the peritumoral brain zone, as confirmed by univariate and multivariate analysis, represents the most favorable prognostic factor.

Metal maps of sclerotic hippocampi of patients with mesial temporal lobe epilepsy.

The loss of metal homeostasis has been implicated in the pathophysiology of mesial temporal lobe epilepsy associated with hippocampal sclerosis (mTLE-HS). Here we applied laser ablation inductively coupled plasma mass spectrometry imaging to establish the spatial distribution of Zn, Fe, Cu and Mn in coronal sections of hippocampi of four patients with drug-resistant mTLE-HS who underwent amygdalohippocampectomy. Detailed maps of the metal concentrations in the different morphological areas/layers were built and analyzed. The highest level of Zn (>20 µg g-1) was found in mossy fiber-rich regions - cornu ammonis field 4 (CA4), gyrus dentatus, and CA3. The distribution of Fe appears to reflect the routes of the main intrahippocampal blood vessels. The highest concentrations of Cu (>10 µg g-1) and Mn (>15 µg g-1) were observed in regions/layers with neuron somata - subiculum, CA4, gyrus dentatus, and stratum pyramidale (SPy) in CA1 and CA2. Alveus and other regions with axons and dendrites generally showed lower levels of Zn, Cu, and Mn. The Cu concentration was decreased in the areas of total neuronal loss in SPy in CA1 (9.73 ± 0.91 µg g-1), compared to the subiculum (13.32 ± 1.29 µg g-1; p = 0.043). The Cu and Mn concentrations correlated positively with neuron density in the SPy in CA1 (R = 0.629, p < 0.001; and R = 0.391, p = 0.004). These results provide a deeper insight into hippocampal metabolism of metals, and pave the road for identifying the components of the mechanism of epileptogenesis among Cu and Mn transporters and metalloproteins.

Intraventricular Meningiomas: A Series of 42 Patients at a Single Institution and Literature Review.

BACKGROUND: Primary intraventricular meningiomas (IVMs) make up 0.5%-5% of all intracranial meningiomas and represent one of the most challenging lesions in neurosurgery. METHODS: Between 1990 and 2013, 42 patients (30 female, 12 male; mean age, 43.6 years) underwent resection of their IVM. The removal was performed by a posterior parietal approach in 19 of the 40 lateral ventricle tumors, and 1 third ventricle meningioma. The transcallosal approach was used for 3 meningiomas, and patients with other lesions underwent temporal (7 cases) and temporoparietal approaches (12 patients), respectively. RESULTS: The most common presenting signs were increased intracranial pressure (83.3%), visual impairment (78.6%) and cognitive changes (50%). Forty lesions (95.2%) arose in the lateral ventricles, and 2 (4.8%) in the third ventricle, ranging in size from 3 to 10 cm. Total removal was achieved in 39 cases and the pathology report disclosed World Health Organization grade I lesions in 41 cases. Hydrocephalus, cerebrospinal fluid leakage, and cerebral edema were the postoperative complications (7.15%); 1 patient died of respiratory problems not directly related to surgery. Thirty-five patients (83.3%) showed a 6-month Glasgow Outcome Scale of 5. One patient, who underwent partial resection, presented a recurrence after 1 year that remained stable until last follow-up. CONCLUSIONS: IVMs usually reach a large size before being diagnosed. Surgical treatment is the most suitable option and total removal should represent the main goal of the procedure. The posterior parietal transulcal approach and the temporoparietal approach are the most common surgical routes used in our series.

Oncogene-Induced Senescence in Pituitary Adenomas--an Immunohistochemical Study.

Oncogene-induced senescence (OIS) serves as an initial barrier to cancer development, being proposed as a possible explanation for the usually benign behavior of the pituitary adenomas. We aimed to explore the immunohistochemical expression of the OIS markers, senescence-associated lysosomal ß-galactosidase (SA-ß-GAL), p16, and p21 in different types of 345 pituitary adenomas and compared it with the expression in the normal pituitary and in the specimens from the repeated surgeries. SA-ß-GAL was overexpressed in the pituitary adenomas, compared to the normal pituitaries. Growth hormone (GH) producing adenomas showed the strongest SA-ß-GAL, with densely granulated (DG)-GH adenomas more reactive than the sparsely granulated (SG). Nuclear p21 was decreased in the adenomas, except for the SG-GH adenomas that had higher p21 than the normal pituitaries and the other adenomas. p16 was significantly lower in the adenomas, without type-related differences. SA-ß-GAL was slightly lower and p16 slightly higher in the recurrences. Our findings indicate alterations of the senescence program in the different types of pituitary adenomas. Activation of senescence in the pituitary adenomas presents one possible explanation for their usually benign behavior, at least in the GH adenomas that show a synchronous increase of two OIS markers. However, subdivision into GH adenoma subtypes reveals differences that reflect complex regulatory mechanisms influenced by the interplay between the granularity pattern and the hormonal factors, with possible impact on the different clinical behavior of the SG- and DG-GH adenoma subtypes. p16 seems to have a more prominent role in the pituitary tumorigenesis than in the senescence. Recurrent growth in a subset of the pituitary adenomas is not associated with consistent changes in the senescence pattern.

Hippocampal antioxidative system in mesial temporal lobe epilepsy.

OBJECTIVE: To examine antioxidative system in hippocampi of patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (mTLE-HS). METHODS: Activity and levels of antioxidative enzymes-catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), manganese superoxide dismutase (MnSOD), and copper-zinc superoxide dismutase (CuZnSOD)-were assessed in hippocampi of nine pharmacoresistant mTLE-HS patients (mean age 37.7 ± [standard deviation] 6.6 years) who underwent amygdalohippocampectomy, and in 10 hippocampi obtained via autopsy from five neurologically intact controls (mean age 34.4 ± 9.0 years). Subfield and cellular (neuron/astrocyte) distribution of CAT, GPx, and MnSOD was analyzed in detail using immunohistochemical staining. RESULTS: Sclerotic hippocampi showed drastically increased activity of hydrogen peroxide-removing enzymes, CAT (p < 0.001), GPx (p < 0.001), and GR (p < 0.001), and significantly higher protein levels of CAT (p = 0.006), GPx (p = 0.040), GR (p = 0.024), and MnSOD (p = 0.004), compared to controls. CAT immunofluorescence was located mainly in neurons in both controls and HS. Control hippocampi showed GPx staining in blood vessels and CA neurons. In HS, GPx-rich loci, representing bundles of astrocytes, emerged in different hippocampal regions, whereas the number of GPx-positive vessels was drastically decreased. Neurons with abnormal morphology and strong MnSOD immunofluorescence were present in all neuronal layers in HS. Small autofluorescent deposits, most likely lipofuscin, were observed, along with astrogliosis, in CA1 in HS. SIGNIFICANCE: Antioxidative system is upregulated in HS. This documents, for the first time, that epileptogenic hippocampi are exposed to oxidative stress. Our findings provide a basis for understanding the potential involvement of redox alterations in the pathology of epilepsy, and may open new pharmacologic perspectives for mTLE-HS treatment.

Immunohistochemical Expression of p16 and p21 in Pituitary Tissue Adjacent to Pituitary Adenoma versus Pituitary Tissue Obtained at Autopsy: Is There a Difference?

Normal pituitary tissue is frequently used for comparison with protein expression in tumor tissue, being obtained either at surgery or at autopsy. p16 and p21 proteins are cyclin-dependent kinase inhibitors, belonging to INK4 and Cip/Kip family, respectively. Their expression is increased in response to DNA damage or other cellular stressors, resulting in the activation of cell cycle checkpoints. They also play important roles in cellular senescence. The purpose of this study was to investigate differences in p16 and p21 immunohistochemical expression in normal pituitary tissue adjacent to pituitary adenoma obtained during neurosurgical procedure with pituitary tissue obtained at autopsy, from patients who died from non-endocrinological diseases. Our results show significant difference in p16 nuclear and p21 cytoplasmic immunohistochemical expression between two types of normal pituitary tissues. One of the reasons for this difference could be the age of subjects because those who underwent autopsy for a non-endocrinological disease were significantly older than subjects who underwent neurosurgery for a pituitary adenoma. Our finding that differences are probably not influenced by postmortem changes is supported by no significant correlation between postmortem interval and immunohistochemical p16 and p21 expression. The influence of the presence of a pituitary adenoma could not be evaluated in these specimens.

Metals and electrolytes in sclerotic hippocampi in patients with drug-resistant mesial temporal lobe epilepsy.

An altered metal and electrolyte profile has been implicated in the pathologic mechanisms of chronic epilepsy; however, no study has comprehensively measured hippocampal concentrations of these elements in patients with mesial temporal lobe epilepsy and hippocampal sclerosis (mTLE-HS). We therefore analyzed hippocampi of 24 patients with drug-resistant mTLE-HS (mean age 35.6 ± 9.4 years) who underwent anterior temporal lobe resection and amygdalohippocampectomy and 17 hippocampi obtained by autopsy from 13 controls (mean age 40.5 ± 12.9 years), using inductively coupled plasma optical emission spectrometry (ICP-OES). Epileptic hippocampi showed significantly lower concentrations (µg/g of tissue) of copper (HS: 2.34 ± 0.12; control [C]: 3.57 ± 0.33; p < 0.001), manganese (HS: 0.205 ± 0.030; C: 0.409 ± 0.064; p = 0.004), and potassium (HS: 2,001 ± 59; C: 2,322 ± 61; p < 0.001), and increased sodium levels (HS: 1,131 ± 22; C: 1,040 ± 25; p = 0.010). Zinc, iron, calcium, and magnesium levels did not differ in HS and controls. In summary, copper and manganese levels are deficient, whereas iron level is unchanged in hippocampi from patients with mTLE-HS. Our results provide a basis for understanding the potential involvement of different metals and electrolytes in the pathology of HS.