Somatic mutational profiling and clinical impact of driver genes in Latin-Iberian medulloblastomas: Towards precision medicine.

Medulloblastoma (MB) is the most prevalent malignant brain tumor in children, known for its heterogeneity and treatment-associated toxicity, and there is a critical need for new therapeutic targets. We analyzed the somatic mutation profile of 15 driver genes in 69 Latin-Iberian molecularly characterized medulloblastomas using the Illumina TruSight Tumor 15 panel. We classified the variants based on their clinical impact and oncogenicity. Among the patients, 66.7% were MBSHH, 13.0% MBWNT, 7.3% MBGrp3, and 13.0% MBGrp4. Among the 63 variants found, 54% were classified as Tier I/II and 31.7% as oncogenic/likely oncogenic. We observed 33.3% of cases harboring at least one mutation. TP53 (23.2%, 16/69) was the most mutated gene, followed by PIK3CA (5.8%, 4/69), KIT (4.3%, 3/69), PDGFRA (2.9%, 2/69), EGFR (1.4%, 1/69), ERBB2 (1.4%, 1/69), and NRAS (1.4%, 1/69). Approximately 41% of MBSHH tumors exhibited mutations, TP53 (32.6%) being the most frequently mutated gene. Tier I/II and oncogenic/likely oncogenic TP53 variants were associated with relapse, progression, and lower survival rates. Potentially actionable variants in the PIK3CA and KIT genes were identified. Latin-Iberian medulloblastomas, particularly the MBSHH, exhibit higher mutation frequencies than other populations. We corroborate the TP53 mutation status as an important prognostic factor, while PIK3CA and KIT are potential therapeutic targets.

Study of hTERT and Histone 3 Mutations in Medulloblastoma.

Hotspot activating mutations of the telomerase reverse transcriptase (hTERT) promoter region were recently described in several tumor types. These mutations lead to enhanced expression of telomerase, being responsible for telomere maintenance and allowing continuous cell division. Additionally, there are alternative telomere maintenance mechanisms, associated with histone H3 mutations, responsible for disrupting the histone code and affecting the regulation of transcription. Here, we investigated the clinical relevance of these mechanistically related molecules in medulloblastoma. Sixty-nine medulloblastomas, formalin fixed and paraffin embedded, from a cohort of patients aged 1.5-70 years, were used to investigate the hotspot mutations of the hTERT promoter region, i.e. H3F3A and HIST1H3B, using Sanger sequencing. We successfully sequenced hTERT in all 69 medulloblastoma samples and identified a total of 19 mutated cases (27.5%). c.-124:G>A and c.-146:G>A mutations were detected, respectively, in 16 and 3 samples. Similar to previous reports, hTERT mutations were more frequent in older patients (p < 0.0001), being found only in 5 patients <20 years of age. In addition, hTERT-mutated tumors were more frequently recurrent (p = 0.026) and hTERT mutations were significantly enriched in tumors located in the right cerebellar hemisphere (p = 0.039). No mutations were found on the H3F3A or HIST1H3B genes. hTERT promoter mutations are frequent in medulloblastoma and are associated with older patients, prone to recurrence and located in the right cerebellar hemisphere. On the other hand, histone 3 mutations do not seem to be present in medulloblastoma.

A controversial question: Can morphometry and clinical history be enough to diagnose hippocampal dysplasia?

The presence of dysmorphic neurons with strong cytoplasmatic accumulation of heavy non-phosphorylated neurofilament is crucial for the diagnostics of focal cortical dysplasia type II (FCDII). While ILAE's classification describes neocortical dysplasias, some groups have reported patients with mesial t abnormal neurons in the hippocampus of mesial temporal lobe epilepsy. Here we report a patient with such abnormal neurons in the hippocampus and compared it with previous reports of hippocampal dysplasia. Finally, we discuss the need for diagnostic criteria of hippocampal dysplasia.

Functions of astrocytes in multiple sclerosis: A review.

BACKGROUND: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), which usually affects young adults between 20 and 40 years old. In chronic neurodegenerative diseases such as multiple sclerosis, CNS cells take on several adaptations during neuroinflammation. The main cells involved in this inflammatory process are the glial cells, in which the astrocytes stand out. These cells play a complex role, and several studies report that reactive astrocytes lose their supporting role and gain toxic function in the progression of these diseases. RESULTS: The beneficial and injurious effects of this group of cells in MS are addressed in this work, as well as some drugs that are already used in the treatment of patients with multiple sclerosis, aiming to regulate astrocytic activities. CONCLUSIONS: The knowledge about the functions of astrocytes is essential for the expansion of scientific research in this area, since these cells are so important and involved in different mechanisms of action, especially in neurodegenerative and autoimmune diseases.

Approaching glioblastoma during COVID-19 pandemic: current recommendations and considerations in Brazil.

BACKGROUND: Cancer patients in general and glioblastoma patients, in particular, have an increased risk of developing complications from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and reaching a balance between the risk of exposure to infection and the clinical benefit of their treatment is ideal. The aggressive behavior of this group of tumors justifies the need for a multidisciplinary team to assist in clinical decisions during the current pandemic. Brazil is now ranked #2 in the number of cases and deaths from COVID-19 pandemic, and existing disparities in the treatment of neuro-oncology patients in Brazil will challenge the clinical and surgical decisions of this population, possibly affecting global survival. OBJECTIVE: To search the literature about the management of glioblastomas during COVID-19 pandemic to guide surgical and clinical decisions in this population of patients in Brazil. METHODS: We performed a systematic search on the PubMed electronic database targeting consensus statements concerning glioblastoma approaches during COVID-19 pandemic up to July 18, 2020. RESULTS: When approaching glioblastoma during the COVID-19 pandemic, important parameters that help in the decision-making process are age, performance status, tumor molecular profile, and patient consent. Younger patients should follow the standard protocol after maximal safe resection, mainly those with MGMT methylated tumors. Aged and underperforming patients should be carefully evaluated, and probably a monotherapy scheme is to be considered. Centers are advised to engage in telemedicine and to elaborate means to reduce local infection. CONCLUSION: Approaching glioblastoma during the COVID-19 pandemic will be challenging worldwide, but particularly in Brazil, where a significant inequality of healthcare exists.

Pilocytic Astrocytoma: A Review of General, Clinical, and Molecular Characteristics.

Pilocytic astrocytomas are the primary tumors most frequently found in children and adolescents, accounting for approximately 15.6% of all brain tumors and 5.4% of all gliomas. They are mostly found in infratentorial structures such as the cerebellum and in midline cerebral structures such as the optic nerve, hypothalamus, and brain stem. The present study aimed to list the main characteristics about this tumor, to better understand the diagnosis and treatment of these patients, and was conducted on search of the published studies available in NCBI, PubMed, MEDLINE, Scielo, and Google Scholar. It was possible to define the main histologic findings observed in these cases, such as mitoses, necrosis, and Rosenthal fibers. We described the locations usually most affected by tumor development, and this was associated with the most frequent clinical features. The comparison between the molecular diagnostic methods showed great use of fluorescent in situ hybridization, polymerase chain reaction (PCR), and reverse transcriptase-PCR, important techniques for the detection of BRAF V600E mutation and BRAF-KIAA1549 fusion, characteristic molecular alterations in pilocytic astrocytomas.

Microsurgical Resection of a Left Supramarginal Gyrus AVM Causing Radionecrosis.

Late radiation necrosis is a rare entity presenting in 2.2% to 9% of radiation-treated arteriovenous malformations (AVMs). It occurs by a mean of 3 years following treatment. There are few reports in the literature of radionecrosis and solid lesions treated with surgery.1-4 To the authors' knowledge, this case has the longest interval between radiosurgery and the presentation of cerebral necrosis. In this surgical video, we present the case of a 51-year-old female with a left supramarginal gyrus AVM that received radiosurgery with gamma knife; after 20 years, she began having seizures and aphasia. The magnetic resonance imaging scan revealed a lesion simulating an intra-axial tumor causing important edema and mass effect. Medical treatment was given including high-dose steroids without success, therefore microsurgery was performed. The surgery was presented in a step-by-step basis and correlation was performed with the involved adjacent anatomy, to illustrate the anatomy of the approach and surgical landmarks. The patient's symptoms resolved completely, and the postoperative magnetic resonance imaging scan showed complete resection and resolution of the edema. The histopathological findings were consistent with a radionecrosis and AVM. The patient signed the Institutional Consent Form, which states that she accepts the procedure and allows the use of her images and videos for any type of medical publications in conferences and/or scientific articles.

Adult Pilocytic Astrocytomas: A Brazilian Series.

OBJECTIVE: Pilocytic astrocytoma (PA) is rare in adults comprising 5.1% of the primary central nervous system tumors. The aim is to describe the first Brazilian series of adult patients with PA and compare its features with the available literature. METHODS: We retrospectively review all patients 18 years or older with PA from our institution's database from 1991 to 2018. We analyzed information regarding clinical presentation, location, imaging features, extent of resection, adjuvant treatments, and follow-up. RESULTS: Twenty-three patients with PA were analyzed: 60.9% male; median age 26 years. The most frequent symptoms were headache (34.8%) and seizure (26.1%). Temporal and parietal lobes were the most common locations, 21.7% each. All patients underwent a surgical procedure, gross total resection in 40.9%, subtotal resection in 22.7%, and biopsy in 27.3%. Adjuvant treatment with radiotherapy was performed in 2 patients. Only 4 patients had disease progression, 2 after gross total resection and 2 after subtotal resection. They were all alive and without evidence of new progression at the last follow-up (October 2018). Median overall survival was not reached after a median follow-up time of 88.9 months. CONCLUSIONS: This is the first Brazilian series regarding adults with PA, and our patients had a favorable outcome as reported in recent literature reviews. The tumor's prevalence reduces within older patients and supratentorial lesions are more frequent, especially on the temporal lobe. There was no significant relationship between location and progression, although according to the literature the extent of resection remains the most important prognostic factor.

Heparanase-2 expression in normal ovarian epithelium and in benign and malignant ovarian tumors.

INTRODUCTION: Studies have highlighted the changes that take place in the environment between the cell and the extracellular matrix during the process of neoplastic expansion. Several papers have associated the expression of heparanase 1 with various malignant tumors. Heparanase 2 is probably related to loss of cell adhesion. OBJECTIVE: The aim of this study was to evaluate the expression of heparanase 2 in epithelial neoplasia of the ovaries and in samples of normal ovarian tissue. METHODS: Seventy-five ovary specimens were analyzed and divided into 3 groups: 23 malignant and 35 benign epithelial ovarian neoplasia and 17 without ovarian disease. We used 2 methodological techniques for evaluating the immunoexpression of heparanase 2. The first followed the qualitative criterion of positive or negative in relation to enzymatic expression, and the second involved computerized quantification of this expression, performed on the same slides. RESULTS: In the quantitative analysis, we found positivity indices for heparanase 2 expression of 72.2% and 87.3% in the samples of benign and malignant neoplasias, respectively. In these, the intensity of expression and the expression index were 147.2 and 121.2, respectively, for the benign neoplasia and 134.1 and 118.0 for the malignant neoplasia. Qualitatively, its expression was strong or moderate in 44.2% of the benign and 78.2% of the malignant tumors; its expression in all of the nonneoplastic samples was negative, with the exception of one that was weakly positive. CONCLUSIONS: Heparanase 2 is involved in neoplastic proliferation, but it was not exclusively associated with the malignant process. Furthermore, there was no difference in its expression between benign and malignant ovarian epithelial neoplasia.

Glioependymal cyst on the third cranial nerve: case report.

Glioependymal cysts are a rare, congenital, and benign condition. The authors report a case of a 2-year-old female patient who presented with a large exophytic glioependymal cyst located in the left cerebral peduncle, which began with a history of deteriorating function of the left third cranial nerve (CN III). A left 3-piece fronto-orbitozygomatic approach and a microsurgical complete excision of the cyst were performed without complications by accessing the midbrain through the perioculomotor entry zone. The patient's CN III function completely recovered after 3 months. Because there are currently no widely approved and used classification systems for these cysts, their reporting, naming, and classification are quite confusing in the literature. Thus, their origin, classification, and most common locations warrant further investigation. In addition to reporting this case, the authors present their review of the literature.

Lack of KBTBD4 Mutations in Molecularly Classified Brazilian Medulloblastomas.

Medulloblastoma is the most frequent malignant brain tumor in children, representing 20% of all childhood brain tumors. Currently, medulloblastomas are molecularly classified in 4 subgroups that are associated with distinctive clinicopathological features. KBTBD4 mutations were recently described in a subset of MBGRP3 and MBGRP4 medulloblastomas subgroups. However, no other studies reported KBTBD4 mutations in medulloblastomas. Thus, our aim was to investigate KBTBD4 mutations in a Brazilian series of medulloblastoma. We evaluated 128 medulloblastoma patients molecularly classified from 4 Brazilian reference centers. DNA from formalin-fixed, paraffin-embedded samples was screened for KBTBD4 hotspot mutations by Sanger sequencing. Most of the patients were male, average age was 16.5 years old and average overall survival was 55.9 months. The predominant histological subtype was the classic subtype, followed by nodular/desmoplastic, and the predominant medulloblastoma molecular subtype was the MBSHH subgroup (46%), followed by MBGRP3 and MBGRP4 (19%/each), and MBWNT (16%). Among the 128 samples, 111 were successfully sequenced. No KBTBD4 mutations were identified in 111 samples. Our findings suggest that KBTBD4 mutations are uncommon in Brazilian MBGRP3 and MBGRP4 medulloblastomas subgroups. Further studies in a larger series of MBGRP3 and MBGRP4 medulloblastomas are warranted to better assess role of KBTBD4 mutations.

[Morphology of the vascular placental bed in chronic arterial hypertension]. / Estudo da morfologia vascular do leito placentário na hipertensão arterial crônica.

OBJECTIVES: To analyze histopathological patterns of placental bed arteries in pregnancies complicated by chronic arterial hypertension. Alterations were considered according to clinical classification of the hypertensive disorders as mild (MG); moderate (MoG) and severe (SG) for comparison with uncomplicated pregnancies, control group (CG). METHODS: Placental bed biopsy was performed in 60 pregnant women; the study group was comprised of pregnant women with hypertension, subdivided in 13 with severe chronic hypertension (CH), 11 with moderate CH and 11 with mild CH, and results were compared to 25 placental bed biopsies from uncomplicated pregnancies. All the pregnant women had a gestational age of at least 28 weeks of gestation with a live fetus and were submitted to cesarean section. Hypertension was considered mild with diastolic blood pressure (DBP) 90 I? 100 mmHg, moderate DBP 100 I? 110 mmHg and severe DBP=110 mmHg. Placental bed variables selected for histological analysis were: unaltered patterns, physiological changes, medial layer disorganization, medial and intimal hyperplasic changes, acute necrosis and atherosis. RESULTS: In cases with SG and MoG there was predominance of abnormal histophysiological findings: medial layer disorganization and hyperplasic changes, with a statistically significant difference when compared to MG and CG. Alteration in the medial layer was observed in these cases. The normal pattern, unaltered patterns and physiologic changes were more frequent in CG and MG. Physiological changes were the most usual finding, further, there was no acute necrosis or atherosis. CONCLUSION: 1. Abnormal histophysiological findings were predominant in hypertensive pregnant women compared to the normotensive ones; 2. These patterns were more frequent, according to the severity of the hypertensive disorders: Severe, Moderate and Mild; 3. More significant abnormal findings were a change in the medial layer, mainly in the group with severe hypertensive disorders; 4. The groups with moderate and severe hypertensive disorders when compared had similar results; 5. The normal histological pattern was higher in the control group and patients with mild hypertensive disorders and disclosed a similarity between them 6. The most usual pattern was physiologic changes, which was more frequent in the control group.

Neurological Patients during the Covid-19 Pandemic / Pacientes neurológicos durante a pandemia de Covid-19

With the current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), measures of social isolation were necessary, and this resulted in the interruption of several treatments. Regarding neuro-oncological patients, especially those with central nervous system (CNS) disorders, this interruption can cause serious damage or even compromise the success of the treatment in the future. It is essential that each case be evaluated separately to decide how to continue treatment during the pandemic, always considering the risk of SARS-CoV-2 infection and the benefits that the treatment will bring. The policy of not prescribing potentially toxic drugs, chemotherapy, and immunosuppressive therapies, as well as the use of techniques like stereotactic biopsy and telemedicine are important strategies at this time.

Com a atual pandemia causada pelo coronavírus da síndrome respiratória aguda grave 2 (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, em inglês), foram necessárias medidas de isolamento social que resultaram na interrupção de alguns tratamentos médicos hospitalares. Em relação aos pacientes neuro-oncológicos, principalmente aqueles com distúrbios do sistema nervoso central (SNC), uma interrupção pode causar sérios danos ou até mesmo comprometer o sucesso do tratamento no futuro. Assim, de acordo com a literatura encontrada, é de fundamental importância que cada caso seja avaliado individualmente, para que se decida como prosseguir com o tratamento durante a pandemia, sempre considerando o risco de infecção por SARS-CoV-2 e os benefícios relacionados ao tratamento. São estratégias importantes neste momento a política de não prescrição de medicamentos potencial mente tóxicos, quimioterapia e terapias imunossupressoras, além do uso de técnicas como biópsia estereotáxica e telemedicina.

Analysis of the expression of estrogen receptor, progesterone receptor and chicken ovalbumin upstream promoter-transcription factor I in ovarian epithelial cancers and normal ovaries.

Sex hormones are involved in the carcinogenesis of some gynecologic cancers, and the status of their receptors represents an indicator of prognosis and of the therapeutic response in breast and endometrial cancers. In the ovary, this role is not clearly defined, with epithelial cancers being poorly responsive to hormone therapy. COUP-TFI (chicken ovalbumin upstream promoter-transcription factor I) is an orphan nuclear receptor, which is expressed in various tissues and regulates the estrogen receptor (ER) by competition for DNA binding. To investigate the role of these receptors in ovarian carcinogenesis and their implications for cancer prognosis, we evaluated the immunohistochemical expression of ER, progesterone receptor (PR) and COUP-TFI in benign and malignant ovarian epithelial neoplasms and in normal ovaries. A total of 113 ovarian specimens, including 40 diagnosed as malignant epithelial neoplasms (group A), 45 as benign epithelial tumors (group B), and 28 from normal ovaries (group C) were analyzed. Immunoexpression of ER was observed in 70% of patients of group A, 57.8% of group B and 57.1% of group C, with no significant difference between groups (p=0.426). Immunoexpression of PR was significantly lower in group A (12.5%) compared to group B (42.2%) and group C (32.1%) (p=0.010). Similarly, COUP-TFI was expressed in only 10% of group A patients, a rate significantly lower than that observed for group B (31.1%) and group C (39.3%) (p=0.014). No association was observed between the expression of these markers and increased survival or clinical prognostic variables. Multivariate analysis revealed a residual tumor <1 cm as the most significant clinical prognostic factor in group A (p=0.010, OR=4.14). These data support the importance of cytoreduction in the treatment of ovarian cancer, the role of steroid receptors in the mechanism of carcinogenesis, and the need for selection of subgroups that may respond to hormone therapy.

Granular cell dispersion and bilamination: two distinct histopathological patterns in epileptic hippocampi?

Cytoarchitectural modifications of the dentate gyrus are among the most obvious abnormalities observed in the hippocampal sclerosis associated with refractory epilepsy. Here, we examined the morphological changes of granular cells (dispersion, bilamination and cell loss) in sclerotic hippocampi from nine TLE patients, comparing abnormal and preserved areas. A total of 2,577 granular cells were analyzed with respect to four different histopathological patterns: areas with bilamination (n = 936), areas with dispersion (n = 905), areas with neuronal loss (n = 279), and preserved areas (n = 457). Quantitative parameters included somatic perimeter (P), area (A) and form factor (ff). Although different patterns were often observed in the same patient, highly significant differences were observed (p < 0.0001) when patterns were compared to one another. Since granular cell dispersion and bilamination have different morphological aspects in sclerotic hippocampi from TLE patients, we suggest that these patterns should be considered separately. Future studies are needed to determine the frequency with which these patterns occur in the general population and whether each one can interfere with seizure susceptibility.

Quantitative and qualitative analysis of collagen types in the fascia transversalis of inguinal hernia patients.

BACKGROUND: Inguinal hernia is the second most common surgical case in our field. The anatomical factors alone are not enough to explain the inguinal hernia. Studies show changes in the proportion and quantity of collagen fibers in the developing of inguinal hernia. The greater production of collagen type III compared to the type I could justify the thinning of the fascia transversalis and its weakness. AIM: To determine the quantitative and qualitative changes of collagen in the fascia transversalis in inguinal hernia patients and compare them to findings from corpses without inguinal hernia. METHOD: Prospective case-control study based on the biopsy of fascia transversalis of 27 patients and 24 corpses. The technique used was hematoxylin-eosin and picrosirius colorimetry. RESULTS: The medium percent area of collagen (types I + III) and collagen type I, in both groups, show no statistic difference. The quantity of collagen type III was greater in the patients. Patients classified with Nyhus IIIa presented greater quantity of collagen type III. CONCLUSION: There is no significant difference in the quantity of collagen in the fascia transversalis of patients compared to the controls. An increase in the quantity of collagen type III was found in patients with inguinal hernia and a greater quantity in those patients classified with Nyhus IIIa.

Matrix metalloproteinase 2: an important genetic marker for cholesteatomas.

AIM: This study is to determine the MMP2s presence in cholesteatomas and whether complicating cholesteatomas show a higher immunohistochemical expression of matrix metalloproteinase 2. Cholesteatoma produces enzymes that cause bone erosion like matrix metalloproteinase 2 (MMP2). MATERIAL AND METHODS: We analyzed the expression of MMP2 in invasive (causing complications) compared to latent cholesteatomas (not causing complications). A cross-sectional study with nineteen slides and paraffin blocks of cholesteatomas derived from mastoidectomies were located and processed, including 8 invasive and 11 latent cholesteatomas. Immunohistochemical technique was empregated to MMP2. RESULTS: The results are expressed as 0, + (to low), ++ and +++(high) according to the quantity and color of the immunohistochemical staining of MMP2. Higher expression of MMP2 was observed in 7 (87.5%) of the 8 invasive cholesteatomas. With respect to latent cholesteatomas, higher expression of MMP2 was observed in 27.3% (3 cases), with Fishers exact test indicating a significant difference (p=0.015). CONCLUSIONS: Cholesteatoamas express MMP2 and Invasive cholesteatomas had high MMP2 compared to latent cholesteatomas.

Unusual Intracerebral Presentation of a Myxoid Neurofibroma.

BACKGROUND: Neurofibromas are benign nerve sheath tumors that usually affect peripheral nerves and are related to neurofibromatosis type 1; however, they have not been described as a cause of intraparenchymal brain tumor. CASE DESCRIPTION: We report a case of intracranial myxoid neurofibroma in a 19-year-old female patient manifested as an intense and progressive cephalea, followed by nausea, vomiting, photophobia, and phonophobia. Computed tomography and magnetic resonance imaging showed an extant, expansive left frontoparietal parafalcine/parasagittal tumor. Histopathologic examination determined S-100 protein and CD34 positivity, as well as sparse expression of Ki67 protein, and indicated Schwann cells with characteristic wavy nuclei and intraneural fibroblasts in a myxoid background. Together, these observations characterized the tumor as myxoid neurofibroma. The tumor was excised, and the patient recovered without deficits and with no signs of recurrence after 6 years of follow-up. CONCLUSIONS: This is a novel presentation of a myxoid neurofibroma. The tumorigenesis mechanisms are likely complex and possibly involve the differentiation of Schwann cells present in adrenergic autonomic nerves in the subarachnoid arterial branches or in trigeminal nerves present in the meningeal convexity.

Spinal thoracic extradural angiolipoma manifesting as acute onset of paraparesis: Case report and review of literature.

BACKGROUND: Angiolipomas are benign tumors most commonly found in the thoracic spine. They are composed of mature adipocytes and abnormal vascular elements that usually present with a slowly progressive course of neurological deterioration. CASE DESCRIPTION: A 35-year-old female, with a prior history of back pain, acutely developed paraparesis. When the thoracic magnetic resonance imaging (MRI) revealed a dorsal epidural mass at the T3-T5 level, she underwent a laminectomy for gross total excision of the lesion that proved to be an angiolipoma. On the second postoperative day, the patient was again able to ambulate. CONCLUSION: The angiolipomas of spine are rare causes of spinal cord compression, and those presenting with acute neurological deficits should be immediately treated.