Predicting the true extent of glioblastoma based on probabilistic tractography.

Glioblastoma is the most frequent type of primary brain tumors. Despite the advanced therapy, most of the patients die within 2 years after the diagnosis. The tumor has a typical appearance on MRI: a central hypointensity surrounded by an inhomogeneous, ring-shaped contrast enhancement along its border. Too small to be recognized by MRI, detached individual tumor cells migrate along white matter fiber tracts several centimeters away from the edge of the tumor. Usually these cells are the source of tumor recurrence. If the infiltrated brain areas could be identified, longer survival time could be achieved through supratotal resection and individually planned radiation therapy. Probabilistic tractography is an advanced imaging method that can potentially be used to identify infiltrated pathways, thus the real extent of the glioblastoma. Our study consisted of twenty high grade glioma patients. Probabilistic tractography was started from the tumor. The location of tumor recurrence on follow-up MRI was considered as the primary infiltrated white matter tracts. The results of probabilistic tractography were evaluated at thirteen different thresholds. The overlap with the tumor recurrence of each threshold level was then defined to calculate the sensitivity and specificity. In the group level, sensitivity (81%) and specificity (90%) were the most reliable at 5% threshold level. There were two outliers in the study group, both with high specificity and very low sensitivity. According to our results, probabilistic tractography can help to define the true extent of the glioblastoma at the time of diagnosis with high sensitivity and specificity. Individually planned surgery and irradiation could provide a better chance of survival in these patients.

Localization of macroscopically undetectable intramedullary hematoma by intraoperative epidural motor evoked potential.

Introduction: Intramedullary hematoma is an uncommon, serious neurological disease, representing a diagnostic challenge. The preferred treatment is surgical. In most of the cases the lesion can be identified macroscopically. Otherwise, finding the optimal place to perform myelotomy is demanding. Intraoperative neurophysiological monitoring plays an important role in preventing surgical complications, but its versatility for localization has not been studied so far. Case report: The present case report describes a 17-year-old patient with flaccid right inferior monoparesis (later paraparesis), ipsilateral loss of proprioception and vibration sense, contralateral analgesia below the T10 dermatome level and urinary retention (Brown-Séquard syndrome). The MRI revealed an intramedullary hematoma at the level of T8-T9 vertebral bodies. Digital subtraction angiography did not identify any vascular malformation. Urgent surgical intervention was performed. In order to prevent any complication somatosensory-evoked potential (SSEP), transcranial and epidural motor-evoked potential (tcMEP, eMEP) recordings were planned. SSEP in response to right tibial nerve stimulation and tcMEP were absent bilaterally. From electrophysiological point of view, the eMEP revealed a total conduction block of the corticospinal tract. In the absence of typical macroscopic signs (discoloration, swelling, abnormal vascularization etc.), the small intramedullary hematoma could not be identified. Therefore, it was decided to adopt eMEP technique for mapping and localizing the conduction block intraoperatively by changing the distance between the two electrodes used for recording. The hematoma was precisely localized and successfully evacuated. Postoperatively, a slow but continuous improvement was noted. Conclusion: Intraoperative neurophysiological monitoring has been suggested to play crucial role in spinal cord surgery. To our knowledge, this is the first case report using eMEP recording for guiding and localizing of an intramedullary hematoma. Beside the clear limitations of our study, it could result in a novel application of the aforementioned monitoring technique.

[The role of low grade glioma prognostic factors in therapeutic choices - summary of international literature and recommendations with conclusions]. / Az alacsony grádusú gliómák prognosztikai faktorainak szerepe a terápia megválasztásában ­ a nemzetközi irodalom és ajánlások összefoglalása konklúziókkal.

Our knowledge on low grade gliomas has grown extensively recently. Both molecular alterations and clinical trials unraveling their clinical significance are difficult to get familiar with. Thus, efforts made to reach any consensus are of upmost importance, so that multidisciplinary teams involved in patient management can make up-to-date, individually-tailored therapeutic plans. Our aims were to synthesize all the molecular and clinical investigations, recommendations and guidelines related to low grade gliomas in Hungarian language, and to define low and high risk prognostic groups with different therapeutic strategies. The roles of 21 molecular pathological markers and their significance levels in low grade gliomas are summarized in this paper. Data from relevant literature, as well as recommendations of neuro-oncological organizations were included. This summary could help to integrate diverse therapeutic plans of the past decades in low grade gliomas. Moreover, this paper may serve as a source for future revisions when updating low and high risk groups in low grade gliomas.

[Prognostic significance of invasion in glioblastoma]. / Az inváziós spektrum prognosztikai jelentôsége glioblastomában.

BACKGROUND AND PURPOSE: Glioblastoma is the most common malignant CNS tumor, its surgical removal is hindered by the tumors invasive nature, while current anti-tumor therapies show limited effectiveness - mean overall survival is 16-24 months. Some patients show minimal response towards standard oncotherapy, however there are no routinely available prognostic and predictive markers in clinical practice to identify the background of mentioned differences in prognosis. This research aims to identify the prognostic significance of invasion-related extracellular (ECM) components. METHODS: Patient groups with different prognoses were created (OS: group A <16 months, group B > 16 months), and internationally recognized prognostic markers (IDH1 mutation and MGMT promoter hyper-methylation) were tested in the flash-frozen tumor samples. Furthermore, the mRNA levels of 46 invasion-related ECM molecules were measured. RESULTS: Clinical data of the patients who have been operated on at the University of Debrecen Clinical Center Department of Neurosurgery and treated at the Department of Clinical Oncology showed no significant differences except for survival data (OS and PFS), and reoperation rate. All samples were IDH wild type. MGMT promoter hypermethylation rate showed significant differences (28.6% vs 68.8%). The expressional pattern of the invasion-related ECM molecules, i.e. the invasion spectrum also showed major differences, integrin ß2, cadherin-12, FLT4/VEGFR-3 and versican molecules having signficantly different mRNA levels. The accuracy of the inivasion spectrum was tested by statistical classifier, 83.3% of the samples was sorted correctly, PPV was 0.93. CONCLUSION: The difference found in the reoperation rate when comparing different prognostic groups aligns with literature data. MGMG promoter region methylation data in Hungarian samples has not been published yet, and further confirming current knowledge urges the implementation of MGMT promoter analysis in clinical practice. Studying the invasion spectrum provides extra information on tumors, as a prognostic marker it helps recognizing more aggressive tumors, and calls attention to the necessity of using anti-invasive agents in GBM therapies in the future.

Prognosis and Treatment Outcomes of Patients Undergoing Resection of Brain Metastases from Breast Cancer.

BACKGROUND: Brain metastases from breast cancer have poor prognosis and are a challenge to treat. Multiple treatment options are available. Descriptive and prognostic data on breast cancer brain metastases is limited. PATIENTS AND METHODS: This study analyzed clinical data of patients who underwent surgical resection of one or more brain metastases. Histological and clinical characteristics, as well as treatment modalities, were analyzed. RESULTS: Initial tumor stage or grade was found not to correlate with the median time to developing brain metastases or survival. Human epidermal growth factor receptor 2 (HER2)-positive status was not associated with shorter median time to developing brain metastases. No correlation was found between the number of brain metastases and patient outcome. Results confirm the survival benefit of surgical resection with or without irradiation. CONCLUSION: Data showed that patients with HER2-positive and those with triple-negative breast cancer develop brain metastases at lower stages but not earlier after diagnosis, and survival is mostly dependent on treatment modality rather than histological subtype.

Significance of liquid biopsy in glioblastoma - A review.

Glioblastoma (GBM) is the most common and most aggressive primary malignant brain tumor with a 16-24 -months overall survival time (OS). Effective management is hindered by intratumoral heterogeneity, a characteristic trait of GBM which results in subpopulations of cells with altered therapeutic responsiveness, different invasiveness and growth potential. Correct initial molecular profiling of the tumor, as well as following its molecular biological changes are further impeded by the intracranial location of the tumors, hence the risks of surgical interventions. Radiological examination, the sole non-invasive method of obtaining information about the tumors, also has limitations. This review article aims to summarize the currently available information about the promising applicability of liquid biopsy, extracellular vesicles (EVs), and circulating cell-free nucleic acids (cf-NAs) in GBM patients. Liquid biopsy is a quick and inexpensive way of obtaining exceptionally relevant information about tumors, and can be performed multiple times during the clinical course of the disease. Furthermore, integrating analyses of EVs and related cf-NAs in clinical practice might also help to establish diagnosis in a non-invasive manner, and complex oncotherapy could be indicated in the future without high-risk neurosurgical interventions.

Extracellular matrix differences in glioblastoma patients with different prognoses.

Glioblastoma is the most common malignant central nervous system tumor. Patient outcome remains poor despite the development of therapy and increased understanding of the disease in the past decades. Glioma cells invade the peritumoral brain, which results in inevitable tumor recurrence. Previous studies have demonstrated that the extracellular matrix (ECM) is altered in gliomas and serves a major role in glioma invasion. The present study focuses on differences in the ECM composition of tumors in patients with poor and improved prognosis. The mRNA and protein expression of 16 invasion-associated ECM molecules was determined using reverse trascription-quantitiative polymerase chain reaction and immunohistochemistry, respectively. Clinical factors of patients with different prognoses was also analyzed. It was determined that age and postoperative Karnofsky performance score were associated with patient survival. Furthermore, Fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR3), murine double minute 2 (MDM2) and matrix metallopeptidase 2 (MMP2) mRNA levels were significantly different between the two prognostic groups. Additionally, brevican, cluster of differentiation 44, hyaluronan mediated motility receptor, integrin-αV and -ß1, and MDM2 protein expression were indicated to be significantly different in immunohistochemistry slides. Using the expression profile, including the invasion spectrum of the samples, it was possible to identify the prognostic group of the sample with high efficacy, particularly in cases with poor prognosis. In conclusion, it was determined that ECM components exhibit different expression levels in tumors with different prognoses and thus the invasion spectrum can be used as a prognostic factor in glioblastoma.

Differences in Extracellular Matrix Composition and its Role in Invasion in Primary and Secondary Intracerebral Malignancies.

BACKGROUND/AIM: The most common malignant primary brain tumor is glioblastoma which infiltrates the peritumoral brain, while secondary brain metastases are well demarcated malignancies. Previous research has proved the pivotal role of the changes in the extracellular matrix (ECM) in cancer cell invasion. MATERIALS AND METHODS: The mRNA expression of 40 ECM molecules was determined using qRT-PCR in 54 fresh-frozen glioblastoma and brain metastasis samples. Seventy-two samples were used to determine the levels of 20 ECM proteins. RESULTS: The mRNA and protein expression pattern of the studied tumors differs greatly. Linear discriminant analysis of mRNA expression identified samples based on their mRNA expression profile with 92.3% probability and highlighted the role of some molecules as their level greatly influenced sample identification. CONCLUSION: Different tumor types with different invasiveness differ in the composition of their ECM and this can be used to identify samples. Furthermore, some ECM molecules greatly contribute to tumor invasiveness and could be targets of anti-invasive oncotherapy.