Clinical Neuroscience

[Occurence and molecular pathology of high grade gliomas]

MURNYÁK Balázs, CSONKA Tamás, HEGYI Katalin, MÉHES Gábor, KLEKNER Álmos, HORTOBÁGYI Tibor

OCTOBER 05, 2013

Clinical Neuroscience - 2013;66(09-10)

[Background - Glial tumours represent the most frequent type of primary brain cancers. Gliomas are characterized by heterogeneity that makes the diagnosis, histological classification and the choosing of correct therapy more difficult. Despite the advances in developing therapeutic strategies patients with malignant gliomas have a poor prognosis; therefore glial tumours represent one of the most important areas of cancer research. There are no detailed data on the epidemiology of gliomas in Hungary. Methods - In the first section of our publication, we analysed the histological diagnosed cases between 2007 and 2011 at the Institute of Pathology, University of Debrecen Medical and Health Science Centre. We analyzed the incidence of 214 high-grade gliomas by tumor grades, gender, age, and the anatomical localization. Results - The majority of cases were glioblastoma (182 cases), and the remaining 32 cases were anaplastic gliomas. The mean age of patients was 57 years (±16.4), and the male:female ratio was 1.1:1. The most frequent area of tumors was the frontal lobe followed by the temporal, parietal and occipital lobe. We include new findings published recently about glioma patogenesis, molecular pathways, mutant genes and chromosomal regions. We explain briefly the role of selected important genes in glioma genesis and give an update on knowledge provided by modern molecular methods, which could beneficially influence future therapy and the diagnosis of gliomas.]

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Clinical Neuroscience

[The impact of the vitamin D in neurological diseases and neurorehabilitation: from demencia to multiple sclerosis. Part I: The role of the vitamin D in the prevetion and treatment of multiple sclerosis]

SPEER Gábor

[The world-wide incidence of vitamin D deficiency is high, independently of age. Multiple sclerosis is a chronic disorder, occuring in those who possess or are exposed to a combination of genetic and environmental risk factors. One of the environmental factors associated with the development is vitamin D. Vitamin D is an immunomodulatory agent, its role is verified in many of autoimmune diseases. Vitamin D inhibits IL-6, IL-17 and IL-23 secretions which are crucial in Th1 and Th17 differentiation and also decreases proinflammatorical cytokine production. Moreover it enhances the immunosuppressive IL-10 cytokine secretion and inhibits the T-reg cell development. These cytokines and cells are essential for the pathomechanism of multiple sclerosis. Data have shown, that the vitamin D levels above 100 nmol/l (40 ng/ml) is essential for the prevention of multiple sclerosis. Below this level the vitamin D supplementation is reasonable. In pregnancy, the vitamin D deficiency at the last two semester increases the risk for the multiple sclerosis of the infant. The optimal vitamin D level for multiple sclerosis patients is 100-150 nmol/l (40-60 ng/ml). There is no consensus for the role of vitamin D in multiple sclerosis yet, but until the achieving this, the diagnosis and the treatment of the vitamin D deficiency is crucial for scelrosis multiplex patients and in cases of elevated risk. Data shows, that in patient with multiple sclerosis the normal vitamin D level is suboptimal, however the exact role of vitamin D and doses must be clarified by interventional studies.]

Clinical Neuroscience

[Occurence and molecular pathology of low grade gliomas]

MURNYÁK Balázs, CSONKA Tamás, KLEKNER Álmos, HORTOBÁGYI Tibor

[Background - The WHO grade I. and II. low-grade gliomas represent nearly the 15% of all primary brain tumors. These tumours contain clinically, hisologically and molecularly distinct tumor types. According to their histologic characteristic, grade II glial tumours are the diffuse astrocytoma, oligodendroglioma and oligoastrocytoma subgroups; the ependymal tumors are not included in this study. Methods - In our publication, we analysed the histological diagnosed glioma cases between 2007 and 2011 at our institution. Results - Low-grade gliomas were diagnosed in 127 cases (62 male / 65 female), and the mean ages were 39 years (±20.3). More than half of the cancers were localizated in the frontal lobe, and the second most frequent area was the temporal lobe. Finally, we comlete our report with an overview of major molecular pathways in low-grade gliomas.]

Clinical Neuroscience

[EDITORIAL MESSAGE]

KOPNICZKY Zsolt

[Editorial message 2013;66(09-10)]

Clinical Neuroscience

[Infection-surveillance experience at a neurological intensive care unit]

CSIMA Zoltán, HRADECZKY Katalin, SIMONNÉ SZAPPANOS Erzsébet, BERECZKI Dániel, SIPOS Ildikó

[Infection-surveillance is an important part of the infection control system serving the protection of patients and healthcare workers as well. The continuous surveillance of health care associated infections is among the most important fields of patient safety and quality management. The aim of this study was to evaluate the frequency of the health care associated infections among patients at the neurointensive care unit. Moreover, we aimed to identify specific infectionforms and the most frequently occurring pathogens. We performed the study for a half-year according to the HELICSmethod proposed by the National Center of Epidemiology. In this setup we evaluated the infections and risk factors for infection (instrument-use, antibiotic therapy etc.) among the patients who spent at least 48 hours in the neurointensive care unit. During the six-month period, we observed 16 health care associated mono- and polymicrobial infections out of the 88 cases. Mainly Gram-positive pathogens were identified, but we found multidrug-resistant pathogens as well. Clinically diagnosed pneumonia was the most frequent among the infections. These infections were detected by a relatively low microbiological testing rate, which warns to increase sampling frequency to ensure more accurate data on infections. Infection control based on a comparative standardized infection dataset seems to be one of the most important preventive measures.]

Clinical Neuroscience

[Split laminotomy and complementary spacer insertion for opening and enlargement of the thoracic spinal canal at infiltrative intramedullary tumor removal]

PAPP Zoltán, VAJDA János, BANCZEROWSKI Péter

[Objective - The author main objective was to improve the previously developed technique of split laminotomy and moderate enlargement of the spinal canal with preservation of the majority of posterior structures, and to avoid the complications of the classic autologous bone grafting procedure. Methods - A multilevel spinous process splitting and distracting laminotomy technique with complementary spacer insertion between the laminar parts was developed. We used Poly-Ether-Ether-Ketone (PEEK) cages. This improved method was used in five patients to remove malignant intramedullary tumors at the thoracic level. Results - Adequate surgery of the tumors located intramedullary, and permanent decompression of the spinal canal was achieved in all patients using our new modified procedure. The results have been postoperatively confirmed with MRI and CT. The affected spine was the thoracic in all cases. The numbers of split laminae were three to five. Histological results were as follows: four intramedullary astrocytomas, one ependymoma. The ependymoma was completely, while the astrocytomas were only subtotally removed. In all cases heterologous grafts were inserted between the sides of the distracted laminas, to achieve the enlargement of the spinal canal. The mean duration of the whole surgical procedure was 118 minutes (range 91 to 145 minutes). The average follow-up was 11.2 months, with the range from five to 16 months. Upon postoperative neurological follow-up, no complications were revealed related to the newly developed procedure. The postoperative followup CT scans demonstrated bony healing, with a cage between the osteotomized faces. No compression or dislocation of the spacer was seen. Instability was not detected in any of the patients by flexion or extension lateral radiographs. Conclusion - This modification of the split laminotomy and heterologous grafting method fulfills the requirements of other laminotomy techniques. The split laminotomy is suitable for removing intramedullary tumors, and the posterior stabilizing structures of the spine, as the vertebral laminae and the longitudinal musculature are completely prevented. Due to use of allograft the complications of the classic hip bone grafting procedures are avoided. The spacers, inserted between the osteotomized faces, provided permanent decompression of the spinal canal, and bony healing - throughout the spacer - of the splitted vertebral laminae, without iliac graft complications.]

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Clinical Neuroscience

[Prognostic significance of invasion in glioblastoma]

SZIVÓS László, VIRGA József, HORTOBÁGYI Tibor, ZAHUCZKY Gábor, URAY Iván, JENEI Adrienn, BOGNÁR László, ÁRKOSY Péter, KLEKNER Álmos

[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. 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. 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 β2, 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. 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.]

Clinical Neuroscience

[Post-operative management of primary glioblastoma multiforme in patients over 60 years of age]

DARÓCZI Borbála, SZÁNTÓ Erika, TÓTH Judit, BARZÓ Pál, BOGNÁR László, BAKÓ Gyula, SZÁNTÓ János, MÓZES Petra, HIDEGHÉTY Katalin

[Background and purpose - Optimal treatment for elderly patients with glioblastoma multiforme is not well defined. We evaluated the efficacy of post-operative radiotherapy with or without concomitant and/or adjuvant temozolomide in patients aged ≥60 years to assess survival and identify prognostic factors of survival. Methods - A retrospective analysis of overall survival and progression-free survival in patients with newly diagnosed glioblastoma multiforme aged ≥60 years treated with postoperative radiotherapy with or without temozolomide chemotherapy was conducted at our institutions. Prognostic factors were determined by univariate and multivariate analyses. Results - Of 75 study participants (54.7% male; median age at first diagnosis, 65.1 years), 29 (38.7%) underwent gross total resection, whereas others underwent partial resection or biopsy only. All but 1 patient received radiotherapy. Twenty patients received concomitant temozolomide only. Adjuvant temozolomide (1-50 cycles) was administered in 42 patients; 16 received ≥6 cycles. Median overall survival was 10.3 months. One- and 2-year overall survival rates were 42.6% and 6.7%, respectively. Median progression-free survival was 4.1 months. Radiochemotherapy was generally well tolerated. Median overall survival was 15.3 and 29.6 months for patients who received 6-12 cycles and >12 cycles of adjuvant temozolomide, respectively. There were no significant differences in overall survival between age groups (60-64, 65-69, and ≥70 years). Adjuvant temozolomide, Karnofsky performance status ≥70, and additional surgery after progression were significant prognostic factors of longer overall survival (p<0.05). Conclusions: Radiochemotherapy, including ≥6 cycles of adjuvant temozolomide, was safe and prolonged survival of glioblastoma patients aged ≥60 years. Aggressive therapy should not be withheld from patients aged ≥60 years with good performance status because of age.]

Clinical Oncology

[Development in the treatment of non-operable, metastatic colorectal cancer]

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[Today, due to the steady improvement, the survival of patients with non-operable, metastasic colorectal cancer is about 30 months. This review discusses the results of recent clinical trials, the new drugs, the treatment protocols as well as the tumor response after surgery. A suggestion will be made not only on an optimal treament strategy, but also how to increase the survival, and the feasibility of a secunder resection.]

Clinical Oncology

[Molecular diagnostics of brain tumors - an up-date]

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[In recent years there have been major advancements in the understanding of molecular events driving brain tumor genesis and progression. Although state-of-the-art techniques are not widely available, many of the molecular discoveries lead to novel antibodies that can assist in identifying the major molecular subgroups by immunohistochemistry. Molecular informations will likely be incorporated into the next World Health Organization (WHO) classifi cation of central nervous system tumors, but clinical practice in many centres have already taken on the available informations and therapeutic decisions are made based on genetic/epigenetic information. In the adult population IDH, ATRX and 1p/19q codeletion studies help to defi ne molecular subgroups that correlate better with prognosis and therapeutic response than traditional histology based diagnosis. The KIAA1549-BRAF fusion gene is a hallmark for pilocytic astrocytomas, while diffuse pediatric gliomas lack the IDH mutations and 1p/19q codeletions that are common in adult astrocytomas and oligodendrogliomas. Uncommon in adults, Histone H3.3 mutations are pathognomic in pediatric brainstem malignant gliomas. Molecular subgroups of medulloblastomas have also been identifi ed, and a corresponding set of antibodies are ready to guide treatment decisions in those centres where molecular techniques are not available. These genetic and epigenetic events determine a tumor’s behaviour, and integrating this level of informations into neuropathology practice is essential to provide the best possible care to both pediatric and adult patients.]

Clinical Oncology

[The role of EGFR receptor family in the oncological practice]

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[The EGFR receptor family is a set of membrane tirosine kinase receptors with signifi cant homology which are responsible for cellular activation through intracellular signaling due to ligand binding. The four members of the family (EGFR1, EGFR2/HER2/neu, EGFR3/HER3, EGFR4/HER4) earned special interest in tumor biology while becoming one of the most potent targets of anti-cancer therapies. Changes in the receptor expression or in the kinase activity fundamentally modify cellular functions, survival and tumorigenic potential. Moreover, mutations are associated with reduced or altered treatment effi cacy. The basic function and major genetic and biological mechanisms affecting the function of EGFR receptors and related therapies are subjects of this overview.]