Primary Intracranial Sarcomas, Myxoid Meningeal Sarcoma - a Case Report and Literature Review.

BACKGROUND: Primary intracranial sarcoma is a rare disease. Due to the scarcity of evidence from randomized clinical trials, we follow the treatment guidelines of their extracranial counterparts or those published in case reports, while taking into consideration the specificity of radiotherapy within the brain, and the limit imposed on chemotherapy by the blood brain barrier. Nevertheless, surgery remains the golden standard of treatment for primary tumours, and also for recurrence. Even though there are usually narrow margins achieved in brain compared with the extracranial sarcomas. Despite significant effort, prognosis remains dismal. CASE: We present a 69-year old woman who was investigated for psychoorganic syndrome and paresis of the left hand. Magnetic resonance imaging revealed a tumour expansion in her frontal lobe with collateral oedema. Surgical resection was indicated. Histology of the specimen suggested a myxoid meningeal sarcoma. Early disease recurrence 4 months after primary resection was treated by reresection and 50 Gy of adjuvant radiotherapy to the tumour bed. Similarly, another recurrence 19 months after the second surgery was treated using the same approach. Systemic treatment has not been indicated so far. At this time, the patient is without evidence of any disease recurrence and continues with regular follow-up. CONCLUSION: Myxoid meningeal sarcoma represents a rare disease with a high risk of recurrence. Unfortunately, there is no clear recommendation for treatment algorithm. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Isocitrate Dehydrogenase Mutations are Better Prognostic Marker than O6-methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastomas - a Retrospective, Single-centre Molecular Genetics Study of Gliomas.

BACKGROUND: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are a promising prognostic biomarker of gliomas. The purpose of our study was to examine the clinical prognostic properties of IDH1/2 mutations in a glioma patient cohort from the Czech Republic using an improved platform for simple and reliable IDH genotyping. MATERIAL AND METHODS: We retrospectively analyzed a group of 145 glioma patients by testing for the three most frequent IDH mutations, IDH1 R132H, IDH1 R132C, and IDH2 R172K, through the competitive amplification of differentially melting amplicons (CADMA) polymerase chain reaction (PCR). O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, copy number of EGFR, p53, RB1, MDM2, CDKN2A genes, and deletions in 1p, 19q and 10p chromosomal regions were also analyzed and correlated with clinical characteristics. RESULTS: Of 145 gliomas, 36 harbored IDH1 R132H mutation and 1 IDH1 R132C mutation. We did not detect any IDH2 R172K mutation. IDH1 mutations were positively associated with MGMT methylation (OR 3.08, 95% CI 1.387-7.282; p = 0.007), 1p/19q co-loss (OR 8.85, 95% CI 2.367-42.786; p = 0.002) and negatively associated with epidermal growth factor receptor amplification (OR 0.12, 95% CI 0.019-0.437; p = 0.006) and 10p loss (OR 0.09, 95% CI 0.005-0.436; p = 0.019). The overall survival of IDH-mutant was 25 months, but only 9 months in IDH-wild type gliomas (p = 0.035); at the same time, survival associated with methylated vs. unmethylated MGMT promoter did not significantly differ (p = 0.166). CONCLUSION: Despite IDH1 mutations being closely associated with MGMT methylation in glioma patients, IDH1 mutations in glioblastoma patients are stronger marker of overall survival than MGMT methylation and should be the marker of choice, especially when using genotyping by CADMA PCR.Key words: isocitrate dehydrogenase - polymerase chain reaction - glioma - glioblastoma.

[A Patient with Primary Intraventricular Gliosarcoma and Long-term Survival - a Case Report]. / Pacientka s primárním intraventrikulárním gliosarkomem s dlouhodobým prezíváním - kazuistika.

BACKGROUND: Gliosarcoma is a rare, malignant CNS tumor with a very poor prognosis. Gliosarcoma is a variant of glioblastoma multiforme, which is characterized by the presence of both glial and mesenchymal components. The treatment strategy for gliosarcomas has not yet been determined clearly. CASE PRESENTATION: This case report presents a 23-year-old female patient who complained of increasing headaches, nausea and vomiting, and slight motor weakness in her left arm. An MRI scan of the brain showed a tumor filling the anterior part of the right lateral ventricle and extending into the right frontal lobe. Tumor extirpation was performed. Histology revealed gliosarcoma. Subsequently, the patient received concomitant chemoradiotherapy with temozolomide in the Stupp regimen. Following the fourth cycle of maintenance temozolomide chemotherapy, at eight months after diagnosis, an MRI scan detected progression of the tumor residue. The patient underwent another surgery and then received 10 cycles of second-line chemotherapy in the ICE (ifosfamide, carboplatin, and etoposide) regimen. She completed oncological therapy with minimal toxicity and follow-up MRI scans showed virtually no residual tumor. Another follow-up MRI scan, performed 28 months after diagnosis, demonstrated progression of the tumor residue again. A third tumor resection was performed 29 months after initial diagnosis. Histology again confirmed gliosarcoma. An early postoperative MRI scan showed subtotal resection with a tumor residue in eloquent areas and also suspected implantation metastasis in the spinal canal at the C2 level. From the neurological perspective, the patient was fully self-sufficient, and had only a very mild motor deficit in her left arm. Currently, at 31 months after initial diagnosis, the patient is in a stable condition and fully self-sufficient. CONCLUSION: Our case report shows that long-term survival can be achieved in a gliosarcoma patient exhibiting all the unfavorable features in clinical-pathological terms. The minimal recommended treatment is maximal resection followed by adjuvant radiotherapy. Our patient also underwent chemoradiotherapy with temozolomide in the Stupp regimen. Recurrence at eight months after diagnosis was managed by a repeat operation and high-dose combination chemotherapy, which kept the disease in remission for 20 months after the initial relapse. The lack of unequivocal rules for chemotherapy provides an opportunity to test less common treatment regimens.Key words: gliosarcoma - surgery - chemotherapy - radiotherapy - survivalThis study was supported in part by the grant No. NT13581-4/2012(86-91) of the Internal Grant Agency of the Czech Ministry of Health.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 26. 3. 2016Accepted: 27. 4. 2016.

[Multimodal Therapy of Recurrent Malignant Schwannoma]. / Kombinovaná lécba recidivujícího maligního schwannomu.

BACKGROUND: Malignant peripheral nerve sheath tumor schwannoma (MPNST), also known as malignant schwannoma, is a very rare tumor accounting for only 2% of all sarcomas. The prognosis is relatively poor, with a 5-year survival rate of 46-69%. The treatment of MPNST has not been standardized yet. Mainstay treatment is radical resection. Oncological adjuvant or neoadjuvant treatment has equivocal indications with unclear effects. CASE: The case report presents a 55-year-old patient who showed resistance in the medial-ventral area of the left lower limb. An MRI scan showed a tumor adjacent to the femoral nerve. Tumor extirpation was performed. Histology revealed malignant schwannoma (MPNST) and the resection was assessed as R0. Postoperative whole-body PET/CT revealed no viable tumor tissue. The patient was regularly followed-up. On a follow-up MRI scan, performed 53 months after initial surgery, tumor recurrence was detected in the left thigh. Extirpation of the recurrent tumor was performed. Histology confirmed MPNST and the resection radicality was assessed as R2. Postoperative PET/CT revealed tumor residues. Therefore, 58 months after the initial surgery, another operation of the residual tumor was performed with R0 resection. Three applicators for interstitial brachytherapy were placed in the resection cavity. Following the operation, radiotherapy with an interstitial brachytherapy boost of 18 Gy followed by external fractionated radiotherapy of 50 Gy were administered. The latest MRI scan, performed 66 months after the diagnosis of MPNST, showed no tumor tissue. The patient had no neurological deficit. CONCLUSION: The mainstay of treatment for MPNST is radical en bloc resection. The use of subsequent oncological therapy depends on the radicality of the resection. In our case, because of the good radicality of the initial surgery, adjuvant oncological therapy was postponed. As part of recurrence management, we again attempted to achieve the most radical resection possible and then apply adjuvant radiotherapy. In MPNST, as in all soft tissue sarcomas, high doses are chosen because of potential radioresistance. Given the confined nature of the disease, we chose this locally intensified therapeutic strategy, which resulted in this case in disease remission. Due to the low incidence of MPNST, it is not possible to test the efficacies of individual oncologic therapeutic procedures in larger patient cohorts.Key words: malignant schwannoma - soft tissue sarcoma - multimodal therapyThe authors declare they have no potential confl icts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 13. 3. 2016Accepted: 25. 4. 2016.

Glioblastoma multiforme in patients with history of extracranial cancer: Case series.

OBJECTIVES: Significant progress in treatment strategies improves the expectations of patients with extracranial cancers. Metastases are the primary consideration in patients with cancer history. In the case of neurologic disorders, the patient should undergo brain MRI. A rationale is presented for surgery, whole-brain or stereotactic radiotherapy, or chemotherapy. Recently, we have encountered misdiagnosed primary malignant brain tumours in patients with oncologic history who had been admitted for surgery for brain metastases. The aim of our study is to evaluate the incidence of concurrent cancers, to assess the relationship between previous cancer staging and primary brain tumour evaluation as well as to determine treatment efficiency. METHODS: From January 2007 to December 2011, we prospectively followed up patients with concurrent history of both extracranial cancer and subsequent glioblastoma multiforme. Information was collected on the clinical condition, imaging, history of extracranial cancer, previous and present surgical and oncologic procedures, and GBM histologic, cytogenetic, and molecular genetic investigations. RESULTS: Five patients were recruited: three females and two males. The average patient age at the time of GBM diagnosis was 65.6 years. Three patients had a history of breast carcinoma, one of renal carcinoma and one of colorectal carcinoma. Following the diagnosis of carcinoma, three patients received chemotherapy and radiotherapy, one patient had radiotherapy alone, and one had no adjuvant therapy. In all the cases, surgery revealed primary GBM, with a standard occurrence of genetic abnormalities (Table 1). The average time from the diagnosis of extracranial cancer to that of GBM was 4 years. Four patients underwent chemoradiotherapy and one had palliative radiotherapy. Two patients completed oncotherapy and their OS was 27 months and 19 months, respectively. One patient had post-surgical progression of hemiparesis. One patient had pulmonary embolism during oncotherapy and one had paraplegia caused by a pathological fracture of vertebras T5 due to breast carcinoma metastases. The OS was 11.8 months (range 3-27 months). All the patients succumbed to GBM progression.

[Patient with atypical neurocytoma -  case report]. / Pacientka s atypickým neurocytomem -  kazuistika.

BACKGROUND: Neurocytoma represents a rare tumor of the central nervous system usually slowly growing and generally with good prognosis after surgical resection with or without adjuvant radiotherapy. CASE: A 25-year- old woman presented with sudden fainting. During the initial workup, brain CT was completed with finding of tumor inside the third ventricle spreading into both lateral ventricles. The patient underwent partial surgical resection followed by radical gross resection, no adjuvant radiotherapy was indicated during the initial treatment and the patient was followed up with regular brain MRIs and clinical examinations. Thirty six months after the initial resection, there was progression on MRI and radiotherapy was recommended. At this moment, patient is 12 months after radiotherapy with stable disease on MRI and with good stable performance status. CONCLUSION: One of the greatest problems in the management of neurocytoma is the timing of adjuvant radiotherapy. From published data, it is clear that adjuvant radiotherapy increases local control; however, this has to be considered carefully against the possible risks from late side effects of radiotherapy considering long-time survival of the patients.

[Percutaneous interspinous dynamic stabilization (in-space) in patients with degenerative disease of the lumbosacral spine - a prospective study]. / Perkutánní interspinózní dynamická stabilizace (In-Space) u nemocných s degenerativním onemocnením lumbosakrální pátere - prospektivní studie.

INTRODUCTION: Interspinous spacers are supposed to reduce the segmental extension with a decrease in the expansion of yellow ligaments into the spinal canal, thus avoiding the dynamic narrowing of the spinal canal and compression of nerve roots. The aim of this study was to evaluate clinical outcomes and post-operative complications during one year in patients mostly having suffered from spinal stenosis and treated by In-Space interspinous spacer (Synthes, USA). MATERIAL AND METHODS: A total of 25 patients aged between 25 and 73 (average age 52.6) years, including 18 males and 7 females, with degenerative disease of the lumbosacral spine were indicated for surgery and prospectively followed up. The patients were operated on under general anaesthesia in the prone position, using a minimally invasive lateral percutaneous approach, under fluoroscopic control. The ODI and VAS values as well as X- rays (Range Of Motion and Sagittal angle of the operated segment) 6 and 12 months after the surgery were compared to each other and to those before surgery. The results were statistically analyzed. RESULTS: The average ODI of the group was 47.2% before surgery and 17.48% 6 months (22.76% 12 months) after surgery, showing a statistically significant improvement by 63% (52% after 12 months). The average VAS of the group was 6.64 points before surgery and 2.96 points 6 months (2.8 points 12 months) after surgery, which showed a statistically significant improvement by 55.4% after 6 months (57.8% after 12 months) when compared to preoperative status. After surgery the lordotic sagittal angle remained in all cases; one year after surgery the angle increased due to the slight sinking of some implants. The extent of segmental motion was minimally changed (6.1° 6 months and 7.24° 12 months after surgery). No serious complications occurred. The effect of interspinous implants proved insufficient in two cases (one year and two years after surgery) and conversion to arthrodesis or decompression was performed. CONCLUSIONS: 1. Percutaneous, minimally invasive insertion of an In-Space interspinous spacer is an effective and safe method of dynamic stabilization not accompanied by any serious complications. 2. ODI improved by 63% 6 months after surgery with a decrease in this effect 12 months after surgery. VAS for axial and radicular pain, as reported by patients, improved on average by 55.4% 6 months and by 57.8% 12 months after surgery. 3. In all cases, the lordotic sagittal angle remained after surgery and the extent of segmental motion from flexion to extension was minimally changed.

[Multiple spinal myeloma and its surgical management]. / Mnohocetný myelom pátere a jeho chirurgická lécba.

INTRODUCTION AND AIM: The management of spinal multiple myeloma (MM) is a complex process, including causal treatment (i.e. efforts to suppress the tumor clone), as well as supportive therapy, including surgery. The aim of this article is to present retrospective evaluation of surgical indications in patients with MM or solitary spinal plasmocytoma. MATERIAL: A total of 10 patients (8 males and 2 females) aged from 32 to 74 years (the mean age of 53.3) were included in the study. The enrolment criteria were the following: patients operated for MM or solitary spinal plasmocytoma during the past 7-year period, with the minimum follow up period of 6 months. The procedures were indicated for progressing neurological deficit (Frankel score) and for axial spinal pain (VAS classification), not responding to conservative therapy. The extent of the disease was assessed based on plain x-ray, MRI and whole- body 18F-FDG PET/CT. Paliative vertebroplasty was indicated in patients with no neurological deficit to control pain, paliative laminectomy without stabilization in subjects with partial neurological lesions, with transpedicular fixation in concomitant pathological fractures or kyphotizations. More radical approach, i.e. the procedure included somatectomy, was indicated in patients with solitary plasmocytoma and in procedures on cervical or thoracolumbar regions. Control clinical and MRI examinations were performed at 6 weeks, at 6 months and then at yearly intervals. At the end of the study, the authors evaluated effectivity of the employed surgical procedures, based on all control findings, and the data were compared with prognostic scoring systems in surgery for spinal metastases (Tomita score, Tokuhashi modified score and Bauer score). RESULTS: No local relapses of the tumor or stabilization failure were detected. The effect of surgery on pain control and on prevention of neurological dysfunction was maintained over the follow up period. The authors concluded that all surgical procedures and their radicality were adequate in all subjects. The agreement between the authors approach (the procedure's radicality) and the Tomita score, the Tokuhashi modified score and the Bauer score were recorded in 50% of patients, 80% of patients and in 50% of patients, respectively. DISCUSSION: MM is characterized by increased oseteolysis, which is not followed by new bone formation. Despite successful conservative therapy of MM, the bone defects fail to heal, cause spinal pain and may result in spinal instability. These specific MM signs represent the principal factor in the decision- making process concerning indication for surgery. Furthermore, favourable prognosis, with survival times usually exceeding the required expected minimum survival time of 3-6 months, is yet another reason for indication for surgical therapy in patients with spinal MM. Due to advances in chemotherapy and the use of autologic grafts of peripheral stem cells and radiotherapy, the prognosis of patients have significantly improved in last 10 years. The mean survival time has increased from 2.5 years to 4.5 years. CONCLUSION: 1. Prevention or improvement of neurological dysfuction and pain control are the main indication criteria for surgery in MM. 2. Surgery should be considered in MM with osteolytic spinal disorder and because of favourable prognosis of the disease when surgery is used. 3. Surgical procedures, including paliative methods resulted in sufficient control of spinal stability in all the study subjects. 4. Using all scoring systems for spinal metastases could result in indications for unnecessary more radical procedures. However, Tokuhashi score appeared to be the most suitable existing prognostic scoring system.

[Surgical treatment of thoracic disc herniation]. / Operace výhrezu hrudní meziobratlové ploténky.

PURPOSE OF THE STUDY: The aim of this study was to compare the efficiency of different surgical approaches to thoracic disc herniation, and to show the role of segmental fusion and selection of an appropriate microsurgical decompression technique for the successful outcome of surgery. MATERIAL: A group of 27 patients, 10 men and 17 women, between 31 and 70 years (average age, 49.33 years) were included in this prospective study. They underwent surgery for thoracic degeneration disc disease in the period from June 1994 to August 2008. METHODS: In all patients, the severity of myelopathy was assessed using the grading Frankel system and JOA score, axial and radicular pain intensity was evaluated with VAS and ODI rating systems. The diagnosis was established on the basis of thoracic spine radiography, thoracic spine MRI and a CT scan of the segment. A total of 30 thoracic segments, in the range of Th4/Th5 to Th12/L1, were indicated for surgery. Localisation of the hernia was medial at 19 segments, mediolateral at three and lateral at eight segments. Soft disc herniation was found in 17 cases and hard disc protrusion at the remaining 13 segments. Surgery for significant myelopathy was carried out in 23 patients and for pain in four patients. According to the surgical procedure used, the patients were allocated to two groups: group A comprised 10 patients treated without disc replacement through a laminectomy or a costotransversectomy exposure, and group B consisted of 17 patients undergo- ing intersomatic fusion via a thoracotomy. Clinical and radiographic examinations were made at regular intervals for at least 1 year of follow-up. The results of clinical assessment, including JOA scores, JOA Recovery Rate, VAS scores at rest and after exercise and ODI, were statistically analysed for each group and compared. RESULTS: There was a statistically significant difference in JOA evaluation of myelopathy between the groups in group A, the mean JOA score declined from 7.9 to 7.0, i.e., -0.9 point, while in group B it increased from 6.71 to 9.12, i.e., +2.41 points. The mean JOA Recovery Rate did not reach a plus value in group A, while in group B it improved by 55 %. JOA Recovery Rate: Of the seven patients in group A evaluated for myelopathy, a fair result was in one, unchanged in two and worse in four patients. Of the 16 patients evaluated for myelopathy in group B, the results were excellent in four, good in six, fair in four and unchanged in two patients. Frankel grade function: In group A, one patient improved by one grade, two remained unchanged, two deteriorated by one grade and two by two grades. In group B, five patients improved by one grade, two patients by two grades and two patients by three grades. Eight patients remained unchanged and no patient deteriorated. The post-operative pain intensity, as assessed by the mean VAS score, was lower at rest and after exercise in both groups; the score was better in group B, but the difference was not statistically significant. The ODI was evaluated only in group B its mean value improved from 41.4% to 26.1%, i.e., by 15.3%. DISCUSSION: Between 7 to 15 % of the patients have asymptomatic thoracic disc herniation, while symptomatic herniation is very rare and accounts for only 0.25 % to 0.57 % of herniated discs in the whole spine. Severe or progressive myelopathy is a clear indication for surgical intervention in thoracic disc herniation, but the role of surgery in pain control is controversial. There are five approaches for thoracic disc herniation. Transpleural anterolateral thoracotomy has an advantage over the other methods because it permits the treatment of all types of herniation, whether localised centrally, laterally or contralaterally, i.e., soft, calcified or sequestered intradural disc herniation. The results of treatment will depend on the outcome of surgical spinal cord decompression and the degree of spinal stabilisation achieved. CONCLUSIONS: The surgical procedure via thoracotomy with intersomatic fusion resulted in a statistically more significant improvement of myelopathy than the posterior approach without disc replacement, and it provided greater pain relief. The authors recommend to treat thoracic disc herniation by discectomy via a thoracotomy and by intersomatic fusion.

Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas.

Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA damage signalling in low- and high-grade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n=41) and grade IV GBM (n=60), we conclude that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (gammaH2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high- or low-oxygen culture conditions and in clinical specimens of both low- and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.

[Studies of YB-1 protein in breast tumors].

The multifunctional mammalian protein YB-1 is involved in multiple DNA- and mRNA-dependent events in the cell and regulates gene expression at different levels. The intracellular localization and relative mRNA content of YB-1 in the breast tumors were studied. The presence of cells with nuclear YB-1 localization in the tumor cell population is a poor predictor that correlates with larger tumors (more than 5 cm). The high YB-1 mRNA content in the breast tumors promotes metastasis of small neoplasms and patients with breast cancer who have high tumor tissue YB-1 mRNA levels may referred to as an early distant metastasis risk group. The findings suggest that combined determination of YB-1 intercellular localization and mRNA levels can ensure a more reliable prognosis of breast cancer.

Analysis of VEGF, Flt-1, Flk-1, nestin and MMP-9 in relation to astrocytoma pathogenesis and progression.

Astrocytomas, particularly high grade astrocytoma, are brain tumors with potent angiogenic activity. Our immnunohistochemical study assessed vascular endothelial growth factor (VEGF), VEGF receptors (Flk-1, and Flt-1), the intermediate filamental protein nestin which plays a role in central nervous system development, and MMP-9, which belongs the family of matrix metalloproteinases implicated in tumor invasion and angiogenesis regulation. We investigated the expression of VEGF, its receptors, nestin and MMP-9 in astrocytomas and their correlation with tumor grade. We used paraffin-embedded samples from 66 patients, 29 with low grade (WHO-grade II) and 37 with high grade (WHO-grade III and IV) astrocytomas. Antibodies against VEGF, Flk-1, Flt1, nestin, CD34 and MMP-9 were used, followed by standard indirect immunohistochemical methods. Expression of Flt-1 and Flk-1 showed no significant differences between low and high grade tumor groups. Expression of VEGF and MMP-9 was increased in the high grade group (p equal to or less than 0.026 and 0.024). Nestin expression in tumor astrocytes and endothelial cells increased in high grade group (p same 0.007 and 0.003). Higher expression of VEGF in high grade astrocytomas may subsequently lead to activation of survival, angiogenesis and migration. Expression of nestin and MMP-9 also suggest their likely role in astrocytoma vascular development and proliferation.

[Role of PTEN protein in multidrug resistance of prostate cancer cells].

In a past decade became evident that phosphatidylinositol-3-kinase controlled signal transduction cascade (PI3K/Akt/PTEN/mTOR) is implicated in resistance of tumor cells to anticancer drugs. Another well studied mechanism of multidrug resistance is associated with the activity of drug transporters of ABC superfamily (first of all P-glycoprotein (Pgp), MRP1, BCRP). Several mechanisms of cell defense can be turned on in one cell. The interconnections between different mechanisms involved in drug resistance are poorly studied. In the present study we used PC3 and DU145 human prostate cell lines to show that PTEN functional status determines level of cell resistance to some drugs, it correlates with expression level of MRP1 and BCRP proteins. We showed that Pgp is not involved in development of drug resistance in these cells. Transfection of PTEN into PTEN-deficient PC3 as well as rapamycin treatment caused the inhibition of PI3K/Akt/mTOR signaling and resulted in cell sensitization to the action of doxorubicin and vinblastine. We showed that PTEN transfection leads to the change in expression of MRP1 and BCRP. Our results show that in prostate cancer cells at least two mechanisms of drug resistance are interconnected. PTEN and mTOR signaling were shown: to be involved into regulation of MRP1 and BCRP.

Could changes in the regulation of the PI3K/PKB/Akt signaling pathway and cell cycle be involved in astrocytic tumor pathogenesis and progression?

The most frequent alterations found in astrocytomas are two major groups of signaling proteins: the cell cycle and the growth factor-regulated signaling pathways. The aim of our study was to detect changes in expression of the following proteins: the tumor suppressors PTEN, p53, and p21Waf1/Cip1, glial fibrillary acidic protein (GFAP, as a marker of astroglial differentiation), the phosphorylated form of protein kinase B/Akt (PKB/Akt), which is downstream to the epidermal growth factor receptor (EGFR), and MDM2, which degrades p53. Paraffin-embedded astrocytoma tissue samples from 89 patients were divided into low grade (grade I-II; 42 samples) and high grade astrocytomas (grade III-IV; 47 samples). Mouse monoclonal antibodies against GFAP, PTEN, PKB/Akt phosphorylated on serine 473, EGFR, p53, p21Waf1/Cip1 and MDM2 were used, followed by standard indirect immunohistochemical method. EGFR protein was detected in 29 % of low grade and in 60 % of high grade astrocytomas. The expression of phosphorylated PKB/Akt was found in roughly the same proportions: in 86% of low grade and in 79% of high grade astrocytomas. PTEN was not found in most of astrocytomas, 64% of low grade and 74% of high grade tumors showed no PTEN staining. Overexpression of the mutated form of p53 or loss of p53 expression, however, was found in about 63% in both groups of astrocytomas with no differences between them. GFAP expression was decreased in tumor astrocytes compared to normal astrocytes and this decreased with grading. GFAP positive tumor cells were detected in only 50% of low grade, and 32% of high grade astrocytomas. The level of MDM2 expression was similar in both grades. Loss of p21Waf1/Cip1 expression was shown in 20% of low and in 45% of high grade tumors. In the subgroup of high grade tumors with wild type p53, 86% showed p21Waf1/Cip1 expression, whereas in the subgroup of high grade tumors with altered p53, only 35% displayed p21Waf1/Cip1. We conclude that EGFR expression increases with astrocytoma grading. EGFR activation may subsequently lead to stimulation of the PKB/Akt survival pathway. PTEN defects may also participate in aggressive tumor behaviour through activation of the PKB/Akt pathway. The alteration of p53 supports the finding that the cell cycle regulation is also disrupted during development of astrocytomas. The changes in PTEN and p53 expression, and activation of PKB/Akt are events in the early stages of astrocytomagenesis. EGFR is one of the factors, which drives the progression of astrocytomas from low to high grade stage.

[Influence of intracranial pressure decrease in the pseudotumor cerebri syndrome on visual function]. / Vliv snízení nitrolebního tlaku u syndromu pseudotumoru mozku na zrakové funkce.

Authors describe ocular and neurological findings in a 68 years old female patient with the intracranial hypertension (pseudotumor cerebri). For developing edema of the optic nerve head on the fundus (oedema papillae), accompanied with lowered visual acuity and visual field defects, an urgent surgical treatment was indicated--the lumboperitoneal shunt was introduced. After the operation, although the atrophy of the optic nerve head atrophy occurred, the visual acuity was maintained and visual fields sensitivity improved.