WHO II-III Research Articles

Raman and autofluorescence spectroscopy for in situ identification of neoplastic tissue during surgical treatment of brain tumors

PurposeRaman spectroscopy (RS) is a promising method for brain tumor detection. Near-infrared autofluorescence (AF) acquired during RS provides additional useful information for tumor identification and was investigated in comparison with RS for delineating brain tumors in situ.MethodsRaman spectra were acquired together with AF in situ within the solid tumor and at the tumor border during routine brain tumor surgeries (218 spectra; glioma WHO II-III, n = 6; GBM, n = 10; metastases, n = 10; meningioma, n = 3). Tissue classification for tumor identification in situ was trained on ex vivo data (375 spectra; glioma/GBM patients, n = 20; metastases, n = 11; meningioma, n = 13; and epileptic hippocampi, n = 4).ResultsBoth in situ and ex vivo data showed that AF intensity in brain tumors was lower than that in border regions and normal brain tissue. Moreover, a positive correlation was observed between the AF intensity and the intensity of the Raman band corresponding to lipids at 1437 cm− 1, while a negative correlation was found with the intensity of the protein band at 1260 cm− 1. The classification of in situ AF and RS datasets matched the surgeon’s evaluation of tissue type, with correct rates of 0.83 and 0.84, respectively. Similar correct rates were achieved in comparison to histopathology of tissue biopsies resected in selected measurement positions (AF: 0.80, RS: 0.83).ConclusionsSpectroscopy was successfully integrated into existing neurosurgical workflows, and in situ spectroscopic data could be classified based on ex vivo data. RS confirmed its ability to detect brain tumors, while AF emerged as a competitive method for intraoperative tumor delineation.

Integrated Analysis of the Clinical and Molecular Characteristics of IDH Wild-Type Gliomas in the Chinese Glioma Genome Atlas.

PurposeCurrent studies and guidelines suggest that the biobehavior of IDH-wild type (IDH-wt) lower-grade glioma (LGG, WHO II-III) is similar to IDH-wt glioblastoma (GBM). However, differences in their clinical and molecular characteristics have not been reported. This study aimed to analyze the clinical and genetic information of gliomas with IDH-wt.Methods389 patients with IDH-wt were enrolled in the study (LGG=165, GBM=224), and their clinical and genetic information was collected from the Chinese Glioma Genome Atlas (CGGA). We conducted an analysis of this information between the two groups of patients and drew conclusions thereof.ResultsThe median age of the LGG patients was 42 (18–74) years, whereas that of the GBM patients was 51 (18–79) years (P < 0.010). GBM patients were more likely to undergo total resection (P = 0.018) and had fewer epileptic seizure symptoms (P < 0.001). The median overall survival (OS) was 55 months for the LGG patients and only 14.83 months for the GBM patients (P < 0.01). The median progression-free survival (PFS) was 44 months for the LGG patients and only 9.767 months for the GBM patients (P < 0.001). GBM patients were more prone to PETN mutations (P = 0.010). Transcriptome analysis showed that the differentially expressed genes in LGG patients were mainly enriched in metabolic pathways and pathways in cancer and in the function of signal transduction and positive regulation of GTPase activity, whereas in GBM patients, they were mainly enriched in the PI3K-Akt signaling pathway and in the functions of apoptotic process and oxidation-reduction process.ConclusionsOur data indicate that these two groups of patients should be re-evaluated and treated differently, despite both having IDH wild type.

Neuropsychological Function and Quality of Life after Resection of Suspected Lower-Grade Glioma in the Face Primary Motor Area.

The negative side effects of neurosurgical resection of the lower third of the primary motor cortex (M1) are often described as relatively mild. However, detailed descriptions of how these resections affect neurocognitive function, speech, mental health and quality of life (QoL) are sparse. In the present study, seven patients with suspected lower-grade glioma (WHO II-III) in the inferior M1 were assessed for facial motor function, cognitive function, anxiety and QoL before and after awake surgical resections. The main finding was that after surgery, six of the seven patients experienced a mild facial motor dysfunction, mainly affecting the mouth, tongue and throat. At the group level, we were also able to observe a significant postoperative decline in maximum verbal speed, whereas no negative effects on measures of word production (i.e., verbal fluency) were seen. Self-reported QoL data suggest that some patients experienced increased social isolation postoperatively but do not lend support to the interpretation that this was caused by direct neurological side effects of the surgery. The results appear to support the general notion that awake surgery in the lower M1 can be performed safely and with postoperative deficits that are most often perceived by the patient as tolerable.

An integrative analysis of genome-wide 5-hydroxymethylcytosines in circulating cell-free DNA detects noninvasive diagnostic markers for gliomas.

BackgroundGliomas, especially the high-grade glioblastomas (GBM), are highly aggressive tumors in the central nervous system (CNS) with dismal clinical outcomes. Effective biomarkers, which are not currently available, may improve clinical outcomes through early detection. We sought to develop a noninvasive diagnostic approach for gliomas based on 5-hydroxymethylcytosines (5hmC) in circulating cell-free DNA (cfDNA).MethodsWe obtained genome-wide 5hmC profiles using the 5hmC-Seal technique in cfDNA samples from 111 prospectively enrolled patients with gliomas and 111 age-, gender-matched healthy individuals, which were split into a training set and a validation set. Integrated models comprised 5hmC levels summarized for gene bodies, long noncoding RNAs (lncRNAs), cis-regulatory elements, and repetitive elements were developed using the elastic net regularization under a case–control design.ResultsThe integrated 5hmC-based models differentiated healthy individuals from gliomas (area under the curve [AUC] = 84%; 95% confidence interval [CI], 74–93%), GBM patients (AUC = 84%; 95% CI, 74–94%), WHO II-III glioma patients (AUC = 86%; 95% CI, 76–96%), regardless of IDH1 (encoding isocitrate dehydrogenase) mutation status or other glioma-related pathological features such as TERT, TP53 in the validation set. Furthermore, the 5hmC biomarkers in cfDNA showed the potential as an independent indicator from IDH1 mutation status and worked in synergy with IDH1 mutation to distinguish GBM from WHO II-III gliomas. Exploration of the 5hmC biomarkers for gliomas revealed relevance to glioma biology.ConclusionsThe 5hmC-Seal in cfDNA offers the promise as a noninvasive approach for effective detection of gliomas in a screening program.

Evaluation of Genetic Variants in Signaling Pathway Genes as Prognostic Biomarkers for Nasopharyngeal Carcinoma

We hypothesized that genetic variants in signaling pathways identified by next generation sequencing (NGS) are novel prognostic biomarkers for nasopharyngeal carcinoma. The purpose of this study was to evaluate gene variants in Adherens junction, PI3K-Akt, AMPK, Wnt and mTOR signaling pathway genes in patients with nasopharyngeal carcinoma (NPC) to predict treatment response and survival. A total of 32 NPC patients were enrolled from February 2018 to November 2018. Eligible patients were aged 33-66 years with histologically proven WHO Ⅱ-Ⅲ, stage Ⅱ-ⅣB (AJCC 7th) NPC. All patients received induction chemotherapy followed by concurrent chemoradiotherapy. Paraffin-embedded endoscopically NPC samples by endoscopic biopsy were available for all patients. The custom next generation sequencing assay was used to detect exons of 288 genes, introns, promoters or fusion in the dot region of 38 genes and partial exons of 728 genes related to NPC. Alterations of genes encoding the components of Adherens junction, PI3K-Akt, AMPK, Wnt and mTOR signaling pathway were detected. The association between genetic variants in these signaling pathway genes and treatment response and survival of NPC patients were analyzed. Patients with genetic variants in PI3K-Akt (HR = 0.32, P = 0.023), AMPK (HR = 0.26, P = 0.033), and mTOR (HR = 0.21, P = 0.016) signaling pathway genes had significantly inferior complete response rates as compared to patients without such genetic variants. Presence of gene variants in PI3K-Akt (P = 0.045), AMPK (P = 0.005) and mTOR signaling pathway (P = 0.001) were associated with significantly inferior 1-year regional failure-free survival (RFFS) and disease-free survival (DFS). No significant differences were observed in local failure-free survival (LFFS), distant metastasis-free survival (DMFS), and overall survival (OS) in patients with or without genetic variants in all of these signaling pathways. Gene variants in PI3K-Akt, AMPK and mTOR signaling pathway were associated with significantly inferior treatment response and disease-free survival in NPC patients. Gene variants in these signaling pathways identified by NGS profiling are potential novel prognostic markers for NPC.

P967 Profile of arrhythmia in pregnant women with different WHO class is similar

Abstract Background Arrhythmia is the most common cardiac complications during pregnancy especially in women with structural heart disease. Methods: Since January 2015 till December 2018 the consecutive 150 pregnant women with different maternal cardiovascular risk according to WHO classification: 100 in WHO I and II (gr 1);50 in WHO II-III, III, IV were enrolled. Each woman had 24-hour Holter- ECG monitoring during at least 2 trimester. Results: Except mild ventricular arrhythmia i.e ventricular extrasystole &amp;gt; 1000 per 24 hour, which occured more often in group1, we did not observe any significant differences in arrhythmic profile of pregnant women with different WHO risk classification (table 1). Delivery: Caesarean section was more frequent in gr 2 (86% vs 62%) but rate of stillbirths were similar among groups. Maternal death did not occurred, there was 2 (4%) foetal mortality in gr 2. Mean duration of pregnancy, children length and birthweight were significantly higher in gr 1(table1).Conclusion: Arrhythmias during pregnancy occurred particularly on the substrate of structural heart disease. According to our observation pregnant women with potentially higher risk of maternal cardiovascular events did not reveal significant arrhythmia including conduction disturbances in comparison to women in WHO class I or II. Holter monitoring resultes Parameter Group 1; no 100 Group 2, no 50 P value Age 31(27-34) 31(28-33) 0,36 NYHA 1,34 1,32 0,76 SVE &amp;gt; 1000/d 2(2,15%) 2(5,88%) 0,28 VE &amp;gt; 1000/d 20(19,23%) 3(5,88%) 0,03 SVT 6(6,5%) 4(11,43%) 0,35 sVT 1(1%) 0 0,65 nsVT 8(8,79%) 3(8,57%) 0,96 AF/AT 0 2(4%) 0,54 AV I 5(5%) 3(6%) 0,32 AV II Mobitz I 1(1,1%) 1(2%) 0,53 AV III 0 1(2%) 0,41 Duration (weeks) 39(38-40) 37,1 0,017 Weight (grams) 3220+-641 2840+-767 g 0,02 Caesareon section 54(62%) 33(86%) 0,00 Stillbirths 22(21,57% 8(17,78%) 0,6

1143P - Induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC)

BackgroundCurrent treatment of locoregionally advanced NPC (LRA-NPC) is CCRT with or without adjuvant chemotherapy (CT). The value of adding IC to CCRT in LRA-NPC is unclear. We retrospectively evaluated LRA-NPC patients treated with IC followed by CCRT in a single tertiary center in Turkey. MethodsBetween 2004 and 2016, 202 patients with nonmetastatic LRA-NPC (stage 3-4), 144 males and 58 females ranging from 17 to 75 (median 49) years old, were treated with IC followed by CCRT. Eleven (%5.4) patients had keratinised (WHO I), and 191 (%94.6) had nonkeratinised or undiffrentiated (WHO II-III) carcinoma. Cumulative radiation dose to primary tumor ranged from 60 to 74 (median 70) Gy. Ninety-one (%45) of the patients received 2-dimensional and 111 (%55) received intensity modulated radiotherapy (IMRT). IC consisted of taxane (T)(75mg/ m2) and platinum (P)(75mg/m2) combination (199 patients) or P and fluorouracil or epirubicine (3 patients) combination and 188 of the patients received 3 cycles of IC. Concomittant P was used either weekly (40mg/m2, 25 patients) or every 3-weekly (100mg/m2, 177 patients) application. Follow-up ranged from 5 to 167 months (median, 72.5 months).Table: 1143PTable: 1143PPatient and treatment characteristicsn ( % )StageIII IVA IVB149 (73.7%) 30 (14.9%) 23 (11.4%)Number of induction courses2 3 410 (5%) 188 (93.1%) 4 (2%)Concomittant typeEvery 3 weeks (100mg/m2) Every week (40mg/m2)177 (87.6%) 25 (12.4%)RT technique2-dimensional Intensity modulated91 (45%) 111 (55%)Radiation dose to primary (Gy)≤ 70 > 708 (4%) 194 (96%) ResultsTreatment failure was observed in 52 (%25.7) of the patients (21 local, 13 regional and 27 distant). Distant failure rate of all the patients exceeds 13%. Five and 10 years disease free survival (DFS) rates are 75.2% and 70.4% and overall survival (OS) rates are 78.9% and 64% respectively. In univariate analysis patient age favoring those below 49 and stage of disease favoring WHO II-III were all significant predictors of DFS and OS. In addition pathology was a significant predictor of DFS. ConclusionsLRA-NPC patients treated with IC followed by CCRT have a high locoregional control (LRC) rate. Despite the use of IC distant control remains insufficient and continues to be a challenge in NPC. Besides improving LRC, more effective systemic therapy is needed. Legal entity responsible for the studyMusa Altun, MD. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma(NPC) patients treated between 2004 and 2016: Patient and treatment characteristics and long term outcome.

e17507 Background: Standard treatment of locoregionally advanced nasopharyngeal carcinoma (LRA-NPC) is CCRT with or without adjuvant chemotherapy (CT). The value of adding IC to CCRT in LRA-NPC is unclear. We aimed to retrospectively evaluate LRA-NPC patients treated with IC followed by CCRT and analyse patient, tumor, treatment characteristics and outcome. Methods: Between 2004 and 2016, 202 patients with nonmetastatic LRA-NPC (stage 3-4), 144 males and 58 females ranging from 17 to 75 (median 49) years old were treated with IC followed by CCRT. Eleven (%5.4) patients had keratinised (WHO I), and 191 (%94.6) had nonkeratinised or undiffrentiated (WHO II-III) carcinoma. Cumulative radiation dose to primary tumor ranged from 60 to 74 (median 70) Gy. Ninety-one (%45) of the patients received 2-dimensional and 111 (%55) received intensity modulated radiotherapy (IMRT). IC consisted of taxane (T)(75 mg/ m2) and platinum (P)(75 mg/m2) combination (199 patients) or P and fluoruracil or epirubicine (3 patients) combination and 188 of the patients received 3 cycles of IC. Concomittant P was used either weekly (40 mg/m2, 25 patients) or every 3-weekly (100 mg/m2, 177 patients) application. Follow-up ranged from 5 to 167 months (median, 72.5 months). Results: Treatment failure was observed in 52 (%25.7) of the patients (21 local, 13 regional and 27 distant failures). Distant failure rate of all the patients exceeds 13%. Five and 10 years disease free survival (DFS) rates are 75.2% and 70.4% and overall survival (OS) rates are 78.9% and 64% respectively. In univariate analysis patient age favoring those below 49 and stage of disease favoring WHO II-III were all significant predictors of DFS and OS. In addition pathology was a significant predictor of DFS. Conclusions: LRA-NPC patients treated with IC followed by CCRT have a high locoregional control rate. Despite the use of systemic (induction) chemotherapy distant control remains insufficient and continues to be a challenge in NPC treatment. Besides improving locoregional control more effective systemic therapy is needed. [Table: see text]

MRI predictive score of pial vascularization of supratentorial intracranial meningioma.

Meningiomas are highly vascularized tumors which may recruit pial blood supply. Pial supply complicates tumor treatment in numerous ways. The objective of this study was to establish a reliable MRI-based diagnostic score to predict the existence of pial blood supply in supratentorial intracranial meningiomas and then correlate the score with clinical and surgical outcomes and histopathological findings. We performed a retrospective analysis of supratentorial histologically proven meningiomas in our institution from 2010 to 2018. A score was built based on MRI criteria and correlated with digital subtraction angiography (DSA) pial vascularization assessment. The score was then validated on a second independent population recruited with the same modalities. Logistic regression identified four parameters related to pial blood supply which were used to build the score: skull base location, tumor size > 45mm, peritumoral flow voids, and incomplete cerebrospinal fluid rim. The overall diagnostic performance in predicting pial blood supply was as follows: sensitivity 97.8%, specificity 76.9%, predictive positive value 88.2%, negative predictive value 95.2%, and accuracy 90.3%. Inter-reader agreement and Cohen's kappa were good, respectively, of 90.7% and 0.69. A high score was associated with aggressive meningioma (World Health Organization II-III) (p = 0.04) and with greater importance of pial supply relative to dural supply. We have identified a reliable way to use MRI to predict the existence of pial blood supply in supratentorial intracranial meningiomas. A higher score also predicted higher grade meningioma. • Accurate and reproducible MRI score composed of four items to predict the existence of pial blood supply in supratentorial meningioma. • High score is associated with high-grade meningioma (WHO II-III) but also with greater importance of pial supply relative to dural supply.

Genetic and Epigenetic Features of Rapidly Progressing IDH-Mutant Astrocytomas.

IDH-mutant astrocytomas are significantly less aggressive than their IDH-wildtype counterparts. We analyzed The Cancer Genome Atlas dataset (TCGA) and identified a small group of IDH-mutant, WHO grade II-III astrocytomas (n = 14) with an unexpectedly poor prognosis characterized by a rapid progression to glioblastoma and death within 3 years of the initial diagnosis. Compared with IDH-mutant tumors with the typical, extended progression-free survival in a control group of age-similar patients, the tumors in the rapidly progressing group were characterized by a markedly increased level of overall copy number alterations ([CNA]; p = 0.006). In contrast, the mutation load was similar, as was the methylation pattern, being consistent with IDH-mutant astrocytoma. Two of the gliomas (14%) in the rapidly progressing, IDH-mutant group but none of the other grade II-III gliomas in the TCGA (n = 283) had pathogenic mutations in genes (FANCB and APC) associated with maintaining chromosomal stability. These results suggest that chromosomal instability can negate the beneficial effect of IDH mutations in WHO II-III astrocytomas. The mechanism of the increased CNA is unknown but in some cases appears to be due to mutations in genes with a role in chromosomal stability. Increased CNA could serve as a biomarker for tumors at risk for rapid progression.

MEGF10, a Glioma Survival-Associated Molecular Signature, Predicts IDH Mutation Status.

Glioma is the most common primary brain tumor with various genetic alterations; among which, IDH mutation is the most common mutation and plays an important role in glioma early development, especially in lower grade glioma (LGG, WHO II-III). Previous studies have found that IDH mutation is tightly associated with extensive methylation across whole genome in glioma. To further investigate the role of IDH, we obtained methylation data of 777 samples from CGGA (Chinese Glioma Genome Atlas) and TCGA (The Cancer Genome Atlas) with IDH mutation status available. A package compiled under R language called Tspair was used as the main analytic tool to find potential probes that were significantly affected by IDH mutation. As a result, we found one pair of probes, cg06940792 and cg26025891, which was capable of predicting IDH mutation status precisely. The hypermethylated probe was cg06940792, designed in the promoter region of MEGF10, while the hypomethylated probe was cg26025891, designed in the promoter region of PSTPIP1. Survival analysis proved that hypermethylation or low expression of MEGF10 indicated a favorable prognosis in 983 glioma samples. Moreover, gene ontology analysis demonstrated that MEGF10 was associated with cell migration, cell proliferation, and regulation of apoptosis in glioma. All findings above can be validated in three other independent cohorts. In a word, our results suggested that methylation level and mRNA expression of MEGF10 in glioma were not only correlated with IDH mutation but also associated with clinical outcome of patients, providing potential guide for future dissection of IDH role in glioma.

Perfusion and diffusion MRI signatures in histologic and genetic subtypes of WHO grade II–III diffuse gliomas

The value of perfusion and diffusion-weighted MRI in differentiating histological subtypes according to the 2007 WHO glioma classification scheme (i.e. astrocytoma vs. oligodendroglioma) and genetic subtypes according to the 2016 WHO reclassification (e.g. 1p/19q co-deletion and IDH1 mutation status) in WHO grade II and III diffuse gliomas remains controversial. In the current study, we describe unique perfusion and diffusion MR signatures between histological and genetic glioma subtypes. Sixty-five patients with 2007 histological designations (astrocytomas and oligodendrogliomas), 1p/19q status (+ = intact/- = co-deleted), and IDH1 mutation status (MUT/WT) were included in this study. In all patients, median relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were estimated within T2 hyperintense lesions. Bootstrap hypothesis testing was used to compare subpopulations of gliomas, separated by WHO grade and 2007 or 2016 glioma classification schemes. A multivariable logistic regression model was also used to differentiate between 1p19q+ and 1p19q- WHO II-III gliomas. Neither rCBV nor ADC differed significantly between histological subtypes of pure astrocytomas and pure oligodendrogliomas. ADC was significantly different between molecular subtypes (p = 0.0016), particularly between IDHWT and IDHMUT/1p19q+ (p = 0.0013). IDHMUT/1p19q+ grade III gliomas had higher median ADC; IDHWT grade III gliomas had higher rCBV with lower ADC; and IDHMUT/1p19q- had intermediate rCBV and ADC values, similar to their grade II counterparts. A multivariable logistic regression model was able to differentiate between IDHWT and IDHMUT WHO II and III gliomas with an AUC of 0.84 (p < 0.0001, 74% sensitivity, 79% specificity). Within IDHMUT WHO II-III gliomas, a separate multivariable logistic regression model was able to differentiate between 1p19q+ and 1p19q- WHO II-III gliomas with an AUC of 0.80 (p = 0.0015, 64% sensitivity, 82% specificity). ADC better differentiated between genetic subtypes of gliomas according to the 2016 WHO guidelines compared to the classification scheme outlined in the 2007 WHO guidelines based on histological features of the tissue. Results suggest a combination of rCBV, ADC, T2 hyperintense volume, and presence of contrast enhancement together may aid in non-invasively identifying genetic subtypes of diffuse gliomas.

Do relevant markers of cancer stem cells CD133 and Nestin indicate a poor prognosis in glioma patients? A systematic review and meta-analysis.

BackgroundCD133 and Nestin, as the markers of cancer stem cells, have recently been reported frequently in the pathogenesis and development of human gliomas. However, the prognostic role of CD133 and Nestin in gliomas still remains controversial. In this study, we aimed to evaluate the association between the expression of CD133 and Nestin and the outcome of glioma patients by conducting a systematic review and meta-analysis.MethodsWe performed systematically electronic and manual searches through the database of Pubmed and embase (until to December 25, 2014) for titles and abstracts which investigated the relationships between CD133 and Nestin expression and outcome of glioma patients. A systematic review and meta-analysis was executed to generate Pooled hazard ratios (HRs) with 95 % confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS).ResultsA total of 1,490 patients from 32 studies (13 articles) were included in the analysis. 19 studies and 13 studies investigated correlation between CD133 expression or Nestin and survival in gliomas, respectively. Our results showed that high CD133 expression in patients with glioma was associated with poor prognosis in terms of OS (HR 1.69; 95 % CI, 1.16–2.47; P =0.0060) and PFS (HR, 1.64; 95 % CI, 1.12–2.39; P = 0.010). In addition, high Nestin expression were associated with worse OS (HR 1.751; 95 % CI, 1.19–2.58, p = 0.004) but has no significant association with PFS (HR 1.55; 95 % CI, 0.96–2.51, p = 0.074). Even more important, the results of the subgroup meta-analyses show that that high CD133 expression was associated with worse prognosis in terms of OS and PFS in patients with WHO IV glioma but not WHO II-III. On the other hand, Nestin high expression was associated with worse prognosis in terms of OS and PFS in patients with WHO II-III glioma but not WHO IV.ConclusionHigh level of CD133 expression trends to correlate with a worse OS and PFS in glioma patients, especially WHO IV gliomas and Nestin high expression trends to correlate with a worse OS in glioma patients especially WHO II–III, revealing both the markers of cancer stem cells may as the potential pathological prognostic markers for glioma patients.

P17.78 * SECONDARY GLIOBLASTOMA - OUTCOME AND PROGNOSTIC FACTORS

BACKGROUND: Prognostic factors and outcome of patients with primary glioblastoma (GBM) are well reported. In contrast, there is limited information about patients with secondary GBM (sGBM). The goal of this work was to report on the outcome of patients with sGBM and to identify prognostic factors. METHODS: We retrospectively analyzed our institutional database of brain tumor patients for clinical patient data. All patients had histological proof of WHO II-III glioma and subsequent WHO IV secondary glioblastoma. Using paraffin embedded tissue we screened for mutations of the isocitrate dehydrogenase-1 (IDH-1) using immunohistochemical staining (IHC) with an R132H (clone H09) specific antibody. We performed uni- and multivariate analyses to identify factors potentially affecting survival. RESULTS: We analyzed 45 patients with histologically proven sGBM. Median age was 41 years. 31 patients underwent radiologically complete resection of sGBM, 14 underwent subtotal resection or biopsy only. Initially, 36 patients had astrocytic tumors, the other suffered from oligodendrogliomas or mixed gliomas; at first diagnosis, there were 18 WHO II tumors, and 27 were WHO III. Median time between first glioma diagnosis and occurence of sGBM was 158.9 weeks; median overall survival (OS) following diagnosis of sGBM was 63.6 weeks. IDH-1 mutations were present in 24 patients and absent in 17; in 4 patients, IHC could not be performed. On univariate analysis, time between first diagnosis and progression to sGBM was a statistically significant factor - patients with an interval >2 years had a better OS (67.4 vs. 60.1 weeks, p = 0.027). Also, patients receiving combined adjuvant radio- and chemotherapy did better than those who only had either therapy (87.3 vs. 54.3 weeks). Following multivariate analysis, IDH-1 (R132H) mutation was associated with longer OS (p = 0.012); there was a trend for patients with initial WHO II tumors having a better prognosis (p = 0.057). Using patient specific data, we established two prognostic groups; patients in the good prognosis group appeared to benefit from complete tumor removal (p = 0.06), while resection did not play a role for the other (p = 0.97). CONCLUSION: Although of relatively young age, prognosis of patients with sGBM is dismal. IDH-1 (R132H) mutation and WHO grade of the initial tumor are associated with OS after progression to sGBM. Patients in the good prognosis group appear to benefit from complete tumor removal, while the others do not.

Epigenetically mediated downregulation of the differentiation-promoting chaperon protein CRABP2 in astrocytic gliomas

Impairment of endogenous differentiation pathways like retinoic acid (RA) signaling seems to be a central pathogenetic event in astrocytic gliomas. Among others, expression of the differentiation-promoting RA chaperon protein cellular retinoic acid binding protein 2 (CRABP2) is extenuated in high-grade gliomas. Against this background, we aimed at identifying potential pathomechanisms underlying reduced CRABP2 expression in these tumors. Using MassARRAY methylation analysis, we detected extensive CpG methylation upstream of the CRABP2 gene locus in a study sample comprising 100 astrocytic gliomas of WHO Grade II to IV. Compared to nontumorous control samples, tumors revealed increased CpG methylation and methylation levels were inversely correlated to CRABP2 mRNA expression. Substantiating our in situ findings, CRABP2 mRNA levels increased in glioma cell lines after exposure to the demethylating agent 5-aza-2'-deoxycytidine. Finally, a distinct CpG methylation signature distinguished between primary glioblastoma on the one hand and the group of astrocytoma WHO II-III and secondary glioblastoma on the other hand. Altogether, our observations suggest that epigenetic silencing of CRABP2 might contribute to an immature phenotype in glioma cells.

FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading

Treatment and prognosis of gliomas depend on their histological tumour grade. The aim of the study was to evaluate the potential of [(18)F]fluoroethyltyrosine (FET) PET for non-invasive tumour grading in untreated patients. Dynamic FET PET studies were performed in 54 patients who, based on MRI, were estimated to have low grade (LG; n = 20), intermediate (WHO II-III; n = 4) or high grade (HG; n = 30) tumours. For standard evaluation, tumour SUV(max) and the ratio to background (SUV(max)/BG) were calculated (sum image: 20-40 min). For dynamic evaluation, mean SUV values within a 90% isocontour ROI (SUV90) and the SUV90/BG ratios were determined for each time frame to evaluate the course of FET uptake. Results were correlated with histopathological findings from PET-guided stereotactic biopsies. Histology revealed gliomas in all patients. Using the standard method a statistically significant difference (p = 0.001) was found between LG (n = 20; SUV(max)/BG: 2.16 +/- 0.98) and HG (n = 34; SUV(max)/BG: 3.29 +/- 1.06) gliomas (opt. threshold 2.58: SN71%/SP85%/area under ROC curve [AUC]:0.798), however, with a marked overlap between WHO II to IV tumours. Time activity curves showed slight increase in LG, whereas HG tumours presented with an early peak (10-20 min) followed by a decrease. Dynamic evaluation successfully separated LG from HG gliomas with higher diagnostic accuracy (SN94%/SP100%/AUC:0.967). Based on the ratio-based method, a statistically significant difference was found between LG and HG gliomas. Due to the interindividual variability, however, no reliable individual grading was possible. In contrast, dynamic evaluation allowed LG and HG gliomas to be differentiated with high diagnostic power and, thus, should supplement the conventional method.

Nitrendipine Treatment in So-Called Therapy-Resistant Arterial Hypertension; Effect as Monotherapy and in Combination with Propranolol on Blood Pressure, Heart Rate, Other Hemodynamic Parameters, Plasma Renin Activity, and Catecholamines

Twenty-three patients [mean age 49.7 +/- 5.6 years (WHO II-III)] with severe hypertension and not responding to previous drug treatment were included in the study to evaluate the effect of nitrendipine (NTP) as monotherapy and also in combination with propranolol (PRO). After a control period of 10 days, NTP was started with 20 mg twice a day and titrated to the maximal dosage of 2 X 40 mg/day. After 1 week of NTP treatment, PRO was added in increasing dosage to a maximal 2 X 100 mg/day. NTP lowered systolic and diastolic blood pressure (BP) significantly (supine BP from 182/119 +/- 19/9 to 157/98 +/- 16/9 mm Hg). After combination with PRO, systolic BP was decreased additionally (supine BP from 157/98 +/- 16/9 to 150/97 +/- 19/9 mm Hg). Plasma norepinephrine (NE) was increased by NTP (from 1.82 +/- 0.78 to 2.38 +/- 1.08 nmol/l, p less than 0.01) and remained elevated during PRO treatment (2.76 +/- 1.10 nmol/l). Plasma renin activity (PRA) showed no significant changes by NTP. Additional effect of PRO on BP correlated significantly with NE and PRA after the NTP period. Plasma epinephrine and dopamine beta-hydroxylase remained unchanged. NTP decreased systemic resistance, calculated from isotope dilution technique (p less than 0.05); after combination with PRO no additional significant changes were registered. Nitrendipine is an effective alternative in so-called therapy-resistant hypertension.