Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial.

PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109.

Increases in both HIV and syphilis among men who have sex with men in Vietnam: Urgent need for comprehensive responses.

The objective of this study was to determine the temporal trends and factors associated with HIV and syphilis infection among men who have sex with men (MSM) in southern Vietnam. Data from the 2014-2018 national HIV sentinel surveillance of MSM aged 16 years or older were collected from three provinces, including An Giang (N = 761), Can Tho (N = 900), and Ho Chi Minh City (N = 1426), and examined for changes in prevalence rates of HIV and syphilis and risk behaviors over time. Multivariate logistic regression was performed to assess the trends and correlates of HIV and syphilis infections among MSM. There were upward trends for HIV (9.5% in 2014 to 14.2% in 2018, p-trend<0.01), syphilis (4.9% in 2014 to 8.0% 2018, p-trend<0.01), and HIV/syphilis co-infection (1.9% in 2014 to 3.1% in 2018, p-trend=0.01). Factors associated with HIV infection included place of residence, early sexual debut, consistent condom use and not engaging in anal sex during the past month, not knowing one's HIV test results, having ever injected drugs, and having active syphilis. Additionally, early sexual debut and being HIV positive were associated with syphilis infection. Rising prevalences of these infections among MSM suggests an urgent need for comprehensive intervention packages for HIV/STI prevention.

How we treat medulloblastoma in adults.

Medulloblastoma is a rare tumour in postpubertal patients and adults that is potentially curable. Several subgroups have been defined that are associated with clinical features, have different prognoses, and in some cases offer personalized treatment options. In adults, the sonic hedgehog (SHH) subtype is the most common subtype, followed by the wingless (WNT) and group 4 subtypes. Multimodal therapies allow 5-year overall survival rates of up to 70%. However, in adults, therapeutic evidence from prospective randomized trials is largely lacking. Therefore, regardless of individual risk, most patients are currently treated uniformly with craniospinal chemoradiation with a boost to the tumour bed, followed by maintenance chemotherapy, usually with alkylating agents. In Europe, the so-called Packer regimen, together with cisplatin-etoposide regimens, is the most commonly used chemotherapy option. Targeted treatment approaches have not yet been implemented, although tumour biology is well understood and offers personalized approaches, especially for the SHH subgroup. At relapse, rapid resistance occurs frequently, necessitating repositioning of these agents in an earlier treatment phase. Due to the good to intermediate prognosis, patients with medulloblastoma require structured long-term clinical follow-up including MRI of the brain, monitoring of side effects, and psychosocial and fertility counselling. Recently, clinical trials have been initiated with the aim of de-escalating treatment to reduce toxicity and adding targeted therapies to increase efficacy, with the main goal of therapy to cure the tumour while maintaining the physical and psychosocial integrity of affected patients. This article summarizes our opinion on the diagnosis and treatment of medulloblastoma in adults.

Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial.

BACKGROUND: Glioblastoma is a rapidly proliferating tumor. Patients bear an inferior prognosis with a median survival time of 14-16 months. Proliferation and repopulation are a major resistance promoting factor for conventionally fractionated radiotherapy. Tumor-Treating-Fields (TTFields) are an antimitotic modality applying low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with radiotherapy were reported in the preclinical setting. This study aims at examining the dosimetric consequences of TTFields applied during the course of radiochemotherapy. METHODS: Cone-beam-computed-tomography (CBCT)-data from the first seven patients of the PriCoTTF-phase-I-trial were used in a predefined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT)-treatment-plans as well as geometric analysis of the transducer-arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT's routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield-unit was assigned to the electrodes. After 6D-fusion with the planning-CT, the dose-distribution was recalculated using a Boltzmann-equation-solver (Acuros XB) and a Monte-Carlo-dose-calculation-engine. RESULTS: Overdosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5% of the prescribed dose in the first 2 mm below and also in deeper layers outside 1cm2 at highest dose as obtained from dose-volume-histogram comparisons. In the clinical target volume (CTV), underdosage was limited to 2.0% due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal-component-analysis (PCA) showed that the first principal-position-component of the variation of repeated array-placement in the direction of the largest variations and the perpendicular second-component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second-principal-component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. CONCLUSION: From a dosimetric point of view, dose deviations in the CTV due to transducer-arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radiochemotherapy and concurrent TTFields. PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. DRKS-ID: DRKS00016667. Date of Registration in DRKS: 2019/02/26. Investigator Sponsored/Initiated Trial (IST/IIT): yes. Ethics Approval/Approval of the Ethics Committee: Approved. (leading) Ethics Committee Nr.: 18-8316-MF, Ethik-Kommission der Medizinischen. Fakultät der Universität Duisburg-Essen. EUDAMED-No. (for studies acc. to Medical Devices act): CIV-18-08-025247.

Imaging Biomarkers for Adult Medulloblastomas: Genetic Entities May Be Identified by Their MR Imaging Radiophenotype.

BACKGROUND AND PURPOSE: The occurrence of medulloblastomas in adults is rare; nevertheless, these tumors can be subdivided into genetic and histologic entities each having distinct prognoses. This study aimed to identify MR imaging biomarkers to classify these entities and to uncover differences in MR imaging biomarkers identified in pediatric medulloblastomas. MATERIALS AND METHODS: Eligible preoperative MRIs from 28 patients (11 women; 22-53 years of age) of the Multicenter Pilot-study for the Therapy of Medulloblastoma of Adults (NOA-7) cohort were assessed by 3 experienced neuroradiologists. Lesions and perifocal edema were volumetrized and multiparametrically evaluated for classic morphologic characteristics, location, hydrocephalus, and Chang criteria. To identify MR imaging biomarkers, we correlated genetic entities sonic hedgehog (SHH) TP53 wild type, wingless (WNT), and non-WNT/non-SHH medulloblastomas (in adults, Group 4), and histologic entities were correlated with the imaging criteria. These MR imaging biomarkers were compared with corresponding data from a pediatric study. RESULTS: There were 19 SHH TP53 wild type (69%), 4 WNT-activated (14%), and 5 Group 4 (17%) medulloblastomas. Six potential MR imaging biomarkers were identified, 3 of which, hydrocephalus (P = .03), intraventricular macrometastases (P = .02), and hemorrhage (P = .04), when combined, could identify WNT medulloblastoma with 100% sensitivity and 88.3% specificity (95% CI, 39.8%-100.0% and 62.6%-95.3%). WNT-activated nuclear ß-catenin accumulating medulloblastomas were smaller than the other entities (95% CI, 5.2-22.3 cm3 versus 35.1-47.6 cm3; P = .03). Hemorrhage was exclusively present in non-WNT/non-SHH medulloblastomas (P = .04; n = 2/5). MR imaging biomarkers were all discordant from those identified in the pediatric cohort. Desmoplastic/nodular medulloblastomas were more rarely in contact with the fourth ventricle (4/15 versus 7/13; P = .04). CONCLUSIONS: MR imaging biomarkers can help distinguish histologic and genetic medulloblastoma entities in adults and appear to be different from those identified in children.

High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study).

To investigate immuno-chemotherapy for elderly immuno-competent patients (⩾65 years) with newly diagnosed primary central nervous system lymphoma, we conducted a multicentre single-arm trial. One cycle consisted of rituximab (375 mg/m2, days 1, 15, 29), high-dose methotrexate (3 g/m2 days 2, 16, 30), procarbazine (60 mg/m2 days 2-11) and lomustine (110 mg/m2, day 2)-R-MPL protocol. Owing to infectious complications, we omitted lomustine during the study and consecutive patients were treated with the R-MP protocol. Three cycles were scheduled and repeated on day 43. Subsequently, patients commenced 4 weekly maintenance treatment with procarbazine (100 mg for 5 days). Primary end point was complete remission (CR) after 3 cycles. We included 107 patients (69 treated with R-MPL and 38 with R-MP). In all, 38/107 patients achieved CR (35.5%) and 15 (14.0%) achieved partial remission. R-MP was associated with a lower CR rate (31.6%) compared with R-MPL (37.7%), but respective 2-year progression-free survival (All 37.3%; R-MP 34.9%; R-MPL 38.8%) and overall survival (All 47.0%; R-MP 47.7%; R-MPL 46.0%) rates were similar. R-MP was associated with less ⩾grade 3 toxicities compared with R-MPL (71.1% vs 87.0%). R-MP is more feasible while still associated with similar efficacy compared with R-MPL and warrants further improvement in future studies.

[Personalized therapy for gliomas]. / Personalisierte Gliomtherapie.

Current therapies for patients with malignant gliomas are starting to integrate molecular factors and age. Nonetheless, these therapies are still not sufficiently individualized. Some positive examples of transfer from basic science to clinical application are currently integrated into the standard treatment and guidelines. These are mainly genetic and other molecular factors that improve diagnosis and classification of gliomas and markers supporting prognostication. Examples for predictive biomarkers are methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter and the codeletion of chromosome arms 1p and 19q (1p/19q codel). The autoactive, truncated form of epidermal growth factor receptor (EGFRvIII) and the R132H mutation of isocitrate dehydrogenase 1 (IDH-1) are used as targets in currently running immunotherapeutic, targeted trials. Integration of functional imaging parameters into the monitoring and development of uniform assessment criteria improve the ability to evaluate therapy response and implement imaging biomarkers to guide therapies. As a result of the current efforts there are better classified prognostic groups and improved survival times with maintained functional and quality of life parameters in some glioma subgroups. Given the current dynamics, an improved, better differentiated classification of brain tumors including molecular parameters as well as more rational precise guiding of therapies with early, uniform response assessment is expected in the near future.

Low entomological impact of new water supply infrastructure in southern Vietnam, with reference to dengue vectors.

We did a prospective study in southern Vietnam where new water infrastructure was added. New 1,200-L tanks may present potential breeding grounds for Aedes aegypti, particularly when sealed lids were not always supplied. Some householders in these communes received a piped water supply, however there was no reduction in water storage practices. The prevalence of Aedes aegypti immatures in tank and tap households reached 73%, but were non-significantly different from each other and from control households that received no infrastructure. In all three communes, standard jars comprised from 48% to 71% of containers but were associated with > 90% of III-IV instars and pupae on occasions. In contrast, project tanks contributed from 0-21% of the total population. Non-functional or no lids were apparent 4 months after installation in 45-76% of new tanks, but there was no difference between communes with lids and without lids.

[Indications and outcome of ventilated patients treated in a neurological intensive care unit]. / Indikationen und Outcome beatmeter Patienten einer neurologischen Intensivstation.

OBJECTIVE: This study characterized artificially ventilated patients in a neurological intensive care unit (NICU) between 2006-2008 in a purely neurological clinic and a so-called stand-alone situation. In addition the long-term prognoses as well as the quality of life of surviving patients were investigated. METHODS: All ventilated patients from October 2006 to December 2008 were enrolled in this descriptive, retrospective study. The duration of stay in intensive care was analyzed and the current quality of life was prospectively assessed based on the patient records. Final diagnoses, duration of intensive care unit and ventilation as well as the highest score in SAPS II (simplified acute physiology score) and complications during hospitalization were determined. The patients were divided into groups based on the diagnoses as vascular, inflammatory, neurodegenerative, hereditary, epileptogenic and others. Additionally patients were contacted and asked to respond by completing questionnaires on the Barthel index (BI) and the modified Rankin scale (mRS). RESULTS: During the study period a total of 512 patients were treated in the NICU of whom 201 required artificial respiration. Cerebrovascular diseases were the main reason for therapy in the NICU in 96 out of 201 cases (47.8%), followed by inflammatory diseases in 46 (22.8%) and epileptogenic diseases in 26 patients (13%). The median duration of artificial respiration was 9 days with a mean treatment duration of 16 days (range 1-57 days). Of the patients 31 (15.4%) died in the NICU and an additional 32 patients (18.8%) died within a median of 2 months after discharge. Outcome data were available from 67 out of 170 sent questionnaires and rehabilitation reports of 86 patients, which enabled the outcome of 121 surviving patients to be analyzed (71.2%). Of these 42.2% showed no or mild impairment in everyday life. However, the remaining 38% had severe impairments according to the BI. The evaluation of the mRS showed that 49.6% of the patients still had severe symptoms. CONCLUSIONS: More than one third of the patients treated in the NICU required artificial ventilation with an emphasis on cerebrovascular diseases, which illustrates the overlap between stroke unit and NICU care. Despite a lengthy duration of ventilation and a long stay in the intensive care unit more than one third of surviving patients showed no or only mild impairment. However, an additional third suffered from severe disability up to nursing care dependency. The study data differ little from the few publications in this field despite the stand alone situation of the NICU. The case mix index per day averaged around 0.3 and underlines the economic importance with respect to other forms of neurological treatment.

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.

BACKGROUND: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. PATIENTS AND METHODS: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. RESULTS: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. CONCLUSIONS: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Targeted therapy for high-grade glioma with the TGF-ß2 inhibitor trabedersen: results of a randomized and controlled phase IIb study.

This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk-benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.

Householder perspectives and preferences on water storage and use, with reference to dengue, in the Mekong Delta, southern Vietnam.

Community-based perceptions and behaviour around water source preference, household water storage patterns and water use, and householders' knowledge and behaviour with respect to dengue etiology and transmission, were examined in three communes located in the Mekong Delta area in southern Vietnam. Through focus group discussions, most participants identified poorly screened or uncovered water containers (including household water storage containers and other types of artificial containers) as habitats for mosquitoes that transmit dengue viruses, and thereby demonstrated a clear understanding of the links between household water storage practices and the threat of dengue. Our qualitative analyses also revealed broader community-based concerns about the limited availability of water and strong preferences for storage of rainwater based upon perceptions of cost, quality and security of supply. These perceptions are central to shaping householders' responses to water infrastructure projects. The limited availability of water during the dry season and insufficient numbers of water storage containers are over-riding community concerns which provide an important context to understanding community behaviours and responses to public health interventions against dengue. Such concerns are important precursors to selecting the type of intervention.

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma.

BACKGROUND: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). METHODS: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). RESULTS: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). CONCLUSIONS: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.

Ultrasonic contrast agents in transcranial perfusion sonography (TPS) for follow-up of patients with high grade gliomas.

PURPOSE: The aim of this study was to evaluate brain perfusion differences in patients with high grade gliomas after partial tumor resection and irradiation/chemotherapy between tumor and non-tumor hemisphere by transcranial perfusion sonography (TPS) employing a contrast burst imaging (CBI) technique. METHODS: Six patients with glioblastoma (WHO Grade IV) in the temporoparietal region within the defined axial diencephalic scanning plane were examined by TPS during follow-up. All subjects had an adequate acoustic temporal bone window. Transtemporal insonation on brain tumor and non-tumor hemisphere was performed with a bolus-injection of sulphur hexafluoride-based contrast agent (10 mg i.v., 5mg/ml--SonoVue, Bracco, Altana, Switzerland). Recorded images were analysed off-line by Quanticon Software (3D-Echotech, Munich, Germany) and time intensity curve parameters [area under the curve (AUC, dB s), peak intensity (PI, dB), time to peak (TTP, s)] in five regions of interest (ROI) [thalamus anterior, thalamus posterior, nucleus lentiformis, white matter, whole hemisphere] were evaluated. Statistical analyses were performed. RESULTS: Perfusion differences between brain tumor and non-tumor hemispheres were detected with contrast burst imaging (CBI) technique with a significantly greater mean AUC (5343.69 dB s vs. 4625.04 dB s, p<0.028) and a significantly prolonged TTP (32.72 s vs. 28.91 s, p<0.046) in the tumor hemisphere. CONCLUSION: Within our study population, TTP and AUC seem to be the most robust parameters for the evaluation of cerebral perfusion differences assessed by transcranial perfusion sonography with CBI technique. We hypothesize that these results correlate with microvascular changes due to treatment regimens, such as microvessel necrosis after irradiation and chemotherapy. Above that, TPS may be of value for the long-term follow-up of brain tumor therapy concept.

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-beta2.

Versican is a large chondroitin sulphate proteoglycan produced by several tumour cell types, including high-grade glioma. The increased expression of certain versican isoforms in the extracellular matrix (ECM) plays a role in tumour cell growth, adhesion and migration. Transforming growth factor-beta2 (TGF-beta2) is an important modulator of glioma invasion, partially by remodeling the ECM. However, it is unknown whether it interacts with versican during malignant progression of glioma cells. Here, we analysed the effect of TGF-beta2 on the expression of versican isoforms. The expression of versican V0/V1 was upregulated by TGF-beta2 detected by quantitative polymerase chain reaction and immunoprecipitation, whereas V2 was not induced. Using time-lapse scratch and spheroid migration assays, we observed that the glioma migration rate is significantly increased by exogenous TGF-beta2 and inhibited by TGF-beta2-specific antisense oligonucleotides. Interestingly, an antibody specific for the DPEAAE region of glycosaminoglycan-beta domain of versican was able to reverse the effect of TGF-beta2 on glioma migration in a dose-dependent manner. Taken together, we report here that TGF-beta2 triggers the malignant phenotype of high-grade gliomas by induction of migration, and that this effect is, at least in part, mediated by versican V0/V1.

Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma.

We surveyed neuro-oncologists regarding patients treated with temozolomide for at least 12 cycles or 12 months. Patients receiving first-line temozolomide for a median 13 cycles had a median progression-free survival (PFS) of 14 months. Patients with recurrent disease receiving a median 14 cycles had a median PFS of 15.5 months. A small percentage of patients experienced grade III to IV toxicity. These results suggest that long-term treatment with temozolomide is feasible and well tolerated.

An imbalance between Smad and MAPK pathways is responsible for TGF-beta tumor promoting effects in high-grade gliomas.

The transforming growth factor-beta (TGF-beta) plays a pivotal role in the pathobiology of human gliomas: during carcinogenesis, it turns from a tumor suppressor to a tumor promoter. The traditional Smad pathway and the more recently discovered MAPK pathway are the most important pathways for TGF-beta related intracellular signal transduction mediating differential pathobiological effects. In this study, we investigated the effects of TGF-beta2 and the TGF-beta2 antisense phosphorothioate oligodeoxynucleotide (PTO) AS-11 on the functionality of both the Smad and MAPK pathways in high-grade gliomas. We aimed to correlate the imbalance between the pathways with differences in the behaviour of high-grade glioma cells. Gene and protein expression studies were used to detect levels of members of the Smad and MAPK pathways under regulation of TGF-beta2 and AS-11. Proliferation and migration assays were functional readouts for effects caused by these regulating tools. Gene arrays were used to detect yet unknown regulators of these functional effects. The Smad pathway was functional in the tested cell lines. Exogenous TGF-beta2 inhibited proliferation but enhanced migration. Smad 2 mRNA expression and activation were significantly reduced by incubation with AS-11. K-ras was reduced both in gene arrays and quPCR under treatment with AS-11, but there was no influence of K-ras down-regulation on the activity of ERK. Ubiquitination-related genes also were specifically down-regulated with AS-11. Our results indicate the involvement of K-ras in TGF-beta signaling in high-grade gliomas. ERK, which is a member of the MAPK pathway, was not influenced and seems to be activated through RAS independent cascades in glioma. These results suggest that combined antagonization of the TGF-beta and MAPK pathways might be a promising approach for glioma therapy. An imbalance between these two pathways might be responsible for TGF-beta switching to a tumor promoter protein in high-grade gliomas.

Low-dose chemotherapy in combination with COX-2 inhibitors and PPAR-gamma agonists in recurrent high-grade gliomas - a phase II study.

OBJECTIVES: Combined treatment approaches targeting tumor as well as other cells contributing to tumor progression may control chemorefractory malignancies. METHODS: A phase II trial was initiated to analyze the activity of continuously administered pioglitazone and rofecoxib combined with low-dose chemotherapy (capecitabine or temozolomide) in patients with high-grade gliomas (glioblastoma or anaplastic glioma). RESULTS: Fourteen patients were evaluable for response and toxicity. Major side effects were palmoplantar erythema, edema and motor neuropathy grade 3. Disease stabilizations lasting longer than 3 months were noted in 4 of 14 patients (29%). Clinical responses did not correspond to immunohistochemical staining for cyclooxygenase 2, peroxisome proliferator-activated receptor-gamma and CD31. DISCUSSION: The study demonstrates that this novel regimen is moderately active and well tolerated in patients with high-grade gliomas. As a comparably small proportion of patients responded, the regimen might only be suitable for a subset of highly selected patients.