Search

Contains fulltext : 299621.pdf (Publisher’s version ) (Closed access), Neurofibromatosis type 1 (NF1) is a hereditary, progressive and unpredictable disease, which can involve many organs. Benign and malignant tumors arise due to unrestrained cell division and cell growth. Recognizing the symptoms of these tumors and using the correct diagnostics is of great importance. In this clinical lesson we show the disease course of 3 patients with NF1. In all 3, the disease course was complicated by a symptomatic tumor. Characteristic in these patients is the relatively long interval between the onset of symptoms and the final tumor diagnosis. In this clinical lesson we examine the causes of this in more detail and we emphasize the importance of the specific knowledge within the Dutch national NF1 care network.

Background: Neurofibromatosis type 1 (NF1) is a neurodevelopmental genetic disorder associated with visual–spatial and visuomotor deficits, which have not been studied well in adults with NF1. Methods: In 22 adults with NF1 and 31 controls, visuomotor functioning was assessed by measuring eye latency, hand latency and hand accuracy during visuomotor tasks. Visual–spatial functioning was assessed by measuring eye movement responses during the Visual Threshold Task. Results: The NF1 group had a significantly shorter eye latency than the control group and was less accurate in their hand movements during specific visuomotor tasks. The groups showed no differences in eye movement responses during the Visual Threshold Task and in hand latency during the visuomotor tasks. Conclusions: In contrast to studies in children with NF1, we found no alterations in visual–spatial information processing in adults. Impairments in eye latency and hand accuracy during specific visuomotor tasks may indicate deficits in visuomotor functioning in adults with NF1.

Contains fulltext : 251555.pdf (Publisher’s version ) (Open Access), BACKGROUND: Ependymomas, pilocytic astrocytomas, medulloblastomas, and intracranial germ cell tumors occur relative frequently in children, but are rare central nervous system (CNS) tumors in adults. In this population-based survey, we established incidence, treatment, and survival patterns for these tumors diagnosed in adult patients (≥18 years) over a 30-year period (1989-2018). METHODS: Data on 1384 ependymomas, 454 pilocytic astrocytomas, 205 medulloblastomas, and 112 intracranial germ cell tumors were obtained from the Netherlands Cancer Registry (NCR) on the basis of a histopathological diagnosis. For each tumor type, age-standardized incidence rates and estimated annual percentage change were calculated. Trends in incidence and main treatment modalities were reported per 5-year periods. Overall survival was calculated using the Kaplan-Meier method, and relative survival rates were estimated using the Pohar-Perme estimator. RESULTS: Incidence and survival rates remained generally stable for pilocytic astrocytomas, medulloblastomas, and germ cell tumors. Increasing incidence was observed for spinal ependymomas, mostly for myxopapillary ependymomas, and survival improved over time for grade II ependymomas (P < .01). Treatment patterns varied over time with shifting roles for surgery in ependymomas and for chemotherapy and radiation in medulloblastomas and germinomas. CONCLUSIONS: The study provides baseline information for highly needed national and international standard treatment protocols, and thus for further improving patient outcomes in these rare CNS tumors.

Objective: The inability to properly process visual information has been frequently associated with neurofibromatosis type 1 (NF1). Based on animal studies, the cause of cognitive disabilities in NF1 is hypothesized to arise from decreased synaptic plasticity. Visual cortical plasticity in humans can be investigated by studying visual evoked potentials (VEPs) in response to visual stimulation. Methods: VEP plasticity was assessed by measuring the increase of the peak amplitudes C1, P1, and N1 induced by 10-min modulation of checkerboard reversals in 22 adult NF1 patients and 30 controls. VEP signals were recorded pre-modulation, during modulation, and at 2, 7, 12, 17, 22, 27 min post-modulation. Results: The P1 amplitude increased significantly comparing post-modulation to pre-modulation in the control group. This potentiation was not observed in the NF1 group. Conclusions: Visual cortical plasticity could be measured using VEPs in response to visual stimulation in the control group. Individuals with NF1 may have reduced visual cortical plasticity, as indicated by their non-potentiated response to VEP induction. These findings should be interpreted with caution due to high inter-subject variability. Significance: The present study contributes to an improved assessment of the feasibility for using neurophysiological outcome measures in intervention studies of cognitive deficits among patients with NF1.

Contains fulltext : 244279.pdf (Publisher’s version ) (Open Access), BACKGROUND: Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poor prognosis: more than half of the patients become bedridden and median survival is less than 12 months. Several lines of evidence suggest a pathogenic T cell-mediated immune response. Therefore, we conducted a prospective open-label phase II trial with natalizumab. METHODS: Twenty Hu-PNS patients with progressive disease were treated with a maximum of three monthly natalizumab cycles (300 mg). The primary outcome measure was functional improvement, this was defined as at least one point decrease in modified Rankin Scale (mRS) score at the last treatment visit. In addition, treatment response was assessed wherein a mRS score ≤3 after treatment was defined as treatment responsive. RESULTS: The median age at onset was 67.8 years (SD 8.4) with a female predominance (n = 17, 85%). The median time from symptom onset to Hu-PNS diagnosis was 5 months (IQR 2-11). Most patients had subacute sensory neuronopathy (n = 15, 75%), with a median mRS of 4 at baseline. Thirteen patients had a tumor, all small cell lung cancer. After natalizumab treatment, two patients (10%) showed functional improvement. Of the remaining patients, 60% had a stable functional outcome, while 30% showed further deterioration. Treatment response was classified as positive in nine patients (45%). CONCLUSIONS: Natalizumab may ameliorate the disease course in Hu-PNS, but no superior effects above other reported immunosuppressive and immunomodulatory were observed. More effective treatment modalities are highly needed. TRIAL REGISTRATION: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000675-13/NL.

Item does not contain fulltext, BACKGROUND: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear. METHODS: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m(2) per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m(2) temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990. FINDINGS: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interi

Contains fulltext : 235663.pdf (Publisher’s version ) (Open Access), Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1(R132H) mutations. Patients harbouring IDH1(R132H) mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1(R132H) have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1(R132H) mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.

Survival in patients with IDH1/2 mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients. The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumour classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using one of two glioma-tailored NGS panels. The primary endpoint was overall survival measured from date of randomization. Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumours. Of these, 432 tumours were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazards model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication. Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.

Objective: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is associated with cognitive disabilities. Based on studies involving animals, the hypothesized cause of these disabilities results from increased activity of inhibitory interneurons that decreases synaptic plasticity. We obtained transcranial magnetic stimulation (TMS)-based measures of cortical

Malignant peripheral nerve sheath tumors (MPNST) are aggressive cancers that occur spontaneously (sporadic MPNST) or from benign plexiform neurofibromas in neurofibromatosis type 1 (NF1) patients. MPNSTs metastasize easily, are therapy resistant and are frequently fatal. The molecular changes underlying the malignant transformation in the NF1 setting are incompletely understood. Here we investigate the involvement of microRNAs in this process. MicroRNA expression profiles were determined from a series of archival, paired samples of plexiform neurofibroma and MPNST. Ninety differentially expressed microRNAs were identified between the paired samples. Three downregulated microRNAs (let-7b-5p, miR-143-3p, miR-145-5p) and two upregulated microRNAs (miR135b-5p and miR-889-3p) in MPNST were selected for functional characterization. In general, their differential expression was validated in a relevant cell line panel but only partly in a series of unpaired, fresh frozen tumor samples. As part of the validation process we also analyzed microRNA expression profiles of sporadic MPNSTs observing that microRNA expression discriminates NF1-associated and sporadic MPNSTs. The role of microRNAs in cancer progression was examined in NF1-derived MPNST cell lines by transiently modulating microRNA levels. Our findings indicate that some microRNAs affect migratory and invasive capabilities and Wnt signaling activity but the effects are distinct in different cell lines. We conclude that miRNAs play essential regulatory roles in MPNST facilitating tumor progression.

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder associated with lifelong tumor growth propensity and neurocognitive impairments. Although follow-up of adults with NF1 often focuses on tumor growth, follow-up of cognitive or social problems and other NF1-related comorbidity is often not a part of standardized care. In order to provide optimal care services for these patients, we explored the care needs of adults with NF1. A qualitative study was performed using semi-structured group interviews, exploring worries and care needs in medical, psychological, and socioeconomic domains, also focusing on the transition from pediatric to adult care. Four focus groups were conducted, including young adult patients, patients over age 30, and parents of young adult patients. In total, 30 patients and 12 parents participated. Data were transcribed verbatim and analyzed by computerized thematic analysis. Themes were organized using the World Health Organization International classification of functioning, disability, and health (ICF). Results indicated many and diverse worries and care needs both during the transitional period and in adulthood in medical, mental health, and socioeconomic domains. Worries could be categorized into 13 themes. Parents reported high stress levels and difficulties with their parental role. Participants expressed the need for more information, access to NF1 experts, daily living support, care for mental health and socioeconomic participation, and closer communication between health-care providers. In conclusion, worries and needs of patients and parents underline the importance of multidisciplinary follow-up and continuity of care during and after the transitional period. Additionally, parental stress requires more attention from care providers.

Here, we describe the development of a Dutch national guideline on metastases and hematological malignancies localized within the spine. The aim was to create a comprehensive guideline focusing on proactive management of these diseases, enabling healthcare professionals to weigh patient perspectives, life expectancy, and expected outcomes to make informed treatment recommendations. A national multidisciplinary panel consisting of clinicians, a nurse, a patient advocate, an epidemiologist, and a methodologist drafted the guideline. The important role of patients in the realization of the guideline enabled us to identify and address perceived shortcomings in patient care. The guideline covers not only metastatic epidural spinal cord compression, but also the treatment of uncomplicated metastases and hematological malignancies localized within the spine. The guideline is applicable in daily practice and provides an up-to-date and concise overview of the diagnostic and treatment possibilities for patients suffering from a disease that can have a serious impact on their quality of life. Suggestions for the practical implementation of patient care in hospitals are also provided, including approaches for pursuing proactive management. The crucial role of the patient in decision making is emphasized in this guideline.

Purpose: For the selection of treatment in patients with spinal bone metastases (SBM), survival estimation plays a crucial role to avoid over- and under-treatment. To aid clinicians in this difficult task, several prediction models have been developed, consisting of many different risk factors. The aim of this systematic review was to identify prognostic factors that are associated with survival in patients with SBM to support development of predictive models. Methods: A systematic review was performed with focus on prognostic factors associated with survival in patients with SBM. Two reviewers independently selected studies for inclusion and assessed the risk of bias. A level of evidence synthesis was performed for each prognostic factor. Inter-observer agreement for the risk of bias assessment was determined by the kappa-statistic. Results: After screening, 142 full-text articles were obtained, of which 22 met the eligibility criteria. A total of 43 different prognostic factors were investigated in the included studies, of which 17 were relevant to pre-treatment survival estimation. The prognostic factors most frequently associated with survival were the primary tumor and the performance status. The prognostic factors most frequently not associated with survival were age, gender, number and location of the SBM and the presence of a pathologic fracture. Conclusions: Prognostication for patients with SBM should be based on an accurate primary tumor classification, combined with a performance score. The benefit of adding other prognostic factors is doubtful.

Item does not contain fulltext, This article is a summary of the revised Dutch multidisciplinary evidence-based guideline 'Spinal metastases' (English translation available at: https://www.oncoline.nl/spinal-metastases) that was published at the end of 2015. This summary provides an easy-to-use overview for physicians to use in their daily practice.

Contains fulltext : 195630.pdf (Publisher’s version ) (Open Access), Here, we describe the development of a Dutch national guideline on metastases and hematological malignancies localized within the spine. The aim was to create a comprehensive guideline focusing on proactive management of these diseases, enabling healthcare professionals to weigh patient perspectives, life expectancy, and expected outcomes to make informed treatment recommendations. A national multidisciplinary panel consisting of clinicians, a nurse, a patient advocate, an epidemiologist, and a methodologist drafted the guideline. The important role of patients in the realization of the guideline enabled us to identify and address perceived shortcomings in patient care. The guideline covers not only metastatic epidural spinal cord compression, but also the treatment of uncomplicated metastases and hematological malignancies localized within the spine. The guideline is applicable in daily practice and provides an up-to-date and concise overview of the diagnostic and treatment possibilities for patients suffering from a disease that can have a serious impact on their quality of life. Suggestions for the practical implementation of patient care in hospitals are also provided, including approaches for pursuing proactive management. The crucial role of the patient in decision making is emphasized in this guideline.

Background. The current method for assessing progressive disease (PD) in glioblastoma is according to the Response Assessment in Neuro-Oncology (RANO) criteria. Bevacizumab-treated patients may show pseudoresponse on postcontrast T1-weighted (T1w) MRI, and a more infltrative non-enhancing growth pattern on T2w/?uid attenuated inversion recovery (FLAIR) images. We investigated whether the RANO criteria remain the method of choice for assessing bevacizumab-treated recurrent glioblastoma when compared with various volumetric methods. Methods. Patients with assessable MRI data from the BELOB trial (n = 148) were included. Patients were treated with bevacizumab, lomustine, or both. At frst and second radiological follow-up (6 and 12 wk), PD was determined using the 2D RANO criteria and various volumetric methods based on enhancing tumor only and enhancing plus non-enhancing tumor. Differences in overall survival (OS) between PD and non-PD patients were assessed with the log-rank test and a Cox model. Hazard ratios (HRs) and their 95% CIs were determined. Results. For all patients together, all methods (except subtraction of non-enhancing from enhancing volume at frst follow-up) showed signifcant differences in OS between PD and non-PD patients (P <.001). The largest risk increase for death in case of PD at both frst and second follow-up was found with the RANO criteria: HR = 2.81 (95% CI, 1.92-4.10) and HR = 2.80 (95% CI, 1.75-4.49), respectively. In the bevacizumab-treated patients, all methods assessed showed signifcant differences in OS between PD and non-PD patients. There were no signifcant differences between methods. Conclusions. In the frst 12 weeks, volumetric methods did not provide signifcant improvement over the RANO criteria as a posttreatment prognostic marker.

Background. As the incidence of pseudo-progressive disease (psPD), or pseudoprogression, in low-grade glioma (LGG) is unknown, we retrospectively investigated this phenomenon in a cohort of LGG patients given radiotherapy (RT). Methods. All MRI scans and clinical data from patients with histologically proven LGG treated with radiation between 2000 and 2011 were reviewed. PsPD was scored when a new enhancing lesion occurred after RT and subsequently disappeared or remained stable for at least a year without therapy, including dexamethasone. Results. Sixty-three out of 71 patients who received RT for LGG were deemed eligible for evaluation of psPD. The median follow-up was 5 years (range 1?10 y). PsPD was seen in 13 patients (20.6%). PsPD occurred after a median of 12 months with a range of 3-78 months. The median duration of psPD was 6 months, with a range of 2-26 months and always occurred within the RT high dose felds of at least 45 Gy. The area of the enhancement at the time of psPD was signifcantly smaller compared with the area of enhancement during "true" progression (median size 54mm2 [range 12-340mm2] vs 270mm2 [range 30-3420mm2], respectively; P =.009). Conclusions. PsPD occurs frequently in LGG patients receiving RT. This supports the policy to postpone a new line of treatment until progression is evident, especially when patients have small contrast enhancing lesions within the RT feld.

Item does not contain fulltext, BACKGROUND: The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas. METHODS: This was a phase 3, randomised, open-label study with a 2 x 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59.4 Gy in 33 fractions of 1.8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150-200 mg/m(2) temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m(2) per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0.0084). This trial is registered with ClinicalTrials.gov, number NCT00626990. FINDINGS: At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0.65 (99.145% CI 0.45-0.93). Overall survival at 5 years was 55.9% (95% CI 47.2-63.8) with and 44.1% (36.3-51.6) without adjuvant temozolomide. Grade 3-4 adverse events were seen in 8-12% of 549 patients assigned temozolomide, and were mainly haematological and reversible. INTERPRETATION: Adjuvant temozolomide chemotherapy

The results from the randomized phase II BELOB trial provided evidence for a potential benefit of bevacizumab (beva), a humanized monoclonal antibody against circulating VEGF-A, when added to CCNU chemotherapy in patients with recurrent glioblastoma (GBM). In this study, we performed gene expression profiling (DASL and RNA-seq) of formalin-fixed, paraffinembedded tumor material from participants of the BELOB trial to identify patients with recurrent GBM who benefitted most from bevaCCNU treatment. We demonstrate that tumors assigned to the IGS-18 or "classical" subtype and treated with bevaCCNU showed a significant benefit in progression-free survival and a trend toward benefit in overall survival, whereas other subtypes did not exhibit such benefit. In particular, expression of FMO4 and OSBPL3 was associated with treatment response. Importantly, the improved outcome in the bevaCCNU treatment arm was not explained by an uneven distribution of prognostically favorable subtypes as all molecular glioma subtypes were evenly distributed along the different study arms. The RNA-seq analysis also highlighted genetic alterations, including mutations, gene fusions, and copy number changes, within this well-defined cohort of tumors that may serve as useful predictive or prognostic biomarkers of patient outcome. Further validation of the identified molecular markers may enable the future stratification of recurrent GBM patients into appropriate treatment regimens.

Gliomas are primary brain tumors and include astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas. Currently, treatment of newly diagnosed diffuse adult gliomas exists of surgery, radiotherapy and chemotherapy. We were the first to show a high incidence of progressive MRI lesions in glioblastomas (WHO grade 4 astrocytomas) immediately after combined chemo-radiotherapy with temozolomide, with spontaneous improvement and termed this phenomenon pseudo-progression. Because of these findings it became a general treatment policy to continue temozolomide in case of progressive lesions immediately after chemo-irradiation. Additionally, this thesis focused on the evaluation of classical chemotherapy in adult diffuse glioma in relation to a variety of prognostic molecular tumor characteristics, including isocitrate dehydrogenase 1 (IDH1) mutations, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and loss of chromosomes 1p and 19q). This thesis has further established the role temozolomide in progressive astrocytomas after radiotherapy and confirmed that IDH1 mutations identify a subgroup of astrocytomas with an improved survival and are strongly correlated with MGMT promotor methylation. Data from this thesis indicated that a more continuous dose dense temozolomide schedule is safe and effective in recurrent glioma, but did not suggest superior efficacy of the dose dense temozolomide schedule, by overcoming tumor resistance mediated by methylation of the MGMT promoter as compared to the standard schedule. The Dutch multicenter phase 2 BELOB study suggests a role of bevacizumab in combination with lomustine in recurrent glioblastoma and justifies further phase 3 studies of this treatment. Our long-term follow-up study in newly diagnosed large oligodendroglial tumors indicated that upfront procarbazine, lomustine and vincristine (PCV) chemotherapy is associated with long (progression free) survival and delays radiotherapy for a considerable period o

Background:Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma.Methods:In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated.Results:The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log 10 CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log 10 CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with

BACKGROUND: Mature circulating endothelial cells (CEC) are surrogate markers of endothelial damage. CEC measured in patients with advanced cancer are thought not only to derive from damaged normal vasculature (n-CEC), but also from damaged (t-CEC). Therefore, assays that allow the discrimination between these two putative types of CEC are thought to improve the specificity of the enumeration of CEC in cancer.METHODS: Identification of tumour-associated endothelial markers (TEM) by comparing antigen expression on normal vs t-CEC and assess the presence of t-CEC in peripheral blood of cancer patients by incorporating TEM in our novel flow cytometry-based CEC detection assay.RESULTS: No difference in antigen expression between normal and malignant endothelial cells (ECs) was found for CD54, CD109, CD137, CD141, CD144 and CXCR7. In contrast, overexpression for CD105, CD146, CD276 and CD309 was observed in tumour ECs compared with normal ECs. CD276 was most differentially expressed and chosen as a marker for further investigation. CD276-expressing CEC were significantly higher in 15 patients with advanced colorectal cancer (median 9 (range 1-293 cell per 4 ml); P<0.005), in 83 patients with a glioblastoma multiforme (median 10 (range 0-804); P<0.0001) and in 14 patients with advanced breast cancer (median 14 (range 0-390) P<0.05) as compared with 24 healthy individuals (median 3 (range 0-11)). Of all patients with malignancies, 58% had CD276(+) CEC counts above the ULN (8 cell per 4 ml).CONCLUSIONS: The present study shows that CD276 can be used to discriminate ECs from malignant tissue from ECs from normal tissue. In addition, CD276(+) CEC do occur in higher frequencies in patients with advanced cancer.