Joost J.C. Verhoeff

Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme

BackgroundThe relevance of angiogenesis inhibition in the treatment of glioblastoma multiforme (GBM) should be considered in the unique context of malignant brain tumours. Although patients benefit greatly from reduced cerebral oedema and intracranial pressure, this important clinical improvement on its own may not be considered as an anti-tumour effect.DiscussionGBM can be roughly separated into an angiogenic component, and an invasive or migratory component. Although this latter component seems inert to anti-angiogenic therapy, it is of major importance for disease progression and survival. We reviewed all relevant literature. Published data support that clinical symptoms are tempered by anti-angiogenic treatment, but that tumour invasion continues. Unfortunately, current imaging modalities are affected by anti-angiogenic treatment too, making it even harder to define tumour margins. To illustrate this we present MRI, biopsy and autopsy specimens from bevacizumab-treated patients.Moreover, while treatment of other tumour types may be improved by combining chemotherapy with anti-angiogenic drugs, inhibiting angiogenesis in GBM may antagonise the efficacy of chemotherapeutic drugs by normalising the blood-brain barrier function.SummaryAlthough angiogenesis inhibition is of considerable value for symptom reduction in GBM patients, lack of proof of a true anti-tumour effect raises concerns about the place of this type of therapy in the treatment of GBM.

Cancer Stem Cell Tumor Model Reveals Invasive Morphology and Increased Phenotypical Heterogeneity

The recently developed concept of cancer stem cells (CSC) sheds new light on various aspects of tumor growth and progression. Here, we present a mathematical model of malignancies to investigate how a hierarchical organized cancer cell population affects the fundamental properties of solid malignancies. We establish that tumors modeled in a CSC context more faithfully resemble human malignancies and show invasive behavior, whereas tumors without a CSC hierarchy do not. These findings are corroborated by in vitro studies. In addition, we provide evidence that the CSC model is accompanied by highly altered evolutionary dynamics compared with the ones predicted to exist in a stochastic, nonhierarchical tumor model. Our main findings indicate that the CSC model allows for significantly higher tumor heterogeneity, which may affect therapy resistance. Moreover, we show that therapy which fails to target the CSC population is not only unsuccessful in curing the patient, but also promotes malignant features in the recurring tumor. These include rapid expansion, increased invasion, and enhanced heterogeneity.

Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma

Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O6-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling.

Bowel Perforation After Radiotherapy in a Patient Receiving Sorafenib

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Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma

BACKGROUND Angiogenesis inhibition is a rational treatment strategy for high-grade glioma (HGG). Combined antiangiogenic therapy and chemotherapy could be beneficial, taking advantage of different mechanisms of antitumour activity of both therapies. We carried out a phase I-II clinical trial with the combination of bevacizumab and continuous dose-intense temozolomide (TMZ) for patients with a recurrent HGG after first- or second-line treatment. PATIENTS AND METHODS Twenty-three HGG patients were treated with bevacizumab (10 mg/kg i.v. every 3 weeks) and TMZ (daily 50 mg/m(2)), until clinical or radiological progression. Conventional and dynamic magnetic resonance imaging (MRI) were carried out on days -4, 3 and 21 and until clinical or radiological progression. RESULTS Overall response rate (20%), 6-month progression-free survival (PFS6) (17.4%), median progression-free survival (13.9 weeks) and median overall survival (OS) (17.1 weeks) were considerably lower compared with most other studies with bevacizumab-containing regimens. The dynamic MRI parameters contrast transfer coefficient and relative cerebral blood volume decreased rapidly during the early phases of treatment, reflecting changes in vascularisation and vessel permeability but not in tumour activity. In addition, >50% of patients showed oedema reduction and a reduced shift on T1 images. CONCLUSION Treatment with bevacizumab and TMZ is feasible and well tolerated but did not improve PFS6 and median OS.

Tumor microvasculature supports proliferation and expansion of glioma-propagating cells.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. The identification of ‘cancer stem cells’ (CSC) has shed new light on the potential mechanism of therapy resistance of these tumors. Because these cells appear to be more resistant to conventional treatments, they are thought to drive tumor regrowth after therapy. Therefore, novel therapeutic approaches that target these cells are needed. Tumor cells interact with their microenvironment. It has been reported that close contact between CSCs and tumor microvascular endothelium in GBM is important for CSCs to preserve their undifferentiated state and self‐renewal ability. However, our understanding of this interaction is still rudimentary. This is in part due to a lack of suitable in vitro models that accurately represent the in vivo situation. Therefore, we set up a co‐culture system consisting of primary brain tumor microvascular endothelial cells (tMVECs) and glioma propagating cells (GPCs) derived from biopsies of GBM patients. We found that tMVECs support the growth of GPCs resulting in higher proliferation rates comparing to GPCs cultured alone. This effect was dependent on direct contact between the 2 cell types. In contrast to GPCs, the FCS‐cultured cell line U87 was stimulated by culturing on tMVEC‐derived ECM alone, suggesting that both cell types interact different with their microenvironment. Together, these results demonstrate the feasibility and utility of our system to model the interaction of GPCs with their microenvironment. Identification of molecules that mediate this interaction could provide novel targets for directed therapy for GBM.

Therapy-resistant tumor microvascular endothelial cells contribute to treatment failure in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a devastating disease with high mortality and poor prognosis. Cancer stem cells (CSCs) have recently been defined as a fraction of tumor cells highly resistant to therapy and subsequently considered to be responsible for tumor recurrence. These cells have been characterized in GBM and suggested to reside in and be supported by the tumor microvascular niche. Here we evaluated the response of tumor microvascular endothelial cells (tMVECs) to radio- and chemotherapy, and analyzed how this affects their interaction with CSCs. Our data demonstrate that tMVECs exhibit extreme resistance to both therapies, with the main response to irradiation being senescence. Importantly, senescent tMVECs can be detected in human GBM samples as well as in mice upon irradiation. Even though permanently arrested, they are still viable and able to support CSC growth with the same efficacy as non-senescent tMVECs. Intriguingly, GBM CSCs themselves are capable of differentiating into cells with similar features as tMVECs that subsequently undergo senescence when exposed to radiation. This indicates that endothelial-like cells are therapy resistant and, more importantly, support expansion of GBM cells.

Tumour control by whole brain irradiation of anti-VEGF-treated mice bearing intracerebral glioma.

AIM OF THE STUDY Tumour angiogenesis and invasion are key features of glioblastoma multiforme (GBM). Angiogenesis inhibitors increase progression-free survival (PFS) of recurrent GBM patients. VEGF inhibition controls the bulk tumour growth by inhibition of angiogenesis, but does not inhibit the invasive tumour component. We investigated if invasive tumour growth can be controlled by combining anti-VEGF treatment with irradiation of tumour plus surrounding brain in an orthotopic murine model for GBM. METHODS AND MATERIALS GBM cell line U251-NG2 was inoculated through a guide screw in the right frontal lobe of 53 athymic nude mice. Pegaptanib (a slow-releasing aptamer against VEGF) was injected in the tumour bed either or not followed by irradiation treatment with implanted I-125 seeds. Pegaptanib and/or irradiation were compared with sham-treated controls, resulting in four groups of 10-15 mice each. After 6 weeks of treatment, histological analysis was performed on all brains. RESULTS VEGF inhibition by locally deposited pegaptanib decreased tumour blood vessel density, and increased tumour hypoxia. Pegaptanib treatment still allowed the formation of tumour satellites. Irradiation decreased tumour size and suppressed formation of satellites. Combined pegaptanib plus irradiation further increased PFS. Tumour size directly correlated with PFS. CONCLUDING STATEMENT The anti-tumour effects of local VEGF inhibition are partially circumvented by the formation of invasive tumour satellites. Additional irradiation is effective in slowing down proliferation of these invasive tumour components.

Model-based, semiquantitative and time intensity curve shape analysis of dynamic contrast-enhanced MRI: a comparison in patients undergoing antiangiogenic treatment for recurrent glioma.

To compare time intensity curve (TIC)‐shape analysis of dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) data with model‐based analysis and semiquantitative analysis in patients with high‐grade glioma treated with the antiangiogenic drug bevacizumab.

Causes of severe visual impairment and blindness in children in the Republic of Suriname

Aims To determine the causes of severe visual impairment and blindness (SVI/BL) in children in Suriname (Dutch Guyana) and to identify preventable and treatable causes. Methods 4643 children under 16 years of age were recruited from two locations: 33 children attending the only school for the blind were examined and 4610 medical records were analysed at an eye clinic. Data have been collected using the WHO Prevention of Blindness Programme eye examination record for children. Results 65 children were identified with SVI/BL, 58.5% were blind and 41.5% were severely visually impaired (SVI). The major anatomical site of SVI/BL was the retina in 33.8%, lens in 15.4% and normal appearing globe in 15.4%. The major underlying aetiology of SVI/BL was undetermined in 56.9% (mainly cataract and abnormality since birth) and perinatal factors 21.5% (mainly retinopathy of prematurity (ROP)). Avoidable causes of SVI/BL accounted for 40% of cases; 7.7% were preventable and 32.3% were treatable with cataracts and ROP the most common causes (15.4% and 12.3%, respectively). Conclusions More than a third of the SVI/BL causes are potentially avoidable, with childhood cataract and ROP the leading causes. Corneal scarring from vitamin A deficiency does not seem to be a continuing issue in Suriname.