Dexamethasone-induced leukocytosis is associated with poor survival in newly diagnosed glioblastoma

Dubinski, Daniel; Won, Sae‐Yeon; Geßler, Florian; Quick-Weller, Johanna; Behmanesh, Bedjan; Bernatz, Simon; Forster, Marie-Thérèse; Franz, Kea; Plate, Karl-Heinz; Seifert, Volker; Harter, Patrick N.; Senft, Christian

doi:10.1007/s11060-018-2761-4

Cited by 41 publications

(44 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A possible implication of this finding is that edema may reduce the efficacy of TTField therapy, and might be considered as a predictor of non-response. However, this latter point will be difficult to test conclusively, given the known association between edema and poor outcomes [32], and the confounding nature of drugs which may reduce edema, but which themselves can be associated with poor outcomes [33]. Moreover, we found contrasting results when PLD was assessed.…”

Section: Discussionmentioning

confidence: 81%

Impact of Peritumoral Edema During Tumor Treatment Field Therapy: A Computational Modelling Study

Lang

Gan

McLennan

et al. 2020

IEEE Trans. Biomed. Eng.

View full text Add to dashboard Cite

Background: Tumor treatment fields (TTFields) are an approved adjuvant therapy for glioblastoma (GBM). The magnitude of applied electrical field has been shown to be related to the anti-tumoral response. However, peritumoral edema may result in shunting of electrical current around the tumor, thereby reducing the intra-tumoral electric field. In this study, we systematically address this issue with computational simulations. Methods: Finite element models are created of a human head with varying amounts of peritumoral edema surrounding a virtual tumor. The electric field distribution was simulated using the standard TTFields electrode montage. Electric field magnitude was extracted from the tumor and related to edema thickness. Two patient specific models were created to confirm these results. Results: The inclusion of peritumoral edema decreased the average magnitude of the electric field within the tumor. In the model considering a frontal tumor and an anterior-posterior electrode configuration, ≥ 6 mm of peritumoral edema decreased the electric field by 52%. In the patient specific models, peritumoral edema decreased the electric field magnitude within the tumor by an average of 26%. The effect of peritumoral edema on the electric field distribution was spatially heterogenous, being most significant at the tissue interface between edema and tumor. Conclusions: The inclusion of peritumoral edema during TTFields modelling may have a dramatic effect on the predicted electric field magnitude within the tumor. Given the importance of electric field magnitude for the anti-tumoral effects of TTFields, the presence of edema should be considered both in future modelling studies and when planning TTField therapy. Index Terms-Glioma, Tumor treatment fields, finite element modelling I. INTRODUCTION LIOBLASTOMA Multiforme (GBM) is an aggressive primary brain tumor with a median survival of approximately 1 year, despite surgical and adjuvant treatment [1]. In recent years, new therapeutic technologies have been proposed in order to improve this prognosis. One technology

show abstract

Section: Discussionmentioning

confidence: 81%

Impact of Peritumoral Edema During Tumor Treatment Field Therapy: A Computational Modelling Study

Lang

Gan

McLennan

et al. 2020

IEEE Trans. Biomed. Eng.

View full text Add to dashboard Cite

show abstract

“…New effective therapeutic strategies are therefore needed to target the BBB dysfunction associated with meningitis [3]. The benefit of dexamethasone has also been questionable in cancer therapy as elaborated in our recent review [20], where it is used in edema management particularly in brain tumors [19,30,66]. Interestingly, one mechanism proposed for the action of dexamethasone on edema reduction in glioma was via downregulation of VEGF leading to reduced permeability; the efficacy of dexamethasone, however, was dramatically reduced during hypoxia [50].…”

Section: Discussionmentioning

confidence: 99%

HIF-1α is involved in blood–brain barrier dysfunction and paracellular migration of bacteria in pneumococcal meningitis

et al. 2020

View full text Add to dashboard Cite

Bacterial meningitis is a deadly disease most commonly caused by Streptococcus pneumoniae, leading to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer of S. pneumoniae from blood to the brain across the blood-cerebrospinal fluid barrier or the blood-brain barrier (BBB). The underlying mechanisms are still poorly understood. Current treatment strategies include adjuvant dexamethasone for inflammation and cerebral edema, followed by antibiotics. The success of dexamethasone is however inconclusive, necessitating new therapies for controlling edema, the primary reason for neurological complications. Since we have previously shown a general activation of hypoxia inducible factor (HIF-1α) in bacterial infections, we hypothesized that HIF-1α, via induction of vascular endothelial growth factor (VEGF) is involved in transmigration of pathogens across the BBB. In human, murine meningitis brain samples, HIF-1α activation was observed by immunohistochemistry. S. pneumoniae infection in brain endothelial cells (EC) resulted in in vitro upregulation of HIF-1α/VEGF (Western blotting/qRT-PCR) associated with increased paracellular permeability (fluorometry, impedance measurements). This was supported by bacterial localization at cell-cell junctions in vitro and in vivo in brain ECs from mouse and humans (confocal, super-resolution, electron microscopy, live-cell imaging). Hematogenously infected mice showed increased permeability, S. pneumoniae deposition in the brain, along with upregulation of genes in the HIF-1α/VEGF pathway (RNA sequencing of brain microvessels). Inhibition of HIF-1α with echinomycin, siRNA in bEnd5 cells or using primary brain ECs from HIF-1α knockout mice revealed reduced endothelial permeability and transmigration of S. pneumoniae. Therapeutic rescue using the HIF-1α inhibitor echinomycin resulted in increased survival and improvement of BBB function in S. pneumoniae-infected mice. We thus demonstrate paracellular migration of bacteria across BBB and a critical role for HIF-1α/VEGF therein and hence propose targeting this pathway to prevent BBB dysfunction and ensuing brain damage in infections.

show abstract

“…Remarkably, the tumor reappeared after 1–4 weeks and was much more aggressive (Buxton et al, 1997; Zaki et al, 2004; Goh et al, 2009). It has also been observed that DEX therapy reduced the OS of a particular subgroup of GBM patients (Dubinski et al, 2018). In this study, 35 patients received preoperative DEX and compared to 78 control patients.…”

Section: Dex Therapy In Gbmmentioning

confidence: 98%

Dexamethasone in Glioblastoma Multiforme Therapy: Mechanisms and Controversies

Cenciarini

Valentino

Belia

et al. 2019

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Glioblastoma multiforme (GBM) is the most common and malignant of the glial tumors. The world-wide estimates of new cases and deaths annually are remarkable, making GBM a crucial public health issue. Despite the combination of radical surgery, radio and chemotherapy prognosis is extremely poor (median survival is approximately 1 year). Thus, current therapeutic interventions are highly unsatisfactory. For many years, GBM-induced brain oedema and inflammation have been widely treated with dexamethasone (DEX), a synthetic glucocorticoid (GC). A number of studies have reported that DEX also inhibits GBM cell proliferation and migration. Nevertheless, recent controversial results provided by different laboratories have challenged the widely accepted dogma concerning DEX therapy for GBM. Here, we have reviewed the main clinical features and genetic and epigenetic abnormalities underlying GBM. Finally, we analyzed current notions and concerns related to DEX effects on cerebral oedema, cancer cell proliferation and migration and clinical outcome.

show abstract

Dexamethasone-induced leukocytosis is associated with poor survival in newly diagnosed glioblastoma

Cited by 41 publications

References 23 publications

Impact of Peritumoral Edema During Tumor Treatment Field Therapy: A Computational Modelling Study

Impact of Peritumoral Edema During Tumor Treatment Field Therapy: A Computational Modelling Study

HIF-1α is involved in blood–brain barrier dysfunction and paracellular migration of bacteria in pneumococcal meningitis

Dexamethasone in Glioblastoma Multiforme Therapy: Mechanisms and Controversies

Contact Info

Product

Resources

About