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Δευτέρα 5 Σεπτεμβρίου 2022

P17.11.A Experience of ketogenic diet with support of liquid formula 3:1 and high-grade gliomas: Case series

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Abstract
Background
High-grade gliomas, including glioblastoma, are the most common primary malignant brain tumors in adults. Despite the efforts to develop new therapies, treatment options remain limited and the prognosis is poor. Ketogenic diet, is an emerging complementary therapy for high-grade gliomas. It is hypothesized that through the change of the energy source from glucose to ketones and the inability of glioma cells to metabolize ketone bodies with the same ease due to inefficient oxidative phosphorylation, tumor growth is slowed. The feasibility of a ketogenic diet is a matter of concern. Its influence on the quality of life of patients with advanced cancers showing that even though it may cause constipation and reflux, quality of life is generally not affected
Material and Methods
We reported a case series of patients with high-grade gliomas using ketogenic diet with liquid formula 3:1 ratio (KDS) as a complementary treatme nt. We describe baseline characteristics, and EORTC-QLQ30 score and symptom evaluation
Results
We describe the case of 3 patients (2 women and 1 man) with diagnoses of grade 4 glioblastoma (2) and grade 3 oligodendroglioma (1), mean age 46.7 years (38- 56 years), ECOG 1 (2) and ECOG2 (1), gross tumor resection (1 glioblastoma patient), subtotal resection (1 glioblastoma patient), and biopsy (1 oligodendroglioma patient). All patients received radiotherapy, 66.7% (n=2) stupp protocol, and 33.3% (n=1) received hypofractionated therapy and adjuvant treatment with temozolomide. All patients received first line with temozolomide, and 33.3% received a total of four lines of chemotherapy. All the patients were fed orally and managed with KDS at the last progression. Median follow up time was 4 months. KDS didn't impact corporal weight and a positive impact was noted in seizure episodes (> 3 per day before vs < 3 per day after DKS) and quality of life (EORTC-QLQ30 61,3 [60 - 66,8] at the begining vs 70,9 [69,8 - 71,2] at the last visit). Regarding tolerance, one patient presented diarrhea and/or constipation grade 1 the first 5 days of treatment. Compliance was measured by days with a median adherence of 90%. Current disease status is stable disease (RANO criteria) in the three patients.
Conclusion
KDS could be an interesting therapy complementary to standard treatment in patients with high grade gliomas, especially in those patients who debut with seizures, improving quality of life and number of convulsive crises. More studies in adult patients are required to confirm this hypothesis
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P10.05.B Platelet-derived growth factor signalling pathways in patient-derived glioblastoma cells

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Abstract
Background
Platelet-derived growth factor (PDGF) signalling is essential in the development and maintenance of the neurovasculature. Of particular importance is PDGFRβ signalling for the recruitment and maintenance of the mural cell type pericytes, which occupy an important position in coordinating blood-brain barrier functions. The PDGF pathway is also implicated in glioblastoma, where overexpression of PDGFRα is a signature of the proneural subtype of the highly malignant and invasive tumour. The expression and signalling of both PDGFRα and β by tumour cells have been implicated in tumorigenesis and progression. Therefore, we sought to study PDGF receptor signalling in primary human-derived glioblastoma tumour cells to gain a better understanding of the signalling mechanisms driven by these receptors.
Material and Methods
Primary human epilepsy pericytes and glioblastoma tumour cells were isolated from surgical resections obtained from consenting patients at Auckland City Hospital. PDGF signalling pathways were investigated through treatment with exogenous PDGF ligands. Pathway activation was quantified using immunocytochemistry, human cytokine XL Proteome Profiler and cytometric bead arrays.
Results
PDGF-BB and PDGF-DD treatment led to the activation of PDGFRβ in pericyte cultures, which mediated the activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt cascades, ultimately increasing pericyte proliferation and cytokine secretion. PDGF-AA treatment resulted in transient MAPK activation, but was not followed by increased proliferation in pericytes. In contrast, although PDGF-AA, -BB and -DD induced PDGFRα internalisation (and PDGF-BB and -DD induced PDGFRβ internalisation) in GBM tumour cells, this did not result in MAPK or PI3K/Akt activation or cell proliferation.
Conclusion
Despite PDGF receptor expression, the GBM tumour cells, in con trast to pericytes, surprisingly displayed a lack of responses to ligand stimulation through either PDGFRα or PDGFRβ. This warrants further investigation into the signalling mechanisms behind tumour cells to better understand tumour biology.
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PL02.2.A Microglia-specific disruption of sialic acid-Siglec-9/E interactions. A novel immunotherapy against glioblastoma?

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Abstract
Background
Recently, 'don't eat me'-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MdM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM.
Material and Methods
We employed a CT-2A orthotopic GBM mouse model with MG specific (Sall1CreERT2 x Sigleceflox) and whole innate-compartment (Cx3cr1CreERT2 x Sigleceflox) spatio-temporal deletion of Siglece. We applied multi-color flow cytometry, transcriptomics and proteomics analysis to decipher the immune response upon Siglece knockout.
Results
TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p < 0.001). In the MG specific spatio-temporal deletion of Siglece (Sall1CreERT2 xSigleceflox), we observed high MG-proliferation upon Siglec-E knockout (Ki-67+ MG 1 4.8% in Cre- vs. 34.9% in Cre+, p < 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p < 0.001). By extending the Siglece knockout to the MdM compartment in our glioma mouse model (Cx3cr1CreERT2 x Sigleceflox) we observed a significantly prolonged survival in the Cx3cr1Cre+ population (21d in Cre- vs. 27d post-tumor injection in Cre+, p = 0.018), which could be further promoted by combining Siglece knockout with CD47 blockade (30d post-tumor injection in Cre+ + anti-CD47). Unbiased proteomics analysis revealed increased antigen processing and presentation capabilities of Siglece knockout MdMs which was confirmed by ex-vivo OT-1 cross-presentation assays. This bridging of innate and adaptive responses with increased T cell priming upon MdM Siglece knockout was further promoted by addition of anti-PD1 antibody to the combined Siglece knockout and anti-CD47 treatment arm. Animals harboring CT-2A tumors, exhibited a sustained survival benefit under the triple therapy, with 23% of animals experiencing long-term remission, even after tumor re-challenge into the contra-lateral hemisphere. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with increased GBM-cell phagocytosis by MG and MdMs and less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003).
Conclusion
These data identify the sialic-acid-Sigl ec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.
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P10.10.A Tumor Treating Fields (TTFields), temozolomide and lomustine co-application is efficacious in glioblastoma cancer cell lines

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Abstract
Background
Temozolomide (TMZ) is the standard of care chemotherapy for newly diagnosed glioblastoma (ndGBM), the most common primary malignant brain tumor in adults. However, 50% of patients do not respond to TMZ due to expression of O6-methylguanine-DNA methyltransferase (MGMT), the enzyme involved in repair of TMZ-induced damage. Tumor Treating Fields (TTFields) are alternating electric fields that display anti-mitotic effects on cancerous cells, and have been shown to induce a state of BRCAness in various cancer types. Concurrent treatment with TMZ and TTFields demonstrated a major advance in treatment of patients with ndGBM, and was approved by the FDA in 2014. Recently, the addition of lomustine (CCNU) to TMZ demonstrated clinical benefit in ndGBM patients, with improved overall and progression free survival. The aim of the current study was to examine in GBM cells the effect of TTFields in conjunction with TMZ and CCNU.
Materi als and Methods
U-87 MG, LN229, U118 and LN18 human GBM cell lines were tested for their MGMT expression levels, and treated with TTFields (200 kHz, of 0.83 V/cm RMS) for 72 h using the inovitro system. Efficacy of concomitant application of TTFields with TMZ and/or CCNU was tested by measuring cell count, colony formation, and apoptosis levels.
Results
U-87 MG and LN229 displayed no expression of MGMT, while U118 and LN18 expressed low and high levels of MGMT, respectively. Application of TMZ and TTFields resulted in increased cytotoxicity compared with each treatment alone, with an additive interaction seen in all examined cell lines. The cytotoxic effect resulting from co-application of CCNU with TTFields suggested a synergistic interaction between the two modalities for U-87 MG, LN229, and U118, an additivity for LN18. Concurrent TTFields/TMZ/CCNU was more efficacious than TTFields or TMZ/CCNU separately in all cell lines.
Conclusions
Application of TTFiel ds with TMZ was additive, irrespective of MGMT expression levels, while TTFields with CCNU was additive when MGMT was plentiful, but displayed tendency to synergism when MGMT was absent or limited. These outcomes are in line with the BRCAness state induced by TTFields, as in the absence of MGMT, DNA damage induced by CCNU requires the BRCA pathway for repair. Application of TTFields together with TMZ and CCNU demonstrated increased efficacy, suggesting potential benefit of such therapy for ndGBM treatment.
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P17.05.A Re-irradiation with bevacizumab for large volume chemo-refractory glioblastoma after prior high-dose chemoradiotherapy

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Abstract
Background
There are limited options for salvage treatment of glioblastoma. The role of re-irradiation (reRT) for large-volume chemo-refractory relapse is not established due to concerns regarding potential toxicity, which may be overcome with use of bevacizumab.
Material and Methods
Patients who received initial post-operative chemoradiotherapy with 60Gy (EORTC-NCIC protocol) for glioblastoma across two centres from 2007-2021 were entered into a prospective database. Patients with progressive chemo-refractory disease, including some progressing on bevacizumab, were considered for reRT. Pseudoprogression and late RT necrosis was actively excluded using sequential MRI and PET. Clinico-pathologic characteristics of the reRT cohort and patients who had progressed but did not undergo reRT were compared. Kaplan-Meier survival analysis was used to assess overall (OS) and progression-free survival (PFS) from diagnosis in the overall a nd reRT cohorts as well as OS post-reRT. Factors associated with improved survival post-reRT were assessed.
Results
Of 447 patients treated for glioblastoma, 372 had progressed of which 71 received reRT. Median follow up for surviving patients was 26 and 37 months from diagnosis for the reRT and overall cohorts respectively. Median PFS and OS from initial diagnosis were 11.6 (95% CI: 9.4-14.2) and 23.6 (95% CI: 21.0-33.1) months respectively for re-RT patients, compared to 11.8 (95% CI: 11.0-12.5) and 18.0 (95% CI 17.0-19.1) months for the overall cohort. The reRT subgroup were more likely to be younger (median 53 vs. 59 years, p<0.001), have ECOG performance status at diagnosis 0-1 (86% vs. 69%, p=0.002) and have MGMT promoter methylation (54% vs. 40% p=0.083). There was no difference in extent of initial resection (p=0.59). The most common reRT schedule was 15 fractions to a total dose of either 40 Gy (32 patients) or 35 Gy (28 patients). Sixty (85%) had progression on bevacizumab prior to reRT; bevacizumab was continued during reRT in these cases. A further 10 (14%) received salvage bevacizumab after reRT. Median reRT PTV volume was 135cc (IQR 69-207cc). Median OS following reRT was 7.1 months (95% CI: 6.3-7.9). Six (8%) patients were admitted to hospital within 30 days of reRT, only one due to reRT toxicity. Median OS post-reRT was 7.7, 6.4 and 6.0 months for patients aged <50, 50-70 and >70 years respectively (p=0.021) and 8.1 vs. 6.3 months for patients with ECOG performance status of 0-1 and 2-3 respectively (p=0.039). Distant versus local progression (p=0.87), anatomical location of disease (p=0.65), MGMT methylation status (p=0.77) and PTV volume (p=0.91) did not predict post-reRT survival.
Conclusion
Large volume reRT for patients with recurrent glioblastoma is feasible, well-tolerated, associated with favourable overall survival and produces meaningful post-radiotherapy survival times.
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P17.03.B Modelling migration of glioblastoma patient-derived cells using human iPSC-derived neural spheroid and high content analysis

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Abstract
Background
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumour in adults. Despite current advances, the existing standard of treatment is ineffective, and the survival prognosis remains just over a year from diagnosis. Migrating tumour cells have been implicated in the therapeutic resistance of GBM. They spread by interacting with structures such as white matter tracts and inevitably cause recurrence of the tumour. Valuable cell models able to capture the invasiveness of GBM are critically needed to develop innovative therapies targeting migrating GBM cells.
Material and Methods
We established an in vitro model mimicking the GBM microenvironment by co-culturing patient-derived GBM cells and human induced pluripotent stem cell-derived cortical neural spheroids with radiating axons. Using high content imaging, we developed a robust workflow to quantify the GBM cells infiltration of the neural spheroid in endpoint assays. Images were acquired on the Operetta CLS high content device (Perkin Elmer) and analysed using the built-in Harmony Imaging and Analysis Software. We also performed live imaging assays using the Livecyte quantitative phase imager (Phasefocus), in which we studied the directionality, displacement and speed of the GBM cells engaged on axons.
Results
Our data indicate that GBM cells change morphology when cultured on axons and that they migrated towards the neural spheroid once engaged on axons. We showed that cell lines from different patients vary in migratory properties as well as in levels of infiltration capability. Finally, we used this model to test several antagonists to pathways involved in migration of GBM cells.
Conclusion
The main deliverable of this project is the setup of a novel model able to mimic the GBM migration on axons and able to screen for compounds affecting cell migration. This could pot entially offer innovative precision-medicine therapies.
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KS05.5.A Alterations in white matter fiber density associated with structural MRI and metabolic PET lesions following multimodal therapy in glioma patients

alexandrossfakianakis shared this article with you from Inoreader
Abstract
Background
In glioma patients, multimodal therapy and recurrent tumor result in local brain tissue changes, characterized by pathologic findings in structural MRI and metabolic PET images. Little is known about these different lesion types' impact on the local white matter fiber architecture and clinical outcome.
Patients and Methods
This study included data from 121 pretreated patients (median age, 52 years; ECOG, 01) with histomolecularly characterized glioma (WHO grade IV glioblastoma, n=81; WHO grade III anaplastic astrocytoma, n=28; WHO grade III anaplastic oligodendroglioma, n=12), who had a resection, radiotherapy, alkylating chemotherapy, or combinations thereof. After a median time of 14 months (range, 1-214 months), post-therapeutic structural and metabolic findings were evaluated using anatomical MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET acquired on a 3T hybrid PET/MR scanner. Local fiber densi ty was estimated from tractography based on highangular resolution diffusion-weighted imaging. A cohort of 121 healthy subjects selected from the 1000BRAINS study and matched for age, gender and education served as a control group.
Results
The median volume of resection cavities, contrast-enhancing regions, regions with pathologically increased FET uptake, and T2/FLAIR hyperintense regions amounted to 20.9, 7.9, 30.3, and 53.4 mL, respectively. Compared to the control group, the average local fiber density in these regions was significantly reduced (p<0.001). Resection cavities showed the highest reduction, followed by contrast-enhancing lesions and metabolically active tumors on FET PET (relative fiber density reduction, -87%, -65%, -55%, respectively). The local fiber density was inversely related (p=0.005) to the FET uptake in recurrent tumors. T2/FLAIR hyperintense lesions, either assigned to peritumoral edema in recurrent glioma or radiation-induced gliosis, had a c omparable impact on reducing fiber density (48% and 41%, respectively). The total fiber loss (average fiber loss multiplied by lesion volume) associated with contrast-enhancing lesions (p=0.006) and T2/FLAIR hyperintense lesions (p=0.013) had a significant impact on the general performance status of the patients (ECOG score).
Conclusions
Our results suggest that apart from resection cavities, reduction in local fiber density is greatest in contrast-enhancing recurrent tumors, but total fiber loss induced by edema or gliosis has an equal detrimental effect on the patients' performance due to the larger volume affected.
Funding
Funded by the 1000BRAINS study (INM, Research Centre Juelich, Germany), Horizon 2020 (Grant No. 945539 (HBP SGA3; SC)), and Heinz Nixdorf Foundation.
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Antiretroviral drug–drug interactions: A comparison of online drug interaction databases

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Antiretroviral drug–drug interactions: A comparison of online drug interaction databases

Actual or Potential Drug–drug Interactions Identified.


Abstract

What is known and objective

Antiretrovirals have a high drug interaction potential, which can lead to increased toxicity and/or decreased efficacy. Multiple databases are available to assess drug–drug interactions. The aim of our study was to compare interaction identification for commonly used ARVs and concomitant medications between six different online drug–drug interaction databases.

Comment

This was a cross-sectional review using each of the following six databases: LexiComp®, Clinical Pharmacology®, Micromedex®, Epocrates®, University of Liverpool, and University of Toronto. Sixteen antiretroviral drugs and 100 of the DrugStats Database "Top 200 of 2019" list of medications were included. Each of the six databases identified a different number of actual or potential interactions. The number of interactions ranged from 211 to 283.

What is new and conclusions

A variety of databases exist with inconsistent identification of actual or potential drug–drug interactions amongst them. It may be beneficial to cross-reference multiple databases prior to making decisions regarding patient care.
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Favipiravir in patients with early mild-to-moderate COVID-19: a randomized controlled trial

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Abstract
Background
Despite vaccination, many remain vulnerable to COVID-19 and its complications. Oral antivirals to prevent COVID-19 progression are vital. Based upon perceived potency and clinical efficacy, favipiravir is widely used to treat COVID-19. Evidence from large randomized controlled trials (RCT) is lacking.
Methods
In this multicenter double-blinded placebo-controlled RCT, adults with early mild-to-moderate COVID-19 were 1:1 randomized to favipiravir or placebo. The study evaluated time to sustained clinical recovery (TT-SCR), COVID-19 progression, and cessation of viral shedding.
Results
Of 1187 analyzed patients across 40 centers, 83.3% were Hispanic, 89.0% unvaccinated, 70.3% SARS-CoV-2 seronegative, and 77.8% had risk factors for COVID-19 progression. The median time from symptom presentation and from positive test to randomization was three and two days, respectively. There was no difference in TT-SCR (median of 7 days for both groups; p = 0.80), COVID-19 progression [11 patients each (1.9% vs. 1.8%); p = 0.96], time to undetectable virus [median = 6 days, 95% CI (6-8) vs. 7 days, 95% CI (6-9)], or in undetectable virus by end of therapy (73.4% vs. 72.3%; p = 0.94). Outcomes were consistent across the analyzed sub-groups. Adverse events were observed in 13.8% and 14.8% of favipiravir-treated and placebo-treated subjects, respectively. Uric acid elevation was more frequent among favipiravir-treated subjects (19.9% vs. 2.8%).
Conclusions
Favipiravir was well tolerated but lacked efficacy in TT-SCR, progression to severe COVID-19, or cessation of viral shedding and should not be used to treat patients with COVID-19.
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