P10.10.A Tumor Treating Fields (TTFields), temozolomide and lomustine co-application is efficacious in glioblastoma cancer cell lines

alexandrossfakianakis shared this article with you from Inoreader P10.10.A Tumor Treating Fields (TTFields), temozolomide and lomustine co-application is efficacious in glioblastoma cancer cell lines via # Neuro-Oncology Current Issue 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. View on Web

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P17.06.B Different dosage of bevacizumab treatment in recurrent IDHwt glioblastoma/IDHmut grade 4 astrocytoma and its impact on outcome

alexandrossfakianakis shared this article with you from Inoreader P17.06.B Different dosage of bevacizumab treatment in recurrent IDHwt glioblastoma/IDHmut grade 4 astrocytoma and its impact on outcome via # Neuro-Oncology Current Issue Abstract Background Angiogenesis is one of the most distinctive hallmarks of glioblastoma (GBM). Although bevacizumab did not show to improve overall survival in phase 3 trials, it was approved by FDA and is often prescribed as off-label therapy in the recurrent clinical setting. The aim of this study is to evaluate the difference in terms of survival and safety between the 5 mg/m2 and 10 mg/m2 bevacizumab schedule in recurrent GBM. Material and methods All pts treated at Veneto Institute of Oncology from May 2013 to March 2022 were retrospectively reviewed. Major inclusion criteria were: histologically confirmed diagnosis of IDHwt GBM/IDHmut grade 4 astrocytoma (according to the WHO 2021 classification), relapse after first or subsequent line of therapy, treatment with bevacizumab at 5 mg/m2 or/and 10 mg/m2 every 2 weeks until progression/death or unacceptable toxicity. Bevacizumab was admini stered as off-label therapy. The treatment schedule was at physician's discretion. RANO criteria and CTCAE v5.0 were used for response and toxicity assessment. Results 81 pts were enrolled. From starting bevacizumab the median follow-up was 10.9ms [95% CI 9.8-14.0] and median age was 53ys (range 18-81). 33 (41%) pts received the 5 mg/m2 schedule. Among them, 2 (6%) were IDHmut grade 4, 8 (24%) had ≥65ys and ECOG-PS was 0-1 in 16 (48%) and ≥2 in 17 (51%), respectively. MGMT was methylated in 15 of 30 (50%) evaluable pts. Median number of prior lines of treatment was 2 (range 1-4) and 30% of pts received bevacizumab at first recurrence. 28 (84.9%) pts were evaluable for response: 7 (21%) and 5 (15%) showed PR and SD. 48 pts received the 10 mg/m2 schedule: 5 (10%) were IDHmut grade 4 astrocytoma; 29 (60%) had an ECOG-PS of 0 or 1 and 4 (8%) had ≥65ys, MGMT was methylated in 20 of 44 (45%) evaluable pts. 36 (75%) pts received bevacizumab beyond the second line of therapy. 46 (96%) pts were evaluable for response: 6 (12%) had PR, 19 (39%) SD. mOS from the start of bevacizumab was 7.3ms (95% CI 4.3-6.4), mPFS was 4.4ms [95% CI 3.7 - 6.4]. At univariate analysis, pts who received the 5 mg/m2 or the 10 mg/m2 schedule had a mOS of 5.4 and 7.7ms (p=0.08); mOS for pts with ECOG-PS < or ≥2 was 9.0 and 5.4ms (p=0.04) while mOS for pts with <2 or ≥2 lines of therapy was 4.7 and 7.7ms (p=0.056). Age and type of the tumor were not statistically significant. At multivariate analysis, MGMT methylated status was the only factor statistically associated with OS (HR=0.48, 95% CI, p=0.002) and PFS (HR=0.33, 95% CI, p=0.001), while a number of prior lines of therapy ≥2 (HR=2.07, 95% CI, p=0.02) was significantly associated only with PFS. Grade 3-4 most common adverse events were hypertension (18%) in pts treated with 5 mg/m2 and hypertension (16%) and proteinuria (2%) in pts treated with 10 mg/m2. Conclusions Bevacizumab tr eatment with a dosage of 5 mg/m2 and 10 mg/m2 seems to give comparable outcome in terms of survival in recurrent GBM pts. No difference was demonstrated for safety. View on Web

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P17.15.A Neoadjuvant immunotherapy in the treatment of recurrent glioblastoma: an overview of last decade

alexandrossfakianakis shared this article with you from Inoreader P17.15.A Neoadjuvant immunotherapy in the treatment of recurrent glioblastoma: an overview of last decade via # Neuro-Oncology Current Issue Abstract Background Recurrent glioblastoma (ArGB) is one of the most common primary malignant brain tumors in adults, with a poor prognosis, with low patient survival even after treatment. Because of this, several studies were carried out evaluating different therapies for the treatment of ArGB, more recently studies have emerged regarding the use of neoadjuvant immunotherapy and its possible advantages in the treatment of such patients. Therefore, the present study aims to analyze the efficacy of neoadjuvant immunotherapy and its effect on the survival of patients with recurrent glioblastoma. Material and Methods A search was performed in PubMed, Embase and Cochrane databases using the keywords: "Immunotherapy, "neoadjuvant" and "recurrent glioblastoma". Articles from the last 10 years were selected and those that did not meet the inclusion criteria were excluded from the research, totaling 7 selected articles. Results P atients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy after surgery, had significantly prolonged survival compared to patients who were randomized to receive adjuvant post-surgical PD-1 blockade alone. Neoadjuvant PD-1 blockade was associated with up-regulation of T cells and interferon-γ-related gene expression, but with down-regulation of cell cycle-related gene expression within the tumor, which was not observed in patients receiving adjuvant therapy. isolated. Conclusion Neoadjuvant immunotherapy, through a PD-1 inhibitor, in patients with ArGB, results in positive biological effects, in addition to the clinical benefit of, on average, increasing overall survival considerably due in large part to the improvement of the immune response , with no noticeable adverse effects, thus being advantageous, although these results are early and the current studies are not very comprehensive. Larger studies are needed for greater reliabil ity and statistical relevance. View on Web

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P17.03.B Modelling migration of glioblastoma patient-derived cells using human iPSC-derived neural spheroid and high content analysis

alexandrossfakianakis shared this article with you from Inoreader P17.03.B Modelling migration of glioblastoma patient-derived cells using human iPSC-derived neural spheroid and high content analysis via # Neuro-Oncology Current Issue 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. View on Web

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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 KS05.5.A Alterations in white matter fiber density associated with structural MRI and metabolic PET lesions following multimodal therapy in glioma patients via # Neuro-Oncology Current Issue 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. View on Web

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

alexandrossfakianakis shared this article with you from Inoreader Antiretroviral drug–drug interactions: A comparison of online drug interaction databases via Journal of Clinical Pharmacy and Therapeutics 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. View on Web

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Favipiravir in patients with early mild-to-moderate COVID-19: a randomized controlled trial

alexandrossfakianakis shared this article with you from Inoreader Favipiravir in patients with early mild-to-moderate COVID-19: a randomized controlled trial via Clinical Infectious Diseases Advance Access 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. View on Web

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