scholarly journals Tumor treating fields in the management of Glioblastoma: opportunities for advanced imaging

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Vikram S. Soni ◽  
Ted K. Yanagihara
Keyword(s):  
Clinical Trials ◽  
Cancer Therapy ◽  
Electric Fields ◽  
Randomized Clinical Trials ◽  
Phase Iii ◽  
Imaging Biomarkers ◽  
Tumor Treating Fields ◽  
Alternating Electric Fields ◽  
Promising Line

AbstractAlternating electric fields have been successfully applied to cancer cells in-vitro to disrupt malignant progression and this antimitotic therapy has now been proven to be efficacious in Phase II and Phase III randomized clinical trials of patients with glioblastoma. With additional clinical trials ongoing in a number of other malignancies, there is a crucial need for a better understanding of the radiographic predictors of response and standardization of surveillance imaging interpretation. However, many radiologists have yet to become familiarized with this emerging cancer therapy and there is little active investigation to develop prognostic or predictive imaging biomarkers. This article provides an overview of the pre-clinical data that elucidate the biologic mechanisms of alternating electric fields as a cancer therapy. Results from clinical trials in patients with glioblastoma are then reviewed while elaborating on the several limitations to adoption of this promising line of treatment. Finally, a proposal for the development of imaging markers as a means of overcoming some of these limitations is made, which may improve treatment utilization by augmenting patient selection not only in glioblastoma, but also other malignant conditions for which this therapy is currently being evaluated.

scholarly journals IMMU-42. DUAL ACTIVATION OF THE cGAS-STING PATHWAY AND AIM2-INDUCED PYROPTOSIS BY TUMOR-TREATING FIELDS PRODUCES ANTI-TUMOR IMMUNITY IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii113-ii114
Author(s):  
Dongjiang Chen ◽  
Mathew Sebastian ◽  
Tarun Hutchinson ◽  
Ashley Ghiaseddin ◽  
Sonisha Warren ◽  
...  
Keyword(s):  
Electric Fields ◽  
Tumor Immunity ◽  
Type I ◽  
Cervical Lymph Nodes ◽  
Tumor Treating Fields ◽  
Type I Ifns ◽  
Alternating Electric Fields ◽  
Dual Activation ◽  
Sting Pathway

Abstract OBJECTIVES Tumor Treating Fields (TTFields) was approved in combination with adjuvant temozolomide chemotherapy for newly diagnosed Glioblastoma (GBM) patients and resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. In many patients, a transient stage of increased peritumoral edema is often observed early during TTFields treatment, suggesting that a major component of therapeutic efficacy by TTFields may be an immune mediated process. We hypothesize that TTFields activate the immune system by triggering pyroptosis and type I Interferon (IFN) response. METHODS A panel of GBM cell lines were treated with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system. Cells were analyzed for the production of micronuclei and activation of both pyroptosis and STING pathways using immunostaining, quantitative PCR, ELISA and cytometry. Pre-treated mouse GBM cells were injected into mouse brain to monitor survive and immunophenotyping. GBM patients’ blood was collected, and PBMC were isolated and analyzed by single cell RNAseq. RESULTS TTFields resulted in a significantly higher rate of micronuclei structures released into the cytoplasm, which were co-localized with two upstream dsDNA sensors AIM2 and cGAS. TTFields-activated micronuclei-dsDNA sensor complexes led to i) induction of pyroptotic cell death, as measured by LDH release assay, and through AIM2-recruited caspase1 activation and cleavage of pyroptosis-specific Gasdermin D; and ii) activation of STING pathway leading to the increase of type I IFNs and pro-inflammatory cytokines. In mouse model, double knocking down of STING/AIM2 eliminated the tumor suppression effects caused by TTFields. TTFields pretreated wild type cells successfully elevated dendritic cell level in mouse cervical lymph nodes which can be reversed by double knocking down. CONCLUSIONS These results provide compelling evidence that TTFields induces effective anti-tumor immunity in GBM cells and patients.

Analysis of the EF-14 phase III trial reveals that tumor treating fields alter progression patterns in glioblastoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2055-2055
Author(s):  
Suriya A. Jeyapalan ◽  
Steven A Toms ◽  
Andreas Felix Hottinger ◽  
Lawrence Kleinberg ◽  
Erqi Pollom ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Electric Fields ◽  
Growth Patterns ◽  
T Test ◽  
Phase Iii ◽  
Tumor Bed ◽  
Tumor Treating Fields ◽  
Alternating Electric Fields ◽  
Trial Testing ◽  
Chi Squared

2055 Background: The EF-14 [NCT00916409] trial showed that addition of alternating electric fields (Tumor Treating Fields, TTFields) to Temozolomide (TMZ) resulted in improved survival in newly diagnosed Glioblastoma (GBM) patients with supratentorial tumors treated compared to TMZ alone. TTFields delivery is planned to optimize dose at the tumor bed, leading to the hypothesis that TTFields treated patients are more likely to exhibit distal progressions, including progression to the infratentorial brain where TTFields dose is minimal when targeting the supratentorium. Here we present analysis of the EF-14 trial testing this hypothesis. Methods: Patients on treatment for more than two months who had an MRI that exhibited progression were included in the study (treatment: N=280/466, control: N=122/229). Regions of enhancing tumor, necrosis and resection were contoured on T1 contrast MRIs acquired at baseline and at the date of first progression. New lesions at progression were classified as distal if they appeared outside of a Proximal Boundary Zone (PBZ) of 20 mm surrounding the lesions identified in the baseline MRI. The rate of occurrence of distal progressions in the TTFields-treated arm was compared to the rate observed in the control arm. Patients with (distal) infratentorial progression were identified. Results: Distal progressions were more common in the treatment arm (49/280 (18%) vs. 10/122 (8%) P<0.02; chi-squared). Infratentorial progression were observed in 4% (10 patients) of the treatment arm vs. 0 patients in the control (P<0.002 t-test). Distal lesions at progression were more distant from the original lesion in the TTFields treated arm (58.57 + 28.12 mm vs 46.61 + 20.48 mm, P<0.02; Wilcoxon rank sum test. The relative tumor growth rates in TTFields treated patients were significantly slower than those observed in the control arm (0.036+ 0.126 ml/day vs. 0.036+ 0.183 ml/day P<0.03; t-test). Conclusions: This analysis indicates that adding TTFields to TMZ could impact GBM growth patterns. The results suggest that TTFields increases local control of tumor growth, emphasizing the need for adaptive treatment after progression to control progressing disease. Clinical trial information: NCT00916409.

scholarly journals INNV-20. A SYSTEMATIC REVIEW OF TUMOR TREATING FIELDS THERAPY FOR PRIMARY FOR RECURRENT AND GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi134-vi135
Author(s):  
Pavan Shah ◽  
Taija White ◽  
Carrie Price ◽  
Debraj Mukherjee
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Electric Fields ◽  
Treatment Modality ◽  
Randomized Clinical Trials ◽  
Treatment Options ◽  
Recurrent Glioblastoma ◽  
Skin Reactions ◽  
Tumor Treating Fields ◽  
Novel Treatment

Abstract BACKGROUND Glioblastoma is an aggressive primary central nervous system malignancy with poor prognosis and limited treatment options. Tumor treating fields (TTFs) are a novel treatment modality utilizing alternating electric fields that have demonstrated promise in randomized clinical trials for primary and recurrent glioblastomas. In addition to these studies, a multitude of smaller investigations have been performed examining their efficacy in a variety of combination therapies. This systematic review of available literature aims to summarize and evaluate the efficacy and safety of TTFs for primary and recurrent glioblastoma patients. METHODS A systematic review of the literature was performed according to PRISMA guidelines from database inception through 2/27/2019. Databases queried include PubMed, Embase, Cochrane, Scopus, Web of Science, and ClinicalTrials.gov. 856 unique studies were initially identified in this search, 9 of which met final inclusion criteria. 2 authors independently performed the screening and data extraction of the studies. RESULTS Excluding historical controls, 1569 patients were identified in these studies, 1191 of which received TTFs therapy. TTFs were evaluated in single-arm clinical trials (n = 2), randomized clinical trials (n = 2), and retrospective studies (n = 5). These 9 studies are presented based on treatments provided, baseline patient characteristics, and patient outcomes. No adverse events appear to be associated with TTFs other than adverse skin reactions. Given the heterogeneity in the presented studies, a quantitative meta-analysis was not performed. CONCLUSIONS TTFs are a novel treatment modality that have demonstrated safety and efficacy in a number of settings and study designs. However, further investigation is needed to continue characterizing treatment outcomes and assessing TTFs interactions with various drug regimens.

scholarly journals Alternating electric tumor treating fields for treatment of glioblastoma: rationale, preclinical, and clinical studies

2018 ◽  
Vol 128 (2) ◽  
pp. 414-421 ◽  
Author(s):  
Sandeep Mittal ◽  
Neil V. Klinger ◽  
Sharon K. Michelhaugh ◽  
Geoffrey R. Barger ◽  
Susan C. Pannullo ◽  
...  
Keyword(s):  
Electric Fields ◽  
Clinical Data ◽  
Combined Treatment ◽  
Current Evidence ◽  
Newly Diagnosed ◽  
Tumor Treating Fields ◽  
Alternating Electric Fields ◽  
Recurrent Gbm

OBJECTIVETreatment for glioblastoma (GBM) remains largely unsuccessful, even with aggressive combined treatment via surgery, radiotherapy, and chemotherapy. Tumor treating fields (TTFs) are low-intensity, intermediate-frequency, alternating electric fields that have antiproliferative properties in vitro and in vivo. The authors provide an up-to-date review of the mechanism of action as well as preclinical and clinical data on TTFs.METHODSA systematic review of the literature was performed using the terms “tumor treating fields,” “alternating electric fields,” “glioblastoma,” “Optune,” “NovoTTF-100A,” and “Novocure.”RESULTSPreclinical and clinical data have demonstrated the potential efficacy of TTFs for treatment of GBM, leading to several pilot studies, clinical trials, and, in 2011, FDA approval for its use as salvage therapy for recurrent GBM and, in 2015, approval for newly diagnosed GBM.CONCLUSIONSCurrent evidence supports the use of TTFs as an efficacious, antimitotic treatment with minimal toxicity in patients with newly diagnosed and recurrent GBM. Additional studies are needed to further optimize patient selection, determine cost-effectiveness, and assess the full impact on quality of life.

scholarly journals Establishment of a New Device for Electrical Stimulation of Non-Degenerative Cartilage Cells In Vitro

2021 ◽  
Vol 22 (1) ◽  
pp. 394
Author(s):  
Simone Krueger ◽  
Alexander Riess ◽  
Anika Jonitz-Heincke ◽  
Alina Weizel ◽  
Anika Seyfarth ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Electric Fields ◽  
Cartilage Tissue ◽  
Type I ◽  
Dependent Manner ◽  
New Device ◽  
Alternating Electric Fields ◽  
Cartilage Cells ◽  
Stimulation Of

In cell-based therapies for cartilage lesions, the main problem is still the formation of fibrous cartilage, caused by underlying de-differentiation processes ex vivo. Biophysical stimulation is a promising approach to optimize cell-based procedures and to adapt them more closely to physiological conditions. The occurrence of mechano-electrical transduction phenomena within cartilage tissue is physiological and based on streaming and diffusion potentials. The application of exogenous electric fields can be used to mimic endogenous fields and, thus, support the differentiation of chondrocytes in vitro. For this purpose, we have developed a new device for electrical stimulation of chondrocytes, which operates on the basis of capacitive coupling of alternating electric fields. The reusable and sterilizable stimulation device allows the simultaneous use of 12 cavities with independently applicable fields using only one main supply. The first parameter settings for the stimulation of human non-degenerative chondrocytes, seeded on collagen type I elastin-based scaffolds, were derived from numerical electric field simulations. Our first results suggest that applied alternating electric fields induce chondrogenic re-differentiation at the gene and especially at the protein level of human de-differentiated chondrocytes in a frequency-dependent manner. In future studies, further parameter optimizations will be performed to improve the differentiation capacity of human cartilage cells.

What are the reciprocal influences of randomized clinical trials and the patient–psychiatrist relationship?

1999 ◽  
Vol 14 (2) ◽  
pp. 93-100
Author(s):  
J. Catteau ◽  
C. Cyran ◽  
R. Bordet ◽  
C.E. Thomas ◽  
B.A. Dupuis
Keyword(s):  
Clinical Trials ◽  
Depressive Disorders ◽  
Randomized Clinical Trials ◽  
Antidepressant Drugs ◽  
Antidepressant Medication ◽  
Study Data ◽  
Phase Iii ◽  
Double Blind ◽  
Phase Iii Clinical Trials ◽  
Reciprocal Influences

SummaryThe goal of this prospective investigation was to study the course and the quality of patient-psychiatrist relationships during phase II / phase III clinical trials of antidepressant medication prescribed for depressive disorders. All patients who participated in the clinical trials (and subsequently in this survey) signed written informed consent statements and were subject to random double blind treatment assignment. Retrospective analysis of 118 investigations was carried out, and the patients involved were questioned concerning their experiences and impressions during and after the study. Data show that the outcome of clinical trials of antidepressant drugs are not a function of pre-existing good patient-psychiatrist relationships. On the other hand, no effects on the patient-psychiatrist relationship were found as a result of the experimental procedure, and it can be concluded that no detrimental effects on future patient-psychiatrist relationships were incurred.

scholarly journals Is Bayesian Analysis Ready for Use in Phase III Randomized Clinical Trials?

Stroke ◽  
2005 ◽  
Vol 36 (7) ◽  
pp. 1622-1623 ◽  
Author(s):  
George Howard ◽  
Christopher S. Coffey ◽  
Gary R. Cutter
Keyword(s):  
Clinical Trials ◽  
Bayesian Analysis ◽  
Randomized Clinical Trials ◽  
Phase Iii

In Vitro Activity of Gepotidacin Against Gram-negative and Gram-positive Anaerobes

2021 ◽  
Author(s):  
Meredith A. Hackel ◽  
James A. Karlowsky ◽  
Michele A. Canino ◽  
Daniel F. Sahm ◽  
Nicole E. Scangarella-Oman
Keyword(s):  
Clinical Trials ◽  
Vitro Activity ◽  
Phase Iii ◽  
In Vitro Activity ◽  
Gram Positive ◽  
Gram Negative ◽  
Phase Iii Clinical Trials ◽  
Agar Dilution

Gepotidacin (formerly GSK2140944) is a first in class triazaacenaphthylene antibacterial currently in Phase III clinical trials. When tested against Gram-negative ( n =333) and Gram-positive ( n =225) anaerobes by agar dilution, gepotidacin inhibited 90% of isolates (MIC 90 ) at concentrations of 4 and 2 μg/ml, respectively. Given gepotidacin’s in vitro activity against the anaerobic isolates tested, further study is warranted to better understand gepotidacin’s utility in the treatment of infections caused by clinically relevant anaerobic organisms.

scholarly journals Targeting Sphingolipids for Cancer Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Osmel Companioni ◽  
Cristina Mir ◽  
Yoelsis Garcia-Mayea ◽  
Matilde E. LLeonart
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Cancer Therapy ◽  
Preclinical Studies ◽  
Hepatic Toxicity ◽  
Multiple Cancers ◽  
Extensive Class ◽  
Effective Drugs

Sphingolipids are an extensive class of lipids with different functions in the cell, ranging from proliferation to cell death. Sphingolipids are modified in multiple cancers and are responsible for tumor proliferation, progression, and metastasis. Several inhibitors or activators of sphingolipid signaling, such as fenretinide, safingol, ABC294640, ceramide nanoliposomes (CNLs), SKI-II, α-galactosylceramide, fingolimod, and sonepcizumab, have been described. The objective of this review was to analyze the results from preclinical and clinical trials of these drugs for the treatment of cancer. Sphingolipid-targeting drugs have been tested alone or in combination with chemotherapy, exhibiting antitumor activity alone and in synergism with chemotherapy in vitro and in vivo. As a consequence of treatments, the most frequent mechanism of cell death is apoptosis, followed by autophagy. Aslthough all these drugs have produced good results in preclinical studies of multiple cancers, the outcomes of clinical trials have not been similar. The most effective drugs are fenretinide and α-galactosylceramide (α-GalCer). In contrast, minor adverse effects restricted to a few subjects and hepatic toxicity have been observed in clinical trials of ABC294640 and safingol, respectively. In the case of CNLs, SKI-II, fingolimod and sonepcizumab there are some limitations and absence of enough clinical studies to demonstrate a benefit. The effectiveness or lack of a major therapeutic effect of sphingolipid modulation by some drugs as a cancer therapy and other aspects related to their mechanism of action are discussed in this review.

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