Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways.

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKß independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.

Tumor-treating fields dosimetry in glioblastoma: Insights into treatment planning, optimization, and dose-response relationships.

Tumor-treating fields (TTFields) are currently a Category 1A treatment recommendation by the US National Comprehensive Cancer Center for patients with newly diagnosed glioblastoma. Although the mechanism of action of TTFields has been partly elucidated, tangible and standardized metrics are lacking to assess antitumor dose and effects of the treatment. This paper outlines and evaluates the current standards and methodologies in the estimation of the TTFields distribution and dose measurement in the brain and highlights the most important principles governing TTFields dosimetry. The focus is on clinical utility to facilitate a practical understanding of these principles and how they can be used to guide treatment. The current evidence for a correlation between TTFields dose, tumor growth, and clinical outcome will be presented and discussed. Furthermore, we will provide perspectives and updated insights into the planning and optimization of TTFields therapy for glioblastoma by reviewing how the dose and thermal effects of TTFields are affected by factors such as tumor location and morphology, peritumoral edema, electrode array position, treatment duration (compliance), array "edge effect," electrical duty cycle, and skull-remodeling surgery. Finally, perspectives are provided on how to optimize the efficacy of future TTFields therapy.

Latency-shift of intra-operative visual evoked potential predicts reversible homonymous hemianopia after intra-ventricular meningioma surgery.

OBJECTIVES: Intraoperative visual evoked potentials (VEPs) are used to monitor the function of optic radiation during neurosurgery with the P100 amplitude decrement as a predictor of post-operative visual deficit. However, there is currently no evidence of early VEP changes indicating reversible visual field affection. METHODS: In this case report, we used VEPs during surgery for a benign meningioma located in the atrium of the right lateral ventricle. The tumor was accessed through a transcortical approach via a two-centimeter corticotomy in the lateral aspect of the superior parietal lobule. We performed flash VEPs and simultaneous recordings of electroretinography alongside with multimodal intraoperative monitoring. RESULTS: We observed a significant and sustained unilateral latency shift of the P100 component of VEPs, while amplitudes temporarily dropped to 80% of baseline but recovered entirely at the end of surgery. After the operation, the patient had a left-sided lower-quadrant anopia, which recovered completely during the following three months. Diagnostic VEP with pattern reversal monocular full field stimulation at one month postoperatively showed normal latencies bilaterally. CONCLUSION: Our case indicates that the VEP (P100) latency may be a new and valuable indicator (in addition to VEP amplitude) of the visual pathways. SIGNIFICANCE: Monitoring VEPs may be useful to detect an imminent injury and a potentially reversible functional deficit.

Comparison of 5-aminolevulinic acid and sodium fluorescein for intraoperative tumor visualization in patients with high-grade gliomas: a single-center retrospective study.

OBJECTIVE: Maximal safe resection is an important surgical goal in the treatment for high-grade gliomas. Fluorescent dyes help the surgeon to distinguish malignant tissue from healthy. The aims of this study were 1) to compare the 2 fluorescent dyes 5-aminolevulinic acid (5-ALA) and sodium fluorescein (fluorescein) regarding extent of resection, progression-free survival, and overall survival; and 2) to assess the influence of other risk factors on clinical outcome and screen for potential disadvantages of the dyes. METHODS: A total of 209 patients with high-grade gliomas were included in this retrospective study. Resections were performed in the period from 2012 to 2017 using 5-ALA or fluorescein. Extent of resection was assessed as the difference in tumor volume between early postoperative and preoperative MRI studies. Tumor progression-free survival and overall survival were analyzed using an adjusted Cox proportional hazards model. RESULTS: One hundred fifty-eight patients were operated on with 5-ALA and 51 with fluorescein. The median duration of follow-up was 46.7 and 21.2 months, respectively. Covariables were evenly distributed. There was no statistically significant difference in volumetrically assessed median extent of resection (96.9% for 5-ALA vs 97.4% for fluorescein, p = 0.46) or the percentage of patients with residual tumor volume less than 0.175 cm3 (29.5% for 5-ALA vs 36.2% for fluorescein, p = 0.39). The median overall survival was 14.8 months for the 5-ALA group and 19.7 months for the fluorescein group (p = 0.06). The median adjusted progression-free survival was 8.7 months for the 5-ALA group and 9.2 months for the fluorescein group (p = 0.03). CONCLUSIONS: Fluorescein can be used as a viable alternative to 5-ALA for intraoperative fluorescent guidance in brain tumor surgery. Comparative, prospective, and randomized studies are much needed.

Enhancing Tumor Treating Fields Therapy with Skull-Remodeling Surgery. The Role of Finite Element Methods in Surgery Planning.

Skull-remodeling surgery has been proposed to enhance the dose of tumor treating fields in glioblastoma treatment. This abstract describes the finite element methods used to plan the surgery and evaluate the treatment efficacy.

Estimating the Intensity and Anisotropy of Tumor Treating Fields Jsing Singular Value Decomposition. Towards a More Comprehensive Estimation of Anti-tumor Efficacy.

Tumor treating fields (TTFields) is an anticancer treatment that inhibits tumor growth with alternating electrical fields. Finite element (FE) methods have been used to estimate the TTFields intensity as a measure of treatment "dose". However, TTFields efficacy also depends on field direction and exposure time. Here we propose a new FE based approach, which uses all these parameters to quantify the average field intensity and the amount of unwanted directional field correlation (fractional anisotropy, FA). The method is based on principal component decomposition of the sequential TTFields over one duty cycle. Using a realistic head model of a glioblastoma patient, we observed significant unwanted FA in many regions of the brain, which may potentially affect therapeutic efficacy. FA varied between different array layouts and indicated a different order of array performance than predicted from the field intensity. Tumor resection nullified differences in field distributions between layouts and increased FA considerably. Our results question the rationale for the use of macroscopically orthogonal array layouts to reduce field correlation and rather indicate that arrays should be placed to maximize pathology coverage and field intensity. The proposed calculation framework has several potential applications, incl. improved treatment planning, technology development, and accurate prognostication models. Future studies are required to validate the method.

A Review on Tumor-Treating Fields (TTFields): Clinical Implications Inferred From Computational Modeling.

Tumor-treating fields (TTFields) are a cancer treatment modality that uses alternating electric fields of intermediate frequency (∼100-500 kHz) and low intensity (1-3 V/cm) to disrupt cell division. TTFields are delivered by transducer arrays placed on the skin close to the tumor and act regionally and noninvasively to inhibit tumor growth. TTFields therapy is U.S. Food and Drug Administration approved for the treatment of glioblastoma multiforme, the most common and aggressive primary human brain cancer. Clinical trials testing the safety and efficacy of TTFields for other solid tumor types are underway. The objective of this paper is to review computational approaches used to characterize TTFields. The review covers studies of the macroscopic spatial distribution of TTFields generated in the human head, and of the microscopic field distribution in tumor cells. In addition, preclinical and clinical findings related to TTFields and principles of its operation are summarized. Particular emphasis is put on outlining the potential clinical value inferred from computational modeling.

Using computational phantoms to improve delivery of Tumor Treating Fields (TTFields) to patients.

This paper reviews the state-of-the-art in simulation-based studies of Tumor Treating Fields (TTFields) and highlights major aspects of TTFields in which simulation-based studies could affect clinical outcomes. A major challenge is how to simulate multiple scenarios rapidly for TTFields delivery. Overcoming this challenge will enable a better understanding of how TTFields distribution is correlated with disease progression, leading to better transducer array designs and field optimization procedures, ultimately improving patient outcomes.

Post-tetanic potentiation of GABAergic IPSCs in cultured hippocampal neurons is exclusively time-dependent.

We have previously shown that post-tetanic potentiation (PTP) of GABAergic IPSCs in cultured hippocampal neurons involves activation of L-type Ca(2+) channels. Although there is little Ca(2+) entry by this route, it is possible that L-type Ca(2+) channels mediate an increase in probability of release (Pr) by a mechanism that remains dormant in the absence of stimulation. We have tested this hypothesis in the present study using dual whole-cell patch clamp recordings. IPSCs were evoked by low-frequency stimulation (LFS; 0.2 Hz) of presynaptic GABAergic neurons. Run-down was corrected by linear regression. Following tetanic stimulation (80 pulses at 40 Hz), the presence of PTP was probed by resuming LFS after various post-tetanic intervals (PTI). To control for possible effects associated with LFS, the train and PTI were replaced by corresponding pauses. Following pauses >or=16 s, the first IPSC was significantly increased by 20-25% (P<0.01, paired t-test). These post-pause responses were subtracted from IPSCs following tetanic stimulation. Following correction, PTP was greatest ( approximately 50%) after the shortest PTI (4 s) and IPSC amplitudes declined back to the baseline value over 1-2 min. With a PTI of 16 s, the first IPSC was potentiated to the same level as that to which PTP with a PTI of 4 s had decayed with continued LFS. There was no significant PTP with PTIs of 64 and 128 s. Since PTP decays entirely in the absence of stimulation, it is concluded that the process(es) mediating the increase in vesicular Pr appear to be time-dependent, but not use-dependent.