Tumor-treating Fields Research Articles

Efficacy of Adding Veliparib to Temozolomide for Patients With MGMT-Methylated Glioblastoma

The prognosis for patients with glioblastoma is poor following standard therapy with surgical resection, radiation, temozolomide, and tumor-treating fields. To evaluate the combination of veliparib and temozolomide in glioblastoma based on preclinical data demonstrating significant chemosensitizing effects of the polyadenosine diphosphate-ribose polymerase 1/2 inhibitor veliparib when combined with temozolomide. Patients with newly diagnosed glioblastoma with MGMT promoter hypermethylation who had completed concomitant radiation and temozolomide were enrolled between December 15, 2014, and December 15, 2018, in this Alliance for Clinical Trials in Oncology trial. The data for this analysis were locked on April 21, 2023. Patients were randomized and treated with standard adjuvant temozolomide (150-200 mg/m2 orally, days 1-5) combined with either placebo or veliparib (40 mg orally, twice daily, days 1-7) for 6 cycles. The primary end point for the phase 3 portion of the trial was overall survival (OS). There were 322 patients randomized during the phase 2 accrual period and an additional 125 patients randomized to complete the phase 3 accrual, for a total of 447 patients in the final phase 3 analysis. The median (range) age for patients was 60 (20-85) years and 190 patients (42.5%) were female. The median OS was 24.8 months (90% CI, 22.6-27.7) for the placebo arm and 28.1 months (90% CI, 24.3-33.3) for the veliparib arm (P = .17). The difference in survival did not meet the prespecified efficacy end point. However, there was a separation of the survival curves that favored the veliparib arm over 24 to 48 months of follow-up. The experimental combination was well tolerated with an acceptable elevation in grade 3 or 4 hematologic toxic effects. This trial found that adding veliparib to adjuvant temozolomide did not significantly extend OS in patients with newly diagnosed, MGMT-hypermethylated glioblastoma. ClinicalTrials.gov Identifier: NCT02152982.

Technical note: Computational study on thermal management schemes for tumor-treating fields therapy.

The study focuses on thermal management in tumor-treating fields (TTFields) therapy, crucial for patient compliance and therapeutic effectiveness. TTFields therapy, an established treatment for glioblastoma, involves applying alternating electric fields to the brain. However, managing the thermal effects generated by electrodes is a major challenge, impacting patient comfort and treatment efficiency. This research aims to explore methods for controlling temperature increases during TTFields therapy without reducing its duty cycle. The study emphasizes optimizing electrode configurations and array arrangements to mitigate temperature rise, thereby maintaining therapy effectiveness and patient compliance. Using a simplified multi-layer tissue model and finite element analysis, various electrode configurations and array shapes were tested in COMSOL Multiphysics v6.0. Adjustments included changing the electrode gel layer radius from 8 to 12mm, electrode spacing, and transitioning to a more uniform array arrangement, such as a square array or a circular array. The study revealed a strong correlation between high temperatures and edge current density distributions on electrodes. It was found that increasing the electrode gel layer's diameter, enlarging electrode spacing, and adopting a uniform array arrangement markedly mitigated temperature rises. By increasing the gel layer radius from the original 10 to 12mm, a reduction in the peak temperature increases of approximately 0.3°C was observed. Changing the layout from rectangular to circular with the same area further reduced the peak temperature rise by 0.5°C. Additionally, enlarging the spacing between electrodes also contributed to temperature control. By integrating these strategies, we designed a new circular electrode array with an electrode spacing of 45mm and a gel radius of 12mm, successfully reducing the peak temperature from 42.1°C to 40.8°C, effectively achieving temperature control. The research demonstrates that improving electrode and array configurations can effectively manage temperature in TTFields therapy without compromising treatment duration. This strategy is crucial as TTFields therapy relies on prolonged field exposure for effectiveness. The findings offer valuable insights into thermal management in electrode array design and could lead to enhanced patient compliance and treatment efficacy in TTFields therapy.

The Patterns of Failure and Prognostic Impact of Tumor Location in Patients Undergoing Reirradiation for Glioblastoma.

Introduction RTOG 1205 is the only randomized study to evaluate the safety and efficacy of reirradiation (reRT) in recurrent glioblastoma (GBM). While this study showed that reRT was safe and improves progression-free survival (PFS), an improved approach to reRT is still needed. In this study, we report on patterns of failure and outcomes in a cohort of patients with recurrent GBM who underwent reRT. We hypothesize that patients at high risk of leptomeningeal spread (LMS) are not good candidates for reRT due to the risk of treatment-related toxicity without clinical benefit. Methods In this retrospective study, patients with recurrent GBM who underwent reRT at a single institution from 2015-2023 were included. Sociodemographic, treatment, and outcomes data were collected via chart review. Time to progression was defined as the time from the start of reRT to progression per the Response Assessment in Neuro-Oncology (RANO) criteria. Overall survival (OS) was defined as the time from the start of reRT to death. PFS and OS were estimated using the Kaplan-Meier method. Results Thirteen patients with recurrent GBM who underwent reRT were identified. The median age at diagnosis was 58 years. Six patients (46.2%) had tumors that were O6-methylguanine-DNA methyltransferase (MGMT) methylated, four (30.8%) were MGMT unmethylated, and three (23.11%) had unknown MGMT status. Eight patients underwent repeat resection after recurrence and before reRT. Most patients (n=7) received 35 Gy in 10 fractions with concurrent bevacizumab, while other patients were treated with 25-40 Gy in 5-15 fractions with grade 1 or less acute toxicity. Three patients were treated with tumor-treating fields. The median follow-up was five months. Median PFS was three months [95% confidence interval (95% CI): one to four months] and median OS was five months (95% CI, 1-8 months) as compared to 7.1 months and 10.1 months, respectively, on RTOG 1205. Five patients developed LMS after reRT, one patient died before progression, and the remaining seven patients all developed progression within one centimeter of the recurrent tumor. Of the patients who developed LMS, all had tumors abutting the ventricles and three underwent resection 2-17 months before reRT. Conclusion Patterns of failure suggest a potential treatment selection approach for patients with recurrent GBM, in which patients at high risk of LMS (tumor abutting ventricles with or without recent surgery) should not undergo reRT, while patients at low risk of LMS are good candidates for reRT. Furthermore, reRT could be administered with reduced margins given that all non-LMS recurrences were within 1cm of the original tumor. Additional studies are needed to validate this approach.

Tumor-treating fields increase cytotoxic degranulation of natural killer cells against cancer cells

Tumor-treating fields increase cytotoxic degranulation of natural killer cells against cancer cells

Revisiting the standards of cancer detection and therapy alongside their comparison to modern methods.

In accordance with the World Health Organization data, cancer remains at the forefront of fatal diseases. An upward trend in cancer incidence and mortality has been observed globally, emphasizing that efforts in developing detection and treatment methods should continue. The diagnostic path typically begins with learning the medical history of a patient; this is followed by basic blood tests and imaging tests to indicate where cancer may be located to schedule a needle biopsy. Prompt initiation of diagnosis is crucial since delayed cancer detection entails higher costs of treatment and hospitalization. Thus, there is a need for novel cancer detection methods such as liquid biopsy, elastography, synthetic biosensors, fluorescence imaging, and reflectance confocal microscopy. Conventional therapeutic methods, although still common in clinical practice, pose many limitations and are unsatisfactory. Nowadays, there is a dynamic advancement of clinical research and the development of more precise and effective methods such as oncolytic virotherapy, exosome-based therapy, nanotechnology, dendritic cells, chimeric antigen receptors, immune checkpoint inhibitors, natural product-based therapy, tumor-treating fields, and photodynamic therapy. The present paper compares available data on conventional and modern methods of cancer detection and therapy to facilitate an understanding of this rapidly advancing field and its future directions. As evidenced, modern methods are not without drawbacks; there is still a need to develop new detection strategies and therapeutic approaches to improve sensitivity, specificity, safety, and efficacy. Nevertheless, an appropriate route has been taken, as confirmed by the approval of some modern methods by the Food and Drug Administration.

DIPG-40. LONG TERM SURVIVAL OF A 14 YEAR OLD GIRL WITH H3K27M MUTATED DIFFUSE MIDLINE GLIOMA FOLLOWING RADIOTHERAPY AND PROLONGED TUMOR TREATING FIELDS (TTFIELDS) -CASE REPORT

Abstract INTRODUCTION Pediatric diffuse midline H3K27M mutated glioma has a dismal prognosis. Most cases are treated by radiotherapy and oral chemotherapy, with surgical resection having a debatable role in some. Tumor-treating fields (TTFields) is a noninvasive modality in which alternating electrical fields exert biophysical force on charged and polarizable molecules known as dipoles. TTFields has been shown to extend survival for adult patients with newly diagnosed and recurrent GBM, and is FDA approved for these indications. There is sparse data about pediatric patients. CASE REPORT A 14-year-old girl presented with headache and vomiting. A large left thalamic tumor was diagnosed and underwent subtotal resection. Diagnosis was diffuse midline glioma, H3K27M positive, IDH negative. Molecular Panel: Tumor mutation burden low, microsatellite stable. Genomic findings: FGFR1, NF1, H3F3A -K28M, ATRX R666, MAP3K1 She was re-operated due to a fast tumor relapse within a few weeks, prior to radiotherapy, followed with radiotherapy with local field 59Gy. She then received temozolamide (12 months) concomitant with TTfields (Optune, Novocure). TTfields therapy was administered for 5 years without adverse effects and excellent compliance (above 85%). After 5 years, therapy was withheld, and she is now off therapy NED for another 15 months. DISCUSSION Diffuse midline H3K27M glioma harbors a poor prognosis in children. Children refrain from this treatment both for lack of evidence and because of the difficulty in adhering to a regimen that demands carrying a battery of 1.5-2kg all day and shaving all hair every 3 days. Our patient had a high compliance and as she wore a head scarf for religious customs, the device was not visible. To our knowledge this is the first pediatric reported case of long-term survival of H3K27mutatted midline glioma using TTFields. Further pediatric studies are warranted.

Tumor-treating fields in cancer therapy: advances of cellular and molecular mechanisms.

Tumor-Treating Fields (TTFields) use intermediate-frequency and low-intensity electric fields to inhibit tumor cells. However, their mechanisms are still not well understood. This article reviews their key antitumor mechanisms at the cellular and molecular levels, including inhibition of proliferation, induction of death, disturbance of migration, and activation of the immune system. The multifaceted biological effects in combination with other cancer treatments are also summarized. The deep insight into their mechanism will help develop more potential antitumor treatments.

HRQoL in patients with GBM: The impact of tumor treating fields.

e24049 Background: Glioblastoma (GBM) is the most common malignant glioma with a dismal prognosis. Patients experience a range of progressively worsening symptoms, including headaches, nausea, seizures, and cognitive deficits throughout their disease course. Initial treatment for newly diagnosed patients consists of maximal safe surgical resection followed by fractionated radiation treatment with concomitant temozolomide. Presently, there are two approved adjuvant treatment modalities following chemoradiation: temozolomide and tumor-treating fields (TTFields). In this poster, we explore the impact of TTFields on the quality of life, assessed through health-related quality of life (HRQoL), in patients with GBM. Methods: Using PubMed, Medline-indexed articles were collected using this structured query: Glioblastoma[MeSH] AND (("Electric Stimulation Therapy*"[MeSH]) OR ("Transcranial Direct Current Stimulation*"[MeSH]) OR "Tumor Treating Fields" OR "TTF") NOT "RAT" This yielded 233 results before the search date (2023). Collected sources were uploaded to Covidence to allow for multi-reviewer screening, review, and extraction. For completeness, limited forward and back citations using the ResearchRabbit tool and limited addition of non-Medline indexed articles via unstructured query yielded four additional results. Sources were filtered by study type and included/excluded based on accessibility, sample population, design, outcome measures, and interventions. Five randomized control studies remained. From this subset, bias, effect size, I2-index, and forest analysis with random effect model estimation were calculated. Results: Data analysis showed that TTFields therapy has demonstrated associations with increased progression-free survival and enhanced overall survival rates without negative effects on HRQoL. Some patients have reported improvement in mobility, self-care, and carrying out regular activities. One notable side effect observed in these patients was increased skin itchiness, which was expected due to the use of transducer arrays. Conclusions: This project identified a research gap in standardizing the assessment of quality of life in patients treated with TTFields. A significant limitation in research on TTFields is an overall lack of HRQoL data, often due to patients failing to follow-up with surveys. Future research should prioritize patient follow-up to obtain more comprehensive and precise longitudinal data on HRQoL while considering disease and treatment characteristics.

Prognostic factors of grade 4 IDH-mutant astrocytoma.

e14019 Background: The data on the prognostic factors of grade 4 IDH-mutant astrocytoma remains limited since the 2021 update of the WHO classification of Central Nervous System tumors. This update recognizes the importance of molecular characteristics and confers a grade 4 diagnosis based on the presence of at least one of either necrosis, microvascular proliferation, or CDKN2A/B homozygous deletion. This study sought to determine the factors that impact prognosis of patients with grade 4 IDH-mutant astrocytoma. Methods: A retrospective review was performed on all patients diagnosed with grade 4 IDH-mutant astrocytoma on initial diagnosis (as defined by the 2021 WHO classification) across the three Mayo clinic campuses (Minnesota, Florida, Arizona) between 2002 and 2023. Datapoints collected included demographic, clinical, imaging, histological and molecular variables. Factors impacting survival outcomes (overall survival [OS] and progression free survival [PFS]) were evaluated using Cox regression models. Results: Sixty-two patients with grade 4 IDH-mutant astrocytoma were identified (43 based on histological criteria alone, 10 based on molecular criteria alone, and 9 based on both). The median age of the patients was 36 years, with 64.5% of the patients identified as male and 93.3% as white. 100% (n=58) of these patients received standard treatment after surgery (radiation/temozolomide). The median follow up was 3.3 years. The median PFS and OS were 3.2 and 6.9 years, respectively. The OS was impacted by an unfavorable tumor location (either tumor involving the midline or at least 3 brain lobes; 2.4 years vs. 12.8 years, HR 10.8 [95% CI 3.29-35.6], p<0.001) and CDKN2A/B homozygous deletion (2.5 years vs. NR, HR=4.3 [95% CI 1.5-12.3], p=0.0065). The PFS was impacted by an unfavorable tumor location (1.4 years vs. 4.6 years, HR=5.3 [95% CI 2.21-12.7], p=0.002), CDKN2A/B homozygous deletion (1.4 years vs. 4.6 years, HR=6.2 [95% CI 2.71-14.2], p<0.001) and MGMT promoter hypermethylation (4.6 years vs. 1.4 years, HR=0.369 [95% CI 0.154-0.883], p=0.025). Age, sex, tumor size and the use of tumor-treating fields did not significantly affect survival outcomes. Using multivariable analyses, PFS remained significantly impacted by CDKN2A/B homozygous deletion (HR=11.3 [95% CI 3.23-39.0], p=0.0001) and MGMT promoter hypermethylation (HR=0.243 [95% CI 0.082-0.717], p=0.0104), but not by an unfavorable tumor location (p=0.819). Conclusions: Both CDKN2A/B homozygous deletion and MGMT status may independently influence the progression-free survival of patients with grade 4 IDH-mutant astrocytoma.

Revolutionizing Glioblastoma Treatment: A Comprehensive Overview of Modern Therapeutic Approaches.

Glioblastoma is the most common malignant primary brain tumor in the adult population, with an average survival of 12.1 to 14.6 months. The standard treatment, combining surgery, radiotherapy, and chemotherapy, is not as efficient as we would like. However, the current possibilities are no longer limited to the standard therapies due to rapid advancements in biotechnology. New methods enable a more precise approach by targeting individual cells and antigens to overcome cancer. For the treatment of glioblastoma, these are gamma knife therapy, proton beam therapy, tumor-treating fields, EGFR and VEGF inhibitors, multiple RTKs inhibitors, and PI3K pathway inhibitors. In addition, the increasing understanding of the role of the immune system in tumorigenesis and the ability to identify tumor-specific antigens helped to develop immunotherapies targeting GBM and immune cells, including CAR-T, CAR-NK cells, dendritic cells, and immune checkpoint inhibitors. Each of the described methods has its advantages and disadvantages and faces problems, such as the inefficient crossing of the blood-brain barrier, various neurological and systemic side effects, and the escape mechanism of the tumor. This work aims to present the current modern treatments of glioblastoma.

Immune Checkpoint Inhibitors and Glioblastoma: A Review on Current State and Future Directions.

Glioblastoma (GBM) is the most prevalent malignant tumor of the central nervous system. The prognosis of GBM is grim, with a median overall survival of 14.6 months and only 6.9% of patients surviving 5 years after the initial diagnosis. Despite poor outcomes, standard therapy of surgical resection, radiotherapy, chemotherapy, and tumor-treating fields has remained largely unchanged. The introduction of immune checkpoint inhibitors (ICI) has been a paradigm shift in oncology, with efficacy across a broad spectrum of cancer types. Nonetheless, investigations of ICIs in both newly diagnosed and recurrent GBM have thus far been disappointing. This lack of clinical benefit has been largely attributed to the highly immunosuppressive nature of GBM. However, immunotherapy still holds promise for the treatment of GBM, with combinatorial strategies offering hope for potentially overcoming these current limitations. In this review, we discuss the outcomes of clinical trials employing ICIs in patients with GBM. Afterward, we review ICI combination strategies and how these combinations may overcome the immunosuppressive microenvironment of GBM in the context of preclinical/clinical evidence and ongoing clinical trials.

Simulation model of tumor-treating fields

Tumor-treating fields (TTFields) is a novel treatment modality for malignant solid tumors, often employing electric field simulations to analyze the distribution of electric fields on the tumor under different parameters of TTFields. Due to the present difficulties and high costs associated with reproducing or implementing the simulation model construction techniques, this study used readily available open-source software tools to construct a highly accurate, easily implementable finite element simulation model for TTFields. The accuracy of the model is at a level of 1 mm 3. Using this simulation model, the study carried out analyses of different factors, such as tissue electrical parameters and electrode configurations. The results show that factors influncing the distribution of the internal electric field of the tumor include changes in scalp and skull conductivity (with a maximum variation of 21.0% in the treatment field of the tumor), changes in tumor conductivity (with a maximum variation of 157.8% in the treatment field of the tumor), and different electrode positions and combinations (with a maximum variation of 74.2% in the treatment field of the tumor). In summary, the results of this study validate the feasibility and effectiveness of the proposed modeling method, which can provide an important reference for future simulation analyses of TTFields and clinical applications.

Tumor Treating Fields for Treatment of Spinal Metastasis

INTRODUCTION: Tumor treating fields(TTF) has never been described for treatment of spinal metastasis. We investigate the anti-mitotic effect of TTF to inhibit the growth of human cancer using cells in vitro and in vivo models of spinal metastasis. METHODS: In-vitro: human derived osteosarcoma (Krib-Luc-1) and lund adenocarcinoma (A549-Luc) cells were seeded in 5x5mm human demineralized bone grafts kept in culture while treated with 0 KHz (control) or 150 KHz of TTF for 14 days. Bioluminescence images (BLI) were obtained at baseline and 14 days. In-vivo: Krib-Luc-1 cells were surgically implanted via trasperitoneal approach to the L3 vertebra in nude mice. Animals were treated with 0 KHz or 150 KHz of TTF for 30 days or until paralysis. BLI were obtained at day 0 and every 7 days. MRI was obtained at day 22. Histological analysis was performed at the end of the experiment. Control and TTF treated groups were compared with two-tailed t-tests. RESULTS: In vitro: BLI of the control grafts demonstrated a median value of 1×10^10 photons/sec at 14 days, significantly higher than 1×10^8 photons/sec observed in the 150 KHz group (p < 0.0001). In Vivo: median time to paralysis in control animals was 25 days, all animals treated with TTF at 150 KHz reached the 30 day mark without deficits. BLI of the control group was 3.5×10^9 photons/sec significantly higher than 1×10^9 photons/sec in the 150 KHz TTF group (p = 0.0212). MRI and histological analysis confirmed significant smaller tumors in the treated group when compared to controls. CONCLUSIONS: Application of TTF 150 KHz reduced cellular proliferation in both in vitro and in vivo models of spinal metastasis. We believe TTF could become a groundbreaking treatment for spinal metastasis.

Combination tumor-treating fields treatment for patients with metastatic non-small cell lung cancer: A cost-effectiveness analysis.

Tumor-treating field (TTFields) was a novel antitumor therapy that provided significant survival for previously treated metastatic non-small cell lung cancer (mNSCLC). The consistency of the cost of the new treatment regimen with its efficacy was the main objective of the study. The primary parameters, derived from the Phase 3 LUNAR study, were collected to evaluate the cost and efficacy of TTFields plus standard-of-care (SOC) (immune checkpoint inhibitors [ICIs] and docetaxel [DTX]) or SOC in patients with mNSCLC by establishing a three-state Markov model over a 15-year time horizon. Primary outcome measures for this study included costs, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs). Sensitivity analyses were performed. The total costs of TTFields plus SOC, TTFields plus ICI, and TTFields plus DTX were $319,358, $338,688, and $298,477, generating 1.23 QALYs, 1.58 QALYs, and 0.89 QALYs, respectively. The ICERs of TTFields plus SOC versus SOC, TTFields plus ICI versus ICI, and TTFields plus DTX versus DTX were $613,379/QALY, $387,542/QALY, and $1,359,559/QALY, respectively. At willingness-to-pay (WTP) thresholds of $150,000/QALY, the probability of combination TTFields being cost-effective was 0%. In addition, TTFields plus SOC exhibited similar efficacy (1.12 QALYs and 1.14 QALYs) and costs ($309,822 and $312,531) in the treatment of squamous cell carcinoma (SCC) and non-squamous cell carcinoma (NSCC) populations. In the United States, TTFields plus SOC as second-line treatment was not a more cost-effective strategy for patients with mNSCLC. Of the analyzed regimens, TTFields plus ICI was associated with most significant health benefits.

Antitumor Effects of Intravenous Natural Killer Cell Infusion in an Orthotopic Glioblastoma Xenograft Murine Model and Gene Expression Profile Analysis.

Despite standard multimodality treatment, containing maximum safety resection, temozolomide, radiotherapy, and a tumor-treating field, patients with glioblastoma (GBM) present with a dismal prognosis. Natural killer cell (NKC)-based immunotherapy would play a critical role in GBM treatment. We have previously reported highly activated and ex vivo expanded NK cells derived from human peripheral blood, which exhibited anti-tumor effect against GBM cells. Here, we performed preclinical evaluation of the NK cells using an in vivo orthotopic xenograft model, the U87MG cell-derived brain tumor in NOD/Shi-scid, IL-2RɤKO (NOG) mouse. In the orthotopic xenograft model, the retro-orbital venous injection of NK cells prolonged overall survival of the NOG mouse, indirectly indicating the growth-inhibition effect of NK cells. In addition, we comprehensively summarized the differentially expressed genes, especially focusing on the expression of the NKC-activating receptors' ligands, inhibitory receptors' ligands, chemokines, and chemokine receptors, between murine brain tumor treated with NKCs and with no agents, by using microarray. Furthermore, we also performed differentially expressed gene analysis between an internal and external brain tumor in the orthotopic xenograft model. Our findings could provide pivotal information for the NK-cell-based immunotherapy for patients with GBM.

Cost-effectiveness of tumor-treating fields plus standard therapy for advanced non-small cell lung cancer progressed after platinum-based therapy in the United States.

Background: Tumor treating fields (TTF) was first approved for treatment of glioblastoma. Recently, the LUNAR study demonstrated that TTF + standard therapy (ST) extended survival in patients with advanced non-small cell lung cancer (NSCLC). This primary objective of this study is to analyze the cost-effectiveness of this treatment from the United States healthcare payers' perspective. Methods: A 3-health-state Markov model was established to compare the cost-effectiveness of TTF + ST and that of ST alone. Clinical data were extracted from the LUNAR study, supplemented by additional cost and utility data obtained from publications or online sources. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis were conducted. The willingness-to-pay (WTP) threshold per quality-adjusted life-years (QALYs) gained was set to $150,000. The main results include total costs, QALYs, incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (INMB). Subgroup analyses were conducted for two types of ST, including immune checkpoint inhibitor, and docetaxel. Results: During a 10-year time horizon, the costs of TTF + ST and ST alone were $431,207.0 and $128,125.9, and the QALYs were 1.809 and 1.124, respectively. The ICER of TTF + ST compared to ST was $442,732.7 per QALY, and the INMB was -$200,395.7 at the WTP threshold. The cost of TTF per month was the most influential factor in cost-effectiveness, and TTF + ST had a 0% probability of being cost-effective at the WTP threshold compared with ST alone. Conclusion: TTF + ST is not a cost-effective treatment for advanced NSCLC patients who progressed after platinum-based therapy from the perspective of the United States healthcare payers.

Lucanthone, a Potential PPT1 Inhibitor, Perturbs Stemness, Reduces Tumor Microtube Formation, and Slows the Growth of Temozolomide-Resistant Gliomas In Vivo.

Glioblastoma (GBM) is the most frequently diagnosed primary central nervous system tumor in adults. Despite the standard of care therapy, which includes surgical resection, temozolomide chemotherapy, radiation and the newly added tumor-treating fields, median survival remains only ∼20 months. Unfortunately, GBM has a ∼100% recurrence rate, but after recurrence there are no Food and Drug Administration-approved therapies to limit tumor growth and enhance patient survival, as these tumors are resistant to temozolomide (TMZ). Recently, our laboratory reported that lucanthone slows GBM by inhibiting autophagic flux through lysosome targeting and decreases the number of Olig2+ glioma stem-like cells (GSC) in vitro and in vivo. We now additionally report that lucanthone efficiently abates stemness in patient-derived GSC and reduces tumor microtube formation in GSC, an emerging hallmark of treatment resistance in GBM. In glioma tumors derived from cells with acquired resistance to TMZ, lucanthone retains the ability to perturb tumor growth, inhibits autophagy by targeting lysosomes, and reduces Olig2 positivity. We also find that lucanthone may act as an inhibitor of palmitoyl protein thioesterase 1. Our results suggest that lucanthone may function as a potential treatment option for GBM tumors that are not amenable to TMZ treatment. SIGNIFICANCE STATEMENT: We report that the antischistosome agent lucanthone impedes tumor growth in a preclinical model of temozolomide-resistant glioblastoma and reduces the numbers of stem-like glioma cells. In addition, it acts as an autophagy inhibitor, and its mechanism of action may be via inhibition of palmitoyl protein thioesterase 1. As there are no defined therapies approved for recurrent, TMZ-resistant tumor, lucanthone could emerge as a treatment for glioblastoma tumors that may not be amenable to TMZ both in the newly diagnosed and recurrent settings.

Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma.

Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative to other cancer types, the glioma immune microenvironment harbors few infiltrating T cells, but abundant tumor-associated myeloid cells, possibly explaining disappointing responses to immune checkpoint blockade therapies in cohorts of patients with glioblastoma. Notably, unlike most extracranial tumors, STING expression is absent in the malignant compartment of gliomas, likely due to methylation of the STING promoter. Nonetheless, several preclinical studies suggest that inducing cGAS/STING signaling in the glioma immune microenvironment could be therapeutically beneficial, and cGAS/STING signaling has been shown to mediate inflammatory and antitumor effects of other modalities either in use or being developed for glioblastoma therapy, including radiation, tumor-treating fields, and oncolytic virotherapy. In this Review, we discuss cGAS/STING signaling in gliomas, its implications for glioma immunobiology, compartment-specific roles for STING signaling in influencing immune surveillance, and efforts to target STING signaling - either directly or indirectly - for antiglioma therapy.

Osimertinib in Combination with Bevacizumab for EGFR Mutated Recurrent Glioblastoma (GBM): A Case Report

Glioblastoma is the most common primary, malignant adult brain tumor with a median overall survival of 12-15 months after diagnosis. The standard of care includes maximal safe resection, chemoradiation, adjuvant chemotherapy with the DNA alkylator, temozolomide and tumor-treating fields. Given the recent advances in targeted molecular therapeutics and tissue sequencing, there is a growing opportunity for precision medicine in GBM treatment. In this case report, we present two patients who were found to have EGFR amplifications on molecular analysis and were treated with the EGFR inhibitor, osimertinib (Tagrisso), in combination with bevacizumab (Avastin) after tumor progression. One patient received osimertinib at first GBM progression, while the other patient received osimertinib after two other treatment regimens had failed. Both patients displayed radiographic stability several months after the expected median overall survival rate of 15 months post-diagnosis for GBM. This case report offers clinical vignettes in support of the use of EGFR inhibitors and bevacizumab in recurrent GBM with EGFR mutations.

Breaking Barriers in Neuro-Oncology: A Scoping Literature Review on Invasive and Non-Invasive Techniques for Blood-Brain Barrier Disruption.

The blood-brain barrier (BBB) poses a significant challenge to drug delivery for brain tumors, with most chemotherapeutics having limited permeability into non-malignant brain tissue and only restricted access to primary and metastatic brain cancers. Consequently, due to the drug's inability to effectively penetrate the BBB, outcomes following brain chemotherapy continue to be suboptimal. Several methods to open the BBB and obtain higher drug concentrations in tumors have been proposed, with the selection of the optimal method depending on the size of the targeted tumor volume, the chosen therapeutic agent, and individual patient characteristics. Herein, we aim to comprehensively describe osmotic disruption with intra-arterial drug administration, intrathecal/intraventricular administration, laser interstitial thermal therapy, convection-enhanced delivery, and ultrasound methods, including high-intensity focused and low-intensity ultrasound as well as tumor-treating fields. We explain the scientific concept behind each method, preclinical/clinical research, advantages and disadvantages, indications, and potential avenues for improvement. Given that each method has its limitations, it is unlikely that the future of BBB disruption will rely on a single method but rather on a synergistic effect of a combined approach. Disruption of the BBB with osmotic infusion or high-intensity focused ultrasound, followed by the intra-arterial delivery of drugs, is a promising approach. Real-time monitoring of drug delivery will be necessary for optimal results.