Image-based assessment of natural killer cell activity against glioblastoma stem cells.

Glioblastoma (GBM) poses a significant challenge in oncology and stands as the most aggressive form of brain cancer. A primary contributor to its relentless nature is the stem-like cancer cells, called glioblastoma stem cells (GSCs). GSCs have the capacity for self-renewal and tumorigenesis, leading to frequent GBM recurrences and complicating treatment modalities. While natural killer (NK) cells exhibit potential in targeting and eliminating stem-like cancer cells, their efficacy within the GBM microenvironment is limited due to constrained infiltration and function. To address this limitation, novel investigations focusing on boosting NK cell activity against GSCs are imperative. This study presents two streamlined image-based assays assessing NK cell migration and cytotoxicity towards GSCs. It details protocols and explores the strengths and limitations of these methods. These assays could aid in identifying novel targets to enhance NK cell activity towards GSCs, facilitating the development of NK cell-based immunotherapy for improved GBM treatment.

Personalized prognosis stratification of newly diagnosed glioblastoma applying a statistical decision tree model.

PURPOSE: Glioblastoma (GBM) is the most frequent glioma in adults with a high treatment resistance resulting into limited survival. The individual prognosis varies depending on individual prognostic factors, that must be considered while counseling patients with newly diagnosed GBM. The aim of this study was to elaborate a risk stratification algorithm based on reliable prognostic factors to facilitate a personalized prognosis estimation early on after diagnosis. METHODS: A consecutive patient cohort with confirmed GBM treated between 2010 and 2021 was retrospectively analyzed. Clinical, radiological, and molecular parameters were assessed and included in the analysis. Overall survival (OS) was the primary outcome parameter. After identifying the strongest prognostic factors, a risk stratification algorithm was elaborated with estimated odds of survival. RESULTS: A total of 462 GBM patients were analyzed. The strongest prognostic factors were Charlson Comorbidity Index (CCI), extent of tumor resection, and adjuvant treatment. Patients with CCI ≤ 1 receiving tumor resection had the highest survival odds (88% for 10 months). On the contrary, patients with CCI > 3 receiving no adjuvant treatment had the lowest survival odds (0% for 10 months). The 10-months survival rate in patients with CCI > 3 receiving adjuvant treatment was 56% for patients younger than 70 years and 22% for patients older than 70 years. CONCLUSION: A risk stratification algorithm based on significant prognostic factors allowed a personalized early prognosis estimation at the time of GBM diagnosis, that can contribute to a more personalized patient counseling.

Real-world cost- effectiveness analysis: Tumor Treating Fields for newly diagnosed glioblastoma in China.

BACKGROUND: Glioblastoma (GBM) stands as the most aggressive and prevalent primary brain malignancy. Tumor Treating Fields (TTFields), an innovative therapy complementing chemotherapy for GBM treatment, which can significantly enhance overall survival, disease progression-free survival, and patient's quality of life. However, there is a dearth of health economics evaluation on TTFields therapy both domestically and internationally. OBJECTIVE: The study aims to assess the cost-effectiveness of TTFields + temozolomide (TMZ) in comparison to TMZ alone for newly diagnosed GBM patients. The intent is to provide robust economic evidence to serve as a foundation for policymaking and decision-making processes in GBM treatment. METHODS: We estimated outcomes for newly diagnosed GBM patients over a lifetime horizon using a partitioned survival model with three states: Progression-Free Survival, Progression Disease, and Death. The survival model was derived from a real-world study in China, with long-term survival data drawn from GBM epidemiology literature. Adverse event rates were sourced from the EF-14 trial data. Cost data, validated by expert consultation, was obtained from public literature and databases. Utility values were extracted from published literature. Using Microsoft Excel, we calculated expected costs and quality-adjusted life years (QALYs) over 15 years from a health system perspective. The willingness-to-pay threshold was set at three times the Chinese per capita Gross Domestic Product (GDP) in 2022, amounting to CN¥242,928 (US$37,655) /QALY. A 5% discount rate was applied to costs and utilities. Results underwent analysis through single factor and probability sensitivity analyses. RESULTS: TTFields + TMZ demonstrated a mean increase in cost by CN¥389,326 (US$57,859) and an increase of 2.46 QALYs compared to TMZ alone. The incremental cost-effectiveness ratio (ICER) was CN¥157,979 (US$23,474) per QALY gained. The model exhibited heightened sensitivity to changes in the discount rate. Probability sensitivity analysis indicates that, under the existing threshold, the probability of TTFields + TMZ being economical is 95.60%. CONCLUSIONS: This cost-effectiveness analysis affirms that incorporating TTFields into TMZ treatment proves to be cost-effective, given a threshold three times the Chinese per capita GDP.

Sex differences in adverse events in Medicare individuals ≥ 66 years of age post glioblastoma treatment.

PURPOSE: Glioblastoma (GB) is the most common primary malignant brain tumor with the highest incidence occurring in older adults with a median age at diagnosis of 64 years old. While treatment often improves survival it brings toxicities and adverse events (AE). Here we identify sex differences in treatment patterns and AE in individuals ≥ 66 years at diagnosis with GB. METHODS: Using the SEER-Medicare dataset sex differences in adverse events were assessed using multivariable logistic regression performed to calculate the male/female odds ratio (M/F OR) and 95% confidence intervals [95% CI] of experiencing an AE adjusted for demographic variables and Elixhauser comorbidity score. RESULTS: Males with GB were more likely to receive standard of care (SOC; Surgery with concurrent radio-chemotherapy) [20%] compared to females [17%], whereas females were more likely to receive no treatment [26%] compared to males [21%]. Females with GB receiving SOC were more likely to develop gastrointestinal disorders (M/F OR = 0.76; 95% CI,0.64-0.91, p = 0.002) or blood and lymphatic system disorders (M/F OR = 0.79; 95% CI,0.66-0.95, p = 0.012). Males with GB receiving SOC were more likely to develop cardiac disorders (M/F OR = 1.21; 95% CI,1.02-1.44, p = 0.029) and renal disorders (M/F OR = 1.65; 95% CI,1.37-2.01, p < 0.001). CONCLUSIONS: Sex differences for individuals, 66 years and older, diagnosed with GB exist in treatment received and adverse events developed across different treatment modalities.

Study protocol for a multicenter randomised controlled trial on the (cost)effectiveness of biopsy combined with same-session MR-guided LITT versus biopsy alone in patients with primary irresectable glioblastoma (EMITT trial).

BACKGROUND: Glioblastoma (GBM) is the most common primary, malignant brain tumour with a 5-year survival of 5%. If possible, a glioblastoma is resected and further treated with chemoradiation therapy (CRT), but resection is not feasible in about 30% of cases. Current standard of care in these cases is a biopsy followed by CRT. Magnetic resonance (MR) imaging-guided laser interstitial thermal therapy (LITT) has been suggested as a minimally invasive alternative when surgery is not feasible. However, high-quality evidence directly comparing LITT with standard of care is lacking, precluding any conclusions on (cost-)effectiveness. We therefore propose a multicenter randomized controlled study to assess the (cost-)effectiveness of MR-guided LITT as compared to current standard of care (EMITT trial). METHODS AND ANALYSIS: The EMITT trial will be a multicenter pragmatic randomized controlled trial in the Netherlands. Seven Dutch hospitals will participate in this study. In total 238 patients will be randomized with 1:1 allocation to receive either biopsy combined with same-session MR-guided LITT therapy followed by CRT or the current standard of care being biopsy followed by CRT. The primary outcomes will be health-related quality of life (HR-QoL) (non-inferiority) using EORTC QLQ-C30 + BN20 scores at 5 months after randomization and overall survival (superiority). Secondary outcomes comprise cost-effectiveness (healthcare and societal perspective) and HR-QoL of life over an 18-month time horizon, progression free survival, tumour response, disease specific survival, longitudinal effects, effects on adjuvant treatment, ablation percentage and complication rates. DISCUSSION: The EMITT trial will be the first RCT on the effectiveness of LITT in patients with glioblastoma as compared with current standard of care. Together with the Dutch Brain Tumour Patient association, we hypothesize that LITT may improve overall survival without substantially affecting patients' quality of life. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT05318612).

Taming Glioblastoma in "Real Time": Integrating Multimodal Advanced Neuroimaging/AI Tools Towards Creating a Robust and Therapy Agnostic Model for Response Assessment in Neuro-Oncology.

The highly aggressive nature of glioblastoma carries a dismal prognosis despite aggressive multimodal therapy. Alternative treatment regimens, such as immunotherapies, are known to intensify the inflammatory response in the treatment field. Follow-up imaging in these scenarios often mimics disease progression on conventional MRI, making accurate evaluation extremely challenging. To this end, revised criteria for assessment of treatment response in high-grade gliomas were successfully proposed by the RANO Working Group to distinguish pseudoprogression from true progression, with intrinsic constraints related to the postcontrast T1-weighted MRI sequence. To address these existing limitations, our group proposes a more objective and quantifiable "treatment agnostic" model, integrating into the RANO criteria advanced multimodal neuroimaging techniques, such as diffusion tensor imaging (DTI), dynamic susceptibility contrast-perfusion weighted imaging (DSC-PWI), dynamic contrast enhanced (DCE)-MRI, MR spectroscopy, and amino acid-based positron emission tomography (PET) imaging tracers, along with artificial intelligence (AI) tools (radiomics, radiogenomics, and radiopathomics) and molecular information to address this complex issue of treatment-related changes versus tumor progression in "real-time", particularly in the early posttreatment window. Our perspective delineates the potential of incorporating multimodal neuroimaging techniques to improve consistency and automation for the assessment of early treatment response in neuro-oncology.

Assessment of treatment response to dendritic cell vaccine in patients with glioblastoma using a multiparametric MRI-based prediction model.

PURPOSE: Autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) is a promising treatment modality for glioblastomas. The purpose of this study was to investigate the potential utility of multiparametric MRI-based prediction model in evaluating treatment response in glioblastoma patients treated with DCVax-L. METHODS: Seventeen glioblastoma patients treated with standard-of-care therapy + DCVax-L were included. When tumor progression (TP) was suspected and repeat surgery was being contemplated, we sought to ascertain the number of cases correctly classified as TP + mixed response or pseudoprogression (PsP) from multiparametric MRI-based prediction model using histopathology/mRANO criteria as ground truth. Multiparametric MRI model consisted of predictive probabilities (PP) of tumor progression computed from diffusion and perfusion MRI-derived parameters. A comparison of overall survival (OS) was performed between patients treated with standard-of-care therapy + DCVax-L and standard-of-care therapy alone (external controls). Additionally, Kaplan-Meier analyses were performed to compare OS between two groups of patients using PsP, Ki-67, and MGMT promoter methylation status as stratification variables. RESULTS: Multiparametric MRI model correctly predicted TP + mixed response in 72.7% of cases (8/11) and PsP in 83.3% (5/6) with an overall concordance rate of 76.5% with final diagnosis as determined by histopathology/mRANO criteria. There was a significant concordant correlation coefficient between PP values and histopathology/mRANO criteria (r = 0.54; p = 0.026). DCVax-L-treated patients had significantly prolonged OS than those treated with standard-of-care therapy (22.38 ± 12.8 vs. 13.8 ± 9.5 months, p = 0.040). Additionally, glioblastomas with PsP, MGMT promoter methylation status, and Ki-67 values below median had longer OS than their counterparts. CONCLUSION: Multiparametric MRI-based prediction model can assess treatment response to DCVax-L in patients with glioblastoma.

Evaluation of Standard Response Assessment in Neuro-Oncology, Modified Response Assessment in Neuro-Oncology, and Immunotherapy Response Assessment in Neuro-Oncology in Newly Diagnosed and Recurrent Glioblastoma.

PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria are widely used in high-grade glioma clinical trials. We compared the RANO criteria with updated modifications (modified RANO [mRANO] and immunotherapy RANO [iRANO] criteria) in patients with newly diagnosed glioblastoma (nGBM) and recurrent GBM (rGBM) to evaluate the performance of each set of criteria and inform the development of the planned RANO 2.0 update. MATERIALS AND METHODS: Evaluation of tumor measurements and fluid-attenuated inversion recovery (FLAIR) sequences were performed by blinded readers to determine disease progression using RANO, mRANO, iRANO, and other response assessment criteria. Spearman's correlations between progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: Five hundred twenty-six nGBM and 580 rGBM cases were included. Spearman's correlations were similar between RANO and mRANO (0.69 [95% CI, 0.62 to 0.75] v 0.67 [95% CI, 0.60 to 0.73]) in nGBM and rGBM (0.48 [95% CI, 0.40 to 0.55] v 0.50 [95% CI, 0.42 to 0.57]). In nGBM, requirement of a confirmation scan within 12 weeks of completion of radiotherapy to determine progression was associated with improved correlations. Use of the postradiation magnetic resonance imaging (MRI) as baseline scan was associated with improved correlation compared with use of the pre-radiation MRI (0.67 [95% CI, 0.60 to 0.73] v 0.53 [95% CI, 0.42 to 0.62]). Evaluation of FLAIR sequences did not improve the correlation. Among patients who received immunotherapy, Spearman's correlations were similar among RANO, mRANO, and iRANO. CONCLUSION: RANO and mRANO demonstrated similar correlations between PFS and OS. Confirmation scans were only beneficial in nGBM within 12 weeks of completion of radiotherapy, and there was a trend in favor of the use of postradiation MRI as the baseline scan in nGBM. Evaluation of FLAIR can be omitted. The iRANO criteria did not add significant benefit in patients who received immune checkpoint inhibitors.

Palliative Care Effects on Survival in Glioblastoma: Who Receives Palliative Care?

BACKGROUND: High-grade glioma has a poor overall survival with profoundly negative effects on the patient's quality of life and their caregivers. In this study, we investigate the factors associated with receiving palliative care in patients diagnosed with glioblastoma (GBM) and the association of receiving or not receiving palliative care with overall survival. METHODS: The National Cancer Database was analyzed for patterns of care in patients ≥18 years old who were diagnosed with histologically confirmed grade IV GBM between 2004 and 2017. All statistical analyses were conducted based on univariate and multivariate regression models. RESULTS: A total of 85,380 patients with the diagnosis of GBM were identified. Of the study population, 2803 patients (3.28%) received palliative therapy. On multivariate logistic regression analysis, age ≥70 years (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.04-1.58; P < 0.001), Medicare (OR, 1.348; CI, 1.13-1.61; P = 0.001), tumor size ≥5 cm (OR, 1.15; CI, 1.01-1.31; P = 0.036), tumor multifocality (OR, 1.69; CI, 1.47-1.96; P < 0.001), lobe overlapping tumor (OR, 2.09; CI, 1.13-3.86; P = 0.018), Charlson-Deyo score >0, receiving treatment at a nonacademic/research program, and medium volume of cancers managed at the treatment facility (OR, 1.19; CI, 1.02-1.38; P = 0.026) were independent risk factors associated with an increased chance of receiving palliative care. In contrast, a household income of ≥$40,227 and high volume of cancer managed at the treatment facility (OR, 0.75; CI, 0.58-0.96; P = 0.02) were independent risk factors associated with decreased palliative care. Patients who received no palliative care had a 2-year overall survival longer than those who received palliative care (22% vs. 8.8%; P < 0.001). In patients receiving palliative care, those who received recommended treatment had a 2-year overall survival longer than those who declined part or whole recommended treatment (9.1% vs. 3.8%; P = 0.009). CONCLUSIONS: In patients with high-grade glioma, receiving palliative care is associated with decreased survival. When receiving palliative care, recommended treatment increases the number of patients who survive more than 2 years approximately 3-fold compared with those declining part or whole treatment.

Assessment and prediction of glioblastoma therapy response: challenges and opportunities.

Glioblastoma is the most aggressive type of primary adult brain tumour. The median survival of patients with glioblastoma remains approximately 15 months, and the 5-year survival rate is <10%. Current treatment options are limited, and the standard of care has remained relatively constant since 2011. Over the last decade, a range of different treatment regimens have been investigated with very limited success. Tumour recurrence is almost inevitable with the current treatment strategies, as glioblastoma tumours are highly heterogeneous and invasive. Additionally, another challenging issue facing patients with glioblastoma is how to distinguish between tumour progression and treatment effects, especially when relying on routine diagnostic imaging techniques in the clinic. The specificity of routine imaging for identifying tumour progression early or in a timely manner is poor due to the appearance similarity of post-treatment effects. Here, we concisely describe the current status and challenges in the assessment and early prediction of therapy response and the early detection of tumour progression or recurrence. We also summarize and discuss studies of advanced approaches such as quantitative imaging, liquid biomarker discovery and machine intelligence that hold exceptional potential to aid in the therapy monitoring of this malignancy and early prediction of therapy response, which may decisively transform the conventional detection methods in the era of precision medicine.

Dispositif OptuneMC pour le traitement des patients adultes atteints d'un glioblastome nouvellement diagnostiqué / Optune™ for the treatment of adult patients with newly diagnosed glioblastoma

MANDAT: L'Institut national d'excellence en santé et en services sociaux (INESSS) a reçu le mandat du Bureau de l'innovation d'estimer la valeur de la technologie OptuneMC et la pertinence de sa couverture par le régime public en tant que dispositif de traitement des patients adultes souffrant d'un glioblastome nouvellement diagnostiqué avec et après la chimiothérapie d'entretien standard au témozolomide. DESCRIPTION: Pour l'indication demandée, le dispositif requiert la pose de matrices de transducteurs fixées sur le crâne rasé des patients afin de délivrer un champ électrique alternatif antitumoral via le générateur de champ OptuneMC. Les champs antitumoraux visent à stopper la progression des tumeurs en ciblant les étapes de la mitose des cellules cancéreuses et ils doivent agir en continu. Le dispositif OptuneMC est donc proposé avec des accessoires permettant un traitement ambulatoire et constant des patients. DÉMARCHE D'ÉVALUATION: Une revue des donn

MANDATE: L'Institut national d'excellence en santé et en services sociaux (INESSS) was mandated by the Bureau de l'innovation to assess the value of OptuneTM technology and the relevance of its coverage by the public plan as a treatment device for adult patients with newly diagnosed glioblastoma with and after standard temozolomide maintenance chemotherapy. DESCRIPTION: For the requested indication, the device requires the placement of transducer arrays to patients' shaved scalp to deliver to deliver a tumour-treating field through the OptuneTM field generator. Tumour treating fields aim to halt tumour progression by targeting the mitosis stages of cancer cells and must act continuously. The OptuneTM device is therefore provided with accessories for constant ambulatory treatment of patients. EVALUATION PROCESS: A review of data from the literature and those provided by the manufacturer was carried out to assess the scientific evidence regarding the application of tumour treating fields provided by Novocure's OptuneTM device for the treatment of newly diagnosed glioblastoma. Contextual and experiential stakeholder data were also collected through an expert advisory committee and one-on-one interviews with caregivers and patients who have used the OptuneTM device. SOCIO-CULTURAL DIMENSION: Despite the media visibility of the OptuneTM device and the enthusiasm for new therapeutic options, the acceptability of the device by Quebec patients is difficult to predict, as several factors need to be taken into consideration - e.g., aesthetic considerations, portability of the device and usage requirements. According to advisory committee members, the maximum acceptability rate could be as high as 50% of eligible patients offered the treatment. Some health technology assessment agencies have assessed OptuneTM and issued divergent recommendations, some favourable from the Haute Autorité de Santé (HAS, France), other unfavourable from the National Institute for Health and Care Excellence (NICE, UK). For their part, publications by listed oncology learned societies have chosen to recommend the OptuneTM device as a complementary treatment option to temozolomide in patients under 70 years of age. POPULATION DIMENSION: Glioblastoma is a heterogeneous cancer, with some subtypes more aggressive than others, affecting an estimated 150 new patient/year in Quebec. Median survival is around 8 months, with a 1-year survival rate of 25%. The disease is both cognitively and physically disabling, and family caregivers play an important role in its management. Current management is mainly based on diagnosis with magnetic resonance imaging (MRI), followed by tumour resection, when possible, combined radiotherapy with temozolomide, and maintenance chemotherapy with temozolomide (Stupp protocol). Despite treatment, 90% of patients will experience a recurrence of their cancer within 7 months. At this stage, there is no recognized standard of care. Glioblastoma is therefore an incurable pathology with limited treatment options, and with high unmet medical needs related to the development of new treatment options to prolong life and reduce the risk of recurrence. CLINICAL DIMENSION: The efficacy of the OptuneTM device is supported by the EF-14 study, an open-label, multicenter, randomized Phase 3 clinical trial conducted in 14 countries, including Canada. This study compared the efficacy of the OptuneTM device / temozolomide combination versus temozolomide alone in adult patients with supratentorial glioblastoma. The EF-14 study is judged to be of good methodological quality, despite the presence of a selection bias favouring the inclusion of individuals with a better prognosis. Moreover, the study population is also younger, has a higher performance index and contains a higher proportion of individuals with MGMT (6-O-Methylguanine-DNA methyltransferase) promoter methylation than the Quebec glioblastoma patient population. The main results of the study showed clinically significant gains in progression-free survival of 2.7 months and overall survival of 4.9 months. A dose-response effect was also observed according to patients' level of adherence to treatment, with a minimum use threshold of 50% to obtain a benefit, i.e., 12 hours per day. Secondary analyses failed to identify a sub-population that might benefit more from treatment and showed that all subgroups treated with the OptuneTM device benefited. The main adverse events attributable to this device were skin reactions and irritations. The results of the quality-of-life assessment indicate that the device is well tolerated by patients, as illustrated by the fact that the 75% adherence threshold was reached by 75% of the cohort. Skin irritation was the main cause of reduced quality of life in the cohort studied. Other results are subject to uncertainty due to the open design of the study, the low response of patients to the quality-of-life questionnaires, and the design of the device used, which was heavier, bulkier, and noisier than the model currently available. ORGANIZATIONAL DIMENSION: The OptuneTM device does not replace current care, but it is added to the standard maintenance treatment. GBM patients' diagnosis MRI images are transmitted to the manufacturer for array creation. Once the healthcare professional has assessed the patient's eligibility and transmitted the prescription to the manufacturer, the latter charges a monthly fee for unlimited array replacement, equipment delivery, patient service (technical assistance and training), and healthcare professional service, which includes training and reporting on patient compliance. This rental model is not common in Quebec, and the real involvement of healthcare network professionals and resources in monitoring patient use of the device is also uncertain, for example regarding skin effects, array repositioning and technical problems. However, Quebec centres participated in the EF-14 study and therefore have some experience with the device and the manufacturer. The OptuneTM device requires the help of a third party to place the electrode arrays, which may represent an issue for patients who have no family caregiver and/or for whom resources from the healthcare network could be solicited. Members of the advisory committee consulted are therefore of the opinion that, without access to such a resource, patients may be unable to use the device. In addition, there is uncertainty as to the optimal discontinuation criteria for patients treated with the OptuneTM device. Indeed, according to the members of the advisory committee consulted, there is no clinical advantage to continuing treatment after a first recurrence. Because of the organizational issues, several uncertainties remain as to whether the results of the clinical study can be reproduced in a real healthcare setting. ECONOMIC DIMENSION: The use of the OptuneTM device to treat patients with newly diagnosed glioblastoma concomitantly with temozolomide versus temozolomide alone is not cost-effective. Public coverage could generate additional costs of $ XX million over 5 years for the treatment of 308 patients. The real costs of adding the OptuneTM device, particularly those associated with its implementation in the health and social services network and with the involvement of healthcare personnel in patient follow-up, are uncertain. Market share for the OptuneTM device is also uncertain, since it depends on the quality of the manufacturer's service offering in Quebec, the organizational capacity of the Quebec healthcare network, and real patient acceptability. INESSS'S RECOMMENDATION: Based on the information available to date, and given the importance of the uncertainties raised, INESSS considers that it would not be fair and equitable to provide public coverage for the OptuneTM device for the treatment of adult patients with newly diagnosed supratentorial glioblastoma following maximal reduction surgery and completion of radiotherapy with and after standard maintenance chemotherapy. INESSS may reassess the OptuneTM device, at the request of the ministère de la Santé et des Services sociaux (MSSS), when more information becomes available, including data in reallife settings that will better reduce uncertainties and mitigate associated risks.

Nomograms for prognostic risk assessment in glioblastoma multiforme: Applications and limitations.

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer. Prognosis evaluation is of great significance in guiding individualized treatment and monitoring of GBM. By integrating different prognostic variables, nomograms simplify the statistical risk prediction model into numerical estimates for death or recurrence, and are hence widely applied in prognosis prediction. In the past two decades, the application of high-throughput profiling technology and the establishment of TCGA database and other public data deposits have provided opportunities to identify cancer-related molecules and prognostic biomarkers. As a result, both molecular features and clinical characteristics of cancer have been reported to be the key factors in nomogram model construction. This article comprehensively reviewed 35 studies of GBM nomograms, analyzed the present situation of GBM nomograms, and discussed the role and significance of nomograms in personalized risk assessment and clinical treatment decision-making. To facilitate the application of nomograms in the prognostic prediction of GBM patients, a website has been established for the online access of nomograms based on the studies of this review, which is called Consensus Nomogram Spectrum for Glioblastoma (CNSgbm) and is accessible through https://bioinfo.henu.edu.cn/nom/NomList.jsp.

Application of blood brain barrier models in pre-clinical assessment of glioblastoma-targeting CAR-T based immunotherapies.

Human blood brain barrier (BBB) models derived from induced pluripotent stem cells (iPSCs) have become an important tool for the discovery and preclinical evaluation of central nervous system (CNS) targeting cell and gene-based therapies. Chimeric antigen receptor (CAR)-T cell therapy is a revolutionary form of gene-modified cell-based immunotherapy with potential for targeting solid tumors, such as glioblastomas. Crossing the BBB is an important step in the systemic application of CAR-T therapy for the treatment of glioblastomas and other CNS malignancies. In addition, even CAR-T therapies targeting non-CNS antigens, such as the well-known CD19-CAR-T therapies, are known to trigger CNS side-effects including brain swelling due to BBB disruption. In this study, we used iPSC-derived brain endothelial-like cell (iBEC) transwell co-culture model to assess BBB extravasation of CAR-T based immunotherapies targeting U87MG human glioblastoma (GBM) cells overexpressing the tumor-specific mutated protein EGFRvIII (U87vIII). Two types of anti-EGFRvIII targeting CAR-T cells, with varying tonic signaling profiles (CAR-F263 and CAR-F269), and control Mock T cells were applied on the luminal side of BBB model in vitro. CAR-F263 and CAR-F269 T cells triggered a decrease in transendothelial electrical resistance (TEER) and an increase in BBB permeability. CAR-T cell extravasation and U87vIII cytotoxicity were assessed from the abluminal compartment using flow cytometry and Incucyte real-time viability imaging, respectively. A significant decrease in U87vIII cell viability was observed over 48 h, with the most robust cytotoxicity response observed for the constitutively activated CAR-F263. CAR-F269 T cells showed a similar cytotoxic profile but were approximately four fold less efficient at killing the U87vIII cells compared to CAR-F263, despite similar transmigration rates. Visualization of CAR-T cell extravasation across the BBB was further confirmed using BBTB-on-CHIP models. The described BBB assay was able to discriminate the cytotoxic efficacies of different EGFRvIII-CARs and provide a measure of potential alterations to BBB integrity. Collectively, we illustrate how BBB models in vitro can be a valuable tool in deciphering the mechanisms of CAR-T-induced BBB disruption, accompanying toxicity and effector function on post-barrier target cells.

Assessment of therapeutic outcome and role of reirradiation in patients with radiation-induced glioma.

BACKGROUND: We sought to clarify the optimal follow-up, therapeutic strategy, especially the role of reirradiation, and the diagnostic impact of isocitrate dehydrogenase (IDH) 1 and 2 mutation status in patients with radiation-induced glioma (RIG). METHODS: We retrospectively reviewed the clinical characteristics and treatment outcomes of 11 patients with high-grade glioma who satisfied Cahan's criteria for RIG in our database during 2001-2021. IDH 1/2 mutations were analyzed by Sanger sequencing and/or pyrosequencing. RESULTS: The RIGs included glioblastoma with IDH 1/2 wild-type (n = 7), glioblastoma not otherwise specified (n = 2), anaplastic astrocytoma with IDH1/2 wild-type (n = 1), and anaplastic astrocytoma not otherwise specified (n = 1). The median period from primary disease and RIG diagnosis was 17 years (range: 9-30 years). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and survival times were 11.3 and 28.3 months. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n = 5) tended to be longer than that of patients that received chemotherapy alone (n = 6) (17.0 vs 8.1 months). However, the median survival time was similar (29.6 vs 27.4 months). Local recurrence was observed in 5 patients treated with chemotherapy alone, whereas in 2 patients among 4 patients treated with reirradiation and chemotherapy. None of the patients developed radiation necrosis. In one case, the primary tumor was diffuse astrocytoma with IDH2 mutant, and the secondary tumor was glioblastoma with IDH 1/2 wild-type. Based on the difference of IDH2 mutation status, the secondary tumor with IDH 1/2 wild-type was diagnosed as a de novo tumor that was related to the previous radiation therapy. CONCLUSIONS: RIG can occur beyond 20 years after successfully treating the primary disease using radiotherapy; thus, cancer survivors should be informed of the long-term risk of developing RIG and the need for timely neuroimaging evaluation. Reirradiation combined with chemotherapy appears to be feasible and has favorable outcomes. Determining the IDH1/2 mutational status is useful to establish RIG diagnosis when the primary tumor is glioma.

Next generation sequencing in adult patients with glioblastoma in Switzerland: a multi-centre decision analysis.

BACKGROUND: Glioblastoma is the most common malignant primary brain tumour in adults and driven by various genomic alterations. Next generation sequencing (NGS) provides timely information about the genetic landscape of tumours and might detect targetable mutations. To date, differences exist in the application and NGS assays used as it remains unclear to what extent these variants may affect clinical decision making. In this survey-based study, we investigated the use of NGS in adult patients with glioblastoma in Switzerland. METHODS: All eight primary care centres for Neuro-Oncology in Switzerland participated in this survey. The NGS assays used as well as the criteria for the application of NGS in newly diagnosed glioblastoma were investigated. Decision trees were analysed for consensus and discrepancies using the objective consensus methodology. RESULTS: Seven out of eight centres perform NGS in patients with newly diagnosed glioblastoma using custom made or commercially available assays. The criteria most relevant to decision making were age, suitability of standard treatment and fitness. NGS is most often used in fitter patients under the age of 60 years who are not suitable for standard therapy, while it is rarely performed in patients in poor general health. CONCLUSION: NGS is frequently applied in glioblastomas in adults in Neuro-Oncology centres in Switzerland despite seldom changing the course of treatment to date.

Regional and socio-economic variation in survival after glioblastoma in Denmark, 2013-2018.

INTRODUCTION: Glioblastoma is the most frequent primary brain tumour in adults. In Denmark, the treatment of glioblastoma is centralised to four neurosurgical and oncological departments located in four of the five Danish administrative regions. The aim of this study was to examine the regional and socioeconomic variation in survival after a diagnosis of glioblastoma in Denmark. METHODS: We included 1,731 patients with histologically confirmed glioblastoma from 2013 to 2018 registered in the Danish Neuro-oncology Registry. The data sources were the Danish National Registries. The exposure was region of residence at diagnosis and household income in the year before diagnosis. Follow-up was initiated at diagnosis and concluded at death or end-of-follow-up on 15 July 2019. Cox regression was used to examine overall mortality by exposure. RESULTS: With adjustment for age, sex, year of diagnosis and comorbidity, mortality rates of glioblastoma patients varied significantly between regions and were lowest in the Region of Southern Denmark and highest in the Capital Region (hazard ratio = 0.79; 95% confidence interval: 0.68-0.91, compared with the Capital Region). Further adjustment for surgical resection attenuated the regional differences in mortality. Income was not a predictor of survival. CONCLUSIONS: We found significant regional variation in survival after a diagnosis of glioblastoma. Differences in treatment patterns between regions may explain part of this mortality variation. Household income and education level did not explain the regional differences. FUNDING: none. TRIAL REGISTRATION: not relevant.

Caregiver burden by treatment and clinical characteristics of patients with glioblastoma.

BACKGROUND: Glioblastoma is an incurable disease with a poor prognosis. For caregivers of people with glioblastoma, the burden of care can be high. Patients often present with different clinical characteristics, which may impact caregiver burden in different ways. This study aimed to evaluate associations between patient clinical characteristics and caregiver burden/quality of life (QoL). METHODS: Caregiver-patient dyads were enrolled at 7 academic cancer centers in the United States. Eligible caregiver participants were self-reported as the primary caregiver of an adult living with glioblastoma and completed a caregiver burden survey. Eligible patients were age ≥ 18 years at glioblastoma diagnosis and alive when their respective caregiver entered the study, with the presence of cognitive dysfunction confirmed by the caregiver. Data were analyzed with descriptive statistics and multivariable analyses. RESULTS: The final cohort included 167 dyads. Poor patient performance status resulted in patient difficulty with mental tasks, more caregiving tasks, and increased caregiving time. Language problems were reported in patients with left-sided lesions. Patient confusion was negatively associated with all caregiver domains: emotional health, social health, general health, ability to work, confidence in finances, and overall QoL. Better caregiver QoL was observed in patients with frontal lobe lesions versus non-frontal lobe lesions. CONCLUSION: This study reinforced that patient performance status is a critical clinical factor that significantly affects caregiver burden, caregiving tasks, and caregiver time. Additionally, patient confusion affects multiple facets of caregiver burden/QoL. These results could be used to support guided intervention for caregiver support, customized to the patient experience.

Treatment options for progression or recurrence of glioblastoma: a network meta-analysis.

BACKGROUND: Glioblastoma (GBM) is a highly malignant brain tumour that almost inevitably progresses or recurs after first line standard of care. There is no consensus regarding the best treatment/s to offer people upon disease progression or recurrence. For the purposes of this review, progression and recurrence are considered as one entity. OBJECTIVES: To evaluate the effectiveness of further treatment/s for first and subsequent progression or recurrence of glioblastoma (GBM) among people who have received the standard of care (Stupp protocol) for primary treatment of the disease; and to prepare a brief economic commentary on the available evidence. SEARCH METHODS: We searched MEDLINE and Embase electronic databases from 2005 to December 2019 and the Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library; Issue 12, 2019). Economic searches included the National Health Service Economic Evaluation Database (NHS EED) up to 2015 (database closure) and MEDLINE and Embase from 2015 to December 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs) and comparative non-randomised studies (NRSs) evaluating effectiveness of treatments for progressive/recurrent GBM. Eligible studies included people with progressive or recurrent GBM who had received first line radiotherapy with concomitant and adjuvant temozolomide (TMZ). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data to a pre-designed data extraction form. We conducted network meta-analyses (NMA) and ranked treatments according to effectiveness for each outcome using the random-effects model and Stata software (version 15). We rated the certainty of evidence using the GRADE approach. MAIN RESULTS: We included 42 studies: these comprised 34 randomised controlled trials (RCTs) and 8 non-randomised studies (NRSs) involving 5236 participants. We judged most RCTs to be at a low risk of bias and NRSs at high risk of bias. Interventions included chemotherapy, re-operation, re-irradiation and novel therapies either used alone or in combination. For first recurrence, we included 11 interventions in the network meta-analysis (NMA) for overall survival (OS), and eight in the NMA for progression-free survival (PFS). Lomustine (LOM; also known as CCNU) was the most common comparator and was used as the reference treatment. No studies in the NMA evaluated surgery, re-irradiation, PCV (procarbazine, lomustine, vincristine), TMZ re-challenge or best supportive care. We could not perform NMA for second or later recurrence due to insufficient data. Quality-of-life data were sparse. First recurrence (NMA findings) Median OS across included studies in the NMA ranged from 5.5 to 12.6 months and median progression-free survival (PFS) ranged from 1.5 months to 4.2 months. We found no high-certainty evidence that any treatments tested were better than lomustine. These treatments included the following. Bevacizumab plus lomustine: Evidence suggested probably little or no difference in OS between bevacizumab (BEV) combined with lomustine (LOM) and LOM monotherapy (hazard ratio (HR) 0.91, 0.75 to 1.10; moderate-certainty evidence), although BEV + LOM may improve PFS (HR 0.57, 95% confidence interval (CI) 0.44 to 0.74; low-certainty evidence). Bevacizumab monotherapy: Low-certainty evidence suggested there may be little or no difference in OS (HR 1.22, 95% CI 0.84 to 1.76) and PFS (HR 0.90, 95% CI 0.58 to 1.38; low-certainty evidence) between BEV and LOM monotherapies; more evidence on BEV is needed. Regorafenib (REG): REG may improve OS compared with LOM (HR 0.50, 95% CI 0.33 to 0.76; low-certainty evidence). Evidence on PFS was very low certainty and more evidence on REG is needed. Temozolomide (TMZ) plus Depatux-M (ABT414): For OS, low-certainty evidence suggested that TMZ plus ABT414 may be more effective than LOM (HR 0.66, 95% CI 0.47 to 0.92) and may be more effective than BEV (HR 0.54, 95% CI 0.33 to 0.89; low-certainty evidence). This may be due to the TMZ component only and more evidence is needed. Fotemustine (FOM): FOM and LOM may have similar effects on OS (HR 0.89, 95% CI 0.51 to 1.57, low-certainty evidence). Bevacizumab and irinotecan (IRI): Evidence on BEV + irinotecan (IRI) versus LOM for both OS and PFS is very uncertain and there is probably little or no difference between BEV + IRI versus BEV monotherapy (OS: HR 0.95, 95% CI 0.70 to 1.30; moderate-certainty evidence). When treatments were ranked for OS, FOM ranked first, BEV + LOM second, LOM third, BEV + IRI fourth, and BEV fifth. Ranking does not take into account the certainty of the evidence, which also suggests there may be little or no difference between FOM and LOM. Other treatments Three studies evaluated re-operation versus no re-operation, with or without re-irradiation and chemotherapy, and these suggested possible survival advantages with re-operation within the context of being able to select suitable candidates for re-operation. A cannabinoid treatment in the early stages of evaluation, in combination with TMZ, merits further evaluation. Second or later recurrence Limited evidence from three heterogeneous studies suggested that radiotherapy with or without BEV may have a beneficial effect on survival but more evidence is needed. Evidence was insufficient to draw conclusions about the best radiotherapy dosage. Other evidence suggested that there may be little difference in survival with tumour-treating fields compared with physician's best choice of treatment. We found no reliable evidence on best supportive care. Severe adverse events (SAEs) The BEV+LOM combination was associated with significantly greater risk of SAEs than LOM monotherapy (RR 2.51, 95% CI 1.72 to 3.66, high-certainty evidence), and ranked joint worst with cediranib + LOM (RR 2.51, 95% CI 1.29 to 4.90; high-certainty evidence). LOM ranked best and REG ranked second best. Adding novel treatments to BEV was generally associated with a higher risk of severe adverse events compared with BEV alone. AUTHORS' CONCLUSIONS: For treatment of first recurrence of GBM, among people previously treated with surgery and standard chemoradiotherapy, the combination treatments evaluated did not improve overall survival compared with LOM monotherapy and were often associated with a higher risk of severe adverse events. Limited evidence suggested that re-operation with or without re-irradiation and chemotherapy may be suitable for selected candidates. Evidence on second recurrence is sparse. Re-irradiation with or without bevacizumab may be of value in selected individuals, but more evidence is needed.

ANTECEDENTES: El glioblastoma (GBM) es un tumor cerebral altamente maligno que casi inevitablemente progresa o recidiva después de un tratamiento de primera línea. No hay consenso sobre el mejor o los mejores tratamientos que se pueden ofrecer a las personas que presentan progresión o recidiva de la enfermedad. A los efectos de la presente revisión, la progresión y la recidiva se consideran como una sola entidad. OBJETIVOS: Evaluar la efectividad de los tratamientos adicionales para la primera y subsiguiente progresión o recidiva del glioblastoma (GBM) entre las personas que han recibido atención estándar (protocolo Stupp) para el tratamiento primario de la enfermedad, así como preparar un breve comentario económico sobre la evidencia disponible. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en las bases de datos electrónicas de MEDLINE y Embase desde 2005 hasta diciembre de 2019 y en el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials) (CENTRAL, en la Cochrane Library; Número 12, 2019). Las búsquedas económicas incluyeron la National Health Service Economic Evaluation Database (NHS EED) hasta 2015 (cierre de la base de datos) y MEDLINE y Embase desde 2015 hasta diciembre de 2019. CRITERIOS DE SELECCIÓN: Ensayos controlados aleatorizados (ECA) y estudios comparativos no aleatorizados (no ECA) que evaluaron la efectividad de los tratamientos para el GBM progresivo/recidivante. Los estudios elegibles incluyeron personas con GBM progresivo o recidivante que habían recibido radioterapia de primera línea con temozolomida (TMZ) concomitante y adyuvante. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión de forma independiente seleccionaron los estudios y extrajeron los datos en un formulario de extracción de datos prediseñado. Se realizaron metanálisis en red (MAR) y los tratamientos se clasificaron según la efectividad de cada desenlace, mediante el modelo de efectos aleatorios y el software Stata (versión 15). La certeza de la evidencia se evaluó mediante los criterios GRADE. RESULTADOS PRINCIPALES: Se incluyeron 42 estudios, que comprendieron 34 ensayos controlados aleatorizados (ECA) y ocho estudios no aleatorizados (no ECA), con 5236 participantes. Se consideró que la mayoría de los ECA tuvieron bajo riesgo de sesgo y que los no ECA tuvieron alto riesgo de sesgo. Las intervenciones incluyeron quimioterapia, reoperación, reirradiación y tratamientos nuevos, ya sea utilizadas solos o en combinación. Para la primera recidiva se incluyeron 11 intervenciones en el metanálisis en red (MAR) para la supervivencia general (SG), y ocho para la supervivencia sin progresión (SSP). La lomustina (LOM; también conocida como CCNU) fue el comparador más frecuente y se utilizó como tratamiento de referencia. Ningún estudio en el MAR evaluó la cirugía, la reirradiación, la PCV (procarbazina, lomustina, vincristina), la reexposición a TMZ o el mejor tratamiento de apoyo. No fue posible realizar un MAR para una segunda o posterior recidiva debido a que los datos no fueron suficientes. Los datos de calidad de vida fueron escasos. Primera recidiva (hallazgos del MAR) La mediana de la SG en los estudios incluidos en el MAR varió entre 5,5 y 12,6 meses y la mediana de la supervivencia sin progresión (SSP) varió entre 1,5 y 4,2 meses. No se encontró evidencia de certeza alta de que los tratamientos probados fueran mejores que la lomustina. Estos tratamientos incluyeron los siguientes. Bevacizumab más lomustina: La evidencia indicó probablemente poca o ninguna diferencia en la SG entre el bevacizumab (BEV) combinado con lomustina (LOM) y la monoterapia con LOM (cociente de riesgos instantáneo [CRI] 0,91; 0,75 a 1,10; evidencia de certeza moderada), aunque BEV + LOM puede mejorar la SSP (CRI 0,57; intervalo de confianza [IC] del 95%: 0,44 a 0,74; evidencia de certeza baja). Monoterapia con bevacizumab: La evidencia de certeza baja indicó que puede haber poca o ninguna diferencia en la SG (CRI 1,22; IC del 95%: 0,84 a 1,76) y la SSP (CRI 0,90; IC del 95%: 0,58 a 1,38; evidencia de certeza baja) entre las monoterapias con BEV y LOM; se necesita más evidencia sobre el BEV. Regorafenib (REG): El REG puede mejorar la SG en comparación con la LOM (CRI 0,50; IC del 95%: 0,33 a 0,76; evidencia de certeza baja). La evidencia sobre la SSP fue de certeza muy baja y se necesita más evidencia sobre el REG. Temozolomida (TMZ) más Depatux­M (ABT414): En cuanto a la SG, evidencia de certeza baja indicó que TMZ más ABT414 puede ser más efectiva que LOM (CRI 0,66; IC del 95%: 0,47 a 0,92) y puede ser más efectiva que BEV (CRI 0,54; IC del 95%: 0,33 a 0,89; evidencia de certeza baja). Lo anterior se puede deber solamente al componente de TMZ, y se necesita más evidencia. Fotemustina (FOM): FOM y LOM pueden tener efectos similares sobre la SG (CRI 0,89; IC del 95%: 0,51 a 1,57, evidencia de certeza baja). Bevacizumab e irinotecan (IRI): La evidencia sobre BEV + irinotecan (IRI) versus LOM para la SG y la SSP no está clara y probablemente hay poca o ninguna diferencia entre BEV + IRI versus la monoterapia con BEV (SG: CRI 0,95; IC del 95%: 0,70 a 1,30; evidencia de certeza moderada). Cuando los tratamientos se clasificaron según la SG, FOM se clasificó primero, BEV + LOM segundo, LOM tercero, BEV + IRI cuarto, y BEV quinto. La clasificación no tiene en cuenta la certeza de la evidencia, lo que también indica que puede haber poca o ninguna diferencia entre FOM y LOM. Otros tratamientos Tres estudios evaluaron la reoperación versus ninguna reoperación, con o sin reirradiación y quimioterapia, e indicaron posibles ventajas en la supervivencia con la reoperación, en el contexto de poder seleccionar candidatos adecuados para esta intervención. Un tratamiento con cannabinoides en las primeras etapas de evaluación, en combinación con TMZ, merece evaluación adicional. Segunda o posterior recidiva La evidencia limitada de tres estudios heterogéneos indicó que la radioterapia con o sin BEV puede tener un efecto beneficioso sobre la supervivencia, pero se necesita más evidencia. La evidencia no fue suficiente para establecer conclusiones sobre la mejor dosis de radioterapia. Otra evidencia indicó que puede haber poca diferencia en la supervivencia con los campos de tratamiento del tumor en comparación con la mejor opción de tratamiento del médico. No se encontró evidencia fiable sobre el mejor tratamiento de apoyo. Eventos adversos graves (EAG) La combinación BEV + LOM se asoció con un riesgo significativamente mayor de EAG que la monoterapia con LOM (RR 2,51; IC del 95%: 1,72 a 3,66; evidencia de certeza alta), y se clasificó peor junto con cediranib + LOM (RR 2,51; IC del 95%: 1,29 a 4,90; evidencia de certeza alta). LOM se clasificó como el mejor y REG como el segundo mejor. Agregar nuevos tratamientos al BEV se asoció generalmente con un mayor riesgo de eventos adversos graves, en comparación con BEV solo. CONCLUSIONES DE LOS AUTORES: Para el tratamiento de la primera recidiva del GBM en personas tratadas previamente con cirugía y quimiorradioterapia estándar, los tratamientos combinados evaluados no mejoraron la supervivencia general en comparación con la monoterapia con LOM, y a menudo se asociaron con un mayor riesgo de eventos adversos graves. Hay evidencia limitada que indica que la reoperación con o sin reirradiación y quimioterapia puede ser adecuada para candidatos seleccionados. La evidencia sobre la segunda recidiva es escasa. La reirradiación con o sin bevacizumab puede ser de valor en determinados individuos, pero se necesita más evidencia.

Distance traveled to glioblastoma treatment: A measure of the impact of socioeconomic status on survival.

BACKGROUND: Previous studies have shown improved post-surgical outcomes in patients who travel farther for glioblastoma treatment. This study investigates socioeconomic and facility factors that may influence this relationship. METHODS: Overall survival was calculated and compared by distance to treatment facility using univariate and multivariate survival models. The analysis was stratified by facility type, income quartile and insurance status and the association re-evaluated. Kaplan-Meier survival curves were created to analyze the relationship between overall survival and distance group. RESULTS: Individuals who traveled less than 5 miles to treatment had the shortest overall survival (11.8 months), while those who traveled greater than 50 miles had the longest survival (12.9 months). Stratification by income quartile failed to demonstrate an association between distance traveled and survival for those making less than $63,000 (adjusted hazard ratio range: 0.94-1.01). There was no association between survival and distance traveled for patients treated at a community cancer center, comprehensive community cancer center or an integrated network cancer program (adjusted hazard ratio range: 0.86-1.04). CONCLUSION: Financial strain, rather than distance traveled to treatment, may be associated with glioblastoma survival.