Salvage reirradiation for recurrent glioblastoma: a retrospective case series analysis.

PURPOSE: To assess the clinical outcome of patients with recurrent glioblastoma treated with salvage reirradiation. METHODS: Between 2005 and 2022, data from adult patients with glioblastoma treated with surgery and radio-chemotherapy Stupp regimen who developed a local in-field relapse and received stereotactic radiotherapy (SRT) were retrospectively reviewed. RESULTS: The study population included 44 patients with recurrent glioblastoma (median of 9.5 months after the first radiotherapy). Reirradiation alone was given to 47.7% of patients. The median maximum diameter of the recurrence was 13.5 mm. The most common SRT regimen (52.3%) was 35 Gy in 10 fractions. Acute toxicity was mild, with transient worsening of previous neurological symptoms in only 15% of patients. After a median follow-up of 15 months, 40% presented radiological response, but a remarkable number of early distant progressions were recorded (32.5%). The median time to progression was 4.8 months, being the dose, the scheme, the size of the recurrence or the strategy (exclusive RT vs. combined) unrelated factors. The median overall survival (OS) was 14.9 months. Karnofsky index < 70 and the size of the recurrence (maximum diameter < 25 mm) were significant factors associated with OS. Radiological changes after reirradiation were commonly seen (> 50% of patients) hindering the response assessment. CONCLUSIONS: Reirradiation is a feasible and safe therapeutic option to treat localized glioblastoma recurrences, able to control the disease for a few months in selected patients, especially those with good functional status and small lesions. Hypofractionated schemes provided a suitable toxicity profile. Radiological changes were common.

Unveiling the Inflammatory Landscape of Recurrent Glioblastoma through Histological-Based Assessments.

The glioblastoma (GBM) tumor microenvironment consists of a heterogeneous mixture of neoplastic and non-neoplastic cells, including immune cells. Tumor recurrence following standard-of-care therapy results in a rich landscape of inflammatory cells throughout the glioma-infiltrated cortex. Immune cells consisting of glioma-associated macrophages and microglia (GAMMs) overwhelmingly constitute the bulk of the recurrent glioblastoma (rGBM) microenvironment, in comparison to the highly cellular and proliferative tumor microenvironment characteristic of primary GBM. These immune cells dynamically interact within the tumor microenvironment and can contribute to disease progression and therapy resistance while also providing novel targets for emerging immunotherapies. Within these varying contexts, histological-based assessments of immune cells in rGBM, including immunohistochemistry (IHC) and immunofluorescence (IF), offer a critical way to visualize and examine the inflammatory landscape. Here, we exhaustively review the available body of literature on the inflammatory landscape in rGBM as identified through histological-based assessments. We highlight the heterogeneity of immune cells throughout the glioma-infiltrated cortex with a focus on microglia and macrophages, drawing insights from canonical and novel immune-cell histological markers to estimate cell phenotypes and function. Lastly, we discuss opportunities for immunomodulatory treatments aiming to harness the inflammatory landscape in rGBM.

Dynamics of tumor in situ fluid circulating tumor DNA in recurrent glioblastomas forecasts treatment efficacy of immune checkpoint blockade coupled with low-dose bevacizumab.

PURPOSE: Immune checkpoint blockade (ICB) therapies have shown efficacy in various tumors, but long-term responses in glioblastoma are less than 10%. Quantifying tumor in situ fluid circulating tumor DNA (TISF-ctDNA) and therapeutic dynamics may enable real-time GBM disease burden evaluation. This study explores the potential of tumor in situ fluid circulating tumor DNA (TISF-ctDNA) dynamics in predicting treatment efficacy. METHODS: TISF and peripheral blood samples were collected from patients with recurrent glioblastoma (rGBM) undergoing tislelizumab (a programmed death 1 inhibitor) combined with low-dose bevacizumab (an anti-vascular endothelial growth factor antibody) treatment before and during each immunotherapy cycle. Biomarkers evaluated included TISF-ctDNA, measured using Next Generation Sequencing (NGS), and host inflammation markers such as the platelet-to-lymphocyte ratio (PLR). RESULTS: All 32 patients received tislelizumab plus low-dose bevacizumab regularly. The median progression-free survival (PFS) was 4.0 months, and overall survival (OS) was 22.3 months. An analysis of 19 patients with continuous evaluable TISF showed baseline TISF-ctDNA abundance did not correlate with OS (p = 0.23) or PFS (p = 0.23). However, a change in TISF-ctDNA maximal Somatic Variant Allelic Frequency (MVAF) after six treatment cycles predicted both PFS (p = 0.02) and OS (p < 0.0001). Lower baseline PLR also correlated with better survival outcomes. CONCLUSION: The combination of tislelizumab and low-dose bevacizumab therapy appears to be effective in extending both OS and PFS in rGBM patients. Continuous TISF-ctDNA testing shows potential utility in complementing radiological monitoring. The temporal change pattern of TISF MVAF is more predictive of immunotherapy response than imaging. PLR before immunotherapy can screen patients likely to benefit from tislelizumab plus low-dose bevacizumab therapy. TRIAL REGISTRATION: The trial registration number: NCT05502991; Date of registration: 2022-08-14.

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.

The role of molecular biomarkers in recurrent glioblastoma trials: an assessment of the current trial landscape of genome-driven oncology.

For glioblastoma patients, the efficacy-targeted therapy is limited to date. Most of the molecular therapies previously studied are lacking efficacy in this population. More trials are needed to study the actual actionability of biomarkers in (recurrent) glioblastoma. This study aimed to assess the current clinical trial landscape to assess the role of molecular biomarkers in trials on recurrent glioblastoma treatment. The database ClinicalTrials.gov was used to identify not yet completed clinical trials on recurrent glioblastoma in adults. Recruiting studies were assessed to investigate the role of molecular criteria, which were retrieved as detailed as possible. Primary outcome was molecular criteria used as selection criteria for study participation. Next to this, details on moment and method of testing, and targets and drugs studied, were collected. In 76% (181/237) of the included studies, molecular criteria were not included in the study design. Of the remaining 56 studies, at least one specific genomic alteration as selection criterium for study participation was required in 33 (59%) studies. Alterations in EGFR, CDKN2A/B or C, CDK4/6, and RB were most frequently investigated, as were the corresponding drugs abemaciclib and ribociclib. Of the immunotherapies, CAR-T therapies were the most frequently studied therapies. Previously, genomics studies have revealed the presence of potentially actionable alterations in glioblastoma. Our study shows that the potential efficacy of targeted treatment is currently not translated into genome-driven trials in patients with recurrent glioblastoma. An intensification of genome-driven trials might help in providing evidence for (in)efficacy of targeted treatments.

A review of sonodynamic therapy for brain tumors.

OBJECTIVE: Sonodynamic therapy (SDT) is gaining attention as a promising new noninvasive brain tumor treatment that targets and selectively kills tumor cells, with limited side effects. This review examines the mechanisms of SDT and ongoing clinical trials looking at optimization of sonication parameters for potential treatment of glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG). The results in the first patient with recurrent GBM treated at the Mayo Clinic are briefly discussed. METHODS: The authors of this literature review used electronic databases including PubMed, EMBASE, and OVID. Articles reporting relevant preclinical and clinical trials were identified by searching for text words/phrases and MeSH terms, including the following: "sonodynamic therapy," "SDT," "focused ultrasound," "5-ALA," "ALA," "brain tumors," "diffuse pontine glioma," "glioblastoma," and "high grade glioma." RESULTS: Preclinical and clinical trials investigating the specific use of SDT in brain tumors were reviewed. In preclinical models of high-grade glioma and GBM, SDT has shown evidence of targeted tumor cell death via the production of reactive oxygen species. Emerging clinical trial results within recurrent GBM and DIPG show evidence of successful treatment response, with minimal side effects experienced by recruited patients. So far, SDT has been shown to be a promising noninvasive cancer treatment that is well tolerated by patients. The authors present pilot data suggesting good radiological response of GBM to a single SDT treatment, with unpublished observation of a lack of off-target effects even after multiple (monthly) sonication outpatient treatments. The scope of the clinical trials of SDT is to investigate whether it can be the means by which the fatal diagnosis of GBM or DIPG is converted into that of a chronic, treatable disease. CONCLUSIONS: SDT is safe, repeatable, and better tolerated than both chemotherapy and radiotherapy. It has been shown to have an effect in human cancer therapy, but more clinical trials are needed to establish standardized protocols for sonosensitizer delivery, treatment parameters, and combination therapies. The most appropriate timing of treatment also remains to be determined-whether to prevent recurrence in the postoperative period, or as a salvage option in patients with recurrent GBM for which redo surgery is inappropriate. It is hoped that SDT will also be developed for a wider spectrum of clinical indications, such as metastases, meningioma, and low-grade glioma. Further clinical trials are in preparation.

Local Delivery of Irinotecan to Recurrent GBM Patients at Reoperation Offers a Safe Route of Administration.

Glioblastomas are impossible to completely resect and almost always recur at the borders of the resection margin. There is no established chemotherapy regimen available to patients who recur, while systemic treatment is hampered by the blood-brain barrier. Here, we report on the first evaluation in humans of the intraparenchymal injection of irinotecan into the resection cavity after surgical resection of recurrent glioblastoma patients. The cytotoxicity of irinotecan was compared to SN-38 in primary cells from recurrent glioblastoma patients. Irinotecan was injected at multiple (~30) sites of the resection cavity wall at a depth of 3 to 5 mm. SN-38 was more cytotoxic than irinotecan at concentrations below 1 µM due to enzyme kinetics. The intraparenchymal administration of irinotecan was safe, with good wound healing and an absence of swelling, inflammation, or pseudo-abscess formation. The median survival post irinotecan administration was 32.6 weeks. The median overall survival was 30.5 months, with a two-year survival rate of 56%. This study demonstrates that local delivery of irinotecan into the brain parenchyma offers a safe route of administration over systemic delivery in the treatment of recurrent glioblastoma.

The efficacy of stereotactic radiotherapy followed by bevacizumab and temozolomide in the treatment of recurrent glioblastoma: a case report.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor among adults. Despite advancements in multimodality therapy for GBM, the overall prognosis remains poor, with an extremely high risk of recurrence. Currently, there is no established consensus on the optimal treatment option for recurrent GBM, which may include reoperation, reirradiation, chemotherapy, or a combination of the above. Bevacizumab is considered a first-line treatment option for recurrent GBM, as is temozolomide. However, in recurrent GBM, it is necessary to balance the risks and benefits of reirradiation in combination with bevacizumab and temozolomide. Herein, we report the case of a patient with recurrent GBM after standard treatment who benefited from stereotactic radiotherapy followed by bevacizumab and temozolomide maintenance therapy. Following 16 months of concurrent chemoradiotherapy (CCRT), the patient was diagnosed with recurrent GBM by a 3-T contrast-enhanced magnetic resonance imaging (MRI). The addition of localized radiotherapy to the ongoing treatment regimen of bevacizumab, in combination with temozolomide therapy, prolonged the patient's disease-free survival to over 2 years, achieving a significant long-term outcome, with no notable adverse effects observed. This clinical case may provide a promising new option for patients with recurrent GBM.

Can Platelet-to-Lymphocyte Ratio (PLR) and Neutrophil-to-Lymphocyte Ratio (NLR) Help Predict Outcomes of Patients With Recurrent Glioblastoma?

BACKGROUND/AIM: In patients with recurrent glioblastoma, very little data are available regarding the prognostic value of platelet-to-lymphocyte (PLR) and neutrophil-to-lymphocyte (NLR) ratios. This study investigated potential associations between PLR or NLR and treatment outcomes. PATIENTS AND METHODS: PLR and NLR at diagnosis of recurrence plus 10 additional characteristics were retrospectively analyzed for associations with progression-free survival (PFS) and overall survival (OS) in 75 patients with recurrent glioblastoma. RESULTS: On multivariate analyses, maximal cumulative diameter of recurrent lesion(s) <40 mm (p=0.015) and systemic therapy (p<0.001) were associated with improved PFS. On multivariate analysis of OS, improved outcomes were significantly associated with PLR ≤150 (p=0.029), maximal cumulative diameter <40 mm (p=0.030), and systemic therapy (p=0.010). CONCLUSION: In addition to other characteristics, PLR at the time of recurrence was identified as an independent predictor of OS in patients with recurrent glioblastoma. PLR may be useful when designing personalized treatment approaches or clinical trials.

The Predictive Value of Different Glasgow Prognostic Scores and the LabBM Score for Patients With Recurrent Glioblastoma.

BACKGROUND/AIM: The prognostic value of scoring instruments was described for newly diagnosed glioblastoma. This study investigated five instruments in patients with recurrent tumors. PATIENTS AND METHODS: Original Glasgow Prognostic Score (oGPS), modified GPS (mGPS), high-sensitivity mGPS (HS-mGPS), high-sensitivity oGPS (HS-oGPS), LabBM score, and 10 other factors were analyzed for progression-free survival (PFS) and overall survival (OS) in 51 patients. RESULTS: On univariate analyses, oGPS 0-1, mGPS 0-1, and LabBM score 0-1.0 were significantly associated with improved OS and showed trends for improved PFS. On multivariate analysis, a trend was found for associations between LabBM score 0-1.0 and better OS. In addition, maximal cumulative diameter ≤40 mm and systemic therapy were independently associated with better PFS and OS, resection with PFS, and in-field recurrence with OS. CONCLUSION: Lower oGPS, mGPS, and LabBM scores were significantly associated with improved OS on univariate analyses. These instruments may be helpful when designing personalized treatment regimens for patients with recurrent glioblastoma.

Stereotactic radiosurgery versus combined stereotactic radiosurgery and bevacizumab for recurrent glioblastoma; a systematic review and meta-analysis of survival.

Recurrent glioblastoma (rGBM) is a brain tumor that is resistant to standard treatments. Although stereotactic radiosurgery (SRS) is a non-invasive radiation technique, it cannot fully prevent tumor recurrence and progression. Bevacizumab blocks tumor blood supply and has been approved for rGBM. However, the best way to combine SRS and bevacizumab is still unclear. We did a systematic review and meta-analysis of studies comparing SRS alone and SRS plus bevacizumab for rGBM. We searched three databases for articles published until June 2023. All statistical analysis was performed by STATA v.17. Our meta-analysis included 20 studies with 926 patients. We found that the combination therapy had a significantly lower rate of overall survival (OS) than SRS alone at 6-month 0.77[95%CI:0.74-0.85] for SRS alone and (100%) for SRS plus bevacizumab. At 1-year OS, 0.39 [95%CI: 0.32-0.47] for SRS alone and 0.61 [95%CI:0.44-0.77] for SRS plus bevacizumab (P-value:0.02). However, this advantage was not seen in the long term (18 months and two years). Additionally, the combination therapy had lower chances of progression-free survival (PFS) than SRS alone at the 6-month and 1-year time points, but the differences were insignificant. Our study indicates that incorporating bevacizumab with SRS may lead to a short-term increase in OS for rGBM patients but not long-term. Additionally, the PFS rate did not show significant improvement in the group receiving combination therapy. Further clinical trials are necessary to validate the enhanced overall survival with combination therapy for rGBM.

Recurrent Glioblastoma-Molecular Underpinnings and Evolving Treatment Paradigms.

Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.

Whole genome sequencing in (recurrent) glioblastoma: challenges related to informed consent procedures and data sharing.

Increased use of whole genome sequencing (WGS) in neuro-oncology for diagnostics and research purposes necessitates a renewed conversation about informed consent procedures and governance structures for sharing personal health data. There is currently no consensus on how to obtain informed consent for WGS in this population. In this narrative review, we analyze the formats and contents of frameworks suggested in literature for WGS in oncology and assess their benefits and limitations. We discuss applicability, specific challenges, and legal context for patients with (recurrent) glioblastoma. This population is characterized by the rarity of the disease, extremely limited prognosis, and the correlation of the stage of the disease with cognitive abilities. Since this has implications for the informed consent procedure for WGS, we suggest that the content of informed consent should be tailor-made for (recurrent) glioblastoma patients.

Prognostic factors to predict postoperative survival in patients with recurrent glioblastoma.

Background: There are no generally accepted criteria for selecting patients with recurrent glioblastoma for surgery. This retrospective study in a Danish population-based cohort aimed to identify prognostic factors affecting postoperative survival after repeated surgery for recurrent glioblastoma and to test if the preoperative New Scale for Recurrent Glioblastoma Surgery (NSGS) developed by Park CK et al could assist in the selection of patients for repeat glioblastoma surgery. Methods: Clinical data from 66 patients with recurrent glioblastoma and repeated surgery were analyzed. Kaplan-Meier plots were produced to illustrate survival in each of the three NSGS prognostic groups, and Cox proportional hazard regression was used to identify prognostic variables. Multivariable analysis was used to identify differences in survival in the three prognostic groups. Results: Six variables significantly affected postoperative survival: preoperative Karnofsky Performance Status (KPS) < 70 (p = 0.002), decreased KPS after second surgery (p = 0.012), ependymal involvement (p = 0.002), tumor volume â‰§ 50 cm3 (p = 0.021), age (p = 0.033) and Ki-67 (p = 0.005). Retrospective application of the criteria previously published by Park CK et al showed that median postoperative survival for the three prognostic groups was 390 days (0 points), 279 days (1 point), and 80 days (2 points), respectively. Conclusion: Several prognostic variables to predict postoperative survival in patients with recurrent glioblastoma were identified and should be considered when selecting patient for repeat surgery. The NSGS scoring system was useful as there were significant differences in postoperative survival between its three prognostic groups.

Health-related quality of life and neurocognitive functioning in patients with recurrent glioblastoma treated with intracerebral immune checkpoint inhibition.

PURPOSE: After glioblastoma (GB) recurrence, prognosis is very cumbersome. Therefore, health-related quality of life (HRQoL) and neurocognitive functioning (NCF) have become important endpoints in clinical trials when evaluating novel treatments. We aimed to evaluate the HRQoL and NCF in patients with recurrent glioblastoma (rGB) treated with a combination of surgical intervention (reoperation or biopsy) and intracerebral immune checkpoint inhibition. METHODS: Patients who participated in the trial (N = 23), at a single-center university hospital were included. Data were collected using 3 patient-reported outcome measures (EORTC-QLQ-C30, EORTC-QLQ-BN20, and HADS) and computerized NCF testing. In the responder group, baseline values were compared to results at a 6-month follow-up. Additionally, exploratory analyses compared baseline HRQoL and NCF between responders and non-responders. RESULTS: There were five responders and 18 non-responders. When comparing the mean and individual baseline with follow-up results for the responders, we observed overall a stable to slight clinically relevant improvement of HRQoL in multiple subsets of the questionnaires while maintaining a stable NCF. One patient deteriorated on anxiety and depression symptoms from baseline to follow-up. CONCLUSIONS: In patients that responded to intracerebral immunotherapy in our institutional trial, HRQoL and NCF remained stable over time, suggesting that no detrimental effect on cognitive function or quality of life may be expected with this treatment approach. Furthermore, there seems to be an overall tendency for responders to score better on HRQoL and NCF than non-responders at baseline.

ALA-RDT in GBM: protocol of the phase I/II dose escalation trial of radiodynamic therapy with 5-Aminolevulinic acid in patients with recurrent glioblastoma.

BACKGROUND: Despite improvements in surgical as well as adjuvant therapies over the last decades, the prognosis for patients with glioblastoma remains poor. Five-Aminolevulinic acid (5-ALA) induced porphyrins are already used for fluorescence-guided resection and as photosensitizer for photodynamic therapy. New findings reveal their potential use as sensitizing agents in combination with ionizing radiation. METHODS: We initiated a phase I/II dose escalation study, treating patients with recurrence of glioblastoma with oral 5-ALA concurrent to radiotherapy (RT). This prospective single-center study based in the University Hospital Münster aims to recruit 30 patients over 18 years of age with histologically verified recurrence of supratentorial glioblastoma in good performance status (KPS ≥ 60). Following a 3 + 3 dose-escalation design, patients having undergone re-resection will receive a 36 Gy RT including radiodynamic therapy fractions (RDT). RDT constitutes of oral administration of 5-ALA before the irradiation session. Two cohorts will additionally receive two fractions of neoadjuvant treatment three and two days before surgery. To determine the maximum tolerated dose of repeated 5-ALA-administration, the number of RDT-fractions will increase, starting with one to a maximum of eight fractions, while closely monitoring for safety and toxicity. Follow-up will be performed at two and five months after treatment. Primary endpoint will be the maximum tolerated dose (MTD) of repeated ALA-administration, secondary endpoints are event-free-, progression-free-, and overall-survival. Additionally, 5-ALA metabolites and radiobiological markers will be analysed throughout the course of therapy and tissue effects after neoadjuvant treatment will be determined in resected tissue. This protocol is in accordance with the SPIRIT guidelines for clinical trial protocols. DISCUSSION: This is the protocol of the ALA-RDT in GBM-study, the first-in-man evaluation of repeated administration of 5-ALA as a radiosensitizer for treatment of recurrent glioblastoma. TRIAL REGISTRATION: This study was approved by the local ethics committee of the Medical Association of Westphalia-Lippe and the University of Münster on 12.10.2022, the German federal institute for Drugs and medical devices on 13.10.2022 and the federal office for radiation protection on 29.08.2022. This trial was registered on the public European EudraCT database (EudraCT-No.: 2021-004631-92) and is registered under www.cliniclatrials.gov (Identifier: NCT05590689).

Clinical activity and safety of sintilimab, bevacizumab, and TMZ in patients with recurrent glioblastoma.

PURPOSE: There are limited and no standard therapies for recurrent glioblastoma. We herein report the antitumour activity and safety of sintilimab, bevacizumab and temozolomide (TMZ) in recurrent glioblastoma. METHODS: We retrospectively analysed eight patients with recurrent glioblastoma treated with sintilimab (200 mg) every three weeks + bevacizumab (10 mg/kg) every three weeks + TMZ (200 mg/m²orally) (5 days orally every 28 days for a total of four weeks). The primary objective was investigator-assessed median progression-free survival(mPFS). Secondary objectives were to assess the 6-month PFS, objective response rate (ORR) and duration of response (DOR) accroding to RANO criteria. RESULTS: The mPFS time for 8 patients was 3.340 months (95% CI: 2.217-4.463), The longest PFS was close to 9 months. Five patients were assessed to have achieved partial response (PR), with an overall remission rate of 62.5%, Four patients experienced a change in tumour volume at the best response time of greater than 60% shrinkage from baseline, and one patient remained progression free upon review, with a DOR of more than 6.57 months. The 6-month PFS was 25% (95% CI: 5.0-55.0%). Three patients had a treatment-related adverse events, though no grade 4 or 5 adverse events occurred. CONCLUSION: In this small retrospective study, the combination regimen of sintilimab, bevacizumab and TMZ showed promising antitumour activity in treatment of recurrent glioblastoma, with a good objective remission rate.

MRI Treatment Response Assessment Maps (TRAMs) for differentiating recurrent glioblastoma from radiation necrosis.

BACKGROUND: MRI treatment response assessment maps (TRAMs) were introduced to distinguish recurrent malignant glioma from therapy related changes. TRAMs are calculated with two contrast-enhanced T1-weighted sequences and reflect the "late" wash-out (or contrast clearance) and wash-in of gadolinium. Vital tumor cells are assumed to produce a wash-out because of their high turnover rate and the associated hypervascularization, whereas contrast medium slowly accumulates in scar tissue. To examine the real value of this method, we compared TRAMs with the pathology findings obtained after a second biopsy or surgery when recurrence was suspected. METHODS: We retrospectively evaluated TRAMs in adult patients with histologically demonstrated glioblastoma, contrast-enhancing tissue and a pre-operative MRI between January 1, 2017, and December 31, 2022. Only patients with a second biopsy or surgery were evaluated. Volumes of the residual tumor, contrast clearance and contrast accumulation before the second surgery were analyzed. RESULTS: Among 339 patients with mGBM who underwent MRI, we identified 29 repeated surgeries/biopsies in 27 patients 59 ± 12 (mean ± standard deviation) years of age. Twenty-eight biopsies were from patients with recurrent glioblastoma histology, and only one was from a patient with radiation necrosis. We volumetrically evaluated the 29 pre-surgery TRAMs. In recurrent glioblastoma, the ratio of wash-out volume to tumor volume was 36 ± 17% (range 1-73%), and the ratio of the wash-out volume to the sum of wash-out and wash-in volumes was 48 ± 21% (range 22-92%). For the one biopsy with radiation necrosis, the ratios were 42% and 54%, respectively. CONCLUSIONS: Typical recurrent glioblastoma shows a > 20%ratio of the wash-out volume to the sum of wash-out and wash-in volumes. The one biopsy with radiation necrosis indicated that such necrosis can also produce high wash-out in individual cases. Nevertheless, the additional information provided by TRAMs increases the reliability of diagnosis.

Magnetic Resonance Imaging-Aided SmartFlow Convection Delivery of DNX-2401: A Pilot, Prospective Case Series.

BACKGROUND: The Combination Adenovirus + Pembrolizumab to Trigger Immune Virus Effects (CAPTIVE) study is a phase II clinical trial testing the efficacy of a recombinant adenovirus DNX-2401 combined with the immune checkpoint inhibitor pembrolizumab. Here, we report the first patients in this study who underwent viral delivery through real-time magnetic resonance imaging (MRI) stereotaxis-guided SmartFlow convection delivery of DNX-2401. METHODS: Patients who underwent real-time MRI-guided DNX-2401 delivery through the SmartFlow convection catheter were prospectively followed. RESULTS: Precise catheter placement was achieved in all patients treated, and no adverse events were noted. Average radial error from target was 0.9 mm. Average procedural time was 3 hours 16 minutes and was comparable to other convection-enhanced delivery techniques. In 2 patients, delivery of DNX-2401 was visualized as >1 cm maximal diameter of T1 hypointensity infusate on MRI obtained immediately after completion of viral infusion. These patients exhibited partial response based on Response Assessment in Neuro-Oncology assessment. The remaining patient showed <1 cm maximal diameter of infusate on immediate postinfusion MRI and showed disease progression on subsequent MRI. CONCLUSIONS: Our pilot case series supports compatibility of the SmartFlow system with oncolytic adenovirus delivery and provides the basis for future validation studies.