Contrast-enhancing Tumor Volume Research Articles

Quantitative assessment of residual tumor is a strong and independent predictor of survival in methylated glioblastoma following radiochemotherapy with CCNU/TMZ.

Maximum tumor resection improves overall survival (OS) in patients with glioblastoma. The extent of resection (EOR) is historically dichotomized. The RANO resect group recently proposed criteria for volumetry-based EOR assessment in patients that were treated according to Stupp´s protocol. The purpose of this study was (1) to investigate the prognostic value of EOR in patients receiving combined chemotherapy with lomustine (CCNU)/temozolomide (TMZ), and (2) to analyse the prognostic performance of binary EOR assessment compared to volumetric assessment. 78 patients with newly diagnosed MGMT-methylated GBM undergoing tumor resection followed by radiochemotherapy with CCNU/TMZ were included in this study. Residual contrast-enhancing (CE) tumor volume after the first resection was measured and its influence on OS and PFS was analysed using uni- and multivariable Cox regression analysis as well as two-sided log rank test. Patients were divided into RTV ≤1 cm³, >1 cm³ - ≤5 cm³ and >5 cm³ following the proposed criteria of the RANO resect group. Prolonged OS was associated with age <60 years, low RTV, and gross total resection (GTR). Residual tumor volume (RTV) had a superior prognostic value compared to binary EOR assessment. Patients with total or near total resection of CE tumor (≤1 cm³ RTV) showed prolonged OS (median 54.4 months, 95% CI 46.94-not reached), with a 5-year survival rate of 49%. Low RTV is associated with increased survival in glioblastoma patients undergoing radiochemotherapy with CCNU/TMZ. This study demonstrates the applicability of the recently proposed RANO resect criteria in this subgroup of patients.

Revisiting oligodendroglioma grading in the 2021 WHO classification: calcification and larger contrast-enhancing tumor volume may predict higher oligodendroglioma grade.

To investigate whether qualitative and quantitative imaging phenotypes can predict the grade of oligodendroglioma. Retrospective chart and imaging reviews were conducted on 180 adults with oligodendroglioma (IDH-mutant and 1p/19q codeleted) between 2005 and 2021. Qualitative imaging characteristics including tumor location, calcification, gliomatosis cerebri, cystic change, necrosis, and infiltrative pattern were analyzed. Quantitative imaging assessment was performed from the tumor mask via automatic segmentation to calculate total, contrast-enhancing (CE), non-enhancing (NE), and necrotic tumor volumes. Logistic analyses were conducted to determine predictors of oligodendroglioma grade. This study included 180 patients (84 [46.7%] with grade 2 and 96 [53.3%] with grade 3 oligodendrogliomas), with a median age of 42 years (range 23-76 years), comprising 91 females and 89 males. On univariable analysis, calcification (odds ratio [OR] = 6.00, P < 0.001), necrosis (OR = 21.84, P = 0.003), presence of CE tumor (OR = 7.86, P < 0.001), larger total (OR = 1.01, P < 0.001), larger CE (OR = 2.22, P = 0.010), and larger NE (OR = 1.01, P < 0.001) tumor volumes were predictors of grade 3 oligodendroglioma. On multivariable analysis, calcification (OR = 3.79, P < 0.001) and larger CE tumor volume (OR = 2.70, P = 0.043) remained as independent predictors of grade 3 oligodendroglioma. The multivariable model exhibited an AUC, accuracy, sensitivity, specificity of 0.78 (95% confidence interval 0.72-0.84), 72.8%, 79.2%, 69.1%, respectively. Presence of calcification and larger CE tumor volume may serve as useful imaging biomarkers for prediction of oligodendroglioma grade. Assessment of intratumoral calcification and CE tumor volume may facilitate accurate preoperative estimation of oligodendroglioma grade. Presence of intratumoral calcification and larger contrast-enhancing tumor volume were the significant predictors of higher grade oligodendroglioma based on the 2021 WHO classification.

Leptomeningeal metastases in isocitrate dehydrogenase-wildtype glioblastomas revisited: Comprehensive analysis of incidence, risk factors, and prognosis based on post-contrast fluid-attenuated inversion recovery.

The incidence of leptomeningeal metastases (LM) has been reported diversely. This study aimed to investigate the incidence, risk factors, and prognosis of LM in patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma. A total of 828 patients with IDH-wildtype glioblastoma were enrolled between 2005 and 2022. Baseline preoperative MRI including post-contrast fluid-attenuated inversion recovery (FLAIR) was used for LM diagnosis. Qualitative and quantitative features, including distance between tumor and subventricular zone (SVZ) and tumor volume by automatic segmentation of the lateral ventricles and tumor, were assessed. Logistic analysis of LM development was performed using clinical, molecular, and imaging data. Survival analysis was performed. The incidence of LM was 11.4%. MGMTp unmethylation (odds ratio [OR] = 1.92, P = .014), shorter distance between tumor and SVZ (OR = 0.94, P = .010), and larger contrast-enhancing tumor volume (OR = 1.02, P < .001) were significantly associated with LM. The overall survival (OS) was significantly shorter in patients with LM than in those without (log-rank test; P < .001), with median OS of 12.2 and 18.5 months, respectively. The presence of LM remained an independent prognostic factor for OS in IDH-wildtype glioblastoma (hazard ratio = 1.42, P = .011), along with other clinical, molecular, imaging, and surgical prognostic factors. The incidence of LM is high in patients with IDH-wildtype glioblastoma, and aggressive molecular and imaging factors are correlated with LM development. The prognostic significance of LM based on post-contrast FLAIR imaging suggests the acknowledgment of post-contrast FLAIR as a reliable diagnostic tool for clinicians.

Does waiting for surgery matter? How time from diagnostic MRI to resection affects outcomes in newly diagnosed glioblastoma.

Maximal safe resection is the standard of care for patients presenting with lesions concerning for glioblastoma (GBM) on magnetic resonance imaging (MRI). Currently, there is no consensus on surgical urgency for patients with an excellent performance status, which complicates patient counseling and may increase patient anxiety. This study aims to assess the impact of time to surgery (TTS) on clinical and survival outcomes in patients with GBM. This is a retrospective study of 145 consecutive patients with newly diagnosed IDH-wild-type GBM who underwent initial resection at the University of California, San Francisco, between 2014 and 2016. Patients were grouped according to the time from diagnostic MRI to surgery (i.e., TTS): ≤ 7, > 7-21, and > 21 days. Contrast-enhancing tumor volumes (CETVs) were measured using software. Initial CETV (CETV1) and preoperative CETV (CETV2) were used to evaluate tumor growth represented as percent change (ΔCETV) and specific growth rate (SPGR; % growth/day). Overall survival (OS) and progression-free survival (PFS) were measured from the date of resection and were analyzed using the Kaplan-Meier method and Cox regression analyses. Of the 145 patients (median TTS 10 days), 56 (39%), 53 (37%), and 36 (25%) underwent surgery ≤ 7, > 7-21, and > 21 days from initial imaging, respectively. Median OS and PFS among the study cohort were 15.5 and 10.3 months, respectively, and did not differ among the TTS groups (p = 0.81 and 0.17, respectively). Median CETV1 was 35.9, 15.7, and 10.2 cm3 across the TTS groups, respectively (p < 0.001). Preoperative biopsy and presenting to an outside hospital emergency department were associated with an average 12.79-day increase and 9.09-day decrease in TTS, respectively. Distance from the treating facility (median 57.19 miles) did not affect TTS. In the growth cohort, TTS was associated with an average 2.21% increase in ΔCETV per day; however, there was no effect of TTS on SPGR, Karnofsky Performance Status (KPS), postoperative deficits, survival, discharge location, or hospital length of stay. Subgroup analyses did not identify any high-risk groups for which a shorter TTS may be beneficial. An increased TTS for patients with imaging concerning for GBM did not impact clinical outcomes, and while there was a significant association with ΔCETV, SPGR remained unaffected. However, SPGR was associated with a worse preoperative KPS, which highlights the importance of tumor growth speed over TTS. Therefore, while it is ill advised to wait an unnecessarily long time after initial imaging studies, these patients do not require urgent/emergency surgery and can seek tertiary care opinions and/or arrange for additional preoperative support/resources. Future studies are needed to explore subgroups for whom TTS may impact clinical outcomes.

SURG-21. THE PROGNOSTIC ROLE OF RE-RESECTION FOR RECURRENT GLIOBLASTOMA: A REPORT OF THE RANO RESECT GROUP USING A NOVEL CLASSIFICATION FOR EXTENT OF RESECTION

Abstract BACKGROUND The role of re-resection in recurrent glioblastoma remains controversial since leaving certain tumor volumes deliberately behind cannot be ethically justified. We aimed to (I) analyze the prognostic value of re-resection using the novel RANO resect classification for quantification of residual tumor, and (II) explore factors that favorably consolidate the effects of re-resection on outcome. METHODS The RANO resect group retrospectively accumulated a global, eight-center cohort of patients with first recurrence from a previously resected glioblastoma. The associations of re-resection and clinical factors with outcome were analyzed. Propensity score-matched analyses were constructed to mimic randomized clinical trials comparing different residual tumor volumes. RESULTS We analyzed 681 patients with first recurrence of IDH-wildtype glioblastoma, including 310 patients who underwent re-resection at first recurrence. The use of re-resection was associated with prolonged survival also when stratifying for molecular and clinical confounders (HR:0.65, CI:0.5-0.8; p = 0.001). Smaller post-operative contrast-enhancing (CE) tumor volumes were favorably associated with outcome of re-resected patients (HR per cm3:1.04, CI:1.0-1.1; p = 0.009), and ≤ 1 cm3 residual CE tumor translated into improved survival compared to non-surgical management. Accordingly, ‘maximal resection’ (class 2) had superior survival compared to ‘submaximal resection’ (class 3) (mOS after recurrence: 12 vs. 9 months; p = 0.003). Adjuvant chemotherapy further augmented the beneficial effects of lower residual CE tumor. Conversely, ‘supramaximal resection’ of non-CE tumor (class 1) was not associated with prolonged survival but frequently accompanied by post-operative deficits, hampering further treatment. The prognostic role of residual CE tumor was confirmed in propensity score analyses. CONCLUSION Residual CE tumor is highly prognostic in recurrent glioblastoma and the RANO resect classification serves to stratify patients accordingly. Chemotherapy may favorably contribute to the prognostic associations of re-resection. When pursuing re-resection of non-CE tumor, intraoperative mapping strategies to minimize the risk of post-operative deficits are recommended.

NIMG-50. TOTAL TUMOR CELLULARITY AND CELLULAR GROWTH RATES ESTIMATED USING A RADIO-PATHOMIC AI MODEL PREDICTS PROGNOSIS AND RESPONSE TO CYTOTOXIC THERAPY IN RECURRENT GBM

Abstract PURPOSE A radio-pathomic machine learning model trained with postmortem tissue samples has recently been developed to estimate tumor cellularity from standard anatomic MR images (Bobholz SA et al. AJNR 2022). The aim of this study was to use this externally developed, machine learning-based model to assess the impact of tumor cellularity and changes in cellularity on survival in recurrent glioblastoma (rGBM) treated with standard cytotoxic therapies. METHODS We retrospectively evaluated 22 cases of rGBM treated with chemotherapy. Radio-pathomic maps of predicted tumor cellularity were generated using the radio-pathomic model using pre- and post-contrast T1-weighted MR images, T2-weighted FLAIR images and apparent diffusion coefficient calculated from diffusion-weighted imaging. Total cellularity was estimated by integrating the cellularity measures within a contrast-enhancing tumor volume of interest. Cellularity growth rates (CGRs) were computed using three pre-treatment scans and available post-treatment scans. Tumor cellularity and CGRs were assessed in terms of their impact on overall survival (OS) using log-rank analysis. RESULTS Patients with baseline tumor cellularity &amp;lt; 8.89x108 cells and those with pre-treatment CGR &amp;lt; 7.55x106 cells/day showed significantly longer OS than those with higher cellularity or CGRs (P = 0.001 and 0.008, respectively). Patients with cellularity &amp;lt; 8.90x108 cells at the 1st follow-up (one month after treatment), those with cellularity at 2nd follow-up &amp;lt; 8.89x108 cells (two months after treatment), post-treatment CGR &amp;lt; 1.51x107 cells/day, and change in CGR after treatment &amp;lt; +5.91x106 cells/day showed significantly longer OS than those with higher values (P = 0.03, &amp;lt; 0.001, &amp;lt; 0.001, = 0.02, respectively). CONCLUSION These preliminary results suggest the potential value of estimating total cellularity within the enhancing tumor as a biomarker for prognosis prediction and cytotoxic therapy effect evaluation in rGBM. Additional analyses with more cases and treatments are warranted.

EXTH-05. ANTI-TUMOR IMMUNE RESPONSE OF ONCOMAGNETIC MONOTHERAPY IN GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most lethal primary malignant brain tumor with a median survival of 15–20 months. Concurrent temozolomide (TMZ) chemotherapy and radiation (XRT) remain the current standard of care (SOC) treatment for newly diagnosed GBM. The addition of tumor treating fields (TTFs) improves median survival for newly diagnosed GBM from 16 to 20.9 months. This modest improvement underscores the urgent need to identify a new treatment modality as a safe and effective therapy. PURPOSE The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) in vitro by generating the spinning oscillating magnetic field (sOMF) which disrupts electron transport chain, leading to a marked increase in reactive oxygen species (ROS) and consequently to cancer cell death. We studied the cellular and molecular effects of sOMF treatment on GBM cell lines and investigated the immune response to Oncomagnetic monotherapy (OMT) in a syngeneic mouse model. RESULTS sOMF significantly reduces cell proliferation and cell survival in vitro . It induces DNA damage and arrests cells in G1-phase of the cell cycle. Whole-body sOMF stimulation caused a substantial retardation of tumor growth and reduction of the contrast-enhanced tumor volume in 9.4T MRI scans. OMT showed significant increase in overall survival in treated mice. We also observed upregulated immune response indicated by RNA sequencing data obtained from sOMF-treated LN229 cells as well as in treated GBM mouse tumor sections by imaging mass cytometry analysis. The tSNE analysis of various immune clusters suggests significant increase in immune response by activating CD4+, CD8+, murine-macrophages and M1-macrophages located at tumor site in the treated group. CONCLUSION The obtained data indicate significant anti-tumor response by inhibiting cancer signaling pathways and an increased immune response. Our findings suggest unique mechanism of action for sOMF stimulation and provide a strong rationale for standalone OMT for GBM.

Radiomics for the non-invasive prediction of PD-L1 expression in patients with brain metastases secondary to non-small cell lung cancer

BackgroundThe expression level of the programmed cell death ligand 1 (PD-L1) appears to be a predictor for response to immunotherapy using checkpoint inhibitors in patients with non-small cell lung cancer (NSCLC). As differences in terms of PD-L1 expression levels in the extracranial primary tumor and the brain metastases may occur, a reliable method for the non-invasive assessment of the intracranial PD-L1 expression is, therefore of clinical value. Here, we evaluated the potential of radiomics for a non-invasive prediction of PD-L1 expression in patients with brain metastases secondary to NSCLC.Patients and methodsFifty-three NSCLC patients with brain metastases from two academic neuro-oncological centers (group 1, n = 36 patients; group 2, n = 17 patients) underwent tumor resection with a subsequent immunohistochemical evaluation of the PD-L1 expression. Brain metastases were manually segmented on preoperative T1-weighted contrast-enhanced MRI. Group 1 was used for model training and validation, group 2 for model testing. After image pre-processing and radiomics feature extraction, a test-retest analysis was performed to identify robust features prior to feature selection. The radiomics model was trained and validated using random stratified cross-validation. Finally, the best-performing radiomics model was applied to the test data. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analyses.ResultsAn intracranial PD-L1 expression (i.e., staining of at least 1% or more of tumor cells) was present in 18 of 36 patients (50%) in group 1, and 7 of 17 patients (41%) in group 2. Univariate analysis identified the contrast-enhancing tumor volume as a significant predictor for PD-L1 expression (area under the ROC curve (AUC), 0.77). A random forest classifier using a four-parameter radiomics signature, including tumor volume, yielded an AUC of 0.83 ± 0.18 in the training data (group 1), and an AUC of 0.84 in the external test data (group 2).ConclusionThe developed radiomics classifiers allows for a non-invasive assessment of the intracranial PD-L1 expression in patients with brain metastases secondary to NSCLC with high accuracy.

Magnetic resonance imaging-derived parameters to predict response to regorafenib in recurrent glioblastoma.

Regorafenib is a multikinase inhibitor, approved as a preferred regimen for recurrent glioblastoma (rGB). Although its effects on prolonging survival could seem modest, it is still unclear whether a subset of patients, potentially identifiable by imaging biomarkers, might experience a more substantial positive effect. Our aim was to evaluate the potential value of magnetic resonance imaging-derived parameters as non-invasive biomarkers to predict response to regorafenib in patients with rGB. 20 patients with rGB underwent conventional and advanced MRI at diagnosis (before surgery), at recurrence and at first follow-up (3months) during regorafenib. Maximum relative cerebral blood volume (rCBVmax) value, intra-tumoral susceptibility signals (ITSS), apparent diffusion coefficient (ADC) values, and contrast-enhancing tumor volumes were tested for correlation with response to treatment, progression-free survival (PFS), and overall survival (OS). Response at first follow-up was assessed according to Response Assessment in Neuro-Oncology (RANO) criteria. 8/20 patients showed stable disease at first follow-up. rCBVmax values of the primary glioblastoma (before surgery) significantly correlated to treatment response; specifically, patients with stable disease displayed higher rCBVmax compared to progressive disease (p = 0.04, 2-group t test). Moreover, patients with stable disease showed longer PFS (p = 0.02, 2-group t test) and OS (p = 0.04, 2-group t test). ITSS, ADC values, and contrast-enhancing tumor volumes showed no correlation with treatment response, PFS nor OS. Our results suggest that rCBVmax of the glioblastoma at diagnosis could serve as a non-invasive biomarker of treatment response to regorafenib in patients with rGB.

CEST imaging of the APT and ssMT predict the overall survival of patients with glioma at the first follow-up after completion of radiotherapy at 3T

Background and purposeOutcome prediction of patients with glioma early after the completion of radiotherapy represents a major clinical challenge. Previously, the prognostic value of chemical exchange saturation transfer (CEST) imaging has been demonstrated in patients with newly diagnosed glioma. The objective of this study was to assess the potential of amide proton transfer (APT)-, relayed nuclear Overhauser effect (rNOE)- and semi-solid magnetization transfer (ssMT)-imaging according to Zhou et al. (APTwasym), Goerke et al. (MTRRexAPT, MTRRexNOE and MTRRexMT) and Mehrabian et al. (PeakAreaAPT, PeakAreaNOE and MTconst) for the prognostication of the overall survival (OS) of patients with glioma at the first follow-up after the completion of radiotherapy. Materials and Methods49 of 72 participants with diffuse glioma, who underwent CEST MRI at 3T between July 2018 and December 2021 4 to 6 weeks after the completion of radiotherapy, were analyzed. Contrast-enhancing tumor (CE) and whole tumor (WT) volumes were segmented on T2w-FLAIR and contrast-enhanced T1w images. Kaplan-Meier analysis and logrank-test were used for statistical analyses. ResultsAPTw imaging demonstrated the strongest association with OS (HR = 4.66, p < 0.001). The MTconst (HR = 2.54, p = 0.044) was associated with the OS of participants with residual contrast-enhancing glioma tissue, whilst the MTRRexAPT (HR = 2.44, p = 0.056) showed a trend in this sub-cohort. The MTRRexNOE, MTRRexMT and PeakAreaNOE were not associated with survival. ConclusionImaging of the APT and ssMT at the first follow-up 4 to 6 weeks after the completion of radiotherapy at 3T were associated with the overall survival of study participants with glioma.

Abstract 337: Antitumor effect of oncomagnetic therapy in glioblastoma

Abstract Background: Glioblastoma (GBM) is the most lethal primary malignant brain tumor with a median survival of 15-20 months. Concurrent temozolomide (TMZ) chemotherapy and radiation (XRT) remain the current standard of care (SOC) treatment for newly diagnosed GBM. The addition of tumor treating fields (TTFs) improves median survival from 16 to 20.9 months. This modest improvement underscores the urgent need to identify a new treatment modality as standalone therapy. We have reported recently that brief 2 - 6 h of daily brain stimulation with a new noninvasive, non-contact, magnetic stimulation device causes &amp;gt;30% reduction of contrast-enhanced tumor (CET) volume in an end-stage recurrent GBM patient after a ~30-day treatment. Purpose: The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) and other cancer cells while sparing normal developing neurons and astrocytes in vitro. The spinning oscillating magnetic field (sOMF) generated by this device disrupts electron transport in the mitochondrial respiratory chain leading to a marked increase in reactive oxygen species (ROS) and consequent cancer cell death. However, the downstream molecular mechanism of sOMF action is under investigation. We studied the cellular and molecular effects of sOMF treatment on GBM cell lines and investigated the response to Oncomagnetic monotherapy (OMT) in a syngeneic mouse model. We treated LN229 and U87 GBM cells with sOMF with and without a sub-therapeutic dose of TMZ in vitro. To study the anticancer effect of sOMF in vivo, we developed syngeneic GBM tumors in BALB/c mice by stereotactic intracranial injection of GL261WT cells. Tumor growth was monitored periodically by MRI scans. Results: Our results showed that sOMF significantly reduce cell proliferation and cell survival in vitro. We observed that sOMF induces DNA damage and arrests cells in G1 phase of cell cycle. OMT of tumor-bearing mice using a whole-body sOMF stimulation method caused a substantial retardation of tumor growth and reduction of the contrast-enhanced tumor volume in 9.4 T MRI scans. OMT also showed significant increase in overall survival in these mice. Conclusion: These experiments contribute to unraveling the mechanism of action underlying the response to OMT in GBM and provide a strong rationale for a standalone Oncomagnetic therapy for GBM. Citation Format: Arvind Pandey, Shashank Hambarde, David S. Baskin, Santosh A. Helekar. Antitumor effect of oncomagnetic therapy in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 337.

EXTH-65. SYNERGISTIC ONCOLYTIC EFFECTS OF TEMOZOLOMIDE AND ONCOMAGNETIC THERAPIES IN GLIOBLASTOMA

Abstract The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) and other cancer cells while sparing normal developing neurons and astrocytes in vitro. We have reported that brief 2 – 6 h of daily Oncomagnetic brain stimulation causes &amp;gt;30% reduction of contrast-enhanced tumor (CET) volume in an end-stage recurrent GBM patient after a ~30-day treatment. We have evidence that the spinning oscillating magnetic fields (sOMF) generated by this device disrupts electron transport in the mitochondrial respiratory chain, at least in part by inhibiting the activity of Complex II succinate dehydrogenase, leading to a marked increase in reactive oxygen species (ROS) and consequent cancer cell death. Here, we further studied the cellular effects of sOMF treatment alone and in combination with Temozolomide (TMZ) on GBM cell lines with other methods and investigated the response to Oncomagnetic monotherapy (OMT) in a mouse GBM model. We treated LN229 and U87 GBM cells with sOMF with and without a sub-therapeutic dose of TMZ. To study the anticancer effect of sOMF in vivo, we developed syngeneic GBM tumors in BALB/c mice by stereotactic intracranial injection of GL261WT cells. Our results show that cytotoxic effects of sOMF or TMZ alone, as measured by the MTT assay and reduced cell survival, are significantly potentiated by combining the two treatments. OMT of tumor-bearing mice using a whole-body sOMF stimulation method causes substantial retardation of tumor growth and reduction of the CET volume in 9.4 T MRI scans. To study the molecular pathways involved in the treatment response we are mapping alterations in various key biomarkers in treated tumor tissues and comparing them with those in untreated controls. These experiments will unravel the molecular mechanism of action underlying the response to OMT in GBM and help develop a sound rationale for an effective therapeutic protocol.

INNV-12. REPRODUCIBLE REDUCTIONS OF CONTRAST-ENHANCED TUMOR VOLUMES IN TWO END-STAGE RECURRENT GLIOBLASTOMA PATIENTS WITH IN-HOME ONCOMAGNETIC MONOTHERAPY

Abstract A spinning oscillating magnetic field-generating device called the Oncomagnetic device selectively kills glioblastoma (GBM) cells. It produced &amp;gt; 30% shrinkage of a recurrent GBM tumor in an end-stage patient after &amp;lt; 5 weeks of Oncomagnetic treatment (OMT). We have now reproduced this treatment response with additional insights into device effectiveness in two more such patients undergoing compassionate use OMT. We provided OMT to a 55-year-old man with massive recurrent tumor regrowth and a 79-year-old woman with multifocal recurrent GBM showing rapid progression, with leptomeningeal spread in both cases. Both had failed standard of care chemoradiotherapy and in the former case had not tolerated Optune treatment. They received one 2-hour, two 2-hour and three 2-hour OMTs per day in the clinic on the first three days under the supervision of the treating physician. 3 2-hour daily treatments were continued subsequently at home. The first patient received a steroid drug along with OMT to control cerebral edema from the start. In the second patient it was added after 14 days while also reducing OMT to 2 hours a day because of significant evidence of edema. MRI scans were done periodically to assess the treatment response. Both patients tolerated OMT well with no serious adverse effects – for 7 months in the first patient, including four 2-hour treatments for the last 5 months, and for 2 months in the second patient. Their last MRI scans at Day 146 and Day 42 showed &amp;gt; 35% and &amp;gt; 91% reduction, respectively, in contrast-enhanced tumor volume compared to pre-OMT scans. A modified treatment response assessment mapping analysis showed substantial reductions in both necrotic and active tumor volumes. These findings strongly support the observations in our published single patient case report and provide firm grounds for proposing in-home OMT monotherapy as a safe and effective noninvasive treatment for GBM.

Patterns of Treatment Failure in PCNSL

<h3>Purpose/Objective(s)</h3> Primary CNS Lymphoma (PCNSL) is a rare and often fatal disease. Despite varied combinations of therapy with a backbone of high-dose methotrexate (HD-MTX), there remains no clear standard of care and treatment failure is a persistent challenge. This analysis evaluates factors that affect local disease control and patterns of failure. <h3>Materials/Methods</h3> Retrospective review of 95 consecutive patients with PCNSL pathologically confirmed from 2002 and 2021. The primary endpoints were Local Failure (LF) and pattern of first failure (distant only vs local). Univariate (UVA) and multivariate analyses (MVA) with backward selection at alpha of 0.2, Log-rank test and Cox proportional hazard models were used for time to event endpoints and associations with age, Karnofsky performance status (KPS; ≥70 vs <70), use of upfront WBRT, number of cycles of HD-MTX (≥6 vs 0-5), 1^st line chemo agents, type of surgery, and size of contrast-enhancing lesion(s) (≥14cc vs <14 cc). <h3>Results</h3> Most patients had KPS ≥70 (64.2%), were HIV negative (89.5%), and had no history of solid organ transplant (95.8%). Diagnosis was made by biopsy (73.7%) or resection (26.3%). 54.3% had <14 cc contrast-enhancing tumor volume (overall median 12.6 cc, range 0.5 - 67.8 cc). Of the 62 patients treated first line with at least 1 cycle of HD-MTX, 61.3% had HD-MTX + Rituximab (R). Of the 60 patients with evaluable CSF, 30.0% had positive cytology. IT chemotherapy (ITc) was administered to 12 patients (cytology positive for 5, negative for 4, and unknown for 3). WBRT for consolidation after chemotherapy used for 3 patients and as monotherapy for 9 patients with poor KPS. At 2-years, OS was 50%, PFS was 39%, and LF was 27%. For patients with progression (n=29), 7 had distant only progression while 5 had local and distant progression and 17 had local only progression. LF was numerically higher in patients with ≥14 cc tumors (2-yr LF 26% vs 42%, p=0.43). On MVA, hazard of LF was significantly associated with age (HR 1.08 per yr, 95% CI: 1.02-1.16, p=0.02), KPS (HR 0.10, 95% CI: 0.01-0.65, p=0.016), completion of at least 6 cycles HD-MTX (HR 0.10, 95% CI 0.03-0.34, p<0.01), and use of ITc (HR 0.03, 95% CI: 0.00-0.32, p<0.01). There were no significant associations with upfront WBRT (p=0.37), use of HD-MTX + R (p = 0.12), or type of surgery (p=0.94). On UVA, distant first failure trended to be significantly associated with age (p=0.06), ITc use (p=0.07), and size of lesion(s) (p=0.08). On MVA, distant only first failure was significantly associated with age (OR 0.91 per year, 95% CI: 0.83-0.99, p=0.04). <h3>Conclusion</h3> The majority of treatment failures were local only. LF of PCNSL was associated with not completing induction HD-MTX and not using ITc. There was no association with LF or type of first failure and use of WBRT or more aggressive surgery. Larger tumors trended to fail locally warranting further investigation as local disease can be devastating.

The longitudinal volumetric response of vestibular schwannomas after Gamma Knife radiosurgery.

Gamma Knife radiosurgery (GKRS) is an effective treatment for vestibular schwannomas (VSs) and has been used in > 100,000 cases worldwide. In the present study the authors sought to define the serial volumetric tumor response of Koos grade I-IV VS after radiosurgery. A total of 201 consecutive VS patients underwent GKRS at a single institution between 2015 and 2019. All patients had a minimum follow-up of 18 months and at least 2 interval postprocedure MRI scans. The contrast-enhanced tumor volumes were contoured manually and compared between pre- and post-GKRS imaging. The percentages of tumor volume change at 18 months (short-term follow-up) and up to 5 years after GKRS (long-term follow-up) were compared with the baseline tumor volume. An increase of 20% was considered a significant increase of tumor volume. Trends of tumor volume over time were assessed with linear models using time as a continuous variable. A test for linear trend was evaluated according to the initial Koos tumor classification. Koos grade II VS was the most frequently occurring tumor (n = 74, 36.8%), followed by grade III (n = 57, 28.4%), grade I (n = 41, 20.4%), and grade IV (n = 29, 14.4%). The mean tumor volume at the time of GKRS was 2.12 ± 2.82 cm3 (range 0.12-18.77 cm3) and the median margin dose was 12 Gy. Short-term follow-up revealed that tumor volumes transiently increased in 34.2% and 28.4% of patients at 6 and 18 months, respectively, regardless of Koos grade. Linear regression analysis of Koos grade II, III, and IV tumors showed a significant longitudinal volume decrease on long-term follow-up. At last follow-up (median 30 months, range 18-54 months), 19 patients (9.4%) showed a persistent increase of tumor volume. Five patients received additional management after GKRS. Although selected VS patients demonstrate an early and measurable transient volumetric increase after GKRS, > 90% have stable or reduced tumor volumes over an observed period of up to 5 years. Volumetric regression is most pronounced in Koos grade II, III, and IV tumors and may not be fully detectable until 3 years after GKRS.

Incidence, molecular characteristics, and imaging features of "clinically-defined pseudoprogression" in newly diagnosed glioblastoma treated with chemoradiation.

Pseudoprogression (PsP) remains an elusive and clinically important, yet ill-defined, phenomena that, generally, involves a period of early radiographic progression (enhancement) followed by a period of radiographic stability or regression. In the current study, we utilized data from the control arm of a phase III clinical trial in newly-diagnosed glioblastoma to explore imaging characteristics of "clinically-defined PsP", or early radiographic progression (PFS < 6months from chemoradiation) followed by a long post-progression residual overall survival (ROS > 12months). One hundred sixty-nine patients with newly-diagnosed GBM from the control arm of the AVAglio trial (NCT00943826) who presented with early radiographic progressive disease (PD) (< 6months) were included. Clinical characteristics, topographical patterns, and radiomic features were compared between newly-diagnosed GBM exhibiting early PD and early death (< 12-month ROS, "true PD") with those exhibiting early PD and a long residual survival (> 12-month ROS, "clinically-defined PsP"). "Clinically-defined PsP" occurred to 38.5% of patients with early PD, and was more associated with MGMT methylation (P = 0.02), younger age (P = 0.003), better neurological performance (P = 0.01), and lower contrast-enhancing tumor volume (P = 0.002) at baseline. GBM showing "true PD" occurred more frequently in the right internal capsule, thalamus, lentiform nucleus, and temporal lobe than those with "clinical PsP". Radiomic analysis predicted "clinical PsP" with > 70% accuracy on the validation dataset. Patients with early PD that eventually exhibit "clinically-defined PsP" have distinct clinical, molecular, and MRI characteristics. This information may be useful for treating clinicians to better understand the potential risks and outcome in patients exhibiting early radiographic changes following chemoradiation.

DIPG-48. MRI volumetric and machine learning based analyses predict survival outcome in pediatric diffuse midline glioma

INTRODUCTION: Diffuse midline glioma (DMG) is a fatal childhood CNS tumor. Magnetic resonance imaging (MRI) is the gold standard for DMG diagnosis and monitoring of response to therapy. Leveraging novel MRI analytical approaches, including volumetric and machine learning based analyses, may aid in the prediction of patient overall survival (OS) and help to identify high-risk cases. METHODS: T1- and T2-weighted MR images were retrospectively collected from children and young adults diagnosed with DMG (n=43). MRI features, including manually determined 3D tumor volume (T2), T1 contrast-enhancing tumor volume, T1 relative to T2 volume (T1/T2), tumor relative to whole brain volume, tumor average intensity, and tumor heterogeneity (i.e., intensity skewness and kurtosis), were evaluated at upfront diagnosis. MRI features were analyzed to identify significant predictors of OS outcome, which was defined as OS shorter, or longer, than one year from diagnosis. A support vector machine was used to predict OS outcomes using combinations of these features. RESULTS: The presence of T1 contrast-enhancing tumor at diagnosis (p=0.01), and a high T1/T2 ratio (>25%, p=0.009), predicted significantly shorter median OS. Moreover, feature selection identified T2 mean intensity (p<0.001), T2 image intensity skew (p=0.006), T1/T2 ratio (p=0.02), and T1 volume relative to whole brain (p=0.03) as significant predictors of OS outcome (short versus long). Combining T2 mean intensity, T2 image skew, T1 segment kurtosis and patient gender resulted in OS outcome prediction accuracy of 83.3% (sensitivity=85%, specificity=81.8%, n=42 cases).CONCLUSION: We have identified MRI volume and imaging features that significantly predict OS outcome in children diagnosed with DMG. Our findings provide a framework for incorporating MRI volumetric and machine learning analyses into the clinical setting, allowing for the customization of treatment based on tumor risk characteristics.

Impact of systemic therapy regimen on survival of PCNSL.

2070 Background: Primary CNS Lymphoma (PCNSL) is a rare and often fatal disease. Treatment includes multi-agent systemic therapy with a backbone of high-dose methotrexate (HD-MTX). Despite multiple drug and radiotherapy combinations for induction and consolidation treatment there remains no clear standard of care. The purpose of this analysis is to evaluate how varying treatment approaches impacted clinical outcomes at our institution. Methods: Data retrospectively collected for 95 consecutive patients with PCNSL pathologically confirmed from 2002 to 2021. Primary endpoint was OS with secondary endpoints of PFS and LC. Progression based on RANO criteria. Kaplan-Meier analyses, Log-rank test and Cox proportional hazard models used for time to event endpoints. MVA by backward selection applying an alpha of 0.2 for associations with 1st line chemo agents, number of cycles of HD-MTX (&gt;6 or 0-5), size of enhancing tumor at presentation, CSF cytology, type of surgery (biopsy, STR, or GTR), and use of WBRT. Results: Most patients had KPS &gt;70 (64.2%), were HIV negative (89.5%), and had no history of solid organ transplant (95.8%). Diagnosis was made by biopsy (73.7%) or resection (GTR 13.7%, STR 12.6%). 54.3% had &lt;14 cc contrast-enhancing tumor volume (median 12.6 cc, range 0.5 - 67.8 cc) and 48.6% had single enhancing lesion. Of the 62 patients treated first line with at least 1 cycle of HD-MTX, 61.3% were treated with HD-MTX + Rituximab (R) and 33.9% with HD-MTX + R + temozolomide (TMZ). With or after induction HD-MTX, 1-3 patients received one or a combination of cytarabine, thiotepa, procarbazine, vincristine, carmustine, or ASCT. Of the 60 patients with evaluable CSF, 30.0% had positive cytology. IT chemotherapy (ITc) was administered to 12 patients (5 with + cytology, 4 with - cytology, 3 with unknown cytology). WBRT for consolidation after chemotherapy used for 3 patients and as monotherapy for 9 patients. 2-year OS and PFS rate was 50.1% (95% CI 38.6%-60.5%) and 38.5% (95% CI 27.9%-49.0%). On MVA, &gt; 6 cycles of MTX was associated with superior OS, PFS, and LC. For patients receiving any chemotherapy, addition of R was associated with inferior OS while ITc was associated with improved OS, PFS, and LC (Table). There was no OS association on MVA with TMZ, GTR, consolidation WBRT, or size or number of initial lesions (p&gt;0.05). Conclusions: Completion of induction HD-MTX and use of ITc was associated with better outcomes in this population. Incorporation of R into 1st line therapy was associated with worse OS. Survival remained poor throughout the study period, underscoring importance of further innovation. [Table: see text]

341 SOncomagnetics: A Potential New Noninvasive Magnetic Stimulation Technology to Treat Glioblastoma

INTRODUCTION: A new noninvasive oscillating magnetic field (OMF)-generating device called Oncomagnetic (OM) device, developed in our laboratory, disrupts mitochondrial electron transport to elevate intracellular reactive oxygen species (ROS) levels in patient derived glioblastoma (GBM) cells. METHODS: GBM cell death, ROS elevation and caspase 3 activation were studied by bright-field and fluorescence microscopy involving specific fluorescent probes. Device treatment of FOXN1-Nude mice with GBM xenografts was for 4 hours twice a day. Treatment of a 53-year-old male patient with recurrent GBM was done under a compassionate use protocol for 2–6 hours each weekday. Contrast-enhanced MRI scans assessed tumor size. RESULTS: OMF caused selective death of GBM cells, but not normal human cortical neurons and astrocytes. It altered mitochondrial oxygen consumption, increased mitochondrial and cellular ROS, and activated caspase 3. The overall survival of xenografted mice was prolonged by 6 days with treatment. A 26-day device treatment was well tolerated by the patient and decreased contrast-enhanced tumor volume by &gt;30%. Patient’s autopsy after his death from closed head injury showed treatment effect, no tumor mass, and some evidence of active tumor. CONCLUSION: Noninvasive stimulation with the OM device is a potential powerful new treatment for GBM involving a novel mechanism of action.

Intracranial meningioma surveillance using volumetrics from T2-weighted MRI.

The gold standard for imaging of meningiomas is MRI with gadolinium-based contrast agent. Due to increased costs, time, and uncertain chronic effects of gadolinium exposure, use of noncontrast T2-weighted imaging (T2WI) in lieu of contrast-enhanced MRI has been an increasing focus of research across various diagnostic scenarios. The purpose of this study was to evaluate the diagnostic accuracy of T2WI in detecting changes in meningioma tumor volume. Imaging and clinical data were reviewed for 82 consecutive patients undergoing MR-surveillance of intracranial meningioma. Using volumetric-T2WI, two neuroradiologists independently calculated tumor volumes. Measurements were compared to a baseline study contrast-enhanced T1 tumor volume. Using contrast-enhanced sequences as the reference standard, statistical analysis was performed to determine the accuracy of T2WI in detecting changes of meningioma volume. Using only T2WI, readers detected meningioma volume change ≥ 20% in 19/82 patients and volume change <20% in 63/82 patients. Reader accuracy for detecting change in tumor volume on T2WI ≥ 20% was 0.85, sensitivity 0.65, specificity 0.93, positive predictive value (PPV) 0.79, and negative predictive value (NPV) 0.87. For meningiomas >1 ml, reader accuracy for detecting change in tumor volume on T2WI ≥20% was 0.90, sensitivity 0.78, specificity 0.95, PPV 0.88, and NPV 0.91. Change in tumor volume on T2WI ≥20% was detected with 100% accuracy for posterior fossa meningiomas. Inter-reader agreement for all meningiomas was moderate (κ = 0.45) improving to substantial agreement (κ = 0.77) with tumor volumes >1 ml. Volumetric-T2WI detects changes in meningioma volume with comparable accuracy to gold standard T1 postcontrast imaging, particularly with higher tumor volumes and posterior fossa locations.