Contrast-enhancing Tumor Research Articles

Radio-pathomic estimates of cellular growth kinetics predict survival in recurrent glioblastoma.

Aim: A radio-pathomic machine learning (ML) model has been developed to estimate tumor cell density, cytoplasm density (Cyt) and extracellular fluid density (ECF) from multimodal MR images and autopsy pathology. In this multicenter study, we implemented this model to test its ability to predict survival in patients with recurrent glioblastoma (rGBM) treated with chemotherapy.Methods: Pre- and post-contrast T1-weighted, FLAIR and ADC images were used to generate radio-pathomic maps for 51 patients with longitudinal pre- and post-treatment scans. Univariate and multivariate Cox regression analyses were used to test the influence of contrast-enhancing tumor volume, total cellularity, mean Cyt and mean ECF at baseline, immediately post-treatment and the pre- and post-treatment rate of change in volume and cellularity on overall survival (OS).Results: Smaller Cyt and larger ECF after treatment were significant predictors of OS, independent of tumor volume and other clinical prognostic factors (HR=3.23×10-6, p<0.001 and HR=2.39×105, p<0.001, respectively). Both post-treatment volumetric growth rate and the rate of change in cellularity were significantly correlated with OS (HR=1.17, p=0.003 and HR=1.14, p=0.01, respectively).Conclusion: Changes in histological characteristics estimated from a radio-pathomic ML model are a promising tool for evaluating treatment response and predicting outcome in rGBM.

NIMG-53. MRI-BASED RADIOMICS FOR DIFFERENTIATION BETWEEN PERIFOCAL EDEMA AND NON-CONTRAST-ENHANCING GLIOBLASTOMA FOCI

Abstract OBJECTIVE Various intracranial tumors can lead to the development of perifocal edema. Differentiating edema from tumor on MRI might be easy in metastases and meningiomas but can be challenging in patients with glioblastoma. We set out to compare and characterize perifocal edema and non-contrast-enhancing glioblastoma foci by means of radiomic feature analysis. METHODS In this single-center, retrospective study, patients with intracranial tumors and perifocal edema on preoperative T2/FLAIR-sequences were included. Patients diagnosed with brain metastasis, meningioma or glioblastoma were eligible. Tumor and edema volumes were semi-automatically segmented and extracted. After image registration, contrast-enhancing tumor and necrosis on T1-weighted sequences were subtracted from T2/FLAIR-hyperintense tumor and perifocal edema. Radiomic features were computed. Distribution of radiomic features were tested using the Shapiro-Wilk test. ANOVA or Kruskal-Wallis tests were applied to compare the features. Significant features were identified based on p-values (&amp;lt;0.05) and post-hoc Tukey’s Honest Significant Difference (HSD) tests were conducted. RESULTS The cohort comprised n=60 patients and was split in three groups according to histopathology (metastases, meningioma, glioblastoma). Each subgroup comprised n=20 patients (33.3%). 107 radiomic features of the T2-hyperintensity, after subtraction of contrast-enhancing tumor and necrosis, were tested for each patient. 18 radiomic features (17%) that mainly comprised measures of shape, texture and intensity distribution, e.g., sphericity (p&amp;lt;0.01), surface/volume (p&amp;lt;0.01), entropy (p&amp;lt;0.01), skewness (p&amp;lt;0.01) and kurtosis (p&amp;lt;0.01), showed no significant difference between metastases and meningiomas but differed significantly from the T2-hyperintensity of glioblastoma. The textual complexity of glioblastoma was significantly higher (p&amp;lt;0.01). CONCLUSION Radiomic feature analysis unraveled many features that might be helpful in differentiating perifocal edema from tumor infiltration. Future studies should aim at validating our results and further exploring the T2-hyperintensity of glioblastoma patients, e.g., suspected edema versus suspected tumor infiltration zone.

EPCO-51. A MULTI-OMIC ANALYSIS OF REGIONAL HETEROGENEITY IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most common malignant brain tumor in adults. A hallmark of GBM is its intratumoral heterogeneity as well as infiltration into the surrounding brain. The growing understanding of the cellular diversity and cellular state diversity within GBM necessitates a need for a more granular evaluation of the molecular landscape of this disease. This study aimed to investigate this using single cell RNA sequencing combined with single-cell ATAC sequencing and spatial transcriptomics in order to delineate cellular states and enriched pathways between malignant cells in different regions of GBM. The study cohort consisted of 15 patients with primary GBM. Tumor samples were taken at the time of surgical resection using intraoperative stereotactic navigation from three anatomically distinct locations: periphery – the cortex or white matter in the peri-tumoral region that is beyond contrast-enhancing tumor, border – the contrast-enhancing border of the tumor on T1-weighted MRI, and core - the hypointense core region on T1-weighted MRI. Samples underwent combined snRNA and ATAC sequencing (10x Multiome) as well as spatial transcriptomics (10x Visium). Single-nucleus RNA + ATAC sequencing captured a total of 37,547 neoplastic cells and 18,498 non-neoplastic cells within the tumor microenvironment. The majority of non-neoplastic cells were identified within the periphery alongside a distinct group of neoplastic cells that exhibited unique a unique distribution of malignant cellular state and differentially regulated genetic pathways compared to malignant cells within the tumor border and core. Gene regulatory analysis of the malignant cells in the periphery identified a previously undefined set of enriched transcription factors that are periphery-specific regulon drivers. Overall, this analysis sheds light on the genetic and epigenetic differences between malignant GBM cells based on their location and warrant further investigation into the biology and targetable aspects of the malignant cells that exist beyond the contrast-enhancing border of the tumor.

SURG-14. PATTERNS OF PROGRESSION OF TEMPORAL LOBE GLIOBLASTOMAS: EVIDENCE FOR THE ROLE OF TEMPORAL LOBECTOMY

Abstract Glioblastomas extend beyond the contrast-enhancing tumor, and supramaximal resections into non-enhancing (NE) tumor improves survival. Yet, supramaximal resection is difficult to achieve in most cases. For temporal lobe tumors, supramaximal anterior temporal lobe resection is feasible and safe. Case series have shown a survival advantage by resecting the anterior temporal lobe. This study aims to explore patterns of tumor progression in temporal lobe glioblastomas and whether the presence of NE tumor in the temporal tip could be used as a biomarker to predict the site of progression. We searched a single institution tumor database looking for patients who had glioblastomas in the temporal lobe, who underwent complete resection of enhancing tumor, and went on to have chemoradiotherapy. Patients needed to have imaging demonstrating first progression. We determined pre-operatively if NE tumor had extended into the temporal tip. At progression, the direction of tumor progression was recorded and assessed if it would have been resected should a lobectomy have been performed. We identified 55 patients that fulfilled our entry criteria (mean age 57.7 years, range 19.6-72.9; 37 male). In 16 cases, the anterior temporal lobe was resected; these patients were not used in further assessments. In 25 cases (64.1%), the tumor progressed into the residual anterior temporal lobe. In 16 cases (41.0%), a lobectomy would have encompassed the area of progression. NE tumor was seen in the tip in 28 cases (71.8%). This could predict progression into the anterior temporal lobe with a sensitivity of 76.2% (95%CI: 54.9-90.6%) and specificity of 33.1% (95%CI: 11.8-61.6%). The likelihood ratio of tumor progression was 1.14 (95%CI: 0.75-1.74). We conclude that temporal lobe glioblastomas most commonly progress into the anterior temporal lobe, but NE tumor is not a suitable predictive biomarker. Developing suitable biomarkers and biomarker-driven trials of temporal lobectomy for glioblastomas are needed.

SURG-29. EXTENDED RESECTION IMPROVES PATIENT SURVIVAL OUTCOMES AFTER GROSS-TOTAL RESECTION OF GLIOBLASTOMA

Abstract In recent years, the effectiveness of extended resection (ER) beyond the contrast-enhanced (CE) lesion has been reported as a surgical strategy for glioblastoma. This study was to determine whether ER of FLAIR-hyperintense area beyond the CE tumor affected the overall survival (OS) and progression-free survival (PFS) of patients with glioblastoma after gross-total resection (GTR). From October 2019 to March 2022, a total of 62 patients who underwent resection of glioblastoma (GBM) at Kobe University Hospital were retrospectively examined. Volumetric measurements of the CE area and surrounding FLAIR-hyperintense area were performed, and clinical variables related with OS and PFS were analyzed. In total, 33 patients with GBM who underwent GTR of the CE tumor met the inclusion criteria. The mean volume of CE tumor and FLAIR hyperintensity area before resection was 36.5 cm3 and 77.2 cm3 respectively. The mean excision rate of FLAIR-hyperintense area was 18.2%. Removal rates of 20% or more in the FLAIR-hyperintense region significantly increased OS and PFS (p=0.040 and 0.026, respectively). In multivariate analysis, age ≥ 65 years (HR 2.73; 95% CI 1.09–7.22; p=0.032) were associated with shorter OS, but ER ≥ 20% (HR 0.41; 95% CI 0.17–0.99; p=0.049) and MGMT promotor methylation (HR 0.36; 95% CI 0.15–0.85; p=0.020) were associated with longer OS. ER of FLAIR-hyperintense lesions of 20% or more in glioblastoma contributed to prolonging patient survival. It is necessary to validate the effect of ER in prospective clinical trials.

NIMG-35. IMPACT OF RESECTION AT TIME OF FIRST RECURRENCE IN WHO GRADE 2 IDH-MUTANT GLIOMAS

Abstract INTRODUCTION Maximal safe resection standard of care treatment of IDH-mutant gliomas and is associated with improved overall survival (OS). However, the impact of extent of resection (EOR) at first recurrence is not well established and there are no data on its impact on prognosis. METHODS We retrospectively collected clinical data on patients with IDH-mutant WHO grade 2 astrocytoma and oligodendroglioma treated at our institution from 1997 to 2023. To assess the impact of EOR at first recurrence, we excluded patients who exclusively underwent diagnostic biopsy. Dates of progression were determined by the treating neuro-oncologist or tumor board consensus. Volumetric measurements of contrast-enhancing (CE) tumor and total T2/FLAIR pre- and post second surgery were obtained with BrainLab SmartBrush tool. RESULTS One-hundred patients with recurrent astrocytoma and 35 patients with recurrent oligodendroglioma were identified, of whom 57 and 25, respectively, underwent a second resection and had imaging available for volumetric analysis. In patients with astrocytoma, 13/57 had CE at diagnosis, and 28/57 at first recurrence. EOR of T2/FLAIR and CE volume correlated with improved OS. In multivariate regression analyses, T2/FLAIR EOR at first recurrence correlated with improved OS adjusted for gender, preoperative T2/FLAIR volume, prior radiotherapy or chemotherapy, and initial CE (HR 0.977, p&amp;lt; 0.001). In patients with CE, contrast-EOR correlated with OS adjusted for gender, initial CE, preoperative contrast volume, and prior radiotherapy or chemotherapy (HR 0.929, p&amp;lt; 0.001). Conversely, in patients with WHO grade 2 oligodendroglioma, T2/FLAIR EOR did not significantly impact OS (EOR&amp;gt; 90% p= 0.92, EOR&amp;gt; 20% p= 0.13). Only 5/25 patients had CE at first recurrence precluding further analysis. CONCLUSIONS The EOR of CE and total FLAIR hyperintensity at first recurrence appears to positively impact prognosis in patients with WHO grade 2 astrocytoma but not in oligodendroglioma. These findings should be evaluated in prospective trials.

TMIC-24. BICARBONATE RECEPTOR SLC4A4 SENSITIZES INFILTRATING GLIOBLASTOMA CELLS TO CHANGES IN EXTRACELLULAR PH

Abstract BACKGROUND Glioblastoma progression involves changes in extracellular pH (pHe) related to rapid cell turnover and growth. There exist differences in pH between contrast-enhancing solid tumor and non-enhancing infiltrating tumor. SLC4A4 is a two-way bicarbonate transporter used in cortical astrocytes to buffer intracellular pH. METHODS In patients undergoing surgery for newly diagnosed IDH wild-type glioblastoma, we obtained tissue from solid tumor and infiltrating tumor. Single-nucleus RNA sequencing (n=15), immunohistochemistry (n=20) were carried out to identify SLC4A4 in infiltrating tumor beyond the contrast enhancing edge. SLC4A4 knock-down models were used to evaluate functional biology of this bicarbonate receptor using our tumor – cortical organoid model of infiltrating glioma and gliomaspheres. pH measurements were recorded using pH sensitive microelectrodes to evaluate changes on pH buffering ability of tumor cells during acid titration assays. RESULTS Single-nucleus RNA sequencing (n=15) and spatial RNA sequencing (n=3) showed SLC4A4 to be the highest expressed transmembrane receptor on infiltrating glioblastoma cells but not solid tumor. IHC (n=20) confirmed higher protein expression in infiltrating tumor (p=0.0390). Infiltrating cells were specifically sensitive to decreasing pHe (p=0.0105). In the infiltrating glioma cortical-organoid model, the slc4a4- had increased proliferation (GFP+ cell quantitation; n=10, p=0.0410). There was also increased proliferation in wild-type cells treated with SLC4A4 inhibitor DIDS (n=10, p=0.0016). Immunostaining of these models showed that downmodulation of SLC4A4 was associated with increased Ki67 and decreased caspase staining. CONCLUSIONS SLC4A4 plays a role in pH buffering in glioblastoma. We hypothesize that loss of SLC4A4 in solid tumor allows for desensitization of these cells to an acidic extracellular environment and allows for increased tumor growth and density while infiltrating tumor remains sensitivity to changes in pHe. An understand of pH regulation may lead to therapeutic efficacy through pH modulation of tumor.

NIMG-30. DEUTERIUM METABOLIC IMAGING (DMI) SHOWS A STRONG RELATION BETWEEN TUMOR GRADE AND GLUCOSE METABOLISM IN PRIMARY BRAIN TUMORS

Abstract BACKGROUND Metabolic imaging using FDG-PET is a key component of disease management in many cancers outside of the brain, but in brain tumors, it often shows low tumor-to-brain contrast because of high background signal from normal brain. Deuterium metabolic imaging (DMI) is a new 2H magnetic resonance spectroscopic imaging-based technique that when combined with administration of 2H-labeled glucose can provide high tumor-to-brain image contrast because it can detect downstream metabolism instead of only glucose uptake. In this observational study, DMI of glucose metabolism was performed in 22 patients with primary brain tumors of different grades, and at different disease stages. METHODS DMI data were acquired using a 4 tesla MRI scanner after oral administration of 0.75g/kg of [6,6’-2H2]-glucose in water. Metabolic maps were generated of 2H-labeled glucose, glutamate+glutamine (Glx), lactate (Lac), and Lac/(Lac+Glx), a proxy for the metabolic shift observed in many cancers known as the Warburg effect. Volumes of interest (VOI) based on contrast-enhancing and non-enhancing tumor regions were created using clinical MRIs and combined with DMI maps to generate tumor-specific values for Lac/(Lac+Glx). Eta-squared was calculated using tumor grade and Lac/(Lac+Glx) as independent and dependent variables; data are reported as mean±SD. Results – Tumor-to-brain image contrast for Lac/(Lac+Glx) was 2.57±0.93 for grade 4 (n=14), 1.74±0.75 for grade 3 (n=6) and 0.94±0.28 for grade 2 lesions (n=3). Lac/(Lac+Glx) was 0.36±0.13 for grade 4; 0.19±0.049 for grade 3; 0.09±0.042 for grade 2 lesions; and 0.14±0.043 for normal brain. Eta-squared between tumor grade and Lac/(Lac+Glx) was 0.52. CONCLUSIONS VOI-based analysis showed a high dependence of metabolism-specific image contrast to tumor grade. The apparent relation between lesion grade and Lac/(Lac+Glx) indicates the potential of DMI to complement anatomical MRI and possibly provide a valuable biomarker indicating active tumor tissue and could improve evaluating disease progression.

NIMG-37. “SYNTHETIC” PERFUSION MRI WITH ADJUSTABLE ACQUISITION PARAMETERS IN BRAIN TUMORS USING DYNAMIC SPIN-AND-GRADIENT-ECHO ECHOPLANAR IMAGING

Abstract INTRODUCTION Dynamic susceptibility contrast (DSC) perfusion MRI can assess normalized relative cerebral blood volume (nrCBV) and percentage of signal recovery (PSR) in brain tumors, which can aid in differential diagnosis, molecular profiling, and identification of disease progression. However, CBV-optimized and PSR-optimized protocols differ in terms of acquisition parameters. Additionally, DSC dependency on acquisition parameters limits the universalizability of diagnostic cutoffs for nrCBV and PSR across institutions and scanners. This study aims to generate “synthetic” DSC datasets with adjustable synthetic acquisition parameters using dynamic spin-and-gradient-echo echoplanar imaging (dynamic SAGE-EPI) to: 1) simultaneously generate nrCBV and PSR with optimal acquisition parameters, 2) compare DSC datasets with heterogeneous external cohorts. METHODS Thirty-eight patients with contrast-enhancing brain tumors were prospectively imaged with dynamic SAGE-EPI during a non-preloaded single-dose contrast injection. Multiple synthetic DSC datasets with desired pulse sequence parameters were generated using the Bloch equations applied to the dual-echo gradient-echo (GE) data extracted from dynamic SAGE-EPI datasets, with or without optional preload simulation. For each patient, synthetic protocols were set to match guideline-compliant CBV-optimized protocols, PSR-optimized protocols, and protocols used in external cohorts from the literature, for comparison. RESULTS Dynamic SAGE-EPI allowed for simultaneous generation of CBV-optimized and PSR-optimized DSC datasets with a single contrast injection. Conversely, suboptimal PSR computation from guideline-compliant CBV-optimized protocols resulted in rank variations within the cohort (Spearman’s ρ=0.83-0.89, i.e. 31%-21% rank variation). Treatment-naïve glioblastoma exhibited lower parameter-matched PSR compared to the external cohorts of treatment-naïve primary CNS lymphomas (PCNSL) (p&amp;lt;0.0001), supporting a role of synthetic DSC for multicenter comparisons. CONCLUSIONS Dynamic SAGE-EPI allows for simultaneous generation of CBV-optimized and PSR-optimized DSC data with a single injection, facilitating use of a single perfusion protocol for all DSC applications. This approach may also be useful for comparisons of perfusion parameters across heterogeneous multicenter datasets.

ANGI-11. SEX DIFFERENCES IN SOX2 GLIOBLASTOMA EXPRESSION OUTSIDE MRI-DEFINED CONTRAST ENHANCEMENT AT AUTOPSY

Abstract INTRODUCTION Sex-determining region Y-box 2 (SOX2) has recently been used as a marker for pluripotency to identify cellular glioblastoma invasion pathologically. This can be used to identify areas of tumor invasion consisting of sparse individual cells, likely highlighting the furthest margin of tumor invasion. This study aligned large format SOX2 stained tissue samples to conventional MRI to determine demographic factors that impact the presence of SOX2 positive invasion outside the T1 contrast-enhanced tumor margin. METHODS The cohort for this study consisted of 36 IDH-wildtype glioblastoma patients (23 male, 13 female, mean age=61.9). Tissue samples from areas of suspected tumor invasion and normal tissue were collected at autopsy, stained for SOX2, digitized at 40X resolution, and automatically segmented for SOX2 positive staining cell percent (SOX2+%) at MR resolution using a color deconvolution algorithm. Contrast enhanced T1 scans from acquisitions close to death were annotated manually for tumor presence and aligned to the T2-weighted FLAIR image. Tissue data was then aligned to MR images using a custom in-house software that relies on manually defined control points to generate a nonlinear transform that warps tissue into MR space while correcting for tissue shrinkage. Mean SOX2+% was computed for each patient outside of contrast enhancement and compared across age and sex as demographic factors. RESULTS Males were found to have a higher SOX2+% than females outside contrast enhancement (t=2.09, p=0.045), while no association with age was observed (r=0.146, p=0.397). CONCLUSIONS Sex differences were observed for non-enhancing SOX2 positivity, which may relate to the more aggressive tumors identified in male patients in some studies. Further research into the mechanisms behind sex differences in tumor growth patterns and molecular characteristics impacting the infiltration of tumor beyond the MR defined region is needed.

DDDR-05. SPATIALLY RESOLVED DRUG SENSITIVITY PROFILING IN GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma is the most common malignant primary brain tumor in adults, characterized by poor overall survival and an urgent need for more effective treatment strategies. Macroscopic heterogeneity, as observed through MR imaging, divides the tumor into distinct regions: a tumor-cell dense contrast-enhancing tumor core and a non-contrast-enhancing infiltration zone that appears hyperintense on T2/FLAIR imaging. The infiltration zone contains both infiltrating tumor cells and non-malignant cells from the local brain microenvironment. Although genomic and transcriptomic differences between the tumor core and the infiltration zone have been reported, functional differences, such as differential drug sensitivities, remain largely unknown. METHODS To investigate this, we collected region-specific glioblastoma patient tissue samples from both the contrast-enhancing tumor core and the non-contrast-enhancing but 5-aminolevulinic acid (5-ALA) fluorescent infiltration zone during surgery. Using pharmacoscopy, a microscopy-based single-cell drug screening platform, we assessed drug responses across regions and patients. RESULTS To determine whether drug responses within a single tumor region were more similar compared to responses across different regions we collected multiple tissue samples from each tumor region in seven patients. We identified region-specific drug responses for temozolomide and lomustine, among other drugs, in some of the patients. However, drug sensitivities were not consistent within the same region across different patients. Thus, across patients, the region-specific drug responses were obscured by patient heterogeneity. To address intra- and inter-tumor drug response heterogeneity, we developed a complementarity score based on region-specific drug response data of 60 drugs across 23 paired samples. The complementarity score identified promising drug combinations that demonstrated strong anti-tumor activity across tumor regions and patients. CONCLUSIONS Monotherapy approaches have largely failed in glioblastoma, despite extensive molecular profiling efforts aimed at identifying tumor-specific vulnerabilities. Identifying drug combinations that synergistically target the locoregional heterogeneity of glioblastoma may open up new avenues of personalized therapy.

NIMG-73. FALSE POSITIVE INTRA-OPERATIVE MAGNETIC RESONANCE IMAGING DURING HIGH GRADE GLIOMA RESECTION

Abstract Intraoperative magnetic resonance imaging (iMRI) allows assessment of extent of resection during surgery for high-grade glioma (HGG). In most cases, contrast-enhancing areas noted on iMRI indicate residual tumor. However, false positives may occur, leading to inappropriate additional resection and patient morbidity. The rate and pattern of false positive findings in iMRI have not been fully described. We analyzed surgical and imaging findings in patients undergoing iMRI during resection of HGG to determine factors linked with potential false positive contrast enhancement. A single-center analysis retrospectively assessed consecutive patients undergoing resection of newly diagnosed high-grade glioma using iMRI guidance. Preoperative, intraoperative and postoperative imaging, as well as pathologic findings were assessed. One hundred seventy-four consecutive patients who underwent surgery from 2016-2023 were included. All patients had preoperative MRI showing contrast-enhancing tumor and all underwent one iMRI during surgery to assess extent of resection. 124/174 cases (71.3%) demonstrated contrast enhancement on iMRI that prompted inspection and additional resection using updated neuronavigation. Enhancement corresponding to residual tumor was identified with or without additional removal in 120/124 cases (96.8%). No residual tumor was found in 4/124 cases (3.2%, false positives). All false positive cases were the result of contrast accumulation in hematomas (2), hemostatic agents (1) or dependent portions of the resection cavity (1). Both hematomas were located in the walls of the resection cavity and confirmed as hematoma, rather than tumor, by separate pathology analysis. False positives were not associated with patient positioning, tumor sub-type, anatomic location of tumor or extent of resection. Gross total resection (GTR) was confirmed in 163/174 (93.7%) cases on postoperative imaging. False-positive iMRI during HGG surgery can mimic residual tumor. This occurs at a low rate due to contrast pooling in the cavity or accumulation within hemostatic agents or hematomas along the cavity wall. Meticulous hemostasis when preparing the patient for iMRI may help prevent false positives and prevent unnecessary additional resection.

CSIG-04. ANTI-TUMOR 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. We studied the cellular and molecular effects of Oncomagnetic monotherapy (OMT) on GBM cell lines and investigated immune response in a syngeneic mouse model. RESULTS OMT significantly reduces cell proliferation and cell survival in vitro. OMT induces persistent ROS primarily by increasing superoxide level in cancer cells and reduces mitochondrial-membrane potential in GBM cells. It also induces DNA damage and arrests cells in G1-phase of the cell cycle. Whole-body Oncomagnetic 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 OMT-treated GBM 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 OMT stimulation and provide a strong rationale for standalone OMT for GBM.

Diagnostic performance of fast brain MRI compared to routine clinical MRI in patients with glioma grade 3 and 4 -a pilot study.

EPIMix is a fast brain MRI technique not previously investigated in patients with glioma grades 3 and 4. This pilot study aimed to investigate the diagnostic performance of EPIMix in the radiological treatment evaluation of adult patients with glioma grades 3 and 4 compared to routine clinical MRI (rcMRI). Patients with glioma grades 3 and 4 investigated with rcMRI and EPIMix were retrospectively included in the study. Three readers (R1-3) participated in the radiological assessment applying Response Assessment for Neuro-oncology Criteria (RANO 2.0), of which two (R1-2) independently evaluated EPIMix and later rcMRI by measuring contrast-enhancing and non-contrastenhancing tumor regions at each follow-up. For cases with discrepant evaluations, an unblinded side-by-side (EPIMix and rcMRI) reading was performed together with a third reader (R3). Comparisons between methods (EPIMix vs. rcMRI) were performed using Weighted Cohen's kappa. The sensitivity and specificity to detect tumor progression (PD) on a follow-up scan were calculated for EPIMix compared to rcMRI with receiver operating characteristic (ROC) curves to assess the area under the curve (AUC). In 35 patients (mean age 53, 31% females), a total of 93 MRIs encompassing 58 follow-up investigations showed PD at blinded reading in 33% of EPIMix (19/58, R1-2), while in 31% (18/58 exams, R1), and 34% (20/58 exams, R2) of rcMRI. An almost perfect agreement for tumor category assessment was found between EPIMix and rcMRI (EPIMixR1 vs. rcMRIR1 ϰ= 0.96; EPIMixR2 vs. rcMRIR2 ϰ= 0.89). The sensitivity for EPIMix to detect PD was 1.00 (0.81-1.00) for R1 and 0.90 (0.68-0.99) for R2, while the specificity was 0.97 (0.86-1.00) for R1-2. The AUC for PD was 0.99 for R1 (EPIMixR1 vs. rcMRIR1) and 0.94 for R2 (EPIMixR2 vs. rcMRIR2), DeLong's test AUCR1 vs. AUCR2 p=0.20 (R1-2). In this pilot study, EPIMix was used as a fast MRI alternative for treatment evaluation of patients with glioma grades 3 and 4, with high, but slightly lower diagnostic performance than rcMRI. CR = complete response; EPIMix = multi-contrast echo-planar imaging-based technique; PD = progressive disease; PR = partial response; RANO = response assessment in neuro-oncology; R1 = reader 1; R2 = reader 2; R3 = reader 3; rcMRI = routine clinical MRI; SD = stable disease.

Pathological tissue changes in brain tumors affect the pH-sensitivity of the T1-corrected apparent exchange dependent relaxation (AREX) of the amide protons.

Measuring the intracellular pH (pHi) is of interest for brain tumor diagnostics. Common metrics of CEST imaging like the amide proton transfer-weighted (APTw) MTRasym are pHi sensitive and allow differentiating malignant tumor from healthy tissue. Yet, the image contrast also depends on additional magnetization transfer effects and T1. In contrast, the apparent exchange-dependent relaxation (AREX) provides a T1 corrected exchange rate of the amide protons. As AREX still depends on amide proton density, its pHi sensitivity remains ambiguous. Hence, we conducted this study to assess the influence of pathologic tissue changes on the pHi sensitivity of AREX in vivo. Patients with newly diagnosed intra-axial brain tumors were prospectively recruited and underwent conventional MRI, quantitative T1 relaxometry, APT-CEST and 31P-MRS on a 3T MRI scanner. Tumors were segmented into contrast-enhancing tumor (CE), surrounding T2 hyperintensity (T2-H) and contralateral normal appearing white matter (CNAWM). T1 mapping and APT-CEST metrics were correlated with 31P-MRS-derived pHi maps (Pearson's correlation). Without differentiating tissue subtypes, pHi did not only correlate significantly with MTRasym (r= 0.46) but also with T1 (r= 0.49). Conversely, AREX only correlated poorly with pHi (r= 0.17). Analyzing different tissue subtypes separately revealed a tissue dependency of the pHi sensitivity of AREX with a significant correlation (r= 0.6) in CNAWM and no correlation in T2-H or CE (r= -0.11/-0.24). CE showed significantly increased MTRasym, pHi, and T1 compared with CNAWM (p< 0.001). In our study, the pHi sensitivity of AREX was limited to CNAWM. The lack of sensitivity in CE and T2-H is probably attributable to altered amide and water proton concentrations in these tissues. Conversely, the correlation of pHi with MTRasym may be explained by the coincidental contrast increase through increased T1 and amide proton density. Therefore, limited structural deviations from CNAWM might be a perquisite for the use of CEST contrasts as pHi-marker.

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.

Clinicopathological characteristics of unicentric Castleman disease: A single-center experience of 12 patients

BackgroundCastleman disease (CD) is an uncommon lymphoproliferative disorder with distinct pathological characteristics. Unicentric Castleman disease (UCD) presents as a single lymph node enlargement, often without significant symptoms. Complete surgical resection is the standard treatment for UCD. This study aimed to explore the clinicopathological features of UCD in a Taiwanese population. MethodsWe retrospectively identified 12 patients with UCD who had undergone surgical treatment between January 1, 2006 and June 30, 2022 at the National Taiwan University Hospital. Clinical and radiological findings were retrieved from medical records. All available pathological slides were reviewed. ResultsThe patients’ mean age was 38.1 years (range, 17 to 69); five (41.7%) were male, and seven (58.3%) were female. Nearly all cases of UCD were in the mediastinum, except for one case in the neck. Most patients were asymptomatic and without abnormal laboratory test results. Computed tomography revealed well-defined tumor borders, contrast enhancement, and occasional calcification. Ten patients underwent en bloc tumor resection, while the remaining two underwent partial resection. Among them, seven (58.3%) underwent video-assisted thoracoscopic surgery (VATS), and four (33.3%) underwent thoracotomy. The mean follow-up duration was 92 months. The patients who underwent total resection had no recurrence. ConclusionDetailed clinicopathological information on UCD in the Taiwanese population is present in our article. Both complete and partial surgery are effective for treatment. VATS may be preferred over thoracotomy due to less operative time and bleeding.

Awake Surgery for Right Frontal Lobe Glioma: Preserving Emotional Recognition and Facilitating Early Return to Work.

Many glioma patients struggle to return to work after surgery because of higher brain dysfunction. Although the right frontal lobe has historically been considered functionally silent, reports of performing awake surgery to evaluate higher brain functions in patients with tumors in this area have increased. We present two cases of patients who underwent awake surgery for malignant glioma in the right frontal lobe to preserve emotional recognition and facilitate an early return to work. Case 1 was a 48-year-old right-handed woman employed as a nursery school teacher and case 2 was a 21-year-old right-handed man employed in sales. Both had contrast-enhancing right frontal lobe tumors exhibiting high signal intensity on fluid attenuated inversion recovery imaging and underwent awake surgery. During the operation, cortical mapping was performed using the Reading the Mind in the Eyes, calculation, and motor tasks. Resection of sites involved in motor and emotional recognition functions was avoided. In case 1, all regions of high signal intensity were completely resected; in case 2, all regions exhibiting enhancement were resected. Both patients were discharged home without neurological deficits and returned to work within 21 days after surgery. It may be important to focus not only on overall survival and progression-free survival in glioma patients, but also on factors associated with life satisfaction, such as time to return to work after surgery and time until work becomes difficult. Awake surgery aimed at preserving higher brain functions is useful and may also improve life satisfaction.

Determinants of long-term survival in patients with IDH-mutant gliomas.

Survival times of patients with IDH-mutant gliomas are variable and can extend to decades. Many studies provide progression-free rather than overall survival times and prognostic factors remain ill-defined. Here we explored characteristics of short- and long-term survivors within a cohort of patients with extended follow-up. This single-center, case-control study included 86 patients diagnosed between 1998 and 2023 who either died within 6 years after diagnosis or survived at least 15 years. Patient characteristics and prognostic factors were stratified by short- (< 6 years) versus long-term (≥ 15 years) survival. Forty-seven patients (55%) diagnosed with astrocytoma and 39 patients (45%) with oligodendroglioma were included retrospectively. Median follow-up of the survivors was 16.6 years (range 15-28.9). Thirty-four deaths (40%) had been reported at database closure. Long-term survival was associated with CNS WHO grade 2 (p < 0.01), smaller tumor volumes (p = 0.01), lack of contrast enhancement (p < 0.01), wait-and-scan strategies (p < 0.01) and female sex (p = 0.04). In multivariate analyses for oligodendroglioma, larger T2 tumor volumes were associated with shorter survival (HR 1.02; 95% CI 1.01-1.05; p = 0.04). In patients with astrocytoma, lack of contrast enhancement (HR 0.38; 95% CI 0.15-0.94; p = 0.04) and wait-and-scan strategies (HR 5.75; 95% CI 1.66-26.61; p = 0.01) were associated with longer survival. Large T2 tumor volume and contrast enhancement may be important risk factors for shorter survival, while age might be of lesser importance. Wait-and-scan strategies may yield excellent long-term survival in some patients with astrocytoma.

Quantifying extent of meningioma preoperative embolization through volumetric analysis: A retrospective case series.

Endovascular embolization is an adjunct to meningioma resection. Isolating the effectiveness of embolization is difficult as MR imaging is typically performed before embolization and after resection, and volumetric assessment of embolization on 2D angiographic imaging is challenging. We investigated the correlation between 2D angiographic and 3D MR measurements of meningioma devascularization following embolization. We implemented a protocol for postembolization, preresection MRI. Angiographic devascularization was graded according to reduction of tumor blush from 1 (partial embolization) to 4 (complete embolization with no residual circulation supply). Volumetric extent of embolization was quantified as the percent of tumor contrast enhancement lost following embolization. Tumor embolization was analyzed according to tumor location and vascular supply. Thirty consecutive patients met inclusionary criteria. Grade 1 devascularization was achieved in 7% of patients, grade 2 in 43%, grade 3 in 20%, and grade 4 in 30%. Average extent of embolization was 37 ± 6%. Extent of tumor embolization was low (<25%) in 40%, moderate (25%-75%) in 40%, and high (>75%) in 20% of patients. Convexity, parasagittal/falcine and sphenoid wing tumors were found to have distinct vascular supply patterns and extent of embolization. Angiographic devascularization grade was significantly correlated with volumetric extent of tumor embolization (p < 0.001, r = 0.758). This is the first study to implement postembolization, preoperative MRI to assess extent of embolization prior to meningioma resection. The study demonstrates that volumetric assessment of contrast reduction following embolization provides a quantitative and spatially resolved framework for assessing extent of tumor embolization.