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The aim of this study was to design a predictive radiobiological model of normal brain tissue in low-grade glioma following radiotherapy based on imaging and molecular biomarkers. Fifteen patients with primary brain tumors prospectively participated in this study and underwent radiation therapy. Magnetic resonance imaging (MRI) was obtained from the patients, including T1- and T2-weighted imaging and diffusion tensor imaging (DTI), and a generalized equivalent dose (gEUD) was calculated. The radiobiological model of the normal tissue complication probability (NTCP) was performed using the variables gEUD; axial diffusivity (AD) and radial diffusivity (RD) of the corpus callosum; and serum protein S100B by univariate and multivariate logistic regression XLIIIrd Sir Peter Freyer Memorial Lecture and Surgical Symposium (2018). Changes in AD, RD, and S100B from baseline up to the 6 months after treatment had an increasing trend and were significant in some time points (P-value < 0.05). The model resulting from RD changes in the 6 months after treatment was significantly more predictable of necrosis than other univariate models. The bivariate model combining RD changes in Gy40 dose-volume and gEUD, as well as the trivariate model obtained using gEUD, RD, and S100B, had a higher predictive value among multivariate models at the sixth month of the treatment. Changes in RD diffusion indices and in serum protein S100B value were used in the early-delayed stage as reliable biomarkers for predicting late-delayed damage (necrosis) caused by radiation in the corpus callosum. Current findings could pave the way for intervention therapies to delay the severity of damage to white matter structures, minimize cognitive impairment, and improve the quality of life of patients with low-grade glioma., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Importance: This report illustrates a case of a low-grade glioma that showed significant disease progression during pregnancy, and then subsequent regression spontaneously in the postpartum period without treatment. This is a rare case of spontaneous glioma regression in the postpartum period, and may suggest underlying mechanisms of hormonal influences upon glioma progression., Clinical Presentation: The patient is a 27-yr-old female who underwent placement of a right-sided ventriculoperitoneal shunt for aqueductal stenosis at 8 wk of age. At the age of 24 yr, she was evaluated for chronic headaches and was found on magnetic resonance imaging (MRI) for the first time to have a small nonenhancing tectal glioma that remained stable on follow-up MRI. At the age of 25 yr, she returned for annual follow-up after giving birth and reported a significant increase in headache frequency and severity during the pregnancy. Repeat imaging now showed a larger, contrast-enhancing lesion. A decision was made to pursue radiosurgery, but during the pretreatment planning phase, the lesion and symptoms regressed spontaneously, and the lesion has remained stable on repeat MRI studies over a 30-mo period since delivery of her child., Conclusion: A young woman with a tectal glioma developed symptomatic disease progression during pregnancy, and subsequently had regression of the lesion and symptoms in the postpartum period without treatment. This case supports watchful waiting in select cases and suggests a potential role of hormones in glioma progression., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Noninvasive imaging methods are sought to objectively predict early response to therapy for high-grade glioma tumors. Quantitative metrics derived from diffusion-weighted imaging, such as apparent diffusion coefficient (ADC), have previously shown promise when used in combination with voxel-based analysis reflecting regional changes. The functional diffusion mapping (fDM) metric is hypothesized to be associated with volume of tumor exhibiting an increasing ADC owing to effective therapeutic action. In this work, the reference fDM-predicted survival (from previous study) for 3 weeks from treatment initiation (midtreatment) is compared to multiple histogram-based metrics using Kaplan-Meier estimator for 80 glioma patients stratified to responders and nonresponders based on the population median value for the given metric. The ADC histogram metric reflecting reduction in midtreatment volume of solid tumor (ADC < 1.25 × 10 -3 mm 2 /s) by >8% population-median with respect to pretreatment is found to have the same predictive power as the reference fDM of increasing midtreatment ADC volume above 4%. This study establishes the level of correlation between fDM increase and low-ADC tumor volume shrinkage for prediction of early response to radiation therapy in patients with glioma malignancies.

During the 6 month period following chemoradiotherapy, gliomas frequently develop new areas of contrast enhancement, which are due to treatment effect rather than tumor progression. We sought to characterize this phenomenon in oligodendrogliomas (OG) and mixed oligoastrocytomas (MOA). We reviewed the imaging findings from 143 patients with a WHO grade II or III OG or MOA for evidence of pseudoprogression (PsP) or early tumor progression. We characterized these cases for 1p/19q codeletions by FISH, IDH1 R132H mutation by immunohistochemistry, and TP53, ATRX, and EGFR mutations by next generation sequencing. We then reviewed the pathologic specimens of the patient cases in which a re-resection was performed. We found that OG and MOA that are 1p/19q intact developed PsP at a higher rate than tumors that are 1p/19q codeleted (27 vs. 8 %). Moreover, IDH1 wild-type (WT) tumors developed PsP at a higher rate than IDH1 R132H cases (27 vs. 11 %). Patients with ATRX or TP53 mutations developed PsP at an intermediate rate of 21 %. Ten patients in our cohort underwent a re-resection for early contrast enhancement; these tumors were predominantly 1p/19q intact (90 %) and had a low rate of IDH1 R132H mutation (50 %). 8 of 10 tumors demonstrated primarily treatment effects, while the remaining 2 of 10 demonstrated recurrent/residual tumor of the same grade. Early contrast enhancement that develops during the first 6 months after chemoradiotherapy is typically due to PsP and occurs primarily in OG and MOA that are 1p/19q intact and IDH WT.

Purpose: To evaluate the tolerability and efficacy of gemcitabine plus radiation therapy (RT) in this phase 1 study of patients with newly diagnosed malignant glioma (HGG)., Patients and Methods: Between 2004 and 2012, 29 adults with HGG were enrolled. After any extent of resection, RT (60 Gy over 6 weeks) was given concurrent with escalating doses of weekly gemcitabine. Using a time-to-event continual reassessment method, 5 dose levels were evaluated starting at 500 mg/m(2) during the last 2 weeks of RT and advanced stepwise into earlier weeks. The primary objective was to determine the recommended phase 2 dose of gemcitabine plus RT. Secondary objectives included progression-free survival, overall survival (OS), and long-term toxicity., Results: Median follow-up was 38.1 months (range, 8.9-117.5 months); 24 patients were evaluable for toxicity. After 2005 when standard practice changed, patients with World Health Organization grade 4 tumors were no longer enrolled. Median progression-free survival for 22 patients with grade 3 tumors was 26.0 months (95% confidence interval [CI] 15.6-inestimable), and OS was 48.5 months (95% CI 26.8-inestimable). In 4 IDH mutated, 1p/19q codeleted patients, no failures occurred, with all but 1 alive at time of last follow-up. Seven with IDH mutated, non-codeleted tumors with ATRX loss had intermediate OS of 73.5 months (95% CI 32.8-inestimable). Six nonmutated, non-codeleted patients had a median OS of 26.5 months (95% CI 25.4-inestimable). The recommended phase 2 dose of gemcitabine plus RT was 750 mg/m(2)/wk given the last 4 weeks of RT. Dose reductions were most commonly due to grade 3 neutropenia; no grade 4 or 5 toxicities were seen., Conclusions: Gemcitabine concurrent with RT is well-tolerated and yields promising outcomes, including in patients with adverse molecular features. It is a candidate for further study, particularly for poor-prognosis patient subgroups with HGG., (Published by Elsevier Inc.)

Background: Diffusion MRI, although having the potential to be a biomarker for early assessment of tumor response to therapy, could be confounded by edema and necrosis in or near the brain tumors. This study aimed to develop and investigate the ability of the diffusion abnormality index (DAI) to be a new imaging biomarker for early assessment of brain metastasis response to radiation therapy (RT)., Methods: Patients with either radiosensitive or radioresistant brain metastases that were treated by whole brain RT alone or combined with bortezomib as a radiation sensitizer had diffusion-weighted (DW) MRI pre-RT and 2 weeks (2W) after starting RT. A patient-specific diffusion abnormality probability function (DAProF) was created to account for abnormal low and high apparent diffusion coefficients differently, reflecting respective high cellularity and edema/necrosis. The DAI of a lesion was then calculated by the integral of DAProF-weighted tumor apparent diffusion coefficient histogram. The changes in DAI from pre-RT to 2W were evaluated for differentiating the responsive, stable, and progressive tumors and compared with the changes in gross tumor volume and conventional diffusion metrics during the same time interval., Results: In lesions treated with whole brain RT, the DAI performed the best among all metrics in predicting the posttreatment response of brain metastases to RT. In lesions treated with whole brain RT + bortezomib, although DAI was the best predictor, the performance of all metrics worsened compared with the first group., Conclusions: The ability of DAI for early assessment of brain metastasis response to RT depends upon treatment regimes.

Although the addition of concurrent and adjuvant temozolomide (TMZ) to standard-dose radiation (60 Gy) improves survival, the pattern of failure continues to be local. Conventional contrast enhanced T1-weighted and T2-weighted magnetic resonance imaging (MRI) used for radiation planning reflect anatomic rather than molecular or functional, properties of the tumor. Functional and metabolic MRI and positron emission tomography are able to detect metabolic and functional abnormalities beyond the tumor volume seen on conventional MRI, assess early response to treatment, and delineate the regions of high risks for failure in high-grade gliomas. This article focuses on the potential of these functional and metabolic imaging techniques to refine our clinical target volumes.

Purpose: To determine whether early assessment of cerebral microvessel injury can predict late neurocognitive dysfunction after brain radiation therapy (RT)., Experimental Design: Ten patients who underwent partial brain RT participated in a prospective dynamic contrast-enhanced magnetic resonance imaging (MRI) study. Dynamic contrast-enhanced MRI was acquired prior to, at weeks 3 and 6 during, and 1 and 6 months after RT. Neuropsychological tests were done pre-RT and at the post-RT MRI follow-ups. The correlations between early delayed changes in neurocognitive functions and early changes in vascular variables during RT were analyzed., Results: No patients had tumor progression up to 6 months after RT. Vascular volumes and blood-brain barrier (BBB) permeability increased significantly in the high-dose regions during RT by 11% and 52% (P<0.05), respectively, followed by a decrease after RT. Changes in both vascular volume and BBB permeability correlated with the doses accumulated at the time of scans at weeks 3 and 6 during RT and 1 month after RT (P<0.03). Changes in verbal learning scores 6 months after RT were significantly correlated with changes in vascular volumes of left temporal (P<0.02) and frontal lobes (P<0.03), and changes in BBB permeability of left frontal lobes during RT (P<0.007). A similar correlation was found between recall scores and BBB permeability., Conclusion: Our data suggest that the early changes in cerebral vasculature may predict delayed alterations in verbal learning and total recall, which are important components of neurocognitive function. Additional studies are required for validation of these findings.

Purpose: To quantify the radiation-induced changes in normal-appearing white matter before, during, and after radiotherapy (RT) in cerebral tumor patients., Methods and Materials: Twenty-five patients with low-grade glioma, high-grade glioma, or benign tumor treated with RT were studied using diffusion tensor magnetic resonance imaging. The biologically corrected doses ranged from 50 to 81 Gy. The temporal changes were assessed before, during, and to 45 weeks after the start of RT. The mean diffusivity of water (), fractional anisotropy of diffusion, diffusivity perpendicular (lambdaperpendicular) and parallel (lambda||) to white matter fibers were calculated in normal-appearing genu and splenium of the corpus callosum., Results: In the genu and splenium, fractional anisotropy decreased and , lambda||, lambdaperpendicular increased linearly and significantly with time (p<0.01). At 45 weeks after the start of RT, lambdaperpendicular had increased approximately 30% in the genu and splenium, and lambda|| had increased 5% in the genu and 9% in the splenium, suggesting that demyelination is predominant. The increases in lambdaperpendicular and lambda|| were dose dependent, starting at 3 weeks and continuing to 32 weeks from the start of RT. The dose-dependent increase in lambdaperpendicular and lambda|| was not sustained after 32 weeks, indicating the transition from focal to diffuse effects., Conclusion: The acute and subacute changes in normal-appearing white matter fibers indicate radiation-induced demyelination and mild structural degradation of axonal fibers. The structural changes after RT are progressive, with early dose-dependent demyelination and subsequent diffuse dose-independent demyelination and mild axonal degradation. Diffusion tensor magnetic resonance imaging is potentially a biomarker for the assessment of radiation-induced white matter injury.

Aberrations in tumor and peritumoral vasculature may not be distinguishable by cerebral blood flow (CBF) or cerebral blood volume (CBV) alone. The relationships between CBF and CBV were examined to estimate vasculature-specific hemodynamic characteristics. Twenty glioma patients were studied with dynamic susceptibility T2*-weighted MRI [(dynamic contrast-enhanced magnetic resonance imaging (DSC-MRI)] before and during week 1 and 3 of radiotherapy (RT). CBF and CBV were calculated from DSC-MRI, and relationships between the two were evaluated: the physiological measure of mean transit time (MTT) = CBV/CBF; empirical fitting using the power law CBV = constant x (CBF)(beta). Three different tissue types were assessed: the Gd-enhancing tumor volume (GEV); non-enhanced abnormal tissue located beyond GEV but within the abnormal hyperintense region on FLAIR images (NEV); normal tissue in the hemisphere contralateral to the tumor (CNT). The effects of tissue types, CBV magnitudes (low, medium and high), before and during RT, on MTT and beta were analyzed by analysis of variance (ANOVA). The MTT and beta for the three tissue types were significantly different (p < 0.009). MTT increased from CNT (1.60 s) to NEV (1.93 s) to GEV (2.28 s) (p < 0.0005). beta was significantly greater in GEV (1.079) and NEV (1.070) than in CNT (1.025). Beta increased with increasing CBV magnitude while MTT was independent of CBV magnitude. There was a significant decrease in MTT of NEV and GEV during week 3 of RT compared with pre-RT values for all CBV magnitudes. There was a significant increase in beta during RT in the tumor and peritumor. Progressive abnormalities in vasculature and hemodynamic characteristics of the vascular bed were delineated, with significant disorder in the tumor but mild abnormality in peritumoral tissue., (John Wiley & Sons, Ltd.)

Magnetic resonance imaging reveals heterogeneous regions within high-grade gliomas, such as a contrast-enhanced rim, a necrotic core, and non-contrast-enhanced abnormalities. It is unclear which of these regions best describes tumor aggressiveness. We hypothesized that the vascular leakage volume, reflecting disorganized angiogenesis typical of glioblastoma, would be a strong predictor of clinical outcome. The FLAIR tumor volume, post-gadolinium T1 tumor volume, tumor vascular leakage volume determined by dynamic contrast-enhanced imaging, and volume of the contrast-enhanced rim seen on post-gadolinium T1-weighted images were defined for 20 patients about to undergo treatment for newly diagnosed high-grade gliomas. The potential for imaging characteristics to improve prediction of survival and time to progression over clinical variables was tested by using Cox regression analysis. Single-variable Cox regression analysis of each of the four tumor subvolumes revealed that the vascular leakage volume was the only significant predictor of survival. When the joint effect of clinical variables and the vascular leakage volume were tested for prediction of survival, only the age and the vascular leakage volume were selected as significant predictors. However, when time to progression was tested as a dependent variable, both the vascular leakage volume and the vascular permeability were selected as copredictors, along with surgical status. Our findings suggest that for patients with high-grade glioma, time to progression after radiation therapy is influenced by both underlying biological aggressiveness (vascularity) and volume of aggressive tumor. In contrast, survival depends chiefly on the volume of aggressive tumor at the time of presentation.

Magnetic resonance (MR) imaging provides excellent soft tissue differentiation and in vivo assessment of physiologic and metabolic properties of tissue. As new and more aggressive treatment modalities and combined modalities are being investigated for brain tumor treatment, it is becoming more important to accurately define tumor volumes for treatment planning, to determine the most aggressive tumor regions for intensified radiation treatment, to identify early regional response to therapy for reoptimization of treatment, and to detect early indicators of developing normal tissue toxicity. Readily available MR techniques of physiologic and metabolic imaging can currently provide useful information regarding tumor tissue properties including chemical composition, cerebral blood volume, perfusion, vascular permeability, and water mobility. This article will focus on the potential value of MR physiologic and metabolic imaging in the clinical management of malignant gliomas.

Diffuse malignant gliomas, the most common type of brain tumor, carry a dire prognosis and are poorly responsive to initial treatment. The response to treatment is typically evaluated by measurements obtained from radiographic images several months after the start of treatment; therefore, an early biomarker of tumor response would be useful for making early treatment decisions and for prognostic information. Thirty-four patients with malignant glioma were examined by diffusion MRI before treatment and 3 weeks later. These images were coregistered, and differences in tumor-water diffusion values were calculated as functional diffusion maps (fDM), which were correlated with the radiographic response, time-to-progression (TTP), and overall survival (OS). Changes in fDM at 3 weeks were closely associated with the radiographic response at 10 weeks. The percentage of the tumor undergoing a significant change in the diffusion of water (V(T)) was different between patients with progressive disease (PD) vs. stable disease (SD) (P < 0.001). Patients classified as PD by fDM analysis at 3 weeks were found to have a shorter TTP compared with SD (median TTP, 4.3 vs. 7.3 months; P < 0.04). By using fDM, early patient stratification also was correlated with shorter OS in the PD group compared with SD patients (median survival, 8.0 vs. 18.2 months; P < 0.01). On the basis of fDM, tumor assessment provided an early biomarker for response, TTP, and OS in patients with malignant glioma. Further evaluation of this technique is warranted to determine whether it may be useful in the individualization of treatment or evaluation of the response in clinical protocols.

Purpose: For chemotherapy to act synergistically and safely with radiation against high-grade gliomas, drugs must pass the endothelial junctions of the blood-tumor barrier (BTB) to reach all tumor cells, and should not pass the blood-brain barrier (BBB) to cause toxicity to normal brain. The objective of this study was to assess BBB/BTB status using magnetic resonance imaging (MRI) during a course of radiotherapy of high-grade gliomas., Patients and Methods: Sixteen patients with grade 3 or 4 supratentorial malignant glioma receiving conformal radiotherapy (RT) underwent contrast-enhanced MRI before, during, and after completion of RT. A gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) uptake index was analyzed with respect to the tumor and RT dose received., Results: In the nonenhanced tumor region, contrast uptake increased significantly after the receipt of approximately 10 Gy (P < .01), and reached a maximum after the receipt of approximately 30 Gy. In the initially contrast-enhanced tumor region, contrast uptake decreased over the course of RT and became significant after completion of RT in patients without progressive disease. The healthy brain showed only nonsignificant changes during and after irradiation., Conclusion: Contrast MRI reveals increases in Gd-DTPA uptake in the initially nonenhanced tumor region but not in the remaining brain during the course of RT, suggesting opening of the BTB. This finding suggests that the effect of conformal radiation is more selective on the BTB than the BBB, and there may be a window extending from 1 week after the initiation of radiotherapy to 1 month after the completion of treatment during which a pharmaceutical agent has maximum access to high-grade gliomas.

Rationale and Objectives: Glioblastoma image evaluation utilizes Magnetic Resonance Imaging contrast-enhanced, T1-weighted, and noncontrast T2-weighted fluid-attenuated inversion recovery (FLAIR) acquisitions. Disease progression assessment relies on changes in tumor diameter, which correlate poorly with survival. To improve treatment monitoring in glioblastoma, we investigated serial voxel-wise comparison of anatomically-aligned FLAIR signal as an early predictor of GBM progression.Materials and Methods: We analyzed longitudinal normalized FLAIR images (rFLAIR) from 52 subjects using voxel-wise Parametric Response Mapping (PRM) to monitor volume fractions of increased (PRMrFLAIR+), decreased (PRMrFLAIR-), or unchanged (PRMrFLAIR0) rFLAIR intensity. We determined response by rFLAIR between pretreatment and 10 weeks posttreatment. Risk of disease progression in a subset of subjects (N = 26) with stable disease or partial response as defined by Response Assessment in Neuro-Oncology (RANO) criteria was assessed by PRMrFLAIR between weeks 10 and 20 and continuously until the PRMrFLAIR+ exceeded a defined threshold. RANO defined criteria were compared with PRM-derived outcomes for tumor progression detection.Results: Patient stratification for progression-free survival (PFS) and overall survival (OS) was achieved at week 10 using RANO criteria (PFS: p <0.0001; OS: p <0.0001), relative change in FLAIR-hyperintense volume (PFS: p = 0.0011; OS: p <0.0001), and PRMrFLAIR+ (PFS: p <0.01; OS: p <0.001). PRMrFLAIR+ also stratified responding patients' progression between weeks 10 and 20 (PFS: p <0.05; OS: p = 0.01) while changes in FLAIR-volume measurements were not predictive. As a continuous evaluation, PRMrFLAIR+ exceeding 10% stratified patients for PFA after 5.6 months (p<0.0001), while RANO criteria did not stratify patients until 15.4 months (p <0.0001).Conclusion: PRMrFLAIR may provide an early biomarker of disease progression in glioblastoma. [ABSTRACT FROM AUTHOR]

Purpose/objectives Radiation injury to parahippocampal cingulum white matter is associated with cognitive decline. Diffusion tensor imaging (DTI) detects micropathologic changes in white matter. Increased radial diffusion (RD) and decreased axial diffusion (AD) correspond to demyelination and axonal degeneration/gliosis respectively. We aimed to develop a predictive model for radiation-induced cognitive changes based upon DTI changes. Materials/methods Twenty-seven adults with benign or low-grade tumors received partial brain radiation therapy (RT) to a median dose of 54 Gy. Patients underwent DTI before RT, during RT, and at the end of RT. Cognitive testing was performed before RT, and 6 and 18 months after RT. Parahippocampal cingulum white matter was contoured to obtain mean values of AD and RD. Results By univariate analysis, decreasing AD and increasing RD during RT predicted declines in verbal memory and verbal fluency. By multivariate analysis, baseline neurocognitive score was the only clinical variable predicting verbal memory change; no clinical variables predicted verbal fluency change. In a multivariate model, increased RD at the end of RT significantly predicted decline in verbal fluency 18 months after RT. Conclusions Imaging biomarkers of white matter injury contributed to predictive models of cognitive function change after RT. [ABSTRACT FROM AUTHOR]