Contrast-enhanced Component Research Articles

Fotemustine in recurrent high‑grade glioma: MRI neuro‑radiological findings.

The use of fotemustine (FTM) has been authorized in certain countries for the treatment of recurrent high-grade gliomas (HGG) after Stupp therapy. However, to the best of our knowledge, no studies have assessed changes in magnetic resonance imaging (MRI) during treatment with FTM monotherapy. The aim of the present study was to assess the neuroradiological findings in a cohort of patients with recurrent HGG treated with FTM monotherapy. Patients with HGG already undergoing the Stupp protocol were retrospectively included. MRIs (pre- and post-FTM treatment) were analyzed by two neuroradiologists in consensus: Volume and diffusion values of the contrast-enhanced component were measured on T1-weighted volumetric sequences after gadolinium injection and on apparent diffusion coefficient (ADC) maps, respectively. A total of 19 patients [median age, 49 years; interquartile range (IQR), 43-57 years] were included, 17 of whom had glioblastoma and 2 had astrocytoma isocitrate dehydrogenase-mutated grade 4. The median duration of FTM therapy was 4 months (IQR, 2-6 months). The median tumor volume measured on the contrast-enhanced component was 2,216 mm3 (IQR, 768-13,169 mm3) at baseline and 9,217 mm3 (IQR, 3,455-16,697 mm3) at the end of treatment, with a median change of +38% (IQR, -45-+574%). A total of seven patients showed a volume decrease. ADC value analysis of the enhancement area demonstrated no significant difference between the pre- and the post-FTM treatment periods (P=0.36); however, in three patients, the decreases in ADC levels were particularly marked. In conclusion, the present study described a series of patients with recurrent HGG treated with FTM in monotherapy, demonstrating a prevalent increase in lesion enhancement and three cases of marked restrictions on diffusion-weighted imaging. Further prospective studies are required to corroborate such preliminary results.

Novel approaches to targeting gliomas at the leading/cutting edge.

Despite decades of clinical trials and surgical advances, the most common high-grade glioma, glioblastoma (GBM), remains an incurable disease with a dismal prognosis. Because of its infiltrative nature, GBM almost always recurs at the margin, or leading edge, where tumor cells invade the surrounding brain parenchyma. This region of GBMs is unique, or heterogeneous, with its own microenvironment that is different from the tumor bulk or core. The GBM microenvironment at the margin contains immunosuppressive constituents as well as invasive and therapy-resistant tumor cells that are difficult to treat. In addition, the blood-brain barrier remains essentially intact at the infiltrative margin of tumors; further limiting the effectiveness of therapies. The invasive margin creates the greatest challenge for neurosurgeons when managing these tumors. The current paradigm of resection of GBM tumors mainly focuses on resection of the contrast-enhancing component of tumors, while GBMs extend well beyond the contrast enhancement. The infiltrative margin represents a unique challenge and opportunity for solutions that may overcome current limitations in tumor treatments. In this review of the current literature, the authors discuss the current and developing advances focused on the detection and treatment of GBM at the infiltrative margin and how this could impact patient outcomes.

EXTH-28. INTRATUMORAL HETEROGENEITY OF THERAPEUTIC VULNERABILITIES ACROSS ENHANCING AND NON-ENHANCING TUMOR COMPONENTS OF GLIOBLASTOMA: A PARADIGM-SHIFTING PERSONALIZED MEDICINE APPROACH

Abstract Glioblastoma (GBM) is the most aggressive adult brain tumor with no effective therapy. Despite advances on its molecular characterization, targeted therapeutics remain out of reach. This lack-of-progress is largely attributed to molecular and spatial heterogeneity and absence of clinically applicable models to guide patient care. Moreover, as standard surgical resection is aimed at contrast-enhancing (CE) tumor, the molecular landscape and treatment response of the remaining non-contrast enhancing (nCE) component is largely unknown despite its active role in tumor progression and local recurrence. Here, we aimed to identify the functional impact of tumor heterogeneity and to explore therapeutic vulnerabilities of both CE and nCE components. Four tumor regions (two CE and two nCE) from each of five GBM patients were collected under neuronavigation. The resulting tissue was subjected to generation of 3D tumor models (a brain tumor initiating-enriched cell line and a spheroid-based mcancer model) with comparable success in both CE and nCE samples. A panel of 25 brain penetrant drugs (alone and in combination) targeting GBM drivers (i.e. RTK/Ras/PI3K, RB/cell cycle, p53/apoptosis, DNA damage repair, transcription addiction) was developed and used to test for therapeutic vulnerabilities. From each tumor region, 4.5 ± 3.7 (average ± SD) different targeting strategies were identified exhibiting at least 70% growth inhibition at Cmax. Drug response heterogeneity was relatively rare, varied among cases, and was independent of tumor enhancement status. To our knowledge, this is the first study to systemically assess treatment response from both CE and nCE patient-derived GBM models. Ongoing studies include comprehensive genome and transcriptome profiling and pathway analysis from these different tumor regions. We postulate that interrogation of molecular landscapes and vulnerability profiles of both CE and nCE tumor regions, will enable us to personalize and prioritize effective targeted interventions for GBM treatment.

Cluster Analysis of DSC MRI, Dynamic Contrast-Enhanced MRI, and DWI Parameters Associated with Prognosis in Patients with Glioblastoma after Removal of the Contrast-Enhancing Component: A Preliminary Study.

No report has been published on the use of DSC MR imaging, DCE MR imaging, and DWI parameters in combination to create a prognostic prediction model in glioblastoma patients. The aim of this study was to develop a machine learning-based model to find preoperative multiparametric MR imaging parameters associated with prognosis in patients with glioblastoma. Normalized CBV, volume transfer constant, and ADC of the nonenhancing T2 high-signal-intensity lesions were evaluated using K-means clustering. A total of 142 patients with glioblastoma who underwent preoperative MR imaging and total resection were included in this retrospective study. From the normalized CBV, volume transfer constant, and ADC maps, the parametric data were sorted using the K-means clustering method. Patients were divided into training and test sets (ratio, 1:1), and the optimal number of clusters was determined using receiver operating characteristic analysis. Kaplan-Meier survival analysis and log-rank tests were performed to identify potential parametric predictors. A multivariate Cox proportional hazard model was conducted to adjust for clinical predictors. The nonenhancing T2 high-signal-intensity lesions were divided into 6 clusters. The cluster (class 4) with the relatively low normalized CBV and volume transfer constant value and the lowest ADC values was most associated with predicting glioblastoma prognosis. The optimal cutoff of the class 4 volume fraction of nonenhancing T2 high-signal-intensity lesions predicting 1-year progression-free survival was 9.70%, below which the cutoff was associated with longer progression-free survival. Two Kaplan-Meier curves based on the cutoff value showed a statistically significant difference (P = .037). When we adjusted for all clinical predictors, the cluster with the relatively low normalized CBV and volume transfer constant values and the lowest ADC value was an independent prognostic marker (hazard ratio, 3.04; P = .048). The multivariate Cox proportional hazard model showed a concordance index of 0.699 for progression-free survival. Our model showed that nonenhancing T2 high-signal-intensity lesions with the relatively low normalized CBV, low volume transfer constant values, and the lowest ADC values could serve as useful prognostic imaging markers for predicting survival outcomes in patients with glioblastoma.

Radiation Associated Brain Necrosis following Proton Therapy for Head and Neck Skull Base and Intracranial Tumors

To characterize the patterns and outcomes of radiation associated brain necrosis (RABN) after proton therapy (PT) for selected head and neck cancers (HNCs) with base of skull and/or intracranial involvement. Outcomes of patients with HNC treated with PT between 2010 and 2018 participating in a prospective clinical study who had one or more follow-up MRIs (≥ 6 months after treatment) and who had received at least 40 Gy(RBE) to brain were analyzed. Those who received re-irradiation were excluded. Diagnostic radiology reports and available images were reviewed for RABN defined as contrast enhanced lesions on T1- and/or edema on T2-weighted sequences. MRIs showing the RABN lesions were co-registered (rigid) with initial treatment planning CT and lesions manually contoured and volume and spatial location determined. Time to RABN was calculated from end of PT to first imaging occurrence using Kaplan-Meier method. 105 patients formed the cohort; 53 (50%) were male. Regarding disease site, 23 (22%) were nasopharynx, 19 (18%) were paranasal sinus, and 17 (16%) were peri-orbital. 62% had also received concurrent chemotherapy. Median follow-up time (from end of PT to latest MRI) was 33 months (range: 6-92). Overall, 18 patients (17.1%) developed RABN after a median latency of 24 months (range: 9-33). Actuarial RABN-free rate was 98.9%, 89.4 %, and 80.9% at 1, 2 and 3 years, respectively. All lesions were incidentally discovered on surveillance imaging and asymptomatic (grade 1) and initially observed. All lesions had a contrast enhancing component on T1 MRI. Location of lesions were temporal lobe in 12, frontal lobe in 4 and cerebellum in 2 patients. Of those with RABN, 13 (72%) had been treated for T4 or unresectable disease and 14 (78%) had intracranial tumor extension and the remainder skull base involvement. Median prescription dose to the most cranial/proximal extent of disease was 69 Gy(RBE) (range: 60-70). Median RABN lesion size (T1) was 0.2cc (range: 0.0 [punctate] to 1cc), and 12 (67%) were inside or overlapping with the high dose target volume (TV). In 5 patients (28%) RABN proved to be transient and completely resolved w/o therapy over a median time of 33 months from onset (range: 8-42), 4 (22%) show regression (2 w/ and 2 w/o medical therapy), and 3 (17%) stability (1 w/ and 2 w/o medical therapy). Three patients (17%) had progression on latest imaging, yet remain asymptomatic; each had received 70 Gy(RBE) to the most cranial TV with concurrent chemotherapy. RABN lesions following PT for skull base/intracranial disease were small, asymptomatic and regressed or completely resolved in half of the patients affected. Observation with surveillance imaging without surgical intervention is recommended for these asymptomatic radiographic lesions.

Current concepts in radiologic assessment of pediatric brain tumors during treatment, part 1.

Pediatric brain tumors differ from those in adults by location, phenotype and genotype. In addition, they show dissimilar imaging characteristics before and after treatment. While adult brain tumor treatment effects are primarily assessed on MRI by measuring the contrast-enhancing components in addition to abnormalities on T2-weighted and fluid-attenuated inversion recovery images, these methods cannot be simply extrapolated to pediatric central nervous system tumors. A number of researchers have attempted to solve the problem of tumor assessment during treatment in pediatric neuro-oncology; specifically, the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group was recently established to deal with the distinct challenges in evaluating treatment-related changes on imaging, but no established criteria are available. In this article we review the current methods to evaluate brain tumor therapy and the numerous challenges that remain. In part 1, we examine the role of T2-weighted imaging and fluid-attenuated inversion recovery sequences, contrast enhancement, volumetrics and diffusion imaging techniques. We pay particular attention to several specific pediatric brain tumors, such as optic pathway glioma, diffuse midline glioma and medulloblastoma. Finally, we review the best means to assess leptomeningeal seeding.

Advanced MRI Techniques in the Monitoring of Treatment of Gliomas.

With advances in treatments and survival of patients with glioblastoma (GBM), it has become apparent that conventional imaging sequences have significant limitations both in terms of assessing response to treatment and monitoring disease progression. Both 'pseudoprogression' after chemoradiation for newly diagnosed GBM and 'pseudoresponse' after anti-angiogenesis treatment for relapsed GBM are well-recognised radiological entities. This in turn has led to revision of response criteria away from the standard MacDonald criteria, which depend on the two-dimensional measurement of contrast-enhancing tumour, and which have been the primary measure of radiological response for over three decades. A working party of experts published RANO (Response Assessment in Neuro-oncology Working Group) criteria in 2010 which take into account signal change on T2/FLAIR sequences as well as the contrast-enhancing component of the tumour. These have recently been modified for immune therapies, which are associated with specific issues related to the timing of radiological response. There has been increasing interest in quantification and validation of physiological and metabolic parameters in GBM over the last 10years utilising the wide range of advanced imaging techniques available on standard MRI platforms. Previously, MRI would provide structural information only on the anatomical location of the tumour and the presence or absence of a disrupted blood-brain barrier. Advanced MRI sequences include proton magnetic resonance spectroscopy (MRS), vascular imaging (perfusion/permeability) and diffusion imaging (diffusion weighted imaging/diffusion tensor imaging) and are now routinely available. They provide biologically relevant functional, haemodynamic, cellular, metabolic and cytoarchitectural information and are being evaluated in clinical trials to determine whether they offer superior biomarkers of early treatment response than conventional imaging, when correlated with hard survival endpoints. Multiparametric imaging, incorporating different combinations of these modalities, improves accuracy over single imaging modalities but has not been widely adopted due to the amount of post-processing analysis required, lack of clinical trial data, lack of radiology training and wide variations in threshold values. New techniques including diffusion kurtosis and radiomics will offer a higher level of quantification but will require validation in clinical trial settings. Given all these considerations, it is clear that there is an urgent need to incorporate advanced techniques into clinical trial design to avoid the problems of under or over assessment of treatment response.

Apparent diffusion coefficient of pediatric cerebellar tumors: A biomarker of tumor grade?

The role of diffusion weighted imaging (DWI) to reliably differentiate tumor types and grades in pediatric cerebellar tumors is controversial. We aimed to clarify the discrepancy reported in previous articles. We retrospectively evaluated the apparent diffusion coefficient (ADC) values of the enhancing, solid parts of cerebellar tumors and correlated the absolute tumor ADC values and cerebellar and thalamic ratios with histology in a cohort of children with cerebellar tumors. Twenty-four children (12 females) were included in the study. The median age at pre-surgical MRI was 10 years (range 29 days-18.5 years). Absolute ADC values (mean 1.49, SD 0.25 vs. 0.63 ± 0.18), cerebellar (2.04 ± 0.33 vs. 0.83 ± 0.25), and thalamic ratio (1.98 ± 0.35 vs. 0.79 ± 0.23) were significantly higher in low- than in high-grade tumors (P < 0.0001). Absolute ADC values and cerebellar and thalamic ratios were significantly higher in low-grade astrocytomas than in MBs. Overlap was seen for WHO grade II and III ependymomas. One hundred percent specific cutoff ADC values of >1.2 × 10(3) and <0.8 × 10(-3) mm(2) /s were established for low- and high-grade tumors. ADC analysis of the solid, contrast enhancing components of pediatric cerebellar tumors may facilitate differentiation between various tumor histologies.

Epileptogenic glioma in a 4-year-old child: a case report

We report a rare case of epileptogenic glioma composed of glial progenitor cells that differentiated into an astrocytic and oligodendrocytic tumor. This 4-year-old girl presented with a 1-year history of complex partial seizure. MR scan showed a mass in the left temporal lobe with a cyst and a contrast-enhanced component. Subtotal resection of the tumor was achieved. Histological examination revealed that the tumor exhibited low cellularity composed of astrocytic and oligodendrocytic components, as well as low mitotic activity (MIB-1 = 1%). Immunohistochemical examination revealed GFAP positivity within the astrocytic cells, olig2 positivity within the oligodendrocytic cells, and S100 positivity in both cell types. MAP2 and CD34 were negative, and neurofilament was only positive in preexisting neurons. The pathological diagnosis was epileptogenic glioma (grade I) composed of glial progenitor cells. The postoperative course has been uneventful with good seizure control for 3 years.

Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group

Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.

Response Assessment Challenges in Clinical Trials of Gliomas

Accurate, reproducible criteria for determining tumor response and progression after therapy are critical for optimal patient care and effective evaluation of novel therapeutic agents. Currently, the most widely used criteria for determining treatment response in gliomas is based on two-dimensional tumor measurements using neuroimaging studies (Macdonald criteria). In recent years, the limitation of these criteria, which only address the contrast-enhancing component of the tumor, have become increasingly apparent. This review discusses challenges that have emerged in assessing response in patients with gliomas and approaches being introduced to address them.

Diffusion-weighted magnetic resonance imaging in radiation-induced cerebral necrosis. Apparent diffusion coefficient in lesion components.

The objective of this retrospective study was to investigate the diffusivity of different components of radiation-induced cerebral necrosis with the hypothesis that the diffusivity of the various components is elevated to different degrees. Twenty-two patients (18 men, 4 women, aged 34-72 years) with radiation injury to the temporal lobes after radiation therapy (RT) for nasopharyngeal carcinoma with diagnosis confirmed on serial magnetic resonance imaging (MRI) were studied with coronal T2-weighted, diffusion-weighted, and gadolinium-enhanced MRI. Using three diffusion directions for diffusion-weighted MRI, the apparent diffusion coefficients (ADCs) of the enhanced component, the cystic or liquefied component, and the edema component were measured. ADCs of all components of RT-induced cerebral necrosis (154 +/- 21.6 x 10(-5) mm2/s for contrast-enhanced component; 188 +/- 47.4 x 10(-5) mm2/s for cystic/liquefied component; 177 +/- 35.4 x 10(-5) mm2/s for edema component) were all significantly higher (P<0.00001) than ADC of the normal frontal lobe white matter (82 +/- 12.4 x 10(-5) mm2/s). The ADC of the enhanced component was significantly lower than that of the cystic/liquefied component (P=0.0096) and the edema component (P=0.003). A significantly lower ADC was shown in the enhanced component in temporal lobes showing both short-term morphologic deterioration (P=0.024) and occurrence of deterioration on long-term follow-up (P=0.04) compared with the temporal lobes that showed improvement or stable morphology. ADCs of the contrast-enhanced component, cystic/liquefied component, and edema in RT-induced cerebral necrosis was significantly higher than in normal brain parenchyma. There is association between a lower ADC in the contrast-enhanced component and morphologic deterioration.