FLAIR Hyperintensity Research Articles

NIMG-68. TEMPORAL CHANGES IN TUMOR COMPOSITION DIFFER ACROSS TUMOR GRADE IN GLIOMA

Abstract Gliomas are the most common primary adult brain tumor in the United States and their biological heterogeneity makes it difficult to assess and treat tumor progression over time. This study used conventional MRI tumor segmentations to determine longitudinal growth differences between low grade (≤ G2), G3, and G4 gliomas. A total of 60 patients with at least three scans collected before death were organized into low-grade (n = 9), G3 (n = 13), and G4 (n = 38) gliomas at initial diagnosis. T1, T1C, FLAIR, and T2 images from every timepoint across all patients were used as input for tumor segmentation, using BraTS, to segment contrast enhancement (CE), FLAIR hyperintensity (FH), and the necrotic core (NC). Volumes within each segmentation and the time between each subsequent MRI was calculated, where the first post-surgical MRI was considered time 0. Linear mixed models were fitted for each segmentation volume, where Time, Group (i.e., G2-4) and their interaction (Group*Time) were fixed effects and subject was a random effect. We found that Time and Group*Time interaction were significant predictors of FH growth (p < 0.001 and 0.04, respectively); however, no group-level differences were observed in FH volumes over time. Group was the only significant predictor of CE growth (p = 0.006). Specifically, G4 growth was greater than G2 and had a trending increase than G3 (p = 0.003 and 0.08, respectively). Group, Time, and Group*Time were all significant predictors of NC growth (p = 0.04, 0.001, and 0.01, respectively). G4 NC growth was significantly greater than both G2 and G3 (both p < 0.05). No difference any of these tumor segmentations growth between G2 and G3 was detected. These results further show the heterogeneity in glioma growth over time and the necessity to assess how treatment effects longitudinal tumor composition progression and overall survival.

STEM-10. SOX2 POSITIVE, PRESUMED TUMOR INVASION MEASURED WELL BEYOND CONTRAST ENHANCEMENT AND FLAIR HYPERINTENSITY IN BOTH TREATED AND UNTREATED GLIOBLASTOMA PATIENTS ASSESSED AT AUTOPSY

Abstract In the treatment of glioblastoma (GBM), MRI is used to determine location and extent of cancer. It is poorly understood how far tumor invasion may exist outside of contrast enhancement (CE) and FLAIR hyperintensity (FL). This study identifies presumed non-enhancing tumor invasion using SOX2 staining on tissue collected at autopsy, which may highlight invading glioma cells. Three patients with primary GBM were included for this study. Patient 1 (P1) with an overall survival (OS) of 148 days received no treatment following sub-total resection. Patient 2 (P2) (OS = 1601) and patient 3 (P3) (OS = 629 days) underwent the clinical standard of care treatment including chemo-radiation and bevacizumab at recurrence. At autopsy, brains were sliced axially to match patients’ last MRI scan. Samples were obtained including regions suspicious of tumor and regions appearing normal. SOX2 positive cells were identified visually on digitized autopsy histology. Samples were visually matched to the patient’s last T1C and FLAIR MRI acquisition prior to death. Approximate distance from CE and FL from SOX2 positive cells was measured digitally, limited to the same MRI slice (2D assessment). For P1 who received no treatment, SOX2 positive cells were identified 3.9cm from CE and 4.1cm from FL within the same hemisphere as the primary tumor, and 2.1cm and 2.3cm within the opposite hemisphere, respectively. For P2 and (P3), SOX2 positive cells were identified approximately 4.4cm (5.2 cm) from CE and 4.0cm (2.0cm) from FL within the same hemisphere as primary tumor, and 4.7cm (4.4cm) from CE and 4.1 cm (4.7cm) from FL within the opposite hemisphere. This study uses SOX2 to identify presumed GBM cells well beyond clinically identified regions of tumor, on T1C and FLAIR imaging. Additional research is necessary to determine SOX2 sensitivity and specificity for identifying GBM cells outside regions with readily identifiable GBM characteristics.

CNSC-36. INDOLENT INTRAVASCULAR LARGE B-CELL LYMPHOMA (IVLBCL) ORIGINALLY PRESENTING AS A STROKE MIMIC

Abstract BACKGROUND IVBCL is a rare subtype of extranodal diffuse large B-cell lymphoma, characterized by the growth of neoplastic cells in blood vessels with no other apparent extravascular mass, making diagnosis a challenge. It usually has an aggressive and fast-paced course; however, there is limited data regarding incidence due to its rarity. CASE A 73 year-old woman presented with progressive gait worsening a year prior to presentation to our institution. Her symptoms then developed to include left-sided hemiparesis with associated headaches, warranting a local emergency department visit. Brain magnetic resonance imaging (MRI) without contrast showed a Flair hyperintense lesion in the right MCA territory with restricted diffusion, assumed to be an ischemic stroke, and she was started on stroke prevention measures. The patient continued to decline, becoming wheelchair-bound and developing short-term memory loss, chronic headaches, and pseudobulbar affect. Repeat brain MRI without contrast five months later showed progression of the Flair hyperintensity to the left hemisphere with restricted diffusion. Brain MRI with contrast followed, revealing subtle enhancement. Vessel imaging was unremarkable, and cerebrospinal fluid (CSF) analysis was normal with negative cytology and flow cytometry, yet elevated beta-2-microglobulin at 3.25 mcg/mL. A year after symptoms onset, the patient presented to our Neuro-Oncology clinic. Repeat Brain MRI with contrast and spectroscopy showed progression on the left-sided lesion with persistent restriction diffusion and enhancement, prompting a biopsy. Pathology confirmed large B cell lymphoma. PET-CT body scan showed no evidence of systematic disease. The patient was treated with Rituximab, Methotrexate, Vincristine, and Procarbazine (RMVP) with complete response demonstrated by complete resolution of the diffusion restriction and symptoms improvement. CONCLUSIONS Although IVLBCL is known for being a fast progressive disease, we present a case of indolent course delaying diagnosis. Unexplained progressive neurological symptoms with restricted diffusion on MRI should prompt consideration for this diagnosis.

NIMG-41. ASSOCIATION BETWEEN PERFUSION IMAGING METRICS AND RADIO-PATHOMIC MAPS OF TUMOR PROBABILITY WITHIN AND BEYOND THE CONTRAST-ENHANCING VOLUME IN GLIOMA PATIENTS

Abstract Perfusion MRI, using both contrast-based techniques such as dynamic susceptibility imaging (DSC) and non-contrast-based techniques like arterial spin labeling (ASL) have been used to monitor blood flow as a marker of angiogenic glioma presence, and showed substantial potential in the differentiation of true progression from pseudoprogression post-treatment. This study uses radio-pathomic maps of cellularity sensitive to areas of non-enhancing tumor to test the hypothesis that perfusion-derived markers of tumor probability will associate with tumor presence within contrast-enhancement but not beyond the enhancing margin. This study included pre-surgical relative cerebral blood volume (rCBV) estimates derived from DSC perfusion data from the PENN-GBM dataset (n=456) and presurgical ASL images from the UCSF-PDGM dataset (n=426) for analyses. The T1, T1C, FLAIR, and ADC images from each patient were used to generate radio-pathomic cell density maps using a previously validated model that excels at accurate detection of non-enhancing tumor presence. Mean cell density, rCBV, and ASL were computed for each corresponding patient within included segmentations for contrast-enhancement (excluding necrotic core) and FLAIR hyperintensity (excluding both necrotic core and enhancement). Pearson’s correlations were then used to quantify the association between perfusion-derived estimates and mean cell density within each region of interest. Both rCBV and ASL showed positive associations with cell density within contrast enhancement (rCBV: R=0.280, p< 0.001; ASL: R=0.117, p=0.016). However, both perfusion metrics also showed no association with cell density within the non-enhancing, FLAIR hyperintense region (rCBV: R=0.0162, p=0.731; ASL: R=-0.213, p=0.634). These results suggest that perfusion imaging successfully identifies angiogenic tumor but may be less efficacious in detecting non-enhancing tumor presence. Future studies should examine how perfusion’s relationship with hypercellular tumor presence evolves in the presence of treatment, as well as in relation to other advanced imaging metrics such as MR spectroscopy and CEST imaging.

NIMG-24. RECURRENT OLIGODENDROGLIOMA DEMONSTRATES EARLY INCREASE IN CEREBRAL BLOOD FLOW AND NORMALIZATION IN RESPONSE TO TREATMENT

Abstract Oligodendrogliomas, molecularly defined by the presence of both IDH mutation and 1p/19q codeletion, are more treatment responsive than other gliomas, and due to short capillary segments, demonstrate elevated CBF regardless of grade or contrast enhancement. Arterial Spin Labeling (ASL) allows noninvasive perfusion imaging assessment of cerebral blood flow (CBF) without contrast administration. Changes in CBF are recognized in association with malignant transformation of gliomas however in the setting of treatment, CBF has only been studied to assist in differentiating radiation treatment effect from progressive glioma. This single center retrospective study was undertaken to evaluate if CBF, measured by ASL, might normalize following treatment of recurrent oligodendrogliomas. Clinical database query identified 151 patients with molecularly confirmed oligodendroglioma, 34 of which had available ASL imaging. Expert reader review of all available MRI sequences, blinded to treatment timeline, were performed by two independent radiologists at a PACS station. There were 6 radiographic recurrences identified and in 5/6 CBF was the first radiographic change. Contrast enhancement did not develop for 1.5-12 months after change in CBF for 4/5 recurrences. ASL imaging before and after non-surgical therapy for recurrent disease was available for 4 patients. Two patients were treated with lomustine, one with bevacizumab and one with proton re-radiation. By the second MRI following treatment initiation, all patients had normalization of CBF. At the first post treatment MRI, 3/4 of patients demonstrated normalization of CBF while only 2/4 demonstrated normalization of dynamic susceptibility contrast-derived cerebral blood volume. During the subsequent 6 months, FLAIR hyperintensities remained stable in all patients. This work supports further study if normalization of ASL-derived CBF may be an early radiographic biomarker for response to treatment, especially in non or minimally enhancing recurrent gliomas.

NIMG-14. AUTOPSY-BASED RADIO-PATHOMIC MAPS REVEAL DEMOGRAPHIC FACTORS IMPACT THE PRESENCE OF TUMOR OUTSIDE CONTRAST ENHANCEMENT IN GLIOMA PATIENTS

Abstract Gliomas are vastly heterogenous tumors with wide-ranging pathological signatures; as such, there is a pressing need to understand how individualized factors affect tumor growth patterns to develop treatment plans and improve prognosis. This study used autopsy-based radio-pathomic maps of tumor probability to test the hypothesis that differences in patient sex and age impact the presence of non-enhancing tumor. This study used pre-surgical imaging and demographic data from 501 glioma patients from the UCSF-PDGM dataset. Specifically, T1, T1C, FLAIR, and ADC images were used to generate maps of tumor probability using a previously validated model. This model used autopsy tissue aligned to imaging as ground truth to develop models sensitive to identifying areas of non-enhancing tumor outside of traditional imaging signatures. Thresholded maps were used to delineate areas of tumor presence, and the non-enhancing tumor volume was computed for each patient as the predicted high probability tumor volume within non-enhancing FLAIR hyperintensity. A general linear model was then fit to assess the effect of age and sex on non-enhancing tumor volumes, using tumor grade and contrast-enhancing volume as covariates. Male patients trended towards greater non-enhancing tumor volumes compared to female patients (B=5676.6, p=0.053). Older patients were also found to have less non-enhancing tumor volume compared to younger patients (B=-261.1, p=0.015). These results suggest that demographic characteristics influence the progression of tumor beyond the angiogenic tumor mass and may therefore influence treatment efficacy and prognoses. Future research is essential to understanding how these sex differences relate to the worse prognosis historically observed for males with glioma, and how the reduced presence of non-enhancing tumor in older patients relates to a reduction in plasticity-induced tumor propagation.

NIMG-11. AUTOPSY-BASED RADIO-PATHOMIC MAPS OF TISSUE COMPOSITION DELINEATE IDH1 STATS IN GLIOMAS

Abstract Isocitrate dehydrogenase 1 (IDH1) mutation status is used as an important prognostic marker for gliomas, where IDH1-wildtype patients see shorter survival than patients with an IDH1 mutation. This study uses radio-pathomic maps of cell, extracellular fluid (ECF), and cytoplasm (Cyt) density developed using conventional MRI and aligned autopsy samples to test the hypothesis that IDH1-mutant tumors differ in contrast-enhancing and non-enhancing tissue composition from IDH1-wildtype tumors. A total of 426 patients from the UCSF-PDGM data set (380 IDH1-wildtype, 46 IDH1-mutant) were included in this study. T1, T1C, FLAIR and ADC images from each patient’s pre-surgical MRI were used to generate whole brain radio-pathomic maps of cell, ECF, and Cyt density using a previously reported algorithm. This tool was trained using aligned autopsy samples as ground truth and is particularly adept at highlighting areas of tumor beyond traditional imaging signatures. The mean value from each feature map was computed for each patient both within non-necrotic contrast enhancement and non-enhancing FLAIR hyperintensity. Higher ECF density (F=15.45, p< 0.001) and lower Cyt density (F=8.51, p=0.004) was observed within contrast-enhancement for IDH1 mutant patients, with no difference observed for cell density within contrast enhancement between mutation statuses (F=0.03, p=0.86). Higher cell density (F=4.16, p< 0.042), Higher ECF density (F=4.65, p=0.032), lower Cyt density (F=4.48, p=0.035) was also found in patients with IDH1 mutations in the non-enhancing FLAIR hyperintense region. These results suggest that the large-scale tissue composition of IDH1-mutant tumors may differ from IDH1-wildtype tumors, suggesting differences in growth patterns and pathological composition between tumor types. Future studies examining how tissue composition post-treatment over time may elucidate how pathological characteristics evolve for each tumor type.

Abstract 117: Digitally Subtracted Angiogram & Biopsy Negative Recurrent Spontaneous Bilateral Anterior Cerebral Artery Territory Intracranial Hemorrhage

Introduction Up to 18% of spontaneous intracerebral hemorrhages are cryptogenic despite a thorough workup, usually noted in a lobar location. Although undetected on DSA, a significant proportion of these represent ruptured micro‐AVM/AVF or cavernous malformations that ultimately are amenable to surgical resection if detected on biopsy. However, occult cerebral amyloid angiopathy can also present similarly, and their management is markedly different. Methods We present a case of recurrent bilateral medial frontal hemorrhage in a patient without known cerebrovascular disease that evaded diagnosis despite hematologic evaluation, MRI, CTA, two DSAs, three clot evacuations with pathology, and brain biopsy. Results The patient is a 60‐year‐old previously healthy woman who presented with sudden onset right hemiparesis and speech arrest. CT revealed a left parasagittal hemorrhage. She was brought to the OR for clot evacuation. Pathology from the clot revealed blood vessels of multiple sizes consistent with meningeal vessels or underlying AVM/AVF. A 6‐vessel cerebral angiogram as unremarkable. The patient’s inpatient course was complicated by new onset Afib with RVR and asymptomatic DVT with PE, however no etiology of coagulopathy was detected. MRI brain showed no evidence of cerebral microbleed or other underlying pathology, noting only DWI + FLAIR hyperintensity in the left ACA territory. The patient was diagnosed with ACA territory stroke complicated by PH2‐type hemorrhagic conversion. She was initially placed on IV Heparin, before transition to apixaban uneventfully. She continued to recover in the hospital and was eventually discharged to rehab. She re‐presented 1 month later with worsening behavioral arrest and right hemiparesis. CT head revealed recurrence of left parasagittal ICH. She underwent clot evacuation in the OR again and repeat pathology was unrevealing. A repeat MRI showed only the evident bleed and a subtle hyperintensity in the right occipital cortex suspicious for an interval subacute occipital lobe stroke with laminar necrosis, ostensibly from Afib. She improved clinically and was discharged to rehab with a diagnosis of recurrent hemorrhage attributed to anticoagulant use and recent stroke. She was discharged this time on no anticoagulant or antiplatelets. She re‐presented 1 month later with sudden onset speech arrest, but now with left hemiparesis. CT revealed a right parasagittal hemorrhage. She was brought to the OR for emergent clot evacuation and parenchymal biopsy – which was initially normal. A repeat 6‐vessel DSA was again unremarkable as was repeat brain MRI. The patient’s parenchymal biopsy was sent for specific congo‐red and immunohistochemistry for beta‐amyloid. IHC revealed beta‐amyloid plaques in the parenchyma and vessel walls, confirming a diagnosis of CAA. Conclusion Apparently cryptogenic lobar hemorrhage may be caused by both occult micro‐AVM/fistula and CAA. As in this case, when a patient experiences recurrent DSA negative lobar hemorrhages, biopsy should be pursued. This case was particularly challenging given the anatomical plausibility of parasagittal AVM/fistula given its midline location and venous drainage, considering the patient’s evident predisposition to systemic venous thrombosis hemorrhagic venous infarction mimicking lobar ICH is also possible. We present this case to raise awareness of the potential need for early biopsy, especially in patients who may also require anticoagulation or antiplatelet medications.

Abstract 265: A Curious Case Of Acute Binocular Diplopia, Ischemic Stroke Of The Interstitial Nucleus Of Cajal

Introduction The nuclei in the periaqueductal gray of the midbrain are critical structures that coordinate and control vertical and torsional gaze, as well as crucial components of the vestibulo‐occular reflex. These structures are so fine that they may be missed on routine imaging however, they represent distinct localizations for the neurological exam, with lesions of these structures being important clinical considerations. The Interstitial Nucleus of Cajal (inC) coordinates signals from the saccadic burst neurons in the rostral interstitial nucleus of the medial longitudinal fasiculus (riMLF), vestibular projections (utricular and semicircular canal pathways from the vestibular nuclei via the MLF), and descending pursuit fibers, the paired interstitial nuclei of Cajal act as neural integrators for vertical gaze and torsion. These nuclei lie adjacent but dorsal and caudal to the riMLF, For upgaze, fibers from the inC cross via the posterior commissure, then connect to the contralateral superior rectus and inferior oblique subnuclei. For downgaze, fibers travel across the posterior commissure, then innervate the contralateral inferior rectus subnucleus and fourth nerve nucleus. Blood supply is derived from the terminal branches of the basilar artery. Lesions of these interstitial nuclei and their tracts may produce vertical and torsional gaze‐holding deficits such as impairments in the vertical vestibulo‐occular reflex, hypertropia, counter‐rolling of the eyes, superior oblique palsy, and see‐saw and torsional nystagmus. Methods Case report and review of literature Results 45‐year‐old, right‐handed woman with history of turner syndrome, anemia, nephrolithiasis, horseshoe kidney, premature ovarian failure on hormone replacement therapy (HRT), suspected adrenal mass of undetermined significant, and degenerative disk disease presented to the emergency department with complaints of acute binocular diplopia and dizziness clarified to be sensation of the ground/objects bobbing in visual field. Neurological exam significant for left hypertropia and exotropia in primary gaze, equal in right/left gaze and right/left head tilt, as well as large amplitude medium frequency (see‐saw) nystagmus characterized by upbeat nystagmus with intorsion on the right, and downbeat nystagmus with extorsion left. Visual fields were intact to finger count with binocular diplopia and oscillopsia noted in primary gaze. CT head and CT angiogram of the head and neck were unrevealing. Initial MRI brain negative for diffusion restriction but with flair hyperintensity in periaqueductal gray prompting repeat MRI brain without contrast with thin slices through the brainstem with showed infarct in periaqueductal gray within the region of the interstitial nuclei, with stroke etiology undetermined at the time of presentation but suspicion of small vessel disease vs hypercoagulability given propensity for thrombophilia in Turner syndrome and patient being on HRT. Full dose aspirin and high intensity statin therapy was initiated given presentation out of tPA window, and hypercoagulability workup initiated prior to discharge. Conclusion Acute ischemic stroke and lesions of the interstitial nuclei in the periaqueductal gray are important, under recognized considerations for the evaluation of binocular diplopia, that may represent an opportunity for thrombolytic administration if providers had a higher index of suspicion. Hypercoagulability and Turner syndrome are also unique qualifiers, underscoring a nuanced approach to determination of stroke diagnosis and etiology in cases of isolated ocular symptomology.

Abstract 106: CHANTER Syndrome: A Case Report Of A 59 Year Old Man With Positive Outcome

Introduction Cerebellar, Hippocampal, and Basal Nuclei Transient Edema with Restricted Diffusion (CHANTER) syndrome was first described in 2019 [1] as a pattern of radiographic findings that are distinct from ischemic, anoxic, or toxic brain injury. Pathophysiology is still uncertain, but some proposed theories include a primary metabolic etiology or a mitochondrial failure of gray matter. Clinically, patients typically present with altered level of consciousness. Radiographically, diffusion weighted imaging shows restriction in the bilateral hippocampi, bilateral cerebelli, and basal nuclei. The cerebral cortex, thalamus, and subcortical white matter are usually spared. Despite the morbid clinical picture on presenation, positive outcomes were reported with early intervention. We describe a case of CHANTER syndrome in a 59 year old man with history of illicit substance abuse. Methods Case report with electronic medical record review. Results 59‐year‐old man with history of illicit substance abuse including cocaine, opioid, and phencyclidine presented to the hospital after being found down at a drug store. Patient did not respond to Naloxone and was eventually intubated due to respiratory compromise. Non‐contrast CT head showed hypoattenuation of the bilateral cerebellar hemispheres with mild effacement of the fourth ventricle. MRI brain showed diffusion signal abnormalities with corresponding T2 FLAIR hyperintensities in the bilateral cerebellar hemispheres, bilateral hippocampi, and bilateral basal ganglia with some involvement of the left occipital lobe suggestive of CHANTER syndrome. As vasogenic edema worsened, hydrocephalus ensued requiring administration of hypertonic saline and eventual external ventricular drain (EVD) insertion in the neurocritical care unit. Despite initial improvement in his level of consciousness after the EVD insertion, his intracranial pressure (ICP) continued to increase and midazolam and ketamine infusion drips were added. A fine balance between lowering the ICP and avoiding respiratory suppresion with sedating infusions was maintained. Consecutive MRI brain images over the course of the following 4 weeks of his stay showed decrease of the abnormal diffusion weighted imaging signal along with improvement in his overall mental status and eventual discharge 12 weeks from his initial presentation. Conclusion This case further strengthens the relationship between CHANTER syndrome and illicit substance use as a likely etiology along with other cases in the literature. Aggressive management in the neurocritical care to control vasogenic edema and avoid ICP elevation is essential to give patients the highest chance of recovery. Clinical improvement At least partial reversal of the radiographic findings of CHANTER syndrome can be attained with treatment, however, unclear if complete reversal is possible.

A - 89 Cognitive Evaluation of Suspected Wernicke- Korsakoff's Encephalopathy in a Woman with Complicated Hyperemesis Gravidarum.

Wernicke-Korsakoff syndrome (WKS) is a neurological disorder caused by the lack of thiamine (vitamin B1) and includes Wernicke encephalopathy and the later stage of Korsakoff amnesic syndrome. WKS could be secondary to malnutrition, including Hyperemesis Gravidarum (HEG), which is characterized by severe vomiting during pregnancy. We present a case of HEG resulting in suspected WKS where neuropsychological evaluation clarified cognitive status with complex cultural, language, and educational factors. Repeat evaluations of a 29-year-old West-African* woman with mental status change, decreased verbal output, agitation, and inability to walk in the context of HEG. Initially referred for inpatient neuropsychological evaluation at 21weeks gestation. MRI demonstrated mild diffuse cerebral atrophy and symmetric foci of T2 FLAIR hyperintensities in periaqueductal gray matter, hypothalamus, bilateral thalami, perirolandic cortex, and bilateral mammillary bodies. Initial inpatient testing with a face-to-face language congruent interpreter demonstrated notable multidomain impairment. Possible Intellectual Disability was considered by the referring team and test performances. Attempts at re-evaluation were limited by medical complications and prolonged hospitalization. Repeat inpatient evaluation 5months later following birth of healthy child and initiation of stimulant medication, demonstrated profound memory impairment but otherwise improved cognitive capacity and engagement. Results aided in discharge planning including cognitive remediation with goal of improving functional independence. Wernicke-Korsakoff syndrome due to Hyperemesis Gravidarum is an uncommon but known complication that can have profound acute and long-term consequences. This case demonstrates that repeat neuropsychological evaluations can clarify cognitive status in complex medical/cultural/language situations. *(country of origin and primary language not provided for patient privacy).

PACS-Integrated Tools for Peritumoral Edema Volumetrics Provide Additional Information to RANO-BM-Based Assessment of Lung Cancer Brain Metastases after Stereotactic Radiotherapy: A Pilot Study.

Stereotactic radiotherapy (SRT) is the standard of care treatment for brain metastases (METS) today. Nevertheless, there is limited understanding of how posttreatment lesional volumetric changes may assist prediction of lesional outcome. This is partly due to the paucity of volumetric segmentation tools. Edema alone can cause significant clinical symptoms and, therefore, needs independent study along with standard measurements of contrast-enhancing tumors. In this study, we aimed to compare volumetric changes of edema to RANO-BM-based measurements of contrast-enhancing lesion size. Patients with NSCLC METS ≥10 mm on post-contrast T1-weighted image and treated with SRT had measurements for up to seven follow-up scans using a PACS-integrated tool segmenting the peritumoral FLAIR hyperintense volume. Two-dimensional contrast-enhancing and volumetric edema changes were compared by creating treatment response curves. Fifty NSCLC METS were included in the study. The initial median peritumoral edema volume post-SRT relative to pre-SRT baseline was 37% (IQR 8-114%). Most of the lesions with edema volume reduction post-SRT experienced no increase in edema during the study. In over 50% of METS, the pattern of edema volume change was different than the pattern of contrast-enhancing lesion change at different timepoints, which was defined as incongruent. Lesions demonstrating incongruence at the first follow-up were more likely to progress subsequently. Therefore, edema assessment of METS post-SRT provides critical additional information to RANO-BM.

Spectroscopic MRI Detects Occult Glioblastoma Invasion during Chemoradiation

The standard of care for glioblastoma (GBM) includes surgical resection followed by adjuvant chemoradiation (chemoRT). Treatment margins are controversial since conventional imaging does not define the extent of infiltrating tumor cells. Whole-brain spectroscopic MRI (sMRI) allows for visualization of native metabolites in normal brain and tumor cells, and the relative choline to N-acetyl-aspartate ratio greater than 2 (rChoNAA>2) strongly correlates with the presence of occult GBM cells in otherwise normal-appearing brain. With an MRI-Linac, we are performing studies of adaptive radiotherapy to measure changes in cavity size, edema, and enhancement during chemoRT. We questioned whether rChoNAA>2 would change along with anatomical changes to inform clinical target volumes for adaptive chemoRT trials. In a prospective study, 18 patients with primary GBM underwent daily MRI-guided chemoRT with standalone 3T sMRI generation of rChoNAA>2 maps at three timepoints before, during, and after chemoradiation. Conventional treatment volumes of T1 post-contrast and cavity (GTV2, i.e., boost) with or without FLAIR hyperintensity (GTV1) were compared to rChoNAA>2 volumes. DICE similarity coefficients were calculated to assess the spatial similarity of these volumes. Hausdorff distances were calculated to identify rChoNAA>2 extending beyond GTVs throughout the course of chemoradiation. The mean GTV1 was 58.1 cc (range 0-251.4 cc), the mean GTV2 was 47.9 cc (range 0-139.9 cc), and the mean rChoNAA>2 volume was 31.1 cc (range 0-103.2 cc). rChoNAA>2 volumes did not significantly change over the course of chemoRT or correlate with measurement timepoint. The mean DICE similarity coefficient between GTV1 and rChoNAA>2 volumes was 0.39 (range 0-0.80), and the mean DICE similarity coefficient between GTV2 and rChoNAA>2 volumes was 0.29 (range 0-0.77). DICE similarity coefficients were significantly different from unity indicating spatial differences between rChoNAA>2 and conventional MRI volumes. The mean Hausdorff distances of rChoNAA>2 extending beyond GTV1 was 1.3 cm (range 0.7-2.1 cm), and the mean Hausdorff distances of rChoNAA>2 extending beyond GTV2 was 1.9 cm (range 0.8-2.9 cm), suggesting high-risk disease invading beyond what is visible on conventional MRI sequences. Whole-brain sMRI with generation of rChoNAA>2 maps suggest conventional MRI does not fully capture the extent of disease in primary GBM throughout the course of chemoradiation. rChoNAA>2 maps often extend up to approximately 2 cm beyond conventional boost radiotherapy volumes. Further studies are ongoing to determine how sMRI can be used to adapt radiation target volumes during chemoradiation and escalate dose to occult disease.

Adjuvant Chemoradiotherapy within One Year of Resection for Molecularly Defined Astrocytoma

Treatments for diffuse low-grade gliomas (LGG) are controversial. Level I evidence supports the use of adjuvant radiotherapy (RT) and PCV chemotherapy for histologic LGG, but integration of molecular biomarkers in recent WHO classification and the emergence of temozolomide chemotherapy for gliomas necessitates additional investigation of the optimal treatment and timing of postoperative interventions. We hypothesized molecularly-defined LGG (IDH-mutant astrocytoma (astro) and IDH-mutant, 1p/19q-codeleted oligodendroglioma (oligo)) may have different clinical outcomes following adjuvant RT (aRT) with chemotherapy (aRT+chemo) vs observation or chemo alone. A retrospective analysis of consecutive adult patients diagnosed with WHO Grade 2 astrocytoma or oligodendroglioma who underwent initial resection at a single institution from January 1998 to November 2017 was performed. Wilcoxon rank sum and Chi-squared tests were used to compare continuous and categorical variables, respectively. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards models. Patients without clinical progression or death were censored at the date of last follow-up. Pre-operative and post-operative T2 FLAIR hyperintense tumor volumes were quantified using 3D Slicer to calculate extent of resection (EOR). A total of 342 patients with molecularly-defined LGG (178 astro, 164 oligo) were identified with a median follow up of 9.1 yr. 171 (50%) patients received RT during their treatment course, of which 31 (18%) were treated with aRT within 1 year of diagnosis. The median aRT dose was 54 Gy (range: 40-60 Gy). aRT was more likely for astro (58%) vs oligo (41%, p = 0.001) and for patients who had resections with lower median EOR (88% vs 95%, p = 0.014). 53 patients (15%) were treated with chemo alone, and 136 patients (40%) were treated with aRT+chemo. Temozolomide was used for 161 patients (85%). For astro, aRT+chemo was associated with longer PFS (median 14.9 yr) compared to observation (4.8 yr, p = 0.05), aRT without chemo (5.2 yr, p = 0.01), or chemo alone (4.7 yr, p = 0.02). For oligo, aRT+chemo was associated with longer PFS (median not reached) compared to aRT without chemo (1.6 yr, p = 0.03), but not when compared to observation (median not reached, p = 0.47), or chemo alone (7.9 yr, p = 0.45). Multivariate analysis showed preoperative tumor volume, EOR, and aRT+chemo (but not aRT or chemo alone) were independently associated with astro PFS compared to observation. Propensity matching based on pre-operative tumor volume, EOR, and age demonstrated longer astro PFS after aRT+chemo (14.9 yr) compared to observation or chemo alone (4.5 yr, p = 0.015), without significant difference in OS (18.2 vs. 11.5 yr, p = 0.40). Retrospective data from a single institution support the use of adjuvant radiotherapy with chemotherapy for patients with molecular astrocytomas, while the role of this approach for oligodendrogliomas is unclear in this cohort.

Dosimetric Implications of Weekly On-Line MR-Guided Adaptive Radiotherapy (RT) for Glioblastomas (GBM) Growing during RT

The UNITED trial (NCT04726397) involves once-weekly on-line adaptive RT for patients with GBM on a 1.5T MRI-Linac (MRL). For tumors that continue to enlarge during the course of RT, we hypothesize that the adaptive strategy improves the dosimetric coverage of the target relative to a non-adaptive strategy. As per the trial protocol, T1+contrast (T1c) and FLAIR MRI sequences were acquired once per week during RT to re-define and adapt the gross tumor volume (GTV) as the contrast enhanced volume, the clinical target volume (CTV) as a 5mm expansion around the GTV plus adjacent FLAIR hyperintense regions considered at-risk by the radiation oncologist, and a 3 mm PTV around the CTV. Nine UNITED patients with tumors that grew throughout RT (GTV and/or CTV) were identified. 5/9 patients were treated with 60 Gy in 30 fractions (6 weekly adaptions) and 4/9 with 40 Gy in 15 fractions (3 weekly adaptions). For the final week's GTV and CTV (GTVfinal and CTVfinal), the dosimetric outcomes of the delivered and adaptive summative plans (Dsum) were compared to dose of the baseline plan (Dbaseline) generated on Fraction 1 of treatment, the latter being indicative of the theoretical situation where no further adaption was taken. We measured the dose to 99% of the GTVfinal and CTVfinal: Dsum99 and Dbaseline99. For each adaptive fraction, the plan was optimized to achieve an objective of D99 greater than 95% of the prescription (D99>95%) for both the GTV and CTV. The relative increase in GTVfinal and CTVfinal from baseline was on average 119% (range: 98% to 144.7%) and 128% (range: 109% to 176%), respectively. The proportion of CTVfinal that was outside the baseline plan's PTV was on average 11.5% (range: 0% to 32%). The GTVfinal did not extend beyond the baseline PTV for any of the 9 cases. GTVfinal Dsum99 was >95% for all cases while CTVfinal Dsum99 was < 95% in 2 of 9 cases (74%, and 87%). By contrast, the baseline plan, if given for all fractions with no further adaptation, yielded a D99 for CTVfinal of <95% in 5 of 9 cases (28%, 52%, 75%, 84%, and 87%). In general, coverage of the CTVfinal decreased with increasing levels of CTVfinal outside of the baseline PTV. For all 5 cases where CTVfinal D99<95% on the baseline plan, more than 10% of CTVfinal was outside of the baseline PTV. Small margin, weekly adaptive RT on an MRL for GBM maintains coverage of the GTV in the presence of tumor growth while minimizing the degree of normal brain tissue irradiated. Dosimetric impact on non-GTV/CTV brain is outside the scope of the present study. Preliminary results indicate that a once weekly adaptive approach for small margin MR-guided RT improves tumor coverage for progressive tumors compared to a static (baseline) plan without adaptation.

PREOPERATIVE BRAIN IRRADIATION IN GLIOBLASTOMA (POBIG TRIAL): FEASIBILITY AND EVALUATION OF TREATMENT RESPONSE IN ENHANCING AND NON-ENHANCING REGIONS

Abstract AIMS Patients with glioblastoma have dismal outcomes and there is an urgent need for new treatment modalities. The POBIG trial is the first to evaluate the safety and feasibility of single-fraction preoperative radiotherapy for newly diagnosed glioblastoma. We report the results from our first dose arm. METHOD POBIG is a phase I radiotherapy dose and volume escalation trial. The first dose arm received 8Gy preoperative radiotherapy to a maximum irradiation volume of 30cm3. The irradiation field included enhancing and non- enhancing FLAIR hyperintense regions judged as highest risk for remaining as postoperative residuum. Part of the tumour remained unirradiated (&amp;lt;2Gy) with a margin for diagnostic sampling. Surgical resection took place within 1 week. Patients underwent diffusion/perfusion MRI scans before/after preoperative radiotherapy. RESULTS Two female and one male patient aged 61, 67 and 45 years, respectively, were enrolled. Preoperative radio- therapy was delivered at a dose of 8Gy to an irradiation volume of 7-30cm3. Near-total surgical resection was performed 2-3 days after preoperative radiotherapy treatment. Pathological examination of irradiated areas showed necrosis including fibrinoid necrosis of vessel walls. There was an increase in Ktrans permeability in both irradiated enhancing tumour (0.097,0.150) and unirradiated enhancing tumour (0.077,0.147) 24-hours after treatment. In contrast, no obvious changes were noted in irradiated (0.002,0.002) and unirradiated (0.002,0.004) non-enhancing FLAIR hyperintense regions or reference unirradiated contralateral white matter (0.000,0.000). CONCLUSIONS Preoperative radiotherapy is feasible in newly diagnosed glioblastoma. Very early radiotherapy changes manifest in enhancing tumour regardless of radiotherapy dose, evident as increased permeability and radiation- induced tumour necrosis.

Seizure-induced reversible magnetic resonance imaging abnormalities: A retrospective cohort study

PurposeSeizure-induced reversible magnetic resonance imaging (MRI) abnormalities (SRMA) present challenges in seizure management. We sought to investigate the frequency, risk factors, evolution and prognostic value of SRMA. MethodsA retrospective observational cohort study of consecutive seizure patients investigated with an MRI of the brain was conducted. Clinical and MRI data were reviewed to determine the clinical characteristics and imaging findings of SRMA. Outcomes (seizure freedom versus uncontrolled seizures and deaths) were assessed upon the last clinic follow-up. Mann-Whitney U test and chi-square test for independence with Bonferroni correction were used to explore the statistical significance of predictive factors. ResultsThe study included 483 consecutive seizure patients with 7.6% developing SRMA. Patients with SRMA were older (median age 57 years, interquartile range-IQR 52–66, p < 0.001) and experienced longer seizures (median 5 minutes, IQR 2–15, p = 0.002) compared with seizure patients with normal MRI. Seizure type (provoked versus unprovoked), recurrence (first versus recurrent) and epileptiform EEG changes did not demonstrate a significant association. Diffusion restriction and ADC reduction observed in SRMA resolved earlier, while T2, FLAIR hyperintensities and temporal lobes changes persisted longer on follow-up scans. The median time interval from seizure to complete resolution of SRMA was 87 days (IQR 45-225). No statistical difference in outcomes was seen between patients with SRMA and normal MRIs (p = 0.19). ConclusionsSRMA is an uncommon finding following seizures. It is not associated with poor seizure control or mortality. Risk factors associated with SRMA include older age and longer seizure duration including status epilepticus.

Undetected pseudoprogressions in the CeTeG/NOA-09 trial: hints from postprogression survival and MRI analyses

PurposeIn the randomized CeTeG/NOA-09 trial, lomustine/temozolomide (CCNU/TMZ) was superior to TMZ therapy regarding overall survival (OS) in MGMT promotor-methylated glioblastoma. Progression-free survival (PFS) and pseudoprogression rates (about 10%) were similar in both arms. Further evaluating this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at first progression according to modified RANO criteria (mRANO).MethodsWe classified the patients of the CeTeG/NOA-09 trial according to long vs. short PPS employing a cut-off of 18 months and compared baseline characteristics and survival times. In patients with available MRIs and confirmed progression, the increase in T1-enhancing, FLAIR hyperintense lesion volume and the change in ADC mean value of contrast-enhancing tumor upon progression were determined.ResultsPatients with long PPS in the CCNU/TMZ arm had a particularly short PFS (5.6 months). PFS in this subgroup was shorter than in the long PPS subgroup of the TMZ arm (11.1 months, p = 0.01). At mRANO-defined progression, patients of the CCNU/TMZ long PPS subgroup had a significantly higher increase of mean ADC values (p = 0.015) and a tendency to a stronger volumetric increase in T1-enhancement (p = 0.22) as compared to long PPS patients of the TMZ arm.ConclusionThe combination of survival and MRI analyses identified a subgroup of CCNU/TMZ-treated patients with features that sets them apart from other patients in the trial: short first PFS despite long PPS and significant increase in mean ADC values upon mRANO-defined progression. The observed pattern is compatible with the features commonly observed in pseudoprogression suggesting mRANO-undetected pseudoprogressions in the CCNU/TMZ arm of CeTeG/NOA-09.

A Multidimensional Connectomics- and Radiomics-Based Advanced Machine-Learning Framework to Distinguish Radiation Necrosis from True Progression in Brain Metastases.

We introduce tumor connectomics, a novel MRI-based complex graph theory framework that describes the intricate network of relationships within the tumor and surrounding tissue, and combine this with multiparametric radiomics (mpRad) in a machine-learning approach to distinguish radiation necrosis (RN) from true progression (TP). Pathologically confirmed cases of RN vs. TP in brain metastases treated with SRS were included from a single institution. The region of interest was manually segmented as the single largest diameter of the T1 post-contrast (T1C) lesion plus the corresponding area of T2 FLAIR hyperintensity. There were 40 mpRad features and 6 connectomics features extracted, as well as 5 clinical and treatment factors. We developed an Integrated Radiomics Informatics System (IRIS) based on an Isomap support vector machine (IsoSVM) model to distinguish TP from RN using leave-one-out cross-validation. Class imbalance was resolved with differential misclassification weighting during model training using the IRIS. In total, 135 lesions in 110 patients were analyzed, including 43 cases (31.9%) of pathologically proven RN and 92 cases (68.1%) of TP. The top-performing connectomics features were three centrality measures of degree, betweenness, and eigenvector centralities. Combining these with the 10 top-performing mpRad features, an optimized IsoSVM model was able to produce a sensitivity of 0.87, specificity of 0.84, AUC-ROC of 0.89 (95% CI: 0.82-0.94), and AUC-PR of 0.94 (95% CI: 0.87-0.97).

SDPS-08 OSSEOUS METASTASES IN H3G34-MUTANT DIFFUSE HEMISPHERIC GLIOMAS

Abstract Subset of patients with H3G34 gliomas may present with extra-CNS metastasis further complicating both diagnosis and treatment. We describe a case of a 19-year-old female presenting initially with focal motor seizure in right leg along with leg pain. MRI of the leg showed an ill-defined right distal femur expansile osteolytic lesion with central fluid signal, thick rim enhancement, endosteal scalloping, cortical invasion, and smooth enhancing periosteal reaction/soft tissue extension associated with surrounding enhancing marrow signal abnormality worrisome for lesion extension. Contrast brain MRI exhibited multiple frontal and partial lobe T2 FLAIR hyperintense lesions. The largest lesion demonstrated contrast enhancement, internal foci of restricted diffusion, and a focus of intratumoral hemorrhage. A whole-body PET/CT showed intensely FDG-avid lytic lesion in the right distal femur, with FDG activity along the biopsy tract. Hypermetabolic lytic metastases to the right femoral head and mid-sacral body were also observed. A craniotomy with brain lesion biopsy two months later indicated preliminary histopathology of malignant small round blue cell neoplasm. A biopsy from the distal right femur was non-diagnostic of malignancy but a sacral bone biopsy reported malignant small blue cell neoplasm, consistent with involvement by the patient's known cranial neoplasm. Final pathological diagnosis including molecular diagnostics was consistent with WHO grade 4 IDH-wildtype H3G34 mutant diffuse hemispheric glioma with osseous metastases. Patient was treated with chemoradiotherapy with temozolomide (TMZ). Following the sixth cycle of TMZ, MRI brain imaging was stable. Apart from holocephalic headaches, the patient had no significant medication side effects and was seizure-free. A second whole-body PET scan showed improvement and interval decrease in FDG uptake of the sacrum and right femoral head. Given the stress that patients with H3G34 can experience and the poor prognosis, it is imperative to expand our knowledge and ascertain accurate screening and diagnostic methodologies.