Aboian, Mariam S

Abstract Background Although response in pediatric low-grade glioma (pLGG) includes volumetric assessment, more simplified 2D-based methods are often used in clinical trials. The study’s purpose was to compare volumetric to 2D methods. Methods An expert neuroradiologist performed solid and whole tumor (including cyst and edema) volumetric measurements on MR images using a PACS-based manual segmentation tool in 43 pLGG participants (213 total follow-up images) from the Pacific Pediatric Neuro-Oncology Consortium (PNOC-001) trial. Classification based on changes in volumetric and 2D measurements of solid tumor were compared to neuroradiologist visual response assessment using the Brain Tumor Reporting and Data System (BT-RADS) criteria for a subset of 65 images using receiver operating characteristic (ROC) analysis. Longitudinal modeling of solid tumor volume was used to predict BT-RADS classification in 54 of the 65 images. Results There was a significant difference in ROC area under the curve between 3D solid tumor volume and 2D area (0.96 vs 0.78, P = .005) and between 3D solid and 3D whole volume (0.96 vs 0.84, P = .006) when classifying BT-RADS progressive disease (PD). Thresholds of 15–25% increase in 3D solid tumor volume had an 80% sensitivity in classifying BT-RADS PD included in their 95% confidence intervals. The longitudinal model of solid volume response had a sensitivity of 82% and a positive predictive value of 67% for detecting BT-RADS PD. Conclusions Volumetric analysis of solid tumor was significantly better than 2D measurements in classifying tumor progression as determined by BT-RADS criteria and will enable more comprehensive clinical management.

Abstract Radiographic response assessment in neuro-oncology is critical in clinical practice and trials. Conventional criteria, such as the MacDonald and response assessment in neuro-oncology (RANO) criteria, rely on bidimensional (2D) measurements of a single tumor cross-section. Although RANO criteria are established for response assessment in clinical trials, there is a critical need to address the complexity of brain tumor treatment response with multiple new approaches being proposed. These include volumetric analysis of tumor compartments, structured MRI reporting systems like the Brain Tumor Reporting and Data System, and standardized approaches to advanced imaging techniques to distinguish tumor response from treatment effects. In this review, we discuss the strengths and limitations of different neuro-oncology response criteria and summarize current research findings on the role of novel response methods in neuro-oncology clinical trials and practice.

Abstract BACKGROUND Gliomas with CDKN2A mutations are known to have worse prognosis but imaging features of these gliomas are unknown. Our goal is to identify CDKN2A specific qualitative imaging biomarkers in glioblastomas using a new informatics workflow that enables rapid analysis of qualitative imaging features with Visually AcceSAble Rembrandtr Images (VASARI) for large datasets in PACS. Gliomas with CDKN2A mutations are known to have worse prognosis but imaging features of these gliomas are unknown. Our goal is to identify CDKN2A specific qualitative imaging biomarkers in glioblastomas using a new informatics workflow that enables rapid analysis of qualitative imaging features withVisually AcceSAble Rembrandtr Images (VASARI) for large datasets in PACS. MATERIAL AND METHODS Sixty nine patients undergoing GBM resection with CDKN2A status determined by whole-exome sequencing were included. GBMs on magnetic resonance images were automatically 3D segmented using deep learning algorithmsincorporated within PACS. VASARI features were assessed using FHIR forms integrated within PACS. RESULTS GBMs without CDKN2A alterations were significantly larger (64% vs. 30%, p=0.007) compared to tumors with homozygous deletion (HOMDEL) and heterozygous loss (HETLOSS). Lesions larger than 8 cm were four times more likely to have no CDKN2A alteration (OR: 4.3; 95% CI:1.5-12.1; p<0.001). The pial invasion was predictive of HOMDEL (OR: 8.1, 95% CI: 1.8-53.2; p<0.012) as tumors with pial invasion were eight times more likely to be HOMDEL, even after adjusting for deep white matter and subependymal invasion. CONCLUSION We developed a novel integrated PACS informatics platform for the assessment of GBM molecular subtypes and show that tumors with HOMDEL are more likely to have radiographic evidence of pial invasion and less likely to have deep white matter invasion or subependymal invasion. These imaging features may allow noninvasive identification of CDKN2A allele status.

Abstract BACKGROUND Differentiating radiation necrosis from tumour progression after radiation therapy (RT) for brain metastases (BM) remains clinically challenging, and accurate imaging is crucial to prevent unnecessary surgery or unwarranted changes in therapy. 18F-Fluciclovine is a PET radiopharmaceutical with low background uptake in the brain and increased uptake in BM. The PURSUE study (NCT04410367) aimed to establish image interpretation criteria (IIC) for detecting suspected recurrent BM after RT using 18F-fluciclovine PET, based on several measures of lesion uptake. MATERIAL AND METHODS Across 7 US sites, 23 patients with solid tumour BM and a previously irradiated ‘reference’ lesion equivocal for recurrence on MRI who were scheduled for craniotomy underwent 18F-fluciclovine PET (185 MBq) <42 days post-MRI and 1-21 days pre-craniotomy. Three independent, blinded readers qualitatively rated lesion 18F-fluciclovine uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid gland), or ‘marked’ (above parotid gland). The primary endpoint was the diagnostic performance of different thresholds of lesion uptake on qualitative (visual) reads vs central histopathology. Secondary endpoints included diagnostic performance, based on different thresholds, of quantitative (e.g., lesion standardized uptake value [SUV]), and dynamic measures. A committee, including two independent imaging physicians, reviewed all data to establish the IIC, which were subsequently used to evaluate the diagnostic performance of 18F-fluciclovine. RESULTS All 23 reference lesions underwent histopathological analysis, with 10 (43%) being pathologically confirmed BM recurrence. The highest performing qualitative measure of 18F-fluciclovine lesion uptake was ‘marked’, rendering 92-100% and variable (40-80%) across readers. SUVmax was a reader-independent, high-performing quantitative metric (AUC 0.87, SUVmax threshold 4.8, 80% sensitivity, 85% specificity). Dynamic measures did not add diagnostic value. Thus, the committee established IIC as: "Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely." Application of these IIC resulted in 80% sensitivity, 77-85% specificity, 73-80% positive predictive value, and 83-85% negative predictive value across readers. CONCLUSION PURSUE is the first prospective, multicentre study to define IIC for 18F-fluciclovine PET for accurate identification of suspected recurrent BM after RT, verified by histopathology. In this initial cohort, the IIC convey excellent diagnostic performance for 18F-fluciclovine and will help evaluate 18F-fluciclovine PET in future studies. This study was sponsored by Blue Earth Diagnostics Ltd.

2001 Background: Differentiating radiation necrosis from tumor progression remains one of the most commonly encountered and clinically challenging scenarios after radiation therapy (RT) for brain metastases (BM). PURSUE (NCT04410367) evaluated the diagnostic performance of 18F-fluciclovine, an amino acid PET radiopharmaceutical, based on various lesion metrics, to establish image interpretation criteria (IIC) for suspected recurrent BM after RT. Methods: Patients with solid tumor BM were enrolled across 7 US sites if they had a previously irradiated ‘reference’ lesion equivocal on MRI for recurrence and were planned for craniotomy. 18F-Fluciclovine PET (185 MBq) took place <42 days post-MRI and 1-21 days pre-craniotomy. The primary endpoint was the diagnostic performance (sensitivity, specificity, positive-, and negative-predictive value [PPV/NPV]) of different thresholds of lesion 18F-fluciclovine uptake on qualitative, visual reads vs central histopathological analysis. Lesion 18F-fluciclovine uptake was assessed qualitatively by 3 independent blinded readers who visually rated the uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid), or ‘marked’ (above parotid). Secondary endpoints included the diagnostic performance based on different thresholds of quantitative (e.g., lesion SUV) and dynamic measures of uptake. A committee, including 2 expert imaging physicians independent to PURSUE, reviewed all data in round-table meetings to establish the IIC, which were subsequently used to assess diagnostic performance. Results: All 23 reference lesions in 23 subjects underwent histopathological analysis, with 10 (43%) confirmed as recurrent tumor. The highest performing qualitative measure was ‘marked’, rendering a sensitivity of 92-100%, with variable specificity of 40-80% across readers. SUVmax was a reader-independent, high-performing quantitative metric on ROC analysis (AUC 0.87, SUVmax threshold 4.8 conferring a sensitivity of 80% and specificity of 85%). Dynamic measures did not provide added diagnostic value. After analyzing these metrics, the committee established IIC as: Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely. Application of the IIC resulted in a sensitivity of 80%, specificity of 77-85%, PPV of 73-80%, and NPV of 83-85% across the readers. Conclusions: This is the first prospective multicenter trial to evaluate PET characteristics of suspected recurrent BM after RT, verified by histopathology. Qualitative and quantitative IIC show 18F-fluciclovine to be a high-performing diagnostic tool. These IIC will help evaluate the diagnostic performance of 18F-fluciclovine PET in future trials. Clinical trial information: NCT04410367 .

Abstract Epilepsy neuroimaging assessment requires exceptional anatomic detail, physiologic and metabolic information. Magnetic resonance (MR) protocols are often time-consuming necessitating sedation and positron emission tomography (PET)/computed tomography (CT) comes with a significant radiation dose. Hybrid PET/MRI protocols allow for exquisite assessment of brain anatomy and structural abnormalities, in addition to metabolic information in a single, convenient imaging session, which limits radiation dose, sedation time, and sedation events. Brain PET/MRI has proven especially useful for accurate localization of epileptogenic zones in pediatric seizure cases, providing critical additional information and guiding surgical decision making in medically refractory cases. Accurate localization of seizure focus is necessary to limit the extent of the surgical resection, preserve healthy brain tissue, and achieve seizure control. This review provides a systematic overview with illustrative examples demonstrating the applications and diagnostic utility of PET/MRI in pediatric epilepsy.

Recent clinical and experimental evidence has challenged the traditional concept of the venous system as a “passive” element in the genesis and evolution of intracranial vascular malformations. The authors review the clinical and experimental evidence linking the venous system and its anomalies to the genesis of various intracranial vascular malformations, including dural arteriovenous fistulas, cavernous malformations, parenchymal arteriovenous malformations, and capillary telangiectasia. They also describe the potential significance of different associations of these vascular anomalies.

A subset of proteins that transit the endosomal system are directed into the intralumenal vesicles of multivesicular bodies (MVBs). MVB formation is critical for a variety of cellular functions including receptor down-regulation, viral budding, antigen presentation, and the generation of lysosome-related organelles. Entry of transmembrane proteins into the intralumenal vesicles of a MVB is a highly regulated process that is positively modulated by covalent modification of cargoes with ubiquitin. To identify additional MVB sorting signals, we examined the previously described ubiquitination-independent MVB cargo Sna3. Although Sna3 ubiquitination is not essential, Sna3 MVB sorting is positively modulated by its ubiquitination. Examination of MVB sorting determinants within a form of Sna3 lacking all lysine residues identified two critical regions: an amino-terminal tyrosine-containing region and a carboxyl-terminal PPAY motif. This PPAY motif interacts with the WW domains of the ubiquitin ligase Rsp5, and mutations in either the WW or, surprisingly, the HECT domains of Rsp5 negatively impacted MVB targeting of lysine-minus Sna3. These data indicate that Rsp5 function is required for MVB targeting of Sna3 in a capacity beyond cargo ubiquitination. These results uncover a series of determinants impacting Sna3 MVB sorting, including unexpected roles for Rsp5.