Andrew Samoyedny

While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.

PURPOSE Many novel therapies for relapsed and refractory neuroblastoma require tumor tissue for genomic sequencing. We analyze our experience with image-guided biopsy in these patients, focusing on safety, yield, adequacy for next-generation sequencing (NGS), and correlation of tumor cell percent (TC%) with quantitative uptake on 123 I-meta-iodobenzylguanidine (MIBG) single-photon emission computed tomography with computed tomography (SPECT/CT). MATERIALS AND METHODS An 11-year retrospective review of image-guided biopsy on 66 patients (30 female), with a median age of 8.7 years (range, 0.9-49 years), who underwent 95 biopsies (55 bone and 40 soft tissue) of relapsed or refractory neuroblastoma lesions was performed. RESULTS There were seven minor complications (7%) and one major complication (1%). Neuroblastoma was detected in 88% of MIBG- or fluorodeoxyglucose-avid foci. The overall NGS adequacy was 69% (64% in bone and 74% in soft tissue, P = .37). NGS adequacy within neuroblastoma-positive biopsies was 88% (82% bone and 96% soft tissue, P = .11). NGS-adequate biopsies had a greater mean TC% than inadequates (51% v 18%, P = .03). NGS-adequate biopsies had a higher mean number of needle passes (7.5 v 3.4, P = .0002). The mean tissue volume from NGS-adequate soft-tissue lesions was 0.16 cm 3 ± 0.12. Lesion:liver and lesion:psoas MIBG uptake ratios correlated with TC% (r = 0.74, r = 0.72, and n = 14). Mean TC% in NGS-adequate samples was 51%, corresponding to a lesion:liver ratio of 2.9 and a lesion:psoas ratio of 9.0. Thirty percent of biopsies showed an actionable ALK mutation or other therapeutically relevant variant. CONCLUSION Image-guided biopsy for relapsed or refractory neuroblastoma was safe and likely to provide NGS data to guide therapy decisions. A lesion:liver MIBG uptake ratio of ≥ 3 or a lesion:psoas ratio of > 9 was associated with a TC% sufficient to deliver NGS results.

INTRODUCTION: Though mesenteric venous thrombosis (MVT) causes bowel ischemia far less frequently than arterial thrombosis, it still has the potential to cause life-threatening bowel infarction. PRESENTATION OF CASE: Presented here is a case of idiopathic MVT of the superior mesenteric vein and multiple distal venous branches causing diffuse peritonitis secondary to small bowel infarction in a 64 year old male. History and physical exam demonstrated severe persistent abdominal pain, hematochezia, and diffuse abdominal tenderness to palpation with guarding. Venous filling defects and segmental enteritis were noted on CT. The patient was treated with immediate IV heparin therapy with subsequent laparotomy and excision of 45 cm of ischemic ileum. The patient had an uncomplicated recovery. Post-operative thrombophilia screen was negative. The patient was discharged on indefinite warfarin therapy. DISCUSSION: MVT is often idiopathic in nature, with up to 49% having no identifiable cause. Risk factors include abdominal inflammation and systemic thrombophilias. Importantly, bowel infarction is more common with occlusion of more distal, smaller caliber mesenteric vessels. The standard of diagnosis is contrast-enhanced abdominal CT, and management is prompt anticoagulation with surgical intervention if severe. If the cause remains unclear, outpatient anticoagulation is continued indefinitely. CONCLUSION: This case provides a valuable demonstration of several important MVT concepts - specifically the high rate of idiopathic etiology, the need for indefinite anticoagulation in idiopathic cases, and the increased risk of infarction in occlusion of smaller, more distal mesenteric veins.

e22521 Background: Relapsed and refractory neuroblastoma (NBL) is a prime target for novel therapies targeting specific mutations. The genomic landscape of NBL can change between time of initial diagnosis and relapse, necessitating subsequent biopsy and next generation sequencing (NGS) to detect mutations within the relapsed neoplasm. Tissue of insufficient quality and quantity leads to specimen failure during NGS. Thus the goal of this study is to review core needle biopsy for relapsed and refractory NBL in a pediatric interventional radiology department and explore factors that enhance biopsy adequacy. Methods: Retrospective review of clinical records and images for 66 patients (36M, 30F) with median age 8.7 years (range 0.9 – 49.3 y) who underwent 95 biopsies (55 bone, 40 soft tissue) over a 12-year period. Results: Biopsy yield for neuroblastic tissue from 123I mIBG-avid masses was 89.7% overall, 84.9% in bone, and 91.6% in soft tissue. 87/95 masses were mIBG-avid; 2 non-avid masses were NBL-positive (but also 18F-FDG avid). 48/59 samples sent for NGS were adequate for analysis (81.4%); bone and soft tissue biopsies did not differ in adequacy (77.1% vs 87.5%, p = 0.32). Tumor cell percent (TC%) for adequate samples was 49.9% vs 11.1% for NGS failures (p = 0.0003). Number of needle passes performed in bone and soft tissue lesions was positively correlated with NGS adequacy (Bone: r 2 = 0.68, Soft: r 2 = 0.33). In bone and soft tissue, adequate biopsies tended towards higher mean needle passes than inadequate ones (Bone: 5.1 vs 3.4, p = 0.0582) (Soft: 10.5 vs 4.7, p = 0.0428). Total needle volume passed into a soft tissue mass (calculated as inner needle cylindrical volume * # of passes) was higher in the “adequate” vs “inadequate” group (0.20 cm 3 vs 0.05 cm 3 , p = 0.0004). Lesion mIBG avidity was quantified with a ratio of lesion:liver SUV; this mIBG SUV ratio was positively correlated with TC% (R 2 = 0.55, N = 14). Using a linear regression line, a TC% of 50% (the mean value for samples adequate for NGS) corresponded to an SUV ratio of 2.89. The rate of minor complications (requiring only nominal therapy) was 7/95 (7.4%). The rate of major complications (requiring longer hospital stay) was 1/95 (1.5%). Conclusions: Image-guided core needle biopsy for relapsed and refractory NBL has a moderately high yield for procuring tumor samples adequate for NGS with a low rate of major complications. Adequate bone and soft tissue biopsies averaged >5 and >10 needle passes, respectively. An approximate lesion:liver mIBG SUV ratio of >3 may maximize specimen quality for NGS.

119 Introduction: Neuroblastoma (NBL) is the most common extracranial solid tumor in children and accounts for nearly 15% of pediatric cancer fatalities. Nepenthe is a clinical trial for high risk NBL patients who are unresponsive to standard treatment. The trial matches genomic aberrations in NBL cells to targeted inhibitor therapy. 123I-methyliodobenzylguanidine (mIBG) has high sensitivity for NBL and can be used to identify a biopsy site. Purpose: The purpose of this study is to assess the utility of using a quantitative 123I-mIBG SPECT/CT standardized uptake value (SUV) to determine an SUV ratio cutoff value above which a successful biopsy with actionable genetic data can be predicted. Methods: This study includes 14 patients with refractory NBL who underwent 123I-mIBG SPECT/CT scans from 2/2018 to 6/2019 within a month of biopsy. Data was obtained via review of patient medical and pathology records (EPIC EMR) as well as Foundation Medicine Next Generation Sequencing (NGS) genetic reports from Nepenthe records. 123I-mIBG scans with SPECT/CT were performed on Siemens Symbia Intevo scanners. All biospies were performed by interventional radiology. The reports were used to identify the biopsy site to be measured. The lesion morphology was recorded as soft tissue or marrow infiltration confirmed on MRI. Using the Siemens syngovia processing package, standardized uptake values (SUV) were measured using a region of interest (ROI) drawn on the lesion (SUVmax) and background ROIs drawn on the right lobe of the liver and the psoas muscle (SUVmean). Results: In this research, max lesion to mean psoas SUV ratio was used due to lower variability within and between participants than max lesion to mean liver SUV ratio (SD = 0.23 vs SD = 0.99). Psoas to liver SUV ratios can be interchanged as the ratios are highly correlated (R = 0.91, p<0.01). There is a correlation between increasing ratio of lesion SUVmax to psoas SUVmean and increasing tumor cell percentage (%) within the specimen (R2=0.355, p=0.0246). A higher tumor cell % was found to correlate with actionable genetic findings (Pearson’s R = 0.602, p<0.05). This data shows that an SUV ratio of at least 5.0 increases the chance of having a biopsy with a successful high tumor cell %. Conclusions: 1. Quantitation of 123I-mIBG uptake can predict biopsy yield for increased chance of successful NGS testing in order to personalize treatment for children with relapsed or refractory NBL. 2. Background activity using psoas 123I-mIBG SUVmean is a reliable alternative to liver 123I-mIBG SUVmean. 3. An SUV ratio minimum would help clinicians determine the best site for biopsy. If a lesion does not reach the 123I-mIBG SUV minimum for biopsy, a PET scan may be a useful alternative in localizing biopsy sites and predicting biopsy yield.