PURPOSE:The best possible outcomes in infantile epileptic spasms syndrome require electroclinical remission; however, determining electrographic remission is not straightforward. Although the determination of hypsarrhythmia has inadequate interrater reliability (IRR), the Burden of AmplitudeS and Epileptiform Discharges (BASED) score has shown promise for the reliable interictal assessment of infantile epileptic spasms syndrome. Our aim was to develop a BASED training program and assess the IRR among learners. We hypothesized moderate or better IRR for the final BASED score and the presence or absence of epileptic encephalopathy (+/-EE). METHODS:Using a web-based application, 31 learners assessed 12 unmarked EEGs (length 1-6 hours) from children with infantile epileptic spasms syndrome. RESULTS:For all readers, the IRR was good for the final BASED score (intraclass correlation coefficient 0.86) and +/-EE (Marginal Multirater Kappa 0.63). For all readers, the IRR was fair to good for all individual BASED score elements. CONCLUSIONS:These findings support the use of our training program to quickly learn the BASED scoring method. The BASED score may be a valuable clinical and research tool. Given that the IRR for the determination of epileptic encephalopathy is not perfect, clinical acumen remains paramount. Additional experience with the BASED scoring technique among learners and advances in collaborative EEG evaluation platforms may improve IRR.

Background and ObjectivesFor children with cerebral malaria, mortality is high, and in survivors, long-term neurologic and cognitive dysfunctions are common. While specific clinical factors are associated with death or long-term neurocognitive morbidity in cerebral malaria, the association of EEG features with these outcomes, particularly neurocognitive outcomes, is less well characterized.MethodsIn this prospective cohort study of 149 children age 6 months to 12 years who survived cerebral malaria in Kampala, Uganda, we evaluated whether depth of coma, number of clinical seizures, or EEG features during hospitalization were associated with mortality during hospitalization, short-term and long-term neurologic deficits, or long-term cognitive outcomes (overall cognition, attention, memory) over the 2-year follow-up.ResultsHigher Blantyre or Glasgow Coma Scores (BCS and GCS, respectively), higher background voltage, and presence of normal reactivity on EEG were each associated with lower mortality. Among clinical and EEG features, the presence of >4 seizures on admission had the best combination of negative and positive predictive values for neurologic deficits in follow-up. In multivariable modeling of cognitive outcomes, the number of seizures and specific EEG features showed independent association with better outcomes. In children younger than 5 years throughout the study, seizure number and presence of vertex sharp waves were independently associated with better posthospitalization cognitive performance, faster dominant frequency with better attention, and higher average background voltage and faster dominant background frequency with better associative memory. In children younger than 5 years at CM episode but 5 years or older at cognitive testing, seizure number, background dominant frequency, and the presence of vertex sharp waves were each associated with changes in cognition, seizure number and variability with attention, and seizure number with working memory.DiscussionIn children with cerebral malaria, seizure number is strongly associated with the risk of long-term neurologic deficits, while seizure number and specific EEG features (average background voltage, dominant rhythm frequency, presence of vertex sharp waves, presence of variability) are independently associated with cognitive outcomes. Future studies should evaluate the predictive value of these findings.

BACKGROUND AND OBJECTIVES:Infantile spasms (IS) are early childhood seizures with potentially devastating consequences. Standard therapies (adrenocorticotropic hormone [ACTH], high-dose prednisolone, and vigabatrin) are strongly recommended as the first treatment for IS. Although this recommendation comes without preference for one standard therapy over another, early remission rates are higher with hormone therapy (ACTH and high-dose prednisolone) when compared with vigabatrin. Using quality improvement (QI) methodology that included hormone therapy as the first treatment, we sought to increase the percentage of children with new-onset nontuberous sclerosis complex (TSC)-associated IS achieving 3-month electroclinical remission from a mean of 53.8% to ≥70%. METHODS:This was an observational consecutive sample cohort study at a single academic tertiary care hospital that compared a prospective intervention cohort (May 2019-January 2022, N = 57) with a retrospective baseline cohort (November 2015-April 2019, N = 67). Our initiative addressed key drivers such as the routine use of vigabatrin over hormone therapy as first treatment and the common initiation of a second treatment after 14 days for initial nonresponders. We included consecutive children without TSC presenting with new-onset IS diagnosed and treated between ages 2 and 24 months. We displayed our primary outcome and process measures as control charts in which the centerline is the quarterly (previous 3 months) mean based on statistical process control methodology. RESULTS:QI interventions that included the standardization of hormone therapy as the first treatment resulted in higher rates of 3-month remission, rising from 53.8% (baseline cohort) to 75.9% (intervention cohort). Process measure results included an increased rate of children receiving hormone therapy as first treatment (mean, 44.6%-100%) and a decreased number of days to both clinical follow-up after first treatment (mean, of 16.3-12.6 days) and starting a second treatment within 14 days for initial nonresponders (mean, 36.3-17.2 days). DISCUSSION:For children with IS, improved rates of 3-month electroclinical remission can be achieved with QI methodology. Implementation of similar QI initiatives at other centers may likewise improve local remission rates.

e19061 Background: Positron Emission Tomography (PET) scans were applied to lymphoma as early as in 1990s. Revised criteria for lymphoma assessment was published in 2007 by International Working Group (IWG). The criteria for PET into response assessment were added due to better sensitivity and superiority of PET over CT and its ability to distinguish between viable tumor and necrosis or fibrosis in residual mass after treatment. PET was primarily recommended for patients with FDG avid curable lymphomas such as Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) and later for the post-treatment assessment of DLBCL and HL. The Lugano Classification 2014 regarded FDG PET/CT to be the standard for staging and assessment of all FDG-avid histologies. Methods: A retrospective review of 10 Lymphoma studies with a total of 1,537 subjects and 17,394 time points was carried out using PET in addition to CT as per imaging schedule. There were 5 clinical trials with a total of 1,169 subjects with 15,480 time points using IWG-NHL classification 2007 while 5 clinical trials with a total of 729 subjects and 1,914 time points using Lugano classification 2014. The number of subjects and time points with PET where PET had an impact on the overall assessment was calculated. Results: PET was available for a total of 1,159 subjects (out of 1,537) and 4,688 time points (out of 17,394) across all 10 studies. Out of 4,688 visits with PET, 956 (20.4%) visits had an impact on overall assessment due to additional metabolic findings. Out of 1,159 subjects with PET, 462 (39.9%) subjects had an impact on overall assessment and study endpoints due to additional uptake related findings. The impact across different studies was between 7% to 59% possibly due to difference in indication, line of therapy and blinded independent review design. The most common impact due to PET was related to complete response and disease progression. Conclusions: It can be concluded that PET significantly impacts assessments and imaging endpoints for lymphoma clinical trials using IWG-NHL classification or Lugano classification. Thus, addition of PET improves the outcome of the response not only in lymphoma treatment and diagnosis, but also clinical trial outcomes. [Table: see text]

e18592 Background: Blinded independent central review utilizing double read with adjudication is a preferred model by regulatory authorities to minimize reader bias in clinical trials. Monitoring of reader performance is critical to trial outcome. Adjudication rate, percent cases triggering adjudication, is commonly used for monitoring read quality. However, this does not consider how often the adjudicator agreed with a given reader (adjudicator agreement rate) or when no adjudication is required. We propose an innovative RDI to more accurately monitor reader quality. Methods: A retrospective review of adjudication data was performed for 20 clinical trials with a total of 7163 subjects (32,536 visits) using Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 or 1.1. The adjudication rate, adjudication agreement rate and RDI were generated per reader per study. RDI for each reader was calculated as below, with high RDI indicating high % disagreement overall: RDI = (# cases where adjudicator disagreed with given reader ÷ Total # of all cases read) × 100 Each RDI was used to identify the discordant reader (ie, reader with the highest level of cases disagreed by the adjudicator). Results: RDI identified the discordant reader in all 20 studies, whereas adjudication rate and adjudication agreement rate identified the discordant reader in 13 and 12 of the 20 studies, respectively. In 3 studies, the reader with highest % adjudicator disagreement had neither the highest adjudication rate nor lowest adjudicator agreement rate. This reader could have been missed without the RDI. Conclusions: Though adjudication and adjudicator agreement rates are widely used to assess reader quality, these rates, individually, do not give full insight into reader performance. A high adjudication rate may not always mean poor reader performance if associated with high adjudicator agreement. Similarly a low adjudicator agreement rate may not always mean poor reader performance if associated with low adjudication rate. RDI proves to be a composite quality indicator by effectively combining adjudication and adjudication agreement rates in identifying potential outliers, and can serve as an excellent tool for identifying the discordant reader for timely intervention.

e18594 Background: With PFS as a primary endpoint, the assessment of Progressive Disease (PD) is the single most important trial assessment. As such, in blinded independent central review (BICR) utilizing a double read with adjudication model, measures should be taken to ensure precision in the assessment of PD. This study seeks to categorize the causes of PD assessment by BICR and identify which have the highest rate of reader disagreement (RD). The outcome provides further insights into measures that may be taken to more effectively ensure precision in PD assessment. Methods: Per RECIST 1.1, an overall assessment of PD can be caused by progression of target lesions (TL) and/or non-target lesions (NTL) and/or the presence of new lesions (NL). A retrospective review of the causes of PD assessment within BICR data was performed for 10 arbitrarily selected trials in phases II or III with indications of breast, non-small cell lung, or ovarian cancer using RECIST 1.1. In total, 4723 subjects and 27214 visits were reviewed, of which 3351 were PD. The following variables for all visits with overall assessment of PD were reported: subject number, visit number, cause of PD, cause of PD category, and RD. Cause of PD was defined by category as: TL (1), NTL (2), NL (3), TL+NTL (4), TL+NL (5), TL+NTL+NL (6), NTL+NL (7) The cause of PD and rate of RD by category was calculated and the highest rates of RD by category were identified. Results: See Table 1. Conclusions: Though it is important to ensure overall precision in BICR data (i.e. assessment criteria training for readers, data/adjudication monitoring), special consideration on how overall assessment of PD based on TLs and/or NLs is determined may be warranted, as PD assessed based on these areas is a common cause of RD. The results suggest the difficult nature of suitable target lesion selection at baseline and the identification of unequivocal NLs. Additional investigation should be performed to identify appropriate measures to increase precision in these areas (i.e TL/NL definition, restriction of lesion type/locations of target lesions at baseline, and enhanced data monitoring). Table 1: Category 1 2 3 4 5 6 7 Visits Assessed as PD (n = 3351) 478 337 1514 323 176 217 306 RD Rate (%) 72 60 66 55 61 46 58

Blockade of the vascular endothelial growth factor (VEGF) pathway shows evidence of activity in gastro-oesophageal (GE) and oesophageal cancer. We investigated the efficacy of sunitinib, a multikinase VEGF inhibitor, in patients with relapsed/refractory GE/oesophageal cancer. This was a single-stage Fleming phase II study. The primary end point was progression-free survival (PFS) at 24 weeks. If five or more patients out of a total of 25 were free of progressive disease at 24 weeks, sunitinib would be recommended for further study. Patients received sunitinib 37.5 mg orally daily and imaged every 6 weeks. Exploratory correlative analysis included serum growth factors, tumour gene expression and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Twenty-five evaluable patients participated in the study. Progression-free survival at 24 weeks was 8% (n=2 patients; confidence interval (CI): 95% 1.4–22.5%), and the duration of best response for the patients was 23 and 72 weeks. Ten patients (42%) had stable disease (SD) for >10 weeks. Overall response rate is 13%. Median PFS is 7 weeks (95% CI: 5.6–11.4 weeks) and the median overall survival is 17 weeks (95% CI: 8.9–25.3 weeks). Most common grade 3/4 toxicities included fatigue (24%), anaemia (20%) thrombocytopenia (16%), and leucopenia (16%). No patients discontinued therapy due to toxicity. Serum VEGF-A and -C levels, tumour complement factor B (CFB) gene expression, and DCE-MRI correlated with clinical benefit, defined as SD or better as best response. Sunitinib is well tolerated but only a select subgroup of patients benefited. Serum VEGF-A and -C may be early predictors of benefit. On this study, patients with clinical benefit from sunitinib had higher tumour CFB expression, and thus has identified CFB as a potential predictor for efficacy of anti-angiogenic therapy. These findings need validation from future prospective trials.

PurposeTo develop a chemical exchange saturation transfer (CEST) scheme sensitive to hydroxyl protons at 3 T. Clinical imaging of hydroxyl moieties can have an impact on osteoarthritis, neuropsychiatric disorders, and cancer.Theory: By varying saturation amplitude linearly with frequency offset, the direct water saturation component of the Z‐spectrum is flattened and can be subtracted to produce a magnetization transfer ratio difference spectrum (MTRdiff) that isolates solute resonances. Variable saturation power allows for near optimization of hydroxyl and amine/amide moieties in one Z‐spectrum.MethodsPhantom studies were used to test vCEST performance in two environments: (1) aqueous single‐solute (glycogen, glucose); (2) aqueous multiple solute (glycogen with bovine serum albumin). In vivo vCEST imaging of glycosaminoglycan content in patellar‐femoral cartilage was performed in a subject with history of cartilage transplant.ResultsIn solutions with overlapping resonances, vCEST resolves separate hydroxyl and amine/amide peaks. CEST hydroxyl signal in cartilage is negligible, but with vCEST, hydroxyl signal ranged from 2 to 5% ppm and showed distinct contrast between lesions and normal appearing cartilage.ConclusionIntroduced a variable saturation amplitude CEST (vCEST) scheme to improve sensitivity to exchangeable hydroxyl moieties at 3 T resulting in detection of hydroxyl in the presence of multiple solutes with overlapping resonances. Magn Reson Med 76:826–837, 2016. © 2015 Wiley Periodicals, Inc.

PurposeTo apply k-means clustering of two pharmacokinetic parameters derived from 3T dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict the chemotherapeutic response in bladder cancer at the mid-cycle timepoint.Materials and MethodsWith the predetermined number of three clusters, k-means clustering was performed on nondimensionalized Amp and k(ep) estimates of each bladder tumor. Three cluster volume fractions (VFs) were calculated for each tumor at baseline and mid-cycle. The changes of three cluster VFs from baseline to mid-cycle were correlated with the tumor's chemotherapeutic response. Receiver-operating-characteristics curve analysis was used to evaluate the performance of each cluster VF change as a biomarker of chemotherapeutic response in bladder cancer.ResultsThe k-means clustering partitioned each bladder tumor into cluster 1 (low k(ep) and low Amp), cluster 2 (low k(ep) and high Amp), cluster 3 (high k(ep) and low Amp). The changes of all three cluster VFs were found to be associated with bladder tumor response to chemotherapy. The VF change of cluster 2 presented with the highest area-under-the-curve value (0.96) and the highest sensitivity/specificity/accuracy (96%/100%/97%) with a selected cutoff value.ConclusionThe k-means clustering of the two DCE-MRI pharmacokinetic parameters can characterize the complex microcirculatory changes within a bladder tumor to enable early prediction of the tumor's chemotherapeutic response. J. Magn. Reson. Imaging 2015;41:1374-1382. (c) 2014 Wiley Periodicals, Inc.

Objectives The objective of this study was to assess the capability of T2-weighted magnetic resonance imaging (T2W-MRI) and the additional diagnostic value of dynamic contrast-enhanced MRI (DCE-MRI) using multitransmit 3 T in the localization of bladder cancer. Materials and Methods This prospective study was approved by the local institutional review board. Thirty-six patients were included in the study and provided informed consent. Magnetic resonance imaging scans were performed with T2W-MRI and DCE-MRI on a 3-T multitransmit system. Two observers (with 12 and 25 years of experience) independently interpreted T2W-MRI before DCE-MRI data (maps of pharmacokinetic parameters) to localize bladder tumors. The pathological examination of cystectomy bladder specimens was used as a reference criteria standard. The McNemar test was performed to evaluate the differences in sensitivity, specificity, and accuracy. Scores of κ were calculated to assess interobserver agreement. Results The sensitivity, specificity, and accuracy of the localization with T2W-MRI alone were 81% (29/36), 63% (5/8), and 77% (34/44) for observer 1 and 72% (26/36), 63% (5/8), and 70% (31/44) for observer 2. With additional DCE-MRI available, these values were 92% (33/36), 75% (6/8), and 89% (39/44) for observer 1 and 92% (33/36), 63% (5/8), and 86% (38/44) for observer 2. Dynamic contrast-enhanced MRI significantly (P < 0.01) improved the sensitivity and accuracy for observer 2. For the 23 patients treated with chemotherapy, DCE-MRI also significantly (P < 0.02) improved the sensitivity and accuracy of bladder cancer localization with T2W-MRI alone for observer 2. Scores of κ were 0.63 for T2W-MRI alone and 0.78 for additional DCE-MRI. Of 7 subcentimeter malignant tumors, 4 (57%) were identified on T2W images and 6 (86%) were identified on DCE maps. Of 11 malignant tumors within the bladder wall thickening, 6 (55%) were found on T2W images and 10 (91%) were found on DCE maps. Conclusions Compared with conventional T2W-MRI alone, the addition of DCE-MRI improved interobserver agreement as well as the localization of small malignant tumors and those within bladder wall thickening.

PURPOSE:To establish the feasibility of chemical exchange saturation transfer (proteinCEST) MRI in the differentiation of osteoarthritis (OA) knee joints from non-OA joints by detecting mobile protein and peptide levels in synovial fluid by determining their relative distribution. MATERIALS AND METHODS:A total of 25 knees in 11 men and 12 women with knee injuries were imaged using whole knee joint proteinCEST MRI sequence at 3 T. The joint synovial fluid was segmented and the asymmetric magnetization transfer ratio at 3.5 ppm MTR(asym) (3.5 ppm) was calculated to assess protein content in the synovial fluid. The 85th percentile of synovial fluid MTR(asym) (3.5 ppm) distribution profile was compared using the independent Student's t test. The diagnostic performance of the 85th percentile of synovial fluid MTR(asym) (3.5 ppm) in differentiating OA and non-OA knee joints was evaluated. RESULTS:The 85th percentile of synovial fluid MTR(asym) (3.5 ppm) in knee joints with OA was 8.6%±3.4% and significantly higher than that in the knee joints without OA (6.3%±1.4%, P<.05). A knee joint with an 85th percentile of synovial fluid MTR(asym) (3.5 ppm) greater than 7.7% was considered to be an OA knee joint. With the threshold, the sensitivity, specificity and overall accuracy for differentiating knee joints with OA from the joints without OA were 54% (7/13), 92% (11/12) and 72% (18/25), respectively. CONCLUSION:proteinCEST MRI appears feasible as a quantitative methodology to determine mobile protein levels in synovial fluid and identify patterns characteristic for OA disease.

OBJECTIVE:To evaluate healing of surgically created large osteochondral defects in a weight-bearing femoral condyle in response to delayed percutaneous direct injection of adenoviral (Ad) vectors containing coding regions for either human bone morphogenetic proteins 2 (BMP-2) or -6.METHODS:Four 13mm diameter and 7mm depth circular osteochondral defects were drilled, 1/femoral condyle (n=20 defects in five ponies). At 2 weeks, Ad-BMP-2, Ad-BMP-6, Ad-green fluorescent protein (GFP), or saline was percutaneously injected into the central drill hole of the defect. Quantitative magnetic resonance imaging (qMRI) and computed tomography (CT) were serially performed at 12, 24, and 52 weeks. At 12 (one pony) or 52 weeks, histomorphometry and microtomographic analyses were performed to assess subchondral bone and cartilage repair tissue quality.RESULTS:Direct delivery of Ad-BMP-6 demonstrated delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) and histologic evidence of greater Glycosaminoglycan (GAG) content in repair tissue at 12 weeks, while Ad-BMP-2 had greater non-mineral cartilage at the surface at 52 weeks (p<0.04). Ad-BMP-2 demonstrated greater CT subchondral bone mineral density (BMD) by 12 weeks and both Ad-BMP-2 and -6 had greater subchondral BMD at 52 weeks (p<0.05). Despite earlier (Ad-BMP-6) and more persistent (Ad-BMP-2) chondral tissue and greater subchondral bone density (Ad-BMP-2 and -6), the tissue within the large weight-bearing defects at 52 weeks was suboptimal in all groups due to poor quality repair cartilage, central fibrocartilage retention, and central bone cavitation. Delivery of either BMP by this method had greater frequency of subchondral bone cystic formation (p<0.05).CONCLUSIONS:Delivery of Ad-BMP-2 or Ad-BMP-6 via direct injection supported cartilage and subchondral bone regeneration but was insufficient to provide long-term quality osteochondral repair.

149 Background: Patients (pts) with relapsed or treatment-refractory E and GE cancers carry a poor prognosis. Inhibition of the vascular endothelial growth factor (VEGF) pathway may be a potential treatment approach. We conducted a phase II trial to assess the efficacy of sunitinib, a tyrosine kinase inhibitor that inhibits VEGFR 1 and 2. Methods: Pts received sunitinib 37.5 mg orally, daily. Primary endpoint was progression free survival (PFS) at 24 weeks. Secondary endpoints included overall response rate (ORR), overall survival (OS), PFS, and toxicity. Pts underwent serial functional imaging with DCE-MRI and measurements of serum VEGF, PIGF, VEGFR 2 and 3. Gene expression profiling and somatic mutational analysis using next-generation sequencing were also performed on tumor specimens (results to be presented at the symposium). Results: Clinical results are in the table. The PFS in the group that had clinical benefit [partial response (PR) + stable disease (SD)] with sunitinib was 99 days (95% CI: 74-161) vs. 39 days (95% CI: 26-42; Log-rank test p-value is <0.0001) in pts who had progressive disease (PD). By RECIST criteria, sunitinib non-responders demonstrated an initial reduction in tumor size but then subsequent rapid tumor size increase by week 6 as compared to baseline values. In contrast, sunitinib responders demonstrated at least stable disease through weeks 2-6. Changes in serum VEGF-A and VEGF-C levels from baseline to 2 weeks were associated with PFS (p=0.04 and p=0.03, respectively). Furthermore, baseline VEGF-C was also associated with PFS (p=0.03) and RECIST response (p=0.04). Conclusions: Although the primary endpoint was not met, these results suggest that there is a subgroup of patients with clinical response to sunitinib. Our correlative analysis indicated that circulating biomarkers, such as VEGF-C, are worthy of further research to help us identify this subgroup. Clinical trial information: NCT00702884. [Table: see text]

The distribution of tritium labeled polysulfated glycosaminoglycans after intramuscular injection of 2 mg PSGAG per pound of body weight was studied in 9 healthy dogs. Drug concentration, hyaluronate concentration, and protein concentration were measured in synovial fluid for 72 hours post injection. Drug concentration in articular cartilage from normal and inflamed joints was measured 72 hours after injection.