Citations

Purpose In lymphomas, the Deauville score (DS) standardizes 18F-FDG PET treatment response assessments. We assessed interobserver agreement of the DS and developed a quantitative PET-based parameter to minimize subjectivity of response assessments. Methods PET scans performed within the Children’s Oncology Group AHOD0831 study were analyzed. One hundred one scans obtained after the first cycle of chemotherapy (PET1) and 83 obtained after the second cycle (PET2) were eligible for inclusion. Each scan was assigned a DS by 2 nuclear medicine radiologists and a Hodgkin lymphoma index (HLI), defined as the ratio of the tumor’s SUVmax or SUVpeak to the liver’s SUVmean. Cohen κ coefficient measured the rate of agreement of the DS assigned by the 2 radiologists. Receiver operating characteristic curves and the Youden index were used with the consensus DS to identify an optimal HLI cutoff value to distinguish PET-negative from PET-positive images. For each HLI cutoff value, sensitivity, specificity, and accuracy were calculated. Results Interobserver agreement in DS was moderate (PET1: κ = 0.480, P < 0.001; PET2: κ = 0.428, P < 0.001). On PET1, the optimal cutoff values for HLImax were 1.19 for DS2/DS3 and 1.78 for DS3/DS4, and for HLIpeak were 1.19 for DS2/DS3 and 1.44 for DS3/DS4. On PET2 images, the corresponding values were 1.18, 1.58, 0.94, and 1.26. The most accurate predictor was HLImax on PET2 when scans were dichotomized as DS1–DS3 versus DS4–DS5 (accuracy, 92.8%; sensitivity, 100%; specificity, 91.8%). Conclusion The HLI provides an objective, quantitative measure of disease response and thus may improve interreader agreement for lymphoma response assessments.

Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15 , in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila , with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.