Multimodal Biomarkers That Predict the Presence of Gleason Pattern 4: Potential Impact for Active Surveillance.

PURPOSE: Latent grade group ≥2 prostate cancer can impact the performance of active surveillance protocols. To date, molecular biomarkers for active surveillance have relied solely on RNA or protein. We trained and independently validated multimodal (mRNA abundance, DNA methylation, and/or DNA copy number) biomarkers that more accurately separate grade group 1 from grade group ≥2 cancers. MATERIALS AND METHODS: Low- and intermediate-risk prostate cancer patients were assigned to training (n=333) and validation (n=202) cohorts. We profiled the abundance of 342 mRNAs, 100 DNA copy number alteration loci, and 14 hypermethylation sites at 2 locations per tumor. Using the training cohort with cross-validation, we evaluated methods for training classifiers of pathological grade group ≥2 in centrally reviewed radical prostatectomies. We trained 2 distinct classifiers, PRONTO-e and PRONTO-m, and validated them in an independent radical prostatectomy cohort. RESULTS: PRONTO-e comprises 353 mRNA and copy number alteration features. PRONTO-m includes 94 clinical, mRNAs, copy number alterations, and methylation features at 14 and 12 loci, respectively. In independent validation, PRONTO-e and PRONTO-m predicted grade group ≥2 with respective true-positive rates of 0.81 and 0.76, and false-positive rates of 0.43 and 0.26. Both classifiers were resistant to sampling error and identified more upgrading cases than a well-validated presurgical risk calculator, CAPRA (Cancer of the Prostate Risk Assessment; P < .001). CONCLUSIONS: Two grade group classifiers with superior accuracy were developed by incorporating RNA and DNA features and validated in an independent cohort. Upon further validation in biopsy samples, classifiers with these performance characteristics could refine selection of men for active surveillance, extending their treatment-free survival and intervals between surveillance.

Filamentous intranuclear inclusion bodies in psittacine birds. A structural and ultrastructural study.

This paper concerns a disease affecting a group of African grey parrots, which involves intranuclear inclusion bodies composed of filamentous material. The disease was characterized by either sudden death or death within 2-3 days from onset of non-specific symptoms. At necropsy, gross lesions included enlarged liver, mild hepatic congestion and focal necrosis. Samples from five birds were fixed in 10% formol and routinely processed for light and electron microscopy. In four birds, numerous hepatocytes displayed an enlarged nucleus, with peripheral margination of chromatin; the nucleus was partially or wholly filled by a basophilic inclusion body. In the remaining bird, inclusion bodies were acidophilic and completely filled the nucleus; nuclear enlargement was less evident than in the other birds. At ultrastructural examination, and in both types of IIB, nuclei contained looped filaments but no evidence of viral structures. However, virion-like structures were observed in the cytoplasm of some hepatocytes.