Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor.

Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a major therapeutic target for B-cell-driven malignancies. However, approved covalent BTK inhibitors (cBTKis) are associated with treatment limitations because of off-target side effects, suboptimal oral pharmacology, and development of resistance mutations (eg, C481) that prevent inhibitor binding. Here, we describe the preclinical profile of pirtobrutinib, a potent, highly selective, noncovalent (reversible) BTK inhibitor. Pirtobrutinib binds BTK with an extensive network of interactions to BTK and water molecules in the adenosine triphosphate binding region and shows no direct interaction with C481. Consequently, pirtobrutinib inhibits both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays with similar potencies. In differential scanning fluorimetry studies, BTK bound to pirtobrutinib exhibited a higher melting temperature than cBTKi-bound BTK. Pirtobrutinib, but not cBTKis, prevented Y551 phosphorylation in the activation loop. These data suggest that pirtobrutinib uniquely stabilizes BTK in a closed, inactive conformation. Pirtobrutinib inhibits BTK signaling and cell proliferation in multiple B-cell lymphoma cell lines, and significantly inhibits tumor growth in human lymphoma xenografts in vivo. Enzymatic profiling showed that pirtobrutinib was highly selective for BTK in >98% of the human kinome, and in follow-up cellular studies pirtobrutinib retained >100-fold selectivity over other tested kinases. Collectively, these findings suggest that pirtobrutinib represents a novel BTK inhibitor with improved selectivity and unique pharmacologic, biophysical, and structural attributes with the potential to treat B-cell-driven cancers with improved precision and tolerability. Pirtobrutinib is being tested in phase 3 clinical studies for a variety of B-cell malignancies.

Artificial Intelligence for Automated Implant Identification in Total Hip Arthroplasty: A Multicenter External Validation Study Exceeding Two Million Plain Radiographs.

BACKGROUND: The surgical management of complications after total hip arthroplasty (THA) necessitates accurate identification of the femoral implant manufacturer and model. Automated image processing using deep learning has been previously developed and internally validated; however, external validation is necessary prior to responsible application of artificial intelligence (AI)-based technologies. METHODS: We trained, validated, and externally tested a deep learning system to classify femoral-sided THA implants as one of the 8 models from 2 manufacturers derived from 2,954 original, deidentified, retrospectively collected anteroposterior plain radiographs across 3 academic referral centers and 13 surgeons. From these radiographs, 2,117 were used for training, 249 for validation, and 588 for external testing. Augmentation was applied to the training set (n = 2,117,000) to increase model robustness. Performance was evaluated by area under the receiver operating characteristic curve, sensitivity, specificity, and accuracy. Implant identification processing speed was calculated. RESULTS: The training and testing sets were drawn from statistically different populations of implants (P < .001). After 1,000 training epochs by the deep learning system, the system discriminated 8 implant models with a mean area under the receiver operating characteristic curve of 0.991, accuracy of 97.9%, sensitivity of 88.6%, and specificity of 98.9% in the external testing dataset of 588 anteroposterior radiographs. The software classified implants at a mean speed of 0.02 seconds per image. CONCLUSION: An AI-based software demonstrated excellent internal and external validation. Although continued surveillance is necessary with implant library expansion, this software represents responsible and meaningful clinical application of AI with immediate potential to globally scale and assist in preoperative planning prior to revision THA.

Refractory Jaundice From Intraductal Papillary Mucinous Neoplasm Treated With Cholangioscopy-Guided Radiofrequency Ablation.

Intraductal papillary mucinous neoplasms (IPMNs) are epithelial neoplasms treated with surgical resection when appropriate. We present a 79-year-old man with jandice refractory to endoscopic stenting. Biliary radiofrequency ablation (RFA) with cholangioscopy was used as palliation of obstructive jaundice due to a mucin-producing pancreatic IPMN with fistulous biliary communication. Clinical improvement permitted surgery, and he returned to pre-illness status at 17 months. The use of cholangioscopy in the setting of mucinous filling defects can guide over-the-wire RFA for palliation and may be a bridge to surgery.

Effect of size and temperature at vaccination on immunization and protection conferred by a live attenuated Francisella noatunensis immersion vaccine in red hybrid tilapia.

Francisella noatunensis subsp. orientalis (Fno) is a pleomorphic, facultative intracellular, Gram-negative, emerging bacterial pathogen of marine and fresh water fish with worldwide distribution. In this study, the efficacy of an attenuated Fno intracellular growth locus C (iglC) mutant was evaluated for use as a live immersion vaccine, when administered to hybrid tilapia at two different stages of growth (5 g fry and 10 g fingerlings) and at two temperatures (25 °C and 30 °C). To determine vaccine efficacy, mortality, days to first death, and Fno genome equivalents (GE) in the spleens of survivors, as well as serum and mucus antibody levels, were evaluated after 30 d in fish challenged with a wild type virulent strain. Both size and temperature at vaccination played an important role in immunization and protection. Fry vaccinated at 25 °C were not protected when compared to non-vaccinated fry at 25 °C (p = 0.870). In contrast, 5 g fry vaccinated at 30 °C were significantly protected compared to non-vaccinated fry at 30 °C (p = 0.038). Although lower mortalities occurred, 10 g fingerlings vaccinated at 25 °C were not protected, compared to non-vaccinated fingerlings at 25 °C (p = 0.328), while, 10 g fingerlings vaccinated at 30 °C were significantly protected, compared to non-vaccinated fingerlings at 30 °C (p = 0.038). Additionally, overall mortality of 5 g fish was significantly higher than in 10 g fish. Mortality was also significantly higher in fish subjected to a 30 to 25 °C temperature change one week prior to challenge, than in fish maintained at the same temperature during vaccination and challenge. This information demonstrates that both temperature and size at vaccination are important factors when implementing immunization prophylaxis in cultured tilapia.