Eribulin is a microtubule destabilizer used in the treatment of triple-negative breast cancer (TNBC). Eribulin and other microtubule targeted drugs, such as the taxanes, have shared antimitotic effects, but differ in their mechanism of microtubule disruption, leading to diverse effects on cellular signaling and trafficking. Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNβ) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials. The mechanism by which eribulin enhances STING signaling is downstream of microtubule disruption and independent of the eribulin-dependent release of mitochondrial DNA. Eribulin did not override the requirement of ER exit for STING activation and did not inhibit subsequent STING degradation; however, eribulin significantly enhanced IRF3 phosphorylation and IFNβ production downstream of the RNA sensing pathway that converges on this transcription factor. Additionally, we found that eribulin enhanced the population of activated CD4⁺ T-cells in vivo when combined with either a STING agonist or tumor, demonstrating the ability to function as an immune adjuvant. We further interrogated the combination of eribulin with ADU-S100 in the MMTV-PyVT spontaneous murine mammary tumor model where we observed significant antitumor efficacy with combination treatment. Together, our findings demonstrate that microtubule targeted chemotherapeutics have distinct immunological effects and that eribulin’s ability to enhance innate immune sensing pathways supports its use in combination with immunotherapies, such as STING agonists, for the more effective treatment of TNBC and other malignancies.

» Orthopaedic surgeons are increasingly likely to encounter patients with obesity and/or type 2 diabetes taking glucagon-like peptide-1 (GLP-1) agonists for weight loss. » GLP-1 agonists are an effective treatment for weight loss with semaglutide and tirzepatide being the most effective agents. Randomized controlled trials using these agents have reported weight loss up to 21 kg (46 lb). » The use of GLP-1 agonists preoperatively can improve glycemic control, which can potentially reduce the risk of postoperative complications. However, multiple cases of intraoperative aspiration/regurgitation have been reported, potentially related to the effect of GLP-1 agonists on gastric emptying. » While efficacious, GLP-1 agonists may not produce sufficient weight loss to achieve body mass index cutoffs for total joint arthroplasty depending on individual patient factors, including starting bodyweight. Multifactorial approaches to weight loss with focus on lifestyle modification in addition to GLP-1 agonists should be considered in such patients. » Although GLP-1 agonists are efficacious agents for weight loss, they may not be accessible or affordable for all patients. Each patient's unique circumstances should be considered when creating an ideal weight loss plan during optimization efforts.

Herein, we report on naturally derived microtubule stabilizers with activity against triple negative breast cancer (TNBC) cell lines, including paclitaxel, fijianolide B/laulimalide (3), fijianolide B di-acetate (4), and two new semisynthetic analogs of 3, which include fijianolide J (5) and fijianolide L (6). Similar to paclitaxel, compound 3 demonstrated classic microtubule stabilizing activity with potent (GI₅₀ = 0.7–17 nM) antiproliferative efficacy among the five molecularly distinct TNBC cell lines. Alternatively, compounds 5 or 6, generated from oxidation of C-20 or C-15 and C-20 respectively, resulted in a unique profile with reduced potency (GI₅₀ = 4–9 μM), but improved efficacy in some lines, suggesting a distinct mechanism of action. The C-15, C-20 di-acetate, and dioxo modifications on 4 and 6 resulted in compounds devoid of classic microtubule stabilizing activity in biochemical assays. While 4 also had no detectable effect on cellular microtubules, 6 promoted a reorganization of the cytoskeleton resulting in an accumulation of microtubules at the cell periphery. Compound 5, with a single C-20 oxo substitution, displayed a mixed phenotype, sharing properties of 3 and 6. These results demonstrate the importance of the C-15/C-20 chiral centers, which appear to be required for the potent microtubule stabilizing activity of this chemotype and that oxidation of these sites promotes unanticipated cytoskeletal alterations that are distinct from classic microtubule stabilization, likely through a distinct mechanism of action.

Novel methods for annotating antero-posterior pelvis radiographs and fluoroscopic images with deep-learning models have recently been developed. However, their clinical use has been limited. Therefore, the purpose of this study was to develop a deep learning model that could annotate clinically relevant pelvic landmarks on both radiographic and fluoroscopic images and automate total hip arthroplasty (THA)-relevant measurements. A deep learning model was developed using imaging from 161 primary THAs. A combination of preoperative and postoperative antero-posterior pelvis radiographs and intraoperative fluoroscopic images were annotated. A landmark detection model was then designed to annotate pelvis radiographs and fluoroscopic images. The algorithm was used to automate the measurement of pelvic tilt, leg length, offset, acetabular component abduction, and inclination. Our novel deep learning model annotated pelvic landmarks as well, if not better, than trained humans at 16 of 20, four of four, and five of eight landmarks for bony landmarks on radiographs, implant landmarks on radiographs, and bony landmarks on fluoroscopy, respectively. Measurements of cup inclination and anteversion, pelvic tilt, offset, and leg length were successfully calculated. We have developed a novel deep-learning model that can automate the identification of clinically relevant pelvic landmarks in real time and provide THA-relevant measurements that are equivalent to those of trained humans. We believe the model could be rapidly incorporated into clinical practice for both surgical and research applications.

Background: Radial height is a radiographic parameter used to guide the treatment of distal radius fractures. However, it is often used synonymously with other terms, and there are substantial discrepancies in its measurement/definition. These discrepancies can alter the measurement of radial height and affect treatment decisions. The purpose of this review is to identify the different definitions of radial height in the literature relevant to distal radius fractures. Methods: A literature review was conducted in the PubMed/MEDLINE database from inception to 2022. Full-length, English-language studies that pertained to distal radius fractures and reported radial height as a recorded measurement were included. The method of radial height measurement (definition) was extracted from included studies. Level of evidence was determined by the Oxford Centre for Evidence-based Medicine Levels of Evidence tool. Results: A total of 385 studies were identified. Of these, 183 (47.5%) did not provide a definition for radial height. Of the studies that defined radial height, 50.9% (103/202) measured radial height from the radial styloid to the distal ulna, 10.9% (22/202) measured from the radial styloid to the distal radius, and 29.2% (59/202) were “other” definitions. Conclusions: There is substantial discrepancy in the way that radial height is measured and reported. We advocate for a standardized measurement of radial height (synonymous with radial length) from the radial styloid to the distal ulnar articular surface. Radial shortening is a different measurement and requires comparison with a reference value.

Carpal tunnel syndrome (CTS) is a debilitating condition that can cause significant morbidity. Corticosteroid injection (CI) is a popular treatment for CTS. Short-term benefits of CI for CTS have been reported, but there is little evidence on long-term outcomes. We performed a systematic review in the PubMed/MEDLINE and Cochrane Library databases to identify studies which reported outcomes of CI for CTS with at least 1-year follow-up. We identified 20 total studies and extracted data on outcomes such as number of patients needing eventual surgery or reinjection, complications, and functional scores. In included studies, 41.6% of patients underwent eventual carpal tunnel release surgery (CTRS), 29% underwent reinjection, there were no major and approximately 34/1133 (3.0%) minor complications, and median/mean time from CI to eventual CTRS ranged from 128 to 446 days. There was disparity on the long-term efficacy of CI for functional outcomes. The evidence indicates that CI is a very low risk procedure that has potential to improve symptoms enough to either prevent or, in most cases, delay the need for further reintervention. However, our conclusions are limited by the heterogeneity of available studies. There is a need for further, high-quality research on this topic.