Macrocyclic Oxindole Peptide Epoxyketones-A Comparative Study of Macrocyclic Inhibitors of the 20S Proteasome.

Peptide macrocycles have recently gained attention as protease inhibitors due to their metabolic stability and specificity. However, the development of peptide macrocycles with improved binding potency has so far been challenging. Here we present macrocyclic peptides derived from the clinically applied proteasome inhibitor carfilzomib with an oxindole group that mimics the natural product TMC-95A. Fluorescence kinetic activity assays reveal a high potency of the oxindole group (IC50 = 0.19 µM) compared with agents lacking this motif. X-ray structures of the ligands with the ß5-subunit of the yeast 20S proteasome illustrate that the installed macrocycle forces strong hydrogen bonding of the oxindole group with ß5-Gly23NH. Thus, the binding of our designed oxindole epoxyketones is entropically and enthalpically favored in contrast to more flexible proteasome inhibitors such as carfilzomib.

Outcomes of Patients with Advanced Hepatocellular Carcinoma Receiving Lenvatinib following Immunotherapy: A Real World Evidence Study.

BACKGROUND: Lenvatinib, a multikinase inhibitor, is an FDA-approved treatment for advanced hepatocellular carcinoma (HCC) in the first-line setting. Recent trial data have established atezolizumab plus bevacizumab as well as tremelimumab plus durvalumab as preferred first-line treatment options for advanced HCC. The role of lenvatinib following progression on immunotherapy in patients with advanced HCC remains unclear. METHODS: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010 and 2021 at the Mayo Clinic in Minnesota, Arizona, and Florida who received immunotherapy followed by lenvatinib. Median overall survival and progression-free survival analyses were performed using the Kaplan-Meier method, and responses were determined using RECIST 1.1. Adverse events were determined using CTCAE v 4.0. RESULTS: We identified 53 patients with advanced HCC who received lenvatinib following progression on immunotherapy. Forty five (85%) patients had a Child Pugh class A at diagnosis, while 30 (58%) patients were still Child Pugh A at time of lenvatinib initiation. Lenvatinib was administered as a second-line treatment in 85% of the patients. The median PFS was 3.7 months (95% CI: 3.2-6.6), and the median OS from the time of lenvatinib initiation was 12.8 months (95% CI: 6.7-19.5). In patients with Child Pugh class A, the median OS and PFS was 14 and 5.2 months, respectively. Race, gender, and Child Pugh class was associated with OS on multivariate analysis. DISCUSSION: Our study, using real-world data, suggests that patients benefit from treatment with lenvatinib following progression on immunotherapy in advanced HCC. The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown, and these results need to be validated in a clinical trial.

Robotic-assisted surgery training (RAST) program: module 1 of a three-module program. Assessment of patient cart docking skills and educational environment.

There is currently no standardized robotic surgery training program in General Surgery Residency. RAST involves three modules: ergonomics, psychomotor, and procedural. This study aimed to report the results of module 1, which assessed the responsiveness of 27 PGY (postgraduate year) 1-5 general surgery residents (GSRs) to simulated patient cart docking, and to evaluate the residents' perception of the educational environment from 2021 to 2022. GSRs prepared with pre-training educational video and multiple-choice questions test (MCQs). Faculty provided one-on-one resident hands-on training and testing. Nine proficiency criteria (deploy cart; boom control; driving cart; docking camera port; targeting anatomy; flex joints; clearance joints; port nozzles; emergency undocking) were assessed with five-point Likert scale. A validated 50-item Dundee Ready Educational Environment Measure (DREEM) inventory was used by GSRs to assess the educational environment. Mean MCQ scores: (90.6 ± 16.1 PGY1), (80.2 ± 18.1PGY2), (91.7 ± 16.5 PGY3) and (PGY4, 86.8 ± 18.1 PGY5) (ANOVA test; p = 0.885). Hands-on docking time decreased at testing when compared to base line: median 17.5 (range 15-20) min vs. 9.5 (range 8-11). Mean hands-on testing score was 4.75 ± 0.29 PGY1; 5.0 ± 0 PGY2 and PGY3, 4.78 ± 0.13 PGY4, and 4.93 ± 0.1 PGY5 (ANOVA test; p = 0.095). No correlation was found between pre-course MCQ score and hands-on training score (Pearson correlation coefficient = - 0.359; p = 0.066). There was no difference in the hands-on scores stratified by PGY. The overall DREEM score was 167.1 ± 16.9 with CAC = 0.908 (excellent internal consistency). Patient cart training impacted the responsiveness of GSRs with 54% docking time reduction and no differences in hands-on testing scores among PGYs with a highly positive perception.

Cabozantinib Following Immunotherapy in Patients with Advanced Hepatocellular Carcinoma.

(1) Background: Cabozantinib, a multikinase inhibitor, is approved by the Food and Drug Administration (FDA) for the treatment of advanced hepatocellular carcinoma (HCC) following progression on sorafenib. Recently, atezolizumab plus bevacizumab has been approved in the first line setting for advanced HCC and has become the new standard of care. Whether cabozantinib improves outcomes following progression on immunotherapy remains unknown. We describe the clinical outcomes following treatment with immunotherapy in patients with advanced HCC who received cabozantinib. (2) Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010-2021 at Mayo Clinic in Minnesota, Arizona, and Florida who received cabozantinib. Median overall survival and progression free survival analyses were performed using the Kaplan-Meier method. Adverse events were determined using Common Terminology Criteria for Adverse Events (CTCAE). (3). Results: We identified 26 patients with advanced HCC who received cabozantinib following progression on immunotherapy. Median progression free survival on cabozantinib therapy was 2.1 months (95% CI: 1.3-3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3-14.9). (4) Conclusion: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. Our study demonstrates that patients may benefit from treatment with cabozantinib following progression on immunotherapy.

Robotic-Assisted Surgery Training (RAST) Program: An Educational Research Protocol.

Technology has had a dramatic impact on how diseases are diagnosed and treated. Although cut, sew, and tie remain the staples of surgical craft, new technical skills are required. While there is no replacement for live operative experience, training outside the operating room offers structured educational opportunities and stress modulation. A stepwise program for acquiring new technical skills required in robotic surgery involves three modules: ergonomic, psychomotor, and procedural. This is a prospective, educational research protocol aiming at evaluating the responsiveness of general surgery residents in Robotic-Assisted Surgery Training (RAST). Responsiveness is defined as change in performance over time. Performance is measured by the following content-valid metrics for each module. Module 1 proficiency in ergonomics includes: cart deploy, boom control, cart driving, camera port docking, targeting anatomy, flex joint, clearance joint and port nozzle adjusting, and routine and emergent undocking. Module 2 proficiency in psychomotor skills includes tissue handling, accuracy error, knot quality, and operating time. Module 3 proficiency in procedural skills prevents deviations from standardized sequential procedural steps in order to test length of specimen resection, angle for transection, vessel stump length post ligation, distance of anastomosis from critical landmarks, and proximal and distal resection margins. Resident responsiveness over time will be assessed comparing the results of baseline testing with final testing. Educational interventions will include viewing one instructional video prior to module commencement, response to module-specific multiple-choice questions, and individual weekly training sessions with a robotic instructor in the operating room. Residents will progress through modules upon successful final testing and will evaluate the educational environment with the Dundee Ready Educational Environment Measure (DREEM) inventory. The RAST program protocol outlined herein is an educational challenge with the primary endpoint to provide evidence that formal instruction has an impact on proficiency and safety in executing robotic skills.