Citations

538 Background: The phase 3 PALLAS trial compared 2 years of the CDK4/6 inhibitor palbociclib with endocrine therapy of provider choice, versus endocrine therapy alone, as adjuvant treatment for patients (pts) with Stage II-III hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer. The SET2,3 index adjusts the measurement of SETER/PR index of endocrine receptor-related transcriptional activity with a baseline prognostic index (BPI) derived from tumor size (T), number of involved lymph nodes (N) and gene expression levels of ESR1, PGR, ERBB2 and AURKA (RNA4 subtype score). High SET2,3 (index ≥ 2.10) represents high endocrine sensitivity with favorable prognosis. Clinical outcome results from PALLAS were previously published, and the trial now has 5-year median follow-up. Methods: Participants in PALLAS provided a tumor tissue block prior to randomization. RNA was extracted from samples with sufficient tumor tissue and cellularity (>25mm2 with ≥20% cancer nuclei). SET2,3 index was measured from 300ng total RNA using the QuantiGene Plex platform (ThermoFisher, Waltham, MA) following the manufacturer’s protocol and using pre-defined quality control (QC) parameters and cut point. Results from primary tumor samples prior to systemic therapy were analyzed. Invasive disease-free survival (iDFS) was summarized with Kaplan-Meier plots using log-rank test. Cox models were adjusted for treatment arm assignment, with a treatment arm by SET index value interaction term to test for prediction of palbociclib benefit. The pre-defined level of significance was a two-sided 0.05. Results: There were 4075 pts from the total PALLAS population (N=5796) who provided a primary tumor sample that met pre-analytical requirements to perform the SET assay, from which 3388 (83%) results passed quality control, including 3093 from a sample obtained prior to receiving systemic therapy (1559 in palbociclib arm and 1534 in the control arm). SET2,3 index could not be calculated for 12 pts due to missing tumor or nodal information. There was no evidence of an interaction between treatment arm and SET indices (continuous) for iDFS: SET2,3 index interaction p=0.12 and SETER/PR index interaction p=0.92. Estimated 5-year iDFS was superior for those with high SET2,3: iDFS was 91.4% (95%CI 89.9–92.8) in 1719 (55.8%) pts with high SET2,3, versus 78.5% (95%CI 76.0–80.8) in 1362 (44.2%) pts with low SET2,3 (HR 0.38, 95%CI 0.31–0.47, p<0.0001). The SETER/PR index was also significantly associated with iDFS (HR 0.70 per 0.5 units, 95%CI 0.65–0.77, p<0.0001). Conclusions: There was no evidence that the SET2,3 or SETER/PR index of endocrine-related transcriptional activity predicts benefit from palbociclib treatment. SET2,3 index was strongly prognostic for pts with Stage II-III breast cancer, with excellent 5-year IDFS for pts classified as SET2,3 high. Clinical trial information: NCT02513394 .

The rapid evolution of artificial intelligence and the widespread embrace of digital technologies have ushered in a new era of clinical research and practice in hepatology. Although its potential is far from realization, these significant strides have generated new opportunities to address existing gaps in the delivery of care for patients with liver disease. In this review, we discuss how artificial intelligence and opportunities for multimodal data integration can improve the diagnosis, prognosis, and management of alcohol-associated liver disease. An emphasis is made on how these approaches will also benefit the detection and management of alcohol use disorder. Our discussion encompasses challenges and limitations, concluding with a glimpse into the promising future of these advancements.

Purpose To create a metric for evaluating the degree of laterality of the patella’s entry into the trochlea, the entry point–trochlear groove (EP‐TG) angle, and to evaluate if this laterality is associated with recurrent patella instability. Methods The time frame of the study was January 2020 to February 2023. The inclusion criteria were patients treated by the senior author (J.P.F.) (with the exception of 2 patients who were treated by another provider at the institution who was aware of the study) who have been diagnosed with recurrent atraumatic patellar dislocations. Controls without knee pathology were selected from the New Mexico Decedent Imaging Database (NMDID). Simpleware ScanIP was used to create 3‐dimensional (3D) models of the distal femurs from computed tomography scans. Anteroposterior images of these 3D models were uploaded to a custom EP‐TG angle measuring tool. Three measurers used the tool to measure the EP‐TG angle of the distal femurs. Results Twenty‐eight patients were included for the recurrent dislocator group. Twenty‐four decedents from the NMDID were selected for the control group, each with a left or right knee chosen randomly for measurement. A 1‐sided Mann‐Whitney U test, used to evaluate whether the recurrent dislocators had higher EP‐TG angle values, yielded a P value <.001, demonstrating a high level of significance. A Bayesian mixed‐effect model, used to determine how different the EP‐TG angles are between the 2 groups, gave a posterior predictive interval of [11.93°, 19.12°] for the EP‐TG angle shift of dislocators. The intraclass correlation coefficient was 0.648. Conclusions The morphologic entry point of the patella into the proximal trochlea is more lateral in recurrent patella dislocators than in controls. This increased laterality can be measured by the EP‐TG angle, which may be useful information for optimizing treatment of recurrent patella instability. Level of Evidence Level III, case control study.

PURPOSE The multicenter, open-label, randomized phase 2 NCI-9944 study ( NCT02595892 ) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.