Citations

Abstract Background. The phase 3 PALLAS trial (NCT02513394) compared two years of the CDK4/6 inhibitor palbociclib with endocrine therapy of provider choice, versus endocrine therapy alone, as adjuvant treatment for patients with Stage II-III hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer. Genomic subtype (PAM50 intrinsic subtype) measured from whole-transcriptome RNA sequencing data was defined in the protocol of the PALLAS trial as the primary biomarker for analysis of prediction and prognosis. Clinical data have been previously presented (Gnant et al, JCO 2022), and the trial now has 5-year median follow-up. Methods. As part of trial eligibility, all participants in PALLAS provided a tumor tissue block prior to randomization (surgical if primary resection, core biopsy if neoadjuvant treatment) for translational analyses (TRANS-PALLAS). The biorepository and laboratory were blinded to identity and processed samples in random order, to minimize bias. Nucleic acids were extracted from samples with sufficient tumor tissue and cellularity (>25 mm2 with ≥20% cancer nuclei). The Genome Sequencing Center at Washington University St. Louis performed whole-transcriptome RNA sequencing. Libraries were prepared from 1 µg DNase-1 treated total RNA, if total RNA DV200 >28 (Agilent Bioanalyzer), using an unbiased library protocol of RNA HyperPrep kit with RiboErase (HMR) (Kapa Biosystems, Wilmington, MA). 100 bp paired-end sequencing was performed on NovaSeq 6000 using S4 Reagent Kit (Illumina, San Diego, CA), with 48 libraries pooled per lane. Intrinsic subtype was determined using Bioclassifier package (Research PAM50 script, Parker et al.) only for the analysis population of primary breast cancer samples that had not been exposed to prior neoadjuvant therapy. Invasive disease-free survival (IDFS) will be visualized using Kaplan-Meier plots, with log-rank test between groups. Cox models of proportional hazards will be developed to evaluate prognosis adjusted for known clinical covariates, or for predictive interactions. The pre-defined level of significance is a two-sided 0.05. Results. From the total study population of 5796 enrolled patients, 4655 tissue blocks had sufficient tumor content to process for RNA, with 3931 yielding sufficient RNA for sequencing, and 2669/4655 (57.3%) submitted tissue blocks had DV200 ≥28 and were successfully sequenced. Clinical unblinding revealed 2370 unique patients (1182 in the palbociclib treatment arm and 1188 in the control arm) with intrinsic subtype defined from their untreated primary tumor: 1555 (65.6%) luminal A, 287 (12.1%) luminal B, 167 (7.0%) HER2-enriched, 310 (13.1%) basal-like, 51 (2.2%) normal-like. We will report the results for association of molecular subtype, proliferation score, and Risk of Recurrence (ROR) scores with invasive disease-free survival (IDFS) by treatment arm at the meeting. Conclusions. The TRANS-PALLAS cohort represents one of the largest biorepositories of HR+/HER2- early breast cancer reflecting contemporary systemic management in the framework of a prospectively randomized global trial. Required tumor block submission in this phase 3 trial yielded data from unbiased whole-transcriptome RNA sequencing of the primary tumor prior to treatment from 41% of the PALLAS participants. The proportion of luminal A cancers was unexpectedly high (66%), indicating a lower-risk distribution of cancers in this population. The planned analyses of prediction and prognosis are ongoing and those results will be presented at the time of the meeting. Support: AFT, ABCSG, Pfizer, ECOG-ACRIN, NSABP Foundation, GBG, BIG; Clinicaltrials.gov Identifier: NCT02513394; https://acknowledgments.alliancefound.org Citation Format: Daniel Stover, Dominik Hlauschek, Erica Mayer, W. Fraser Symmans, Mark Watson, Iros Barozzi, Martin Filipits, Karla Ballman, Meritxell Bellet- Ezquerra, Justin Balko, Gabor Rubovszky, Nicholas Zdenkowski, Adam Brufsky, Guenther Steger, Claudine Isaacs, Sibylle Loibl, Fernando Henao, Meredith Regan, Yuan Liu, Christian Fesl, Patrick O'Brien, Angela DeMichele, Michael Gnant, Otto Metzger. Protocol-defined biomarker analysis in the PALLAS (AFT-05) adjuvant trial: Genomic subtype derived from RNA sequencing of HR+/HER2- early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-07.

AbstractObjectiveTo elucidate the relationship between USP19 and O(6)‐methylguanine‐DNA methyltransferase (MGMT) after temozolomide treatment in glioblastoma (GBM) patients with chemotherapy resistance.MethodsScreening the deubiquitinase pannel and identifying the deubiquitinase directly interacts with and deubiquitination MGMT. Deubiquitination assay to confirm USP19 deubiquitinates MGMT. The colony formation and tumor growth study in xenograft assess USP19 affects the GBM sensitive to TMZ was performed by T98G, LN18, U251, and U87 cell lines. Immunohistochemistry staining and survival analysis were performed to explore how USP19 is correlated to MGMT in GBM clinical management.ResultsUSP19 removes the ubiquitination of MGMT to facilitate the DNA methylation damage repair. Depletion of USP19 results in the glioblastoma cell sensitivity to temozolomide, which can be rescued by overexpressing MGMT. USP19 is overexpressed in glioblastoma patient samples, which positively correlates with the level of MGMT protein and poor prognosis in these patients.ConclusionThe regulation of MGMT ubiquitination by USP19 plays a critical role in DNA methylation damage repair and GBM patients’ temozolomide chemotherapy response.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel's discussions for the 2024 update to the guidelines with regard to initial risk stratification, initial management of very-low-risk disease, and the treatment of nonmetastatic recurrence.

Case: A 51-year-old man and 64-year-old woman with bilateral cruciate-retaining total knee arthroplasties (CR-TKAs) who sustained unilateral periprosthetic distal femur fractures above their CR-TKA and experienced knee instability secondary to an iatrogenic posterior-cruciate-ligament (posterior cruciate ligament [PCL]) injury from retrograde intramedullary nailing. Both patients recovered knee stability after undergoing revision surgery. Conclusion: Many CR-TKA designs have sufficient medial-lateral intercondylar distance to place a retrograde nail, femoral components with a relatively posterior transition from the trochlear groove to the intercondylar box will necessitate a nail starting point closer to the PCL origin. This may contribute to iatrogenic postoperative knee instability for patients with CR-TKA designs.

Fixation of olecranon fractures, especially those with minimal proximal bone and those that present with significant comminution, can be technically challenging. Current open reduction and internal fixation (ORIF) methods, such as tension band wire (TBW) constructs, plate fixation (PF), and intramedullary screws (IMSF), have demonstrated high rates of reoperation and symptomatic implants. We present the omega plate technique, which utilizes a mini-fragment plate passed under the triceps tendon insertion, allowing maximal implant surface area contact with small, proximal olecranon fracture fragments. The mini-fragment plate is not placed on the dorsal subcutaneous border of the ulna, which allows it to capture medial and lateral fragments of cortical comminution and may contribute to less soft tissue irritation.

Abstract Objective To assess for improvement in comfort in participating in advocacy for migraine and headache disorders and knowledge needed for successful advocacy. Background The Advocacy Connection Team (ACT)‐Now program is an educational program offered through Miles for Migraine, a non‐profit advocacy organization. It is designed to teach headache fellows and patients advocacy skills. Methods In a cross‐sectional pre‐test–post‐test design, the 2021 ACT‐Now cohort of 98 participants were administered a set of 11 pre‐course survey questions identifying their role (healthcare provider/headache fellow or patient/caregiver), baseline knowledge of migraine‐related disability and stigma, and baseline engagement and comfort with advocating. The post‐course survey questions were the same as the pre‐course questions, with the addition of one question assessing knowledge of migraine‐related disability, additional questions addressing comfort levels advocating with insurance and policymakers, as well as creating an advocacy plan. Results For the pre‐course survey, 69 participants responded and for the post‐course survey, 40 participants responded. Compared to the pre‐course survey, participants were able to correctly identify epidemiological data about migraine following the ACT‐Now course (pre‐course 46% correct, post‐course 58% correct, p = 0.263). There was also an increase in the comfort level of participants in advocacy activities, including the creation of an advocacy action plan (pre‐course 23% were “very comfortable” advocating, post‐course 63%, p < 0.05). Conclusion These results demonstrate that ACT‐Now is effective at improving advocacy skills in a mixed cohort of patients and headache fellows, giving them the skills to create advocacy plans and engage with other patients and physicians, payers, and policymakers to create a more understanding, equitable and compassionate world for persons with migraine and other headache diseases.

Abstract Background Native joint septic arthritis (NJSA) is definitively diagnosed by a positive Gram stain or culture, along with supportive clinical findings. Preoperative antibiotics are known to alter synovial fluid cell count, Gram stain, and culture results and are typically postponed until after arthrocentesis to optimize diagnostic accuracy. However, data on the impact of preoperative antibiotics on operative culture yield for NJSA diagnosis are limited. Methods We retrospectively reviewed adult cases of NJSA who underwent surgery at Mayo Clinic facilities from 2012 to 2021 to analyze the effect of preoperative antibiotics on operative culture yield through a paired analysis of preoperative culture (POC) and operative culture (OC) results using logistic regression and generalized estimating equations. Results Two hundred ninety-nine patients with NJSA affecting 321 joints were included. Among those receiving preoperative antibiotics, yield significantly decreased from 68.0% at POC to 57.1% at OC (P &lt; .001). In contrast, for patients without preoperative antibiotics there was a non-significant increase in yield from 60.9% at POC to 67.4% at OC (P = .244). In a logistic regression model for paired data, preoperative antibiotic exposure was more likely to decrease OC yield compared to non-exposure (odds ratio [OR] = 2.12; 95% confidence interval [CI] = 1.24–3.64; P = .006). Within the preoperative antibiotic group, additional antibiotic doses and earlier antibiotic initiation were associated with lower OC yield. Conclusions In patients with NJSA, preoperative antibiotic exposure resulted in a significant decrease in microbiologic yield of operative cultures as compared to patients in whom antibiotic therapy was held prior to obtaining operative cultures.