Citations

1037 Background: TBCRC041, a randomized phase 2 trial of alisertib (A) ± fulvestrant (F) in women with HR+/HER2- MBC demonstrated promising clinical activity for alisertib (1). Interrogation of baseline (PreC1) and end of cycle 1 (EOC1) cfDNA and CTCs may identify biomarkers associated with response to A±F. Methods: Plasma cfDNA was sequenced using the Guardant INFINITY platform, which includes genomic and methylated tumor fraction (mTF) analysis. Pathogenic variants were determined using publicly available databases and Mayo Clinic annotation pipelines. CTCs were identified as nucleated, EpCAM+/ cytokeratin+/ CD45- cells and assessed for ER/HER2 staining (RareCyte, Seattle). PFS was defined as the time from randomization to progression or death. EOC1-PFS differs from PFS as time starts at C2D1. Stratified log-rank tests and conditional Cox modeling were used to assess whether PFS or EOC1-PFS differed by mutations in ESR1 or PIK3CA, pre-CTC ≥ 5, or mTF>1%. Results: Of the 91 eligible pts, 84 progressed, and 73 were deceased. In the 86 pts with PreC1-cfDNA results, variants were identified in ESR1 (42; 48.8%), PIK3CA (36; 41.9%), AKT1 (7; 8.1%), PTEN(7; 8.1%), BRCA1 (4; 4.7%), and BRCA2 (7; 8.1%). Pts with a PIK3CAmut had significantly decreased PFS (HR 1.8; 95%CI: 1.1 -2.9, p=0.014) but not by ESR1mut status (p=0.583). PreC1 and EOC1-mTF were determined for 78 and 76 pts, respectively. PreC1-mTF was 0-1% in 21; 1.1-10.0% in 27; and 10.1-100% in 30. mTF levels remained between 0-1% in 17 pts fell to 0-1% in 11 pts, and was 0-1% in 5 pts without a preC1-mTF determination. PFS did not differ with respect to PreC1-mTF (p=0.210), but EOC1-PFS was worse in pts with mTF >1% (HR 3.0; 95%CI: 1.6 -5.2, p<0.001). PreC1 and EOC1-CTC were determined for 78 and 76 pts. 36 (46.2%) pts had a PreC1 CTC count ≥ 5. EOC1-CTC levels remained at (n=17) or increased to (n=1) ≥ 5 and was ≥ 5 in 2 pts without a preC1-CTC determination. EOC1-PFS was not significantly different for EOC1-CTC ≥ 5 (p=0.065), but was significantly decreased in pts with PreC1-CTC≥5 (HR=1.8; 95%CI: 1.1-3.0; p=0.018). Broader cfDNA NGS panel and CTC-derived ER/HER2 staining results will be presented at the meeting. Conclusions: Among patients receiving A±F, PFS varied based on the PIK3CAmutation status. cfDNA and CTC assessment PreC1 and EOC1 provided complementary information. Further validation in larger datasets is needed. 1. JAMA Oncol 2023;9:815. Clinical trial information: NCT02860000 .

AbstractDNA damage plays a significant role in the tumorigenesis and progression of the disease. Abnormal DNA repair affects the therapy and prognosis of cancer. In this study, it is demonstrated that the deubiquitinase USP25 promotes non‐homologous end joining (NHEJ), which in turn contributes to chemoresistance in cancer. It is shown that USP25 deubiquitinates SHLD2 at the K64 site, which enhances its binding with REV7 and promotes NHEJ. Furthermore, USP25 deficiency impairs NHEJ‐mediated DNA repair and reduces class switch recombination (CSR) in USP25‐deficient mice. USP25 is overexpressed in a subset of colon cancers. Depletion of USP25 sensitizes colon cancer cells to IR, 5‐Fu, and cisplatin. TRIM25 is also identified, an E3 ligase, as the enzyme responsible for degrading USP25. Downregulation of TRIM25 leads to an increase in USP25 levels, which in turn induces chemoresistance in colon cancer cells. Finally, a peptide that disrupts the USP25‐SHLD2 interaction is successfully identified, impairing NHEJ and increasing sensitivity to chemotherapy in PDX model. Overall, these findings reveal USP25 as a critical effector of SHLD2 in regulating the NHEJ repair pathway and suggest its potential as a therapeutic target for cancer therapy.

Abstract Background The extravascular implantable cardioverter defibrillator (EV ICD) has recently emerged as a new option for guideline indicated ICD patients. Previous study results from the EV ICD Pilot and Pivotal studies have demonstrated that the device can provide safe and effective therapy through chronic follow up. However, less has been reported regarding EV ICD lead removal. Purpose To report on the experience of lead removal in the EV ICD Pivotal Study. Methods The EV ICD Pivotal study was an international, prospective, single-arm, premarket clinical study. Patients with a class I or IIa indication for a single-chamber ICD per ESC or ACC/AHA/HRS guidelines were enrolled. Lead removal summary data was reported. Results Of 316 patients with an implant attempt, (74.7% male, age 53.8±13.1 years, 82% primary prevention, LVEF of 38.9%±15.4%, and NYHA Class I [23.7%] or II/III [65.5%]) 299 were fully implanted; 17 (5.7%) of which had a lead removal procedure (14–752 days post-implant, at 13 sites) with 3 of them having been implanted for more than 1 year. Reasons for lead removal were lead dislodgement (n=7), infection (n=5), high impedance alert due to lead fracture (n=2), pacing indication (n=1), cardiac transplant (n=1), or scheduled sternotomy (n=1). New EV ICD leads were placed in 7/17 (41.2%) patients. No serious adverse events were adjudicated as related to the explant procedures. There was a single observation of incision site haemorrhage, that was resolved with wound care. Additional details on lead removal will be included at the time of presentation. Conclusions The EV ICD lead was successfully removed 14-752 days post implant. Nine patients were re-implanted with either extravascular or transvenous systems. Longer term extraction data collection is ongoing through the EV ICD Pivotal study and through the EV ICD post-approval study and will continue to provide additional insights.Lead removed 24 months post-implant.

AbstractBackground and AimIn recent years, there has been a growing incidence of gastrointestinal cancer in young individuals. Despite its significant morbidity and mortality, research on upper gastrointestinal (UGI) cancer in young populations has been relatively limited. Therefore, studies on the epidemiological changes of this cancer are needed.MethodsUsing data from the Global Burden of Disease Study 2019, we examined the incidence, death, and disability‐adjusted life years (DALYs) from UGI cancers in the young, namely, early‐onset esophageal cancer (EOEC) and early‐onset gastric cancer (EOGC). These results were stratified by sex, geographical region, country, and sociodemographic index.ResultsThere was a total of 185 140 cases, 120 289 deaths, and 5.70 million DALYs attributable to early‐onset UGI cancers globally. From 2010 to 2019, the global incidence, death, and DALYs rates of early‐onset UGI cancers decreased. In contrast, the incidence rates increased in both EOEC (+1.15%) and EOGC (+0.21%) in the Eastern Mediterranean region.ConclusionsOver the past decade, the burden of UGI cancer in the young has decreased. However, it has increased in the Eastern Mediterranean region. Further research to elucidate the attributable risk factors in this population is warranted.

Background. Minority race, ethnicity, and financial barriers are associated with lower rates of living donor (LD) kidney transplantation (LDKT). Financial reimbursement for LD costs may impact social determinants of health and, therefore, impact disparities in access to LDKT. Methods. Among US LDKTs, we studied associations between racial and ethnic minority status and utilization of the National Living Donor Assistance Center (NLDAC), a means-tested reimbursement program for nonmedical LD costs. We analyzed demographic, clinical, income, and survey data from NLDAC and the Scientific Registry of Transplant Recipients (January 1, 2011, to December 31, 2022) to identify predictors of NLDAC utilization. Results. Among 70 069 US LDKTs, 6093 NLDAC applicants were identified (9% of US LDKTs). Racial and ethnic minorities were over-represented in NLDAC-supported LDKTs compared with non-NLDAC US LDKTs (Black donors 12% versus 9%; Black recipients 15% versus 12%; Hispanic donors 21% versus 14%; Hispanic recipients 23% versus 15%; all P < 0.001). Among preemptive transplants, use of NLDAC by donors to Hispanic recipients (11%) was nearly twice as high as that of non-Hispanic recipients (6%) (P < 0.001). At time of NLDAC application, 72% stated NLDAC “will make it possible” to donate; higher proportions of minority applicants agreed (Black 80%, White 70%, P < 0.001; Hispanic 79%, non-Hispanic 70%, P < 0.001). Racial and ethnic minority-concordant transplants were significantly more likely to use NLDAC (donor/recipient: Black/Black risk-adjusted odds ratio [OR], 1.85, other/other OR 2.59, Hispanic/Hispanic OR 1.53; all P < 0.05). Conclusions. Reduction of LD financial barriers may increase access to LDKT, particularly in racial and ethnic minority communities.

AbstractPreviously, lysosomes were primarily referred to as the digestive organelles and recycling centers within cells. Recent discoveries have expanded the lysosomal functional scope and revealed their critical roles in nutrient sensing, epigenetic regulation, plasma membrane repair, lipid transport, ion homeostasis, and cellular stress response. Lysosomal dysfunction is also found to be associated with aging and several diseases. Therefore, function of macroautophagy, a lysosome‐dependent intracellular degradation system, has been identified as one of the updated twelve hallmarks of aging. In this review, we begin by introducing the concept of lysosomal quality control (LQC), which is a cellular machinery that maintains the number, morphology, and function of lysosomes through different processes such as lysosomal biogenesis, reformation, fission, fusion, turnover, lysophagy, exocytosis, and membrane permeabilization and repair. Next, we summarize the results from studies reporting the association between LQC dysregulation and aging/various disorders. Subsequently, we explore the emerging therapeutic strategies that target distinct aspects of LQC for treating diseases and combatting aging. Lastly, we underscore the existing knowledge gap and propose potential avenues for future research.