Citations

Abstract Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma. However, the mechanistic link with established drivers of this disease remains in part elusive. In this study, using a new genetically engineered mouse model overexpressing constitutively active mouse form of GLI2 and a combination of genome-wide assays, we provide evidence of a novel mechanism underlying the interplay between KRAS, a major driver of pancreatic ductal adenocarcinoma development, and GLI2 to control oncogenic gene expression. These mice, also expressing KrasG12D, show significantly reduced median survival rate and accelerated tumorigenesis compared with the KrasG12D only expressing mice. Analysis of the mechanism using RNA sequencing demonstrate higher levels of GLI2 targets, particularly tumor growth–promoting genes, including Ccnd1, N-Myc, and Bcl2, in KrasG12D mutant cells. Furthermore, chromatin immunoprecipitation sequencing studies showed that in these cells KrasG12D increases the levels of trimethylation of lysine 4 of the histone 3 (H3K4me3) at the promoter of GLI2 targets without affecting significantly the levels of other major active chromatin marks. Importantly, Gli2 knockdown reduces H3K4me3 enrichment and gene expression induced by mutant Kras. In summary, we demonstrate that Gli2 plays a significant role in pancreatic carcinogenesis by acting as a downstream effector of KrasG12D to control gene expression.

e15589 Background: Most patients with mCRC eventually develop disease progression or intolerance to first- and second-line therapy. Fruquintinib, a selective oral tyrosine kinase inhibitor of VEGFRs 1, 2, and 3, has emerged as a novel treatment option for refractory mCRC. We conducted a meta-analysis to assess the safety and efficacy of Fruquintinib for the treatment of refractory mCRC compared to placebo in specific patient subgroups of interest. Methods: We systematically searched PubMed, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) reporting Fruquintinib efficacy. The data extraction followed PRISMA guidelines and our protocol was registered in PROSPERO (CRD42023477783). Summary hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were calculated using a random-effects model. The likelihood of Fruquintinib being associated with adverse events (AEs) was expressed by odds ratios (ORs). Results: Of the 1138 studies yielded by the search, three were included, totaling 1178 patients, of whom 786 (67%) received Fruquintinib. This meta-analysis of three randomized trials assessed the clinical outcomes of Fruquintinib in the intervention group compared with placebo in refractory mCRC. Pooled results from all three studies suggested the superiority of Fruquintinib in PFS (HR: 0.29 [0.25, 0.34], 95% CI, I² = 10%, p < 0.01) and OS (HR: 0.66 [0.57, 0.76], 95% CI, p < 0.01). Notably, subgroup analysis showed that Fruquintinib was associated with improved PFS in patients with prior use of VEGF inhibitors (HR: 0.32 [0.27, 0.38], 95% CI, p < 0.01) and those with more than three prior lines of treatment (HR: 0.37 [0.25, 0.53], 95% CI, p < 0.01), RAS wild-type status (HR: 0.25 [0.13, 0.35], 95% CI, p < 0.01), or RAS mutated (HR: 0.33 [0.28, 0.40], 95% CI, p < 0.01). In the safety analysis, fruquintinib and placebo showed no significant differences in serious AEs; nonetheless, the VEGFR inhibitor was associated with more frequent grade ≥ 3 AEs (OR: 3.13 [1.15, 8.53], 95% CI, p = 0.03). Conclusions: This meta-analysis supports the efficacy of Fruquintinib for refractory mCRC regardless of previous use of VEGF inhibitors, the number of previous treatment lines, and gene RAS mutational status, without a significant increase in serious adverse events. [Table: see text]

TPS3173 Background: ELU001, pasifolate exatecan, is an ultra-small nanoparticle drug conjugate, known as a CDC (~6 nm), designed to target and penetrate into solid tumors. Due to its size, ELU001 exhibits rapid renal elimination which is expected to reduce or eliminate the toxicities associated with many antibody drug conjugates. ELU001 has ~13 folic acid targeting moieties and ~21 cathepsin-B cleavable exatecan topoisomerase-1 inhibitor payloads covalently bound to short polyethylene glycol chains surrounding a silica core, the C’Dot. ELU001 binds to cancer cells expressing FRα and is internalized into the lysosome where it releases the exatecan payload. ELU001’s dose escalation study reported at ESMO Congress 2023 (1), examined weekly, bi-weekly (Q2W), and tri-weekly schedules over a range of doses in 42 patients. The study revealed that ELU001 could be administered safely and identified a dose level and schedule for the Expansion Studies described below. 22 of the patients with ovarian or endometrial cancers had >1 post-baseline scan(s), of these 2 had a PR and 19 had SD by RECIST v1.1 criteria. ELU001 demonstrated activity against tumors across a range of FRα expression levels, from low to high, retrospectively assessed using the VENTANA FOLR1 RxDx assay and the PS2+ scoring system. Methods: The current multicenter, Tumor Group Expansion open-label phase 1/2 clinical trial investigates ELU001 in patients with ovarian and endometrial cancers and is enrolling three cohorts; 1) ovarian cancer with high FRα expression, 2) ovarian cancer with moderate and low expression and 3) endometrial cancer with low to high expression with assessments based upon the PS2+ scoring system (high = ≥ 75%, moderate = ≥ 50% to < 75%, low = 25% to < 50%, negative = <25% of tumor cells with 2+ or 3+ staining intensity). An initial exploratory dose of 2.0 mg/m2 Q2W was employed in all three cohorts and a second dose of 1.7 mg/m2 Q2W will be studied in the ovarian cancer cohorts. Patients will ultimately be randomized to one of two or more doses to optimize dosing for registration. Primary endpoint: Objective Response Rate (ORR); secondary endpoints include DOR, PFS, TFST, PFS2, OS, adverse events, PK, and ADA assessments. Approximately 20 patients per tumor group will be recruited in the U.S. 1. Ann. Oncol. (2023) 34 (suppl_2): S458-S497. Clinical trial information: NCT05001282 .

Abstract Background/Aim Limited data exists on 30-day readmission rates, readmission causes and predictors following Ischemic Colitis (IC). The aim is to identify etiologies for the above using a national database. Methods A retrospective cohort study using the 2019 National Readmission Database (NRD) of adult patients with an index admission (IA) for IC from January to November and were readmitted within 30 days of discharge was performed. The primary outcome was readmission of any cause. Secondary outcomes were mortality and resource utilization associated with readmission. Independent risk factors for all-cause readmission were identified using Cox regression analysis. Results A total of 6,853 IC patients were identified. Readmission within 30 days occurred in 762 (11%). The primary readmission cause was sepsis. A total of 325 patients died during the IA and additional 30 patients died within 30 days of discharge. Independent predictors of readmission were discharge to short term hospital, a Charlson comorbidity index score ≥ 2 and admission at large size hospital. Having private insurance and undergoing colonoscopy were associated with lower readmission odds. Economic burden of readmission was $12 million in total costs and $51.4 million in total charges. Conclusion Among admitted IC patients, 30-day readmission rate was 11% with half of those secondary to sepsis. Undergoing colonoscopy during the IA is associated with 34% less risk of readmission and disposition to other facilities appears associated with increased early readmission risk. Prospective evaluation to confirm these findings along with development of optimal care strategies to reduce readmission post IC episodes are needed.

Abstract Aims Aortic valve calcification (AVC) is prognostic in patients with aortic stenosis (AS). We assessed the AVC prognostic value in non-severe AS patients. Methods and results We conducted a retrospective study of 395 patients with non-severe AS, LVEF ≥ 50%. The Agatston method was used for CT AVC assessment. The log-rank test determined the best AVC cut-offs for survival under medical surveillance: 1185 arbitrary unit (AU) in men and 850 AU in women, lower than the established cut-offs for severe AS (2064 AU in men and 1274 AU in women). Patients were divided into 3 AVC groups based on these cut-offs: low (&lt;1185 AU in men and &lt;850 AU in women), sub-severe (1185–2064 AU in men and 850–1274 AU in women), and severe (&gt;2064 AU in men and &gt;1274 AU in women). Of 395 patients (mean age 73 ± 12 years, 60.5% men, aortic valve area 1.23 ± 0.30 cm2, mean pressure gradient 28 ± 8 mmHg), 218 underwent aortic valve intervention (AVI) and 158 deaths occurred during follow-up, 82 before AVI. Median survival time under medical surveillance was 2.1 (0.7–4.9) years. Compared with the low AVC group, both sub-severe and severe AVC groups had higher risk for all-cause death under medical surveillance after comprehensive adjustment including echocardiographic AS severity and coronary artery calcium score (all P ≤ 0.006); while mortality risk was similar between sub-severe and severe AVC groups (all P ≥ 0.2). This mortality risk pattern persisted in the overall survival analysis after adjustment for AVI. AVI was protective of all-cause death in the sub-severe and severe AVC (all P ≤ 0.01), but not in the low AVC groups. Conclusion Sub-severe AVC is a robust risk stratification parameter in patients with non-severe AS and may inform AVI timing.

OBJECTIVE Deficiency in patient education has been correlated with increased disease-related morbidity and decreased access to care. However, the associations between educational level, preoperative disease severity, and postoperative outcomes in patients with lumbar spondylolisthesis have yet to be explored. METHODS The spondylolisthesis dataset of the Quality Outcomes Database (QOD)—a cohort with prospectively collected data by the SpineCORe study team of the 12 highest enrolling sites with an 81% follow-up at 5 years —was utilized and stratified for educational level. Patients were classified into three categories (high school or less, graduate, or postgraduate). Patient-reported outcome measures (PROMs) documented at baseline and follow-up included Oswestry Disability Index (ODI) score, EQ-5D in quality-adjusted life years, and numeric rating scale (NRS) scores for back and leg pain. Disease severity was measured with PROMs. Postoperatively, patients also completed the North American Spine Society assessment to measure their satisfaction with surgery. Multivariable regression analysis was used to compare education level with disease severity and postoperative outcomes. RESULTS A total of 608 patients underwent analysis, with 260 individuals (42.8%) at an educational level of high school or less. On univariate analysis, baseline disease severity was worse among patients with lower levels of education. On multivariable regression analysis, patients with postgraduate level of education had significantly lower ODI scores (β = −3.75, 95% CI −7.31 to −0.2, p = 0.039) compared to graduates, while the other PROMs were not associated with significant differences at baseline. Five years postoperatively, patients from various educational backgrounds exhibited similar rates of minimal clinically important differences in PROMs. Nevertheless, patients with the lowest educational level had higher ODI scores (27.1, p < 0.01), lower EQ-5D scores (0.701, p < 0.01), and higher NRS leg pain (3.0, p < 0.01) and back pain (4.0, p < 0.01) scores compared to those with graduate or postgraduate levels of education. The odds for postoperative satisfaction were also comparable between cohorts at 5 years (reference, graduate level; high school or less, OR 0.87, 95% CI 0.46–1.64, p = 0.659; postgraduate, OR 1.6, 95% CI 0.7–3.65, p = 0.262). CONCLUSIONS Lower patient education level was associated with a greater baseline disease severity in patients with lumbar spondylolisthesis. Surgery demonstrated similar benefits irrespective of educational background; however, individuals with lower educational level reported lower outcomes overall. This emphasizes the need for enhanced health literacy to mitigate disparities for reported outcomes.

AbstractINTRODUCTIONWhile Latin America (LatAm) is facing an increasing burden of dementia due to the rapid aging of the population, it remains underrepresented in dementia research, diagnostics, and care.METHODSIn 2023, the Alzheimer's Association hosted its eighth satellite symposium in Mexico, highlighting emerging dementia research, priorities, and challenges within LatAm.RESULTSSignificant initiatives in the region, including intracountry support, showcased their efforts in fostering national and international collaborations; genetic studies unveiled the unique genetic admixture in LatAm; researchers conducting emerging clinical trials discussed ongoing culturally specific interventions; and the urgent need to harmonize practices and studies, improve diagnosis and care, and use affordable biomarkers in the region was highlighted.DISCUSSIONThe myriad of topics discussed at the 2023 AAIC satellite symposium highlighted the growing research efforts in LatAm, providing valuable insights into dementia biology, genetics, epidemiology, treatment, and care.

Abstract Primary thyroid lymphoma is a rare thyroid cancer, comprising ˂5% of thyroid neoplasms. Most cases are diffuse large B-cell lymphoma (DLBCL). Coexistence with papillary thyroid cancer (PTC) is extremely rare. This study presents a case of a 55-year-old woman with DLBCL and micropapillary thyroid cancer who underwent lobectomy, chemotherapy, and radiotherapy. Additionally, we performed a systematic review of 10 cases, including the reported case. The risk of bias in case reports varied. DLBCL diagnoses were mainly made after surgery, with total thyroidectomy being the most common surgical procedure. Chemotherapy was administered in most cases, and radiotherapy was used in some cases. Long-term outcomes indicated a low recurrence rate. While some debate the role of surgery in thyroid lymphoma, this study suggests that surgery should be considered in selected cases. Further research is needed to determine optimal treatment strategies for DLBCL with PTC.