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e16331 Background: Elraglusib (9-ING-41), a potent and selective GSK-3 inhibitor, is a targeted anticancer agent with clinical activity in phase 1 trial and undergoing clinical development for the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC). Elraglusib (9-ING-41) displayed immune-modulatory activity in preclinical models and modulation of serum cytokine profile in clinical specimens. Here, we investigated the correlation between plasma levels of cytokines/chemokines/soluble cell receptors/growth factors (CCSG) and clinical outcomes of patients with mPDAC treated with elraglusib and gemcitabine/nab-paclitaxel (GnP) in an exploratory study. Methods: CCSGs were evaluated in the pre-dose plasma samples of patients with newly diagnosed mPDAC enrolled in the 1801 phase 2 study (NCT03678883) treated with GnP (n = 13) or elraglusib/GnP (n = 32). Using a Luminex immunoassay, 40 CCSGs were screened as predictive biomarkers of median overall survival (mOS) in the elraglusib/GnP arm using 5-fold cross-validation and maximally selected rank statistic cutpoint determination. A subset of CCSGs (n = 10) was remeasured using an MSD immunoassay with greater sensitivity. Maximally selected rank statistic cutpoint determinations were conducted using MSD results for elraglusib/GnP samples with mOS and median progression free survival (mPFS). P values < 0.05 were considered statistically significant. Results: Luminex screening revealed several CCSGs significantly stratified elraglusib/GnP patients by mOS. IL-6 and IL-8 were identified as top candidates with stable and significant results on cross-validation. Using the MSD assay, both were confirmed to stratify elraglusib/GnP patients by OS and extended to analyze PFS. Low level of IL-8 conferred a better OS prognosis (HR: 0.0919, 95%, CI: 0.0205-0.411, P < 0.001) than low IL-6 (HR: 0.205, 95%, CI: 0.063-0.665, P = 0.005) in the elraglusib/GnP treated patients. Correlations with mPFS were similar in the elraglusib/GnP patients for IL-6 (HR: 0.248, 95% CI: 0.072-0.848, P = 0.02) and IL-8 (HR: 0.297, 95%, CI: 0.111-0.743, P = 0.01). Conclusions: Preliminary results of our exploratory study identified low plasma levels of IL-6 and IL-8 prior to elraglusib/GnP treatment as potential predictive biomarkers associated with improved outcomes in previously untreated patients with mPDAC. The 1801 Part 3 Arm B clinical trial recruitment has been completed. We plan to analyze additional pre-dose plasma samples obtained from approximately 200 patients by April 2024. These will be analyzed using interim OS data available by April 2024 and included in the final presentation. Clinical trial information: NCT03678883 .

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy.

Background Acute ischemic stroke (AIS) caused by distal medium vessel occlusions (DMVOs) represents a significant proportion of overall stroke cases. While intravenous thrombolysis (IVT) has been a primary treatment, advancements in endovascular procedures have led to increased use of mechanical thrombectomy (MT) in DMVO stroke patients. However, symptomatic intracerebral hemorrhage (sICH) remains a critical complication of AIS, particularly after undergoing intervention. This study aims to identify factors associated with sICH in DMVO stroke patients undergoing MT. Methods This retrospective analysis utilized data from the Multicenter Analysis of Distal Medium Vessel Occlusions: Effect of Mechanical Thrombectomy (MAD-MT) registry, involving 37 centers across North America, Asia, and Europe. Middle cerebral artery (MCA) DMVO stroke patients were included. The primary outcome measured was sICH, as defined per the Heidelberg Bleeding Classification. Univariable and multivariable logistic regression were used to identify factors independently associated with sICH. Results Among 1708 DMVO stroke patients, 148 (8.7%) developed sICH. Factors associated with sICH in DMVO patients treated with MT included older age (adjusted odds ratio (aOR) 1.01, 95% confidence interval (95% CI) 1.00 to 1.03, P=0.048), distal occlusion site (M3, M4) compared with medium occlusions (M2) (aOR 1.71, 95% CI 1.07 to 2.74, P=0.026), prior use of antiplatelet drugs (aOR 2.06, 95% CI 1.41 to 2.99, P<0.001), lower Alberta Stroke Program Early CT Scores (ASPECTS) (aOR 0.75, 95% CI 0.66 to 0.84, P<0.001), higher preoperative blood glucose level (aOR 1.00, 95% CI 1.00 to 1.01, P=0.012), number of passes (aOR 1.27, 95% CI 1.15 to 1.39, P<0.001), and successful recanalization (Thrombolysis In Cerebral Infarction (TICI) 2b-3) (aOR 0.43, 95% CI 0.28 to 0.66, P<0.001). Conclusion This study provides novel insight into factors associated with sICH in patients undergoing MT for DMVO, emphasizing the importance of age, distal occlusion site, prior use of antiplatelet drugs, lower ASPECTS, higher preoperative blood glucose level, and procedural factors such as the number of passes and successful recanalization. Pending confirmation, consideration of these factors may improve personalized treatment strategies.

INTRODUCTION: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is frequently used to risk-stratify pancreatic cystic lesions (PCLs). Rising PCL incidence and developments in tissue acquisition and specimen analysis necessitate updated appraisal of EUS-FNA safety, particularly the risk of postprocedure pancreatitis, the most common EUS-FNA-related adverse event. Our systematic review aims to accurately quantify the risk of EUS-FNA-related pancreatitis to best inform decisions regarding EUS-FNA's optimal role in PCL workup. METHODS: We performed systematic searches in 4 databases from inception to April 2024 for original English-language studies investigating EUS-FNA-related pancreatitis. We extracted data on demographics and EUS-FNA-related pancreatitis risk, severity, and risk factors. These were meta-analyzed through the DerSimonian Laird Method using a random-effects model. Meta-regression of pancreatitis risk was performed to delineate associations with clinical and procedural characteristics. RESULTS: Sixty-four studies comprised 8,086 patients and reported 110 EUS-FNA-related pancreatitis events. Pooled risk of EUS-FNA-related pancreatitis was 1.4% (95% confidence intervals, −0.8% to 3.5%; I 2 = 0.00), which was predominantly of mild severity (67%) and uniformly nonfatal. Pancreatitis risk lacked significant association with sample size, age, sex, cyst size, needle caliber, or passes, although we noted trends toward higher risk in studies published after 2015, those using higher gauge needles (19 G vs 22 G/25 G), and those performing EUS-guided through-the-needle biopsy. DISCUSSION: We note with high certainty that pancreatitis after EUS-FNA of PCLs is infrequent and mild in severity with no mortality in the included cohort. EUS-guided through-the-needle biopsy may serve as a significant risk factor for EUS-FNA-related pancreatitis risk; however, further studies are needed to delineate other predisposing characteristics.

Purpose To assess the consistency and quality of risk factor reporting for rotator cuff repair (RCR) retear and identify risk factors most frequently associated with retear. Methods A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA) guidelines. Of the initial 3,158 studies, a total of 31 met the following inclusion criteria: (1) clinical studies regarding RCR failure, (2) arthroscopic procedures involving RCR, (3) reporting of clinical outcomes, (4) publication within the past 5 years, and (5) studies investigating preoperative risk factors for retear. After full‐text review, 18 risk factors were analyzed. Results The most consistently significant risk factors were acromiohumeral distance (80%), critical shoulder angle (67%), tear size (63%), anterior‐posterior dimension (60%), fatty infiltration (FI) (58%), and retraction size (56%). FI was analyzed using different methods among studies, with 63% finding significant results and 50% of all studies performing ordinal analysis. Tear size was inconsistently analyzed quantitatively or qualitatively, with 58% of studies finding significant results and 63% of all studies performing quantitative analysis. Risk factors consistently found to be nonsignificant included age, sex, diabetes mellitus, symptom duration, hand dominance, repair technique, smoking, and body mass index. Conclusions Tear size, FI, and retraction size were found to be significant risk factors in most of the included studies evaluating rotator cuff retear. Risk factors less likely reported as predictive included repair technique, age, sex, diabetes mellitus, symptom duration, hand dominance, repair technique, smoking, and body mass index. Risk factors that require further investigation include critical shoulder angle, acromiohumeral distance, and anterior‐posterior tear dimension. Level of Evidence Level III, systematic review of Level III‐IV studies.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder marked by the development of cysts in the kidneys and other organs, leading to diverse clinical manifestations, including kidney failure. The psychological burden of ADPKD is substantial, with significant contributors including pain, daily life disruptions, depression, anxiety, and the guilt associated with transmitting ADPKD to offspring. This review details the psychological impacts of ADPKD on patients, addressing how they navigate physical and emotional challenges, including pain management, genetic guilt, mood disorders, and disease acceptance. This review also underscores the need for comprehensive research into the psychological aspects of ADPKD, focusing on the prevalence and contributing factors of emotional distress and identifying effective strategies for managing anxiety and depression. Furthermore, it highlights the importance of understanding the diverse factors that influence patients' quality of life and advocates for holistic interventions to address these psychological challenges.

INTRODUCTION: There are limited real-world data comparing the effectiveness of upadacitinib and tofacitinib in patients with ulcerative colitis (UC). METHODS: We conducted a retrospective cohort study using TriNetX, a multi-institutional database, to compare the effectiveness of upadacitinib and tofacitinib in patients with UC. The primary aim was to assess the risk of a composite outcome of hospitalization requiring intravenous steroids and/or colectomy within 6 and 12 months. One-to-one propensity score matching was performed for demographics, comorbid conditions, mean hemoglobin, C-reactive protein, albumin, and calprotectin, and prior UC medications including recent oral or intravenous steroid use between the cohorts. Risk was expressed as adjusted odds ratio (aOR) with 95% confidence intervals (CI). RESULTS: There were 526 patients in the upadacitinib cohort (mean age 40.4 ± 16.3, 44.8% female sex, 76.6% White race) and 1,149 patients in the tofacitinib cohort (mean age 42 ± 17.1, 41.9% female sex, 76% White race). After propensity score matching, there was no significant difference in the risk of the composite outcome of need for intravenous steroids and/or colectomy within 6 months (aOR 0.75, 95% CI 0.49–1.09). However, there was a lower risk of the composite outcome (aOR 0.63, 95% CI 0.44–0.89) in the upadacitinib cohort compared with the tofacitinib cohort within 12 months. There was no difference in the risk of intravenous steroid use (aOR 0.70, 95% CI 0.48–1.02) but lower risk of colectomy (aOR 0.46, 95% CI 0.27–0.79). In sensitivity analysis, there was also a lower risk of the composite outcome (aOR 0.64, 95% CI 0.44–0.94), including lower risk of intravenous steroid use (aOR 0.67, 95% CI 0.45–0.99) and colectomy (aOR 0.49, 95% CI 0.26–0.92) in the upadacitinib cohort compared with the tofacitinib cohort within 12 months. DISCUSSION: This study utilizing real-world data showed that upadacitinib was associated with improved disease-specific outcomes at 12 months compared with tofacitinib in patients with UC.

INTRODUCTION: Pharmacologic therapies for symptoms of gastroparesis (GP) have limited efficacy, and it is difficult to predict which patients will respond. In this study, we implemented a machine learning model to predict the response to prokinetics and/or neuromodulators in patients with GP-like symptoms. METHODS: Subjects with suspected GP underwent simultaneous gastric emptying scintigraphy (GES) and wireless motility capsule and were followed for 6 months. Subjects were included if they were started on neuromodulators and/or prokinetics. Subjects were considered responders if their GP Cardinal Symptom Index at 6 months decreased by ≥1 from baseline. A machine learning model was trained using lasso regression, ridge regression, or random forest. Five-fold cross-validation was used to train the models, and the area under the receiver operator characteristic curve (AUC-ROC) was calculated using the test set. RESULTS: Of the 150 patients enrolled, 123 patients received either a prokinetic and/or a neuromodulator. Of the 123, 45 were considered responders and 78 were nonresponders. A ridge regression model with the variables, such as body mass index, infectious prodrome, delayed gastric emptying scintigraphy, no diabetes, had the highest AUC-ROC of 0.72. The model performed well for subjects on prokinetics without neuromodulators (AUC-ROC of 0.83) but poorly for those on neuromodulators without prokinetics. A separate model with gastric emptying time, duodenal motility index, no diabetes, and functional dyspepsia performed better (AUC-ROC of 0.75). DISCUSSION: This machine learning model has an acceptable accuracy in predicting those who will respond to neuromodulators and/or prokinetics. If validated, our model provides valuable data in predicting treatment outcomes in patients with GP-like symptoms.