Treating pancreatic ductal adenocarcinoma (PDAC) remains a major hurdle in the field of oncology. Less than half of patients respond to frontline chemotherapy and the pancreatic tumor microenvironment limits the efficacy of immunotherapeutic approaches. Targeted therapies could serve as effective treatments to enhance the clinical response rate. One potential therapeutic target is survivin, a protein that is normally expressed during embryonic and fetal development and has a critical impact on cell cycle control and apoptosis. In adulthood, survivin is not present in most normal adult cells, but is significantly re-expressed in tumor tissues. In PDAC, elevated survivin expression is correlated with treatment resistance and lower patient survival, although the underlying mechanisms of survivin's action in this type of cancer is poorly understood. Using patient derived xenografts of PDAC and their corresponding primary pancreatic cancer lines (PPCL-46 and PPCL-LM1) possessing increased expression of survivin, we aimed to evaluate the therapeutic response of a novel survivin inhibitor, UFSHR, with respect to survivin expression and the tumorigenic characteristics of PDAC. Cell viability and apoptosis analyses revealed that repressing survivin expression by UFSHR or YM155, a well-known inhibitor of survivin, in PPCLs effectively reduces cell proliferation by inducing apoptosis. Tumor cell migration was also hindered following treatment with YM155 and UFSHR. In addition, both survivin inhibitors, particularly UFSHR, effectively reduced progression of PPCL-46 and PPCL-LM1 tumors, when compared to the untreated cohort. Overall, this study provides solid evidence to support the critical role of survivin in PDAC progression and proposes a novel survivin inhibitor UFSHR that can become an alternative strategy for this type of cancer.
Introduction: Frailty is an important predictor of clinical outcomes, but its contribution to resource utilization remains understudied. This study investigates the impact of frailty on high resource utilization (HRU) in patients undergoing Coronary Artery Bypass Graft Surgery (CABG). Methods: We reviewed data on patients who underwent CABG at a single center between 04/2018 and 12/2019. A Frailty score (FS) was calculated using the Essential Frailty Toolset (EFT). Patients were divided into two groups: Frail (FS ≥ 3/5) & Non-Frail (FS <3/5). Baseline clinical characteristics and outcomes were compared in both groups. The primary outcome was HRU (post-operative length of stay > 7 days or readmission within 30-days). Secondary outcomes included operative time, prolonged ventilation, & direct procedure costs. Multivariable logistic regression was used to assess the effect of frailty on HRU. Results: The study included 740 patients of whom 18% (n=132) were frail. Compared to Non-Frail patients, Frail patients were older (66 vs. 70 yrs. P<0.001) and more likely to be high risk for operative mortality (1.3% vs. 14%, p<0.001). The incidence of HRU was 28% vs. 53%, p<0.001, in Non-Frail vs. Frail patients. Frail patients had longer operative times (272 vs. 247 mins; p<0.001), and a higher incidence of prolonged ventilation (9.9% vs. 4%; p<0.001). Median direct costs were also higher in Frail subjects ($33,434 vs. $22, 207; p<0.001). On multivariable logistic regression analysis, independent predictors of HRU were (OR: 95% C.I.) Frailty: 2.19(1.44, 3.33; p=0.003), Sex (Female): 1.66 (1.14, 2.40; p=0.008), and history of COPD: 2.32(1.53, 3.54; p<0.001). Conclusions: About one out of every five patients undergoing CABG was classified as frail by the EFT. Frailty was associated with higher direct costs and found to be an independent predictor of high resource utilization. Further attention is required to optimize outcomes and resource use in this vulnerable population.
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