Faculty Bibliography

BACKGROUND:Robotic surgery for right-sided colon and rectal cancer has rapidly increased; however, there is limited evidence in the literature of advantages of robotic left colectomy (RLC) for left-sided colon cancer. The purpose of this study was to compare the outcomes of RLC versus laparoscopic left colectomy (LLC) with complete mesocolic excision (CME) for left-sided colon cancer. METHODS:Patients who had RLC or LLC with CME for left-sided colon cancer at 5 hospitals in China between January 2014 and April 2022 were included. A one-to-one propensity score matched analysis was performed to decrease confounding. The primary outcome was postoperative complications occurring within 30 days of surgery. Secondary outcomes were disease-free survival, overall survival and the number of harvested lymph nodes. RESULTS:A total of 292 patients (187 males; median age 61.0 [20.0-85.0] years) were eligible for this study, and propensity score matching yielded 102 patients in each group. The clinical-pathological characteristics were well-matched between groups. The two groups did not differ in estimated blood loss, conversion to open rate, time to first flatus, reoperation rate, or postoperative length of hospital stay (p > 0.05). RLC was associated with a longer operation time (192.9 ± 53.2 vs. 168.9 ± 52.8 minutes, p=0.001). The incidence of postoperative complications did not differ between the RLC and LLC groups (18.6% vs. 17.6%, p = 0.856). The total number of lymph nodes harvested in the RLC group was higher than that in the LLC group (15.7 ± 8.3 vs. 12.1 ± 5.9, p< 0.001). There were no significant differences in 3-year and 5-year overall survival or 3-year and 5-year disease-free survival. CONCLUSIONS:Compared to laparoscopic surgery, RLC with CME for left-sided colon cancer was found to be associated with higher numbers of lymph nodes harvested and similar postoperative complications and long-term survival outcomes.

Dysfunction of endothelial cells is now recognized as an important contributor to the pathogenesis of atherosclerosis (AS). Circular RNAs (circRNAs) have been demonstrated to be involved in AS pathogenesis. The purpose of this study was to explore the biological action of circRNA BTG3 associated nuclear protein (circ-BANP, hsa_circ_0040824) on the dysfunction of human umbilical vein endothelial cells (HUVECs) induced by oxidized low-density lipoprotein (ox-LDL). The levels of circ-BANP, miR-370 and thioredoxin-interacting protein (TXNIP) were gauged by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Subcellular fractionation assay was used to determine the localization of circ-BANP, and ribonuclease R (RNase R) assay was performed to evaluate the stability of circ-BANP. Cell viability, apoptosis, migration, invasion and tube formation abilities were assessed by the Cell Counting Kit-8 (CCK-8), flow cytometry, transwell, and tube formation assays. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and IL-1β were detected by enzyme-linked immunosorbent assay (ELISA). Targeted relationships among circ-BANP, miR-370 and TXNIP were confirmed by a dual-luciferase reporter assay. Our data showed that circ-BANP expression was up-regulated in AS blood and ox-LDL-induced HUVECs. The inhibition of circ-BANP promoted cell viability, migration, invasion, tube formation, and repressed cell inflammation and apoptosis in ox-LDL-induced HUVECs, demonstrating that circ-BANP silencing alleviated ox-LDL-induced HUVEC injury. Mechanistically, circ-BANP directly targeted miR-370. Moreover, miR-370 mediated the regulation of circ-BANP in ox-LDL-induced cell injury in HUVECs. TXNIP was a target of miR-370, and miR-370 overexpression relieved ox-LDL-induced HUVEC injury by down-regulating TXNIP. Furthermore, circ-BANP modulated TXNIP expression by targeting miR-370. Our findings demonstrated that circ-BANP regulated ox-LDL-induced cell injury in HUVECs at least in part through targeting the miR-370/TXNIP axis, illuminating circ-BANP as a potential target for AS detection and treatment.

Background: The US Food and Drug Administration (FDA) possesses regulatory flexibility in determining the evidence necessary to support new drug approval. This has increasingly been exercised through special regulatory programs, such as Accelerated Approval and Breakthrough Designation. These permit the use of different clinical evidentiary standards to support approval, such as surrogate markers of disease (e.g. biomarkers) rather than clinical (e.g. overall survival) endpoints. This study examined whether clinical trial evidence supporting FDA approval of new drugs has changed over three decades.
Method(s): We performed a cross-sectional analysis of all new drugs (small molecule and biologic) approved by the FDA between 1995-1997, 2005-2007, and 2015-2017. Using the publicly-available Drugs@FDA database, we identified drug approvals and classified them by therapeutic area and use of special regulatory programs. Next, we identified the pivotal efficacy trials supporting each drug's approval, and characterized use of randomization, double-blinding, choice of comparators and endpoints, number of participants, and trial duration. Comparisons between time periods were performed using chi-square and Kruskal-Wallis tests. Analyses were repeated aggregated by indication and stratified by product therapeutic area and use of special regulatory programs.
Result(s): We identified 273 new drugs approved by the FDA in these 3 periods, representing 339 indications supported by 802 pivotal efficacy trials. The proportion of approvals receiving priority review increased from 1995-1997 to 2015-2017 (34% vs. 61%; p< 0.001), as did those receiving an orphan designation (13% vs. 38%; p< 0.001). Rates of accelerated approval did not differ (11% vs. 17%; p=0.23). The most common therapeutic area for approvals differed over time (infectious disease [34%] in 1995-1997 vs. oncology [27%] in 2015-2017; p=0.002). The median number of pivotal trials supporting an indication decreased from 2 (IQR 2-3) to 1 (IQR 1-3; p< 0.001). The proportion of indications based on at least one pivotal trial using an active comparator decreased (57.3% vs. 30.2%; p< 0.001), whereas use of only single-arm trials increased (4.0% vs. 17.0%; p=0.005). The median number of enrolled patients per indication remained steady (774 [IQR, 464-1314] vs. 816 [IQR, 199-2112]; p=0.47). The proportion with at least one pivotal trial of at least 6 months' duration increased (25.8% vs. 46.2%; p=0.006). Differences in pivotal trial characteristics over time were consistent in analyses stratified by therapeutic area and use of special regulatory programs.
Conclusion(s): Clinical trial evidence supporting new drugs at the time of approval has changed over time, in part reflecting increasingly flexible evidentiary standards. This was consistent regardless of use of special regulatory programs. Diminished quantity and quality of premarket evidence suggests an increasing need for continued evaluation after market approval