Exogenous DNA enhances DUOX2 expression and function in human pancreatic cancer cells by activating the cGAS-STING signaling pathway.

Pro-inflammatory cytokines upregulate the expression of the H2O2-producing NADPH oxidase dual oxidase 2 (DUOX2)2 which, when elevated, adversely affects survival from pancreatic ductal adenocarcinoma (PDAC). Because the cGAS-STING pathway is known to initiate pro-inflammatory cytokine expression following uptake of exogenous DNA, we examined whether activation of cGAS-STING could play a role in the generation of reactive oxygen species by PDAC cells. Here, we found that a variety of exogenous DNA species markedly increased the production of cGAMP, the phosphorylation of TBK1 and IRF3, and the translocation of phosphorylated IRF3 into the nucleus, leading to a significant, IRF3-dependent enhancement of DUOX2 expression, and a significant flux of H2O2 in PDAC cells. However, unlike the canonical cGAS-STING pathway, DNA-related DUOX2 upregulation was not mediated by NF-κB. Although exogenous IFN-ß significantly increased Stat1/2-associated DUOX2 expression, intracellular IFN-ß signaling that followed cGAMP or DNA exposure did not itself increase DUOX2 levels. Finally, DUOX2 upregulation subsequent to cGAS-STING activation was accompanied by the enhanced, normoxic expression of HIF-1α and VEGF-A as well as DNA double strand cleavage, suggesting that cGAS-STING signaling may support the development of an oxidative, pro-angiogenic microenvironment that could contribute to the inflammation-related genetic instability of pancreatic cancer.

Complex Inferior Vena Cava Filter Retrievals: Success Rate and Predictors of Adverse Events at a Large Specialized Referral Center.

BACKGROUND. Specialized inferior vena cava (IVC) filter referral centers can achieve improved retrieval outcomes, potentially facilitating complex retrievals after long filter dwell times. OBJECTIVE. The purpose of this study was to determine the success rate of complex IVC filter retrievals at a large specialized IVC filter referral center and to identify predictors of adverse events during complex retrievals. METHODS. This retrospective study included patients who underwent complex IVC filter retrieval from March 2014 to June 2018 at a large regional health system with specialized complex retrieval referral centers and interventional radiologists with expertise in such procedures. Complex retrievals methods included a range of loop snare, coaxial sheath, forceps, and snare techniques. Data were collected from the electronic medical record. The success rate of complex retrieval was determined. Factors associated with adverse events during retrieval procedures were explored. RESULTS. The study included 125 patients (51 women, 74 men; mean age, 60 years). The mean filter dwell time at retrieval was 47.5 months (median, 21.8 months). The complex retrieval success rate was 99.2% on the first attempt and 100.0% overall. A total of 11.2% (14/125) of patients experienced an adverse event during retrieval, including 10.4% (13/125) with minor and 0.8% (1/125) with major events. Prolonged dwell time was the only indication for complex retrieval that was significantly associated with adverse events (adverse event rate, 16.7% for patients with this indication vs 5.1% for patients without this indication; p = .04). In multiple regression analysis, the only significant independent predictor of adverse events was a filter dwell time of 5 years or longer (odds ratio, 6.98 [95% CI, 1.64-29.81]; p = .009). CONCLUSION. In a specialized referral system with expertise in complex retrieval methods, high retrieval success rates can be achieved in patients who have filters with long dwell times. Nonetheless, longer dwell times are associated with adverse events during retrieval procedures. CLINICAL IMPACT. The observations support performing early filter retrieval and referring patients who have filters with prolonged dwell times to specialized centers.

Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

Thrombotic Risk Associated with Inferior Vena Cava Filter Placement in Patients with Heparin-Induced Thrombocytopenia.

PURPOSE: This study sought to define thromboembolic risk and mortality in patients with heparin-induced thrombocytopenia (HIT) undergoing inferior vena cava filter (IVCF) placement, in light of the American Society of Hematology's 2018 guidelines against routine use of IVCFs in this population. METHODS: A total of 26 patients with HIT who received IVCFs were retrospectively reviewed, and the outcomes of this group were compared with those of 4,707 controls with either HIT or IVCFs alone and with reported outcomes in prior studies. RESULTS: The patient group demonstrated 6- and 12-month mortality rates of 26.9% and 30.8%, respectively, which did not differ significantly from those of the control groups and were in line with published mortality rates in the literature. The measured thromboembolic risk of 19.2% in the patient group was also within the range of published rates for patients with HIT or IVCF alone. CONCLUSIONS: IVCF placement did not significantly increase the risk of thromboembolism or death in patients with HIT and may be a viable option in the subset of these patients who are not candidates for anticoagulation.

Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase.

PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation. Many potent PROTACs with specificity for dissimilar targets have been developed; however, the factors governing degradation selectivity within closely-related protein families remain elusive. Here, we generate isoform-selective PROTACs for the p38 MAPK family using a single warhead (foretinib) and recruited E3 ligase (von Hippel-Lindau). Based on their distinct linker attachments and lengths, these two PROTACs differentially recruit VHL, resulting in degradation of p38α or p38δ. We characterize the role of ternary complex formation in driving selectivity, showing that it is necessary, but insufficient, for PROTAC-induced substrate ubiquitination. Lastly, we explore the p38δ:PROTAC:VHL complex to explain the different selectivity profiles of these PROTACs. Our work attributes the selective degradation of two closely-related proteins using the same warhead and E3 ligase to heretofore underappreciated aspects of the ternary complex model.

Long-term complications of inferior vena cava filters.

OBJECTIVE: Some inferior vena cava filter (IVCF) complications only manifest after prolonged dwell time (IVCF fracture, inferior vena cava [IVC] occlusion, and IVC perforation). Incidence of these complications is often based on mathematical projections given the lack of long-term imaging follow-up. The aim of this study was to assess the incidence of long-term complications of IVCFs using ideal imaging, contrast-enhanced computed tomography (CT). METHODS: From 2007 to 2009, 3303 IVCFs were placed across a large healthcare region. Only patients with contrast enhanced CTs of the abdomen at a minimum of 4 years post-IVCF implantation were selected. A retrospective observational study was performed in 96 patients. Primary outcomes were prevalence and predictive factors for IVCF fracture, IVC thrombosis, and IVC perforation. RESULTS: Of 96 patients, 39 had permanent IVCFs and 57 had retrievable IVCFs. Mean dwell time at most recent CT scan was 61 months. Overall rate of fracture was 14% with the majority (92%) in Cordis OptEase and TrapEase filters (Cordis, Fremont, Calif; P < .0001). Overall rate of partial/complete IVC occlusion was 13% (7.3% total and 5.2% partial). IVC perforation rates were higher among retrievable devices (70%) compared with permanent devices (15%; P < .0001). Perforation involving retroperitoneal structures was 68% among conical retrievable devices and 5% among permanent devices (P < .0001). CONCLUSIONS: Long-term complications related to chronic IVCFs are relatively common, and the incidence of fracture and IVC perforation varies with device type. Higher rates of fracture were seen with the Cordis OptEase and TrapEase filters, whereas higher rate and degree of IVC perforation were seen with retrievable conical type devices.

Impact of Physician Education and a Dedicated Inferior Vena Cava Filter Tracking System on Inferior Vena Cava Filter Use and Retrieval Rates Across a Large US Health Care Region.

PURPOSE: To evaluate the effects of physician familiarity with current evidence and guidelines on inferior vena cava (IVC) filter use and the availability of IVC filter tracking infrastructure on retrieval rates. MATERIALS AND METHODS: Fourteen continuing medical education-approved in-hospital grand rounds covering evidence-based review of the literature on IVC filter efficacy, patient-centered outcomes, guidelines for IVC filter indications, and complications were performed across a large United States (US) health care region serving more than 3.5 million members. A computer-based IVC filter tracking system was deployed simultaneously. IVC filter use, rates of attempted retrieval, and fulfillment of guidelines for IVC filter indications were retrospectively evaluated at each facility for 12 months before intervention (n = 427) and for 12 months after intervention (n = 347). RESULTS: After education, IVC filter use decreased 18.7%, with a member enrollment-adjusted decrease of 22.2%, despite an increasing IVC filter use trend for 4 years. Reduction in IVC filter use at each facility strongly correlated with physician attendance at grand rounds (r = -0.69; P = .007). Rates of attempted retrieval increased from 38.9% to 54.0% (P = .0006), with similar rates of successful retrieval (82.3% before education and 85.8% after education on first attempt). Improvement in IVC filter retrieval attempts correlated with physician attendance at grand rounds (r = 0.51; P = .051). IVC filter dwell times at first retrieval attempt were similar (10.2 wk before and 10.8 wk after). CONCLUSIONS: Physician education dramatically reduced IVC filter use across a large US health care region, and represents a learning opportunity for physicians who request and place them. Education and a novel tracking system improved rates of retrieval for IVC filter devices.

Clinical review: inferior vena cava filters in the age of patient-centered outcomes.

Inferior vena cava filter (IVCF) use continues to increase in the United States (US) despite questionable clinical benefit and increasing concerns over long-term complications. For this review we comprehensively examine the randomized, prospective data on IVC filter efficacy, compare relative rates of IVCF placement in the US and Europe, compare commonly considered guidelines for IVCF indications, and the current data on IVCF complications. Searches of MEDLINE and Cochrane databases were conducted for randomized prospective IVCF studies. Only three randomized prospective studies for IVCFs were identified. Commonly cited IVCF guidelines were reviewed with attention to their evolution over time. No evidence has shown a survival benefit with IVCF use. Despite this, continued rising utilization, especially for primary prophylactic indications, is concerning, given increasing evidence of long-term filter-related complications. This is particularly noted in the US where IVCF placements for 2012 are projected to be 25 times that of an equivalent population in Europe (224,700 versus 9,070). Pending much-needed randomized controlled trials that also evaluate long-term safety, we support the more stringent American College of Chest Physicians (ACCP) guidelines for IVCF placement indications and advocate a close, structured follow-up of retrievable IVCFs to improve filter retrieval rates.

Modeling hemodynamics in an unoccluded and partially occluded inferior vena cava under rest and exercise conditions.

Pulmonary embolism is the third leading cause of death in hospitalized patients in the US. Vena cava filters are medical devices inserted into the inferior vena cava (IVC) and are designed to trap thrombi before they reach the lungs. Once trapped in a filter, however, thrombi disturb otherwise natural flow patterns, which may be clinically significant. The goal of this work is to use computational modeling to study the hemodynamics of an unoccluded and partially occluded IVC under rest and exercise conditions. A realistic, three-dimensional model of the IVC, iliac, and renal veins represents the vessel geometry and spherical clots represent thombi trapped by several conical filter designs. Inflow rates correspond to rest and exercise conditions, and a transitional turbulence model captures transitional flow features, if they are present. The flow equations are discretized and solved using a second-order finite-volume method. No significant regions of transitional flow are observed. Nonetheless, the volume of stagnant and recirculating flow increases with partial occlusion and exercise. For the partially occluded vessel, large wall shear stresses are observed on the IVC and on the model thrombus, especially under exercise conditions. These large wall shear stresses may have mixed clinical implications: thrombotic-like behavior may initiate on the vessel wall, which is undesirable; and thrombolysis may be accelerated, which is desirable.

Modeling blood flow in a tilted inferior vena cava filter: does tilt adversely affect hemodynamics?

PURPOSE: Filter tilt is often seen with conical filters and adversely affects retrievability and clot trapping efficiency. In addition, tilt may also alter flow dynamics. This study uses computational fluid dynamics to evaluate flow past an unoccluded and partially occluded Celect inferior vena cava filter (Cook, Bloomington, Indiana). In particular, the hemodynamic response to thrombus volume and filter tilt is examined, and the results are compared with flow conditions known to be thrombogenic. MATERIALS AND METHODS: Computer models of an upright and tilted Celect filter are constructed using high-resolution digital photographs and methods of computer-aided design. The three-dimensional models are placed inside a model cava, and steady-state flow past unoccluded and partially occluded filters is computed. RESULTS: The volume of stagnant and recirculating flow increases with thrombus volume. In addition, as filter tilt increases, the cava wall in the direction of filter tilt is subjected to low-velocity flow and gives rise to regions of low wall shear stress. CONCLUSIONS: Flow conditions caused by the tilted Celect filter may elevate the risk of intra/perifilter thrombosis and facilitate vascular remodeling. This latter condition may increase the potential for incorporation of the hook of the filter into the vena cava wall, thereby complicating filter retrieval. These findings also suggest that further long-term clinical follow-up with conical filters should be pursued with a specific evaluation of tilt as a factor of intrafilter thrombus and thrombosis.

Design optimization of vena cava filters: an application to dual filtration devices.

Pulmonary embolism (PE) is a significant medical problem that results in over 300,000 fatalities per year. A common preventative treatment for PE is the insertion of a metallic filter into the inferior vena cava that traps thrombi before they reach the lungs. The goal of this work is to use methods of mathematical modeling and design optimization to determine the configuration of trapped thrombi that minimizes the hemodynamic disruption. The resulting configuration has implications for constructing an optimally designed vena cava filter. Computational fluid dynamics is coupled with a nonlinear optimization algorithm to determine the optimal configuration of a trapped model thrombus in the inferior vena cava. The location and shape of the thrombus are parametrized, and an objective function, based on wall shear stresses, determines the worthiness of a given configuration. The methods are fully automated and demonstrate the capabilities of a design optimization framework that is broadly applicable. Changes to thrombus location and shape alter the velocity contours and wall shear stress profiles significantly. For vena cava filters that trap two thrombi simultaneously, the undesirable flow dynamics past one thrombus can be mitigated by leveraging the flow past the other thrombus. Streamlining the shape of the thrombus trapped along the cava wall reduces the disruption to the flow but increases the area exposed to low wall shear stress. Computer-based design optimization is a useful tool for developing vena cava filters. Characterizing and parametrizing the design requirements and constraints is essential for constructing devices that address clinical complications. In addition, formulating a well-defined objective function that quantifies clinical risks and benefits is needed for designing devices that are clinically viable.

Toward an optimal position for inferior vena cava filters: computational modeling of the impact of renal vein inflow with Celect and TrapEase filters.

PURPOSE: To evaluate the hemodynamic effects of renal vein inflow and filter position on unoccluded and partially occluded inferior vena cava (IVC) filters with use of three-dimensional computational fluid dynamics. MATERIALS AND METHODS: Three-dimensional models of the TrapEase and Günther Celect IVC filters, spherical thrombi, and an IVC with renal veins were constructed. Hemodynamics of steady-state flow was examined for unoccluded and partially occluded TrapEase and Günther Celect IVC filters in varying proximity to the renal veins. RESULTS: Flow past the unoccluded filters demonstrated minimal disruption. Natural regions of stagnant/recirculating flow in the IVC were observed superior to the bilateral renal vein inflows. High flow velocities and elevated shear stresses were observed in the vicinity of renal inflow. Spherical thrombi induce stagnant/recirculating flow downstream of the thrombus. Placement of the TrapEase filter in the suprarenal position resulted in a large area of low shear stress/stagnant flow within the filter just downstream of thrombus trapped in the upstream trapping position. CONCLUSIONS: Filter position with respect to renal vein inflow influences filter trapping hemodynamics. Placement of the TrapEase filter in a suprarenal location may be thrombogenic, with redundant areas of stagnant/recirculating flow and low shear stress along the caval wall caused by the upstream trapping position and the naturally occurring region of stagnant flow from the renal veins. Infrarenal vein placement of IVC filters in a near-juxtarenal position with the downstream cone near the renal vein inflow likely confers increased levels of mechanical lysis of trapped thrombi from increased shear stress from renal vein inflow.

Computational modeling of blood flow in the TrapEase inferior vena cava filter.

PURPOSE: To evaluate the hemodynamics of the TrapEase vena cava filter (Cordis, Miami Lakes, Florida) by using three-dimensional computational fluid dynamics, including simulated thrombi of multiple shapes, sizes, and trapping positions. The study was performed to identify areas of stagnant and/or recirculating flow that may have an effect on intrafilter thrombosis. MATERIALS AND METHODS: Three-dimensional computer models of the TrapEase filter, various thrombi shapes and sizes, and a 23-mm-diameter cava were constructed. The hemodynamics of steady-state flow were examined for the unoccluded and partially occluded filter. RESULTS: Flow in the unoccluded TrapEase filter experienced minimal disruption. Spherical thrombi in the downstream trapping position induced stagnant and/or recirculating flow downstream of the thrombus. The volume of stagnant flow and the peak wall shear stress increased with thrombus volume. For spherical thrombi trapped upstream, disruption of flow was observed along the cava wall ipsilateral to the thrombus and within the filter. Peak wall shear stress was greatest with conical thrombi, less with spherical thrombi, and least with ellipsoidal thrombi. CONCLUSIONS: The authors have designed a computer model to study the hemodynamics of the TrapEase filter with various thrombi and trapping positions. The model offers advantages over in vitro techniques, specifically improved resolution and easy adaptation for new filter designs, thrombus morphologies and/or sizes, and flow parameters. The results agree with those of previous bench experiments that suggest the upstream trapping position of the TrapEase filter leads to a potentially thrombogenic region of stagnant and/or recirculating flow with low shear stress. These findings are supported by clinical studies showing an increased incidence of occlusive and/or nonocclusive thrombus within the TrapEase filter and the retrievable, nearly structurally identical, OptEase filter.

Intravascular US-guided direct intrahepatic portocaval shunt with an expanded polytetrafluoroethylene-covered stent-graft.

PURPOSE: To retrospectively evaluate the midterm patency rate of the nitinol (Viatorr, W.L. Gore and Associates, Flagstaff, Ariz) stent-graft for direct intrahepatic portacaval shunt (DIPS) creation. MATERIALS AND METHODS: Institutional Review Board approval for this retrospective HIPAA-compliant study was obtained with waiver of informed consent. DIPS was created in 18 men and one woman (median age, 54 years; range, 45-65 years) by using nitinol polytetrafluoroethylene (PTFE)-covered stent-grafts. The primary indications were intractable ascites (n = 14), acute variceal bleeding (n = 3), and hydrothorax (n = 2). Follow-up included Doppler ultrasonography at 1, 6, and 12 months and venography with manometry at 6-month intervals after the procedure. Shunt patency and cumulative survival were evaluated by using the Kaplan-Meier method and survival curves were plotted. Differences in mean portosystemic gradients (PSGs) were evaluated by using the Student t test. Multiple regression analysis for survival and DIPS patency were performed for the following parameters: Child-Pugh class, model of end-stage liver disease score, pre- and post-DIPS PSGs, pre-DIPS liver function tests, and pre-DIPS creatinine levels. RESULTS: DIPS creation was successful in all patients. Effective portal decompression and free antegrade shunt flow was achieved in all patients. Intraperitoneal bleeding occurred in one patient during the procedure and was controlled during the same procedure by placing a second nitinol stent-graft. The primary patency rate was 100% at all times during the follow-up period (range, 2 days to 30 months; mean, 256 days; median, 160 days). Flow restrictors were deployed in two (11%) of 19 patients. The 1-year mortality rate was 37% (seven of 19). CONCLUSION: Patency after DIPS creation with the nitinol PTFE-covered stent-graft was superior to that after TIPS with the nitinol stent-graft.

Estimation of trapped thrombus volumes in retrievable inferior vena cava filters: a visual scale.

PURPOSE: To establish a visual, objective scale for estimating trapped thrombus volumes in five types of retrievable inferior vena cava filters. MATERIAL AND METHODS: Silicone-based radiopaque polymer volumes of 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, and 4.0 mL were created. Both sphere and cone shapes were used. Polymer volumes were confirmed by means of the water displacement method. The volumes were then positioned to simulate trapped thrombus in five retrievable filters: Recovery and G2 (Bard Peripheral Vascular, Tempe, Ariz), Günther Tulip and Celect (Cook, Bloomington, Ind), and OptEase (Cordis Endovascular, Warren, NJ). Radiographs were obtained by using conventional parameters. Visual scales of thrombus volume were created for each filter type. RESULTS: Visual scales for each retrievable filter type were created with simulated thrombi in typical trapping positions. CONCLUSION: The authors developed a visual, objective scale for estimating trapped thrombus volume in five types of retrievable IVC filters. This could facilitate standardized reporting of thrombus volumes in studies of optional vena cava filters.

Treatment of hepatic venous outflow obstruction after piggyback liver transplantation.

PURPOSE: To evaluate retrospectively the endovascular management of hepatic venous outflow obstruction after piggyback orthotopic liver transplantation. MATERIALS AND METHODS: The study was performed with the approval and under the guidelines of the institutional review board and complied with the Health Insurance Portability and Accountability Act. Informed consent from patients was not required by the institutional review board for this retrospective study. From 1995 to 2003, 13 patients (eight male, five female), including 12 adults and one adolescent (age range, 14-67 years; median age, 52 years), underwent endovascular treatment of hepatic venous outflow obstruction after piggyback orthotopic liver transplantation. Patients gave informed consent for all procedures. Eleven patients received whole livers, and two received living-related donor right liver lobes. Four underwent repeat piggyback orthotopic liver transplantation prior to intervention. Primary stent placement was performed in 12 patients. One patient refused primary stent placement and chose venoplasty alone, but required a stent 5 months later. Short balloon-expandable stents (mean diameter, 14.6 mm +/- 1.1 [standard deviation]) were used to minimize jailing of branch vessels and to resist recoil. Pre- and post-procedural pressure gradients were measured. Follow-up included venography, cross-sectional imaging, and laboratory tests. The Wilcoxon signed rank test or the sign test was performed to compare pre- and post-procedural pressure gradients, body weights, and laboratory values. RESULTS: Technical success (pressure gradient < or = 3 mm Hg) was achieved in 13 of 13 patients, and clinical success, in 12 of 13. Mean pre- and post-procedural pressure gradients were 13.0 mm Hg +/- 1.4 and 0.8 mm Hg +/- 0.3. Mean interval from transplantation to intervention was 348 days +/- 159. Mean follow-up was 678 days (range, 16-2880 days). Technical success did not result in clinical improvement in one patient. Biopsy demonstrated severe hepatic necrosis, likely from prolonged venous congestion, and the patient required repeat transplantation. Only one patient required reintervention for stent migration, and no other complications occurred. No significant restenosis was encountered after stent placement. CONCLUSION: Hepatic venous outflow obstruction is an uncommon but potentially fatal complication of piggyback orthotopic liver transplantation. Endovascular treatment with balloon-expandable stents is effective, safe, and apparently durable.