Autophagy has been implicated in the progression and chemoresistance of various cancers. In this study, we have shown that osteosarcoma Saos-2 cells lacking ATG4B, a cysteine proteinase that ...activates LC3B, are defective in autophagy and fail to form tumors in mouse models. By combining in silico docking with in vitro and cell-based assays, we identified small compounds that suppressed starvation-induced protein degradation, LC3B lipidation, and formation of autophagic vacuoles. NSC185058 effectively inhibited ATG4B activity in vitro and in cells while having no effect on MTOR and PtdIns3K activities. In addition, this ATG4B antagonist had a negative impact on the development of Saos-2 osteosarcoma tumors in vivo. We concluded that tumor suppression was due to a reduction in ATG4B activity, since we found autophagy suppressed within treated tumors and the compound had no effects on oncogenic protein kinases. Our findings demonstrate that ATG4B is a suitable anti-autophagy target and a promising therapeutic target to treat osteosarcoma.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Objective Spinal cord ischemia (SCI) is a devastating but potentially preventable complication of thoracic endovascular aortic repair (TEVAR). The purpose of this analysis was to determine what ...factors predict SCI after TEVAR. Methods All TEVAR procedures at a single institution were reviewed for patient characteristics, prior aortic repair history, aortic centerline of flow analysis, and procedural characteristics. SCI was defined as any lower extremity neurologic deficit that was not attributable to an intracranial process or peripheral neuropathy. Forty-three patient and procedural variables were evaluated individually for association with SCI. Those with the strongest relationships to SCI ( P < .1) were included in a multivariable logistic regression model, and a stepwise variable elimination algorithm was bootstrapped to derive a best subset of predictors from this model. Results From 2002 to 2013, 741 patients underwent TEVAR for various indications, and 68 (9.2%) developed SCI (permanent: n = 38; 5.1%). Because of the lack of adequate imaging for centerline analysis, 586 patients (any SCI, n = 43; 7.4%) were subsequently analyzed. Patients experiencing SCI after TEVAR were older (SCI, 72 ± 11 years; no SCI, 65 ± 15 years; P < .0001) and had significantly higher rates of multiple cardiovascular risk factors. The stepwise selection procedure identified five variables as the most important predictors of SCI: age (odds ratio OR multiplies by 1.3 per 10 years; 95% confidence interval CI, 0.9-1.8, P = .06), aortic coverage length (OR multiplies by 1.3 per 5 cm; CI, 1.1-1.6; P = .002), chronic obstructive pulmonary disease (OR, 1.9; CI, 0.9-4.1; P = .1), chronic renal insufficiency (creatinine concentration ≥ 1.6 mg/dL; OR, 1.9; CI, 0.8-4.2; P = .1), and hypertension (defined as chart history or medication; OR, 6.4; CI, 2.6-18; P < .0001). A logistic regression model with just these five covariates had excellent discrimination (area under the receiver operating characteristic curve = .83) and calibration ( χ2 = 9.8; P = .28). Conclusions This analysis generated a simple model that reliably predicts SCI after TEVAR. This clinical tool can assist decision-making about when to proceed with TEVAR, guide discussions about intervention risk, and help determine when maneuvers to mitigate SCI risk should be implemented.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In the United States, over 200,000 new patients are diagnosed with abdominal aortic aneurysm (AAA) each year. Consequently, over 40,000 highly morbid aortic reconstructions are performed each year to ...prevent aneurysm rupture, a catastrophic event associated with near-certain mortality. No pharmaceutical currently exists to slow aneurysm growth, but a 50% reduction in diameter growth per annum could halve the number of aortic reconstructions required. Therefore, successful use of cell therapy to modulate chronic inflammation hallmark to AAA to slow diameter expansion represents a potentially paradigm-altering treatment.
The outcomes associated with transcarotid revascularization (TCAR) have proved to be noninferior to the historical results established for carotid endarterectomy (CEA). Therefore, TCAR has been ...increasingly offered to patients with neck anatomy hostile for traditional CEA. The present investigation was completed to evaluate whether a difference exists for patients undergoing TCAR in de novo anatomy with unviolated surgical planes compared with those undergoing TCAR in necks with hostile anatomy.
The demographic data and outcomes were captured at two high-volume TCAR institutions from December 2015 to December 2021 via a query of two parallel, prospectively maintained, carotid intervention databases at these two health institutions. A hostile neck anatomy was defined as a history of previous ipsilateral neck radiation, oncologic dissection, or CEA. Univariate analysis was performed to compare the two cohorts at an α of 0.05.
During the inclusion period, the data from 750 TCARs were captured, including 108 procedures in hostile neck anatomy and 642 in de novo necks. No significant differences were found in the baseline comorbidity burden using the Charlson comorbidity index or the indication for revascularization. Intraoperatively, no significant increase in case complexity was observed with respect to those with a hostile neck, except for the operative time, which was 10% longer (69.5 vs 63.4 minutes; P = .01). The flow reversal and fluoroscopic times, blood loss, radiation exposure, and contrast use were identical. Postoperatively, no differences were observed between the hostile and de novo necks with respect to stroke (0.9% vs 2.5%; P = .49), myocardial infarction (0.9% vs 0.2%; P = .27), and death (0% vs 1.5%; P = .37). Additionally, hematoma formation and the need for reintervention did not seem to vary between the two groups. Similarly, no differences in the two cohorts were noted during follow-up.
According to the findings from our large, dual-institutional series, the performance of TCAR in surgical fields traditionally hostile for CEA was not associated with increased intraoperative complexity or postoperative morbidity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The purpose of this investigation was to determine our limb-related contemporary pediatric revascularization perioperative and follow-up outcomes after major blunt and penetrating trauma.
A ...retrospective review was performed of a prospectively maintained pediatric trauma database spanning January 2010 to December 2017 to capture all level I trauma activations that resulted in a peripheral arterial revascularization procedure. All preoperative, intraoperative, and postoperative continuous variables are reported as a mean ± standard deviation; categorical variables are reported as a percentage of the population of interest.
During the study period, 1399 level I trauma activations occurred at a large-volume, urban children's hospital. The vascular surgery service was consulted in 2.6% (n = 36) of these cases for suspected vascular injury based on imaging or physical examination. Our study population included only patients who received an arterial revascularization, which was performed in 23 of the 36 consultations (1.6% of total traumas; median age, 11 years). These injuries were localized to the upper extremity in 60.9% (n = 14), lower extremity in 30.4% (n = 7), and neck in 8.7% (n = 2). The mean Injury Severity Score in the revascularized cohort was 14.0 (±7.6). Bone fractures were associated with 39.1% of the vascular injuries (90% of blunt injuries). Restoration of in-line flow was achieved by an endovascular solution in one patient and open surgery in the remainder, consisting of arterial bypass in 59.1% and direct repair in 40.9%. Within 30 days of the operation, we observed no deaths, no infections of the arterial reconstruction, and no major amputations. One patient required perioperative reintervention by the vascular team secondary to the development of a superficial seroma without evidence of graft involvement. Mean follow-up in our cohort was 43.3 (±35.4) months. During this phase, no additional deaths, amputations, chronic wounds, or limb length discrepancies were observed. All vascular repairs were patent, and all but one patient reported normal function of the affected limb at the latest clinic visit.
Traumatic peripheral vascular injury is rare in the pediatric population but is often observed secondary to a penetrating force or after long bone fracture. However, contemporary perioperative and long-term outcomes after surgical revascularization are excellent as demonstrated in this institutional case series.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The extent of practice setting's influence on transcarotid artery revascularization (TCAR) outcomes is not yet established. This study seeks to assess and compare TCAR outcomes in academic and ...community-based healthcare settings.
Retrospective review of prospectively maintained, systemwide TCAR databases from 2 institutions was performed between 2015 and 2022. Patients were stratified based on the setting of surgical intervention (i.e., academic or community-based hospitals). Relevant demographics, medical conditions, anatomic characteristics, intraoperative and postoperative courses, and adverse events were captured for multivariate analysis.
We identified 973 patients who underwent TCAR, 570 (58.6%) were performed at academic and 403 (41.4%) at community-based hospitals. An academic facility was defined as a designated teaching hospital with 24/7 service-line coverage by a trainee-led surgical team. Baseline comorbidity between cohorts were similar but cases performed at academic institutions were associated with increased complexity, defined by high cervical stenosis (P < 0.001), prior dissection (P < 0.01), and prior neck radiation (P < 0.001). Intraoperatively, academic hospitals were associated with longer operative time (67 min vs. 58 min, P < 0.001), higher blood loss (55 mLs vs. 37 mLs, P < 0.001), and longer flow reversal time (9.5 min vs. 8.4 min, P < 0.05). Technical success rate was not statistically different. In the 30-day perioperative period, we observed no significant difference with respect to reintervention (1.5% vs. 1.5%, P ≥ 0.9) or ipsilateral stroke (2.7% vs. 2.0%, P = 0.51). Additionally, no difference in postoperative myocardial infarction (academic 0.7% vs. community 0.2%, P < 0.32), death (academic 1.9% vs. community 1.4%, P < 0.57), or length of stay (1 day vs. 1 day, P < 0.62) was seen between the cohorts.
Cases performed at academic centers were characterized by more challenging anatomy, more frequent cardiovascular risk factors, and less efficient intraoperative variables, potentially attributable to case complexity and trainee involvement. However, there were no differences in perioperative outcomes and adverse events between the cohorts, suggesting TCAR can be safely performed regardless of practice setting.
Dual antiplatelet therapy (DAPT) continues to be the preferred medication regimen after the placement of a carotid stent using the transcarotid revascularization (TCAR) technique despite a dearth of ...quality data. Therefore, this investigation was performed to define the risks associated with antiplatelet choice.
We queried all patients who underwent TCAR captured by the Vascular Quality Initiative from September 2016 to June 2022, to determine the association between antiplatelet choice and outcomes. Patients maintained on DAPT were compared with those receiving alternative regimens consisting of single antiplatelet, anticoagulation, or a combination of the two. A 1:1 propensity-score match was performed with respect to baseline comorbidities, functional status, anatomic/physiologic risk, medications, and intraoperative characteristics. In-hospital and 1-year outcomes were compared between the groups.
During the study period, 29,802 procedures were included in our study population, with 24,651 (82.7%) receiving DAPT and 5151 (17.3%) receiving an alternative antiplatelet regimen. A propensity-score match with respect to 29 variables generated 4876 unique pairs. Compared with patients on DAPT, in-hospital ipsilateral stroke was significantly higher in patients receiving alternative antiplatelet regimens (1.7% vs 1.1%, odds ratio 95% confidence interval: 1.54 1.10-2.16, P = .01), whereas no statistically significant difference was noted with respect to mortality (0.6% vs 0.5%, 1.35 0.72-2.54, P = .35). A composite of stroke/death was also more likely in patients receiving an alternative regimen (2.4% vs 1.7%, 1.47 1.12-1.93, P = .01). Immediate stent thrombosis (2.75 1.16-6.51) and a nonsignificant trend toward increased return to the operating room were more common in the alternative patients. Conversely, the incidence of perioperative myocardial infarction was lower in the alternative regimen group (0.4% vs 0.7%, 0.53 0.31-0.90, P = .02). At 1 year after the procedure, we observed an increased risk of mortality (hazard ratio 95% confidence interval: 1.34 1.11-1.63, P < .01) but not stroke (0.52 0.27-0.99, P = .06) in patients treated with an alternative medication regimen.
This propensity-score-matched analysis demonstrates an increased risk of in-hospital stroke and 1-year mortality after TCAR in patients treated with an alternative medication regimen instead of DAPT. Further studies are needed to elucidate the drivers of DAPT failure in patients undergoing TCAR to improve outcomes for carotid stenting patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To determine whether a vascular surgery trainee's participation in transcarotid revascularization (TCAR), a new technology, affects patient safety and outcomes.
Retrospective, institutional review of ...our carotid database was performed. Patients who underwent TCAR were stratified based on whether a vascular trainee was present during the procedure. Relevant demographics, comorbidities, anatomical indication, perioperative courses, and adverse events in the postoperative period were captured for statistical analysis.
Data were obtained from affiliated Memorial Hermann Hospitals in Houston, Texas.
All patients who underwent TCAR from September 2017 to January 2022 were included.
Of 486 patients who underwent TCAR, 173 (35.6%) were performed in the presence of a trainee, and 313 (64.4%) were performed without a trainee. Subjects in the trainee cohort had more challenging anatomy, defined as a higher rate of carotid bifurcation above C2, restenotic disease, previous ipsilateral neck dissection, and neck radiation. The trainee cohort had higher rates of estimated blood loss (61.1 ± 66 vs. 35.5 ± 39 mL,
< 0.01), longer operative time (64.8 ± 30.3 vs. 57.9 ± 20.4 min,
< .01), longer cerebral blood flow reversal time (8.9 ± 6.1 vs. 7.9 ± 6.6 min,
= .01), and higher contrast administration (25.7 ± 12.0 vs. 21.1 ± 9.4 mL,
< .01). The ability to achieve technical success was similar between the two cohorts. There was no difference in the rates of cranial nerve palsy, ipsilateral stroke, hematoma, and stent thrombosis. Hospital length of stay, death (0% vs. 1.6%,
= .10), and stroke (1.1% vs. 2.8%,
= .22) were also similar between the two cohorts.
Vascular surgery trainee's involvement during TCAR did not increase adverse outcomes, such as stroke and death, in the perioperative period. The results presented herein should encourage other teaching institutions to provide surgical trainees with supervised, hands-on experience during TCAR.
This investigation describes the perioperative and early follow-up results associated with transcarotid artery revascularization (TCAR) in patients not participating in the Safety and Efficacy Study ...for Reverse Flow Used During Carotid Artery Stenting Procedure II (ROADSTER-2) registry using the ENROUTE neuroprotection system (ENPS; Silk Road Medical, Sunnyvale, Calif).
A retrospective review was performed capturing all TCAR/ENPS procedures in patients deemed to be at high risk for complications after traditional carotid endarterectomy. All patients enrolled in the ROADSTER-2 registry were excluded, leaving only those treated outside trial regulations for analysis. Preoperative demographics, intraoperative variables, and perioperative and follow-up outcomes were abstracted and reported herein.
From December 2015 to January 2018, there were 75 carotid arteries treated at our institution. All interventions were performed on carotid arteries that were symptomatic with ≥50% stenosis (46.7%) or asymptomatic with ≥80% stenosis (53.3%) by duplex ultrasound and computed tomography angiography. Technical success in our series was 97.3% (73/75), with treatment failures attributed to one case of common carotid artery dissection and another secondary to stent maldeployment in the external carotid artery. Perioperative (30-day) ipsilateral stroke rate was 2.7% (n = 2), myocardial infarction incidence was 0%, and mortality rate was 2.7% (n = 2). We did not observe any cranial nerve injuries. After a mean follow-up of 8.0 ± 6.7 months, no carotid stents required reintervention. However, we noted one instance of minor (<50%) in-stent stenosis and one asymptomatic stent thrombosis. One additional ipsilateral stroke was observed on follow-up, probably from a cardiac source.
We report that dynamic reverse-flow TCAR using the ENPS continues to be safe, feasible, and efficacious with minimal risks of postoperative stroke, myocardial infarction, and mortality outside of ROADSTER-2 regulations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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