Low Risk of Neurological Recurrence while Awaiting Carotid Endarterectomy: Results From a Danish Multicentre Study.

OBJECTIVE: The risk of ipsilateral neurological recurrence (NR) was assessed in patients awaiting carotid endarterectomy (CEA) due to symptomatic carotid artery stenosis and whether current national guidelines of performing CEA within 14 days are adequate in present day practice. METHODS: This was a retrospective multicentre observational cohort study. Patients scheduled for CEA due to symptomatic carotid artery stenosis in a five year period, 1 January 2014 to 31 December 2018, from four centres were included. Data from the Danish Vascular Registry (www.karbase.dk), operative managing systems, and electronic medical records were reviewed. RESULTS: In total, 1 125 patients scheduled for CEA were included and 1 095 (97%) underwent the planned surgery. During a median delay from index event to CEA of 11 days (interquartile range 8-16 days), 40 patients (3.6%; 95% confidence interval [CI] 2.5%-5%) experienced a NR. One third were minor strokes (n = 12, 30%); half were transient ischaemic attacks (TIA) (n = 22, 55%); and amaurosis fugax accounted for 15% (n = 6). Twenty-six (2%) CEA procedures was cancelled, of which one was due to a disabling recurrent ischaemic event (aphasia). There were no deaths or major strokes in the waiting time for CEA. Best medical treatment (BMT) with platelet inhibitory or anticoagulation drugs and a statin was initiated in nearly all patients (98%) at first assessment. The overall 30 day risk of a post-operative major event (death or stroke) was (Kaplan-Meier [KM] estimate) 2.7% (95% CI 1.8-3.8), and not significantly correlated with the timing of surgery. Most (69%) occurred within the first three days. One, two, and three year mortality rate for CEA patients was (KM estimate) 4.8%, 7.8%, and 11.5% respectively. CONCLUSION: In symptomatic carotid artery stenosis patients awaiting CEA, very few NRs occurred within 14 days. Institution of immediate BMT in specialised TIA/stroke units followed by early, but not necessarily urgent, CEA is a reasonable course of action in patients with high grade symptomatic carotid artery stenosis.

p38 MAPK Inhibition Mitigates Hypoxia-Induced AR Signaling in Castration-Resistant Prostate Cancer.

BACKGROUND: Aberrant androgen receptor (AR) signaling is a major driver of castration-resistant prostate cancer (CRPC). Tumor hypoxia increases AR signaling and is associated with treatment resistance in prostate cancer. Heat shock protein 27 (Hsp27) is a molecular chaperone that is activated in response to heat shock and hypoxia. Hsp27 has previously been reported to facilitate AR nuclear translocation in a p38 mitogen-activated protein kinase (MAPK) dependent manner in castration-sensitive prostate cancer cell lines. Here, we evaluated the potential for inhibiting p38 MAPK/Hsp27 mediated AR signaling under normoxia and hypoxia in experimental models of CRPC. METHODS: We inhibited p38 MAPK with SB203580 in prostate cancer cell lines and measured Hsp27 phosphorylation, AR activity, cell proliferation, and clonogenicity under normoxia and hypoxia. AR activity was measured using an androgen response element driven reporter assay and qPCR to measure expression of AR target genes. Xenograft-bearing mice were treated with SB203580 to measure tumor growth and serum prostate specific antigen (PSA). RESULTS: Our results indicate that p38 MAPK and Hsp27 are activated under normoxia and hypoxia in response to androgens in CRPC cells. p38 MAPK inhibition diminished Hsp27 activation and the hypoxia-mediated increase in AR activity. Additionally, inhibition of p38 MAPK activity decreased proliferation and survival of CRPC cells in vitro and prolonged the survival of tumor-bearing mice. CONCLUSIONS: These results suggest that p38 MAPK inhibition may represent a therapeutic strategy to disrupt AR signaling in the heterogeneous CRPC tumor microenvironment.

Effect of low vs high haemoglobin transfusion trigger on cardiac output in patients undergoing elective vascular surgery: Post-hoc analysis of a randomized trial.

BACKGROUND: During vascular surgery, restricted red-cell transfusion reduces frontal lobe oxygen (ScO2 ) saturation as determined by near-infrared spectroscopy. We evaluated whether inadequate increase in cardiac output (CO) following haemodilution explains reduction in ScO2 . METHODS: This is a post-hoc analysis of data from the Transfusion in Vascular surgery (TV) Trial where patients were randomized on haemoglobin drop below 9.7 g/dL to red-cell transfusion at haemoglobin below 8.0 (low-trigger) vs 9.7 g/dL (high-trigger). Fluid administration was guided by optimizing stroke volume. We compared mean intraoperative levels of CO, haemoglobin, oxygen delivery, and CO at nadir ScO2 with linear regression adjusted for age, operation type and baseline. Data for 46 patients randomized before end of surgery were included for analysis. RESULTS: The low-trigger resulted in a 7.1% lower mean intraoperative haemoglobin level (mean difference, -0.74 g/dL; P < .001) and reduced volume of red-cell transfused (median [inter-quartile range], 0 [0-300] vs 450 mL [300-675]; P < .001) compared with the high-trigger group. Mean CO during surgery was numerically 7.3% higher in the low-trigger compared with the high-trigger group (mean difference, 0.36 L/min; 95% confidence interval (CI.95), -0.05 to 0.78; P = .092; n = 42). At the nadir ScO2 -level, CO was 11.9% higher in the low-trigger group (mean difference, 0.58 L/min; CI.95, 0.10-1.07; P = .024). No difference in oxygen delivery was detected between trial groups (MD, 1.39 dLO2 /min; CI.95, -6.16 to 8.93; P = .721). CONCLUSION: Vascular surgical patients exposed to restrictive RBC transfusion elicit the expected increase in CO making it unlikely that their potentially limited cardiac capacity explains the associated ScO2 decrease.

Misconceptions regarding the adequacy of best medical intervention alone for asymptomatic carotid stenosis.

BACKGROUND: Medical intervention (risk factor identification, lifestyle coaching, and medication) for stroke prevention has improved significantly. It is likely that no more than 5.5% of persons with advanced asymptomatic carotid stenosis (ACS) will now benefit from a carotid procedure during their lifetime. However, some question the adequacy of medical intervention alone for such persons and propose using markers of high stroke risk to intervene with carotid endarterectomy (CEA) and/or carotid angioplasty/stenting (CAS). Our aim was to examine the scientific validity and implications of this proposal. METHODS: We reviewed the evidence for using medical intervention alone or with additional CEA or CAS in persons with ACS. We also reviewed the evidence regarding the validity of using commonly cited makers of high stroke risk to select such persons for CEA or CAS, including markers proposed by the European Society for Vascular Surgery in 2017. RESULTS: Randomized trials of medical intervention alone versus additional CEA showed a definite statistically significant CEA stroke prevention benefit for ACS only for selected average surgical risk men aged less than 75 to 80 years with 60% or greater stenosis using the North American Symptomatic Carotid Endarterectomy Trial criteria. However, the most recent measurements of stroke rate with ACS using medical intervention alone are overall lower than for those who had CEA or CAS in randomized trials. Randomized trials of CEA versus CAS in persons with ACS were underpowered. However, the trend was for higher stroke and death rates with CAS. There are no randomized trial results related to comparing current optimal medical intervention with CEA or CAS. Commonly cited markers of high stroke risk in relation to ACS lack specificity, have not been assessed in conjunction with current optimal medical intervention, and have not been shown in randomized trials to identify those who benefit from a carotid procedure in addition to current optimal medical intervention. CONCLUSIONS: Medical intervention has an established role in the current routine management of persons with ACS. Stroke risk stratification studies using current optimal medical intervention alone are the highest research priority for identifying persons likely to benefit from adding a carotid procedure.

Low vs high hemoglobin trigger for transfusion in vascular surgery: a randomized clinical feasibility trial.

Current guidelines advocate to limit red blood cell (RBC) transfusion during surgery, but the feasibility and safety of such a strategy remain unclear, as the majority of evidence is based on postoperatively stable patients. We assessed the effects of a protocol aiming to restrict RBC transfusion throughout hospitalization for vascular surgery. Fifty-eight patients scheduled for lower limb bypass or open abdominal aortic aneurysm repair were randomly assigned, on hemoglobin drop below 9.7 g/dL, to either a low-trigger (hemoglobin < 8.0 g/dL) or a high-trigger (hemoglobin < 9.7 g/dL) group for RBC transfusion. Near-infrared spectroscopy assessed intraoperative oxygen desaturation in brain and muscle. Explorative outcomes included nationwide registry data on death and major vascular complications. The primary outcome, mean hemoglobin within 15 days of surgery, was significantly lower in the low-trigger group, at 9.46 vs 10.33 g/dL in the high-trigger group (mean difference, -0.87 g/dL; P = .022), as were units of RBCs transfused (median [interquartile range (IQR)], 1 [0-2] vs 3 [2-6]; P = .0015). Although the duration and magnitude of cerebral oxygen desaturation increased in the low-trigger group (median [IQR], 421 [42-888] vs 127 [11-331] minutes × %; P = .0036), muscle oxygenation was unaffected. The low-trigger group associated to a higher rate of death or major vascular complications (19/29 vs 8/29; hazard ratio, 3.20; P = .006) and fewer days alive outside the hospital within 90 days (median [IQR], 76 [67-82] vs 82 [76-84] days; P = .049). In conclusion, a perioperative protocol restricting RBC transfusion successfully separated hemoglobin levels and RBC units transfused. Exploratory outcomes suggested potential harm with the low-trigger group and warrant further trials before such a strategy is universally adopted. This trial was registered at www.clinicaltrials.gov as #NCT02465125.

Midt-Term Results after Fast-Track Prophylactic Carotid Surgery Program: The Risk of Overlooking Occult Cancer.

BACKGROUND: Most guidelines recommend fast-track carotid endarterectomy (CEA) within 14 days of the last ischemic event. Long-term survival after fast-track CEA is unknown. The purpose of this study was to determine whether the fast-track CEA program in our region was associated with a reduced or increased 2-year survival and overall complication rate in our population. METHODS: Prospective 2-year follow-up in patients after the implementation of a fast-track CEA program during a period of 3½ years. Data on recurrent stroke, myocardial infarction, and death in a 2-year period after CEA were collected along with the indication for surgery and the time from ischemic event to the operation. RESULTS: Two hundred patients underwent CEA. The overall complication rate for 30 days was 3.5% (95% confidence interval [CI], 2%-5%) and 15.5% (95% CI, 13%-18%) for 2 years. During the 2-year follow-up 17 patients (8.5%; 95% CI, 7%-10%) died. Eight patients (4%; 95% CI, 2%-6%) died of advanced cancer (undiagnosed at the index event and CEA time). Of the 6 deaths occurring in patients undergoing CEA 14 days after the index event or earlier, 5 patients (83%; 95% CI, 55%-95%) died of advanced cancer. In the 11 deaths in patients who underwent CEA more than 14 days after the index event, 3 patients (27%; 95% CI, 5%-50%) died of cancer. This was a statistically significant difference (P = .049). CONCLUSION: Fast-track CEA is a safe procedure in selected patients. Our results show a potential significant risk of overlooking occult cancer, which may affect the long-term benefit from prophylactic CEA.

Allosteric fine-tuning of the conformational equilibrium poises the chaperone BiP for post-translational regulation.

BiP is the only Hsp70 chaperone in the endoplasmic reticulum (ER) and similar to other Hsp70s, its activity relies on nucleotide- and substrate-controllable docking and undocking of its nucleotide-binding domain (NBD) and substrate-binding domain (SBD). However, little is known of specific features of the BiP conformational landscape that tune BiP to its unique tasks and the ER environment. We present methyl NMR analysis of the BiP chaperone cycle that reveals surprising conformational heterogeneity of ATP-bound BiP that distinguishes BiP from its bacterial homologue DnaK. This unusual poise enables gradual post-translational regulation of the BiP chaperone cycle and its chaperone activity by subtle local perturbations at SBD allosteric 'hotspots'. In particular, BiP inactivation by AMPylation of its SBD does not disturb Hsp70 inter-domain allostery and preserves BiP structure. Instead it relies on a redistribution of the BiP conformational ensemble and stabilization the domain-docked conformation in presence of ADP and ATP.

Clinical validation of 40-mmHg carotid stump pressure for patients undergoing carotid endarterectomy under general anesthesia.

BACKGROUND: The aim of this study was to validate a mean stump pressure (SP) of 40 mmHg as the cut off threshold for shunting during carotid endarterectomy (CEA). METHODS: A prospective analysis of recently symptomatic carotid stenosis patients undergoing fast-track CEA under general anesthesia. An arbitrary cut-off threshold of 40 mmHg (mean) was defined as the indication for shunt insertion. With an SP<40 mmHg systemic blood pressure was increased 10-20% using sympathomimetic drugs. Patients with an SP≥40 mmHg CEA were operated without a shunt. A neurological observation scheme was filled out preoperatively by the anesthesiologist and postoperatively during the first 24 hours after surgery. Endpoints for validation of SP were per new transient ischemic attack (TIA) or stroke (ipsilateral or contralateral), hypoperfusion/hypoxia syndrome or death before discharge from hospital. RESULTS: One hundred and twenty consecutive CEAs were performed in recently symptomatic patients. A significant correlation between SP and the contralateral stenosis degree of internal carotid artery (ICA) was found in our study P=0.05. Sixteen patients (14%) had SP<40 mmHg after clamping the carotid arteries. Raising blood pressure intra-operatively by 10-20% reduced the incidence of shunt insertion to only three patients (80% reduction). Of the 120 CEAs, only 2.5% (95% CI 1-6%) of patients required shunt. There was no post-operative TIA or stroke in our study. Two patients (1.65%) suffered early TIA from ipsilateral ICA after discharge from the vascular unit. CONCLUSIONS: Using a mean SP of 40 mmHg as a threshold seems to be a safe, easy and cheap method for selective shunt insertion in fast track CEA under general anesthesia with a zero false-negative rate. Raising the systemic blood pressure by 10-20% during cross clamping increased SP above the threshold value 40 mmHg, thus avoiding shunt insertion in a number of patients.

Emergency endovascular coiling of a ruptured giant splenic artery aneurysm.

Splenic artery aneurysms (SAAs) are the third most common abdominal aneurysm. Endovascular treatment of SAAs is preferred, and coiling is the most commonly used technique. Ruptured giant (>5 cm) SAAs are usually treated with open surgery including splenectomy. We present a rare case of a ruptured 15-cm giant SAA in an 84-year-old woman treated successfully with emergency endovascular coiling. To our knowledge, this is one of the few reports of emergency endovascular treatment for ruptured giant SAA.

Urgent best medical therapy may obviate the need for urgent surgery in patients with symptomatic carotid stenosis.

BACKGROUND AND PURPOSE: The purpose of this study was to analyze the 30-day outcome after introduction of a rapid carotid endarterectomy (CEA) program. Reasons for delay in CEA and the incidence of early recurrence neurological symptoms were recorded. METHODS: This is a prospective population-based study of delays to CEA and 30-day outcome in patients with symptomatic carotid stenosis. Neurological recurrence (NR) rate was determined after initiation of urgent best medical treatment (loading dose aspirin/clopidogrel and duel therapy with aspirin plus clopidogrel with a statin) until CEA and compared with NR ≤90 days prior index event. RESULTS: Of a total of 4905 (transient ischemic attack/ischemic stroke, and ocular events) patients, 115 symptomatic patients underwent CEA, 42% within 14 days of the index event and 99% within 14 days of surgical referral. The overall NR from index event to CEA in symptomatic carotid stenosis patients was significantly lower (2.5% [95% confidence interval, 1%-6%]) after best medical treatment when compared with NR ≤90 days in those before referral to a stroke clinic (29% [95% confidence interval, 22%-37%]; P<0.00001). There were no significant differences in outcomes among 48 early (<14 days), 46 intermediate (14-30 days), and 21 delayed (>30 days) CEAs. CONCLUSIONS: CEA can be performed in the subacute period without significantly increasing the operative risk. The urgent best medical treatment was associated with significant reduction in the risk of early NR in CEA patients. It seems that urgent aggressive best medical treatment may obviate the need for urgent CEA.

[Mortality and morbidity in surgery for abdominal aortic aneurysm]. / Mortalitet og morbiditet ved operation for rumperet abdominalt aortaaneurisme.

INTRODUCTION: Patients undergoing surgery for ruptured abdominal aortic aneurysm (rAAA) have a mortality of 40-50%. The purpose of the present investigation is to document the mortality and morbidity of such patients at Rigshospitalet (RH) in 2005. The results are compared with the best results published internationally (benchmark) and with predicted mortality. Factors in postoperative intensive therapy that can improve morbidity and mortality are identified. MATERIAL AND METHODS: This is a retrospective calculation and analysis of mortality and morbidity. Data were collected from an Intensive Care Unit's (ICU) Critical Information System, a blood bank and the database of a vascular surgery unit. RESULTS: The perioperative mortality was 8%, ICU mortality 22%, postoperative mortality 33% and 30-day mortality 39%. The ICU mortality for patients with renal failure and septic shock was significantly higher than the overall ICU mortality. The ICU mortality and morbidity increased with the amount of postoperative blood loss. Patients with an initial serum creatinine concentration of <0.100 mmol/l had a 30-day mortality that was lower than that of patients with a higher initial serum creatinine concentration. CONCLUSION: The treatment of patients with rAAA at RH is comparable to leading clinical practice results. Postoperative bleeding, septic shock and renal failure are identified as predictive factors for increased ICU mortality and morbidity, for which reason future monitoring and postoperative rAAA therapy should include improved monitoring and intervention against postoperative bleeding and early identification of signs of sepsis and renal dysfunction.

Detection of abdominal aortic graft infection: comparison of magnetic resonance imaging and indium-labeled white blood cell scanning.

Infected abdominal aortic grafts rank as one of the most severe complications of vascular surgery, with high mortality and morbidity. The incidence of infection after prosthetic aortic reconstruction is 1-3%. Diagnosis of vascular graft infection can be occasionally difficult. Clinical manifestations and assessment of the extent of graft infection are usually nonspecific, and their detection by radiographic methods, such as computed tomography (CT), magnetic resonance imaging (MRI), and leukocyte -imaging, can be difficult. The purpose of this study was to evaluate the predictive value (PV) of indium-111-labeled white blood cell scanning (WBCS) and MRI in patients who were suspected of having intracavitary vascular graft infection (IGF). The study was done as a cross-control retrospective, single-center study. Fifty-eight In-111-labeled WBC scans and 59 MRIs were performed in suspected patients between January 1995 and January 2005. Among the 40 suspected patients, 35 cases of aorta graft infection were identified intraoperatively. The diagnosis of IGF was based on clinical signs, microbiological and histological examination, MRI and leukocyte imaging, and lack of graft incorporation with surrounding fluid observed intraoperatively. The positive PV (PPV) of MRI was 95% (95% confidence interval [CI] 84-105%) compared to In-111-labeled WBCS, which was 80% (95% CI 62-96%). The negative PV (NPV) of MRI was 80% (95% CI 68-92%) compared to 82% (95% CI 69-94%) for In-111-labeled WBCS. MRI showed a nonsignificant but better PPV for detecting IGF compared to In-111 leukocyte imaging. The NPVs for MRI and In-111-labeled WBCS were very near each other, with a very small advantage for In-111-WBCS. This comparison study suggested MRI as a primary diagnostic modality to investigate patients suspected of having aortic graft infections before In-111-labeled WBCS.