Risk Of Adverse Neurologic Events Research Articles

A pilot study of axicabtagene ciloleucel (axi-cel) for relapsed/refractory primary and secondary central nervous system lymphoma (PCNSL and SCNSL).

2006 Background: Prognosis of patients with relapsed/refractory (R/R) CNSL is poor with no standard of care treatment options. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel) has shown efficacy in R/R systemic large B-cell lymphoma (LBCL) and could be considered for R/R CNSL. Methods: We conducted a pilot study of axi-cel in patients with R/R CNS LBCL. No bridging therapy except corticosteroids was allowed after enrollment. Ommaya reservoir was placed before infusion. Patients underwent lymphodepletion with fludarabine and cyclophosphamide followed by axi-cel dosing of 2x106 cells/kg intravenous infusion. The study enrolled 18 patients, of whom the first 6 patients were observed for treatment-limiting toxicities (TLTs). Primary endpoint was safety, measured by rate of TLTs and grade 3+ adverse events (AEs). Secondary endpoints included objective response rate (ORR), complete response (CR) rate, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Exploratory analyses include paired peripheral blood (PB) and CSF analyses for axi-cel pharmacokinetics, pharmacodynamics, flow cytometry, single-cell RNA-Seq. Results: We report the results of the entire cohort of 18 patients (13 PCNSL, 4 SCNSL, 1 concurrent systemic & ocular L) enrolled. Median age was 62 years (33-80), 8/18 were women. Median number of prior therapies was 3 (1-7). No TLTs were observed; 16/18 (89%) patients developed cytokine release syndrome/CRS (grade 3+, 0%); 8/18 (44%) developed immune effector cell-associated neurologic syndrome/ICANS, 5/18 (28%) grade 3+. Two patients developed Ommaya-related meningitis requiring explant with recovery. One patient had grade 3 seizures that resolved with anti-epileptic agents. The ORR was 94% (17/18); 67% CR (12/18). The median time to best response was 3 months. As of January 25, 2024, the median follow up was 24.2 months, median DOR 13.4 months and 9 patients had progressed. The median PFS was 14.3 months (95% CI: 6.3-NR) and median OS, 26.4 months (95% CI: 11.2-NR). Seven patients have died, all from disease progression. At the time of presentation, there will be a minimum follow-up of 12 months. Correlative data on all 18 patients will be presented at the meeting. Axi-cel pharmacokinetics in the first 12 CNSL patients was similar to that previously reported for DLBCL patients without CNS involvement in ZUMA-1 and ZUMA-7. Patients with CR demonstrated increased peak levels of pro-inflammatory cytokines. CSF CAR T cells exhibit Type I interferon (IFN) transcriptomic signature compared to proliferative signature in blood. Conclusions: Axi-cel was safe and well-tolerated in CNSL patients with encouraging efficacy and median PFS and durability of response of more than 1 year. There was no apparent additional risk of adverse neurologic events including ICANS from axi-cel. Clinical trial information: NCT04608487 .

Abstract 135: Efficacy and Safety of PCSK9 Inhibitors for Stroke Prevention: Systematic Review and Meta-Analysis

Objective: Investigate the efficacy and safety of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on stroke prevention. Background: PCSK9i reduce low-density lipoprotein cholesterol (LDL-Chol) and lipoprotein a (LpA) levels. Their efficacy in reducing the risk of major cardiovascular events has been shown in multiple randomized clinical trials (RCT). However, clinical equipoise remains on the magnitude and mechanisms by which PCSK9i decrease the risk of stroke. Methods: We performed a systematic search of biomedical databases from inception to July 15, 2023, to identify RCTs that investigated the efficacy of PCSK9i versus placebo for major cardiovascular event prevention. The primary outcome was total stroke. The safety outcome was the risk of adverse neurological events, as defined by each trial. Effect size was represented by risk ratio (RR), and analysis was done using random-effects meta-analysis. Heterogeneity was assessed by I 2 and Cochrane Q statistics. Meta-regression analyses were performed to assess the association between LDL-Chol and LpA reduction and stroke risk. Results: Overall, 19 studies with 92,786 patients were included. The quality of the evidence was moderate and heterogeneity for all comparisons was low ( I 2 <25%). The mean age was 60.1 years for the PCSK9i group and 59.6 years for the placebo group, with a mean follow-up time of 60.1 weeks. PCSK9i reduced the LDL-Chol levels by 11% and LpA levels by 8%. PCSK9i were associated with a significant reduction in stroke risk (RR 0.71, 95% CI 0.62-0.81, I 2 =0%), without an increase in mortality (RR 0.94, 95% CI 0.85-1.05, I 2 =0%). The risk of adverse neurological events was similar between groups (RR 1.02, 95% CI 0.88-1.18, I 2 =0%). In meta-regression analyses, the stroke risk was not associated with the magnitude of the effect of PCSK9i on LDL-Chol (LDL Chol β=-0.01, 95% CI=-0.03-0.01) and LpA (β=-0.01, 95% CI=-0.06-0.03) levels. Conclusions: PCSK9i significantly reduced the stroke risk, without increasing mortality or the risk of adverse neurological events. Our findings also suggest that the beneficial effect of PCSK9i on stroke risk is mediated by LDL-Chol- and LpA-independent mechanisms.

CTIM-37. A PILOT STUDY OF AXICABTAGENE CILOLEUCEL (AXI-CEL) FOR THE TREATMENT OF RELAPSED/REFRACTORY PRIMARY AND SECONDARY CENTRAL NERVOUS SYSTEM LYMPHOMA (PCNSL AND SCNSL)

Abstract BACKGROUND Optimal therapy for patients with relapsed/refractory (R/R) CNSL is not defined, and their prognosis is poor. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel(axi-cel) has demonstrated superior efficacy over standard of care in R/R systemic diffuse large B-cell lymphoma and could be an effective regimen for R/R CNSL. METHODS This is a pilot study of axi-cel in patients with R/R CNSL. Only corticosteroids were allowed for bridging. Patients underwent lymphodepletion with fludarabine and cyclophosphamide followed by standard axi-cel dosing of 2x106 cells/kg infusion. An Ommaya reservoir was placed prior to infusion. The first 6 patients enrolled were observed for treatment-limiting toxicities(TLTs). The study enrolled a total of 17 patients. Primary endpoint was safety, measured by rate of TLTs and grade 3+ adverse events(AEs). Secondary endpoints included objective response rate(ORR), complete response(CR) rate, duration of response(DOR), progression-free survival(PFS) and overall survival(OS). Exploratory analyses included paired peripheral blood and CSF analyses for axi-cel pharmacokinetics, cytokine levels, flow cytometry, single-cell RNA-Seq and circulating tumor-DNA. RESULTS We report the results of all 17 patients(13 PCNSL, 4 SCNSL) enrolled. Median age was 64 years (34-80), 8/17 were women. As of 6/2023, 14 treated patients had >1 month follow-up, with 86%(12/14) ORR and 64%(9/14) CR. Six patients progressed. No TLTs were observed; 15/16(94%) patients developed cytokine release syndrome/CRS (grade 3+, 0%), 8/16(50%) developed immune effector cell-associated neurologic syndrome/ICANS, (grade 3+, 5/16(31%)). PFS, OS, DOR and correlatives will be reported at the meeting. Daily examination of CAR T-cells in blood and CSF by scRNA-Seq revealed evolution of a prominent Type I interferon (IFN) transcriptomic signature of CAR-Ts in the CSF. CONCLUSION Axi-cel is safe and well-tolerated in CNSL patients with promising efficacy and no apparent additional risk of adverse neurologic events including ICANS. IFN pathway may play a major role in CAR-T efficacy in CNSL.

Endovascular and Hybrid Open and Endovascular Management of Blunt and Penetrating Zone III Carotid Artery Injuries

Injuries to zone III of the carotid artery, located between the angle of the mandible and the skull base, are uncommon, associated with a high risk of adverse neurologic events and mortality, and challenging to treat. These lesions are difficult to access and treat surgically due to their anatomic location. Therefore, endovascular and hybrid open and endovascular techniques have emerged as a minimally invasive, and in many cases, safer and more effective alternative to open surgery. Endovascular techniques for use in this anatomical region include balloon catheter tamponade, embolization, balloon angioplasty, and endovascular stenting. Selection of the most appropriate treatment strategy is dependent on the: 1) concomitant injuries of the patient, 2) location (external versus internal carotid artery) and nature (intimal tear, dissection, pseudoaneurysm, transection, occlusion, or arteriovenous fistula) of the injury, and 3) whether the operating surgeon believes it is necessary to revascularize or sacrifice the injured carotid artery. The purpose of this article is to review the present endovascular and hybrid open and endovascular therapies available for zone III penetrating and blunt carotid trauma. We begin by describing the clinical presentation and diagnosis of these injuries and then discuss management of an undifferentiated zone III vascular injury. This is followed by a discussion of the management of zone III external and then internal carotid artery injuries. We conclude by describing postoperative management, follow up, and future directions.

TCT-347 Neurologic Events in Patients Treated with Surgical Versus Transfemoral Transcatheter Aortic Valve Replacement: Insights from the PARTNER (Placement of Aortic Transcatheter Valves) Trial

The relative risk of adverse neurologic events after surgical aortic valve replacement (SAVR) vs. transfemoral transcatheter aortic valve replacement (TF-TAVR) remains understudied. Of a total of 5637 patients treated with SAVR or TF-TAVR from April 2007 to October 2014 in the PARTNER 1 (1802, 32

Carotid or Coronary Intervention which is to be done First?

AbstractIn carotid artery disease patients with concomitant significant coronary artery disease (CAD - especially left main diseases – LMCA), the risk of perioperative myocardial infarction and early and late death are increased. Conversely, in patients undergoing coronary artery bypass surgery (CABG), uncorrected severe carotid disease increases the risk of adverse neurologic events [1]. The optimal management of these co-existing conditions and the timing and sequence of correcting them remain controversial. Over the past 2 decades, staged carotid revascularisation followed by CABG, staged CABG followed by carotid revascularisation, or combined coronary and carotid revascularisation simultaneously in one operative setting have each been advocated. Our patient presented with both carotid and significant LMCA CAD, first we have done carotid intervention followed one week later by LMCA percutaneous coronary intervention (PCI).

Influence of access site choice for cardiac catheterization on risk of adverse neurological events: A systematic review and meta-analysis

Stroke is a rare but potentially catastrophic complication of cardiac catheterization. Although some procedural aspects are known to influence stroke risk, the impact of radial versus femoral access site use is unclear. Early observational studies and limited randomized trial data suggested more frequent embolic events with radial access. Subsequently, larger pooled analyses have shown no clear differences in stroke risk but were limited by low event rates. Recent publication of relevant new data prompted our reevaluation of this concern. Therefore, we conducted a systematic review and meta-analysis to evaluate stroke complicating cardiac catheterization with use of transradial versus transfemoral access. A search of MEDLINE and EMBASE was undertaken using OVID SP with appropriate search terms. RevMan 5.3.5 was used to conduct a random-effects meta-analysis using the inverse variance method for pooling risk ratios (RRs) or the Mantel-Haenszel method for pooling dichotomous data. Pooled data from >24,000 patients in randomized controlled trials and >475,000 patients from observational studies were used. The risk ratio (RR) for (any) stroke, using randomized controlled trial data, was not significant (RR 0.87, 95% CI 0.58-1.29). Using observational data, a significant difference favoring radial access was seen (RR 0.71, 95% CI 0.52-0.98). Radial access site utilization for cardiac catheterization is not associated with an increased risk of stroke events. These data provide reassurance and should remove another potential barrier to conversion to a "default" radial practice among those who are currently predominantly femoral operators.

Usefulness of Neuron-Specific Enolase to Detect Silent Neuronal Ischemia After Percutaneous Coronary Intervention

Increased plasma levels of neuron-specific enolase (NSE) are related to damage of neurons and neuroendocrine cells. We aimed to investigate elevation of NSE after elective percutaneous coronary intervention (PCI) on the prediction of silent cerebral infarct (SCI). Study population consisted of 2 groups of patients. Group 1 included 92 consecutive patients with normal coronary angiograms, whereas group 2 consisted of 89 patients who underwent elective coronary stenting. NSE levels were studied before and 12hours after the procedure. Elevation of >0.12μg/L was considered as SCI. Forty-seven of 181 study patients (26%) had SCI after the procedure. NSE elevation was significantly more prevalent in patients with PCI than that of controls. Elevation of NSE was observed in 42% of patients who underwent elective PCI (n= 37) and 11% of the normal coronary artery group (n= 10) (p<0.001). The incidence of SCI was higher in active smokers and patients who had history of myocardial infarction (MI) (55% vs 10%, p <0.001 for active smokers and 40% vs 8%, p<0.001 for history of MI, respectively). Multivariate analysis demonstrated history of smoking (odds ratio [OR] 9.9; 95% confidence interval [CI] 3.7 to 26.9; p <0.001) and previous MI (OR 4.4; 95% CI 1.7 to 11.4; p= 0.01) as independent predictors of SCI. For patients who underwent elective PCI, NSE levels after procedure increases. Invasive coronary procedures have risk of SCIs, even in patients with normal coronary arteries. In conclusion, increased diagnosis of SCIs might improve understanding of their relation with invasive cardiac procedures, facilitate to prevent occurrence of silent microemboli and decrease the risk of adverse neurologic events.

In-hospital mortality and stroke after surgical aortic valve replacement: A nationwide perspective

BackgroundStroke is a widely recognized complication after aortic valve replacement (AVR), especially among elderly patients. The literature contains substantial variability in reports of the actual incidence of stroke after AVR among high-risk patients. Our objective was to define risk of stroke in patients undergoing surgical AVR, using a large national database. MethodsWe used the 2002 to 2011 Nationwide Inpatient Sample database for this analysis. All patients undergoing isolated AVR, or AVR with coronary artery bypass grafting (AVR + CABG), were identified using standard International Classification of Diseases codes. In-hospital mortality and any adverse neurologic event were the primary outcomes of the study. ResultsThe incidence of in-hospital mortality was 3.0% and 5.1%, respectively, among patients undergoing isolated AVR and AVR + CABG; it was significantly lower in high-volume centers. The incidence of any adverse neurologic event was 2.0% and 2.9%, respectively, among patients undergoing isolated AVR, and AVR + CABG. We demonstrated a progressive increase in the risk of in-hospital mortality and adverse neurologic events with increasing age. Neurologic events increased with age, from 1.3% for patients aged <70 years, to 3.2% for those aged >85 years, for isolated AVR; and from 2.3% to 3.6% for AVR + CABG. The incidence of in-hospital mortality was as high as 5.7% and 7.4%, respectively, among patients aged >85 years undergoing isolated AVR, and AVR + CABG. Similarly, the incidence of any adverse neurologic event was 3.2% and 3.6%, respectively, among patients aged >85 years undergoing isolated AVR, and AVR + CABG. In addition, the risk of adverse neurologic events was significantly higher in the high-risk surgical cohort, compared with the low-risk surgical cohort (odds ratio [95% confidence interval]; isolated AVR: 2.38 [1.99-2.86]; AVR + CABG: 1.88 [1.57-2.24]). ConclusionsThe incidence of in-hospital mortality and adverse neurologic events was significantly higher among patients with advanced age and elevated surgical risk.

Abstract 13322: In-hospital Death and Stroke Following Surgical Aortic Valve Replacement: a Nationwide Perspective

Significant heterogeneity exists in the current literature around the actual incidence of stroke following aortic valve replacement (AVR) among high-risk patients. We aimed to evaluate the risk of stroke in patients undergoing surgical AVR from a large national database. Methods: We used the 2002-2011 Nationwide Inpatient Sample for this analysis. All patients undergoing isolated AVR or AVR with coronary artery bypass grafting (AVR+CABG) were identified using ICD codes. In-hospital death and any adverse neurological event were co-primary outcomes. Based on predicted death estimates, the study population was classified into low (&lt;8%) and high (≤8%) surgical risk Results: Incidence of in-hospital death was 3.0% and 5.1% among patients undergoing isolated AVR and AVR+CABG respectively. The incidence of adverse neurological event was 2.0% and 2.9% among patients undergoing AVR and AVR+CABG respectively. We demonstrated a progressive increase in the risk of in-hospital death and adverse neurological events with increasing age (Fig 1). The incidence of in-hospital death was as high as 5.7% and 7.4% among patients aged ≤ 85 years undergoing isolated AVR and AVR+CABG respectively. Similarly, the incidence of any adverse neurologic event was 3.2% and 3.6% among patients aged ≤ 85 years undergoing isolated AVR and AVR+CABG respectively. We demonstrated a significantly higher risk of adverse neurological events among the high-risk cohort as compared to the low-risk cohort. Among patients undergoing isolated AVR, the incidence of any adverse neurological event was 1.8% and 4.8% in the low-risk and the high-risk cohorts respectively. Similarly, among patients undergoing AVR+CABG, the incidence of any adverse neurological event was 2.7% and 5.4% in the low-risk and the high-risk cohorts respectively. Conclusions: The incidence of in-hospital death and adverse neurological events was significantly higher among patients with advanced age and elevated surgical risk.

Risk Prediction for Adverse Events After Carotid Artery Stenting in Higher Surgical Risk Patients

The goal of carotid artery stenting is to decrease the risk of stroke or other adverse events from carotid artery disease. Choosing a treatment strategy requires patient-specific information regarding periprocedural risk of adverse neurologic events. The aim of this study was to predict individual patient risk after carotid artery stenting in patients at higher risk for carotid endarterectomy. Subjects enrolled in the Stenting and Angioplasty with Protection in Patients at High-Risk for Endarterectomy (SAPPHIRE) worldwide study underwent carotid artery stenting with distal protection. Only patients with at least 1 anatomic or comorbid factor associated with elevated surgical risk were included. Preprocedural factors were used to develop a model and integer-based risk score predicting stroke or death within 30 days. The model was calibrated and internally validated using bootstrap resampling. Ten thousand one hundred eighty-six patients were included in the analysis. The overall rate of stroke or death was 3.6% at 30 days after carotid artery stenting. Independent predictors of adverse outcomes were increased age (P=0.006), history of stroke (P<0.001), history of transient ischemic attack presentation (P=0.001), recent (<4 weeks) myocardial infarction (P=0.006), dialysis treatment (P=0.007), need for cardiac surgery in addition to carotid revascularization (P=0.005), a right-sided carotid stenosis (P=0.006), a longer carotid plaque (P=0.012), the presence of a Type II or III aortic arch (P=0.035), and a tortuous carotid arterial system (P=0.004). The optimism-adjusted C-statistic was 0.691. Commonly collected clinical and anatomic variables can identify patients at high and low risk for stroke or death after carotid artery stenting.

Predicting and Preventing Adverse Neurologic Outcomes with Cardiac Surgery

Adverse neurologic outcomes after cardiac surgery can have devastating consequences, among them increased mortality risk and, among survivors, loss of independence and a diminished quality of life. They also represent a burden on the health-care system, requiring prolonged hospitalizations and additional aftercare and, therefore, greater costs. Adverse outcomes are classified by their severity. Frank stroke is the most serious. This complication is associated with patient age; however, the presence of significant ascending aortic disease represents the greatest hazard. Multivariable analysis also indicates that prior neurologic events, diabetes, chronic obstructive pulmonary disease, preoperative status, and diffuse vascular disease are predictive. The second type of adverse cerebral outcome includes neurocognitive abnormalities such as memory loss and diminished emotional health. The strongest predictors of these abnormalities are hypertension and a history of alcohol use, as well as age. These predictive factors have been incorporated into the Multicenter Study of Perioperative Ischemia stroke-risk index, which clinicians can use to better assess the risk of adverse neurologic events. Clinical research examining the relationship between the predictive variables for neurologic adverse events and cerebral blood flow has suggested some surgical strategies for minimizing risk, such as limiting manipulation of the ascending aorta. The benefits of strategies such as using low or high mean arterial pressures and manipulating pump flow remain unclear. Off-pump coronary bypass surgery has been proposed as a means of reducing neurologic risk, but its effectiveness is unproved in this area. One pharmacologic strategy, the administration of aprotinin, has been shown to reduce the incidence of stroke in high-risk patients.

Potential for patient harm from intrathecal administration of preserved solutions.

Intrathecal drug administration is an important component of the management of malignancy and symptom control. This route of administration reduces systemic adverse effects, but can increase the risk of local adverse effects such as arachnoiditis. It is accepted practice that any spinal injection should not contain any preservatives (such as benzyl alcohol and parabens-containing compounds). The intrathecal administration of solutions preserved with benzyl alcohol has been shown in case studies to increase the risk of adverse neurological events. Available data do not support the safety of intrathecal injection of products preserved with parabens; rather, they demonstrate a need for further investigation. Steps should be taken to ensure that preservative-free products are used. Staff involved with the preparation and administration of intrathecal preparations need to be educated about the risks associated with preservatives in this setting.

A Critical Assessment of Neurological Risk During Warm Heart Surgery

A prospective randomized trial comparing retrograde warm blood cardioplegia with cold oxygenated crystalloid cardioplegia in coronary bypass patients at Emory University revealed an increased risk of adverse neurological events in the warm group (4.5% vs 1.4%, p < 0.005). Multivariant analysis found four variables to be independent predictors of adverse neurological outcome: congestive heart failure (p = 0.002); age (p = 0.002); aortic cross-clamp time (p = 0.02); and randomization to the warm group (p = 0.026). In Toronto, a prospective randomized trial compared antegrade warm blood cardioplegia with antegrade cold blood cardioplegia. Compared to the Emory trial, the Toronto series contained fewer female patients (16% vs 25%), fewer patients older than age 70 (16% vs 30%), and fewer redo operations (4% vs 14%). The other prominent differences between the Emory series and the Toronto series were: extensive use of retrograde cardioplegia in the Emory series; mild hypothermia in the warm group in the Toronto series; and elevated serum glucose in the warm group in the Emory series. The Toronto series showed no difference in adverse neurological events comparing cold versus warm cardioplegia groups. A comparison of these two series suggests that mild hypothermia in the Toronto series, elevated glucose in the Emory series, or the use of retrograde cardioplegia may be operative in the elevated incidence of adverse neurological events seen in the Emory series in addition to a relatively larger number of high-risk patients (female, elderly, and redo) in the Emory series.

Retrograde cerebral perfusion during hypothermic circulatory arrest reduces neurologic morbidity

Hypothermic circulatory arrest has become an accepted technique for a variety of cardiac and complex aortic operations. However, prolonged periods (>45 min) of hypothermic circulatory arrest in older patients is associated with marginal cerebral protection and an increased inicidence of adverse neurologic events. In an effort to minimize such morbidity, we used a technique of retrograde cerebral perfusion with continuous monitoring of cerebral hemoglobin oxygen saturation during hypothermic circulatory arrest in 35 patients who understand thoracic aortic operations or resection of intracardiac tumor. There were 27 men and 8 women (mean age 60 years, range 21 to 83 years). Sixteen patients has acute dissection, 6 had contained rupture of a thoracic aortic aneurysm, 10 had total either a chronic dissection or aneurysm and 3 had hypernephromas, extending into the heart. Six patients underwent root replacement by means of an open technique for their distal anastomosis, 7 underwent root and partial arch replacement, 12 had root and total arch replacement, 7 had total arch replacemetn, and 3 had resection of tumor in the heart and retrohepatec vena cava. Seven vessels, and 2 patients had a cesarean section. Sixteen cases were emergency, 6 urgent, and 13 elective. Nine (26%) were reoperations. Thrity-four patients underwent the procedure via a median sternotomy and one patient through a posterolateral thoracotomy. The mean retrograde cerebral perfusion time was 63 minutes (range 35 to 128 minutes), with 30 (86%) patients having more than 45 minutes, 12 (34%) having more than 65 minutes, and 4 (11%) having more than 90 minutes. There was 1 operative death caused by preoperative myocardial infraction from an aortic dissection, and there were 2 late deaths (multiple organ failure and ruptured total aortic aneurysm). One patient had a stroke with a residual right hemiplegia and a pronounced aphasia. There were no other significant neurologic events or reoperations for bleeding. The average length of stay for patients having elective operations was 11 days and for those having emergency operations, 27 days. At a mean follow-up of 6 months all surviving patients (91%) are well. Hypothermic circulatory arrest is a relatively simple technique that provides a bloodless field and good visualization without the need for aortic crossclamps. Moreover, retrograde cerebral perfusion with continuous monitoring of cerebral oxygen saturation extends the "safe" time for hypothermic circulatory arrest, allowing ample opportunity to perform complicated cardiac operations with reduced risk of adverse neurologic events. ( J T horac C ardiovasc S urg 1995;109-259-68)