A Repurposing Programme Evaluating Transdermal Oestradiol Patches for the Treatment of Prostate Cancer Within the PATCH and STAMPEDE Trials: Current Results and Adapting Trial Design.

AIMS: Androgen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer. MATERIALS AND METHODS: The PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE [NCT00268476] platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately. RESULTS: Recruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of -3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3-13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80-1.53; P = 0.54). Oncological outcomes are awaited. FUTURE: Efficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure - overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway.

Perioperative ischaemia in aortic surgery: combined epidural/general anaesthesia and epidural analgesia vs general anaesthesia and i.v. analgesia.

PURPOSE: The goal of this randomized study was to determine whether combined general and epidural anaesthesia with postoperative epidural analgesia, compared with general anaesthesia and postoperative intravenous analgesia, reduced the incidence of perioperative myocardial ischaemia in patients undergoing elective aortic surgery. METHOD: Patients were randomly assigned to one of two groups. One group (EPI, n = 48) received combined general and epidural anaesthesia and postoperative epidural analgesia for 48 hrs. The other group (GA, n = 51) received general anaesthesia followed by postoperative intravenous analgesia. Anaesthetic goals were to maintain haemodynamic stability (+/- 20% of preoperative values), and a stroke volume > 1 ml.kg-1. A Holter monitor was attached to each patient the day before surgery. Leads 11, V2, and V5 were monitored. Myocardial ischaemia was defined as ST segment depression > 1 mm measured at 80 millisec beyond the J point or an elevation of 2 mm 60 millisec beyond the J point which lasted > 60 sec. An event that lasted > 60 sec but returned to the baseline for > 60 sec and then recurred, was counted as two separate events. The Holter tapes were reviewed by a cardiologist blind to the patient's group. RESULTS: There were no demographic differences between the two groups. Myocardial ischaemia was common; it occurred in 55% of patients. In hospital, preoperative ischaemia was uncommon (GA = 3, EPI = 8). Intraoperative ischaemia was common (GA = 18, EPI = 25). Mesenteric traction produced the largest number of ischaemic (GA = 11, EPI = 11) events. Postoperative ischaemia was most common on the day of surgery. Termination of epidural analgesia produced a burst of ischaemia (60 events in 9 patients). CONCLUSION: Combined general and epidural anaesthesia and postoperative epidural analgesia do not reduce the incidence of myocardial ischaemia or morbidity compared with general anaesthesia and postoperative intravenous analgesia.

The history of vascular surgery in Canada.

The clinical specialty of vascular surgery in Canada began before the Second World War with the introduction of heparin into clinical practice by Gordon Murray of Toronto. He showed that heparin could prevent thrombosis during the repair of blood vessels and was useful in the treatment of spontaneous arterial and venous occlusion. The unfavourable war experience with arterial ligation for trauma led to an interest in the direct repair of vascular injuries by surgeons returning to civilian practice. Embolectomy, first performed in the late 1940s, was the other early vascular operation. Aortic surgery initially depended upon the use of cadaver homografts, and a number of programs were started in the early 1950s, only to be abandoned as synthetic grafts became available. Infrainguinal bypass grafting with saphenous vein evolved in clinics set up to treat varicose veins and varicose ulcers. The first in-situ grafts were done by Paul Cartier of Montreal in 1960. By this time, reconstruction for aneurysmal and occlusive disease was well established throughout Canada. Specific fellowships in vascular surgery were first offered in the 1970s, as clinical units were set up in teaching hospitals. Surgeons concentrating on vascular disease founded the Canadian Society for Vascular Surgery (CSVS) in 1978 and approached the Royal College of Physicians and Surgeons of Canada to establish training requirements in their specialty. The first qualifying examination was held in 1983, and by 1994 certificates of special competence had been awarded to 178 candidates. The pioneers in Canadian vascular surgery are acknowledged and their contributions summarized.

Endarterectomy versus angioplasty in the treatment of localized stenosis of the abdominal aorta.

OBJECTIVE: To compare the outcome after aortoiliac endarterectomy and percutaneous transluminal angioplasty (PTA) of the aorta for localized stenosis of the lower abdominal aorta. DESIGN: Chart review of patients treated over a 5-year period. SETTING: A university centre. PATIENTS: Sixteen women, all of whom were smokers; 5 had hyperlipidemia, 4 had evidence of coronary artery disease, 3 were hypertensive, and 1 was diabetic. INTERVENTIONS: Aortoiliac endarterectomy (eight women) and PTA (eight women). MAIN OUTCOME MEASURES: Ankle-brachial pressure index (ABI), degree of claudication and clinical outcome. RESULTS: Angiography showed localized stenosis of the lower aorta in all patients, aortic hypoplasia in nine patients and associated common iliac disease in seven. None of the eight patients managed by aortoiliac endarterectomy had complications or died. All were free of claudication at a mean follow-up of 29 months and had durable improvement in their ABI: mean ABI preoperatively was 0.69 (standard deviation [SD] 0.1) and postoperatively was 1.06 (SD 0.07). Of the eight patients treated by PTA, only one had partial dilatation; another had a subintimal tear with worsening symptoms and a fall in ABI, requiring surgery within 18 months. The remaining six were symptom free after a mean follow-up of 13.4 months. Aortic PTA resulted in improvement of the ABI: mean ABI before PTA was 0.69 (SD 0.19) and after PTA was 1.06 (SD 0.15). CONCLUSIONS: Endarterectomy is a safe and effective method of treating occlusive disease limited to the distal aorta. PTA appears to be less reliable. However, it is recommended as the initial treatment of choice in patients with angiographically suitable lesions because it is less invasive.

Cardiac risk stratification using dipyridamole myocardial perfusion imaging and ambulatory ECG monitoring prior to vascular surgery.

Both dipyridamole myocardial perfusion imaging (cardiolite) and ambulatory ECG monitoring (Holter) for silent ischaemia have been found to be useful for stratification of cardiac risk in patients undergoing vascular surgery. The purpose of this study was to compare the diagnostic accuracy of these two non-invasive tests for prediction of perioperative cardiac events. One hundred patients (86 males, 14 females; mean age 67 +/- 8 years) underwent out-patient 48 h Holter monitoring and cardiolite imaging prior to vascular surgery (70 abdominal aortic aneurysm, 21 aortobifemoral, nine femoralpopliteal grafts). Ischaemia on Holter was defined as one or more episodes of ST segment depression 1 mm or greater, lasting 1 min or longer. Myocardial perfusion imaging was carried out with the high dose dipyridamole protocol (0.84 mg/kg), cardiolite and planar imaging. Ischaemia was defined as a segmental perfusion abnormality following dipyridamole with improved perfusion on rest imaging. Holter was positive for ischaemia in 34/100 patients (34%). Cardiolite scans were positive for ischaemia in 30/100 patients (30%). Perioperative myocardial infarction occurred in nine patients (two cardiac deaths). [table: see text] The diagnostic accuracy of the two tests was similar, with a low positive predictive value of 15-20%, and an extremely high negative predictive value of 94-96%. The event rate in patients with both tests negative was 2/48 (4.2%), with only one test positive 3/40 (7.5%) and with both tests positive 4/12 (33%). A reasonable approach to risk stratification would be to obtain either a Holter or cardiolite scan initially.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphatic fistula after vascular reconstruction: a case-control study.

A retrospective case-control study was carried out to assess the importance of lymphatic fistulas that develop after vascular reconstruction and to determine the risk factors associated with them. The authors compared 35 patients who had lymphatic fistula after vascular reconstruction with 70 control patients, taken from the same database. They found a significant difference between the two groups only in age and indication for surgery: lymphatic fistulas were more likely to develop in older patients and in patients who underwent aortobifemoral bypass for limb salvage rather than for claudication (p less than 0.05).

Factors affecting survival after rupture of abdominal aortic aneurysm: effect of size on management and outcome.

Between 1970 and 1985, 172 consecutive patients (146 men, 26 women) underwent repair of ruptured abdominal aortic aneurysms. The mean age was 69.8 years. The overall death rate was 49.4%. The most significant predictors of death were an intraoperative urine output under 100 ml, systolic blood pressure less than 90 mm Hg on admission or in the operating room, cardiac arrest and a history of collapse. Discriminant analysis correctly classified 90% of the survivors and 84% of the nonsurvivors. Aneurysm size was documented in 133 cases; the average diameter was 8.78 cm, and 13 (10%) of the aneurysms were smaller than 6.0 cm. A correct diagnosis was made preoperatively in 46% of these 13 cases compared with 77% overall (p less than 0.05), and the time from arrival to transfer to the operating room was 6.71 versus 2.37 hours (p less than 0.05). The death rate for patients who had the small aneurysms was 77% versus 45% for those with larger aneurysms (p less than 0.06). This study confirms the continuing poor results after repair of ruptured abdominal aortic aneurysms. A subset of patients having small aneurysms (less than 6.0 cm) require an aggressive approach to diagnosis and treatment.

Inflammatory aneurysms of the abdominal aorta.

The treatment of inflammatory aneurysms of the abdominal aorta presents a formidable challenge to the surgeon. The retroperitoneal inflammatory reaction obliterates normal tissue planes, limiting access to the infrarenal aorta. During a 70-month period 25 (6%) of 439 patients operated on for abdominal aortic aneurysms were found to have the inflammatory type. These patients were more likely to be symptomatic than patients with noninflammatory aneurysms and they were more likely to be male. Although surgical repair of the aneurysms required longer aortic occlusion time and more blood replacement, the outcome was similar to that for patients treated for noninflammatory aneurysms.

Comparison of left ventricular function and myocardial perfusion for evaluating perioperative cardiac risk of abdominal aortic surgery.

The measurement of left ventricular function by gated blood pool scanning and of myocardial perfusion by dipyridamole thallium imaging were compared in a prospective study of patients who had abdominal aortic aneurysm or aortoiliac occlusive disease to determine which measurement was the better predictor of postoperative cardiac complications. Sixty-six men and 19 women (mean age 67 years) underwent both tests before admission for surgery. Fifty-six had repair of an abdominal aortic aneurysm, and 29 had reconstruction for aortoiliac occlusive disease. In 17 patients the left ventricular ejection fraction was less than 50%. Dipyridamole thallium imaging was positive, showing redistribution, in 45 patients. Postoperative cardiac complications occurred in 33 patients. The sensitivity of dipyridamole thallium imaging (91%) was significantly (p less than 0.01) greater than that observed with gated blood pool scanning (27%). However, the specificity of gated blood pool scanning (85%) was similar to that of dipyridamole thallium imaging (71%). Diagnostic accuracy was greatest with dipyridamole thallium imaging (79% versus 62% [p less than 0.02]). Dipyridamole thallium imaging is superior to gated blood pool scanning for perioperative evaluation of vascular surgical patients.

Chylous ascites following abdominal aortic aneurysmectomy: surgical management with a peritoneovenous shunt.

The development of chylous ascites after emergency repair of a ruptured abdominal aortic aneurysm (AAA) is an extremely rare complication with potentially grave mechanical, nutritional, and immunologic consequences. A 54-year-old man with recurrent, symptomatic chylous ascites ultimately required insertion of a peritoneovenous shunt after non-operative measures failed to provide relief. This is the fourth reported case of chylous ascites following ruptured AAA and only the second treated by peritoneovenous shunt placement.

A comparison of dipyridamole-thallium imaging and exercise testing in the prediction of postoperative cardiac complications in patients requiring arterial reconstruction.

The individual and combined predictive values of dipyridamole-thallium imaging and exercise testing were compared in a prospective study of 70 patients who had abdominal aortic aneurysms or aortoiliac occlusive disease that required surgical repair. All patients were evaluated clinically by the same cardiologist and had exercise stress testing and dipyridamole-thallium imaging before admission for surgery. Ten patients were excluded from the study because they had evidence of severe ischemia when tested (ST segment depression greater than 2 mm on exercise testing, severe multivessel disease on thallium imaging). The remaining 60 patients were operated on (abdominal aortic aneurysm repair, 40; aortobifemoral repair, 17; femorofemoral graft, 3). The test results were withheld from the surgeon, anesthetist, and cardiologist before surgery. A total of 22 patients experienced major cardiac complications postoperatively (acute pulmonary edema, 17; acute myocardial, infarction, 5; cardiac death, 2). Thallium imaging showed myocardial ischemia in 31/60 patients. Exercise testing was positive (greater than or equal to 1 mm ST segment depression) in 10/60 patients. Dipyridamole-thallium imaging with a high sensitivity and reasonable specificity is the initial test of choice. Exercise testing is a poor screening test because of its low sensitivity. The combination of the two tests gives the highest positive predictive value and the greatest likelihood ratio. Thus patients assessed initially and found to have positive thallium scan results may be further stratified by exercise testing.

Abdominal aortic aneurysm: consequences of a positive family history.

To assess the prevalence of coexisting abdominal aortic aneurysm (AAA) within certain families, a retrospective review was carried out of patients who had undergone AAA repair over a 5-year period. Contact was made with 305 families (52%) and a positive history of an affected, first-degree relative was obtained in 34 (11%). A known AAA was reported to affect approximately 20% of siblings at risk when the proband had an affected parent or sibling. Siblings of patients with an affected first-degree relative represent a high-risk group that may benefit from a screening program for earlier detection and elective management of AAA.

Popliteal aneurysms: an index of generalized vascular disease.

A review of 59 popliteal aneurysms in 38 patients seen over 10 years revealed that 34 (58%) aneurysms were symptomatic. Symptoms included gangrene (15%), ischemia due to thrombosis (38%) and embolism (5%). Patients with unilateral aneurysms (45%) were a median of 7 years younger than those with bilateral lesions (55%). The latter group had more frequent manifestations of occlusive disease, which included previous myocardial infarction, coronary artery bypass grafting and stroke. They also had more concomitant aneurysms, those of the abdominal aorta and femoral and iliac arteries being the most common. Management consisted of bypass grafting in 34 limbs and immediate amputation in 9; 16 inoperable limbs remained viable. At last follow-up (median 32 months) or time of death, 30 of 34 grafts were patent. Four grafts occluded, one perioperatively and the others at 4, 5, and 32 months respectively, resulting in two amputations. The cumulative patency rate in the asymptomatic group was 94% compared with 81% in the symptomatic group. These data illustrate that patients with popliteal aneurysms may have associated vascular disease, the likelihood of which is increased when aneurysms are bilateral.

The use of preoperative exercise testing to predict cardiac complications after arterial reconstruction.

To assess the value of exercise testing in the prediction of cardiac risk, 100 patients requiring arterial reconstructive surgery had either treadmill testing or arm ergometry before operation. Thirty-four patients then had abdominal aortic aneurysm repair, 48 had reconstructions for aortoiliac occlusive disease, and 18 had infrainguinal revascularization procedures. Cardiac complications included myocardial infarction in 10%, acute congestive failure in 5%, malignant ventricular arrhythmias in 7%, and cardiac death in 7%. Contingency table analysis showed that patients who achieved less than 85% of their predicted maximum heart rate (PMHR) during exercise testing had a complication rate of 24%, whereas patients who achieved more than 85% of PMHR had a 6% complication rate (p = 0.0396). The degree of ST segment depression during exercise testing was not a significant predictor of cardiac complications. However, patients who had a positive stress test (ST depression more than 1 mm) and achieved less than 85% of their PMHR had a complication rate of 33%, whereas patients with a positive stress test who achieved more than 85% of their PMHR had no complications (p = 0.048). Statistical analysis with a logistic regression model showed two factors to be significant. Patients who achieved a high maximum heart rate during exercise testing had a low probability of developing postoperative cardiac complications (p = 0.04), as did patients who achieved high cardiac work load maximal oxygen uptake (p = 0.03). We conclude that preoperative exercise testing is useful to predict cardiac complications after arterial reconstruction. Patients who are able to achieve more than 85% of their PMHR and a high maximal oxygen uptake represent a low-risk group.

Abdominal aortic ectasia resulting from peripheral traumatic arteriovenous fistulization.

A 61-year-old World War II fighter pilot sustained a gunshot injury to the right fibula and an arteriovenous fistula subsequently developed. Angiographic examination 44 years later for evaluation of an abdominal aortic aneurysm showed an unusually shaped aneurysm and the right arteriovenous fistula with antegrade dilation of the ipsilateral arterial system in continuity with the aneurysm. We hypothesize that this arteriovenous fistula, which involved the peroneal and anterior tibial arteries of the right leg of 44 years' duration, was responsible for the development of this man's abdominal aortic aneurysm.

Management of primary acute arterial occlusion.

The management of primary acute arterial occlusion depends upon distinguishing between embolism and thrombosis. Emboli are sudden in onset, have a demonstrable source and lodge most frequently at the common femoral bifurcation. Embolectomy is the treatment of choice. Acute thrombosis is usually preceded by prolonged, progressive, ischemia, is less abrupt in onset and occurs most commonly in the superficial femoral artery. The initial treatment is anticoagulation with heparin, followed by artery repair if indicated. Emergency surgical reconstruction is necessary if the condition of the limb deteriorates despite heparin therapy. Nonviable limbs are best amputated early, and ischemic myositis is the best clinical predictor of viability. The use of streptokinase intra-arterially is a reasonable alternative in patients with thrombosis, although the selection of patients is difficult. It must be followed by treatment of the underlying lesion, using either balloon angioplasty or surgical repair.

Cardiac mortality and morbidity after vascular surgery.

To determine the clinical, hemodynamic and pathological features that contribute to major cardiac complications after vascular surgery, six patients with early postoperative cardiogenic shock (group 1) were analysed retrospectively and compared to nine patients without complications (group 2) who were carefully analysed prospectively. Four group 1 patients had elective repair of an abdominal aortic aneurysm, one had repair of a false iliac artery aneurysm and one had a femoropopliteal graft inserted. Four group 2 patients had elective repair of an abdominal aortic aneurysm and five had aortobifemoral reconstruction. The Goldman multifactorial index was similar in both groups and indicated an expected death rate of 2% and a morbidity rate of 5%. In group 1, the earliest sign of cardiovascular compromise was an elevated pulmonary wedge pressure during operation. Postoperatively, electrocardiographic evidence of myocardial ischemia was present in all six patients and preceded cardiogenic shock. Autopsy of the four patients who died demonstrated triple-vessel disease in all but recent occlusion in only one patient. There was evidence of extensive subendocardial infarction in all four. Angiography of the two survivors in group 1 also demonstrated triple-vessel disease. The authors conclude that by using ordinary clinical methods it is difficult to identify patients likely to have major complications postoperatively. Elevated pulmonary wedge pressures or electrocardiographic evidence of myocardial ischemia may be early warning signs of impending cardiac catastrophe and should be treated aggressively. The underlying pathophysiology appears to be perioperative stress in a setting of severe triple-vessel coronary artery disease.

Statistical prediction of cardiac risk in patients who undergo vascular surgery.

Since August 1982, an extensive computerized data base has been developed on all patients admitted to the Division of Vascular Surgery at the Ottawa Civic Hospital. For each patient, 180 variables are recorded, including information about preoperative risk factors and postoperative complications. Since cardiac complications are a major cause of mortality and morbidity, the data file has been used to study postoperative cardiac complications in patients who undergo arterial reconstructive operations. Between August 1982 and December 1983, 353 artery repairs were performed, excluding ruptured aneurysms. Cardiac complications developed following surgery in 56 patients. Risk factors were initially studied using contingency table analysis. Four of these factors were found to be significant: electrocardiographic evidence of previous myocardial infarction (p = 0.0003), nonspecific ST-segment changes (p = 0.0007), New York Heart Association classification of symptoms (p = 0.0003) and age (p = 0.01). A further statistical study was based upon multiple logistic regression. The authors believe that the identification of a high-risk group, using these criteria, is helpful in selecting patients for intensive preoperative investigation, including coronary arteriography.