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Biomedical subjects

C S McArdle

Publications and source records attributed to C S McArdle.

At least 19 recordsLinked to original sources
PubMed1992

Elective versus emergency surgery for patients with colorectal cancer.

A prospective study of 570 patients presenting with colorectal cancer over a 6-year period was undertaken. Of these, 363 were admitted electively and 207 presented as emergencies. The outcome following elective admission was more favourable than after emergency admission. In the elective group the proportion of resected tumours was greater (77 versus 64 per cent, P less than 0.001), the operative mortality rate lower (9 versus 19 per cent, P less than 0.001) and the 5-year disease-related survival rate higher (37 versus 19 per cent, P less than 0.001). These differences may relate to the greater resection rates in the elective situation. Results of surgical intervention might be improved if emergency colorectal operations were undertaken by surgeons with more experience of this type of surgery.

Aged↗
PubMed1992

The effect of angiotensin II on tumor blood flow and the delivery of microparticulate cytotoxic drugs.

Colorectal hepatic metastases have a notoriously poor response to conventional systemic chemotherapy. We have synthesised cytotoxic drug (doxorubicin and mitomycin C) containing spheres 40 microns in diameter, using human albumin and ethyl cellulose as matrices. Introduction of these cytotoxic microspheres into the hepatic artery should embolise to the tumor and provide a controlled release depot for the anticancer agent. The vasoconstrictor, angiotensin II (AII) has been shown to increase tumor blood flow relative to normal tissue when administered via the hepatic artery, therefore we have investigated the effect of AII on targeting of cytotoxic microspheres to hepatic metastases. Patients with hepatic metastatic colorectal carcinoma had hepatic arterial catheters inserted at laparotomy and connected to subcutaneous injection ports. Peroperatively, 99mTc-labelled albumin microspheres were administered via the arterial catheter. Fifteen minutes later, AII was infused (10 micrograms per minuter for 4 min) via the catheter and 131I-labelled albumin microspheres were administered as a bolus at the midpoint of the AII infusion. Multiple biopsies were taken of normal liver and tumor metastasis and the tissue radioactivity counted for 99mTc and 131I. Further studies were performed postoperatively in which 99mTc-labelled microspheres were administered via the hepatic artery catheter and their distribution was followed using tomographic SPECT scanning. Combined results of this study suggested that AII can increase tumor SPECT scanning. Combined results of this study suggested that AII can increase tumor blood flow rates relative to normal hepatic tissue by approximately 3-fold.

Angiotensin II↗
PubMed1992

Glass yttrium-90 microspheres for patients with colorectal liver metastases.

Total calculated uniform liver doses of up to 150 Gy were achieved using glass yttrium-90 microspheres administered via the hepatic artery and targeted to tumour using angiotensin II in seven patients with colorectal liver metastases. No toxicity was observed. Hepatic metastatic progression was delayed in six patients. Median survival was 11 months (range 5-25 + months).

Angiotensin II↗
PubMed1992

Clinical correlation of high activity dynamic hepatic scintigraphy in patients with colorectal cancer.

The hepatic perfusion index, the ratio of hepatic arterial to total liver blood flow, was measured in 50 consecutive patients with colorectal cancer using radiolabelled colloid with high administered activity. In patients with proven liver metastases the diagnostic sensitivity of the HPI was 96% and the predictive value of a negative test was 92%. Dynamic hepatic scintigraphy is of value in the management of patients with colorectal cancer.

Colorectal Neoplasms↗
PubMed1992

A phase I study of regional 5-fluorouracil and systemic folinic acid for patients with colorectal liver metastases.

A phase I study was undertaken in order to establish the maximum tolerated dose of intra-hepatic arterial 5-fluorouracil (5-FU) when given in combination with systemic folinic acid. Patients with colorectal liver metastases (n = 10) received escalating doses of 5-FU as a 24 h infusion with a fixed dose (400 mg m-2) of intravenous folinic acid once per week. Dose limiting toxicity (WHO grade greater than 2) was encountered at 2 g m-2 5-FU. Principal adverse effects were diarrhoea, vomiting and oral ulceration. The recommended dose for phase II studies is 1.5 g m-2 week-1 24 h 5-FU regional infusion with 400 mg m-2 week-1 intravenous folinic acid.

Aged↗
PubMed1992

Is there a relationship between regional microsphere distribution and hepatic arterial blood flow?

The relationship between hepatic arterial albumin microsphere distribution and hepatic arterial blood flow and the effects of regional angiotensin II were studied in a rat liver metastases model. Hooded-Lister rats were inoculated subcapsularly with 2 x 10(6) HSN sarcoma cells. At 20 days, hepatic arterial blood flow was measured using the reference microsphere technique. Animals then randomly received 50 microliters hepatic arterial saline or albumin microspheres (40 microns, 20 mg ml-1). Hepatic arterial blood flow measurements were then repeated at 5 min. After 5 min, animals were killed and tissues were weighed and counted in a gamma well counter. There were no significant differences between the hepatic blood flow measurements recorded before and after the control hepatic arterial saline infusion. However, regional albumin microspheres produced a significant reduction in tumour and normal liver blood flow and an 80% reduction in mean T/N blood flow ratio. Regional albumin microspheres were delivered to tumour in greater proportions (mean T/N ratio 3.89, SE 0.49) than would be expected from baseline hepatic arterial blood flow (mean T/N ratio 1.28, SE 0.22. P = 0.006). There was no correlation between T/N for baseline blood flow and albumin microsphere distribution.

Animals↗
PubMed1992

A pharmacokinetic comparison of intravenous versus intra-arterial folinic acid.

Recent clinical trials have suggested that a combination of folinic acid and 5-fluorouracil (5-FU) may improve response rates and survival in patients with advanced colorectal cancer. However, this regimen has been complicated by potentially life threatening toxicity. Regional delivery of folinic acid via a hepatic artery catheter might be expected to reduce systemic exposure and subsequent adverse effects. The present study compared the pharmacokinetic profiles of intravenous and intra-hepatic arterial infusions of folinic acid in patients with colorectal liver metastases (n = 6) who were being treated with weekly regional infusions of 5-FU. The mean area under the plasma concentration--time curve, the peak plasma concentration and the steady state volume of distribution were 163 micrograms ml-1 h-1 (SD 41), 18.5 micrograms ml-1 (SD 1.2) and 7.41 m-2 (SD 0.44) respectively following intravenous administration of folinic acid compared with 142 micrograms ml-1 h-1 (SD 45), 14.8 micrograms ml-1 (SD 2.4) and 11.21 m-2 (SD 1.22) following intra-hepatic arterial administration (P less than 0.05). Regional folinic acid was therefore associated with a statistically significant reduction in systemic exposure compared with the intravenous route.

Adenocarcinoma↗
PubMed1992

Monitoring blood flow to colorectal liver metastases using laser Doppler flowmetry: the effect of angiotensin II.

Many colorectal liver metastases are hypovascular, and their low level of perfusion is associated with limited drug uptake and poor response rates with regional chemotherapy. We have previously shown that hepatic arterial vasoconstrictors may increase drug delivery to liver tumours, but the underlying haemodynamic changes have not been defined. Using intraoperative laser Doppler flowmetry (LDF) we have assessed the effect of intraarterial angiotensin II (AI) on tumour blood flow in ten patients with colorectal liver metastases. Measurements were performed during placement of infusion catheters for regional chemotherapy. Blood flow was recorded continuously with a Periflux PF3 perfusion monitor via a probe held on the tumour surface, following hepatic arterial infusion of 15 micrograms AII over 90 s. Six patients with isolated small metastases (< 5 cm in diameter) showed increases in flow, which reached a peak at 170-240 s from the start of AII infusion, and which were closely correlated with the corresponding increase in arterial pressure (r = 0.92, P = 0.009). Of the four patients with large confluent tumour deposits, two showed smaller transient increases in flow over the first 60 s of AII infusion and two had no measurable flow response. Increased blood flow following AII infusion may increase the exposure of tumour to therapeutic agents. This study suggests that both tumour size and the effect upon systemic arterial pressure may be important determinants of the blood flow response to AII. LDF may provide useful information about the potential of AII and other vasoconstrictors to enhance targeting precision.

Angiotensin II↗
PubMed1992

The combination of degradable starch microspheres and angiotensin II in the manipulation of drug delivery in an animal model of colorectal metastasis.

Both biodegradable emboli and pharmacological agents can enhance regional therapy for hepatic targeting. Using a rat model with similar haemodynamic characteristics to human colorectal liver tumour and a radio-labelled marker of similar molecular weight to Adriamycin, we have combined the two approaches to see if the effect was addictive. Following induction of liver tumour in male hooded rats by intrahepatic injection of HSN sarcoma cells, the relative distribution of marker, 99mTc methylene diphosphonate (MDP), was studied in three groups given the following by injection into the hepatic artery. (1) Saline (Control) + MDP; (2) Degradable Starch Microspheres (DSM) + MDP; and (3) Angiotensin II + DSM + MDP. Both Degradable Starch Microspheres alone (P less than 0.001) and Degradable Starch Microspheres + Angiotensin II (P = 0.003) significantly increased the retention of marker in liver and tumour at 1 min following injection, with a 12-fold improvement over controls, but the tumour:liver ratio was unaltered. By 90 min the MDP levels in normal hepatic parenchyma had returned to control values. There was relatively less washout with significant retention in tumour tissue in both DSM (P = 0.03) and combination treated animals (P = 0.001), with a significantly improved (P = 0.001) tumour to liver ratio (5.22:1) in combination treated animal relative to those treated with DSM alone.

Angiotensin II↗
PubMed1992

Flow measurement using duplex Doppler ultrasound: haemodynamic changes in patients with colorectal liver metastases.

Duplex Doppler ultrasound has been used to make measurements of liver blood flow. The relationship between time average velocity as measured using pulsed Doppler and the true mean velocity was determined using a flow phantom. Correction factors were applied to measured time average velocities of blood in the hepatic artery and portal vein. Blood flow was calculated from the product of corrected velocities and the cross-sectional area of the vessels. There was no significant difference in total liver blood flow for patients with colorectal liver metastases when compared with controls. However, the ratio of the hepatic arterial flow to the sum of the portal and hepatic arterial flows (Doppler perfusion index, DPI) was markedly elevated (P < 0.0001) in the patients with metastases when compared with the controls. The DPI values for a third group of subjects who had undergone resection for colonic cancer but who had no proven liver metastases overlapped the values for the other two groups. When attention is paid to technique, the procedure can detect and quantify the changes in liver blood flow which occur in the presence of metastases.

Blood Flow Velocity↗
PubMed1992

Effects of ketorolac trometamol on renal function.

We have compared the renal effects of ketorolac trometamol 10 mg administered 4-hourly by intermittent i.m. injection or by continuous i.m. infusion with placebo in a double-blind study in 67 patients who had undergone upper abdominal surgery. Ketorolac was supplemented during the 48-h postoperative study period with bolus doses of morphine delivered by a patient controlled analgesia system. The only significant effect of ketorolac on renal function compared with patients who received placebo was reduced excretion of potassium. The overall changes caused by surgery alone were of much greater magnitude. Bleeding time was increased with ketorolac, but there were no adverse events related to this.

Adult↗
PubMed1992

Ketorolac trometamol for postoperative analgesia after orthopaedic surgery.

We have compared the postoperative morphine requirements and analgesic efficacy of four doses of i.m. ketorolac 30 mg administered 6-hourly with placebo in a double-blind study of patients undergoing major or minor orthopaedic surgery. During the 24-h postoperative study period which began at the end of surgery, patients were prescribed i.m. morphine 10 mg as required 2-hourly and assessments were made of pain at 4 and 24 h. After major surgery, the median morphine consumption over 24 h was 10 mg in patients who received ketorolac, compared with 30 mg in those who received placebo (P = 0.008). Visual analogue pain scores and verbal pain assessments were better than placebo at 4 h (P = 0.028 and P = 0.008, respectively), but were not statistically different between the groups at 24 h. Overall assessment of pain was similar in both groups who had undergone major surgery. In the minor surgery groups, median morphine consumption was 0 mg in patients who received ketorolac, compared with 10 mg in those given placebo (ns). Visual analogue pain scores at 24 h after surgery were significantly less in patients who had received ketorolac compared with placebo (P = 0.046) and the overall assessment of pain relief was better in the ketorolac group (P = 0.0007). Mandatory administration of ketorolac appeared to be of benefit in both major and minor orthopaedic surgery, although the principal effects were reduction in requirement for supplementary morphine for major surgery and better overall analgesia for minor surgery.

Adolescent↗
PubMed1992

Saphenous vein grafts for anatomical variations encountered at surgical insertion of a hepatic artery catheter.

Fifty-five consecutive patients, with colorectal metastases confined to the liver, underwent surgical placement of a hepatic artery catheter. At angiography, abnormal hepatic arterial anatomy was present in 33% of patients. In the majority of patients, the hepatic artery catheter was inserted in the conventional manner. In eleven patients with unusual arterial anatomy, a saphenous vein graft was used to create a conduit for the catheter. Satisfactory perfusion was obtained in all patients.

Adenocarcinoma↗
PubMed1991

Impact of variability among surgeons on postoperative morbidity and mortality and ultimate survival.

OBJECTIVE: To assess the differences among surgeons in postoperative complications, postoperative mortality, and survival in patients undergoing surgery for colorectal cancer. DESIGN: Prospective study of patients with colorectal cancer managed by one of 13 consultant surgeons, none of whom had a special interest in colorectal surgery. SETTING: Royal Infirmary, Glasgow. PATIENTS: 645 sequential patients with colorectal cancer presenting over the six years from 1974 to 1979. MAIN OUTCOME MEASURES: Postoperative complications, postoperative mortality (within 30 days), and survival (up to 10 years); predictive factors for postoperative mortality and survival; and relative hazard rate ratios for individual surgeons. RESULTS: The proportion of patients undergoing apparently curative resection varied among surgeons from 40% to 76%; overall postoperative mortality varied from 8% to 30%. After curative resection postoperative mortality varied from 0% to 20%, local recurrence from 0% to 21%, and the rate of anastomotic leak from 0% to 25%. Survival at 10 years in patients who underwent curative resection varied from 20% to 63%, two year survival in those who underwent palliative resection varied from 7% to 32%, and median survival in those who underwent palliative diversion varied from one to eight months. The hazard rate ratios among individual surgeons, taking into account the identified risk factors, varied from 0.56 to 2.03, from 0.17 to 1.92, and from 0.57 to 1.50 for curative resection, palliative resection, and palliative diversion, respectively. CONCLUSION: There were significant variations in patient outcome among surgeons after surgery for colorectal cancer; such differences compromise survival. A considerable improvement in overall survival might be achieved if such surgery were undertaken by surgeons with a special interest in colorectal surgery or surgical oncology.

Clinical Competence↗
PubMed1991

Mitomycin C-loaded microcapsules in the treatment of colorectal liver metastases. Pharmacokinetics of regionally administered particulate chemotherapy.

Microencapsulated mitomycin C has been used for the treatment of intrahepatic tumors in Japan, but there have been no reports of its use in western countries. In this study, the pharmacokinetic profile of intrahepatic arterial mitomycin C microcapsules is reported. Regional mitomycin C was administered to six patients, both in the microencapsulated form and in solution. The clearance (140 +/- 31 1/hour, mean +/- SD) and half-life of drug in plasma (0.39 +/- 0.03 hours), and volume distribution (246 +/- 23 1) were significantly higher, and peak drug concentrations (80 +/- 75 ng/ml) significantly lower with the microencapsulated preparation than with the free drug (clearance, 46 +/- 8 1/hour; half-life, 0.11 +/- 0.02 hours; volume distribution, 33 +/- 4; peak drug concentration, 812 +/- 423 ng/ml), on Student's t testing (P less than 0.05). The results show that very little systemic exposure is associated with the microencapsulated form of mitomycin C. Dose escalation should be feasible without increasing systemic toxicity.

Antineoplastic Agents↗
PubMed1991

The value of oral antibiotic prophylaxis in biliary tract surgery.

In this study the relationship between the presence or absence of organisms in bile or on closing wound swabs and the subsequent development of wound sepsis was confirmed. There was no significant difference in the incidence of septic complications among three treatment groups in which cefuroxime (iv) and ciprofloxacin (iv or oral) were administered. Consideration of costs attributable to the choice of antibiotic prophylaxis suggests that oral ciprofloxacin in biliary tract surgery may offer significant advantages.

Anti-Bacterial Agents↗