Previous studies using dynamic scintigraphy have shown that the measurement of changes in hepatic perfusion may be exploited to detect liver metastases. Similar hepatic haemodynamic changes also occur in cirrhosis, however, thereby reducing the diagnostic power of the technique. The ability of duplex colour Doppler sonography (DCDS) to differentiate between the changes in liver perfusion in patients with cirrhosis and those with hepatic metastases was assessed. Hepatic arterial and portal venous blood flows were measured in 30 control subjects, 20 patients with cirrhosis, and 55 patients with overt liver metastases.The Doppler perfusion index (DPI) (the rate of hepatic arterial to total liver blood flow) and the congestive index (ratio of the cross sectional area of the vessel to time averaged velocity of blood flow in the vessel) of the hepatic artery (HCI) and portal vein (PCI) were calculated. The hepatic arterial blood flow of the cirrhotic and metastatic groups was significantly raised compared with that of controls, and the portal venous blood flow of the former groups were reduced (p<00001). The DPIs of the cirrhotic and metastatic groups were therefore significantly raised compared with those of controls (p<0l0001). No significant difference was noted in HCI values between the three groups. The PCI values of the cirrhotic group, however, were significantly raised compared with those of controls and patients with metastases (p<00001). The data suggest that DCDS measurement of PCI may be of value in differentiating between the hepatic perfusion changes caused by cirrhosis and those resulting from hepatic metastases, thereby increasing the diagnostic power of this technique. (Gut 1993; 34: 554-557) The normal liver receives about 25% of its blood supply via the hepatic artery and the remainder through the portal vein. Parkin et al postulated that the presence of liver tumour might increase the hepatic arterial blood flow, as the blood supply of the tumour is almost exclusively arterial.' using dynamic scintigraphy as an indirect method of measuring blood flow, they calculated the ratio of hepatic arterial to total liver blood flow, the hepatic perfusion index (HPI), and found that it was raised in patients with liver metastases. In this study, we investigated the flow changes associated with hepatic metastases and cirrhosis to assess the value of DCDS in differentiating between the hepatic haemodynamic changes in patients with cirrhosis and those with colorectal liver metastases. MethodsThirty healthy volunteers (age range 23-77 years), 55 patients with histologically proved overt colorectal liver metastases (age range 31-75 years), and 20 patients with cirrhosis (age range 37-70 years) were included in the study. The cirrhosis was caused by alcohol abuse and all these patients had oesophageal varices at endoscopy. The severity of cirrhosis was evaluated according to Child-Pugh's classification. The score of the patients ranged from 2 to 13 with a mean of 7-1.All subjects were examined in the sup...

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Summary Conventional imaging techniques are of limited value in identifying small liver metastases. Indirect methods of measuring blood-flow have shown that metastases may be associated with subtle changes in liver blood-flow. Doppler ultrasonography has the ability to measure liver blood-flow directly. In this study, the role of duplex sonography in the detection of hepatic metastases was evaluated. Hepatic arterial and portal venous blood-flows were In 1983, Parkin and colleagues suggested that changes in liver blood-flow occurring in patients with intra-hepatic tumour could be measured indirectly by dynamic scintigraphy. They described an increase in the ratio of hepatic arterial: total liver blood-flow in patients with overt hepatic metastases. However, this technique has not been widely used in clinical practice because of difficulties in interpretation and reproducibility (Laird et al., 1987).In contrast, duplex sonography has the capacity to measure liver blood-flow directly. In this study, the crosssectional area and velocity of blood-flow within the hepatic artery and portal vein were measured and blood-flow calculated. This technique is less invasive, independent of hepatic function and can be more readily standardised.The aim of this study was to assess the value of duplex sonography in the detection of colorectal liver metastases. StatisticsThe data were analysed using a Mann-Whitney test.

Current imaging modalities are unable to detect small liver metastases because of limited resolution and contrast differentiation. The association between liver metastases and altered liver blood flow has been demonstrated by dynamic scintigraphy, but the clinical feasibility of this test has been questioned. In this study a novel approach to detecting liver metastases was assessed by measurement of liver blood flow using a duplex/color Doppler System. Hepatic arterial and portal venous blood flows were measured in 16 controls, 50 patients with gastrointestinal cancer, and 6 patients with breast cancer. The ratio of hepatic arterial to total liver blood flow (Doppler perfusion index, DPI) and the ratio of hepatic arterial: portal venous blood flow (Doppler flow ratio, DFR) were calculated. The DPI and DFR values of controls and patients with overt liver metastases were clearly separated (p less than 0.0001). The results suggest that duplex/color Doppler ultrasound measurement of hepatic perfusion changes may be of value in the detection of liver metastases.

Summary Regional chemotherapy is commonly used to treat patients with colorectal liver metastases. However, improvement in survival has still not been demonstrated. Cytotoxic loaded albumin microspheres for arterial administration have been described as a means of improving the therapeutic index, but their distribution depends upon the prevailing pattern of arterial blood-flow at the time of injection. In this study, the ability of the vasoactive drug angiotensin II to target arterially injected microspheres to colorectal liver metastases is assessed in nine patients using scintigraphic planar and tomographic imaging.The median tumour: normal ratio in nine patients with colorectal liver metastases was 3.4:1 before the administration of angiotensin II. The corresponding ratio after administration of angiotensin II was 7.3:1. The median improvement factor was 1.8 (P <0.05).The data suggest that worthwhile tumour targeting can be achieved with angiotensin II in patients with colorectal liver metastases.Post-mortem studies have shown that up to 70% of patients dying after a potentially curative resection for colorectal cancer, die with liver metastases. The prognosis of patients with colorectal liver metastases is generally poor, survival being in the range of 3 to 9 months (Woods, 1984;Nielsen et al., 1971).Surgical resection of colorectal hepatic metastases may be effective in patients with limited disease (Bradpiece et al., 1987), but may not be feasible in the majority of patients where multiple tumours are present. Although some recent studies of combined systemic 5 fluorouracil and folinic acid or interferon show promising results (O'Connell, 1989;Kerr, 1989;Wadler et al., 1989), conventional systemic chemotherapy has been associated with poor response rates. Attention has therefore turned to regional chemotherapy.It is known that established colorectal liver metastases receive their blood supply from the hepatic artery and the administration of anti-cancer drugs via an indwelling hepatic arterial catheter is now widely practised (Ridge et al., 1987). Unfortunately, although the tumour response rates may increase when chemotherapeutic agents are administered intraarterially rather than systemically (Berger, 1981) a significant increase in survival among treated patients has not been demonstrated by randomised controlled trial (Malik & Wrigley, 1988).Novel chemotherapeutic drug delivery systems including cytotoxic loaded or radioactive microspheres for administration by the arterial route, have been developed. We have previously described cytotoxic loaded albumin microspheres (diameter 20-40IAm) which are trapped in the liver when injected into the hepatic artery (McArdle et al., 1988;Willmott et al., 1985), the drug being released as the microsphere degrades. However intra-arterial injection of such particles results in their unselective distribution throughout the liver, microsphere concentration within different regions of the organ being dependent upon the prevailing distribution of arterial blood-flow. How...

Summary By measuring peripheral drug levels in plasma, the effect of combining albumin microspheres with angiotensin II on systemic exposure to 5FU when administered by bolus injection into the hepatic artery in patients with advanced colorectal liver metastases has been assessed. The results suggest that despite hepatic arterial administration of 5FU, there was no reduction in systemic exposure when compared with that associated with intravenous injection of the same dose. Neither albumin microspheres nor angiotensin II appeared to improve the regional advantage. There have been a number of reports relating the plasma levels of cytotoxic agents with pharmacodynamic parameters. We have shown significant direct correlations between 5FU clearance and 1 week post treatment platelet and white cell counts, and an inverse relationship between the area under the 5FU plasma concentration-time curve (AUC) and 1 week post treatment platelet count and white cell count respectively.The failure and toxicity of systemic chemotherapy in the treatment of liver metastases of colorectal origin has led to increasing interest in locoregional therapy (Taylor, 1985). Most antineoplastic agents have steep dose response curves and systemic toxicity can often be related to some aspect of the drug's plasma concentration-time profile (Powis, 1986 the right chest wall and the peritoneal cavity. The reservoir was then sutured into position over a rib within the subcutaneous pocket. The gastroduodenal artery was ligated distally and cannulated so that the catheter tip lay at the junction of the gastroduodenal and hepatic arteries. The catheter and reservoir were then filled with heparinised saline, which was replaced by flushing daily in the immediate post-operative period, and then once weekly.Albumin microspheres were prepared by a technique involving stabilisation with glutaraldehyde of a water in oil emulsion containing protein (Lee et al., 1981). The basic system has been modified by us to produce microspheres of a size suitable for entrapment in terminal capillaries. (Willmott et al., 1985). Human serum albumin (600mg) was dissolved in 1 mM phosphate buffer containing 0.1% SDS (1 ml) and diluted with water (1.8 ml). The albumin solution is emulsified in an oil phase of cotton seed oil and petroleum ether, and the protein cross-linked with 25% gluteraldehyde (150 jil) to stabilise the microspheres. Following consecutive washes in petroleum ether/isopropanol/PBS/0.5% tween, and PBS/0.2% tween to remove particles <7,um in diameter, the microspheres were ready for use. All procedures were carried out in a sterile products unit which maintains a sterile environment to the required British standard. This ensured that the microspheres were sterile, and an aliquot from each dose was formally checked by solubilisation with trypsin prior to sterility testing. The size of the microspheres was measured by Coulter counter or laser diffraction (Malvern Instruments, Malvern, UK) and was found to be 20-40,jm in diameter (50% weight average). Betwee...

Summary Cytotoxic microspheres have been developed for intra-arterial use in patients with liver metastases. Following injection, the distribution of microspheres reflects the pattern of hepatic arterial blood-flow. Vasoactive agents, such as angiotensin II, by producing vasoconstriction in normal liver, might divert arterial blood toward tumour and thereby enhtance the delivery of drug-loaded particles. Using a double isotope technique, the distribution of radiolablled microspheres to tumour and normal liver tissue was measured before and after angiotensin II infusion in nine patients with multiple liver metastases. The median increase in tumour: normal ratio following angiotensin II infusion was by a factor of 2.8 (range 0.8-11.7, P<0.05). This novel approach to regional chemotherapy, using a combination of angiotensin II infusion and cytotoxic microspheres, increases the exposure of tumour to cytotoxic agents and may, therefore, enhance tumour response rates.Sixty percent of patients dying after resection of colorectal cancer are known to have liver metastases at the time of death (Welch & Donaldson, 1979;Ridge & Daly, 1985). The results of systemic chemotherapy have been disappointing; escalation of dose or multi-drug regimes may increase the response rate but are associated with unacceptable toxicity.It is known that liver metastases derive their blood-supply predominantly from the hepatic artery (Ridge et al., 1987) and attention has therefore turned to the concept of regional chemotherapy. In theory, the administration of cytotoxic drugs via the hepatic artery should increase drug levels within the tumour while minimising systemic toxicity (Kato et al., 1981). To date, however, improved survival following bolus intra-hepatic arterial chemotherapy has not been demonstrated (Malik & Wrigley, 1988; Allen-Mersh, 1989). This may be because, following bolus injection, the tumour-bearing liver is exposed to high drug levels only transiently (Goldberg et al., 1988).One means of retaining anti-cancer agents more effectively within the liver might be to load the active agent into embolising particles. There have been reports of chemotherapeutic agents such as adriamycin and mitomycin C being carried in biodegradable particles which act as slowrelease systems when administered via the hepatic artery (McArdle et al., 1988;Fujimoto et al., 1985). Unfortunately, the distribution of arterially administered particles reflects the pattern of arterial blood-flow within the liver, and the proportion of drug reaching hypovascular tumours will be low.Previous studies in animal models have suggested that vasoactive agents such as noradrenaline and angiotensin II modify the pattern of arterial blood-flow by causing temporary arteriolar constriction in normal blood-vessels (Burton et al., 1985). Hepatic tumour vasculature is immature, possessing neither smooth muscle nor an adrenergic nerve supply, and is therefore unable to respond to arterio-constrictors in the same way as normal vasculature (Hafstrom et al., 1980;Mattson et a...

The effect ofispaghula husk on colonic motility of the right and left side was examined in 10 patients with left sided diverticular disease using an untethered pressure sensitive radiotelemetry capsule. After treatment, ispaghula husk reduced mouth to rectum transit by a median of 8*8 hours and the time to midtransverse colon by five hours. In the right colon there was an increase in the median percentage activity of 7% and the median number of pressure waves >5 mm Hg/hour rose by 35-3. Motility changes in the left colon were less pronounced. Five of the seven patients with abdominal pain and six of the nine patients with altered bowel habit responded to treatment. These results suggest that it is ispaghula husk's action on the right unaffected colon which alleviates the symptoms of left sided diverticular disease.