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Biomedical subjects

T G Cooke

Publications and source records attributed to T G Cooke.

At least 91 records · Page 5Linked to original sources
PubMed1992

The effect of portal venous flow on the washout of a regionally injected marker substance 99mTc-methylene diphosphonate after hepatic arterial blockade with degradable starch microspheres.

Patients with hepatic metastases derived from colorectal carcinoma have a poor prognosis. Regional chemotherapy, either alone, or combined with agents such as degradable starch microspheres (DSM) that reduce or abolish intrahepatic arterial flow and potentiate the delivery of cytotoxics to hepatic metastases, have not significantly improved survival. We have investigated one positive mechanism, namely the effect of portal venous washout of cytotoxics, for the poor efficacy of drugs administered either alone or in combination with DSM via the hepatic artery in the rat. Using a radiolabelled marker, 99mTc-methylene diphosphonate (MDP), to represent a cytotoxic drug, the initial studies indicated that with the hepatic artery and portal vein clamped, a volume of 0.05 ml of the marker administered via the hepatic artery resulted in the most uniform intrahepatic distribution with minimal washout into the systemic circulation (21 +/- 3.7%). When the hepatic artery was clamped, the washout of MDP was reduced from 100% (with clamps on the portal vein and hepatic artery) to 84.2 +/- 7.7%. DSM administered concomitantly with MDP, resulted in a greater reduction of the portal venous washout of the marker (63 +/- 2.4%). Administration of DSM and MDP via the hepatic artery and with the portal vein clamped further reduced the washout of the marker to (21 +/- 2.26), results similar to those observed with inflow vessel clamps. Following restoration of portal venous flow, there was a rapid washout of 53.7 +/- 7.6% of the marker into the systemic circulation. The results of this study suggest that portal venous washout of regionally delivered cytotoxics, either alone or in combination with DSM, offer an explanation for the poor efficacy of regional chemotherapy in improving the prognosis of patients with hepatic metastases.

Animals↗
PubMed1991

Changes in hepatic haemodynamics and hepatic perfusion index during the growth and development of hypovascular HSN sarcoma in rats.

Experimental liver tumours were induced in the Hooded Lister rat by the intraportal inoculation of 10(6) HSN sarcoma cells. The hepatic perfusion index was raised 10 days after the inoculation of cells (at the micrometastatic stage) and when overt tumour was present 20 days after inoculation. Overt tumours were hypovascular compared with normal liver. Portal venous flow and portal venous inflow fell significantly when the hepatic perfusion index was increased, but hepatic arterial flow did not alter. Portal vascular resistance and splanchnic vascular resistance were both increased in tumour-bearing animals but portal pressure, arteriosystemic shunting and portosystemic shunting did not increase significantly at any stage during the growth of hepatic tumour. These findings confirm that the hepatic perfusion index can be elevated in the presence of both micrometastic and overt hepatic tumour and that the changes are not due to either arteriosystemic shunting or mechanical portal venous obstruction.

Animals↗
PubMed1991

The effects of intra-arterial vasoconstrictors on the distribution of a radiolabelled low molecular weight marker in an experimental model of liver tumour.

Regional chemotherapy for colorectal liver metastases has not demonstrated a convincing survival benefit over systemic chemotherapy. This may be due to poor delivery of chemotherapeutic drugs to hypovascular liver tumour. Since vasoactive agents may influence hepatic blood flow this study investigated the effects of systemic and regional vasoconstrictors on the delivery of a regionally delivered marker in an experimental model of liver tumour. Systemic administration of angiotensin II caused a significant retention of marker in normal liver, but not in tumour compared to controls. Regional delivery of angiotensin II and phenylephrine caused significantly greater retention of marker in tumour than liver with an overall 4-fold increased retention of marker one minute after its injection. Ninety minutes after injection there was still significant retention of marker compared to control animals. Regional delivery of hepatic artery vasoconstrictors increase delivery of marker and may increase delivery of chemotherapeutic drug to liver tumour.

Angiotensin II↗
PubMed1991

The effects of vasopressin infusion on hepatic haemodynamics in an experimental model of liver metastases.

Vasoactive drugs have a variety of effects upon splanchnic and hepatic haemodynamics which may alter tumour blood flow and potentiate the delivery of a chemotherapeutic drug to hepatic tumour. We have investigated the effects of vasopressin infusion on hepatic tumour blood flow in an experimental model of liver tumour. Hepatic tumour was induced by the intraportal inoculation of HSN sarcoma cells. Hepatic and splanchnic blood flow was determined using a dual reference microsphere technique before and after an intravenous infusion of vasopressin at a dose of 0.1 mU kg-1 min-1 for 10 min. There was a significant increase in systemic arterial blood pressure associated with a rise in portal venous inflow (P less than 0.01, Wilcoxen Signed rank Test) and a significant fall in hepatic arterial flow (P less than 0.05). The tumour: liver blood flow ratio was significantly increased by vasopressin infusion (P less than 0.02). Vasopressin infusion decreases hepatic arterial flow and increases tumour blood flow which may potentiate the delivery of a regionally delivered chemotherapeutic drug to hepatic tumour.

Animals↗
PubMed1991

Regional delivery of microspheres to liver metastases: the effects of particle size and concentration on intrahepatic distribution.

There is increasing interest in the use of microspheres, loaded with chemotherapeutic agents, for regional therapy to hepatic metastases. It is necessary to deliver these particles predominately to tumour rather than to normal liver. This study investigates factors influencing the distribution of regionally injected microspheres. Discreet tumour was induced in rats by subcapsular hepatic inoculations of HSN cells. At 20 days, 12.5 microns, 25 microns or 40 microns diameter, radiolabelled albumin microspheres were administered, in various concentrations, via the gastroduodenal artery. Tumour to normal liver microsphere distribution ratios were determined and median values ranged from 0.1 (0.2 mg ml-1 12.5 microns microspheres) to 1.8 (20 mg ml 40 microns microspheres). Concentrated suspensions (20 mg ml-1) of large microspheres (40 microns) produced the most favourable tumour to normal liver distribution ratios. These results not only have implications for the therapeutic administration of microspheres but also for their use in blood-flow studies.

Albumins↗
PubMed1991

Changes in hepatic haemodynamics in rats with overt liver tumour.

Overt liver tumour was induced in Fisher rats by intraportal administration of 1.6 x 10(7) Walker carcinosarcoma cells. Control groups of rats received similar volumes of dead cells or saline intraportally. All animals were studied at 3 weeks when overt tumour was present. The Hepatic Perfusion Index (HPI) was significantly raised in rats with overt tumour compared to both groups of control animals. Portal flow and portal venous inflow were significantly reduced in the presence of overt tumour but hepatic arterial flow did not alter. These observations suggest that the alteration in the HPI in the presence of overt tumour results from an alteration in portal venous flow and inflow even though the blood supply to the tumour is principally derived from the hepatic artery. The changes in hepatic haemodynamics in the presence of tumour were accompanied by a reduction in portal pressure, an increase in splanchnic vascular resistance and an increase in the degree of arteriovenous shunting through the liver. Portal vascular resistance was unchanged. These findings indicate that the presence of overt hepatic tumour results in gross derangements of hepatic blood flow. These changes must be taken into consideration when attempting to potentiate the delivery of cytotoxic drugs to hepatic tumour by manipulation of hepatic haemodynamics.

Animals↗
PubMed1991

Detection of hepatic metastases using duplex/color Doppler sonography.

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.

Adult↗
PubMed1991

Dynamic hepatic scintigraphy: the effect of using high administered activity on reproducibility of hepatic perfusion index value.

The hepatic perfusion index (HPI) may be of value in the detection of both overt and occult hepatic metastases in patients with colorectal carcinoma. Using the standard technique, the low counts obtained in each region of interest can produce statistical unreliability in the curve generation and render many studies unsuitable for analysis. In this study the effects of a high administered activity (400 MBq) on the inter- and intra-observer reproducibility of dynamic hepatic scintigraphy was investigated in 18 consecutive patients with colorectal cancer. All 18 patient studies were suitable for analysis by two observers. The correlation coefficient of measurements between observers was 0.98 (P less than 0.000 01 linear regression analysis), with a root mean square difference of replicate HPI measurements between observers of 0.045. The median range of HPI for four reprocessings by one observer was 0.035, with a maximum range of 0.11. Although high administered activity improves count statistics, for the individual patient study the activity used is not the major source of uncertainty in the derived HPI value.

Colorectal Neoplasms↗
PubMed1990

Ploidy as a prognostic indicator in end stage squamous cell carcinoma of the head and neck region treated with cisplatinum.

We measured tumour cellular DNA in 102 patients entered into two phase III trials of chemotherapy for end stage squamous carcinoma of the head and neck. The median survival of untreated patients with aneuploid tumours was 55 days compared with 224 days for patients treated with cisplatinum. This difference was highly significant. In contrast the median survival of untreated patients with diploid tumours was 74 days compared with 118 days for treated patients. Although this difference is statistically significant, the increased survival of 6 weeks is of no clinical benefit compared with the prolongation of survival of 6 months in patients with aneuploid tumours. Multivariate analysis showed that the significant predictors of survival were Karnofsky status, response to chemotherapy and ploidy.

Aged↗
PubMed1989

Changes in the hepatic perfusion index during the development of experimental hepatic tumours.

A model of microscopic liver tumour has been developed in the Fisher rat by intraportal injection of 1.6 x 10(7) Walker 256 carcinosarcoma cells. Rats were studied at 2, 4 and 6 days after the inoculation of live Walker cells. A control group received dead Walker cells. No tumour was visible in control groups at 2, 4 and 6 days after inoculation. Similarly in rats injected with live cells no tumour was visible at 2 days after inoculation but at 4 and 6 days the percentage hepatic replacement was (mean +/- s.d.) 7.0 +/- 2.3 and 27.9 +/- 6.80 respectively. The hepatic perfusion index was significantly raised at 4 and 6 days after inoculation of live cells compared with control animals and those receiving viable cells after 2 days inoculation. Portal flow and portal venous inflow were significantly reduced when the hepatic perfusion index increased but hepatic arterial flow did not alter. Changes in the hepatic haemodynamics were accompanied by increases in the portal and splanchnic vascular resistance and an increase in the amount of arteriovenous shunting through the liver. These findings confirm studies that the hepatic perfusion index is useful in the detection of occult liver metastases but that the change is not a consequence of an increase in the hepatic arterial flow.

Animals↗
PubMed1989

Effects of a somatostatin analogue (SMS 201-995) on the growth and development of hepatic tumour derived by intraportal injection of Walker cells in the rat.

Administration of a long active analogue of somatostatin, SMS 201-995 (2 micrograms subcutaneously twice a day) for 3 weeks after intraportal administration of Walker cells significantly inhibited their growth and development in the liver. This was not due to a direct cytotoxic effect of the analogue on Walker cells whose growth was stimulated in vitro. Furthermore, SMS 201-995 had no effect on the growth of Walker cells implanted into the thigh of rats suggesting that the inhibitory action of the analogue could be confined to tumour cells growing in the liver. Further studies suggested that the inhibitory effect of SMS 201-995 on the growth of Walker cells in the liver could be related to a marked stimulation of the hepatic reticuloendothelial system, by a reduction in portal venous flow in the early stages of treatment or by a combination of these effects. Further studies are required to delineate more precisely the mechanism whereby SMS 201-995 inhibits the growth of hepatic tumour derived from intraportal administration of Walker cells.

Animals↗
PubMed1989

Morphometric analysis, ploidy and response to chemotherapy in squamous carcinomas of the head and neck.

The histopathology of 54 squamous carcinomas of the head and neck was evaluated by qualitative grading and morphometry in order to identify those features which predicted a good response to cisplatinum chemotherapy. The histopathology of 66 cases was correlated with tumour ploidy, determined by flow cytometry of paraffin-embedded material, since a separate study has shown that aneuploid carcinomas respond better to chemotherapy. The degree of differentiation was a poor predictor of ploidy, although diploid carcinomas did show more keratin and less nuclear pleomorphism than aneuploid carcinomas. The prominence of nucleoli in tumour cells and the surface area to volume (s/v) ratio of the tumour islands were the variables most strongly correlated with ploidy, with diploid carcinomas having prominent nucleoli and a low s/v ratio. A good response to chemotherapy was related partly to the architecture of the carcinoma (pushing border and low s/v ratio), and partly to the tumour cells (well differentiated) and the percentage of necrotic tumour. A lack of inflammatory reaction or desmoplasia was associated with a poor response. The results indicate that both subjective and objective histopathological criteria may be used to predict ploidy and the response to cisplatinum chemotherapy of squamous carcinoma of the head and neck. A combination of s/v ratio and the percentage of necrotic tumour can be used to identify a group of patients with a relatively good survival.

Adult↗