Day surgery and gastroenterology.
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Ambulatory Surgical Procedures↗
Biomedical subjects
T G Cooke
Publications and source records attributed to T G Cooke.
An allelotype of squamous carcinoma of the head and neck using microsatellite markers.
The detection in tumors of genomic regions with a high frequency of loss of heterozygosity has led to the localization and subsequent cloning of a number of tumour suppressor genes. To identify such regions involved in the development of squamous carcinoma of the head and neck we have analyzed 28 paired normal and tumor DNA samples. Using the polymerase chain reaction to amplify 50 simple sequence repeats or microsatellite markers we have studied all 22 q limbs and 17 of the p limbs in 21 patients. In informative cases we observed a high incidence of loss of heterozygosity at five specific chromosomal regions: 3p (44%); 5q (43%); 9q (35%); 11q (45%); and 17p (31%). In addition, further analysis of tumors showing loss of heterozygosity at 5q suggests that a gene at or near the APC locus is involved in squamous carcinoma of the head and neck.
Carcinoma, Squamous Cell↗
Polymorphism at the tumour necrosis factor locus: a marker of genetic predisposition to colorectal cancer?
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Alleles↗
Prognostic value of ploidy of primary tumour and nodal secondaries in colorectal cancers.
Tumour ploidy is of prognostic value in colorectal cancer, DNA aneuploid tumours having a worse outlook. Nearly all studies have concentrated on the DNA content of the primary tumour. We have examined the ploidy of the primary tumour and its lymph node metastases in 71 cases of Dukes' stage C disease, to see whether this provides greater prognostic information than the primary alone. Analysis was performed using formalin-fixed, paraffin-embedded tumour sections. Ploidy of primary and metastases was different in 20 cases (28%), aneuploid nodes being seen with diploid primaries and vice versa. Ploidy of both the primary (chi 2 = 4.86, P = 0.03) and secondary (chi 2 = 4.86, P = 0.03) tumours predicted survival in univariate analysis. Combining the ploidy of primary and nodes, three prognostic groups could be defined--diploid primaries with diploid metastases (hazard relative to both aneuploid, 0.36) had significantly better survival than cases where the ploidy of the primary and nodes were mixed (relative hazard 0.47-0.56), which did better than cases with aneuploid primary and nodes. This study demonstrates that ploidy variation between primary and secondary tumours is common, and better prognostic information may be gained by studying both.
Aneuploidy↗
A comparison of cellular proliferation markers in squamous cell carcinoma of the head and neck.
Head and neck squamous cell carcinoma has a relatively good prognosis but treatment may be at the expense of function and quality of life. Various host and tumour parameters have been studied in an attempt to predict the course of the disease but without success. It has been hoped that laboratory based methods, particularly those based on molecular biology, may prove more useful. Cell kinetic parameters are studied in this paper. The present study includes 75 patients with a proven squamous cell carcinoma of the head and neck at various sites and undergoing various forms of treatment. The patient's mean age was 62 years and the median survival rate 45 months. Immunohistochemical techniques using Ki67 and PCNA were compared with flow cytometric analysis which included the BRDU labelling index, the duration of S phase, ploidy and potential doubling time. The median PCNA index was 560 and the Ki67 index 298. These indices varied between 980 and 150 for PCNA and 808 and 110 for Ki67. The BRDU labelling index measured by flow cytometry was 8.9 with a range from 25 to 1.6 and the duration of S phase was 14.8 hours. The PCNA index failed to correlate with any host or tumour factors and this failure was also seen in Ki67 indices and also in the flow cytometric parameters. There was a strong correlation between PCNA and Ki67 expression (p < 0.0001). Neither PCNA nor Ki67 values were significantly different between irradiated and nonirradiated tissues nor in sites or in patients who later developed lymph node metastases.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Prospective evaluation of cell kinetics in head and neck squamous carcinoma: the relationship to tumour factors and survival.
Tumour growth rates were measured in 105 patients using in vivo incorporation of bromodeoxyuridine (BrdU) and investigated for any relationship to tumour factors or survival. The median labelling index (LI) was 8.7%, the duration of S-phase (Ts) was 14 h and the potential doubling time (Tpot) was 5.9 days. The labelling index in aneuploid tumours was significantly higher than that in diploid tumours. However the total labelling index (TLI) did not differ significantly between aneuploid and diploid tumours, and so it would seem likely that the difference in LI is due to the dilutional effect of benign tissue upon the calculation of LI in diploid tumours. The total labelling index, duration of S-phase and potential doubling time were not related to the tumour factors examined (site, T stage, N stage, stage grouping). Interim survival analysis was carried out and there was no difference in survival between those patients with high values for TLI, Ts, and Tpot and those with low values.
Adult↗
Splanchnic blood flow changes in the presence of hepatic tumour: evidence of a humoral mediator.
Intrahepatic tumour is associated with alterations in splanchnic haemodynamics. To investigate the hypothesis that these are the result of a circulating vasoactive agent, rat small bowel segments were cross-perfused with arterial blood from groups (n = 12) of paired tumour-bearing (intrahepatic HSN sarcoma) and control rats. The vascular resistance of the segment was significantly greater during perfusion by tumour-bearing animals (91.6 mmHg ml-1 min, s.e. 21.5, vs 51.7 mmHg ml-1 min, s.e. 7.4, P < 0.05), suggesting that intrahepatic tumour may be associated with a circulating vasoactive agent. A similar mechanism may underlie changes in the hepatic perfusion index in patients with liver metastases.
Animals↗
A phase II study of regional 5-fluorouracil infusion with intravenous folinic acid for colorectal liver metastases.
Regional chemotherapy, delivered via the hepatic artery, may significantly increase tumour response rates in patients with colorectal liver metastases. However, survival is limited by extrahepatic disease progression. We have developed a novel therapeutic approach for patients with metastases confined to the liver. In order to achieve high local response rates and also inhibit extrahepatic progression, 5-fluorouracil (5-FU) was infused intra-arterially at a dose previously calculated to achieve both high-dose regional therapy and adequate systemic levels. To enhance efficacy further, 5-FU was combined with high-dose systemic folinic acid (FA). Thirty-one patients were evaluated in a phase II study. 5-FU (1.5 g m2) was infused via a surgically implanted hepatic artery catheter over a 24 h period; FA (total 400 mg m-2) was infused intravenously during the initial and final 2 h. Treatments were given weekly for cycles of 6 weeks' duration. To date, median duration of treatment is 6 months and the median follow-up period is 17 months. The overall response rate was 48% with two complete and 13 partial responses. Predicted median time to progression is 8 months. The site of first progression was hepatic in 10 (42%) and extrahepatic in 14 (58%) patients. Seven patients developed local complications; one required emergency surgery. Side-effects were limited to grade 3 toxicity (four patients) or less. Predicted median survival is 19 months. This approach, which is associated with a high response rate and low systemic toxicity, warrants further evaluation. A phase III study is planned.
Adult↗
Comparison of the Doppler perfusion index and intraoperative ultrasonography in diagnosing colorectal liver metastases. Evaluation with postoperative follow-up results.
OBJECTIVE: The authors compared the accuracy of intraoperative ultrasound with the Doppler perfusion index (DPI) in the detection of occult liver metastases. SUMMARY BACKGROUND DATA: Intraoperative ultrasound is well recognized to be very sensitive in the detection of small liver tumors. Previous studies using duplex/color Doppler sonography have shown that the measurement of the DPI (hepatic arterial to total liver blood flow ratio) can detect the presence of occult colorectal liver metastases. METHODS: Intraoperative ultrasound and DPI were evaluated in 90 patients with colorectal cancer with apparently disease-free livers (on the basis of computed tomography scans and laparotomies). All patients subsequently were observed for follow-up with 3 monthly clinical examinations, ultrasound scans, and yearly computed tomography scans. RESULTS: Intraoperative ultrasound detected liver metastases in 4 of the 23 patients who subsequently developed overt liver metastases during 1-year follow-up. However, DPI predicted the development of hepatic metastases in all 23 cases. CONCLUSION: The results suggest that DPI is more sensitive than intraoperative ultrasound in the early detection of occult colorectal liver metastases. The Doppler technique can identify patients at high risk, suitable for adjuvant therapy. The routine use of intraoperative ultrasound in screening for occult colorectal liver metastases is not recommended.
Adult↗
An improved method for semiquantification of gene amplification from archival material.
A differential PCR-based assay is presented that increases the accuracy of quantification of C-erbB-2 gene-copy number in DNA extracted from archival tumors. The C-erbB-2 gene is amplified in a high percentage of human adenocarcinomas arising at numerous sites, including breast, lung, and stomach. A number of studies have correlated C-erbB-2 with poor prognosis. Gene copy number may be relevant in identifying patients with different clinical outcomes. In this study a target gene and a single copy reference gene were coamplified in the same reaction tube. The level of target gene amplification was reflected by the ratio of the two resulting PCR products. Cell lines exhibiting variable copies ranging from 1 to > 8 of the C-erbB-2 gene were used as quality controls. This technique can reliably show a single copy difference between cell lines and can be used to semiquantitatively estimate gene copy number in DNA extracted from archival paraffin-embedded samples.
Adenocarcinoma↗
Flow cytometric analysis of DNA content in squamous carcinoma of the tongue: the relationship to host and tumour factors and survival.
Cellular DNA content has been found to be an important prognostic factor in many human tumours, yet within the head and neck region few studies have examined its effect on survival and in those that have, findings differ. Eighty-one consecutive patients with squamous carcinoma of the tongue mainly treated by surgery and post-operative radiotherapy were studied. The DNA content of archival paraffin embedded tumours was measured by flow cytometry. Fifty-seven tumours were diploid and 24 were aneuploid. There was no association between ploidy status and age, sex, tumour size or nodal status. Ploidy status was not related to survival. These findings indicate that analysis of tumour DNA content in squamous carcinoma of the tongue does not provide any additional prognostic information for the individual patient.
Aneuploidy↗
Stercoral perforation with verapamil.
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Aged↗
Localization of EGF receptors in frozen tissue sections by antibody and biotinylated EGF-based techniques.
We developed a sensitive EGF receptor detection method for frozen tissue sections using biotinylated EGF as the primary reagent. The method was directly compared with an immunohistochemical technique based on an anti-EGF receptor monoclonal antibody (MAb EGFR1) in normal human and rat tissues and in human tumors. The method was more sensitive than a previously published biotinylated EGF-based technique. In normal human tissues and in 37 of the 50 tumors, the binding pattern mirrored that of positive staining with EGFR1. Five further tumors showed weak immunoreactivity, but in these no binding of biotinylated EGF was detected. The remaining eight tumors were negative by both techniques. The discordant cases may reflect a lower level of sensitivity of the ligand-binding technique or, alternatively, abnormal receptors may have been expressed in these tissues. EGF receptors could be detected in rat liver with biotinylated EGF but not with the antibody, indicating the usefulness of the ligand-based technique in cross-species studies.
Animals↗
Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer.
Current studies of tumor angiogenesis rely on the concept that endothelium proliferates 30-40 times faster in tumors than in normal tissues. This evidence is based on histological autoradiographic data largely from animal studies. To assess endothelial cell proliferation in human cancer we used the more sensitive and specific technique of immunohistochemistry. We measured the frequency and distribution of endothelial cell proliferation and examined their relationship to tumor cell proliferation. For the first time, we also correlated endothelial and tumor cell proliferation with tumor vascularity. Twenty breast carcinomas from patients exposed to bromodeoxyuridine 3-8 h prior to surgery were double immunostained using antibodies to CD31 (as a marker of endothelium) and bromodeoxyuridine (as a marker of proliferation). The labeling index (LI) for both tumor and endothelial cells was determined and tumor vascularity was assessed by counting the number of CD31 positive vessels. Endothelial cell proliferation was predominantly at the tumor periphery while tumor cell proliferation occurred throughout the lesion. The mean LIs for endothelium and tumor were 2.2% (range, 0.8-5.3) and 7.3% (range, 1.3-17.1), respectively. There was no correlation between tumor and endothelial cell LI (P = 0.414) or between the tumor LI or endothelial cell LI and tumor vascularity (P = 0.08 and P = 0.39, respectively). These findings suggest that previous studies in animal tumors have significantly overestimated endothelial cell proliferation and that its importance in tumor angiogenesis may be related more to continual remodeling and migration of vessels than to proliferation alone.
Adult↗
Changes in liver blood flow associated with the growth of hepatic LV10 and MC28 sarcomas in rats.
Abnormalities in liver blood flow are known to occur in patients and animals with overt hepatic tumour. This study investigated the changes in liver blood flow associated with the development of overt hepatic tumour in two different models. Hepatic tumour was induced by intraportal inoculation of either 300 LV10 sarcoma cells or 10(5) MC28 sarcoma cells in rats. Liver blood flow and hepatic haemodynamics were measured 3 weeks later when overt liver tumour was present. The hepatic perfusion index (HPI), the ratio of hepatic arterial to total liver blood flow, was raised and portal venous inflow reduced in rats with LV10 tumours, but not in those with MC28 lesions. Hepatic arterial flow was unchanged in LV10 tumours when the HPI was raised and neither model demonstrated arteriosystemic or portosystemic shunting. The changes in portal venous inflow were associated with a significant increase in portal and splanchnic vascular resistance. These studies suggest that liver blood flow changes in the presence of overt hepatic tumour are not related to portal venous obstruction but may be caused by a circulating splanchnic vasoconstrictor.
Animals↗
Early detection of occult colorectal hepatic metastases using duplex colour Doppler sonography.
Previous studies have shown that overt intrahepatic tumours are associated with subtle changes in liver perfusion that can be measured directly using duplex colour Doppler sonography (DCDS). This study assessed the predictive value of DCDS in the early detection of occult colorectal hepatic metastases. Hepatic arterial and portal venous blood flow was measured in 50 control subjects and 135 patients with colorectal cancer, 67 with overt liver metastases and 68 with an apparently disease-free liver on the basis of computed tomography and laparotomy findings. The Doppler perfusion index (DPI), defined as the ratio of hepatic arterial to total liver blood flow, was calculated. Clear separation of the DPI values of controls and those of patients with overt metastases was observed (P < 0.0001). Thirty-eight of the 68 patients with a disease-free liver also had an abnormally high DPI value. After 1 year of follow-up, 21 patients with an abnormally high DPI at the time of apparently curative primary resection had developed liver metastases and a further four had died without post-mortem examination. The 30 patients with normal DPI remain disease-free. The data suggest that DPI is of value in the early detection of occult liver metastases.
Adult↗
Image-directed Doppler ultrasonography: a novel technique for the diagnosis of colorectal liver metastases.
Image-directed Doppler ultrasonography has been used to measure changes in hepatic arterial and portal venous blood flows in 22 controls and 88 patients with colorectal cancer. Doppler Perfusion Index, (DPI, ratio of hepatic arterial to total liver blood flow) and Doppler Flow Ratio (DFR, ratio of hepatic arterial to portal venous blood flow) of controls and patients with overt liver metastases were clearly separated (p < 0.0001). There was a significant reduction in the Hepatic Arterial Resistive Index (HARI) of patients with overt liver metastases (p < 0.0001). Percentage Hepatic Replacement (PHR) by metastases, measured using a computed tomography scanner, did not correlate with DFR or DPI. The results suggest that the measurement of hepatic perfusion changes using image-directed Doppler ultrasonography may be of value in the detection of small liver metastases.
Adult↗
Hepatic arterial haemodynamics changes following intra-arterial angiotensin II infusion: duplex/colour Doppler sonography.
Previous studies have shown that the delivery of cytotoxic microspheres to liver tumours may be improved by manipulating the tumour to normal liver blood flow ratio using angiotensin II (AT-II). The optimization of this targeting requires the assessment of the temporal blood flow changes induced by agents such as AT-II. Duplex/colour Doppler sonography (DCDS) was evaluated as a means of studying the effects of AT-II infusion on hepatic arterial blood flow (HABF) and arterial resistance in patients with colorectal liver metastases. HABF was measured continuously in six patients with colorectal liver metastases using DCDS before, during and after an infusion of AT-II (15 micrograms in 3 ml of saline over 90 s) via a hepatic artery catheter. The baseline level of HABF was 320 +/- 87 ml/min (mean +/- S.D.), and this was reduced by 70-76% within 30 s of the start of AT-II infusion. HABF recovered rapidly from the end of the infusion, and increased by up to 20% above the baseline for approximately 2 min. Arterial resistance showed reciprocal changes in all cases. These changes were both quantitatively and qualitatively similar to intra-operative measurements previously performed in the same patients using a standard intra-operative flowmeter. The degree of concordance obtained from the intra- and post-operative measurements confirms the effectiveness of DCDS in assessing the temporal changes in hepatic arterial blood flow caused by AT-II. Prior to the start of therapy, the evaluation of vasoconstrictor agents should be carried out in individual patients to predict response, in order to establish the optimal phase for the injection of cytotoxic microspheres.
Aged↗