Outcome predictors in acute surgical admissions for lower gastrointestinal bleeding.

AIM: The BLEED criterion is a triaging model for lower gastrointestinal bleeding (LGIB), which was developed and validated in the USA. We assessed the BLEED criteria in a UK population and aimed to elucidate factors that can be implemented for early risk stratification. METHOD: Patients were identified from a prospectively maintained surgical admission database at a central London teaching hospital. Data were collected on 26 clinical factors available on initial presentation. The primary-outcome end-points included severe bleeding (persistent bleeding within the first 24 h, blood transfusion, a decrease in haematocrit of ≥ 20% or recurrent bleeding after ≥ 24 hours of stability) and adverse outcome (emergency surgery to control bleeding, intensive care unit [ITU] admission or death). RESULTS: One hundred and eighty-four clinical episodes were identified, representing 3% of all surgical referrals. Twelve patients with upper gastrointestinal bleeding were excluded. Severe bleeding occurred in 110 (64%) patients. An adverse outcome was recorded in 20 (11.6%) patients, and 10 (5.4%) patients died during admission. The commonest aetiologies were diverticular disease, haemorrhoids and malignancy. Four prognosticators of adverse outcome were identified, these being: creatinine > 150 µm (P = 0.002); age > 60 years (P = 0.001); abnormal haemodynamic parameters on presentation (P = 0.05); persistent bleeding within the first 24 h (P = 0.05); and area under the receiver-operating characteristics curve (AUC) = 0.79. The BLEED criteria were shown to be nonpredictive (AUC = 0.60). CONCLUSION: The BLEED criterion was not shown to have any predictive value in this patient cohort. Our study has determined an independent set of prognostic factors that could be incorporated into initial triaging of patients presenting with LGIB. This may facilitate the early identification of patients requiring more aggressive resuscitation, admission to a monitored bed and consideration for early radiological or surgical intervention.

A comparison of the effect of different surgical gloves on objective measurement of fingertip cutaneous sensibility.

INTRODUCTION: The prudent selection of surgical gloves can deliver significant efficiency savings. However, objective data are lacking to compare differences in cutaneous sensibility between competing gloves. Therefore, the present study examined the use of a single comparable model of sterile surgical glove from two competing providers, Gammex PF HyGrip(®) (Ansell Limited, Red Bank, NJ, USA) with Biogel(®) (Mölnlycke Health Care AB, Göteborg, Sweden). SUBJECTS AND METHODS: Cutaneous pressure threshold, static and moving two-point discrimination were measured as indices of objective surgical glove performance in 52 blinded healthcare professionals. RESULTS: The mean cutaneous pressure threshold was 0.0680 ± 0.0923 g for skin, 0.411 ± 0.661 g for Ansell gloves and 0.472 ± 0.768 g for Biogel gloves. Skin was significantly more sensitive than Ansell (P < 0.0001) or Biogel (P < 0.0001) gloves (Wilcoxon signed rank test). There was no statistical difference between Biogel and Ansell gloves (P = 0.359). There was no significant difference between static or moving 2-point discrimination of skin and Ansell gloves (P = 0.556, P = 0.617; Wilcoxon signed rank test), skin and Biogel gloves (P = 0.486, P = 0.437; Wilcoxon signed rank test) or Ansell and Biogel gloves (P = 0.843, P = 0.670; Wilcoxon signed rank test). CONCLUSIONS: No demonstrable objective difference was found between competing gloves in the outcome measures of cutaneous sensibility and two-point discrimination. However, a difference in subjective preference was noted. Untested factors may underlie this discrepancy, and further research should employ more sophisticated measurements of surgical performance using competing models of surgical glove.

Minichromosome maintenance protein 2 (MCM2) is a stronger discriminator of increased proliferation in mucosa adjacent to colorectal cancer than Ki-67.

BACKGROUND: Loss of control of mucosal crypt cell proliferation resulting in a hyperproliferative field change occurs early in the adenoma-carcinoma sequence. Ki-67, the current gold-standard marker of cellular proliferation, is a cell cycle protein that may lack sensitivity in demonstrating altered mucosal crypt cell dynamics. Minichromosome maintenance protein 2 (MCM2) has a specific role in DNA replication and has been proposed as a new marker for screening for colorectal cancer. AIM: To compare the expression of Ki-67 with that of MCM2 in colorectal mucosa associated with colorectal cancer. METHODS: Ki-67 and MCM2 immunostaining was performed on serial sections taken from formalin-fixed, paraffin-embedded specimens. Labelling indices were calculated by counting the proportion of positively stained nuclei in representative areas of adenocarcinoma, and in equivalent superficial, middle and basal crypt compartments of mucosa sampled 1 cm from tumour (Ca1) and 10 cm from tumour (Ca10). RESULTS: Specimens were obtained from 43 patients (27 adenocarcinoma, 16 no-cancer controls). Most nuclei in specimens of adenocarcinoma stained positively for MCM2 and Ki-67. In Ca1 and Ca10 samples, significantly greater staining of MCM2 than Ki-67 was seen in all crypt compartments. Receiver operator characteristic curve analysis suggested that proliferation changes (assessed by either MCM2 or Ki-67 staining) in Ca10, but not in Ca1, mucosa significantly predicted origin from a carcinoma-associated colon. CONCLUSIONS: MCM2 was more sensitive than Ki-67 in identifying colorectal mucosal proliferation. Increased proliferation (assessed by either MCM2 or Ki-67 staining) in mucosa at 10 cm, but not at 1 cm, from carcinoma significantly predicted origin from a carcinoma-associated colon.

Role of circulating tumour cells in predicting recurrence after excision of primary colorectal carcinoma.

BACKGROUND: This study assessed the potential for reverse transcriptase-polymerase chain reaction (RT-PCR)-based circulating tumour cell identification to predict colorectal cancer recurrence. METHODS: mRNA for carcinoembryonic antigen and cytokeratin 20 was identified by RT-PCR in blood from patients with colorectal cancer, before and after primary tumour resection. Cancer recurrence was assessed at follow-up, and the accuracy of RT-PCR and primary tumour lymph node positivity in predicting recurrence was estimated. RESULTS: One hundred and ninety-six patients with colorectal cancer were studied over a median follow-up of 1393 days from surgery. Regression analysis selected 24-h post-resection RT-PCR positivity (hazard ratio for a positive test in predicting recurrence 8.66 (95 per cent confidence interval (c.i.) 3.08 to 24.33)) before lymph node involvement (hazard ratio 7.92 (95 per cent c.i. 3.26 to 19.20)). When 24-h post-resection RT-PCR was combined with lymph node positivity, the hazard ratio increased to 18.54 (95 per cent c.i. 4.01 to 85.11), attributing a 3 per cent recurrence risk to 52 per cent, and a 50 per cent recurrence risk to 48 per cent, of patients with colorectal cancer resected with curative intent. CONCLUSION: RT-PCR positivity within 24 h of primary colorectal cancer resection is a strong predictor of colorectal cancer recurrence, and may be useful clinically.

A "field change" of inhibited apoptosis occurs in colorectal mucosa adjacent to colorectal adenocarcinoma.

BACKGROUND: Colorectal cancer is associated with a "field change" of increased proliferation throughout the colonic and rectal mucosa. Both proliferation and apoptosis are disrupted during carcinogenesis. Whether altered apoptosis contributes to this field change of microscopic abnormality is, however, unclear. Bcl-xL is an anti-apoptotic protein that inhibits apoptosis by preventing release of cytochrome c, a recognised pathway to cell death. AIM: To determine whether Bcl-xL inhibition of apoptosis is increased in colorectal mucosa adjacent to colorectal adenocarcinoma over that in normal non-neoplastic colorectal mucosa. PATIENTS: PATIENTS undergoing surgical resection for neoplastic (adenocarcinoma) or non-neoplastic disease of the colorectum (rectal prolapse, diverticular disease or volvulus). METHODS: Formalin-fixed, paraffin-wax-embedded surgical colorectal resection specimens were immunostained for Bcl-xL protein. Labelling indices were determined by counting the proportion of positively stained cells in mucosal crypts. RESULTS: 85 patients were studied. Bcl-xL immunostaining was most marked in the upper third of mucosal crypts. It occurred in a minority of samples from non-neoplastic colorectal mucosa, but was seen in most mucosal samples adjacent to colorectal adenocarcinoma. Significant increases (p<0.001) were observed in Bcl-xL labelling indices in the mucosa at 1 cm (n = 46, median labelling index 31.8%, interquartile range 8.3-43.9%) and at 10 cm (n = 52, median labelling index 22.0%, interquartile range 0.0-36.3%) from colorectal carcinoma, compared with normal, non-neoplastic colorectal mucosa (n = 22, median labelling index 0.0%, interquartile range 0.0-0.0%). CONCLUSIONS: The findings are consistent with a field change of inhibited apoptosis in mucosa adjacent to colorectal carcinoma.

Immune responses in advanced colorectal cancer following repeated intradermal vaccination with the anti-CEA murine monoclonal antibody, PR1A3: results of a phase I study.

BACKGROUND AND AIMS: The aim was to determine the toxicity, clinical and immune responses to the murine monoclonal anti-carcinoembryonic antigen (CEA) antibody, PR1A3, in patients with advanced colorectal cancer. MATERIALS AND METHODS: Fifteen patients with advanced colorectal cancer received either 0.5-, 1.0- or 5.0-mg doses of PR1A3 mixed with 10% w/v Alum adjuvant (Superfos Biosector, Denmark) intradermally at 4-week intervals for 3 months. Patient serum was assessed for anti-idiotypic (Ab2), anti-anti-idiotypic (Ab3) and human anti-mouse antibody (HAMA) reactivity. Peripheral blood mononuclear cell (PBMC) proliferation with phytohaemagglutinin (PHA), CEA and PR1A3, stimulated IL-2, IL-4 and IFN-gamma levels and PR1A3-stimulated IL-2 receptor expression during immunotherapy were determined. Comparisons were made with 16 age-matched controls without malignant disease. RESULTS: Hyperimmune sera from 12 of the 15 patients showed Ab2 reactivity with no detectable Ab3 responses. Strong HAMA reactivity was recorded in 7 of the 15 cases with no adverse clinical effect. Delayed-type hypersensitivity (DTH) responses developed in 12 of the 15 patients. Pre-treatment PBMC proliferation with PHA was subnormal in each patient compared with controls, becoming normal (or supranormal) in all patients during immunisation (P<0.001). PBMC proliferation with CEA and PR1A3 increased during immunotherapy (P<0.001) along with stimulated production of IL-2, IFN-gamma and IL-2 receptor expression. Progressive disease was observed in 14 of the 15 patients with minimal toxicity. CONCLUSION: PR1A3 generated limited idiotypic responses but robust DTH reactivity in most patients. In vitro PBMC proliferation with mitogens and recall antigens is greatly increased during the course of immunisation, with a shift in stimulated cytokine profile.

The value of anal cytology and human papillomavirus typing in the detection of anal intraepithelial neoplasia: a review of cases from an anoscopy clinic.

BACKGROUND: Previous studies have reached differing conclusions about the utility of anal cytology as a screening tool for anal intraepithelial neoplasia (AIN). There is a need also to establish whether HPV typing offers a useful adjunct to screening. METHODS: We analysed data from 99 consecutive homosexual/bisexual male patients (89 HIV-1 positive) who underwent high resolution anoscopy. Follow up visits for these patients were also included, giving a total of 160 anoscopic procedures. Comparison was made between results of anal cytology using the sampling method of Palefsky, and histological findings of biopsies taken from abnormal areas seen on high resolution anoscopic examination of the anal canal. Swabs taken concurrently with the cytology were analysed for the presence of human papillomavirus (HPV) DNA and compared with the cytological and histological findings. RESULTS: The sensitivity of the cytology was 83%, and the specificity 38% when compared with histology. At screening of 34 asymptomatic men, 83% had anal cytological dysplasia and 78% had AIN. There were no significant differences in the prevalence of hrHPV genotypes between different cytological or histological grades of abnormalities. CONCLUSION: Anal cytology by the Palefsky method is simple to undertake, has a sensitivity and specificity comparable with cervical cytology, and can therefore be used as the basis of a pilot screening project in centres with large cohorts of HIV positive homosexual men who have a high risk of developing anal carcinoma. HPV genotyping is not a useful adjunct to cytological screening.

Epidural analgesia in gastrointestinal surgery.

BACKGROUND: The ideal perioperative analgesia should provide effective pain relief, avoid the detrimental effects of the stress response, be simple to administer without the need for intensive monitoring, and have a low risk of complications. METHODS: This review defines the physiological effects of epidural analgesia and assesses whether the available evidence supports its preferential use in gastrointestinal surgery. All papers studied were identified from a Medline search or selected by cross-referencing. RESULTS: Epidural analgesia is associated with a shorter duration of postoperative ileus, attenuation of the stress response, fewer pulmonary complications, and improved postoperative pain control and recovery. It does not reduce anastomotic leakage, intraoperative blood loss, transfusion requirement, risk of thromboembolism or cardiac morbidity, or hospital stay compared with that after conventional analgesia in unselected patients undergoing gastrointestinal surgery. Thoracic epidural analgesia reduces hospital costs and stay in patients at high risk of cardiac or pulmonary complications. CONCLUSIONS: Epidural analgesia enhances recovery after gastrointestinal surgery. The results support the development of structured regimens of early postoperative feeding and mobilization to exploit the potential for thoracic epidural analgesia to reduce hospital stay after gastrointestinal surgery.

Increased serum transforming growth factor-beta1 in human colorectal cancer correlates with reduced circulating dendritic cells and increased colonic Langerhans cell infiltration.

Cancer-related cytokines may interfere with the differentiation and migration of dendritic cells (DCs) and with the associated up-regulation of co-stimulatory molecules in vitro. We determined whether cytokines affected the distribution and activation of DCs in patients with colorectal cancer by measuring the levels of serum cytokines [transforming growth factor (TGF)-beta1 and vascular endothelial growth factor (VEGF)], DC numbers and phenotype from peripheral blood and mesenteric lymph nodes draining the cancer, and the infiltration of DCs into colorectal cancer. A significant increase in the serum level of TGF-beta1 correlated with a significant reduction in the level of circulating DCs in cancer patients that was associated with an increased infiltration of Langerhans cells into colorectal mucosa. The prevalence but not intensity of co-stimulatory molecule expression in circulating and mesenteric lymph node DCs was reduced in patients with colorectal cancer compared to patients with inflammatory bowel conditions. There was no correlation between co-stimulatory molecule expression and serum TGF-beta1. Thus the circulating DC depletion in colorectal cancer could be explained by a TGF-beta1-related DC redistribution from the circulation into the colorectal cancer and adjacent mucosa where DC levels were increased. There was an impairment of DC activation within colorectal cancer that was not related to serum level of cytokines.

Pelvic connective tissue resilience decreases with vaginal delivery, menopause and uterine prolapse.

BACKGROUND: The late onset of pelvic visceral prolapse and incontinence after childbirth injury could be explained by menopause-associated connective tissue weakening. Uterosacral ligament resilience (UsR) was assessed to determine whether it influenced uterine or pelvic floor mobility, or varied with age, vaginal delivery, menopause or histological variations in the ligament. METHODS: UsR was measured by tensiometry in ligaments from 85 hysterectomy specimens, and was correlated with the presence of symptomatic uterocervical prolapse, prehysterectomy uterine and anorectal mobility, patient age, history of vaginal delivery and menopause. Forty-five of these ligaments were examined for ligament thickness, muscle to collagen ratio, and oestrogen and progesterone receptor density. The results were correlated with UsR. RESULTS: UsR was significantly reduced (P = 0.02) in symptomatic uterovaginal prolapse, but there was no correlation with either uterocervical or anorectal descent in women without symptomatic prolapse. There was a significant decrease in UsR with vaginal delivery (P = 0.003), menopause (P = 0.009) and older age (P = 0.005). The uterosacral ligament was significantly thinner and contained fewer oestrogen and progesterone receptors after menopause, but this did not affect UsR. CONCLUSION: Where pelvic floor muscles are weakened, decreases in pelvic connective tissue resilience related to the menopause may facilitate progression to symptomatic pelvic visceral prolapse.

Flow cytometry correlates with RT-PCR for detection of spiked but not circulating colorectal cancer cells.

The aim of this study was to determine whether flow cytometry (FACS) could detect spiked or circulating colorectal cancer cells. A flow cytometric assay was developed and its sensitivity compared with the reverse transcription polymerase-chain reaction (RT-PCR), using carcinoembryonic antigen (CEA) and cytokeratin (CK) 20 mRNA as target markers. Sensitivity limits for RT-PCR and flow cytometry (FACS) were established using spiked blood, and pre-operative blood samples from 20 colorectal cancer patients and 16 healthy no-cancer controls were analysed for circulating tumour cells (CTC) using both methods. Blood samples for FACS analysis were immuno-magnetically enriched using ferrofluid particles. CTC were defined as positive for pan-cytokeratin and negative for CD45 pan-leucocyte antigen (CK+/CD45- events). There was a significant (P < 0.0001) correlation between the number of spiked cancer cells and their recovery using FACS. The lowest detectable concentration was 20 spiked cancer cells in 14 ml blood for both RT-PCR and FACS. A positive FACS result significantly (P < 0.05) concurred with a positive RT-PCR result in spiked blood. The number of CK+/CD45- events detected in the blood of colorectal cancer patients was not significantly greater (P = 0.07) than in blood taken from 'no cancer' controls and furthermore there was no concordance (P = 1) between RT-PCR and FACS positivity in cancer patients' blood. FACS detection of tumour cells was feasible in vitro, and correlated with RT-PCR. However, its sensitivity in vivo was poor and did not correlate with RT-PCR detection of CTC. Uncertainties about antigen expression on normal circulating cells and about CTC phenotype need to be resolved, before FACS can be developed for detection of tumour cells within the circulation.

Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer.

Cancer-related indoleamine (2,3)-dioxygenase up-regulation by interferon-gamma might influence quality of life by depleting serum tryptophan. We correlated serum tryptophan levels with immune activation and quality of life in patients with colorectal liver metastases. Venous blood was sampled from patients with primary colorectal cancer and from patients with metachronous colorectal liver metastases who completed quality of life and psychological questionnaires. Serum tryptophan, kynurenine, neopterin, interleukin 2 soluble receptor alpha (IL-2 sRalpha), soluble tumour necrosis factor receptor I (sTNF RI), interleukin 6, and C-reactive protein were measured. Liver metastasis volume was estimated by computerised tomography, and survival from blood sampling was noted. Sixty-six patients with colorectal cancer were studied (39 males; median age 66 years) of whom 25 had colorectal liver metastases only (17 males; median age 62 years; median liver metastasis volume 208 ml; median survival 234 days). Reduced serum tryptophan was significantly associated with Rotterdam Symptom Checklist physical symptom (r=-0.51, P=0.01) and Sickness Impact Profile (r=-0.42, P=0.04) scores, and correlated with increased serum neopterin (r=-0.36, P=0.003), IL-2 sRalpha (r=-0.51, P=0.01) and sTNF RI (r=-0.45, P=0.02) levels. Stepwise regression analyses suggested that serum tryptophan was an independent predictor of Rotterdam Symptom Checklist physical symptom (regression coefficient -20.78, P=0.01) and Sickness Impact Profile (regression coefficient -109.09, P=0.04) scores. The results supported a role for interferon-gamma-mediated serum tryptophan decrease in cancer-induced quality of life deterioration.

Accuracy of investigations for asymptomatic colorectal liver metastases.

PURPOSE: The aim of this study was to prospectively assess the accuracy of the most promising imaging and tumor marker tests in liver metastasis diagnosis on follow-up of asymptomatic colorectal cancer patients during a median of 57 months after primary tumor resection. METHODS: One hundred patients, who were considered free of liver metastases after primary colorectal cancer resection and conventional follow-up, were screened for liver metastases by computerized tomography, magnetic resonance and ultrasound scans, ultrasound Doppler and isotope assessment of changes in hepatic arterial and portal venous flow, and serum estimation of carcinoembryonic antigen. Patients were followed up during a median of 41 months to identify those who developed liver metastases. RESULTS: The most sensitive technique was computerized tomography (sensitivity 0.67, specificity 0.91). Computerized tomography and magnetic resonance but not ultrasound were 100 percent accurate in differentiating liver metastases from other hepatic lesions. Techniques based on changes in hepatic arterial and portal venous flow had lower diagnostic accuracies (Doppler perfusion index, sensitivity 0.58, specificity 0.57; hepatic perfusion index, sensitivity 0.50, specificity 0.55), whereas ultrasound scanning identified only 43 percent (sensitivity 0.43, specificity 0.96) and serum carcinoembryonic antigen 33 percent (sensitivity 0.33, specificity 0.81) of patients with asymptomatic liver metastasis. Sensitivity could be improved by using tests in combination but this reduced specificity. CONCLUSIONS: Computerized tomography was the most sensitive test for asymptomatic colorectal liver metastases, but only 67 percent of affected patients were identified.

Phase I study of percutaneous cryotherapy for colorectal liver metastasis.

BACKGROUND: The aim was to determine the safety and feasibility of percutaneous cryotherapy for treating irresectable colorectal liver metastases. METHODS: Liquid nitrogen cryoprobes were inserted percutaneously into metastases using the Seldinger technique under computed tomographic guidance. Single-probe treatments were performed with either 3.6- or 6.3-mm cryoprobes (ice-ball volumes 18 and 59 cm3 respectively), or dual-probe treatments with two adjacent 6.3-mm probes (ice-ball volume 205 cm3). Treatment involved a single freeze--thaw cycle. RESULTS: Fifteen patients received 25 single-probe treatments and seven patients received 14 dual-probe treatments. The treatment-related mortality rate was zero and complications occurred after six of 39 treatments. Liver metastasis growth was significantly delayed for 2 months after dual-probe but not single-probe treatment. Metastasis cryotherapy stimulated an immediate rise, followed by a fall, in serum carcinoembryonic antigen (CEA) level, associated with immune upregulation that was significantly greater after dual-probe treatments. CONCLUSION: Ablation zones that were approximately four times larger than those produced by previously described percutaneous techniques delayed the growth of metastases, reduced serum CEA concentration, and induced detectable inflammatory and T-lymphocyte responses. Percutaneous cryotherapy for treatment of colorectal liver metastases is feasible and may have a place in conjunction with chemotherapy.

Effect of manipulation of primary tumour vascularity on metastasis in an adenocarcinoma model.

One explanation for the clinical association between tumour vascularity and probability of metastasis is that increased primary tumour vascularity enhances haematogenous dissemination by offering greater opportunity for tumour cell invasion into the circulation (intravasation). We devised an experimental tumour metastasis model that allowed manipulation of primary tumour vascularity with differential exposure of the primary and metastatic tumour site to angiogenic agents. We used this model to assess the effects of local and systemic increases in the level of the angiogenic agent basic fibroblast growth factor on metastasis. BDIX rats with implanted hind limb K12/TR adenocarcinoma tumours received either intratumoural or systemic, basic fibroblast growth factor or saline infusion. Both intratumoural and systemic basic fibroblast growth factor infusion resulted in significant increases in tumour vascularity, blood flow and growth, but not lung metastasis, compared with saline-infused controls. Raised basic fibroblast growth factor levels and increase in primary tumour vascularity did not increase metastasis. The clinical association between tumour vascularity and metastasis is most likely to arise from a metastatic tumour genotype that links increased tumour vascularity with greater metastatic potential.

Does sentinel lymph node biopsy have a role in colorectal cancer?

Sentinel lymph node (SLN) biopsy in colorectal cancer is feasible, and may offer a means of reducing histopathology workload while maintaining staging accuracy. Although SLN biopsy allows use of sensitive molecular markers that can identify isolated tumour cells and micrometastases, these findings require more extensive clinical evaluation before they can be used to guide patient management. The application of molecular markers to identification of minimal residual disease after primary tumour resection, shows promise as a means of indicating patients requiring chemotherapy.

Continuous angiotensin II infusion increases tumour: normal blood flow ratio in colo-rectal liver metastases.

Insufficient blood flow within colo-rectal hepatic metastases is a factor which may limit drug delivery to, and thus the response of, these tumours to regional chemotherapy. Loco-regional flow may be manipulated pharmacologically to enhance the tumour blood flow relative to that of the normal liver. However, as yet, only transient effects have been studied. Patients receiving regional chemotherapy for unresectable hepatic disease were given a 45 min regional infusion of the vasoconstrictor Angiotensin II. Intrahepatic blood flow distribution was assessed serially by Positron Emission Tomography (PET) imaging together with the trapping tracer copper(II) pyruvaldehyde bis(N-4-methylthiosemicarbazone) (Cu-PTSM) labelled using copper-62. Eleven lesions in nine patients were studied, with no adverse effects. Prior to Angiotensin II administration tumour blood flow was generally found to be greater than that of liver (10/11 lesions; 8/9 patients; median TNR 1.3, iqr 0.9-2.5). A significant increase in relative flow to tumour was seen in response to 10 min Angiotensin II infusion in most cases (7/11 lesions; 7/9 patients; median TNR 2.1, iqr 1.4-4.1; P = 0.008), which appeared to be sustained throughout the 45 min infusion period (median TNR 1.85, iqr 1.3-3.8; P = 0.03). These effects were accompanied by transient elevation of mean arterial pressure, but no change in pulse rate. These observations suggest that prolonged regional vasoconstrictor administration could prove useful in the management of unresectable colo-rectal hepatic metastases, and that further development of vascular manipulation to enhance tumour targeting and drug delivery is warranted.

P53 mutation and response to hepatic arterial floxuridine in patients with colorectal liver metastases.

PURPOSE: To establish the relationship between the number and site of p53 genomic mutations in metastatic colorectal cancer, and the response to hepatic arterial floxuridine. METHODS: Liver metastasis biopsies were collected, at the time of laparotomy for hepatic arterial cannulation. in 28 patients with metachronous colorectal liver metastases. p53 Gene mutations were assessed using reverse transcription, nested polymerase chain reaction, single strand conformational polymorphism and gene sequencing. Chemotherapy response was determined from computerised liver tomograms after 4 months of treatment. RESULTS: Liver metastasis p53 mutation was identified in 21 (75%), and p53 "hot spot" mutation in 11 (39%) patients. There was a significantly lower prevalence (Fisher's, P=0.001) of patients with p53 "hot spot"-mutated liver metastases in stable disease and partial response (5/22) than in progressive (6/6) disease groups. Significantly fewer (Mann-Whitney U, P=0.002) p53 "hot spot" mutations/biopsy were observed in liver metastases from stable disease and partial response (median 0, iqr. 0-0) than in progressive (median 1, iqr 1-2) disease patients. p53 "Hot spot"-mutated liver metastases were associated with significantly shorter survival times (logrank P=0.05) after hepatic arterial floxuridine. Significant response or survival-time differences by total or L2/L3 zinc-binding site p53 mutations were not detected. CONCLUSIONS: The results support a role for p53 "hot spot" mutations in colorectal liver metastasis resistance to fluorinated pyrimidines, and suggest that the presence of such mutations may be a contra-indication to treatment of colorectal liver metastases with hepatic arterial floxuridine.

Detection and clinical significance of occult tumour cells in colorectal cancer.

BACKGROUND: A variety of techniques have been employed for the detection of occult tumour cells in the blood, bone marrow and lymph nodes of patients with colorectal cancer. This review examines the methods used, results obtained and the clinical significance of studies in this field. METHODS: A Medline literature search was performed using the terms colorectal cancer, minimal residual disease, micrometastasis, polymerase chain reaction, reverse transcriptase polymerase chain reaction and immunocytochemistry; further references were obtained from key articles. RESULTS: Immunocytochemical examination of bone marrow is the benchmark for detecting clinically significant occult disease. Larger standardized studies are required to confirm the prognostic significance of molecular assays for the detection of tumour cells in blood and bone marrow. The prognostic significance of lymph node tumour cells detected by either immunohistochemical or molecular methods awaits further affirmation. CONCLUSION: Standardization of terminology and techniques used, combined with large prospective clinical studies, is required if detection of occult residual disease is to become a prognostic marker for recurrence in colorectal cancer.