Straight to flexible sigmoidoscopy: rationalization of 2-week wait referrals in suspected colorectal cancer.

AIM: The 2-week wait pathway was designed to decrease the time from presentation to primary care of patients with 'red flag' symptoms of suspected cancer for review by a specialist for the diagnosis or exclusion of cancer. In our tertiary referral centre we have found that 968 colonoscopies per year are required to satisfy the demand for the 2-week wait, leading to limited colonoscopy availability for other services. We sought to determine the yield of colorectal cancer found at colonoscopy referred via the 2-week wait and referenced to the original red flag symptoms. This was in order to select the most efficacious alternative primary investigation based upon presenting symptoms. METHOD: Electronic records were retrospectively analysed. All patients who went through the 2-week wait for suspicion of colorectal cancer in 2013 and were found to have colorectal cancer on colonoscopy were included. Patients not undergoing colonoscopy as the first investigation were excluded. The splenic flexure was deemed to be within the range of a flexible sigmoidoscope. RESULTS: In all, 2950 referrals were made. 968 colonoscopies were performed as the primary investigation of which 35 were found to have colorectal cancer. No patients referred with rectal bleeding and another symptom had a tumour more proximal to the range of flexible sigmoidoscopy. 80% of tumours proximal to the splenic flexure were suitable for CT diagnosis alone. CONCLUSION: Our data support the use of flexible sigmoidoscopy alone as an initial investigation for patients presenting with rectal bleeding with or without additional colorectal symptoms. Patients with anaemia (without bleeding) or change in bowel habit (without bleeding) may be investigated with CT colonography alone; colonoscopy may then be used selectively prior to surgery.

The prognostic value of circulating big endothelin-1 in patients undergoing potentially curative resection for colorectal cancer.

AIM: Elevated circulating endothelin-1 (ET-1) has been demonstrated in patients with colorectal cancer (CRC). The aim of this study was to examine the prognostic value of plasma big ET-1, the stable precursor of ET-1, in cancer-specific survival in patients having curative surgery for CRC. METHOD: Seventy-seven patients undergoing potentially curative surgery for CRC between January 2000 and January 2001 were studied. Clinicopathological data were obtained from a prospectively maintained database including long-term follow-up information (median follow up 84 months). The influence of plasma big ET-1 and clinicopathological variables upon over cancer-specific survival was determined by univariate and multivariable analysis. RESULTS: On univariate analysis, advanced Dukes' stage, tumour size and patient age were associated with shortened overall survival. Advanced Dukes' stage was the only factor associated with shortened survival on multivariable analysis. Plasma big ET-1 showed no association with either overall or cancer-specific survival following CRC resection. CONCLUSION: Plasma big ET-1 appears to have no prognostic value in primary CRC.

The RAPID protocol enhances patient recovery after both laparoscopic and open colorectal resections.

BACKGROUND: Enhanced recovery after surgery (ERAS) programs can accelerate recovery and shorten the hospital stay after colorectal resections. The RAPID (remove, ambulate, postoperative analgesia, introduce diet) protocol is a simplified ERAS program that consists of a simplified, user-friendly single-page pro forma schedule. This study aimed to evaluate the impact of the RAPID protocol on patients undergoing both laparoscopic and open colorectal resections in two specialized colorectal units. METHODS: A prospective, two-center study assessed 117 age-matched patients undergoing open or laparoscopic colorectal resection to compare the postoperative course for patients using the RAPID protocol with those treated in a traditional manner. RESULTS: Of the 117 patients studied, 70 underwent laparoscopic resection (55 with the RAPID protocol) and 47 underwent open resection (25 with the RAPID protocol). Patients undergoing laparoscopic resections with the RAPID protocol had a significantly shorter hospital stay (p = 0.01) and tolerance of a full diet (p = 0.002). Similarly, patients undergoing open resections with the RAPID protocol also have a significantly shorter hospital stay (p = 0.04). CONCLUSION: The RAPID protocol is a user-friendly, easy, and effective tool that facilitates earlier tolerance of diet and discharge from the hospital for patients undergoing laparoscopic or open colorectal resections.

Straight to test: introduction of a city-wide protocol driven investigation of suspected colorectal cancer.

OBJECTIVE: To decrease waiting times for colorectal cancer diagnosis. METHODS: Following extensive negotiations on three sites, we replaced the standard referral route of GP to outpatient clinic with city-wide implementation of a protocol driven sequence based on the patient's declared symptoms, the initial consultation being replaced by the first test taking place within 31 days. No choice in test allocation was granted; difficult cases were adjudicated by named consultants. We used a 'dry run' to make sure that our planned changes would not overload our local capacity, leading to a pilot run involving 1/3 clinicians, followed by a full cross-city implementation over two months. RESULTS: In 2001, before the pilot only 116/188 (62%) of our colorectal cancers who were referred either under the 2-week-wait arrangements or on a 'soon' basis were diagnosed within 31 days of referral. Our 'dry run' established that we did have the capacity to service our planned sequence of tests. In the pilot, all colorectal cancers were diagnosed within 31 days of referral, and 95% of all diagnoses (no abnormality or benign disease) were reached within 31 days of referral. After full implementation 19/19 (100%) of our cancers coming through our protocol system were diagnosed within 31 days and 95% of patients with benign disease. CONCLUSION: Follow-up audit of our system one and two years later shows that we now diagnose approximately 80% of our colorectal cancers who are referred under the 2 week wait or as 'soon' referrals within 31 days. We have successfully redesigned our service, at minimal expense, in a way, which should enable us to meet the government targets in the National Cancer Plan.

Prognostic significance of elevated endothelin-1 levels in patients with colorectal cancer.

BACKGROUND: Prognostic factors from clinical, laboratory and pathological data of patients with colorectal cancer are essential to identify high-risk groups to whom beneficial adjuvant therapy could be given. Endothelin-1, a growth factor, has been associated with the development and spread of solid tumours. This prospective study was performed to determine whether preoperative plasma big ET-1 levels might be useful as a prognostic indicator in patients with colorectal carcinoma. METHOD: Sixty-five consecutive patients with colorectal cancer confirmed by biopsy were included prospectively into this study over a 12-month period. Plasma samples from a peripheral vein were obtained prior to surgery. Univariate analysis of survival using age (< or > 70 years), sex, Dukes' stage (A&B versus C), tumour size (< or > 50 mm), vascular invasion and plasma big ET-1 levels was performed and significant factors were then analysed with the Cox regression model. RESULTS: Three variables, age, Dukes' tumour stage and plasma big ET-1 levels, were found to have prognostic significance (p<0.05). Factors associated with a poorer prognosis were age >70 years (p=0.02), Dukes' C tumours (p=0.04) and plasma big ET-1 levels >4.2 pg/mL (p=0.02). The Cox regression model identified the same three variables as having independent prognostic value for overall survival. CONCLUSION: Preoperative plasma big ET-1 levels may be useful in predicting overall survival in patients with colorectal cancer. Plasma big ET-1 levels may be useful in the selection of high-risk lymph node-negative patients with colorectal cancer for adjuvant therapy.

Randomised controlled clinical trial of stapled haemorrhoidectomy vs conventional haemorrhoidectomy; a three and a half year follow up.

OBJECTIVE: This article presents the results of a three and a half year follow up of patients recruited to a randomised controlled clinical trial comparing circumferential mucosectomy (stapled haemorrhoidectomy) vs conventional haemorrhoidectomy. METHODS: Patients were assessed in an outpatient setting to examine a number of outcome measures. RESULTS: Our data suggest that at the three and a half year follow up, there are no significant differences in outcome between the two groups. CONCLUSIONS: It will be important to review the long-term results of larger trials.

Endothelin-1 is a novel prognostic factor in non-small cell lung cancer.

Endothelin-1 (ET-1) is a potent vasoactive peptide and a hypoxia-inducible angiogenic growth factor associated with the development and growth of solid tumours. This study evaluated the expression of big endothelin-1 (big ET-1), a stable precursor of ET-1, and ET-1 in non-small cell lung cancer (NSCLC). Big ET-1 expression was evaluated in paraffin-embedded tissue sections from 10 NSCLC tumours using immunohistochemistry and in situ hybridisation. The production of big ET-1 and ET-1 was studied in six established NSCLC cell lines. The plasma concentrations of big ET-1 were measured in 30 patients with proven NSCLC prior to chemotherapy by means of a sandwich enzyme-linked immunoassay and compared to levels in 20 normal controls. Big ET-1 immunostaining was detected in the cancer cells of all tumours studied. Using in situ hybridisation, tumour cell big ET-1 mRNA expression was demonstrated in all samples. All six NSCLC cell lines expressed ET-1, with big ET-1 being detected in three. The median big ET-1 plasma level in patients with NSCLC was 5.4 pg/mL (range 0-22.7 pg/mL) and was significantly elevated compared to median big ET-1 plasma levels in controls, 2.1 pg/mL (1.2-13.4 pg/mL) (p = 0.0001). Furthermore, patients with plasma big ET-1 levels above the normal range (upper tertile) had a worse outcome (p = 0.01). In conclusion, big ET-1/ET-1 is expressed by resected NSCLC specimens and tumour cell lines. Plasma big ET-1 levels are elevated in NSCLC patients compared to controls with levels > 7.8 pg/mL being associated with a worse outcome. The development of selective ET-1 antagonists such as Atrasentan indicates that ET-1 may be a therapeutic target in NSCLC.

The role of big endothelin-1 in colorectal cancer.

INTRODUCTION: Changes in liver blood flow caused by an unknown splanchnic vasoconstrictor have been noted in colorectal cancer patients with liver metastases. This prospective study was performed to assess whether plasma levels of big endothelin-1 (big ET-1) were raised in patients with colorectal cancer. METHODS: Plasma samples from peripheral vein of patients who underwent surgery for primary colorectal cancer (n=60) and those with known colorectal liver metastases (n=45) for a period of 15 months were taken prior to treatment and compared to age- and sex-matched controls (n=20). Plasma samples were analysed by using a single-step sandwich enzyme immunoassay. Immunohistochemistry and in situ hybridisation were also performed on tumour sections to investigate the expression of ET-1 by cancer cells. RESULTS: The median (range) plasma concentration of big ET-1 in controls was 2.1 pg/mL (1.2-13.4 pg/mL). The median (range) plasma concentration of big ET-1 in colorectal cancer patients with no overt hepatic metastases was 3.8 pg/mL (1.2-15.8 pg/mL), p=0.002, and the median (range) plasma concentration of big ET-1 in colorectal cancer patients with hepatic metastases was 5.2 pg/mL (1.7-30 pg/mL), p=0.0001; both were significantly elevated compared to the control group. A significant difference in immunostaining for big ET-1 was noted between paired normal colonic mucosa (median score-1) and tumour sections (median score-3), p=0.01. CONCLUSION: This study has demonstrated elevated concentrations of big ET-1 in colorectal cancer patients, especially in those with hepatic metastases. Upregulation of ET activity in colorectal cancer could be inferred by the increased immunostaining of big ET-1 in cancer cells. Therefore, plasma big ET-1 levels should be evaluated as a potential tumour marker for the identification of hepatic metastases at an earlier stage.

Ubiquitous elevation of matrix metalloproteinase-2 expression in the vasculature of patients with abdominal aneurysms.

BACKGROUND: Patients with abdominal aortic aneurysms (AAAs) exhibit arterial dilation and altered matrix composition throughout the vasculature. Matrix metalloproteinase-2 (MMP-2) is the dominant elastase in small AAAs, and overexpression of MMP-2 in vascular smooth muscle cells (SMCs) may be a primary etiological event in aneurysm genesis. The aim of this study was to investigate MMP-2 production in vascular tissue remote from the abdominal aorta. METHODS AND RESULTS: Inferior mesenteric vein (IMV) was harvested from patients undergoing aneurysm repair (n=21) or colectomy for diverticular disease (n=13, control). Matrix composition of the vessels was determined by stereological techniques. MMPs were extracted from tissue homogenates and quantified by gelatin zymography and ELISA. MMP-2, membrane type-1 MMP (MT1-MMP), and tissue inhibitor of metalloproteinases type 2 (TIMP-2) expression were determined by Northern analysis. SMCs were isolated from IMV, and the production and expression of MMP-2 and TIMP-2 in the SMC lines were quantified. Tissue homogenates and isolated inferior mesenteric SMCs from patients with aneurysms demonstrated significantly elevated MMP-2 levels, with no difference in TIMP-2 or MT1-MMP. These differences were a result of increased MMP-2 expression. Histological examination revealed fragmentation of elastin fibers within venous tissue obtained from patients with AAA and a significant depletion of the elastin within the media. In situ zymography localized elastolysis to medial SMCs. CONCLUSIONS: Patients with AAA have elevated MMP-2 levels in the vasculature remote from the aorta. This finding is due to increased MMP-2 expression from SMCs, a characteristic maintained in tissue culture. These data support both the systemic nature of aneurysmal disease and a primary role of MMP-2 in aneurysm formation.

Raised levels of plasma big endothelin 1 in patients with colorectal cancer.

BACKGROUND: The aim was to assess the role of plasma Big Endothelin (ET) 1 levels as a marker of disease presence and stage in colorectal adenocarcinoma. METHODS: Big ET-1 was measured in the plasma of 37 patients with colorectal cancer. Preoperative systemic plasma levels of Big ET-1 in patients with cancer were compared with levels in 20 age- and sex-matched controls. Portal plasma samples were collected at operation in addition to peripheral venous samples. Immunohistochemical staining for Big ET-1 was performed on a selection of primary tumour specimens and liver metastases. RESULTS: Median (range) preoperative systemic plasma levels of Big ET-1 were significantly higher in patients with cancer than in controls (1.0 (0.3-9.7) versus 0.2 (0.0-6.0) fmol/ml; P = 0.0001). Intraoperative portal plasma levels of Big ET-1 were significantly higher in patients with Dukes' 'D' disease than in patients with Dukes' A, B and C disease (2.1 (1.4-10.0) versus 1.2 (0.3-6.6) fmol/ml; P = 0. 01). Similarly, systemic plasma levels were significantly higher in patients with Dukes' 'D' disease than in those with localized disease (1.9 (1.2-9.7) versus 1.2 (0.2-8.3) fmol/ml; P = 0.01). The presence of microvascular invasion in the tumour specimens was associated with a significantly raised portal plasma level of Big ET-1 (1.6 (1.5-2.1) versus 1.1 (0.8-1.3) fmol/ml; P = 0.04). Immunohistochemistry localized Big ET-1 to the cancer epithelial cells. CONCLUSION: The plasma level of Big ET-1 is significantly raised in patients with colorectal cancer. Patients with liver metastases have significantly higher levels than those with localized disease.

Effect of colectomy on gastric emptying in idiopathic slow-transit constipation.

INTRODUCTION: Gastric emptying is delayed in patients with idiopathic slow-transit constipation (ISTC). Gastric emptying was measured before and after colectomy and ileorectal anastomosis in patients with ISTC to determine whether the abnormality persists after operation. METHODS: Twelve patients undergoing colectomy for severe ISTC had solid-phase gastric emptying measured after an overnight fast. All 12 had an uncomplicated subtotal colectomy and ileorectal anastomosis; 11 had an excellent functional outcome. In ten of these patients gastric emptying was repeated within 3 months of operation. Seven patients (including the remaining two) had the study performed at 1 year. RESULTS: All 12 patients had severely delayed gastric emptying before operation. Gastric emptying remained delayed in the ten patients who underwent an early postoperative gastric emptying study. Six of seven patients assessed at 1 year had improved gastric emptying, of whom four had returned to normal. Functional outcome did not relate to gastric emptying. CONCLUSION: Patients with ISTC have delayed gastric emptying. In some patients this returns to normal after colectomy, but is persistent in others. This may have implications for our understanding of ISTC.

Circumferential mucosectomy (stapled haemorrhoidectomy) versus conventional haemorrhoidectomy: randomised controlled trial.

BACKGROUND: Haemorrhoidectomy is commonly an inpatient procedure because it is frequently associated with postoperative pain. Day case haemorrhoidectomy is a similar operation to that used on inpatients but with different strategies for managing postoperative pain. Circumferential mucosectomy (stapled haemorrhoidectomy) may be associated with less postoperative pain than conventional haemorrhoidectomy. We compared stapled haemorrhoidectomy with conventional haemorrhoidectomy in patients with third degree haemorrhoids. METHODS: We randomly assigned 22 patients to conventional haemorrhoidectomy by the diathermy dissection or to stapled haemorrhoidectomy with the use of an intraluminal stapling device. Patients were discharged when free of pain, took co-codamol as required, completed visual analogue charts each day, and were assessed at 1 and 6 weeks postoperatively for symptom control. FINDINGS: All patients received the assigned treatment. Mean inpatient stay was lower in the group assigned to stapled as opposed to conventional haemorrhoidectomy (1.09 [0.3] vs 2.82 [0.09] nights, p<0.001), experienced less pain overall (p=0.003), and returned to normal activities sooner (8.1 [1.53] vs 16.9 [2.33] days, p<0.005). Stapled haemorrhoidectomy controlled symptoms of prolapse, discharge and bleeding in all patients. INTERPRETATION: Stapled haemorrhoidectomy is an effective treatment for third degree haemorrhoids with significant advantages for patients compared with conventional haemorrhoidectomy.

Prospective assessment of the hepatic perfusion index in patients with colorectal cancer.

BACKGROUND: This prospective study was designed to test the hypothesis that abnormal liver blood flow is related to poor prognosis in patients with colorectal cancer. METHODS: The hepatic perfusion index (HPI), measured by dynamic hepatic scintigraphy, was assessed in 202 patients with colorectal cancer. Assessment for overt hepatic metastasis included liver palpation at laparotomy and perioperative computed tomography (CT). Follow-up at a dedicated clinic included regular abdominal ultrasonography and CT. RESULTS: The HPI was abnormal (greater than 0.37) in 92 (88 per cent) of 105 patients with overt liver metastases. Of 89 patients with no evidence of overt metastases or residual tumour after primary resection, 52 had an abnormal and 37 a normal HPI. At a median follow-up of 39 (range 13-76) months, 25 of 38 patients with recurrence had an abnormal HPI. Some 31 of 45 patients who died had an abnormal HPI. The HPI predicted overall recurrence (P=0.04, log rank test). Multivariate analysis showed the HPI was independent of Dukes stage for predicting disease-free survival (P=0.04, relative risk 1.94 (95 per cent confidence interval (c.i.) 1.03-3.67)) but this just failed to attain significance for overall survival (P=0.055, relative hazard 1.88 (95 per cent c.i. 1.00-3.58)). CONCLUSION: The HPI predicts a poor outcome in patients with colorectal cancer and may be useful in patient selection for adjuvant chemotherapy.

Dynamic hepatic scintigraphy in colorectal cancer.

The clinical usefulness of the hepatic perfusion index (HPI) at the time of presentation has been evaluated in patients with colorectal cancer. In 83 consecutive patients, the HPI was abnormally elevated in 34 of 37 (93%) patients with overt metastases. This study confirms that the HPI is elevated in most patients with overt hepatic metastases. Long-term follow-up of patients with abnormal HPI and no obvious liver metastases is continuing.

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.

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.

Streptococcus milleri and complex groin abscesses in intravenous drug abusers.

Intravenous drug abuse is an increasing problem. Septic complications occur frequently at the injection site, especially in the groin where large abscesses around the femoral vessels can threaten life or limb. We report four patients with extensive or complex groin abscesses following attempted self-injection into the femoral vein. Streptococcus milleri was cultured from all of these abscesses and prompted a review of the isolation of this organism in this hospital.

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.

The effects of sandostatin (Octreotide, SMS 201-995) infusion on splanchnic and hepatic blood flow in an experimental model of hepatic metastases.

Manipulation of hepatic blood flow may improve drug delivery to hepatic tumour. Somatostatin and its long acting analogues are known to elicit effects upon hepatic and splanchnic blood flow in experimental animals and patients with portal hypertension. This study investigates the effects of SMS 201-995 (sandostatin) infusion on hepatic, splanchnic and tumour blood flow in an experimental model of liver metastases. Hepatic tumour was induced by the intraportal inoculation of 10(6) HSN sarcoma cells and blood flow measured using the dual reference microsphere method before and after infusion of SMS 201-995. There was a significant decrease in hepatic arterial flow and a significant increase in the tumour:liver blood flow ratio associated with a marked reduction in blood flow to normal hepatic parenchyma. Portal venous inflow and tumour blood flow were not significantly affected. SMS 201-995 infusion may lead to preferential delivery of concomitantly injected cytotoxic drugs to hepatic tumour. In addition, the reduction in growth of hepatic tumour may be due to a reduction in nutritive, arterial blood flow to hepatic tumour.