Balancing law, ethics and reality in informed consent for surgery.

Informed consent has different implications and requirements in law and bioethics, and some irreconcilable disputes with the reality of surgical practice in the National Health Service. This article explores and discusses various aspects of informed consent that are of critical importance for practising surgeons in all specialties.

Activity and heart rate-based measures for outpatient cardiac rehabilitation.

OBJECTIVES: Derive activity and heart rate (HR) monitor-based clinically relevant measures for outpatient cardiac rehabilitation (CR). METHODS: We are currently collecting activity/ECG data from patients undergoing cardiac rehabilitation over duration of six weeks. From these data sets, we a) derive various measures which can be used in assessing home-based CR patients remotely and b) investigate the usefulness of continuous ambulatory HR and heart rate variability (HRV) for various core components of CR. RESULTS: The information provided by these measures is interpreted according to the CR guidelines framework by American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR), thus showing how these tools can be used in assessing the progress of patients' condition. The usefulness and significance of these measures from a health care professional perspective is also presented by evaluating them against the existing hospital-based measures through examples. CONCLUSIONS: Hospital-based CR programs, despite their clinical benefits are severely under-utilized and resource-demanding. Ambulatory monitoring technologies, which provide a means for continuous physiological monitoring of patients at home compared to hospital-based tools, can enable home-based CR. The clinically relevant measures derived from these tools not only reflect patients' condition in a similar way as conventional tools but also show the continuous status of functional capacity (FC).

Minimally invasive management of chylous fistula after esophagectomy.

Chyle leak is an unwelcome complication of esophagectomy that is associated with a high mortality. The diagnosis of this condition may be difficult or delayed and requires a high index of suspicion. Management varies from conservative treatment with drainage, intravenous nutrition, treatment and prevention of septic complications, to re-operation, either by thoracotomy or laparotomy to control the fistula. To reduce the mortality, early surgical intervention is advised and a minimally invasive approach has recently been reported in several cases. From June 2002 through August 2005 we have used video-assisted thoracoscopic surgery to diagnose and treat chyle fistulas from 6/129 (5%) patients who underwent esophagectomy for resectable carcinoma of the esophagus or high-grade dysplasia. The fistula was successfully controlled in 5/6 cases by direct thoracoscopic application of a suture, clips or fibrin glue. One patient required a laparotomy and ligation of the cysterna chyli after thoracoscopy failed to identify an intrathoracic source of the leak. An early minimally invasive approach can be safely and effectively applied to the diagnosis and management of post-esophagectomy chylous fistula in the majority of cases. Open surgery may be appropriate where minimally invasive approaches fail or where the availability of such skills is limited.

Hepatic and mesenteric nitric oxide synthase expression in a rat model of CCl(4)-induced cirrhosis.

BACKGROUND: Cirrhosis and portal hypertension are frequently linked with changes in expression of nitric oxide synthase (NOS) and/or endotoxaemia. AIMS: This study tested the following hypothesis: that inducible (i)NOS activity is increased within the visceral circulation concurrently with decreased constitutive (c)NOS activity in the hepatic sinusoids and that the concentration of NO metabolites in portal blood is consequent on endotoxin concentration. MATERIALS AND METHODS: Plasma concentrations of (nitrite + nitrate) and endotoxin, together with hepatic and mesenteric NOS activity (arginine/citrulline method) and protein expression (histochemistry) plus portal and arterial blood pressure, were determined in rats made severely cirrhotic by intragastric CCl(4) over 14 weeks (n = 6) compared with age-matched controls (n = 5). The concentrations of [nitrite + nitrate] and endotoxin in portal plasma were also directly compared in rats made cirrhotic for a period of 8-14 weeks (n = 10). RESULTS: In rats with advanced cirrhosis, arterial [nitrite + nitrate] was 93.1 (22.4) micromol/L (mean, SEM) compared with 29.1 (6.1) micromol/L in controls (P < 0.05); portal plasma [NO(2)(-) + NO3(-)] was 127.1 (27.2) compared with 24.7 (4.7) micromol/L in controls (P < 0.05). Cirrhotic rats had higher endotoxin concentration in plasma compared with controls (systemic: 85.0 (24.5) versus 1.7 (0.2) EU/ml, P < 0.05; portal: 180.3 (47.9) versus 1.7 (0.2) EU/ml, P < 0.05). The same severely cirrhotic rats possessed decreased cNOS activity in liver (2.95 [0.40] versus 5.29 [0.85] pmol/min/g; P < 0.05) and increased iNOS activity in mesentery (4.83 [1.23] versus 1.47 [0.15] pmol/min/g; P < 0.05) compared with controls. Histochemical observations confirmed these findings. Rats given CCl(4) for a period of 8-14 weeks possessed high endotoxin concentration in portal plasma, with correspondingly high [nitrite + nitrate] (r(2) = 0.954; P < 0.001). CONCLUSIONS: An endotoxin-induced increase in mesenteric iNOS activity and a decrease in hepatic cNOS activity may account for, respectively, the hyperdynamic visceral circulation and the increased intrahepatic resistance of cirrhosis.

Expression of survivin, a novel inhibitor of apoptosis and cell cycle regulatory protein, in pancreatic adenocarcinoma.

Survivin is unique for its expression in human malignancies but not in normal adult cells. It has been implicated in sensitisation to chemotherapy and as a prognostic marker in several common cancers. Immunohistochemistry for Survivin, P53 and BCL-2 expression as well as cell proliferative index (Ki-67) and apoptosis index (TUNEL) was conducted on 52 pancreatic and 12 ampullary adenocarcinomas. Survivin was detected in the cytoplasm of carcinoma cells in 46 (88%) of pancreatic tumours. P53 and BCL-2 were detected in 54% and 12% of pancreatic tumours, respectively. Proliferative index was 26.2+/-10.5% and apoptosis index was 1.38+/-0.69%. Prevalence of Survivin expression was significantly higher in P53-positive than in P53-negative cases (P=0.05) but was not associated with BCL-2 expression. Incrementally higher weighted scores of Survivin expression were associated with increased proliferative index (P=0.001). Furthermore, there was linear correlation between increased proliferative index and higher apoptosis index (P<0.001). Surprisingly, higher scores of Survivin expression were associated with increased apoptosis index (P=0.007). Survival characteristics were not influenced by Survivin, P53 or BCL-2 expression, apoptosis index or proliferative index. Ampullary carcinoma showed Survivin expression in 83% of cases. However, unlike pancreatic carcinoma, there was no correlation between Survivin and P53 expression or proliferative index. In conclusion, Survivin is expressed in the majority of pancreatic adenocarcinomas and correlates with both cellular proliferation and apoptosis. Molecular manipulation of Survivin expression may enhance chemotherapy and radiation therapy for pancreatic cancer.

Non-operative management of the primary tumour in patients with incurable stage IV colorectal cancer.

BACKGROUND: Excision of primary colorectal cancer associated with irresectable synchronous metastases confers high morbidity and mortality with uncertain benefit. METHODS: For patients with incurable stage IV colorectal cancer, minimally symptomatic primary tumours were left in situ and 5-fluorouracil-based chemotherapy was administered systemically. Primary tumour-specific complications and survival were monitored. RESULTS: There were 13 men and 11 women with primary tumours in the right colon (eight), transverse colon (one), sigmoid colon (eight) or rectum (seven). Eleven patients had metastases limited to the liver (liver replacement less than 25 per cent in one, 25-50 per cent in four and more than 50 per cent in six) and 13 patients had extrahepatic disease (lung or peritoneum). Four patients with sigmoid colon tumours developed bowel obstruction, which required an uncomplicated operation in two and deployment of colonic stents in two patients, at 1, 3, 12 and 20 months from diagnosis. Three further patients underwent right hemicolectomy for abdominal pain of uncertain aetiology, with poor symptomatic relief, and another had a potentially curative operation following disease downstaging. The overall median survival was 10.3 months with a 1-year actuarial survival rate of 44 per cent. CONCLUSION: A policy to defer resection of minimally symptomatic primary colorectal cancer is associated with a low risk of complications before death from progressive systemic disease.

Immunohistochemical detection of the anti-apoptosis protein, survivin, predicts survival after curative resection of stage II colorectal carcinomas.

BACKGROUND: This study examined the role of Survivin protein, a novel inhibitor of apoptosis, in determining prognosis after curative resection of stage II colorectal carcinomas. METHODS: Expression of Survivin, P53, and BCL-2 was evaluated immunohistochemically in stage II colorectal carcinomas from 49 patients who were followed for up to 9 years after operation. The Cox proportional hazards regression model was used to examine the predictive value of several covariates. RESULTS: The patients comprised 33 men and 16 women with a median age of 71 years. There were 32 colonic and 17 rectal cancers comprising 40 T3 and nine T4 primary tumors. Survivin was expressed in 30 (61.2%), P53 in 30 (61.2%), and BCL-2 in 21 (42.9%) tumors. Expression of Survivin was independent of P53 or BCL-2 expression and histopathological characteristics of the tumor. The 5-year survival rate of patients with Survivin-positive tumors was significantly lower than that of patients with Survivin-negative tumors (52.5% vs. 94.1%, respectively; P = .01). On multivariate analysis, expression of Survivin (Hazard Ratio [HR] = 9; P = .03), and rectal origin of cancer (HR = 3; P = .05) were the only factors which independently predicted an increased risk of death from recurrent cancer. CONCLUSION: Survivin expression within the tumor can identify patients with stage II colorectal carcinoma who are at increased risk of death from recurrent disease and might particularly benefit from adjuvant therapy.

Death from early colorectal cancer is predicted by the presence of transcripts of the REG gene family.

An intrinsic component of colorectal carcinogenesis may be the capacity to activate regenerative responses simultaneously with inhibition of apoptosis. Since apoptosis is known to be inhibited in colorectal cancer, this study sought evidence for the activation of the REG family of genes which are considered to be activated during regeneration of intestinal mucosa. Transcripts for the REG gene were found in 53% of colorectal cancers and for the PAP gene in 60% of colorectal cancers, by RT-PCR. Using in situ hybridization, the REG transcripts were found to be present in the tumour cells themselves rather than inflammatory or stromal cells. There were no significant correlations between the expression of these two genes and tumour stage, age or sex of the patient population or tumour site. However, in patients with non-metastatic disease who underwent ostensibly curative surgery, the expression of REG alone and co-expression of REG with PAP had a highly significantly adverse effect on survival. These data provide support for the concept that, in some tumours, carcinogenesis involves a regenerative process which co-exists with apoptotic inhibition and may provide a valuable selective indicator of the need for adjuvant therapy in those patients with early-stage colorectal cancer whose disease is destined to recur after curative surgery.

Expression of the antiapoptosis gene, survivin, predicts death from recurrent colorectal carcinoma.

BACKGROUND/AIMS: Inhibition of programmed cell death (apoptosis) is associated with increased tumour aggressiveness, and expression of Survivin, an antiapoptosis gene, in colorectal carcinomas may provide important prognostic information. PATIENTS/METHODS: Expression of Survivin messenger RNA was evaluated by reverse transcription-polymerase chain reaction in 144 colorectal carcinomas and 86 adjacent histologically normal mucosa samples from patients for whom long term follow up data were available. RESULTS: Survivin transcripts were detected in a significantly greater proportion of carcinomas (63.5%) than normal mucosa samples (29.1%; p<0.001). The prevalence of Survivin expression was independent of advancing pathological stage. Death due to recurrent cancer following curative resection was predicted independently by tumour expression of Survivin (hazard ratio (HR) 2.60; 95% confidence interval (95% CI) 1. 17-5.75) and lymph node metastases (HR 2.38; 95% CI 1.21-4.70). On stage wise analysis, the predictive value of Survivin expression was limited to patients with stage II colorectal carcinomas; those with Survivin negative tumours had a five year survival rate of 94.4% compared with 44.8% for patients with Survivin positive tumours (p=0. 004, log rank test). CONCLUSION: In patients with stage II colorectal carcinomas, Survivin expression provides prognostic information that may have important therapeutic implications.

Abnormal hepatic perfusion index predicts recurrence of colorectal carcinoma.

OBJECTIVE: The hepatic perfusion index (HPI) is a ratio of the gradient of hepatic arterial to total hepatic blood flow. This study correlated HPI with histopathological indicators of prognosis and disease-free survival following curative resection of colorectal cancer. PATIENTS AND METHODS: HPI was measured preoperatively by dynamic hepatic scintigraphy in 37 patients with a primary colorectal cancer and no evidence of distant metastases who underwent a curative resection. RESULTS: Abnormally elevated HPI were detected in 49% of patients and were significantly more frequent in association with locally advanced tumours (T3 and T4) in comparison with early tumours (T1 and T2; 59% vs 20%, respectively; P=0.04). There was no association between abnormal HPI and presence of lymph node metastases or degree of tumour differentiation. The 18-month disease-free survival rate of patients with abnormal HPI was significantly shorter than that of patients with normal HPI (53% vs 100%, respectively; P=0.01), and this was independent of the T category. CONCLUSION: HPI predicts the risk of recurrent colorectal carcinoma, and this measurement should be included in the panel of prognostic markers in future clinical trials.

Hepatic and splanchnic nitric oxide activity in patients with cirrhosis.

BACKGROUND: In animal models of cirrhosis, altered activity of nitric oxide (NO) has been implicated in the pathogenesis of increased intrahepatic portal vascular resistance and abnormal mesenteric vasodilatation. AIMS: To investigate NO activity in the liver and splanchnic vascular bed of patients with cirrhosis. METHODS: Activity of the calcium dependent constitutive and calcium independent inducible isoforms of NO synthase (cNOS and iNOS, respectively) was assayed biochemically in biopsy specimens of liver and a vascular portion of the greater omentum (representative of mesenteric vasculature) obtained from patients with cirrhosis undergoing liver transplantation (n=14) and non-cirrhotic control patients undergoing liver resection for metastases (n=9). The concentration of NO metabolites (NO2 + NO3) in portal and peripheral venous plasma was measured. RESULTS: The activity of cNOS was lower in cirrhotic compared with non-cirrhotic subjects for both liver and omentum. Hepatic and omental iNOS activities did not differ significantly between the two groups. Portal (NO2 + NO3) was threefold higher in cirrhotic than non-cirrhotic patients, but no differences were observed in systemic venous samples from the two groups. CONCLUSIONS: The activity of cNOS is diminished in the cirrhotic human liver. The resultant decrease in constitutive NO release may promote an increase in the intrahepatic portal vascular resistance. Elevated portal venous (NO2 + NO3) indicates enhanced splanchnic vascular release of NO in cirrhotic patients, but the absence of increased NOS activity in the mesenteric vasculature suggests differential regulation of NO synthesis within the splanchnic vascular bed.

The candidate tumour suppressor gene, ING1, is retained in colorectal carcinomas.

ING1 plays a critical role in regulating cell cycle progression and susceptibility to apoptosis. The present study aimed to investigate allelic deletion of, and mutations within, the ING1 gene in colorectal carcinomas. Genomic DNA was extracted from 29 sporadic colorectal carcinomas and samples of adjacent normal mucosa. Losses of heterozygosity of two polymorphic dinucleotide repeat markers close to the ING1 locus at chromosome 13q32-34 were analysed. Single-stranded conformational polymorphisms of polymerase chain reaction amplified regions within the coding sequence of ING1 were examined. Microsatellite instability was noted in 5 (17%) colorectal carcinomas; this confirms selection of a subject sample representative of the population. Neither losses of heterozygosity nor changes in electrophoretic mobility of single-stranded polymerase chain reaction products were detected in any colorectal carcinoma. Thus, in common with tumour suppressor genes such as RB and BRCA2 on chromosome 13q, ING1 appears to be retained intact in colorectal carcinomas.