Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in bile aspirates.

Biliary brush cytology is the standard method of sampling a biliary stricture but has a low sensitivity for the detection of malignancy. We have previously shown that minichromosome maintenance (MCM) replication proteins (Mcm2-7) are markers of dysplasia and have utilised these novel biomarkers of growth for the diagnosis of cervical and bladder cancer. We aimed to determine if MCM proteins are dysregulated in malignant pancreaticobiliary disease and if levels in bile are a sensitive marker of malignancy. In 30 tissue specimens from patients with malignant/benign biliary strictures, we studied Mcm2 and -5 expression by immunohistochemistry. Bile samples were also collected prospectively at endoscopic retrograde cholangiopancreatography from 102 consecutive patients with biliary strictures of established (n=42) or indeterminate aetiology (n=60). Patients with indeterminate strictures also underwent brush cytology as part of standard practice. Bile sediment Mcm5 levels were analysed using an automated immunofluorometric assay. In benign biliary strictures, Mcm2 and -5 protein expression was confined to the basal epithelial proliferative compartment - in contrast to malignant strictures where expression was seen in all tissue layers. The percentage of nuclei positive for Mcm2 was higher in malignant tissue (median 76.5%, range 42-92%) than in benign tissue (median 5%, range 0-33%) (P<0.0005), with similar results for Mcm5. Minichromosome maintenance protein 5 levels in bile were significantly more sensitive than brush cytology (66 vs 20%; P=0.004) for the detection of malignancy in patients with an indeterminate stricture, with a comparable positive predictive value (97 vs 100%; P=ns). In this study, we demonstrate that Mcm5 in bile detected by a simple automated test is a more sensitive indicator of pancreaticobiliary malignancy than routine brush cytology.

A 5-year follow-up of self-expanding metal stents in the endoscopic management of patients with benign bile duct strictures.

BACKGROUND: Metal stents offer superior biliary drainage in patients with malignant bile duct obstruction, with fewer episodes of stent occlusion compared with polyethylene stents. Metal stent patency has only been studied over limited time periods in such patients with malignant disease. OBJECTIVE: To assess the long-term patency of metal stents in a group of patients with benign bile duct strictures who are suitable for extended follow-up. METHODS: Between May 1989 and May 1992, eight patients (median age 59.0 years; range 26-88 years) with benign biliary strictures were selected at a tertiary referral centre for insertion of a metal stent. Strictures were secondary to bile duct trauma (n = 5), chronic pancreatitis (n = 2) or idiopathic (n = 1). A long metal stent was inserted in three patients and a short metal stent in five patients. RESULTS: After a median follow-up of 64.5 months (range 26-81 months, seven of the eight patients are alive. Baby scope examination at 1 year showed complete epithelialization of the metal stent in all subjects examined. Median stent patency was 35 months (range 7-72 months). Symptomatic episodes of metal stent occlusion have occurred on nine occasions in five patients (62.5%) secondary to mucosal hypertrophy (n = 3) or biliary calculi (n = 2). CONCLUSION: The long-term management of selected patients with benign bile duct strictures may be significantly improved by the use of metal stents avoiding the need for frequent polyethylene stent changes.

A retrospective comparison of endoscopic stenting alone with stenting and radiotherapy in non-resectable cholangiocarcinoma.

BACKGROUND AND AIMS: Radiotherapy has been reported to be of benefit in prolonging the survival of patients with cholangiocarcinoma. This study examined whether radiotherapy in addition to endoscopic stenting improved survival. SUBJECTS: 56 patients with obstructive jaundice due to histologically confirmed non-resectable cholangiocarcinoma. METHODS: A retrospective analysis of these patients who were treated either with endoscopic biliary stenting followed by external beam radiotherapy and internal iridium-192 brachytherapy (n = 28) or with stenting alone (control group; n = 28). RESULTS: The two groups were well matched in age, sex, and stricture type. Eighteen patients had a type I stricture (control group: 11; radiotherapy group: 7) at the time of diagnosis and 38 had a type II or III stricture (control group: 17; radiotherapy group: 21). The median (range) overall survival from diagnosis was seven (1-29) and 10 (4-75) months in the control and radiotherapy groups respectively: This difference did not reach statistical significance (p = 0.06), but survival plots indicated a survival advantage in the radiotherapy group in the first nine months after diagnosis. Approximately one third survived longer than one year in both groups. More patients in the radiotherapy group required a stent change (1.9 v 0.9: p = 0.05), and also had a longer overall inpatient stay (42 days v 19: p < 0.001). When examined on the basis of stricture type, there was a survival advantage in the first 10 months after diagnosis in those with a type II/III stricture (seven and 11 months in the radiotherapy and control groups respectively: 0.01 < p < 0.05). There was no difference in survival between the groups in those with a type I stricture. Numbers surviving longer than one year, stent survival, and number of stent changes were all similar between the two groups when examined on the basis of stricture type, but length of hospital stay remained considerably longer in all patients receiving radiotherapy. CONCLUSION: The survival advantage of radiotherapy in those with a type II/III stricture is seen only in the first 10 months after diagnosis. The costs of radiotherapy and significantly increased time spent in hospital, however, raise doubts over its routine use in the management of non-resectable cholangiocarcinoma.

Management of bile leaks after laparoscopic cholecystectomy.

The success of laparoscopic cholecystectomy has been tarnished by the increased risk of bile duct damage associated with the operation. Many of these injuries can be managed by endoscopic techniques. Experience of such injuries between 1991 and 1994 was reviewed. Twenty-four patients were referred: 11 with injuries to the cystic duct alone, five with complete hepatic duct obstruction and eight with high bile duct leaks. All patients with leaks from the cystic duct were managed successfully endoscopically (sphincterotomy, four; stent, seven) without recourse to further surgery. Patients with complete obstruction were aided in their recovery by endoscopic and percutaneous techniques, either for postoperative problems (two patients) or in preparation for surgery (three). The eight patients with high bile duct leaks were managed endoscopically by stenting (seven patients) or sphincterotomy (one). Stenting appeared to encourage leaks to heal better than sphincterotomy alone; stents should probably be left in situ for 2 months before removal. There were no deaths and all but one patient had normal biliary function at follow-up. It is suggested that all suspected injuries after biliary surgery require management by a combination of interventional radiology and endoscopic interventional techniques. Surgery may be required only if there is complete obstruction of the biliary tree.

A three year follow up of self expanding metal stents in the endoscopic palliation of longterm survivors with malignant biliary obstruction.

Effective palliation of malignant biliary obstruction with conventional 10 or 12 French gauge straight polyethylene endoprostheses is limited by stent occlusion, which typically occurs four to five months after insertion. Short term follow up studies of self expanding metal stents (Wallstent, Schneider, UK) in the treatment of patients with malignant biliary obstruction have shown that their use is associated with fewer episodes of stent occlusion compared with plastic stents. There are few data, however, on the longterm patency and durability of metal stents in malignant disease. Between May 1989 and May 1992, metal stents were inserted in 28 patients with malignant bile duct strictures secondary to ampullary tumour (n = 10), pancreatic carcinoma (n = 10), cholangiocarcinoma (n = 7), and porta hepatis nodes from colorectal carcinoma (n = 1). The follow up of these patients until May 1993 is reported with a median follow up of 14.6 months. Twenty two of 28 (78.6%) patients remained free of jaundice or cholangitis. The median period of stent patency was 8.2 months (range 1.0-32.5). Thirteen patients represented with jaundice or cholangitis and endoscopic retrograde cholangiopancreatography showed evidence of stent occlusion due to tumour ingrowth. Successful clearance of metal stents was achieved by balloon trawling, or insertion of a polyethylene stent. In conclusion, metal stents provide improved longterm palliation for patients with malignant biliary strictures with fewer episodes of occlusion compared with conventional stents.

Photosensitisation and photodynamic therapy of oesophageal, duodenal, and colorectal tumours using 5 aminolaevulinic acid induced protoporphyrin IX--a pilot study.

The first study of photodynamic therapy in the human gastrointestinal tract using 5 aminolaevulinic acid (ALA) induced protoporphyrin IX as the photosensitising agent is described. Eighteen patients with colorectal, duodenal, and oesophageal tumours were studied. After 30-60 mg/kg of ALA given orally, biopsy specimens of tumour and adjacent normal mucosa were taken 1-72 hours later. These specimens were examined by quantitative fluorescence microscopy for assessment of sensitisation with protoporphyrin IX. Ten patients were given a second dose of ALA a few weeks later and their tumours were treated with red laser light (628 nm). With 30 mg/kg ALA, the highest fluorescence values were detected in the duodenum and oesophagus, and the lowest in the large bowel. Doubling the ALA dose in patients with colorectal tumours gave protoporphyrin IX fluorescence intensities similar to those in patients with upper gastrointestinal lesions and improved the tumour:normal mucosa protoporphyrin IX sensitisation ratio. The treated patients showed superficial mucosal necrosis in the areas exposed to laser light. Six patients had transient rises in serum aspartate aminotransferases, two mild skin photosensitivity reactions, and five mild nausea and vomiting. In conclusion, photodynamic therapy with systemically administered ALA may be a promising technique for the treatment of small tumours and areas of dysplasia such as in Barrett's oesophagus.

Randomised trial of endoscopic stenting versus surgical bypass in malignant low bileduct obstruction.

The development of non-surgical techniques for the relief of malignant low bileduct obstruction has cast doubt on the best way of relieving jaundice, particularly in patients fit for surgery whose life expectancy is more than a few weeks. We did a randomised prospective controlled trial comparing endoscopic stent insertion and surgical biliary bypass in patients with malignant low bileduct obstruction. 204 patients were randomised (surgery 103, stent 101); 3 subsequently proved to have benign disease and were excluded, leaving 101 surgical and 100 stented patients for assessment. Technical success was achieved in 94 surgical and 95 stented patients, with functional biliary decompression obtained in 92 patients in both groups. In stented patients, there was a lower procedure-related mortality (3% vs 14%, p = 0.01), major complication rate (11% vs 29%, p = 0.02), and median total hospital stay (20 vs 26 days, p = 0.001). Recurrent jaundice occurred in 36 stented patients and 2 surgical patients. Late gastric outlet obstruction occurred in 17% of stented patients and 7% of the surgical group. Despite the early benefits of stenting there was no significant difference in overall survival between the two groups (median survival: surgical 26 weeks; stented 21 weeks; p = 0.065). Endoscopic stenting and surgery are effective palliative treatments with the former having fewer early treatment-related complications and the latter fewer late complications.

Biopsy of inoperable pancreatic tumors does not adversely influence patient survival time.

PURPOSE: To determine the influence of pancreatic biopsy on the survival times of patients with inoperable tumors of the pancreas. MATERIALS AND METHODS: One hundred seventy patients were examined; results of histologic analysis confirmed pancreatic malignancy in 119. The biopsy and nonbiopsy groups were comparable for age, sex, the presence of liver metastases, and nodal status. RESULTS: No statistically significant difference was demonstrated between the survival time for the biopsy group (median, 23 weeks) and that for the nonbiopsy group (median, 22 weeks). The estimated relative risk for death (biopsy group compared with nonbiopsy group) was 0.85 (95% confidence limits = 0.61, 1.18). CONCLUSION: Pancreatic biopsy does not appear to adversely influence survival time for patients with inoperable pancreatic tumors. Because histologic examination aids clinical management, biopsy should be part of the diagnostic work-up for patients with suspected inoperable pancreatic carcinoma.

MR cholangiography: clinical evaluation in 40 cases.

PURPOSE: To determine the reliability and efficacy of magnetic resonance (MR) cholangiography in demonstrating the site and extent of stricture. MATERIALS AND METHODS: In 40 patients with obstructive jaundice, three-dimensional MR cholangiography was performed with a sequence of mirrored fast imaging with steady-state precession and was compared with conventional cholangiography in 39 cases. The level of obstruction was determined by examining all imaging data available. RESULTS: Diagnostic MR cholangiograms were acquired in 39 patients; absence of obstruction was confirmed in three, and obstruction was seen in 36. The level of obstruction or absence of obstruction was accurately shown in 36 of 40 patients with MR cholangiography and in 37 of 39 patients with conventional cholangiography. The peripheral biliary tree was shown more completely with MR cholangiography than with endoscopic retrograde cholangiography in all 32 patients undergoing diagnostic studies with both modalities. CONCLUSION: Three-dimensional MR cholangiography shows particular promise for the assessment of complex strictures, in which conventional cholangiography carries a higher risk of sepsis, for planning optimal drainage before intervention.

The percutaneous rotary lithotrite: a new approach to the treatment of symptomatic cholecystolithiasis.

This report evaluates the use of a new device for destruction of gall stones, the Kensey-Nash Lithotrite (Baxter Corporation, California, USA). The principle of the instrument is that of a liquidiser with an impeller that emulsifies stones. Twenty five patients were treated; 13 patients were considered unfit for conventional treatment (complex group) and 12 elected to have the procedure (non-complex group). In the complex group nine patients were treated under local anaesthesia. Only six of the 13 patients had a clear gall bladder at the end of the first procedure, but after further treatments that included cholecystoscopy, endoscopic sphincterotomy, and percutaneous cholecystolithotomy 11 patients had a gall bladder free of stones. The morbidity was high, mainly due to pain and bile leaks, causing prolonged stays in hospital (median 18 days). In the non-complex group six patients had the procedure performed under local anaesthesia. Ten patients had a successful clearance of the gall bladder, and the remaining two patients had the stones removed at cholecystoscopy. Despite good clearance, the morbidity was high, with eight emergency admissions on account of complications and a prolonged duration of stay (median 13 days). In conclusion the technique is effective, but the morbidity is high. Further development is required if this technique is to be included in the alternative treatments for the management of gall stones.

Selection, management, and early outcome of 113 patients with symptomatic gall stones treated by percutaneous cholecystolithotomy.

Between January 1988 and December 1990, 283 patients with symptomatic gall stones were referred for non-operative treatment. After ultrasound scanning including a functional assessment, 220 (78%) patients were found to be suitable for percutaneous cholecystolithotomy. Of these, 113 underwent the procedure including 10 in whom extracorporeal shock-wave lithotripsy or methyl tert-butyl ether therapy had failed. Forty four patients underwent extracorporeal shockwave lithotripsy, methyl tert-butyl ether therapy or rotary lithotripsy, 46 chose laparoscopic cholecystectomy or minicholecystectomy and 27 declined treatment. Percutaneous cholecystolithotomy was successfully performed in 100 patients. Thirty four patients were a high operative risk and 14 presented with an acute complication of gall stone disease. Complications developed in 15 patients, all of whom were managed conservatively and most occurred during development of the technique. Outcome has been assessed clinically and by ultrasound scanning in 92 patients with a median follow up period of 14 months (six to 37 months). Seventy nine per cent were completely cured of their symptoms. Ninety three per cent of gall bladders were shown to be functioning and nine (9.8%) contained stones, although five of these are believed to have developed from residual fragments. Percutaneous cholecystolithotomy is a safe, non-operative treatment for symptomatic gall stones and enabled the patient to fully recover within two to three weeks; it has a definite role in the management of the elderly and high risk patient but its use for the treatment of other groups is likely to remain controversial.

Biliary stent occlusion--a problem solved with self-expanding metal stents? European Wallstent Study Group.

The main limitation in the endoscopic palliation of malignant biliary obstruction is due to stent blockage. One of the factors thought to be of importance is the diameter of the endoprosthesis. In this paper, we report the results of a multicenter European study with a one cm diameter self-expanding metal stent (Wallstent) in 103 patients with malignant biliary obstruction. Insertion of the stent following guidewire positioning was successful in 97.1% of the patients without any cases of de novo cholangitis developing after the endoscopic procedure. The median follow-up for the entire group was 145 days. In all but 3 patients, the stent expanded to more than 80% of its maximum diameter. Two patients had ongoing cholangitis after stent insertion. Long-term complications manifested by late cholangitis, were seen in 18% of the cases after a median interval of 125 days. The occlusion rate by biliary sludge was 5% after a median time period of 175 days which is substantially less than the 21% occlusion rate reported for polyethylene stents. In conclusion, our results show that the Wallstent can be easily placed in distal and mid-CBD strictures after guidewire passage, with most of the patients having a- good drainage effect. The occlusion rate by biliary sludge is significantly less than for conventional polyethylene stents, but the occlusion by tumor ingrowth is substantial. A disadvantage is the high cost of the Wallstent. Further randomized trials will be required to determine the cost-benefit ratio for the use of this stent.

Percutaneous techniques for the management of symptomatic gallbladder stones.

Several non-operative treatments for the management of patients with symptomatic gallstones have been developed with the purpose of avoiding the considerable morbidity associated with open cholecystectomy. Minimally invasive techniques utilizing direct percutaneous puncture of the gallbladder are being increasingly used for the diagnosis and treatment of gallbladder disease and are the subject of this review. With the emergence of laparoscopic cholecystectomy the role of these techniques is less certain but they are likely to continue to be important in the management of high risk, elderly or medically unfit patients.

Gallbladder sepsis after stent insertion for bile duct obstruction: management by percutaneous cholecystostomy.

Of 364 patients undergoing insertion of a biliary endoprosthesis in 1989, six (1.6 per cent) developed gallbladder sepsis. Three patients had cholangiocarcinoma, two had carcinoma of the pancreas and one had a benign biliary stricture. Two of the five patients with malignancy had gallbladder stones, and the patient with a benign stricture developed stones after 3 years of stenting. Three patients developed gallbladder sepsis early after endoprosthesis insertion (less than 6 days), while in the other three it occurred late (greater than 6 months). All six patients failed to respond to antibiotics and were successfully managed by percutaneous cholecystostomy; the patient with a benign biliary stricture also had cholecystolithotomy. The gallbladder drainage tubes were removed or became dislodged at intervals varying from 2 weeks to 6 months without complications. Percutaneous cholecystostomy is the treatment of choice for gallbladder sepsis unresponsive to antibiotics in patients with a biliary endoprosthesis in situ.

Palliation of proximal malignant biliary obstruction by endoscopic endoprosthesis insertion.

For four years up to December 1987, 190 patients (median age 73 years) with proximal malignant biliary obstruction were treated by endoscopic endoprosthesis insertion. Altogether 101 had cholangiocarcinoma, 21 gall bladder carcinoma, 20 local spread of pancreatic carcinoma, and 48 metastatic malignancy. Fifty eight patients had type I, 54 type II, and 78 type III proximal biliary strictures (Bismuth classification). All patients were either unfit or unsuitable for an attempt at curative surgical resection. A single endoprosthesis was placed initially, with a further stent being placed only if relief of cholestasis was insufficient or sepsis developed in undrained segments. The combined percutaneous-endoscopic technique was used to place the endoprosthesis when appropriate, after failed endoscopic endoprosthesis insertion or for second endoprosthesis placement. Full follow up was available in 97%. Thirteen patients were still alive at the time of review and all but one had been treated within the past six months. Initial endoprosthesis insertion succeeded technically at the first attempt in 127 patients, at the second in 30, and at a combined procedure in a further 13 (cumulative total success rate 89% - type I: 93%; type II: 94%; and type III: 84%). There was adequate biliary drainage after single endoprosthesis insertion in 152 of the 170 successful placements, giving an overall successful drainage rate of 80%. Three patients had a second stent placed by combined procedure because of insufficient drainage, giving an overall successful drainage rate of 82% (155 of 190). The final overall drainage success rates were type I: 91%; type II: 83%; and type III: 73%. The early complication rates were type I: 7%; type II: 14%; and type III: 31%. The principle early complication was clinical cholangitis, which occurred in 13 patients (7%) and required second stent placement in five. The 30 day mortality was 22% overall (type I: 14%; type II: 15%; and type III: 32%) but the direct procedure related mortality was only 3%. Median survival overall for types I, II, and III strictures were 21, 12, and 10 weeks respectively but survival was significantly shorter for metastatic than primary malignancy (p<0.05). Endoscopic insertion of a single endoprosthesis will provide good palliation of proximal malignant biliary obstruction caused by unresectable malignancy in 80% of patients. Second stents should be placed only if required. Extensive structuring because of metastatic disease carries a poor prognosis and careful patient selection for treatment is requires.