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Biliary/pancreas free papers 150–166

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150 THE POTENTIAL ROLE OF GASTRIN IN PANCREATIC CANCER PROGRESSION-RAISED SERUM AMIDATED GASTRIN AND PROGASTRIN LEVELS IN PATIENTS WITH ADVANCED PANCREATIC CANCER

A.D. Gilliam, P.A. Clarke, B.J. Rowlands, I.J. Beckingham, S.A. Watson. Academic Unit of Cancer Studies, Academic Department of Surgery, University Hospital, Nottingham NG7 2UH, UK

Aim: To assess the endocrine role of gastrin in pancreatic carcinoma progression.

Method: A prospective study was established in which patients with resectable (n=17) and advanced (n=68) pancreatic carcinoma had their serum assayed for amidated and progastrin. Hormone levels were compared to positive controls (patients undergoing liver resection for colonic metastases, n=24). Gastrin and CCK 2 receptor expression was measured in 17 resected pancreatic tumours and four pancreatic tumour cell lines by RT-PCR, using the SYBR green dye, and immunohistochemical staining or western blotting using antibodies directed against gastrin and CCK2.

Results: There was a significantly greater serum amidated gastrin and progastrin levels in patients with advanced pancreatic cancer when compared to patients with resectable disease (p=0.008* and 0.046*). Patients with advanced pancreatic cancer also had significantly greater amidated gastrin and progastrin levels than patients undergoing liver resection for colonic metastases (p=0.023*). There was, however, no significant difference in amidated gastrin levels in patients with resectable pancreatic carcinoma and patients with metastatic colonic carcinoma (p=0.09*). Gastrin and CCK 2 expression was confirmed at the gene level in 13 pancreatic adenocarcinomas by RT-PCR, and immunocytochemistry in 17 pancreatic tumours. Gastrin and CCK-2 expression was also demonstrated in all four pancreatic tumour cell lines at the gene and protein levels by RT-PCR and western blotting. (*Independent samples T-test.)

Conclusion: This study confirms the autocrine, paracrine and endocrine role of gastrin in pancreatic carcinoma progression. Increased plasma levels of amidated gastrin may be a future biomarker for advanced pancreatic cancer. Anti-gastrin therapy may represent a novel therapeutic strategy for the management of pancreatic cancer.

151 GEMCITABINE DOES NOT INHIBIT THE BIOLOGICAL ACTIVITY OF A HUMAN PANCREATIC TUMOUR GROWING IN THE PANCREAS OF IMMUNODEFICIENT MICE.

A.D. Gilliam, W.J. Speake, R.A. Dean, D. McWilliams, P.A. Clarke, T. Morris, S.A. Watson. Academic Unit of Cancer Studies, Academic Department of Surgery, University Hospital, Nottingham NG7 2UH, UK

Introduction: Gemcitabine (Gemzar), a novel nucleoside analogue, exerts its action by inhibiting DNA synthesis. Gemcitabine is licensed as a first line treatment for patients with locally advanced or metastatic adenocarcinoma of the pancreas and as a second line treatment of patients with 5-FU refractory pancreatic cancer (NICE guidelines 2001). The aim of this study was to assess the effect of gemcitabine on matrix metalloproteinase (MMP), Epidermal Growth Factor Receptor (EGFR), gastrin, Cyclo-oxygenase2 (COX-2) and Cholecystokinin-2 (CCK2) receptor expression of a human pancreatic tumour growing in the pancreas of immunodeficient mice.

Method: The human pancreatic cell line, PAN1, cells were injected into the body of the pancreas in immunodeficient mice (1x106 in a 20μl volume). Mice were treated with saline or gemcitabine infusions. The tumours were examined for MMP 2 and 9, EGFR, COX-2, gastrin and CCK2 receptor expression by real time PCR at the gene level, by use of the SYBR green dye, and by western blotting and zyomography at the protein level.

Results: The gemcitabine treated mice had a 40% reduction in their tumour weights (p=0.045*) however there was no significant alteration in MMP gene or protein expression (p>0.1*), EGFR (p=0.48*), gastrin (p=0.15*), COX-2 (p=0.33*) and CCK2 receptor (p=0.20*) gene expression. (*Student's t Test.)

Conclusion: Gemcitabine does not affect the expression of several molecular biological targets suggesting an important potential role for novel biological therapies for use in conjunction with new chemotherapeutic agents in patients with pancreatic cancer.

152 MANAGEMENT OF ACUTE PANCREATITIS IN WALES: HOW GOOD ARE WE?

P.J. Arumugam, P.J. Shankar, P.N. Haray (introduced by V.I. Shah). Prince Charles Hospital, Merthyr Tydfil, Wales, UK

Aims: To review the existing practices of Welsh Surgical Consultants in managing acute pancreatitis and compare it with published UK guidelines.

Methods: We designed a questionnaire based on the national guidelines regarding the assessment, indications for intensive management, timing of elective cholecystectomy, ERCP and surgical intervention. This questionnaire was mailed to all the consultants in Wales and the replies were analyzed.

Results: 50 consultants responded. 33 units assess patients with a scoring system and almost all do routine blood gas analysis and liver function tests on admission, but only 29(60%) perform C-Reactive protein to assess prognosis. 10 units managed this problem with a multidisciplinary team approach. 17 of these units did not have access to HDU facilities. CT scan was used by a majority of these units as required by guidelines. Antibiotics were prescribed by most units in severe cases while surprisingly 10(20%) of these units prescribed antibiotics routinely without specific indications even in mild cases. Only one in three of these units routinely performed cholecystectomy within four weeks of an acute attack as recommended. ERCP and peroperative cholangiograms were not used in accordance with the guidelines.

Conclusion: Consultants in Wales do feel a specialist, multidisciplinary approach is necessary but practical difficulties prevent implementation of the guidelines. However, it is a matter of some concern that despite national guidelines, there is a varied approach across Wales.

153 PREDICTION OF SEVERITY IN ACUTE PANCREATITIS: A COMPARATIVE STUDY OF RANSON'S SCORE AND 24 AND 48 HOURS APACHE II AND III SCORING SYSTEMS

C. Chatzikostas1, G. Notas2, M. Roussomoustakaki1, I. Mouzas1, I. Koutroubakis1, P. Skordilis1, E. Matrella1, F. Dimoulios1, A. Theodoropoulou1, D. Samonakis1, E. Vardas1, P. Antoniou1, E. Kouroumalis1,2. 1Department of Gastroenterology, University Hospital, Heraklion, Crete, Greece' 2Liver Research Laboratory, University of Crete Medical School, Crete, Greece

Background/Aims: We assessed the prognostic accuracy of Ranson's, APACHE II, and APACHE III scores in predicting acute pancreatitis (AP) severity in non-intensive care unit (ICU) patients. APACHE III has not been previously evaluated outside ICU settings.

Methods: 126 patients with AP (56% gallstone and 9% alcoholic-related, 7% secondary, 28% idiopathic) were studied prospectively. Data conforming to scoring systems were recorded 24 (APACHE II and III) and 48 hr (Ranson, APACHE II and III) after admission. Analysis was performed by using t-test, Pearson correlation, receiver operating characteristic (ROC) curves and area under a ROC curve (AUC).

Results: On discharge, 117 patients (76.9%) were classified as mild and 35 (23%) as severe. There were 4 deaths (2.6%). The mean Ranson's score and the mean 24 and 48 hr APACHE II and III scores of patients with severe AP were each significantly higher than those of patients with an uncomplicated outcome. All five scores correlated strongly with length of stay. When ROC curves were plotted, AUC for Ranson's score (0.799; cutoff 3; sensitivity, 72%; specificity, 79%; correct 73%) was found to be larger than AUC for 24 hr APACHE II (0.644; cutoff, 8; sensitivity, 53%; specificity, 62%; correct, 55%), 24 hr APACHE III (0,654; cutoff, 32; sensitivity, 60%; specificity, 58%; correct, 60%), 48 hr APACHE II (0.649; cutoff, 8; sensitivity, 53%; specificity, 69%; correct, 57%), and 48 hr APACHE III (0.652; cutoff, 27; sensitivity, 52%; specificity, 72%, correct, 52%). The difference between 24 and 48 hr APACHE II and III scores AUC did not reach statistical significance.

Conclusion: Ranson's score is superior to APACHE II and III in predicting acute pancreatitis severity. APACHE III score is no superior to APACHE II, and sequential 24 and 48 hr recording offers no advantage over 24 hour recording.

154 ACUTE AND CHRONIC PANCREATITIS: DISEASES ON THE INCREASE

D.A.J. Lloyd1, A. Tinto2, A. Majeed3, R.C.N. Williamson4, J.D. Maxwell1, J-Y. Kang1. 1St George's Hospital; 2Office for National Statistics; 3University College; 4Hammersmith Hospital, London, UK

Aim: To investigate time trends for the numbers of hospital admissions for acute and chronic pancreatitis in England from 1989/90 to 1999/00.

Methods: Data were obtained from the Hospital Episodes Statistics (HES) service from 1989/90 to 1999/00 based on `Finished Consultant Episodes', excluding day cases, in England. Hospital admissions were selected by primary diagnosis and admissions where surgical operations (excluding endoscopic procedures) were performed were identified. Age standardised hospital admission rates were calculated using the European standard population. Mortality statistics were also obtained.

Results: Over the 11-year study period, admission rates for acute pancreatitis rose by 43% while those for chronic pancreatitis rose by 100% (see table). Admission rates for acute pancreatitis increased progressively with age whereas those for chronic pancreatitis peaked at 35–54 years of age. For both sexes, the proportions of admissions requiring surgical operations increased for acute pancreatitis but decreased for chronic pancreatitis. There was a gradual decline among both sexes in case fatality rates for acute pancreatitis.

Abstract 154

Conclusions: There has been a steady increase in admission rates for both acute and chronic pancreatitis. The rate of increase was greater among females for acute pancreatitis, but greater among males for chronic pancreatitis. These trends are likely to reflect genuine changes in disease epidemiology rather than alterations in diagnostic and management practice. The proportions requiring operations have increased for acute pancreatitis but decreased for chronic pancreatitis.

155 HEREDITARY PANCREATITIS (HP) AND THE RISK OF PANCREATIC DUCTAL ADENOCARCINOMA (PDAC)

N. Howes, M.M. Lerch, R. Charnley, J. Mössner, S. Endres, J. Deviere, V. Verreman, V. Lucidi, A. Ohla, I. Ihse, C. Imrie, W. Steenbergan, A. Poll, W. Greenhalf, I. Ellis, R. Mountford, D.C. Whitcomb, J.P. Neoptolemos for the UK and Ireland consortium of EUROPAC

Introduction: HP has an early age of symptom onset and is associated with a high incidence of complications, of particular importance is the reported high life time risk of PDAC. The European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC) was established in 1997 to investigate HP in Europe.

Aims: To establish the risk of PDAC in HP patients in Europe.

Methods: Recruitment started in 1997,HP was diagnosed on the basis of two family members with chronic pancreatitis of unknown aetiology. PRSS1 mutation screening was undertaken for the published mutations, with sequencing in negative families. The Standardised Incidence Ratio (SIR) which is the ratio of observed PDAC to expected PDAC was calculated for histologically confirmed PDAC from families with at least three generations of HP adjusted for age, sex, nationality and surgical intervention. The cumulative lifetime incidence was calculated, and a multivariate analysis undertaken for potential confounding factors.

Results: 109 families (n=342)were recruited. 47 families (n=197; 99M, 98F) were suitable for PDAC analysis. 15 patients (8M, 7F) developed PDAC during 7648 person-years. Mean age of cancer diagnosis was 56(48–69) Yrs. Expected number of cancers was 0.21 yielding an overall SIR of 71(53–88). The SIR in males was 72(49–94) and in females was 70(47–93). The overall lifetime risk for the development of PDAC in our cohort of patients with HP was 40% [95%C/I];( 30–50%). The risk appeared to be minimal below the age of 40yrs, where after it increased sharply. Multivariate analysis showed that the risk of PDAC appeared to be independent of potential confounding variables.

Conclusion: PDAC is a real and significant independent complication of Hereditary Pancreatitis.

156 AUDIT OF SECHAT TESTS: WHO TO TARGET?

B.C. McKaig, N. Simpson, I. Amarkone, R.F.A. Logan. Division of Gastroenterology, University Hospital, Nottingham NG7 2UH, UK

Introduction and Aims:75Selenium cholic acid taurate (SeCHAT) tests are accurate in the diagnosis of bile acid malabsorption (BAM). We have audited the use of SeCHAT tests in a teaching hospital to assess if their use was appropriate, influenced patient management and to determine the prevalence of primary bile acid malabsorption (PBAM).

Methods: Patients undergoing SeCHAT tests from 1994–2001 were identified and the case notes examined for the SeCHAT result (<10% being a positive test), indication, known terminal ileal pathology, previous investigations and influence on patient management.

Results: 120 patients were identified undergoing SeCHAT tests of which 51 were positive, 48 negative and 21 indeterminate (mean retention of 75SeCHAT at 7 days 3.75%, 33.8% and 12.4%, respectively). The indication in all cases was diarrhoea. Of the 51 positive tests, 21 had previous surgery (16 terminal ileal (TI) resections, 5 cholecystectomy); 21 had known TI Crohn's disease; one had received radiotherapy involving the TI; and 2 had documented prior enteric infection. Of the negative and indeterminate tests, 4 patients had previous enteric infection, one had coeliac disease but none had known TI Crohn's disease, previous surgery or other known predisposing factors for BAM. Prior to a positive SeCHAT test, most (90%) had imaging of the TI compared to only 40% of those with negative tests. Of those with positive tests, 47% had a short term (3 month) response to bile acid sequestrants (BAS), but this was only sustained at 6 months in 20% of patients, the remainder being intolerant of BAS. 6 patients therefore had a diagnosis of PBAM. After 3 years of follow up, one was diagnosed with Zollinger Ellison syndrome and another with carcinoid syndrome, leaving only 4 patients with PBAM (3 male, 1 female). The incidence of PBAM was therefore 6% in our group of patients with diarrhoea.

Conclusions: Patients presenting with diarrhoea known to have TI disease or dysfunction have a high probability of a positive SeCHAT test and therefore, can be assumed to have BAM as a contributor to their symptoms and do not require formal testing. The frequency of PBAM in our audit was 6% and BAM should be considered in these patients with a diagnosis of diarrhoea predominant irritable bowel syndrome.

157 IS HORMONE REPLACEMENT THERAPY ASSOCIATED WITH GALLSTONE FORMATION? A PROSPECTIVE COHORT STUDY

A.R. Hart1, R. Luben2, S. Oakes2, J. Camus2, A. Welch2, N. Wareham2, S.A. Bingham2, K-T Khaw2, N.E. Day2. 1School of Medicine, University of East Anglia, Norwich NR4 7TJ; 2Strangeways Research Laboratories, Cambridge CB1 4RN, UK

Background: The aetiology of gallstones is unknown. High oestrogen levels, whether endogenous or through exogenous hormone replacement therapy (hrt), have been implicated. Oestrogens increase the cholesterol saturation of the bile which may precipitate stone formation. The few epidemiological studies investigating this association have given conflicting results and clarification is needed. The aim of this study was to investigate if an association existed in a prospective cohort investigation.

Methods: A total of 13 433 women aged 45–79 years were recruited into EPIC-Norfolk (European Prospective Investigation Into Cancer). Participants supplied information at recruitment on use of hormone replacement therapy and were followed up for the development of symptomatic gallstones. Each case was matched with four controls for age and gender.

Results: Fifty-eight women developed symptomatic gallstones at a median age of 64.6 years (range 43.8–79.3 yrs) after a median follow-up of 3.2 years (range 1.5 - 6.8 years). Use of hrt was associated with a relative risk of 2.6 (95% CI=1.4–5.0) for symptomatic gallstones. The risk increased slightly after adjusting for factors associated with stone formation, namely alcohol, parity and BMI (RR = 3.0, 95% CI = 1.5–5.8). There was no association with duration of hrt use: women taking hrt for two or more years had a similar risk to those taking it for less than 2 years (RR= 3.4, 95% CI=1.5–7.6 vs RR=3.1, 95% CI=1.1–8.6).

Conclusions: Use of hormone replacement therapy is a risk factor for gallstones. Whether this is an aetiological relationship remains to be established, but the findings raise intriguing questions about the role of oestrogen in gallstone formation.

158 INCIDENCE OF EMERGENCY ADMISSION WITH GALLSTONE RELATED PROBLEMS IN PATIENTS AWAITING CHOLECYSTECTOMY AND ITS COST IMPLICATIONS

K. Somasekar, P.J. Shanker, M.H. Lewis, M.E. Foster (introduced by P.S. Davies). Royal Glamorgan Hospital, Llantrisant, Mid Glamorgan, Wales, UK

Introduction: Many patients awaiting cholecystectomy are admitted as an emergency with recurrent gallstone related problems. In addition to the morbidity, significant costs are involved in treating these patients.

Aims: To study the incidence of emergency admission due to gallstone related problems among patients awaiting cholecystectomy, and to assess the costs of treating these patients.

Methods: A retrospective analysis was performed of all the patients who underwent elective cholecystectomy by 3 consultants in a district general hospital between 1999–2000. Data was collected on demographics, the specific indication for including the patient in the waiting list, the waiting time, details of emergency admissions during their waiting period and the investigations and treatment given during these episodes.

Results: A total number of 156 patients underwent elective cholecystectomy of which 122 were females and 34 were males. The mean duration of the waiting time for cholecystectomy was 1 year. The mean age of the patients was 54 years (range 19–82 years). Of the 156 patients, 37 patients (24%) were admitted as an emergency with gallstone related symptoms while awaiting surgery. Twenty eight patients were admitted once, 8 patients were admitted twice and 1 patient was admitted three times. Of the 47 episodes of admissions, 32 were for biliary colic, 13 were for acute cholecystitis and 2 were for acute pancreatitis. The average duration of each episode was 3 days. The cost of each episode was £ 946 and the total cost was calculated to be £44,462.

Conclusions: Emergency admission with gallstone related problems is common among patients awaiting cholecystectomy. By recognising the patients prone to recurrent gallstone related problems, it is possible to offer them early surgery, thereby reducing patient morbidity and hospital costs.

159 PLACEMENT OF BILATERAL SELF-EXPANDING METAL STENTS FOR COMPLEX HILAR OBSTRUCTION DUE TO CHOLANGIOCARCINOMA

S.G. Nugent, A.F. Stone, J. Gilford, M.J. Benson. Department of Gastroenterology, St. Helier Hospital, Carshalton, Surrey, UK

Background: In cholangiocarcinoma, complete decompression of obstructed biliary systems is desirable to relieve symptoms, avoid secondary cholangitis and facilitate palliative chemotherapy regimes. Occlusion and migration of plastic stents limit their role. Although self-expanding metal stents (SEMS) reduce these problems, their unilateral placement for complex hilar strictures often fails to achieve adequate drainage. We report our experience of bilateral placement of SEMS for complex hilar strictures.

Methods: During a 32/12 period, 13 patients median age 67 years (range 50 – 88 years), underwent therapeutic ERCP for obstructive jaundice. All patients were found to have a cholangiocarcinoma (Bismuth stage II or higher). In these patients, following 5–10mm papillotomy, left and right intra-hepatic biliary systems were accessed with separate 035 hydrophilic guidewires. Following brushing for cytology, both strictures were balloon dilated to 6mm. SEMS (Wallstent, Boston Scientific) were deployed into both intra-hepatic systems, the most `angulated', usually the left, first. In the event of failure to stent both sides at ERCP, the procedure was completed as a combined ERCP/PTC or PTC.

Results: In 8/13, SEMS were deployed into both left and right ducts at the time of the initial ERCP. In 6/13, after placement of the first SEM at ERCP, the second SEM was deployed during either a combined ERCP/PTC (3) or PTC (3). Double stent placement at the initial ERCP failed for several reasons: hyperacute `angulation' within the stricture (4); friction between second and in situ SEM within mid CBD (1); loss of wire access to the obstructed system (1). No procedure related complications occurred in the 11 patients double stented at ERCP. In all patients good drainage was achieved (resolution of jaundice and symptoms, with no secondary cholangitis). Two patients required further ERCP and stenting for tumour ingrowth (2 months,6 months).

Conclusions: Bilateral SEM placement provides good, cost-effective palliation for many patients with complex hilar malignant strictures. Modifications to the stent/delivery system design to facilitate placement across strictures with hyperacute `angulation' may improve success rates.

160 MRCP IN A DISTRICT HOSPITAL: INDICATIONS AND IMPACT ON AN ERCP SERVICE

N. Hussain, E. Breeze, P.M. Irving, D. Fowler, G.P. Bray. Department of Gastroenterology, Southend Hospital, Westcliff-on-Sea, Essex SS0 0RY, UK

MRCP was developed in 1991 and has been available in our hospital for three years. We reviewed the indications for and use of MRCP. We also assessed the effect of MRCP on ERCP usage.

116 MRCPs were done in an eight-month period in our hospital (Nov 2000 to June 2001) compared to 161 ERCPs. Annual rate of MRCP was 183 per year for a population of 350,000 (approx 1 per 2000) compared to 254 ERCPs per year (approx 1.5 per 2000). A sample of 60 MRCPs was analysed by notes and X-ray review.

Female to male ratio was 1.86:1. 8% were under age 35yrs, 30% age 36–55yrs, 45% age 56–75yrs and 17% over 75yrs. Most examinations were requested by surgical teams (65%) with 22% by gastroenterology, 13% by others and none by GPs.

Indications for MRCP were: (1) Possible stone in CBD in 44 (73%) as suggested by pain, acute pancreatitis, bout of jaundice, abnormal biochemistry or dilated common bile duct on ultrasound, (2) Pain post cholecystectomy (9; 15%); (3) Failed ERCP (4; 7%); (4) Unexplained jaundice (2; 3%); (5) Possible bile leak post cholecystectomy (1; 2%).

In only six of the 60 cases was ERCP necessary after MRCP (10%). In 90% of patients who underwent MRCP, ERCP was therefore avoided. Over the eight-month period this implies ERCP usage was reduced by the use of MRCP from a possible 265 to 161 (by 39%).

Conclusions: (1) There is a high demand for MRCP in a large district hospital. (2) Most MRCP is requested by general surgeons to exclude a CBD stone prior to cholecystectomy. (3) MRCP reduces demand for ERCP and its complications by approx 40%. (4) MRCP should be readily available in all large hospitals.

161 FURTHER EXPERIENCE WITH SPIRAL CT CHOLANGIOGRAPHY IN PATIENTS WITH BILIARY SYMPTOMS POST CHOLECYSTECTOMY

A.C. Ashdown, I.D. Morrison, A.F. Muller. Kent and Canterbury Hospital, UK

Introduction: Because of the recognised complications associated with ERCP, it is valuable to diagnose choledocholithiasis by non– interventional techniques. Ultrasound (US) has limited use in patients with small bile duct stones or when the common bile duct (CBD) calibre is normal. We report our experience using spiral CT Cholangiography (sCTC), which has been shown to be sensitive for the detection of bile duct filling defects, in a group of pts post cholecystectomy with biliary type pain referred for E.R.C.P.

Methods: 59 patients (43 female, 16 male, age range 24-83 years), who had had a cholecystectomy up to 20 years prior to referral, in whom ERCP was not thought to be immediately indicated gave informed consent to sCTC. All had an abdominal US performed by an experienced ultrasonographer or consultant radiologist and liver function tests (LFTs) measured. This was followed by a sCTC using a Toshiba Asteion C.T. scanner, capable of 1 rotation every 0.75 seconds. 3mm slices were taken every 1mm at a pitch of 1.2mm/ rotation. Biloscopin was used as the contrast medium.

Results: Of 23 patients with abnormal LFTs,16pts on US had a CBD >/= to 6mm; only one pt had a stone (10mm in size) on US. Of these patients with a `distended' CBD 6 pts had stones seen on sCTC. 2 pts had failed sCTC. 1 pt had a mild allergic reaction to i.v. biloscopin. At sCTC 15 pts had a CBD >/= 6mm and stones were detected in 13. 2 pts with a normal cbd were shown to have stones at sCTC. 4 pts with normal LFTs had abnormalities detected on sCTC, 3 stones and 1 ampullary tumour. Of the 17 pts selected for ERCP in only 1 pt were the sCTC findings (3 small diameter stones) not confirmed, at ERCP, though 3 months later. Stones not detected by US measured between 4 and 15 mm at sCTC.

Conclusion: SCTC is more sensitive in detecting CBD stones than US. It should be considered in pts with biliary symptoms, where US has failed to confirm biliary pathology. This practice should reduce referral for diagnostic ERCP.

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