Expectant management of patients with gallbladder stones diagnosed at planned investigation. A prospective 5- to 7-year follow-up study of 153 patients. A survey of the timing and approach to the surgical management of cholelithiasis in patients with acute biliary pancreatitis and acute cholecystitis in the UK. Acute cholecystitis: delayed surgery or observation. A randomized clinical trial. Conservative treatment versus endoscopic sphincterotomy in the initial management of acute cholecystitis in elderly patients at high surgical risk. Ten-year incidence and natural history of gallstone disease in a rural population of women in central Italy. The Rome Group for the Epidemiology and Prevention of Cholelithiasis (GREPCO). Long-term ursodeoxycholic acid therapy is associated with reduced risk of biliary pain and acute cholecystitis in patients with gallbladder stones: a cohort analysis. Long-term follow-up of a randomized controlled trial of observation versus surgery for acute cholecystitis: Non-operative management is an option in some patients A Randomized Controlled Study of Uncomplicated Gallstone Disease with a 14-Year Follow-Up Showed that Operation Was the Preferred Treatment Is biliary pain exclusively related to gallbladder stones? A controlled prospective study. Pain persists in many patients five years after removal of the gallbladder: Observations from two randomized controlled trials of symptomatic, noncomplicated gallstone disease and acute cholecystitis The natural history of cholelithiasis: the National Cooperative Gallstone Study. Impact of Choice of Therapeutic Strategy for Acute Cholecystitis on Patient’s Health-Related Quality of Life Occult microlithiasis in 'idiopathic' acute pancreatitis: prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy. Laparoscopic Cholecystectomy for Acute Cholecystitis: Prospective Trial Comparison of the Rating Scale and the Standard Gamble in Measuring Patient Preferences for Outcomes of Gallstone Disease Treatment of biliary colic with diclofenac: a randomized, double-blind, placebo-controlled study. Symptomatic and silent gall stones in the community. Incidence, Risk Factors, and Prevention of Biliary Tract Injuries during Laparoscopic Cholecystectomy in Switzerland [Acute cholecystitis--early or delayed cholecystectomy]. The natural history of gallstones: the GREPCO experience. The GREPCO Group. Prospective evaluation of patients with acute cholecystitis treated with percutaneous cholecystostomy and interval laparoscopic cholecystectomy. Laparoscopic Cholecystectomy Without Prophylactic Antibiotics: A Prospective Study Relationship between persistence of abdominal symptoms and successful outcome after cholecystectomy. Effect of Estrogen plus Progestin on Risk for Biliary Tract Surgery in Postmenopausal Women with Coronary Artery Disease: The Heart and Estrogen/progestin Replacement Study Pain and quality of life in patients with symptomatic, non‐complicated gallbladder stones: results of a randomized controlled trial Urgent Laparoscopic Cholecystectomy Is the Best Management for Biliary Colic Postcholecystectomy biliary leaks in the laparoscopic era: risk factors, presentation, and management. McGill Gallstone Treatment Group. Wait-and-see policy or laparoscopic cholecystectomy after endoscopic sphincterotomy for bile-duct stones: a randomised trial Biliary colic treatment and acute cholecystitis prevention by prostaglandin inhibitor Prospective Evaluation of Emergency Versus Delayed Laparoscopic Cholecystectomy for Early Cholecystitis Effect of estrogen therapy on gallbladder disease. Viscero-visceral hyperalgesia: Characterization in different clinical models Comparison of frequency of wound infection: open vs laparoscopic cholecystectomy. Randomization to surgery or observation in patients with symptomatic gallbladder stone disease. The problem of evidence-based medicine in clinical practice. The analgesic effect of intravenous tenoxicam in symptomatic treatment of biliary colic: a comparison with hyoscine N-butylbromide. [Acute cholecystitis: timing of surgery]. Surgical infections after laparoscopic cholecystectomy: ceftriaxone vs ceftazidime antibiotic prophylaxis. A prospective study. Fish oil (n-3) polyunsaturated fatty acids beneficially affect biliary cholesterol nucleation time in obese women losing weight. Acute Cholecystitis: Early Versus Delayed Cholecystectomy, A Multicenter Randomized Trial (ACDC Study, NCT00447304) Management of acute cholecystitis in the laparoscopic era: Results of a prospective, randomized clinical trial
BACKGROUND Few studies have been done on the expectant management of patients with cholelithiasis diagnosed by planned investigation , and results are conflicting . METHODS A prospect i ve 6-year follow-up study of 153 patients with cholelithiasis diagnosed by oral cholecystography  was carried out . RESULTS An acute gallstone complication occurred during the follow-up period in 23 patients (15%)-that is , acute cholecystitis ( n = 18 ) , acute pancreatitis ( n = 2 ) , and jaundice ( n = 3 ) . The annual risk of developing an acute biliary complication was 3.1 % . A history of a gallstone complication predicted further gallstone complications during follow-up . The overall cholecystectomy rate was 20 % during the 1st year but fell to about 3 % during the 5th year of follow-up . Young age and frequent attacks of biliary pain episodes predicted the need for gallstone surgery . CONCLUSIONS Expectant management of patients with electively diagnosed cholelithiasis may be justified , especially in those with only occasional biliary symptoms and no history of gallstone complications BACKGROUND Recent management guidelines and r and omised clinical trials have provided evidence -based guidance to the management of acute  biliary pancreatitis and acute cholecystitis . METHODS A question naire was sent to the 1086 members of the Association of Surgeons of Great Britain and Irel and . There were 583 responders ( 54 % ) . RESULTS A policy of cholecystectomy during the index admission or within 4 weeks in fit patients recovering from mild acute biliary pancreatitis was adopted by 58 % of surgeons , and was significantly associated with an upper gastrointestinal and hepato-pancreato-biliary subspecialty interest and a volume of more than 50 cholecystectomies per annum ( OR , 0.43 ; 95 % CI , 0.26 - 0.72 ; P = 0.001 : and OR , 0.46 ; 95 % CI , 0.29 - 0.74 ; P = 0.001 , respectively ) . A policy of urgent cholecystectomy for acute cholecystitis was adopted by 20 % of surgeons , and was significantly associated with an upper gastrointestinal/hepato-pancreato-biliary subspecialty interest and the ' routine ' adoption of laparoscopic approach to  cholecystectomy  ( OR , 0.34 ; 95 % CI , 0.19 - 0.60 ; P < 0.001 : and OR , 0.51 ; 95 % CI , 0.3 - 0.86 ; P = 0.01 , respectively ) . CONCLUSIONS The management of cholelithiasis in patients with acute biliary pancreatitis in the UK remains suboptimal . Moreover , only a minority of surgeons offer patients presenting with acute cholecystitis the benefits of early laparoscopic cholecystectomy . The management of acute biliary disease may be improved if these cases were concentrated in the h and s of surgeons with upper gastrointestinal/hepato-pancreato-biliary interest and those who perform laparoscopic cholecystectomy regularly BACKGROUND The aim of the present study was to compare the risk of observation versus that of cholecystectomy in acute cholecystitis in patients r and omly allocated to delayed operation or conservative treatment . METHODS One-hundred- and -eighty patients were considered for participation in the study ; 71 were excluded according to predefined criteria and 45 did not join for other reasons . The remaining 64 patients were r and omized to cholecystectomy ( n = 31 ) or observation ( n = 33 ) . R and omized patients were contacted regularly and followed up for a median of 67 months . All gallstone-related hospital contacts were registered in both r and omized and excluded patients . RESULTS Gallstone-related complications or emergency admissions for pain occurred in six patients in the operation group ( 19 % ; 95 % CI 5%-33 % ) and in 12 patients ( 36 % ; 9 % CI 20%-53 % ) in the observation group . Twenty-seven of 31 patients r and omized to cholecystectomy had a  cholecystectomy  at a median of 3.6 months after r and omization , and , of these , 3 ( 11 % ; 95 % CI 0%-23 % ) suffered a major and 7 ( 26 % ; 95 % CI 9%-42 % ) a minor complication . Ten patients r and omized to observation later had their gallbladders removed , 1 ( 10 % ; 95 % CI 0%-29 % ) patient had a major and 1 ( 10 % ; 95 % CI 0%-29 % ) a minor complication . We found no mortality after cholecystectomy . CONCLUSIONS We found a certain risk of subsequent gallstone-related events following conservative treatment of acute cholecystitis , but the data also show that cholecystectomy should not necessarily be compulsory after acute cholecystitis BACKGROUND AND STUDY AIMS Surgery in elderly patients with acute cholecystitis is quite a high-risk procedure . The recent finding that activated pancreatic enzyme is present in sterile bile from the acutely inflamed gallbladder suggests that obstruction at the level of the common channel is a possible precipitating factor . It was therefore hypothesized that an initial endoscopic sphincterotomy in patients with acute cholecystitis might improve the clinical course . PATIENTS AND METHODS A prospect i ve unselected series of 105 patients over 65 years of age ( 52 men , 53 women ; mean age 78 ) suffering from acute cholecystitis were initially treated on a r and om basis with either conservative methods or endoscopic sphincterotomy . Within the first 72 h after the onset of symptoms , all 52 patients in the endoscopic sphincterotomy group were managed by endoscopic retro grade cholangiopancreatography ( ERCP ) , combined with endoscopic sphincterotomy in 50 cases . The main study parameter was the need for emergency cholecystectomy  within the first week after admission . RESULTS Biliary sepsis requiring emergency surgery occurred in 15 patients in the conservatively treated group , in contrast with none of the 52 patients in the endoscopic sphincterotomy group ( P < 0.001 ) . Iatrogenic complications after endoscopic sphincterotomy  occurred in three patients , one of whom required surgery , while two were managed by conservative means . The clinical course improved , avoiding the need for emergency cholecystectomy and other interventions , in 48 patients in the endoscopic sphincterotomy group and in 36 patients in the conservatively treated group ( P < 0.01 ) . CONCLUSIONS The clinical course after endoscopic sphincterotomy  improved in the majority of elderly patients suffering from acute cholecystitis , suggesting that early relief of obstruction at the level of the common channel reduces the risk of developing biliary sepsis . The majority of these patients can undergo surgery electively or can receive further conservative treatment AIMS To investigate the incidence , risk factors and natural history of gallstone disease , a r and om sample of females belonging to a rural population was enrolled in a ten-year longitudinal study . METHODS The study has been performed in a small town on the hills south of Rome . In 1985 , a r and om sample of 426 females , aged 20 - 69 years , was screened by real-time ultrasonography for gallstones and previous cholecystectomy .  Screening methods included anthropometry , collection of a blood sample and a question naire on the occurrence of abdominal symptoms . During 1995 , all these subjects were invited for a 10-year follow-up examination . RESULTS The overall 10-year incidence of gallstone disease was 6.3 % ( 5.5 % of new gallstones and 0.8 % of cholecystectomies ) . Only 23.1 % of the women with gallstones were aware of their condition . More than three quarters ( 76.9 % ) had not suffered biliary pain . Univariate and multivariate analyses demonstrated a positive independent association of new gallstone disease with body mass index and parity . Out of the initially asymptomatic gallstone women , 15.4 % experienced at least one episode of biliary pain , 23.1 % were su bmi tted to elective cholecystectomy and 61.5 % remained asymptomatic . CONCLUSIONS The study demonstrates a high incidence of gallstone disease in women belonging to a rural free-living population in Italy and suggests body mass index and parity as possible true risk factors . Moreover , it confirms that a remarkable proportion of asymptomatic patients become symptomatic and eventually undergo cholecystectomy Whether ursodeoxycholic acid ( UDCA ) therapy alters the long-term clinical course of gallstones ( GS ) without stone dissolution remains unknown . We aim ed to clarify the relationship between long-term UDCA therapy and risks of biliary pain or acute cholecystitis in GS patients . We also aim ed to identify factors affecting the natural course , and to explore a simple patient selection criteria for UDCA therapy . A cohort of 527 uncomplicated GS patients with or without UDCA ( 600 mg/d ) followed for up to 18 years was analyzed . Patients who had frequent attacks or were complicated with cholecystitis were converted to cholecystectomy . History and UDCA therapy were identified on Cox analysis as 2 factors affecting the long-term clinical course . In patients without therapy , history was the only predictor of biliary pain among various patient or stone characteristics ; biliary pain was rare in asymptomatic patients , while frequent in symptomatic patients ( P < .001 ) . UDCA therapy was associated with reduced risk for biliary pain in both symptomatic ( 62 % vs. 92 % in untreated patients at 10 years ; P < .001 ; relative risk , 0.19 ; 95 % CI , 0.10 - 0.34 ) and asymptomatic patients ( 6 % vs. 12 % in untreated patients at 10 years ; P = .037 ; relative risk , 0.19 ; 95 % CI , 0.04 - 0.91 ) . Risk for the conversion was also reduced in UDCA-treated symptomatic patients ( 26 % vs. 88 % in untreated patients at 10 years , P < .001 ; relative risk , 0.08 ; 95 % CI , 0.03 - 0.22 ) . These effects were independent of stone dissolution . Three factors were identified on Cox analysis as affecting GS dissolution : radiolucency , small size ( < 10 mm ) of stones , and visualized gallbladder ( GB ) on cholecystogram . A selection criteria based on these appears to exhibit high sensitivity ( 74 % ) and specificity ( 95 % ) for dissolution . UDCA therapy might be considered in symptomatic patients fulfilling these criteria , and also in patients who have significant surgical risk , because the longterm therapy is clearly associated with reduced risk of biliary pain and acute cholecystitis Abstract Background . Cholecystectomy is routinely recommended to prevent recurrent disease after an initial episode of acute cholecystitis . Therefore , r and omized controlled trials have mainly focused on the timing of surgery , but many patients scheduled for cholecystectomy have deferred surgery with long periods of symptom-free intervals . Our present aim is to examine the long-term feasibility and safety of observation compared with surgery . Methods . Trial of 64 patients with acute cholecystitis previously r and omized to observation or cholecystectomy  , which examined outcome in terms of completed r and omized treatment and appearance of further symptoms and the need for surgical treatment .  Thirty-three patients were r and omized to observation and 31 patients to cholecystectomy .  Median follow-up was 14 years . Results . Of the 33 patients r and omized to observation , 11 ( 33 % ) experienced a new event of gallstone-related disease ( eight ( 24.2 % ) had acute cholecystitis ) and 11 ( 33 % ) were operated . No significant difference ( p = 0.565 ) was found between the two r and omized groups with regard to recurrent disease or complications . Virtually no surgery took place after 5 years of follow-up . The difference in completed r and omized treatment between the groups was not significant ( p = 0.077 ) . Long-term mortality was equal in those operated and in those observed . Conclusions . Twenty-four percent of the patients experienced recurrent cholecystitis , but escalation of disease severity or increased mortality was not observed . Long-term observation after acute cholecystitis was feasible in two-thirds of the patients as the risk for recurrent disease was negligible after 5 years Background / Aims : Cholecystectomy is considered the treatment of choice for symptomatic gallstone disease . Some patients abstain from surgery and provide the opportunity to study the natural history of cholelithiasis . The aim of the present study was to examine the feasibility and safety of observation after extended long-term follow-up in a r and omized controlled trial . Methods : A total of 137 patients ( 40.5 % of those assessed ) were r and omized to observation or cholecystectomy and followed up for 14 years . The prevalence of symptomatic events or major complications after treatment was the primary end point . A secondary end point was completion of r and omized treatment . Results : There were no differences in outcome between the observation group and the surgical group ( p = 0.298 ) . Virtually no  cholecystectomy  was performed after 5 years of follow-up , and no clear escalation in the severity of the disease was observed . A total of 50.7 % of patients from the observation group and 88.2 % from the surgical group underwent surgery . The group r and omized to surgery completed their design ated treatment significantly more often ( p < 0.001 ) , especially among patients younger than 70 years of age ( p = 0.005 ) . Conclusion : Cholecystectomy was the preferred treatment after extended long-term follow-up , but conservative management for symptomatic gallstone disease is an alternative to surgery in the elderly BACKGROUND The uncertainty around true clinical manifestations of gallbladder stone disease is in contrast with the unanimous recommendation that only symptomatic gallstones should be treated . AIM To evaluate the relationship between biliary pain , other gastrointestinal symptoms and gallstones . DESIGN OF STUDY A pragmatic , prospect i ve cohort question naire study . SETTING Seventy-five general practice s in Rotterdam , The Netherl and s. METHOD All patients suspected by their general practitioner ( GP ) to have gallstone disease underwent ultrasound examination of the upper abdomen .  Using a self-administered question naire , the presence of 11 gastrointestinal symptoms was assessed at inclusion and after 1 year . Likelihood ratios ( LRs ) for the presence of gallstones and symptom relief rates after 1 year were calculated . The mean difference in health status at inclusion and after follow-up was calculated for patients without gallstones , for patients with gallstones who were operated on and for patients with gallstones who were not operated on . RESULTS In total , 61 % of the patients with gallstones diagnosed by ultrasound scan reported biliary pain , as did 45 % of the patients without gallstones ( LR = 1.34 , 95 % confidence interval [ CI ] = 1.05 to 1.71 ) . Patients operated on for gallstone disease did not show significant relief of biliary pain compared to patients not operated on for gallstones or patients without gallstones ( 87 % , 63 % and 83 % , respectively ) . Health status improved in all patients . The mean improvement in health status did not differ between the three patient groups . GPs were able to discriminate between patients with high and low probability of gallbladder stones by ultrasound examination ( 53 % versus 23 % ) . This selection , however , did not predict the outcome of cholecystectomy . CONCLUSION Neither biliary pain nor any other gastrointestinal symptom was consistently related to gallstone disease . Therefore , the indication for elective cholecystectomy can not be based on the presence of biliary pain alone . Relief of biliary pain in patients operated on for gallstones should not simply be attributed to a successful cholecystectomy After removal of the gallbladder , pain may persist in some patients . To study this condition , 124 patients from two r and omized trials , including those with symptomatic noncomplicated gallbladder stones ( n = 90 ) and acute cholecystitis ( n = 34 ) , were interviewed , while 139 patients ( 90 % ) excluded from both trials responded to a question naire 5 years after the operation . Thirty-four patients ( 27 % ) of those r and omized had pain ; 23 ( 18 % ) had diffuse , steady pain ; and 11 ( 9 % ) had pain attacks resembling their preoperative symptoms . Asignificant dominance of diffuse pain occurred inwomen(P = 0.024 ) , especially those younger than 60 years ( P = 0.004 ) . A tendency for the diffuse type to be dominant was also present in the group of female patients with symptomatic noncomplicated gallbladder stones ( P = 0.052 ) . Of the excluded patients , 18 % ( 25/139 ) had pain , but 88 % of them ( 96 % of the men and 87 % of the women ) were satisfied with the result of the operation . The overall number of patients with postoperative pain was 22 % ( 59/263 ) . We conclude that persisting abdominal pain 5 years after the operation was mainly of a nonspecific type , found mostly in younger women who had had noncomplicated gallstone disease . Eightyeight percent of the excluded patients declared themselves satisfied with the result of cholecystectomy The National Cooperative Gallstone Study , a double-masked , placebo-controlled , therapeutic trial of chenodiol ( chenodeoxycholic acid ) , provided an opportunity to study the natural history of cholelithiasis in patients who choose nonsurgical management . The major component of the study comprised 916 patients , 305 of whom were r and omly assigned to receive a placebo for 24 months . Among these 305 patients , the probability of having biliary tract pain during the 24 months of prospect i ve evaluation was significantly increased if the patient had had a history of biliary tract pain in the 12 months before entry into the study ( 69 % versus 31 % ) . Thirty-eight percent of patients had stone growth ( greater than 0.5 cm3 ) , and 18 % had a spontaneous decrease in stone volume . Despite the high incidence of biliary tract pain , nonelective cholecystectomy was required in only 4 % of patients during the 24 months Background : The aim of this prospect i ve , r and omized study was to determine if health related quality of life is affected by the choice of surgical strategy in the management of acute cholecystitis . Material and Methods : After diagnostic workup , patients were r and omized to one of two groups : ( 1 ) early laparoscopic cholecystectomy  ( i.e. within 7 days after onset of symptoms ) or ( 2 ) initial conservative treatment followed by delayed laparoscopic cholecystectomy .  Seventy-four patients entered the early operation group and 71 patients were assigned to the delayed  operation  strategy . Assessment s of quality of life were made at 1 , 3 and 6 months after surgery , and in the delayed operation group also one month after the initial conservative treatment . Results : The gastrointestinal symptom scores were significantly better in three dimensions ( diarrhea , indigestion , abdominal pain ) one month after surgery for the acute operation group ( p < 0.01 ) . Three and 6 months after the operation we were unable to detect any significant differences between the groups . The patients in the delayed operation group did not appear to suffer from more symptoms in the period of time waiting for their elective operation . Psychological general well-being showed no major differences between the groups . Conclusion : Cholecystectomy in the acute phase of acute cholecystitis offers a significant reduction of gastrointestinal symptoms during the first postoperative month and to that associated improved quality of life in this group of patients Gallstone pancreatitis is usually related to small stones , which may not be detected by conventional cholecystographic techniques . In the current study , it was hypothesized that some patients with acute pancreatitis of unknown cause could harbor occult microstones in the gallbladder . Therefore , evidence was sought prospect ively of missed gallstones by biliary drainage and microscopic examination of centrifuged duodenal bile in 51 patients recovering from an attack of acute pancreatitis , including 24 patients with relapsing episodes . Clusters of cholesterol monohydrate crystals , calcium bilirubinate granules , and /or CaCO3 microspheroliths were found in 67 % of the patients . Biliary drainage showed no abnormal findings in 12 patients convalescing from a bout of known alcoholic pancreatitis . Examination of gallbladder bile at cholecystectomy and /or serial ultrasonography of the gallbladder for up to 12 months showed that 73 % of the patients with unexplained pancreatitis had biliary sludge or microlithiasis ; the prior finding of biliary crystal/solid markers predicted their existence with both a sensitivity and a specificity of 86 % and a predictive value of 94 % . The probability of harboring occult gallstones was also associated with age ( P = 0.004 ) , prior recurrent pancreatitis ( P = 0.024 ) , and altered liver function tests results during an index episode ( P = 0.003 ) . In 13 patients with cholesterol monohydrate crystals in bile , ursodeoxycholic acid ( 10 mg.kg-1.day-1 ) eliminated gallbladder microlithiasis within 3 - 6 months , and subsequent maintenance treatment with a daily dose of 300 mg prevented both gallstone recurrence and further attacks of pancreatitis over a mean follow-up period of 44 months . Cholecystectomy also prevented gallstone-associated relapses in 17 of 18 patients followed up for a mean postoperative period of 36 months . This study provides firm evidence showing that in most patients with idiopathic acute pancreatitis , the disease is related to microscopic gallstones , as evidence d by the follow-up development of macroscopic stones or sludge and by the prevention of relapses with either cholecystectomy or a cholelitholytic bile acid . Occult gallstones should be strongly suspected when acute pancreatitis of unknown cause occurs in a relapsing manner and in aged patients and when it is associated with altered liver function test results . Biliary microscopy and /or follow-up ultrasonography of the gallbladder provide a simple means of uncovering them to institute appropriate therapy and prevent further attacks Abstract . This prospect i ve study determines the indications for and the optimal timing of laparoscopic cholecystectomy ( LC ) following the onset of acute cholecystitis . It also evaluates preoperative and operative factors associated with conversion from laparoscopic cholecystectomy to open cholecystectomy in the presence of acute cholecystitis . Having been established as the procedure of choice for elective cholelithiasis , LC is now also used for management of acute cholecystitis . Under these circumstances the procedure may be difficult and challenging . Certain favorable and unfavorable conditions may be present that influence the conversion and complication rates . Information about these conditions may be helpful for elucidating the optimal circumstances for LC or when the procedure is best avoided . We performed LC on an emergency basis as soon as the diagnosis was made on all patients presenting with acute cholecystitis from January 1994 to December 1995 . All preoperative , operative , and postoperative data were collected on st and ardized forms . Of the 137 patients registered , 130 were eligible for the audit . Seven patients found by laparoscopic intraoperative cholangiography to have choledocholithiasis were converted for common bile duct exploration and were excluded from the study . Altogether 93 patients ( 72 % ) underwent successful LC and 37 ( 28 % ) needed conversion to open cholecystectomy . The conversion rate of acute gangrenous cholecystitis ( 49 % ) was significantly higher than that for uncomplicated acute cholecystitis ( 4.5 % ) ( p < 0.00001 ) and for hydrops ( 28.5 % ) and empyema of the gallbladder ( 28.5 % ) ( p= 0.004 ) . The difference in conversion between the group with acute necrotizing ( gangrenous ) cholecystitis and the two groups with hydrops and empyema of the gallbladder was not statistically significant ( p= 0.07 ) . The complication rates of acute cholecystitis , hydrops , empyema of the gallbladder , and gangrenous cholecystitis were 9.0 % , 9.5 % , 14.0 % , and 20.0 % , respectively ( p= NS ) . Patients with an operative delay of 96 hours or less from the onset of acute cholecystitis had a conversion rate of 23 % , whereas a delay of more than 96 hours was associated with a conversion rate of 47 % ( p= 0.022 ) . The complication rate was 8.5 % in the laparoscopic group and 27 % in the converted group ( p= 0.013 ) . Patients over 65 years of age , with a history of biliary disease , a nonpalpable gallbladder , WBC count over 13,000/cc , and acute gangrenous cholecystitis were independently associated with a high LC conversion rate ; male patients , finding large bile stones , serum bilirubin over 0.8 mg/dl , and WBC count over 13,000/cc were independently associated with a high complication rate following laparoscopic surgery with or without conversion . Generally , LC can be performed safely for acute cholecystitis , with acceptably low conversion and complication rates . Different forms of cholecystitis carry various conversion and complication rates in selected cases . LC for acute cholecystitis should be performed within 96 hours of the onset of disease . Predictors of conversion and complications may be helpful when planning the laparoscopic approach to acute cholecystitis To estimate patient preferences for gallstone-related treatments and outcomes , and assess how preferences vary by patient characteristics and scaling technique , the authors r and omly assigned 40 patients without gallstones to interviews based on a rating scale ( n = 22 ) and a st and ard gamble ( n = 18 ) . The patients assigned preference values ( possible values 0 to 1 ) to open cholecystectomy ( mean 0.45 by rating scale , 0.78 by st and ard gamble ) , laparoscopic cholecystectomy ( 0.71 , 0.91 ) , extracorporeal shock-wave lithotripsy ( 0.77 , 0.89 ) , acute cholecystitis ( 0.36 , 0.77 ) , lifetime biliary colic ( 0.41 , 0.71 ) , postcholecystectomy syn drome ( 0.43 , 0.79 ) , asymptomatic stone necessitating treatment with bile acids ( 0.76 , 0.96 ) , and surgical scar ( 0.79 , 0.998 ) . Preferences varied little by age , gender , or race . St and ard gamble values were highly correlated with , but significantly greater than , rating scale values . The authors conclude that  patients ' preferences for gallstone-related conditions generally are significantly less than one , and differ markedly by the scaling technique used to derive them . These results should be considered when patient preferences are incorporated into analyses of gallstone treatments . Key words : patient preference values ; rating scale ; stan dard gamble ; gallstones ; cholecystectomy ; lithotripsy . ( Med Decis Making 1994;14:307- 314 BACKGROUND & AIMS Nonsteroidal anti-inflammatory drugs ( NSAIDs ) have been used to relieve biliary colic . Follow-up was limited in previous studies , and the role of NSAIDs in the natural history of biliary colic has not been clarified . The purpose of this study was to evaluate the efficacy of diclofenac , a potent NSAID , in the the immediate symptomatic relief of biliary colic and the prevention of cholelithiasis-related complications . METHODS Fifty-three patients with cholelithiasis and biliary colic were enrolled in this r and omized , double-blind , placebo-controlled study . They received a single 75-mg ( 3 mL ) intramuscular injection of diclofenac ( n = 27 ) or similarly administered 3 mL of saline ( n = 26 ) . All patients were followed up for at least 3 days . The effect of either treatment was assessed by changes in the severity of pain and the development of cholelithiasis-related complications . RESULTS Complete relief of pain was obtained in 21 diclofenac and in 7 placebo patients ; progression to acute cholecystitis was observed in 4 and 11 patients , respectively . Fewer overall complications were observed in the diclofenac group . CONCLUSIONS In patients with cholelithiasis who present with biliary colic , a single 75-mg intramuscular dose of diclofenac can provide satisfactory pain relief and decrease substantially the rate of progression to acute cholecystitis The prevalence of gall stone disease in a stratified r and om sample of 1896 British adults ( 72.2 % of those approached ) was established using real time ultrasound . The prevalence rose with age , except in women of 40 - 49 years , so that at 60 - 69 years , 22.4 % of women and 11.5 % of men had gall stones or had undergone cholecystectomy . The  cholecystectomy rate of people with gall stone disease was higher in women than in men ( 43.5 % v 24 % , p less than 0.05 ) . Very few subjects with gall stones had convincing biliary symptoms . In women , 10.4 % had symptoms according to a question naire definition of biliary pain and 6.3 % according to conventional history taking , while no men at all admitted to biliary pain . Nevertheless , cholecystectomy in men had nearly always been preceded by convincing biliary symptoms . The age at cholecystectomy  was , on average , nine years less than the age at detection of silent gall stones in both sexes . It is concluded that either gall stones are especially prone to cause symptoms in younger people or that there are two kinds of cholelithiasis - symptomatic and silent . The lack of symptomatic gall stones in cross sectional surveys is probably due to their rapid diagnosis and treatment Abstract . Bile duct injury ( BDI ) during  laparoscopic cholecystectomy ( LC )  which may result in patient disability or death are reported to occur more frequently when compared to open surgery . The aim of this nationwide prospect i ve study beyond the laparoscopic learning curve was to analyze the incidence , risk factors , and management of major BDI . During a 3-year period ( 1995–1997 ) 130 items of all LC data were collected on a central computer system from 84 surgical institutions in Switzerl and by the Swiss Association of Laparoscopic and Thoracoscopic Surgery and evaluated for major BDIs . Simple biliary leakage was excluded from analysis . There were 12,111 patients with a mean age of 55 years ( 3–98 years ) enrolled in the study .  The overall BDI incidence was 0.3 % , 0.18 % for symptomatic gallstones , and 0.36 % for acute cholecystitis . In cases of severe chronic cholecystitis with shrunken gallbladder , the incidence was as high as 3 % . Morbidity and mortality rates were significantly increased in BDIs . BDI was recognized intraoperatively in 80.6 % , in 64 % of cases by help of intraoperative cholangiography . Immediate surgical repair was performed laparoscopically ( suture or T-drainage ) in 21 % ; in 79 % , open repair ( 34 % simple suture , 66 % Roux-en-Y reconstruction ) was needed . The BDI incidence did not decrease during the last 7 years . In 47 % , BDIs were caused by experienced laparoscopic surgeons , perhaps because they tend to operate on more difficult patients . In conclusion , the incidence of major BDIs remains constant in Switzerl and at a level of 0.3 % , which is still higher when compared to open surgery . However , most cases are now detected intraoperatively and immediately repaired which ensures a good long-term outcome . For preventing such injuries , exact anatomical knowledge with its variants and a meticulous surgical dissecting technique especially in case of acute inflammation or shrunken gallbladder are m and atory INTRODUCTION In our population biliary tract diseases are the most frequent surgical entity . If the diagnosis of acute cholecystitis is relatively clear and the time from onset of the disease does not exceed 72 hours , early cholecystectomy is recommended . The aim of this prospect i ve study was to use certain analytical procedures in order to compare early and late results of early and delayed cholecystectomy . MATERIAL AND METHODS 240 patients were divided into two groups : Group I : patients treated by early cholecystectomy and Group II : patients treated by delayed cholecystectomy .  We compared the following : intraoperative findings , postoperative morbidity and mortality , complications , average number of patient-days and histopathological changes . RESULTS During the investigated period ( 1998 - 1999 ) , 599 ( 35.95 % ) patients with acute and 1.067 ( 64.05 % ) patients with chronic cholecystitis were treated at the Clinic of Abdominal and Endocrine Surgery of the Clinical Center Novi Sad . Out of 599 patients with acute cholecystitis , 489 ( 81.63 % ) patients underwent surgery , whereas 110 ( 18.37 % ) were treated conservatively . In regard to chronic cholecystitis , 963 ( 90.25 % ) patients were surgically treated , and 104 ( 9.75 % ) patients were conservatively treated . All patients from Group I were operated within 24 - 48 hours from onset of the disease or during 24 hours of hospitalization . They were hospitalized due to signs of cholecystitis for the first time , whereas this was the second hospitalization for all patients from Group II , 42 + /- 2.3 days after first hospitalization on average . Regarding sick leave in Group I patients it was calculated as follows : hospital days + home treatment and it made 32 + /- 3.7 days . In Group II it was calculated as follows : first hospitalization + home treatment + second hospitalization + home treatment making 53 + /- 6.7 days . CONCLUSIONS The number and type of early and late complications in Group II patients justifies early cholecystectomy ; in acute cholecystitis , cholecystectomy should be performed within 24 - 48 hours from the onset of the disease ; in regard to late , early cholecystectomies are characterized by significantly shorter period of recovery and sick leave During the cross-sectional studies ( February 1981 to July 1984 ) performed by the Group for Epidemiology and Prevention of Cholelithiasis ( GREPCO ) in Rome , Italy , 161 subjects were identified as having gallstones . Ten subjects did not participate in the prospect i ve follow-up . At entry , 33 of the 151 remaining subjects were symptomatic , and 118 were asymptomatic . Data on incidence of biliary colics , complications , cholecystectomy , and death were collected at least every 2 years . In the initially asymptomatic group , the cumulative probability ( % + /- SE ) of developing biliary colic was 11.9 + /- 3.0 at 2 years , 16.5 + /- 3.5 at 4 years , and 25.8 + /- 4.6 at 10 years . None of the variables considered as possible modifiers of the natural history were found to be associated with an increased risk of developing biliary colic . The cumulative probability ( % + /- SE ) of developing complications after 10 years was 3.0 + /- 1.8 in the initially asymptomatic group and 6.5 + /- 4.4 in the symptomatic group ( P = NS ) . Incidence of cholecystectomy was higher in the initially symptomatic than in the asymptomatic group ( log-rank test = 2.27 ; P = .02 ) . Fifteen ( 53.6 % ) of the 28 operated in the initially asymptomatic group were su bmi tted to cholecystectomy , although specific symptoms did not occur . Twelve ( 10.2 % ) and 2 ( 6.1 % ) of the initially asymptomatic and symptomatic subjects died during the follow-up . One patient in the former group died at age 64 of a histologically proven adenocarcinoma of the gallbladder . In conclusion , this study demonstrates that the natural history of gallstones is less benign than is generally considered BACKGROUND Emergency laparoscopic cholecystectomy has been advocated for the treatment of acute cholecystitis ; however it can be a difficult task , especially in public hospitals , with relatively high conversion and complication rates . Percutaneous cholecystostomy is a simple and effective procedure allowing patients to recover from the acute event and undergo elective laparoscopic surgery at a later stage . METHODS We prospect ively assessed a protocol of initial conservative treatment in patients admitted with acute cholecystitis . Patients who did not respond to medical treatment were treated by percutaneous cholecystostomy .  Following discharge the patients were seen in the outpatient clinic and elective laparoscopic cholecystectomy was considered and scheduled as necessary . The details of the operation were collected with emphasis on complications and conversion rate . RESULTS During a 3-year period , 224 patients who were admitted with acute calculous cholecystitis entered the protocol . Fifty-four patients did not improve under medical treatment and percutaneous cholecystostomy was performed . In spite of adequate drainage , 5 patients still did not improve : 3 patients were successfully operated upon urgently and recovered , while 2 patients who had severe concomitant diseases and multi-organ failure , died . Forty-nine patients were discharged with the catheter and later re-evaluated for elective operation . In 7 patients common bile duct stones were found and were removed by ERCP prior to the elective operation . Twenty-five patients underwent delayed laparoscopic cholecystectomy with a low conversion rate ( 8 % ) , and only minor complications ( 16 % ) . CONCLUSIONS Conservative treatment and delayed operation is still an acceptable choice in the treatment of acute cholecystitis . Percutaneous cholecystostomy is an effective tool , with high success rate and low morbidity , and allows for better pre-operative evaluation of the biliary system and safe interval laparoscopic surgery . Laparoscopic cholecystectomy after drainage of the gall bladder is a low morbidity procedure with relatively low conversion rate Laparoscopic cholecystectomy has become the new gold st and ard for management of symptomatic gallstones .  Prophylactic antibiotics are used in elective surgery by the majority of surgeons , and their role in biliary tract surgery has been well established for a sub population of high-risk patients . This consensus has been derived from multiple studies involving biliary tract surgery before and in the era of laparoscopic cholecystectomy . But the use of prophylactic antibiotics in laparoscopic cholecystectomy especially in the low-risk group is now controversial and varied among the surgeons all over the world . To study the role of prophylactic antibiotics in laparoscopic cholecystectomy in different risk groups of patients , a prospect i ve study was conducted in the Department of Surgery of Bankura Sammilani Medical College and Hospital from January 2010 to July 2011 . All patients with symptomatic gallstones who underwent elective laparoscopic cholecystectomy during this period are included in this study . One hundred and two patients with symptomatic gallstones were operated on by laparoscopic technique  without receiving preoperative  antibiotics and studied over a period of 1.5 years . Ages ranged from 11 to 70 years ( mean age of 33 years ) . There were 14 males ( 13.72 % of the patients ) and 88 females ( 86.27 % of the patients ) . There was no wound infection ( class I ) in 99 patients , and class II type of wound infection , i.e. , surgical site infection , occurred in three patients ( i.e. , 2.94 % ) out of a total of 102 patients . Swabs were taken for culture and sensitivity ; Staphylococcus aureus was found in two patients and Streptococcus viridans in one patient . In all three patients , infection occurred at the umbilical port sites , detected on the 3rd and 4th postoperative days . Antibiotic prophylaxis is not necessary in low-risk patients with symptomatic gallstone disease undergoing elective laparoscopic cholecystectomy to prevent postoperative infection-related complications . Preoperative skin preparation with chlorhexidine gluconate scrub may replace the use of prophylactic antibiotics for prevention of infection-related complications in patients undergoing elective laparoscopic cholecystectomy BACKGROUND Patients frequently have persistent abdominal symptoms after undergoing cholecystectomy .  The relationship between abdominal symptoms and biliary dysfunction is often unclear . OBJECTIVES To describe the persistence rate of abdominal symptoms in a large cohort of patients after elective cholecystectomy  , to identify predictors of symptom persistence and operative success , to underst and which symptoms improve after cholecystectomy , and to describe the important determinants of an unsuccessful operation . METHODS Secondary analysis of a prospect i ve , multisite cohort study of 2481 patients undergoing elective cholecystectomy .  RESULTS The mean + /- SD number of abdominal symptoms per patient decreased from 3.1 + /- 2.0 to 1.1 + /- 1.3 ; 27 % of patients who identified a symptom as most bothersome before surgery still had the symptom 6 months after surgery . Symptom persistence rates ranged from 5.6 % ( vomiting ) to 40.2 % ( gas/flatulence ) . A balance score that quantified the abdominal symptom mix between dyspeptic and biliary symptoms shifted after surgery to the dyspeptic category . Predictors of persistence of a most bothersome symptom were dyspeptic symptom category , worse operative risk and self-rated health status , symptom duration longer than 6 months , and no previous episodes of acute cholecystitis . The major correlate of not achieving a very successful outcome ( 15.2 % of patients ) was the presence of postoperative abdominal pain . Other predictors included worse self-rated health status and physical functioning , symptom duration longer than 6 months before surgery , and no previous episodes of acute cholecystitis . CONCLUSIONS Symptoms categorized as dyspeptic were more likely to persist than were biliary symptoms , although all symptoms showed a decrease in prevalence after cholecystectomy . More attention to the rationale for gallbladder removal and clarification of patient expectations for symptom relief might be necessary to improve outcomes after elective cholecystectomy Data from the Third National Health and Nutrition Examination Survey ( 1 ) indicate that 11 % of U.S. women have a history of clinical gallbladder diseasethat is , either previous cholecystectomy or self-reported history of gallstones . Factors associated with gallbladder disease , at least in some studies , include older age , female sex , white ethnicity/race , obesity , rapid weight loss , and , among women , greater parity , use of oral estrogencontaining contraceptives , and postmenopausal estrogen therapy ( 2 ) . These associations , in general , have been based on observational data and may partly reflect the effects of ascertainment and recall bias , as well as confounding . While some observational studies suggest that estrogens increase the risk for gallbladder disease by as much as twofold to fourfold ( 3 ) , such an association has not been reported consistently ( 2 , 3 ) . The effect of combined estrogen plus progestin therapy has been less well studied , and no recent clinical trial data exist on the relation of such therapy to the risk for biliary tract surgery among postmenopausal women . To determine whether estrogen plus progestin therapy is associated with the risk for biliary tract surgery among postmenopausal women , we analyzed data from the Heart and Estrogen/progestin Replacement Study ( HERS ) , the first large r and omized , double-blind trial of estrogen plus progestin therapy for the secondary prevention of coronary heart disease ( 4 ) . Gallbladder disease events , including biliary tract surgery , were among several prespecified secondary outcomes of interest . Methods Participants Between 1 February 1993 and 1 October 1994 , 2763 postmenopausal women with coronary artery disease were recruited from 20 clinical centers across the United States for participation in HERS , a r and omized , double-blind study of the effect of combined , continuous estrogenprogestin therapy ( conjugated equine estrogens , 0.625 mg/d , and medroxyprogesterone acetate , 2.5 mg/d ) on recurrent coronary heart disease events . Baseline data , which were collected at the visits for initial screening and r and om allocation , included demographic characteristics , medical history , risk factors for coronary heart disease , physical examination , and laboratory data . Women were not eligible to enroll in HERS if they had used any estrogen or female hormones within the previous 3 months , including pills , suppositories , injections , vaginal creams , or transdermal patches . We excluded 510 women from these analyses who reported at enrollment a history of surgical gallbladder removal . We did include , however , 123 women with a self-reported history of gallstones who had not undergone cholecystectomy . After these exclusions , data from 2253 participants were available for analysis . Measurements Baseline data included participant age , years of education , number of pregnancies , ethnicity/race ( white , African American , or other ) , past use of postmenopausal estrogen therapy , history of cigarette smoking , history of alcohol consumption , and diabetes mellitus . Data were also obtained on use of lipid-lowering medications and antihypertensive medications , including thiazide diuretics .  Participants who stated that they had smoked at least 100 cigarettes in their life were considered to have a history of smoking . Participants were asked , Has a doctor told you that you had diabetes , sugar diabetes , or high blood sugar ? Those who answered yes were classified as having a history of diabetes . Women with a history of gestational diabetes only were classified as not having diabetes mellitus . Participants were weighed without shoes or outdoor clothing on a st and ard balance-beam scale to the nearest 0.1 kg . Height was measured to the nearest 0.1 cm by using the height rod of a st and ard beam scale or , where available , a wall-mounted stadiometer . We calculated the body mass index as weight (kg)/height ( m2 ) . At baseline , year 1 , and the end of the study , serum lipid and lipoprotein levels were obtained from all participants and were measured at the Johns Hopkins Lipoprotein Analytical Laboratory , Baltimore , Maryl and , which is certified by the U.S. Centers for Disease Control and Prevention for the measurement of serum lipids and lipoproteins . Ascertainment of End Points Participants were determined to have incident gallbladder disease by physician adjudicators who were blinded to the r and omization status [ active hormone treatment or placebo ] . Symptomatic nonsurgical biliary tract disease was defined as a hospital admission for acute cholecystitis , choledocholithiasis , or gallstone pancreatitis and was established on the basis of 1 ) reported symptoms in combination with elevated levels on liver function testing and gallstones with dilated biliary ducts on abdominal ultrasonography or 2 ) nuclear medicine scan diagnostic of acute gallbladder disease . Incident biliary tract surgery , which included  cholecystectomy , sphincterotomy , or bile duct exploration  , was established by review of operative reports and discharge summaries . All biliary tract surgeries were cholecystectomies with the exception of 12 sphincterotomies and 2 stent insertions . Nonsurgical and surgical gallbladder disease events were considered separate end points and are mutually exclusive . The main HERS results , reported in 1998 ( 4 ) , were based on the near-final data available at that time . We present the up date d and final results for incident biliary tract events ( 5 ) . Statistical Analysis We used unpaired two-tailed t-tests to compare the age , level of education , number of pregnancies , body mass index , alcohol consumption , serum lipid level , and lipoprotein levels of the women r and omly assigned to receive postmenopausal hormone therapy or placebo .  Using chi-square tests , we compared the hormone therapy and placebo groups according to ethnicity/race , history of lipid-lowering medication use , pre study postmenopausal estrogen use , thiazide diuretic use , cigarette smoking , ascorbic acid supplement use , history of gallbladder disease , and diabetes mellitus . The treatment groups were divided fairly equally with respect to baseline variables , except for statin use . To analyze the association between postmenopausal hormone therapy and incident gallbladder disease events , we used unadjusted and statin useadjusted proportional hazards models . All risk estimates were derived solely from proportional hazards models . We also estimated KaplanMeier curves for time to occurrence of biliary tract surgery , according to treatment assignment . The number of participants needed to be treated for a new case of biliary tract surgery to occur was calculated by using the incidence rates per person-year of observation . For predictor variables other than treatment assignment , we calculated the hazard ratio and 95 % CI by using proportional hazards regression models to estimate the risk for incident biliary tract surgery . We used simple regression models that controlled only for treatment assignment ; we also used multivariable regression models that included variables with a previously reported association with gallbladder disease . Our model-fitting methods relied primarily on biological criteria ; we began by including factors previously reported to be associated with gallbladder disease . Although the risk for type I errors is always present when c and i date predictors are many relative to the number of outcomes , our model-building process accounted for this possibility when we considered the statistical significance of the result ing multivariable model . Results were confirmed by using stepwise and backwards selection methods . We identified one statistically significant interaction between postmenopausal hormone treatment and smoking . Adjustment for this interaction did not substantially affect the hazard ratios for other variables entered in the multivariable models . We performed these analyses by using SAS software ( 6 ) . A correlation between outcomes at each clinical center could potentially affect the SEs for the relative hazard estimates . Therefore , to control for such potential clustering by center , we used STATA software ( 7 ) to generate robust SEs for the proportional hazards models ( 8) . Because site-specific practice patterns could confound the relation of statin use to biliary tract surgery , we also examined statistical models that included clinical center as a fixed effect . We calculated the number of participants needed to be treated to result in one additional biliary tract surgery  by using the reciprocal of the absolute risk increase . However , because the 95 % CI for the absolute risk increase included zero , the CI for the number needed to treat for harm ( NNTH ) included . We use a method described by Altman ( 9 ) to present the CI in these circumstances . The CI around the NNTH will therefore range from an NNTH to to a number needed to treat for benefit ( NNTB ) . Role of the Funding Source Wyeth-Ayerst Research funded HERS . The study was design ed and carried out by the HERS investigators , including scientists from Wyeth-Ayerst Research . Investigators at the HERS Coordinating Center at the University of California , San Francisco , collected the outcome data , supervised the adjudication of outcome events , and analyzed the data . Results Gallbladder disease was particularly prevalent among this cohort of postmenopausal women with coronary artery disease . Twenty-three percent of women reported a history of cholelithiasis or cholecystectomy at baseline ( 10 ) . With the exception of statin use , which was more prevalent among women assigned to receive placebo ( P = 0.01 ) , the distribution of baseline variables was similar in both treatment groups ( Table 1 ) . Approximately 23 % of the HERS participants had a history of pre-enrollment hormone use ; the type and duration did not differ between the treatment groups . Table 1 . Selected Baseline Characteristics of Postmenopausal Women Receiving Hormone Therapy or Placebo  in the Heart and Estrogen/progestin Replacement Study ( HERS ) A Background : Cholecystectomy is intended to relieve symptoms of gallstones , but unfortunately some patients will experience postcholecystectomy symptoms , including pain . There is limited information in the literature on gallstone‐related pain and its influence on quality of life . The aim of this study was to examine how pain and quality of life in patients with symptomatic , uncomplicated gallbladder stones were affected by observation of their condition compared with removal of the gallbladder . Methods : One‐hundred and thirty‐seven patients were r and omized to observation ( watchful waiting ; n = 69 ) or cholecystectomy ( n = 68 ) and answered question naires on pain , quality of life ( PGWB index and NHP Part II ) at r and omization and fixed intervals ( 6 , 12 and 60 months ) . All gallstone‐related events ( hospital admission for pain , complications of gallstone disease and cholecystectomy ) and crossover between treatment groups were recorded . Results : Of patients r and omized to observation , 35 of 69 patients ( 51 % ) eventually underwent a cholecystectomy . Significant improvements in quality of life and pain scores were detected regardless of surgical treatment . Patients that subsequently experienced gallstone‐related events had significantly higher pain scores at r and omization than patients that did not experience any subsequent events , and this difference was maintained throughout follow‐up . Conclusions : Unexpectedly , in the majority of patients symptoms did abate without any significant differences between groups in pain and quality of life . Patients that had high intensity and frequency of pain at r and omization had a higher risk of experiencing subsequent events Background / Aim : Delay of laparoscopic cholecystectomy after the diagnosis of biliary colic may increase the probability of recurrent emergency admission while awaiting elective cholecystectomy . The aim of this study was to compare the possible advantages and safety of urgent laparoscopic cholecystectomy ( ULC ) with elective laparoscopic cholecystectomy ( ELC ) in patients with biliary colic . Patients and Methods : Between 2001 and 2003 , 75 patients with biliary colic were included in this study . The patients were classified into following two groups : patients who had ULC in 24 h were in group I ( n = 28 ) and patients who had ELC ( mean interval 4.22 ± 1.42 months ) were in group II ( n = 35 ) . Conversion to open cholecystectomy , operative time , postoperative hospital stay , costs , and complications were evaluated . Results : In group II , 9 patients made a total of 13 return visits to the emergency department with recurrent attacks of biliary colic or complications of gallstone disease . Mean operative time increased from 35.1 ± 6.74 min for urgent laparascopic cholecystectomy to 49.9 ± 6.12 min for ELC ( p > 0.05 ) and hospital stay time increased from 1.06 ± 0.4 to 2.31 ± 2.36 days ( p < 0.05 ) . Conversion to open cholecystectomy increased from 0 % in group I to 17.2 % in group II ( p < 0.05 ) . Discussion : ULC for biliary colic may be the most medically efficacious and cost-effective treatment BACKGROUND The management of  bile leaks  has evolved in the laparoscopic era . This study characterizes risk factors for their developmental and their clinical course and management . METHODS Data on a cohort of patients who developed bile leaks after cholecystectomy in the laparoscopic era  were gathered prospect ively and retrospectively from an ongoing surgical data base and following a review of hospital charts . RESULTS Sixty-four patients ( mean age 56 + /- 17.1 years , 72 % women ) were included over a 5-year study period . The incidence of leaks was 1.1 % among patients entered in a  laparoscopic cholecystectomy data base . Intraoperative complications were encountered in 36 % . Rates of intraoperative complication and conversion to open surgery were greater among patients who developed leaks ( 5.2 % vs 0.6 % and 33 % vs 6.3 % , respectively , p < 0.00001 ) . Patients presented 5.3 + /- 4.2 days following surgery with abdominal pain ( 89 % ) , fever ( 74 % ) , and tenderness ( 81 % ) . Ultrasound diagnosed a suspected leak in 73 % , which ERCP showed as originating from the cystic duct stump in 77 % . Biliary obstruction was noted in 20 ( 31 % ) patients ( 14 with stones ) . Treatments included percutaneous ( 13 % ) , endoscopic ( 28 % ) , primary or secondary operative procedures ( 14 % ) , or a combination thereof ( 45 % ) . CONCLUSION A complication at laparoscopic cholecystectomy increases the likelihood of a subsequent bile leak . Most patients present early with a patent cystic duct stump in the absence of biliary obstruction . Endoscopic therapy is successful in the majority of cases , but otherwise percutaneous or operative procedures may be needed BACKGROUND Patients who undergo endoscopic sphincterotomy for common bile-duct stones , who have residual gallbladder stones , are referred for  laparoscopic cholecystectomy .  However , only 10 % of patients who do not have this operation are reported to develop recurrent biliary symptoms . We aim ed to assess whether a wait- and -see policy is justified . METHODS We did a prospect i ve , r and omised , multicentre trial in 120 patients ( age 18 - 80 years ) who underwent endoscopic sphincterotomy and stone extraction , with proven gallbladder stones . Patients were r and omly allocated to wait and see ( n=64 ) or laparoscopic cholecystectomy ( 56 ) . Primary outcome was recurrence of at least one biliary event during 2-year follow-up , and secondary outcomes were complications of cholecystectomy and quality of life . Analysis was by intention to treat . FINDINGS 12 patients were lost to follow-up immediately . Of 59 patients allocated to wait and see , 27 ( 47 % ) had recurrent biliary symptoms compared with one ( 2 % ) of 49 patients after laparoscopic cholecystectomy ( relative risk 22.42 , 95 % CI 3.16 - 159.14 , p<0.0001 ) . 22 ( 81 % ) of 27 patients underwent cholecystectomy , mainly for biliary pain ( n=13 ) or acute cholecystitis ( 7 ) . Conversion rate to open surgery was 55 % in patients allocated to wait and see who underwent cholecystectomy compared with 23 % in those who were allocated laparoscopic cholecystectomy ( p=0.0104 ) . Morbidity was 32 % versus 14 % ( p=0.1048 ) , and median hospital stay was 9 versus 7 days . Quality of life returned to normal within 3 months after either treatment policy . INTERPRETATION A wait- and -see policy after endoscopic sphincterotomy in combined cholecystodocholithiasis can not be recommended as st and ard treatment , since 47 % of expectantly managed patients developed at least one recurrent biliary event and 37 % needed cholecystectomy . No major biliary complications arose , but conversion rate was high Sixty patients were treated in the emergency ward for biliary colic . Cholelithiasis was proven by ultrasonography . Twenty patients ( group I ) were treated by placebo . Twenty patients ( group II ) were treated by papaverine , and 20 patients were treated by diclofenac sodium ( Voltaren ) ( group III ) . Twenty more patients ( group IV ) with low back pain ( LBP ) were treated with diclofenac sodium ( Voltaren ) as a control to assess the analgesic effect of Voltaren . Two interesting observations were made : Voltaren was proven more efficient for pain relief ( P<0.002 ) , and none of the patients treated with Voltaren were in need of hospitalization and immediate surgery . In comparison , nine patients of the other two groups progressed to acute cholecystitis and needed surgical intervention . The possible anticolic and anti-biliary inflammation properties and the indications for use of Voltaren are discussed Treatment of acute cholecystitis is still under debate . The aim of this study was to evaluate the efficacy of early laparoscopic cholecystectomy ( ELC ) in comparison with conservative treatment followed by delayed laparoscopic cholecystectomy ( DLC ) in the management of acute cholecystitis . This prospect i ve comparative study involved two groups of patients presenting with acute cholecystitis within 72 hours of the onset of symptoms . ELC was performed in 82 consecutive patients , whereas DLC was performed in 87 patients who previously underwent medical treatment .  Surgical variables , hospital stay , and postoperative morbidity were evaluated in both groups . Time of surgery and conversion rate were lower in the ELC group . Postoperative morbidity was similar in both groups . Overall hospital stay was shorter in the ELC group . ELC within 72 hours of the onset of acute cholecystitis is a safe procedure with better results than DLC in terms of surgical timing , conversion rate , and hospital stay CONTEXT Estrogen therapy is thought to promote gallstone formation and cholecystitis but most data derive from observational studies rather than r and omized trials . OBJECTIVE To determine the effect of estrogen therapy in healthy postmenopausal women on gallbladder disease outcomes . DESIGN , SETTING , AND PARTICIPANTS Two r and omized , double-blind , placebo-controlled trials conducted at 40 US clinical centers . The volunteer sample was 22,579 community-dwelling women aged 50 to 79 years without prior cholecystectomy . INTERVENTION Women with hysterectomy were r and omized to 0.625 mg/d of conjugated equine estrogens ( CEE ) or placebo ( n = 8376 ) . Women without hysterectomy were r and omized to estrogen plus progestin ( E + P ) , given as CEE plus 2.5 mg/d of medroxyprogesterone acetate ( n = 14,203 ) . MAIN OUTCOME MEASURES Participants reported hospitalizations for gallbladder diseases and gallbladder-related procedures , with events ascertained through medical record review . Cox proportional hazards regression was used to assess hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) using intention-to-treat and time-to-event methods . RESULTS The CEE and the E + P groups were similar to their respective placebo groups at baseline . The mean follow-up times were 7.1 years and 5.6 years for the CEE and the E + P trials , respectively . The annual incidence rate for any gallbladder event was 78 events per 10,000 person-years for the CEE group ( vs 47/10,000 person-years for placebo ) and 55 per 10,000 person-years for E + P ( vs 35/10,000 person-years for placebo ) . Both trials showed greater risk of any gallbladder disease or surgery with estrogen ( CEE : HR , 1.67 ; 95 % CI , 1.35 - 2.06 ; E + P : HR , 1.59 ; 95 % CI , 1.28 - 1.97 ) . Both trials indicated a higher risk for cholecystitis ( CEE : HR , 1.80 ; 95 % CI , 1.42 - 2.28 ; E + P : HR , 1.54 ; 95 % CI 1.22 - 1.94 ) ; and for cholelithiasis ( CEE : HR , 1.86 ; 95 % CI , 1.48 - 2.35 ; E + P : HR , 1.68 ; 95 % CI , 1.34 - 2.11 ) for estrogen users . Also , women undergoing estrogen therapy were more likely to receive cholecystectomy ( CEE : HR , 1.93 ; 95 % CI , 1.52 - 2.44 ; E + P : HR , 1.67 ; 95 % CI , 1.32 - 2.11 ) , but not other biliary tract surgery ( CEE : HR , 1.18 ; 95 % CI , 0.68 - 2.04 ; E + P : HR , 1.49 ; 95 % CI , 0.78 - 2.84 ) . CONCLUSIONS These data suggest an increase in risk of biliary tract disease among postmenopausal women using estrogen therapy .  The morbidity and cost associated with these outcomes may need to be considered in decisions regarding the use of estrogen therapy & NA ; Co‐existing algogenic conditions in two internal organs in the same patient may mutually enhance pain symptoms ( viscero‐visceral hyperalgesia ) . The present study assessed this phenomenon in different models of visceral interaction . In a prospect i ve evaluation , patients with : ( a ) coronary artery disease ( CAD ) + gallstone ( Gs ) ( common sensory projection : T5 ) ; ( b ) irritable bowel syndrome ( IBS ) + dysmenorrhea ( Dys ) ( T10‐L1 ) ; ( c ) dysmenorrhea/endometriosis + urinary calculosis (Cal)(T10‐L1 ) ; and ( d ) gallstone + left urinary calculosis ( Gs + LCal ) ( unknown common projection ) were compared with patients with CAD , Gs , IBS , Dys or Cal only , for spontaneous symptoms ( number/intensity of pain episodes ) over comparable time periods and for referred symptoms ( muscle hyperalgesia ; pressure/electrical pain thresholds ) from each visceral location . In patients ’ subgroups , symptoms were also re‐assessed after treatment of each condition or after no treatment . ( a ) CAD + Gs presented more numerous/intense angina/biliary episodes and more referred muscle chest/abdominal hyperalgesia than CAD or Gs ; cardiac revascularization or cholecystectomy also reduced biliary or cardiac symptoms , respectively ( 0.001 < p < 0.05 ) . ( b ) IBS + Dys had more intestinal/menstrual pain and abdomino/pelvic muscle hyperalgesia than IBS or Dys ; hormonal dysmenorrhea treatment also reduced IBS symptoms ; IBS dietary treatment also improved dysmenorrhea ( 0.001 < p < 0.05 ) while no treatment of either conditions result ed in no improvement in time of symptoms from both . ( c ) Cal + Dys had more urinary/menstrual pain and referred lumbar/abdominal hyperalgesia than Cal or Dys ; hormonal dysmenorrhea treatment/laser treatment for endometriosis also improved urinary symptoms ; lithotripsy for urinary stone also reduced menstrual symptoms ( 0.001 < p < 0.05 ) . ( d ) In Gs + LCal , cholecystectomy or urinary lithotripsy did not improve urinary or biliary symptoms , respectively . Mechanisms of viscero‐visceral hyperalgesia between organs with documented partially common sensory projection probably involve sensitization of viscero‐viscero‐somatic convergent neurons BACKGROUND The objective of this quasi experimental study was to compare the frequency of wound infection between  open cholecystectomy ( OC ) and laparoscopic cholecystectomy ( LC ) conducted in Surgical Unit IV , Jinnah Hospital Lahore from June 2005 to January 2006 . METHODS 100 patients undergoing elective cholecystectomy for symptomatic gallstones were studied . The patients were allocated in the two groups of 50 each by simple r and om technique . Group-I underwent OC and Group-II underwent LC . The patients were then followed up for four weeks to pick up signs of wound infection . In case of infection , the degree of infection and the remedial measures done were documented and the results analysed . RESULTS In LC group there was only one case of Class-II wound infection i.e. 2 % . In case of OC there were three cases of wound infection i.e. 6 % . Out of these , two were of Class-IIl and one of Class-Il . CONCLUSION While there was no wound infection in cases of chronic Cholecystitis in both groups , the frequency of wound infection was three times as common in OC as compared to LC in Acute Cholecystitis/Empyema BACKGROUND The description and underst and ing of gallbladder stone disease in the medical literature are difficult because an assessment of the natural course of this symptomatic disease , with separation of patients in strictly defined groups , is generally lacking . METHOD A multicenter study was carried out with patients r and omized to either surgery or conservative , expectant treatment to examine optimal treatment and natural history in well-defined groups of symptomatic gallbladder stone disease with pain , episodes only ( study group 1 ) or acute cholecystitis ( study group 2 ) . The patients were between 18 and 80 years of age and had right upper quadrant or midline epigastric pain and ultrasonographic evidence of gallbladder stone , with or without acute cholecystitis . Medical treatment was ordinated on the basis of signs and symptom severity . Patients r and omized to surgery  were placed on the hospital 's waiting list and electively operated on with cholecystectomy as soon as conveniently possible . Preliminary results of follow-up are based on question naires mailed at regular intervals and consultations if required by the patients ' symptoms . Quality of life and freedom from pain are study end points for evaluation . RESULTS Five hundred and one patients were considered for the study , 318 patients ( 63.5 % ) belonging to group 1 and 183 ( 36.5 % ) to group 2 . One hundred and eighty-four patients ( 36.7 % ) were r and omized , 120 ( 24 % ) in group 1 and 64 ( 12.7 % ) in group 2 . Three hundred and seventeen patients ( 63.3 % ) , with an equal proportion from each study group , were excluded , the largest number of patients because of incapacitating pain or serious presenting symptoms ( 26 % ) . More women ( 81 % ) than men ( 19 % ) had pain alone ( group 1 ) , but the sex ratio was reduced , 56 % women and 44 % men , in patients with acute cholecystitis ( group 2 ) , with a highly significant difference ( P = < 0.001 ) between the two groups . A significant difference in patient withdrawal from r and omized treatment was registered , with 24 % from observation and 12 % from surgery ( P = 0.032 ) , but with an equal distribution in the two study groups . CONCLUSIONS A r and omized trial of this nature is feasible but extremely difficult to perform because of the heterogeneous nature of gallbladder stone disease , leading to exclusion of many patients and difficulties in measuring and evaluating outcome variables This was conducted to evaluate the analgesic effect of intravenous tenoxicam ( non-steroidal anti-inflammatory drug ) in the treatment of biliary colic pain and compared with spasmolytics . Thirtytwo patients ( 26 women , 6 men , mean age 47 , range 38 - 55 years ) with acute biliary colic were entered for study . They were allocated r and omly to receive either tenoxicam 20 mg i.v . or hyoscine N-butylbromide 20 mg i.v . The patients recorded their pain severity on 5 point scale . The results showed that tenoxicam caused significant pain relief in 10 out of 16 patients at 30 min ( mean pain score decreased from 2.75 + /- 0.93 to 0.49 + /- 0.51 , p < 0.05 ) and in other 4 patients at 60 min ( mean pain score decreased to 0.58 + 5.7 , p < 0.05 ) . None of these patients developed acute cholecystitis or pain relapse over a period of 24 h follow up . With use of hyoscine N-butylbromide , 7 out 16 patients had significant pain relief at 30 min ( mean pain score decreased from 2.62 + /- 1.01 to 0.57 + /- 0.53 , p < 0.05 ) and 3 other patients relieved at 60 min ( mean pain score decreased to 0.66 + /- 0.57 , p < 0.05 ) . Four patients showed pain relapse within 24 h and needed pethidine-rescue treatment , two of them developed acute cholecystitis . Three out of 6 patients who showed no response to hyoscine N-butylbropmide and treated with 100 mg pethidine progressed to acute cholecystitis . We concluded that intravenous tenoxicam has rapid and prolong analgesic effects in the treatment of acute biliary colic as compared to hyoscine N-butylbroimde and it prevents the progression to acute cholecystitis The authors report their own experience about 156 cases of acute cholecystitis observed between January 1991 and October 1992 . The most part of the patients were between 30 and 65 years old ( 84 cases observed ) . In 27 cases , for the positive evolution of the pathology , it was put on practice a non operative treatment . The other 129 cases were treated surgically . The patients with lithiasic cholecystitis were 148 ; those affected by non lithiasic cholecystitis were 5 ; and 3 of them presented an acute cholecystitis as a manifestation of a carcinoma . Between the various diagnostic methods , the echography , executed in emergency , is considered as an indispensable one , for having changed completely the diagnostic approach . It is discussed , particularly , the timing of surgery , an aspect able to influence considerably the therapeutic iter and its results . There are analysed the criteria for whom some authors are favourable to a medical treatment of the acute cholecystitis , postponing the operation , while other of them are favourable to an early surgical treatment . The authors ' casuistry put in evidence 110 operations effectuated in emergency ( < 12 hours ) , 19 operations after an 12 - 72 hours interval , no operations at a long distance ( 1 - 10 months ) . The results are to be considered satisfactory : 1 deceased ( on 129 operated cases , 0.78 % ) ; 10 immediate complications ( 7.75 % ) : 8 suppurations of the wound , 1 biliar fistula and 1 internal hemorrhage after video-laparoscopic operation ; 2 late complications ( 1.55 % ) : they were relapsing gallstones . The aim of this work is to offer a contribution to codification of the treatment of the acute cholecystitis , on the ground of the acquired experience The incidence of surgical infections  after laparoscopic cholecystectomy is reported to be < 2 % , because of the minimal trauma due to this approach . We report the results of a prospect i ve study of antibiotic prophylaxis in laparoscopic cholecystectomy , comparing ceftriaxone vs ceftazidime .  From Jan 1 to Dec 31 2002 a consecutive series of 242 cholecystectomies were performed , consisting in 18 open cholecystectomies and 224 laparoscopic cholecystectomies , 7 of which ( 3.1 % ) were converted to open cholecystectomies for technical and /or anatomical reasons . One hundred and eleven patients received 1 g i.v . ceftazidime 1 h before surgery , and 105 patients 1 g i.v . ceftriaxone on an alternate basis . Thirty-nine patients ( 17.4 % ) with acute cholecystitis received at least one booster dose at the end of the operation ; 30 out of 39 were given further therapy for 2 - 3 days , i.e. 1 g i.v . bid . Twenty-two patients treated elsewhere with ceftriaxone or ceftazidime before surgery were transferred to another prophylactic regimen . The final diagnosis in the laparoscopic cholecystectomy group was 219 bile stones , 3 adenomas , and 2 occult carcinomas .  We had 4 complications ( 1.8 % of 217 laparoscopic cholecystectomies ) , 2 of which were minor ( infection of the umbilical access by S. aureus ) and 2 major ( 1 biliary fistula [ accessory duct ] and 1 acute pancreatitis ) , both treated conservatively . Positive bile cultures ( 27 cases ) were unrelated to the clinical course . The incidence of infections after laparoscopic cholecystectomy in our prospect i ve series was < 2 % . Ceftriaxone is confirmed as the gold st and ard in biliary tract surgery , but ceftazidime was equivalent ( no statistical difference between the two antibiotics , P=0.59 NS ) . Ultra-short prophylaxis is enough in most cases , except in cholecystitis . We found no correlation between positive bile cultures and surgical infections after laparoscopic cholecystectomy . The umbilicus was the preferred site of infection in obese patients after the laparoscopic procedure . Major complications are usually related to technical pitfalls It has been reported that intake of ( n-3 ) polyunsaturated fatty acids ( PUFA ) reduces the risk of coronary heart disease and decreases biliary cholesterol saturation in the bile of gallstone patients . We investigated the effect of n-3 PUFA on cholesterol saturation index ( CSI ) and nucleation time ( NT ) in obese subjects who were losing weight . This was a double-blind , placebo-controlled clinical trial . Obese women ( n = 35 ) with a body mass index ( BMI ) > or = 30 kg/m(2 ) , with no prior history of gallstones or cholecystectomy by ultrasound were first studied to ensure absence of stones or biliary sludge . The women were then assigned to a hypocaloric regimen [ 5.02 MJ ( 1200 kcal)/d ] and to receive 1200 mg/d of ursodeoxycholic acid ( UDCA ) , 11.3 g/d of ( n-3 ) PUFA or a placebo for 6 wk . BMI , CSI and NT were recorded at baseline and at the end of the experimental period . BMI decreased 5.75 + /- 2.7%/mo ( range , 1.5 - 12.42%/mo ) during the experiment . The CSI did not change in any of the groups . Cholesterol NT decreased significantly in the UDCA and placebo groups , but not in the ( n-3 ) PUFA group . None of the women had developed gallstones at 6 wk . These results suggest that ( n-3 ) PUFA maintain the CSI and NT in obese women during rapid weight loss , which probably results in the prevention of cholesterol gallstone formation Objective : Acute cholecystitis is a common disease , and laparoscopic surgery is the st and ard of care . Background : Optimal timing of surgery for acute cholecystitis remains controversial : either early surgery shortly after hospital admission or delayed elective surgery after a conservative treatment with antibiotics . Methods : The ACDC ( “ Acute Cholecystitis — early laparoscopic surgery versus antibiotic therapy and Delayed elective Cholecystectomy ” ) study is a r and omized , prospect i ve , open-label , parallel group trial . Patients were r and omly assigned to receive immediate surgery within 24 hours of hospital admission ( group ILC ) or initial antibiotic treatment , followed by delayed laparoscopic cholecystectomy at days 7 to 45 ( group DLC ) . For infection , all patients were treated with moxifloxacin for at least 48 hours . Primary endpoint was occurrence of predefined relevant morbidity within 75 days . Secondary endpoints were as follows : ( 1 ) 75-day morbidity using a scoring system ; ( 2 ) conversion rate ; ( 3 ) change of antibiotic therapy ; ( 4 ) mortality ; ( 5 ) costs ; and ( 6 ) length of hospital stay . Results : Morbidity rate was significantly lower in group ILC ( 304 patients ) than in group DLC ( 314 patients ): 11.8 % versus 34.4 % . Conversion rate to open surgery and mortality did not differ significantly between groups . Mean length of hospital stay ( 5.4 days vs 10.0 days ; P < 0.001 ) and total hospital costs ( & OV0556;2919 vs & OV0556;4262 ; P < 0.001 ) were significantly lower in group ILC . Conclusions : In this large , r and omized trial , laparoscopic cholecystectomy within 24 hours of hospital admission was shown to be superior to the conservative approach concerning morbidity and costs . Therefore , we believe that immediate laparoscopic cholecystectomy should become therapy of choice for acute cholecystitis in operable patients . ( NCT00447304 The aim of this prospect i ve , r and omized study was to determine whether laparoscopic cholecystectomy should be performed as an early or a delayed operation in patients with acute cholecystitis . After diagnostic workup , patients were r and omized to one of two groups : ( 1 ) early laparoscopic cholecystectomy  ( i.e. , within 7 days after onset of symptoms ) or ( 2 ) initial conservative treatment followed by delayed laparoscopic cholecystectomy 6 to 8 weeks later .  Seventy-four patients were placed in the early-operation group , and 71 patients were assigned to the delayed-operation strategy . There was no significant difference in conversion rates ( early 31 % vs. delayed 29 % ) , operating times ( early 98 [ range 30 to 355 ] minutes vs. delayed 100 [ 45 to 280 ] minutes ) , or complications . Failure with the conservative treatment strategy was noted in 26 % of these patients . The total hospital stay was significantly shorter in the early group ( 5 [ range 3 to 63 ] days ) vs. the delayed group ( 8 [ range 4 to 50 ] days ; P < 0.05 ) . Despite a high conversion rate , early laparoscopic cholecystectomy offered significant advantages in the management of acute cholecystitis compared to a conservative strategy . The greatest advantage was a reduced total hospital stay
The results of the economic evaluation suggest that , on average , the surgery strategy costs £ 1236 more per patient than the conservative management strategy but was , on average , more effective .
An increase in the number of people requiring surgery while treated conservatively corresponded to a reduction in the cost-effectiveness of the conservative strategy .
The results of this assessment indicate that cholecystectomy is still the treatment of choice for many symptomatic people .
However , approximately half of the people in the observation group did not require surgery or suffer complications in the long term indicating that a conservative therapeutic approach may represent a valid alternative to surgery in this group of people .
BACKGROUND Approximately 10 - 15 % of the adult population suffer from gallstone disease , cholelithiasis , with more women than men being affected .
Cholecystectomy is the treatment of choice for people who present with biliary pain or acute cholecystitis and evidence of gallstones .
However , some people do not experience a recurrence after an initial episode of biliary pain or cholecystitis .
As most of the current research focuses on the surgical management of the disease , less attention has been dedicated to the consequences of conservative management .
OBJECTIVES To determine the clinical effectiveness and cost-effectiveness of  cholecystectomy  compared with observation/conservative management in people presenting with uncomplicated symptomatic gallstones ( biliary pain ) or cholecystitis .