Optimising the antibiotic treatment of uncomplicated acute appendicitis: a protocol for a multicentre randomised clinical trial (APPAC II trial).

BACKGROUND: Based on epidemiological and clinical data acute appendicitis can present either as uncomplicated (70-80%) or complicated (20-30%) disease. Recent studies have shown that antibiotic therapy is both safe and cost-effective for a CT-scan confirmed uncomplicated acute appendicitis. However, based on the study protocols to ensure patient safety, these randomised studies used mainly broad-spectrum intravenous antibiotics requiring additional hospital resources and prolonged hospital stay. As we now know that antibiotic therapy for uncomplicated acute appendicitis is feasible and safe, further studies evaluating optimisation of the antibiotic treatment regarding both antibiotic spectrum and shorter hospital stay are needed to evaluate antibiotics as the first-line treatment for uncomplicated acute appendicitis. METHODS: APPAC II trial is a multicentre, open-label, non-inferiority randomised controlled trial comparing per oral (p.o.) antibiotic monotherapy with intravenous (i.v.) antibiotic therapy followed by p.o. antibiotics in the treatment of CT-scan confirmed uncomplicated acute appendicitis. Adult patients with CT-scan diagnosed uncomplicated acute appendicitis will be enrolled in nine Finnish hospitals. The intended sample size is 552 patients. Primary endpoint is the success of the randomised treatment, defined as resolution of acute appendicitis resulting in discharge from the hospital without the need for surgical intervention and no recurrent appendicitis during one-year follow-up. Secondary endpoints include post-intervention complications, late recurrence of acute appendicitis after one year, duration of hospital stay, pain, quality of life, sick leave and treatment costs. Primary endpoint will be evaluated in two stages: point estimates with 95% confidence interval (CI) will be calculated for both groups and proportion difference between groups with 95% CI will be calculated and evaluated based on 6 percentage point non-inferiority margin. DISCUSSION: To our knowledge, APPAC II trial is the first randomised controlled trial comparing per oral antibiotic monotherapy with intravenous antibiotic therapy continued by per oral antibiotics in the treatment of uncomplicated acute appendicitis. The APPAC II trial aims to add clinical evidence on the debated role of antibiotics as the first-line treatment for a CT-confirmed uncomplicated acute appendicitis as well as to optimise the non-operative treatment for uncomplicated acute appendicitis. TRIAL REGISTRATION: Clinicaltrials.gov , NCT03236961, retrospectively registered on the 2nd of August 2017.

Extralevator versus standard abdominoperineal excision in locally advanced rectal cancer: a retrospective study with long-term follow-up.

PURPOSE: To analyze the results of abdominoperineal excisions (APE) for locally advanced rectal cancer at our institution before and after the adoption of extralevator abdominoperineal excision (ELAPE) with a special reference to long-term survival. METHODS: A retrospective cohort study conducted in a tertiary referral center. All consecutive patients operated for locally advanced (TNM classification T3-4) rectal cancer with APE in 2004-2009 were compared to patients with similar tumors operated with ELAPE in 2009-2016. RESULTS: Forty-two ELAPE and 27 APE patients were included. Circumferential resection margin (CRM) was less than 1 mm (R1-resection) in 10 (24%) of ELAPE patients and 11 (41%) of APE patients (p = 0.1358). Intraoperative perforation (IOP) occurred in 4 (10%) patients and 6 (22%) patients in ELAPE and APE groups, respectively (p = 0.1336). There were 3 (7%) local recurrences (LRs) in ELAPE group and 5 (19%) in APE (p = 0.2473). There were no statistical differences in adverse events, overall survival, or disease-free survival between ELAPE and APE groups. CONCLUSIONS: We found a non-significant tendency to lower rates of IOP and positive CRM as well as lower rate of LR in the ELAPE group. Long-term survival and adverse events did not differ between the groups. ELAPE is beneficial for the surgeon in offering better vicinity to the perineal area and better work ergonomics. These technical aspects and the clinically very important tendency to lower rate of LR support the use of ELAPE technique in spite of the lack of survival benefit.

The Accuracy of the Computed Tomography Diagnosis of Acute Appendicitis: Does the Experience of the Radiologist Matter?

BACKGROUND AND AIMS: To assess the accuracy of computed tomography in diagnosing acute appendicitis with a special reference to radiologist experience. MATERIAL AND METHODS: Data were collected prospectively in our randomized controlled trial comparing surgery and antibiotic treatment for uncomplicated acute appendicitis (APPAC trial, NCT01022567). We evaluated 1065 patients who underwent computed tomography for suspected appendicitis. The on-call radiologist preoperatively analyzed these computed tomography images. In this study, the radiologists were divided into experienced (consultants) and inexperienced (residents) ones, and the comparison of interpretations was made between these two radiologist groups. RESULTS: Out of the 1065 patients, 714 had acute appendicitis and 351 had other or no diagnosis on computed tomography. There were 700 true-positive, 327 true-negative, 14 false-positive, and 24 false-negative cases. The sensitivity and the specificity of computed tomography were 96.7% (95% confidence interval, 95.1-97.8) and 95.9% (95% confidence interval, 93.2-97.5), respectively. The rate of false computed tomography diagnosis was 4.2% for experienced consultant radiologists and 2.2% for inexperienced resident radiologists (p = 0.071). Thus, the experience of the radiologist had no effect on the accuracy of computed tomography diagnosis. CONCLUSION: The accuracy of computed tomography in diagnosing acute appendicitis was high. The experience of the radiologist did not improve the diagnostic accuracy. The results emphasize the role of computed tomography as an accurate modality in daily routine diagnostics for acute appendicitis in all clinical emergency settings.

Economic evaluation of antibiotic therapy versus appendicectomy for the treatment of uncomplicated acute appendicitis from the APPAC randomized clinical trial.

BACKGROUND: An increasing amount of evidence supports antibiotic therapy for treating uncomplicated acute appendicitis. The objective of this study was to compare the costs of antibiotics alone versus appendicectomy in treating uncomplicated acute appendicitis within the randomized controlled APPAC (APPendicitis ACuta) trial. METHODS: The APPAC multicentre, non-inferiority RCT was conducted on patients with CT-confirmed uncomplicated acute appendicitis. Patients were assigned randomly to appendicectomy or antibiotic treatment. All costs were recorded, whether generated by the initial visit and subsequent treatment or possible recurrent appendicitis during the 1-year follow-up. The cost estimates were based on cost levels for the year 2012. RESULTS: Some 273 patients were assigned to the appendicectomy group and 257 to antibiotic treatment. Most patients randomized to antibiotic treatment did not require appendicectomy during the 1-year follow-up. In the operative group, overall societal costs (€5989·2, 95 per cent c.i. 5787·3 to 6191·1) were 1·6 times higher (€2244·8, 1940·5 to 2549·1) than those in the antibiotic group (€3744·4, 3514·6 to 3974·2). In both groups, productivity losses represented a slightly higher proportion of overall societal costs than all treatment costs together, with diagnostics and medicines having a minor role. Those in the operative group were prescribed significantly more sick leave than those in the antibiotic group (mean(s.d.) 17·0(8·3) (95 per cent c.i. 16·0 to 18·0) versus 9·2(6·9) (8·3 to 10·0) days respectively; P < 0·001). When the age and sex of the patient as well as the hospital were controlled for simultaneously, the operative treatment generated significantly more costs in all models. CONCLUSION: Patients receiving antibiotic therapy for uncomplicated appendicitis incurred lower costs than those who had surgery.

Adoption of single incision laparoscopic cholecystectomy in small-volume hospitals: initial experiences of 51 consecutive procedures.

BACKGROUND AND AIMS: Laparoscopic cholecystectomy (LC) via three or four ports has been the standard operation for gallstone disease. Recently, the development of multichannel port devices has allowed LCs to be performed through a single fascial incision in the umbilicus. Here, we report our experiences of the adoption of the single incision laparoscopic cholecystectomy (SILC) in two small-volume community hospitals. MATERIAL AND METHODS: From January until July 2010, 51 consecutive patients (41 females and 10 males, the mean age 44 (21-75) years, BMI 26 (18-35)) underwent elective SILC for symptomatic gallstone disease in Salo (n = 29) and Loimaa (n = 22) hospitals. RESULTS: Of the 51 operations, 42 (82%) were accomplished without additional troacars. Seven (14%) procedures were converted to multiple-port technique and two (4%) to open cholecystectomy. In 25 (49%) operations, transabdominal retraction sutures through the gallbladder were used to maintain a good view of the triangle of Calot. The mean operative time was 74 (31-155) min. No major intraoperative complications occurred. The mean hospital stay was 0.6 (0-3) days. During a mean follow up of 4 (1-7) months, five (10%) patients had wound infection, and one (2%) had hematoma and prolonged pain in the insertion site of the retraction suture. One (2%) patient was reoperated for continuous pain in umbilical wound without findings at operation but with good results. One (2%) patient had subphrenic abscess seven months postoperatively. CONCLUSIONS: Our initial experiences indicate that SILC can be adopted without major complications in small-volume hospitals but the rate of wound infections seems to increase with the introduction of SIL.

Treatment of biliary complications after laparoscopic cholecystectomy.

The incidence of iatrogenic bile duct injury remains high despite increased awareness of the problem. This major complication following laparoscopic cholecystectomy (LC) has a significant impact on patient's well-being and even survival despite seemingly adequate therapy. The management of bile duct injury (BDI) includes education to avoid the insult, proper and early diagnosis and preferably early treatment. It is of utmost importance to involve experienced hepatobiliary surgeon early enough to perform corrective reconstruction or to plan other therapies with a multidisciplinary team including interventional radiologist and advanced endoscopist. The selection of correct therapy at the earliest possible phase has significant effect on patient outcome. The treatment options are surgery and endoscopy, either immediately or delayed. By constant and continuous analysis of the problem and information to the surgical community it should be possible to decrease the prevalence of iatrogenic BDI and even to avoid it.

Quality of life after surgery for rectal cancer with special reference to pelvic floor dysfunction.

AIM: Conventional outcomes such as survival, tumour recurrence and complication rates after surgery for rectal cancer have been rigorously assessed, but the importance of maintaining quality of life (QOL) after surgery for rectal cancer has received less attention. The aim of the current study was to analyse QOL and the occurrence of pelvic dysfunction after the surgical treatment of rectal cancer. METHOD: Between May 2005 and May 2008, 150 patients with rectal cancer underwent abdominoperineal resection (APR) or anterior resection (AR). Seventy-four answered two preoperative questionnaires. At a follow up of 1 year, 65 were alive without sign of recurrence and answered the same questionnaires: (a) validated RAND 36-item health survey QOL questionnaire; and (b) self-administered disease-related questionnaire with special reference to anorectal and urogenital function. RESULTS: The postoperative general QOL was similar after surgery, and mental functioning was better (P < 0.001). Problems with physical functions were associated with anal dysfunction after AR (P < 0.001) and problems with social functioning were associated with urinary dysfunction (P = 0.038). At 1 year after surgery, urinary incontinence was worse (P = 0.026) after all operations, and the incidence of dysuria was higher after APR than AR (P = 0.001). Male sexual function also worsened (P = 0.060). Anorectal dysfunction caused more inconvenience among patients who underwent AR (P = 0.028). Preoperative radiation was associated with postoperative ejaculation problems (P = 0.028) and anal incontinence (P = 0.012). CONCLUSION: Factors affecting QOL and pelvic floor function should be taken into account when making treatment decisions in rectal cancer.

Elective laparoscopic cholecystectomy without routine intraoperative cholangiography: a retrospective analysis of 1101 consecutive cases.

BACKGROUND: Laparoscopic cholecystectomy (LC) is today the operation of choice for symptomatic gallstone disease. Before the laparoscopic era intraoperative cholangiography (IOC) was generally considered as a fundamental step in cholecystectomy while nowadays the role of IOC is controversial: is there a need for IOC to specify anatomy of biliary tree in order to avoid bile duct injuries (BDI) and to detect possible common bile duct (CBD) stones or not? PATIENTS AND METHODS: We studied retrospectively all the elective LCs done in Turku City Hospital for Surgery during the ten years (1992-2001). Cholecystectomy was performed to 1101 patients, 874 (79%) female and 227 (21%) male patients, mean age 53y (range 15-89). LC was possible in 1022 (93%) cases while 79 (7%) had to be converted to open procedure. The number and severity of bile duct injuries were recorded. The cases with endoscopic retrograde cholangiopancreatography (ERCP) and/or magnetic resonance cholangiopancreatography (MRCP) during the follow-up and the findings in ERCP and MRCP were recorded from patient records and radiological database. RESULTS: IOC was performed in 32 operations (20 in LC and 12 after conversion) and CBD stones were found in seven patients. There were four primary BDIs: two CBD injuries and two minor bile leaks. During a mean follow-up of 72 months (range 36-144) ERCP was performed in 16 and MRCP in three patients. Three patients underwent both MRCP and ERCP. CBD stones were detected in ten patients and a postoperative late CBD stricture was found in one case. CONCLUSIONS: According to our data, both the incidence of BDIs (0.5%) and symptomatic postoperative CBD stones (0.9%) remain low without the routine use of IOC.

Thromboprophylaxis following surgery for colorectal cancer - is it worthwhile after hospital discharge?

BACKGROUND: The efficacy of low-molecular-weight heparin (LMWH) in preventing venous thromboembolism (VTE) after surgery for colorectal cancer is well documented, but the optimal duration of postoperative thromboprophylaxis is not known. The aim of this retrospective study was to assess the occurrence of symptomatic VTE after surgery for colorectal cancer in patients in whom LMWH was continued only until hospital discharge. METHODS: During 2003-2006 a total of 494 patients underwent abdominal surgery for colorectal cancer at our institution. Enoxaparin (Klexane 40mg s.c.) prophylaxis was started 12 hours before surgery and continued once a day until hospital discharge. The median duration of thromboprophylaxis was 11 days. The follow-up data were collected retrospectively from electronic archives and analyzed up to three months after the operation. RESULTS: Only three (0.6%) symptomatic VTEs occurred during the follow-up period. One patient presented with pulmonary embolism, while the remaining two had proximal deep-vein thrombosis. The 30-day-mortality was 1.6%. None of the deaths were obviously associated with VTE. CONCLUSION: LMWH given for a median of 11 days until hospital discharge seems to provide sufficient thromboprophylaxis after surgery for colorectal cancer combined with the use of graded compression stockings and early mobilization.

Mesh repair of common abdominal hernias: a review on experimental and clinical studies.

Results on hernia surgery from numerous centers confirm that tensionless repair with various meshes reduces the complication rates and the frequency of recurrences. Some evidence on incisional hernias suggests, however, that the use of mesh seems to transfer the onset of recurrences by several years. Persistent pain and other discomfort is also an unpleasant complication of otherwise successful surgery in a number of patients. Thus, improved, slowly degrading, mesh materials, with strong connective tissue-inducing action, might be more optimal for hernia surgery. Accumulating evidence also suggests that recurrent hernias appear in patients having inherited weakness of connective tissues. Numerous tissue specific collagens, in addition to the classical fibrillar I-III collagens and numerous substrate specific matrix proteinases, have recently been described in biochemical literature, and their roles as possible causes of tissue weakness are discussed.

Value of blood tests including serum group IIA phospholipase A2 and bactericidal/permeability-increasing protein in Crohn's disease.

OBJECTIVE: Determination of the activity of Crohn's disease at a defined time-point is a challenging task since only endoscopy guidelines are given and secondary clinical findings, subjective symptoms and non-specific laboratory tests have therefore to be relied on. The purpose of the current study was to investigate the ability of blood tests to differentiate patient groups with different clinical disease activity and different clinical outcomes during follow-up in Crohn's disease. MATERIAL AND METHODS: During a visit to hospital, 73 outpatients with Crohn's disease were examined, a clinical score was calculated and blood samples were collected for 22 laboratory tests. The patients were also grouped according to clinical outcome during a 6-year follow-up. RESULTS: Serum group IIA phospholipase A2 and alpha-1-antitrypsin values were outside the reference interval more frequently (62% and 42%, respectively) than the other tests in active Crohn's disease. Only weak correlations were found between the clinical score and the test values, and the best correlation was found with serum lysozyme (r = 0.40). In a logistic regression model, the best prediction of disease activity at entry to the study was reached with a model including serum orosomucoid and serum lysozyme and the best prediction of clinical outcome during follow-up was reached using a model including serum albumin. CONCLUSIONS: Serum group IIA phospholipase A2 appeared to be the most sensitive marker of inflammation in Crohn's disease among the 22 blood tests compared. No reliable predictions of disease activity at the time of blood sampling or clinical outcome later during follow-up could be made from the blood tests studied.

Roles of group IIA phospholipase A2 and complement in killing of bacteria by acute phase serum.

The complement system is regarded as an important component of the innate defence system against invading bacteria. However, synergistic actions between the complement and the other components of innate immunity are incompletely known. Human group IIA phospholipase A(2) (hGIIA PLA(2)) is an effective antibacterial enzyme in serum of patients with severe bacterial infections. Our aim was to investigate the significance of complement and hGIIA PLA(2) in acute phase serum. Serum samples were collected from patients with acute bacterial infections and from healthy control subjects. We prepared hGIIA PLA(2)-depleted serum by immunoadsorption and inhibited the activity of complement by a specific inhibitor, compstatin. The bactericidal effects of treated and untreated serum were compared by incubating Staphylococcus aureus and Listeria monocytogenes in the presence of serum. Acute phase serum effectively killed S. aureus and L. monocytogenes, and depletion of hGIIA PLA(2) significantly reduced the antibacterial effect. Complement had a weak bactericidal effect against L. monocytogenes. We conclude that hGIIA PLA(2) is the major antibacterial factor in human acute phase serum against the gram-positive bacteria S. aureus and L. monocytogenes, exceeding complement in efficiency.

Needle-knife assisted ERCP.

BACKGROUND: During endoscopic retrograde cholangiopancreatography (ERCP), incising through the wall of the major papilla with an electrocautery needle-knife is a method for achieving access into the bile duct. This procedure, often referred to as a "precut," may be used when cannulation attempts via the orifice of the papilla are unsuccessful. Potential complications include hemorrhage, duodenal perforation, and acute pancreatitis. METHODS: The 172 patients who underwent an attempt of a needle-knife assisted ERCP during the years 1997-2003 at our institution were retrospectively evaluated. RESULTS: A selective bile duct cannulation was achieved after needle-knife incision in 148 out of 172 patients (86%) at the primary session. In 10 additional patients (6%), a repeated procedure proved successful for cannulation. In the remaining 14 patients (8%), the biliary cannulation failed and was not attempted again. Complications after needle-knife assisted ERCP occurred as follows: three patients (2%) presented with late bleeding after the ERCP and three patients (2%) developed acute pancreatitis. None of the patients required operative treatment for complications. There was no mortality. CONCLUSION: The use of the needle-knife markedly improves the success rate of selective biliary cannulation in ERCP without increasing the rate of complications.

Splanchnic and pancreatic tissue perfusion in experimental acute pancreatitis.

BACKGROUND: Gut hypoperfusion has a major role in the pathogenesis of multiple organ failure, which is the main cause of death in severe acute pancreatitis. The effects of experimental acute pancreatitis on splanchnic and pancreatic perfusion and oxygenation were studied to find out whether gut hypoperfusion occurs already at the same time as changes in pancreatic perfusion. METHODS: Twenty-four domestic pigs weighing 21-27 kg were randomized to severe or mild acute pancreatitis or control groups. Eight anaesthetized and mechanically ventilated pigs were intraductally infused with taurocholic acid to induce severe acute pancreatitis and eight received intraductal saline to induce mild acute pancreatitis. Eight pigs served as controls. RESULTS: Intraductally infused taurocholic acid rapidly induced severe necrotizing acute pancreatitis as assessed macroscopically and histologically. Histological changes of mild acute pancreatitis were seen in animals after intraductal saline infusion. After the induction, pancreatic tissue oxygen tension decreased promptly in severe acute pancreatitis and increased in mild acute pancreatitis. Laser-Doppler red cell flux decreased in severe acute pancreatitis. Gut pH gap and pCO2 gap decreased in 2 h after the induction of severe acute pancreatitis. Central haemodynamics were fairly stable throughout the study period in all groups. CONCLUSION: In experimental severe acute pancreatitis, splanchnic malperfusion seems to begin with pancreatic hypoperfusion before disturbances in gut microcirculation.

Source of group II phospholipase A2 in gastric juice.

Gastric juice contains both pancreatic group I phospholipase A2 (PLA2-I) and synovial-type group II phospholipase A2 (PLA2-II), which may play a crucial role in Helicobacter pylori infection and gastric mucosal injury. PLA2-I present in gastric juice is derived from pancreatic acinar cells. The cellular source of PLA2-II found in gastric juice is unknown. A specific cell type of the intestinal mucosa, the Paneth cell, is known to secrete PLA2-II. The purpose of the present study was to define the source of PLA2-II present in gastric juice. For this purpose, gastric juice was collected from 29 individuals during gastroscopy, and mucosal biopsies were taken from the antrum and body of the stomach and from the duodenum as well as from the jejunum of individuals with resected stomach, for immunohistochemical detection of PLA2-II. The concentration of bilirubin in the gastric juice samples was determined to identify duodenogastric regurgitation. The PLA2-II content was significantly higher in bilirubin-positive than in bilirubin-negative gastric juice samples. PLA2-II was localized by immunohistochemistry in Paneth cells in three patients with areas of intestinal metaplasia of the gastric mucosa and in Paneth cells of duodenal and jejunal mucosa in all patients, but not in any other epithelial cell type of the mucosa of the stomach or the small intestine. Inflammatory cells did not contain PLA2-II. The current results suggest that PLA2-II found in gastric juice is derived from the Paneth cells of the small intestinal mucosa.

Do normal leucocyte count and C-reactive protein on admission to hospital exclude a life-threatening attack of acute pancreatitis?

BACKGROUND AND AIMS: The early severity assessment of an attack of acute pancreatitis is clinically of utmost importance. The aim of the present work was to study the role of leucocyte count and C-reactive protein (CRP) measurements on admission to hospital in assessing the severity of an attack of acute pancreatitis. In particular, patients with a life-threatening attack of acute pancreatitis but a normal leucocyte count and CRP level were sought. MATERIAL AND METHODS: A total of 1050 attacks of acute pancreatitis were treated at Turku University Central Hospital during the years 1995-1999. Leucocyte count and C-reactive protein (CRP) value were determined on admission to hospital. There were 58 life-threatening attacks of acute pancreatitis (group A). Fifty-eight consecutive mild attacks served as controls (group B). The number of patients with both values normal, only leucocyte count raised, only CRP level raised and both values raised were calculated in the groups A and B. RESULTS: Both leucocyte count and CRP level were significantly (P < 0.001 in both comparisons) higher on admission to hospital in patients with a life-threatening disease (group A) than in those with a mild disease (group B). Group A contained no patients with both values in the normal range. In group B, one fifth of the patients had both values normal. CONCLUSION: It is very unlikely that acute pancreatitis proves to be a life-threatening one when both the leucocyte count and CRP are normal on admission to hospital. In the present 1050 acute pancreatitis there were no patients with life-threatening disease but normal laboratory values on admission.

Do normal leucocyte count and C-reactive protein value exclude acute appendicitis in children?

UNLABELLED: The present study aimed to determine the role of leucocyte count and C-reactive protein (CRP) measurements in the diagnosis of acute appendicitis in children. In particular, children with acute appendicitis but normal leucocyte count and CRP level were sought. The present study protocol was identical to those used in earlier studies on adult patients with suspected acute appendicitis. The mean preoperative leucocyte count and CRP value in 100 consecutive children with an uninflamed appendix at appendicectomy (group A) and in 100 consecutive patients with acute appendicitis (group B) were calculated. The numbers of patients with (i) both values normal, (ii) only leucocyte count raised, (iii) only CRP level raised, and (iv) both values raised were calculated in both groups A and B. Leucocyte count effectively (p < 0.001) separated children with uninflamed appendix (mean +/- SEM 10.2 +/- 0.4 x 10(9) l(-1)) from those with acute appendicitis (15.0 +/- 0.4 x 10(9) l(-1)), but the CRP value was of no use in this respect (p = 0.866; 31 +/- 4 mg l(-1) and 30 +/- 4 mg l(-1)). The most conspicuous finding was that in children with acute appendicitis, both values were normal in 7 out of 100 patients. CONCLUSION: Contrary to adult patients, normal leucocyte count and CRP value do not effectively exclude acute appendicitis in children.