Markus Menges

Acute cholecystitis: early versus delayed cholecystectomy, a multicenter randomized trial (ACDC study, NCT00447304).

Objective:Acute cholecystitis is a common disease, and laparoscopic surgery is the standard 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 randomized, prospective, open-label, parallel group trial. Patients were randomly 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, randomized 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)

Increased acid and bile reflux in Barrett’s esophagus compared to reflux esophagitis, and effect of proton pump inhibitor therapy

OBJECTIVES:Barretts metaplasia is an aquired condition resulting from longstanding gastroesophageal reflux disease. Approximately 10% of esophagitis patients develop Barretts esophagus. There is increasing evidence that duodenogastroesophageal reflux plays a role in the progression of disease. We further analyzed the correlation of acid and biliary reflux with reflux esophagitis and Barretts esophagus and tested the effects of proton pump inhibitor therapy.METHODS:Patients with either reflux esophagitis (group 1) or Barretts esophagus (group 2) prospectively underwent simultaneous 24-h esophageal pH and bile reflux testing without any therapy affecting acid secretion or GI motility. A total of 16 patients in group 1 and 18 patients in group 2 were tested again under proton pump inhibitor therapy.RESULTS:Acid and bile exposure were significantly increased in Barretts patients (n = 23) compared to 20 esophagitis patients (median percentage of time that pH was <4 was 24.6% vs 12.4%, p = 0.01, median percentage of time that bilirubin absorbance was >0.2 was 34.7% vs 12.8%, p < 0.05). During therapy, both acid and bile reflux decreased significantly in both groups. Median percentage of time that pH was <4 and bilirubin absorbance was >0.2 before and during therapy was 18.2%/2.3% and 29.8%/0.7% (p = 0.001 and p = 0.001) in Barretts esophagus patients versus 14.5%/3.6% and 21.5%/0.9% (p = 0.002 and p = 0.011) in esophagitis patients. There was no significant difference between the groups. In two esophagitis patients, bile reflux increased during therapy.CONCLUSIONS:There is a good correlation of the duration of esophageal exposure to acid and bile with the severity of pathological change in the esophagus. Both acid and bile reflux is significantly suppressed by proton pump inhibitor therapy with exceptions among individual esophagitis patients. The prolonged simultaneous attack of bile and acid may play a key role in the development of Barretts metaplasia.

Low Sensitivity of the ki-ras Polymerase Chain Reaction for Diagnosing Pancreatic Cancer From Pancreatic Juice and Bile: A Multicenter Prospective Trial

PURPOSE Early detection of pancreatic cancer using molecular markers may improve outcome. Mutations of the ki-ras oncogene are detected in 70% to 90% of pancreatic adenocarcinomas. A prospective, partially blinded, multicenter diagnostic trial was performed to test the sensitivity and specificity of the ki-ras polymerase chain reaction (PCR) analysis of pancreatic juice and bile specimens. PATIENTS AND METHODS Specimens of pancreatic juice and bile were collected from 532 consecutive patients. Mutations in codon 12 of the ki-ras gene were identified by two independent enrichment PCRs and confirmed by direct sequencing. RESULTS One hundred seventy-four of 532 patients were excluded from the final analysis (reasons: no amplifiable DNA, no specimen or only duodenal juice sent, lost to follow-up). Sixty-three of 358 patients had ductal pancreatic cancer. In 24 (38.1%) of 63 patients, a mutated ki-ras gene was identified in pancreatic juice and/or bile. Ki-ras mutations were found in four (8%) of 50 cases of chronic pancreatitis, in 10 (18.7%) of 53 cases of other malignancies of the pancreaticobiliary tree, and in 14 (7.3%) of 192 cases of benign diseases or normal findings. Sensitivity and specificity of the ki-ras PCR analysis for the detection of pancreatic cancer was 38.1% and 90.5%, respectively. CONCLUSION In this prospective trial performed in nonselected patients, mutations of the ki-ras gene were detected in 38.1% of cases with pancreatic cancer. This test in its present form is not appropriate to confirm or screen for pancreatic cancer. More sensitive and/or quantitative PCR tests may improve the molecular diagnosis of pancreatic cancer.

Current strategies in systemic treatment of gastric cancer and cancer of the gastroesophageal junction

Gastric cancer is a major health issue and a leading cause of death worldwide. The results of standard therapy remain unsatisfactory mainly because of diagnosis at the late stage of disease. Innovative strategies such as neoadjuvant chemotherapy in locally advanced cancer have improved the outcome even in operable cases. Whether an adjuvant radiochemotherapy is of benefit after curative resection including systematic lymphadenectomy remains yet unclear. Some progress has been made in the palliative setting by introducing new substances. This review examines recent advances in the systemic treatment of gastric and gastroesophageal junction cancer.

Increased matrix metalloproteinase 2 concentration and transcript expression in advanced colorectal carcinomas

Abstract. Colorectal cancer is one of the most common malignant tumors and entails a relatively poor prognosis. Clinical outcome depends on the extent of local and metastatic tumor spread. Results of in vivo and in vitro studies suggest that the balance between matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases TIMPs) is altered in neoplasia, contributing to the invasive and metastatic properties of malignant tumors. We quantified tissue concentrations of MMP-2 and TIMP-2 in 65 malignant colorectal lesions and corresponding normal mucosa by enzyme-linked immunosorbent assay, western blotting, and in situ hybridization. In situ hybridization and western blot analyses demonstrated a clear increase in both stromal expression of MMP-2 transcripts and protein in primary carcinomas. The protein concentration of MMP-2 was higher in all tumor stages, except stage I tumors, than in normal mucosa and adenomas. MMP-2 concentrations were not related to tumor differentiation or to colonic versus rectal location. Surprisingly, the MMP-2 concentration was not increased in metastases. Interestingly, tissue concentrations and epithelial mRNA expression of TIMP-2 decreased significantly in primary colorectal cancer (UICC stages III and IV) but increased in metastases. Therefore an increased ratio of MMP-2 to TIMP-2 is strongly associated with advanced tumor stages, but a decreased ratio was observed in metastases. These findings suggest that the MMP-2:TIMP-2 ratio may prove useful as a marker of local invasion but not of metastasis in colorectal cancer.

Lichen planus with Oesophageal Involvement

Background: Lichen planus is a common mucocutaneous disease of unknown aetiology. Oral disease affecting the mouth and the pharynx occurs in 30–70% of the cases. Oesophageal disease is considered to be extremely rare. The diagnosis of oesophageal involvement is often not made until complications occur. Case Report: A 56-year-old woman with oral and genital erosive lichen planus for more than 4 years complained of odynophagia and dysphagia. Episodes of oesophageal bolus obstruction started 2 months earlier. Upper endoscopy revealed a high-grade concentric stenosis at 21–24 cm from the incisors. Biopsy specimens taken after bougienage showed a squamous epithelium with dense leukocyte infiltration and Civatte bodies. The bougienage led to complete relief, but due to recurrent symptomatic stenosis, endoscopic dilatation had to be performed another four times within 5 years of follow-up. Immunosuppressive therapy with systemic and local steroid application did not prevent recurrent stenosis. Conclusions: Patients with lichen planus should be evaluated for gastrointestinal symptoms because oesophageal involvement is a rare but severe complication leading to inflammatory stenosis. The benefit of immunosuppressive therapy in the prevention of recurrent stenosis is not established. A review of all reported cases is done with particular regard to therapy.

Increased cytokine transcripts in pouchitis reflect the degree of inflammation but not the underlying entity

Background and aimsAfter ileopouch anal anastomosis (IPAA), 10–40% of patients with ulcerative colitis (UC) but only 5% of patients with familial adenomatous polyposis (FAP) develop pouchitis. Immunoregulatory abnormalities might be of importance in the pathogenesis of the disease. Therefore, we characterized cytokine and chemokine transcripts in inflamed and non-inflamed pouches in patients with UC compared to those with FAP and Crohns disease (CD).Patients and methodsMucosal biopsies were taken from 87 patients with IPAA [UC (n=70), CD (n=8) or FAP (n=9)]. Patients with active ileal CD (n=14), active UC (n=17) and non-inflammatory conditions (n=12) served as controls. The expression of 20 gene transcripts was quantified using real-time polymerase chain reaction.Results and findingsPro-inflammatory cytokines and chemokines are significantly increased in IPAA patients with acute pouchitis. This increase is independent of the underlying disease (UC or CD) and reflects the degree of inflammation. A good correlation between pouchitis activity (using the Pouchitis Disease Activity Index) and the MRP-14, interleukin-8, macrophage inflammatory protein-2α and matrix metalloproteinase-1 transcripts was observed.Interpretations and conclusionsOur data support the view that pouchitis reflects an inflammatory process that is different from that of underlying inflammatory bowel diseases, as the cytokine and chemokine patterns in pouchitis are neither typical of CD nor of UC, but maybe due to bacterial intestinal microflora overgrowth in the pouch lumen. Quantification of transcript levels allows an estimation of the extent of mucosal inflammation and may become helpful in the evaluation of the disease, especially in clinical trials.

CASE REPORT: Groove Pancreatitis

The German term Rinnenpankreatitis, later literally translated to “groove pancreatitis,” was first used in 1973 by Becker to describe a segmental type of chronic pancreatitis, which involves the anatomic space (“groove”) between pancreatic head, common bile duct, and duodenum (1). In 1982, members of Becker’s group reported 30 cases of groove pancreatitis among 123 resectates after duodenopancreatectomy for chronic pancreatitis (2). They distinguished between a genuine and a segmental form, using the term “pure groove pancreatitis” in cases where scarring was only found in the groove, “segmental groove pancreatitis” if dorsocranial parts of the pancreatic head were also involved. The main morphologic features included replacement of pancreatic parenchyma by scar tissue in the segmental form and at most minimal dilatation of the biliary duct. Cicatrization and stenosis of the duodenal wall, accompanied by hyperplasia of Brunner’s glands has often been identified. Cuffing or encasement of the common bile duct was present in “almost all” specimens, while duct stenosis was seen in 67% and 27% of pure and segmental forms, respectively. The authors concluded that these features might help to distinguish the disease from pancreatic carcinoma, where hyperplasia of Brunner’s glands is usually absent, duodenal stenosis less frequent, and tubular bile duct stenosis rare. Pancreatic carcinoma instead usually shows irregular stenosis of biliar and pancreatic duct. No significant differences in patients’ age, sex, or alcohol consumption have been detected when comparing with patients with segmental or nonsegmental forms of chronic pancreatitis. A history of peptic ulcer disease was markedly more frequent in the segmental form. Cicatrization in this anatomical space following acute pancreatitis in pancreatic heterotopies is discussed as the most probable cause for groove pancreatitis. In a large study with a series of 600 pancreatic resections for chronic pancreatitis, 12 and 39 showed typical features of pure and segmental groove pancreatitis, respectively (3, 4). In an additional 66 patients, a nonsegmental chronic pancreatitis involved the groove. Although already described more than 25 years ago, this condition is virtually unknown to most clinicians, and only a few cases have been reported from authors except those who created the term (5–11). Even some major textbooks on gastroenterology do not mention the existence of a segmental type of chronic pancreatitis. Therefore, it is frequently not included in differential diagnosis of pancreatic head enlargement. We report two cases of groove pancreatitis, initially mistaken as pancreatic or duodenal carcinoma, and describe criteria, that might be helpful identifying this condition.

Neoadjuvant Therapy of Gastric Cancer: A Decisive Step Forward

Background: Although its incidence has been steadily decreasing in Western countries, gastric cancer remains a leading cause of cancer deaths worldwide. The detection rate of early-stage cancers is improving; nevertheless, the majority of cases is still diagnosed at later stages with a poor prognosis. Furthermore, the results that can be achieved with surgery have reached a plateau of effectiveness. Summary: Neoadjuvant chemotherapy was successfully introduced first in patients with non-curatively resectable disease. In the last decade, neoadjuvant chemotherapy has also been established in potentially curatively resectable cases and has become the state-of-the-art treatment. Esophagogastric junction (EGJ) tumors are not optimally treated with chemotherapy alone, and combined radiochemotherapy (RCT) seems to yield superior outcomes. Key Message: The use of neoadjuvant therapy has been successfully established in patients with curatively resectable disease. Neoadjuvant chemotherapy is now a cornerstone in the treatment of gastric cancer and cancer of the EGJ, although further work is needed in order to define the optimal combination regimen. Practical Implications: Neoadjuvant chemotherapy is currently the gold standard for the treatment of gastric cancer and cancer of the EGJ. Several independent studies have shown the benefits of using combination regimens that included cisplatin and 5-fluorouracil, though recently the use of the EOX (epirubicin, oxaliplatin and capecitabine) regimen has been widely accepted in this setting. Tumors of the EGJ benefit from neoadjuvant treatment with combined RCT. It should be noted that the optimal neoadjuvant regimen in EGJ tumors has not yet been defined, and the survival advantage of neoadjuvant RCT over neoadjuvant chemotherapy remains to be established in this patient population.