E. H. Farthmann

Elevation of serum interleukin-6 concentration precedes acute-phase response and reflects severity in acute pancreatitis

Experimental studies have shown that interleukin-6 induces all major acute-phase proteins in the liver, including C-reactive protein. In 50 patients with acute pancreatitis, the serum concentrations of interleukin-6 and C-reactive protein were determined daily during the first week of hospitalization. Patients were divided into three groups according to clinical criteria: mild pancreatitis (less than or equal to 1 complication; n = 25), severe pancreatitis (greater than or equal to 2 complications; n = 15), and lethal outcome (n = 10). Patients with mild disease showed initially slightly elevated levels of interleukin-6 (22.0 +/- 9.8 U/mL) that decreased to low levels within 4 days (5.0 +/- 1.0 U/mL). In patients with severe pancreatitis, serum concentrations of interleukin-6 were initially clearly elevated (35.0 +/- 7.5 U/mL) and remained slightly elevated until day 7 (13.0 +/- 2.0 U/mL). Patients with lethal outcome had markedly elevated initial interleukin-6 concentrations (61.0 +/- 15.0 U/mL) that decreased but were still elevated at day 7 (26.0 +/- 2.5 U/mL). In all three groups, C-reactive protein concentrations followed the course of interleukin-6 concentrations by 1 day. There was a positive correlation between maximal interleukin 6 concentrations and maximal increases in the serum concentrations of C-reactive protein (r = 0.66). At days 1 and 2, increased (greater than 15 U/mL) interleukin-6 concentrations (positive predictive value, 91%; negative predictive value, 82%) predicted a severe or lethal course of the disease more accurately than elevated [greater than 0.10 g/L (greater than 10 mg/dL)] C-reactive protein concentrations (positive predictive value, 67%; negative predictive value, 79%). In conclusion, elevated serum concentrations of interleukin-6 followed by increased levels of C-reactive protein reflect the severity of acute pancreatitis.

Interleukin-8 and neutrophil activation in acute pancreatitis

Abstract. It has been suggested that leucocytes play an important role in the pathogenesis of complicated pancreatitis. Indeed, increased plasma concentrations of neutrophil elastase as a marker of neutrophil activation could be detected in patients with a severe course of the disease. Recently, interleukin‐8 (IL‐8) has been described as a novel neutrophil activating peptide. To determine the role of IL‐8 in acute pancreatitis we measured its serum concentrations by a specific enzyme‐linked immunosorbent assay in 10 patients with acute pancreatitis daily during the first week of hospitalization. IL‐8 levels were compared with plasma concentrations of neutrophil elastase and the clinical course of the disease. Three of the patients had uncomplicated pancreatitis, while seven showed various extrapancreatic complications. Patients with complicated pancreatitis had statistically significant (P<0.05) higher mean values of IL‐8 (121 ±41 pg ml‐1 vs. 13 ± 6 pg ml‐1, mean ± SEM) and neutrophil elastase (547 ± 35 ng ml‐1 vs. 250±20 ng ml‐1) than patients with uncomplicated disease. There was a positive correlation (r= 0.52, P < 0.0001) between IL‐8 and neutrophil elastase in the lower concentration range of IL‐8 (< 100 pg ml‐1). At IL‐8 levels > 100 pg ml‐1 neutrophil elastase was always greatly elevated; however, under these conditions the relationship between IL‐8 and elastase was no longer linear. No measurable IL‐8 concentrations were found when plasma elastase was < 200 ng ml‐1. During follow‐up, initially elevated IL‐8 concentrations decreased in correlation with clinical improvement. In conclusion, the results suggest that IL‐8 contributes to initial neutrophil activation during acute pancreatitis. IL‐8 seems thus to be a factor involved in the pathogenesis of complicated pancreatitis.

Impact of 18F-FDG-positron emission tomography for decision making in colorectal cancer recurrences

Abstract Diagnostic imaging for suspected tumour recurrence of primary colorectal cancer frequently lacks specificity and sensitivity. The impact of whole body 18F-FDG-positron-emission tomography (PET) on detection of local recurrences and hepatic or pulmonary metastases was evaluated in a prospective study. Results were compared with computed tomography (CT), ultrasonography, magnetic resonance imaging and conventional chest X-ray. The study included 71 patients (77 investigations) with suspected local recurrence, hepatic metastases or unexplained raised level of the tumour marker carcinoembryonic antigen (CEA). The results demonstrate that 18F-FDG-PET was clearly superior to CT with regard to detection of hepatic metastases. Sensitivity was 1.0 and specificity 0.98 compared with 0.87 and 0.91 for CT. In four cases, 18F-FDG-PET clarified otherwise unclear local recurrences. In five patients, 18F-FDG-PET showed pulmonary metastases that had previously been unknown. In a total of 16 patients (20.8%), 18F-FDG-PET provided additional information leading to a change of the treatment strategy. 18F-FDG-PET clearly has the ability to detect colorectal tumour recurrence and its metastases in a whole body format. Therefore, it may be applied in the follow-up of patients with primary colorectal cancer. Despite the costs, it is certainly recommended for patients with an otherwise unclear increase of CEA level or with unproven local recurrence.

Expression of gastrin, gastrin/CCK-B and gastrin/CCK-C receptors in human colorectal carcinomas.

To investigate further the presence of an autocrine proliferative loop involving gastrin in colorectal carcinomas and to clarify the receptor responsible, 102 human colorectal carcinomas and 10 hepatic metastases were investigated for the expression of the genes encoding gastrin, the gastrin/CCK-B receptor and the gastrin/CCK-C receptor. Levels of RNA expression were assayed by RNase protection assay. In addition, gastrin/CCK receptors on crude membranes of tumour tissue were assayed by radioligand binding. High-affinity gastrin/CCK-B receptors were not detected in any of the carcinomas investigated, whereas in 36% low-affinity binding was observed, consistent with the expression of the gastrin/CCK-C receptor. RNase protection assay detected the RNA for the gastrin/CCK-B receptor in 11% of the carcinomas investigated, whereas the RNA for the gastrin/CCK-C receptor was demonstrated in 75% and the RNA for gastrin in 86% of the carcinomas investigated. These results confirm the recent demonstration of progastrin fragments in colorectal carcinomas. One possible explanation for progastrin expression is that such progastrin fragments may participate in an autocrine proliferative loop. The receptor involved in this loop is more likely to be the low-affinity gastrin/CCK-C receptor rather than the gastrin/CCK-B receptor, which is rarely expressed in colorectal carcinomas.

Predictive factors for response to neoadjuvant therapy in patients with oesophageal cancer

BACKGROUND Preoperative radio-chemotherapy (RCX) was introduced to improve the outcome of patients with oesophageal cancer (EC), but conflicting results have been released. Some 20-30% of patients show a complete pathological response, however, the perioperative morbidity and mortality is increased. To search for factors indicating response prior to the onset of RCX we investigated the proliferative activity (MIB-1), the expression of vascular endothelial growth factor (VEGF), and the capillary density (CD34) in samples of EC obtained by endoscopy prior to the start of the treatment. METHODS Forty-six (MIB-1) and 21 (VEGF, CD34) tissue specimens of ECs were available from 56 patients undergoing pretherapeutic endoscopy, RCX and surgery. Perioperative morbidity was divided into surgery and non-surgery related morbidity. MIB-1, VEGF and CD34 expression were investigated immunohistochemically. Multivariate analysis was carried out to prove independence of investigated variables. RESULTS Postoperative morbidity was noticed in 54 of 56 operated patients. Eight of 56 patients who received RCX died in hospital. Survival was significantly different between the group of complete responders (n=14) and non-responders (n=23; P=0.0026). None of the investigated tumour samples from patients with a complete response (CR) had a proliferation index of less than 45. Tumour samples from patients with a CR showed a VEGF expression of 10.7 compared with 36.58 of tumours with no response (P=0.035). CD34 expression showed a correlation with VEGF expression. The relation of mean indices of VEGF expression and proliferative activity in tumours from patients with complete, partial or no response was 10.7:58.8, 18.3:53.8 and 36.6:43.5, respectively. CONCLUSIONS According to these results, it may be expected that tumours with a VEGF/MIB-1 ratio of 1:6 or less prior to RCX will respond to this therapy.

Evidence-based surgery: diverticulitis – a surgical disease?

Abstract Sigmoid diverticulitis is an increasingly common disorder. While there is no gender difference, the incidence increases with age. Many reports have been published on the topic, but there is no consensus on certain aspects of treatment. We conducted a literature search covering the past 30 years and report our own data. Two major areas of controversy exist. One concerns indications for elective surgery for symptomatic diverticulitis. The consensus is that there is no indication for prophylactic surgery. The first attack should be treated conservatively; elective surgery is considered following a second attack, but in immunocompromised patients earlier. The second controversy concerns surgical strategy in peritonitis from perforation. Three-stage operations have generally been abandoned. The question is whether to perform a sigmoid resection with primary anastomosis. One end of the spectrum is recent perforation which can be treated safely by resection and anastomosis. The other end is advanced feculent peritonitis in high-risk patients. In this situation a Hartmann procedure is recommended. Although data from prospective randomized studies are lacking, there seem to be indicators in the individual situation that allow a rational selection of the appropriate procedure. Diverticulitis can thus be treated surgically for a broad range of its forms of presentation.

Local Inflammatory Peritoneal Response to Operative Trauma: Studies on Cell Activity, Cytokine Expression, and Adhesion Molecules

OBJECTIVE To test the hypothesis that different surgical procedures may lead to different degrees of activation of the human peritoneal response. DESIGN Clinical laboratory study. SETTING University Hospital, Germany. MATERIAL Peritoneal specimens taken from the incision or parietal resection margins at the beginning and end of laparoscopic or open cholecystectomy, or other conventional open operations (n = 5 in each group). MAIN OUTCOME MEASURES Detection of indicators of the inflammatory response: interleukin 1 (IL-1), interleukin 6 (IL-6), intercellular adhesion molecule- (ICAM-1), antibacterial protein (defensin 3 that reflects the activation of granulocytes), the antibody clone HAM 56 (for detection of local macrophages), and antibodies against macrophage inhibiting factor (MIF)-related proteins 8 and 14 (MRP 8 and 14). RESULTS The rise between preoperative and postoperative evaluations was significant for each variable (p < 0.05). With one single exception (IL-6 between laparoscopic cholecystectomy and other operations), the one way analysis of variance (ANOVA) showed no significant differences among the three groups in the detectable increases in staining. Linear regression analysis showed no correlation between length of operation and increases in immunohistochemically detected inflammatory variables. CONCLUSION Minimally invasive surgery does not necessarily mean minimal peritoneal damage. The immunohistochemical evaluation of the local cellular response may provide additional objective criteria for the grading of operative trauma.

Relapsing pancreatitis associated with duodenal wall cysts. Diagnostic approach and treatment.

A case of enterogenous cysts of the duodenum in a 44-yr-old man complicated by duodenal obstruction and relapsing pancreatitis is presented. The cystic duodenal lesions were visualized by endoscopic retrograde cholangiopancreatography and for the first time by computed tomography and abdominal sonography. Thus, the diagnosis was made preoperatively. The cysts were excised successfully during a Whipple procedure. Awareness of this rare condition combined with modern x-ray, sonographic, and endoscopic techniques permit accurate preoperative diagnosis.

Detection of biliary origin of acute pancreatitis. Comparison of laboratory tests, ultrasound, computed tomography, and ERCP.

Fifty consecutive patients with acute pancreatitis were assessed with respect to a biliary origin of the disease. Endoscopie retrograde cholangiopancreaticography, surgery, and autopsy were used to define biliary pancreatitis. Ultrasound, computed tomography, and several laboratory tests (SGOT, SGPT, alkaline phosphatase, and bilirubin) were analyzed for their ability to detect a biliary origin of the disease. Ultrasound and computed tomography could not reliably make the diagnosis in the 10 patients found to have biliary disease. Receiver-operator-characteristic curves revealed that none of the laboratory tests assessed had sufficient sensitivity and specificity to determine the diagnosis, although all tests showed higher mean values in biliary pancreatitis. SGPT gave the best discrimination (positive predictive value 53%, negative predictive value 94%, cut off 40 Units/liter). Therefore, initial ERCP is suggested for a reliable diagnosis of biliary origin of acute pancreatitis.

Is MIB-1 proliferation index a predictor for response to neoadjuvant therapy in patients with esophageal cancer?

BACKGROUND The overall survival rate for patients with an esophageal cancer remains poor. As a consequence, preoperative chemoradiation was introduced for patients with tumor stage T >1 M0 regardless of tumor histology or localization. However, factors predicting response to this therapy pretherapeutically are largely unknown. METHODS Clinical results of preoperative chemoradiation were investigated. The rates of proliferation and apoptosis were determined in pretherapeutic tumor samples and correlated with tumor response and long-term survival after surgery. RESULTS A complete tumor response due to chemoradiation (n = 42; cervically localized tumors excluded) was achieved in 11 patients (26%) after resection. Five-year survival rate was significantly improved in these patients compared with those who did not respond to chemoradiation (48% versus 5.5%; P = 0.003). Chemoradiation was performed without benefit in 43%. Perioperative hospital mortality rate was 14.3% in all patients. No correlation of apoptosis with response to chemoradiation or postoperative long-term survival was observed. However, there was a clear correlation between the proliferation rate as determined by MIB-1 immunohistology. Five-year survival rate of patients with a proliferation index (PI) >/=39% was 38% compared with 0% in tumors with a PI <39%. Tumors with a PI >/=39% responded to chemoradiation in 71.4%, but 100% of tumors with a PI <39% did not. Mean survival time of these patients was 33 months and 11 months, respectively (P = 0.015). CONCLUSIONS The results indicate that the PI may be used for stratification of patients treatment prior surgery. However, these results need further validation in larger patient numbers in the search for factors indicating response pretherapeutically to preoperative chemoradiation in esophageal cancer.