Endoscopic ultrasound staging in gastric cancer: Does it help management decisions in the era of neoadjuvant treatment?

BACKGROUND AND STUDY AIMS: Endoscopic ultrasonography (EUS) has been shown to be the most accurate test for locoregional staging of upper gastrointestinal tumors; however, recent studies have questioned its accuracy level in daily clinical application. The present retrospective study analyzes the accuracy of EUS in guiding interdisciplinary treatment decisions. PATIENTS AND METHODS: 123 primarily operated patients (63 % men, mean age 61.4 years) were included; only cases with tumor-free resection margins and without evidence of distant metastases were selected. EUS and histopathological findings were compared. Main outcome parameter was the distinction between tumors to be primarily operated (T1 /2N0) and those to be treated by neoadjuvant or perioperative chemotherapy (T3/4, or any N + ), based on an assumed algorithm for treatment stratification. RESULTS: Overall staging accuracy of EUS was 44.7 % for T and 71.5 % for N status irrespective of tumor location. Overstaging was the main problem (44.9 % for T, 42.9 % for N staging). The overall EUS classification was correct in 79.7 % (accuracy), with a sensitivity 91.9 % and specificity 51.4 %; only 19 out of 37 cases with histopathological T1/2N0 were correctly classified by EUS. Positive and negative predictive values of EUS in diagnosing advanced tumor stage for assignment to neoadjuvant therapy were 81.4 % and 73.1 %, respectively. CONCLUSIONS: Whereas EUS has a high sensitivity in the diagnosis of locally advanced gastric cancer, endosonographic overstaging of T2 cancers appears to be a frequent problem. EUS stratification between local (T1 /2N0) and advanced (T3/4 or any N + ) tumors would thus result in incorrect assignment to neoadjuvant treatment in half of cases.

Is Toupet fundoplication the procedure of choice for treating gastroesophageal reflux disease? Results of a prospective randomized experimental trial comparing three major antireflux operations in a porcine model.

BACKGROUND: Gastroesophageal reflux disease (GERD) is among the most common dysfunctions of the upper gastrointestinal tract. It interferes with quality of life and is a risk factor for the development of adenocarcinoma in the lower esophagus. Laparoscopic fundoplication is an effective treatment of GERD, but the physiologic mechanisms of the different available procedures had not been investigated to date. METHODS: In this study, 28 German Landrace pigs underwent baseline manometry and 24-h pH monitoring followed by myotomy to induce reflux esophagitis. After new-onset reflux was proved, the pigs were randomized to groups based on four treatments: total fundoplication, anterior hemifundoplication, posterior hemifundoplication, and control. On days 10 and 60 after the intervention, the effectiveness of the different fundoplication modifications was compared with that of the control subjects by 24-h pH monitoring manometry. Finally, the pigs were killed, after which the minimum volume and pressure required to breach the gastroesophageal junction were recorded. RESULTS: After myotomy, a significant increase in the reflux could be confirmed. The findings after fundoplication showed a significant decrease in the fraction of time that the pH fell below four and an increase in the vector volume compared with the measurement after myotomy. Total fundoplication and posterior hemifundoplication were highly effective, whereas measurements after anterior fundoplication still showed increased fraction times. Pharmacologic stimulation with pentagastrin showed an increase in the vector volume of the esophageal sphincter. CONCLUSIONS: Total fundoplication and posterior hemifundoplication are potent operations for the treatment of GERD. Anterior hemifundoplication reduces the reflux as well, but the effects are significantly less than with total and posterior fundoplication. Pharmacologic stimulation showed excellent results after posterior hemifundoplication, and a tendency to overcorrection was shown after total fundoplication.

Arterial en bloc resection for pancreatic carcinoma.

BACKGROUND: Surgery for locally advanced pancreatic cancer with arterial involvement of the hepatic artery, coeliac trunk and superior mesenteric artery (SMA) is highly controversial. In a retrospective review, the benefits and harms of arterial en bloc resection (AEBR) for pancreatic adenocarcinoma with arterial involvement were analysed. METHODS: Patients were divided into three groups: 29 patients who had pancreatic resection and AEBR (group 1), 449 who had pancreatic resection with no arterial resection or reconstruction (group 2), and 40 with unresectable tumours who underwent palliative bypass (group 3). RESULTS: Eighteen patients underwent reconstruction of the hepatic artery, eight of the coeliac trunk and three of the SMA. Additional reconstruction of portal vein was required in 15 patients and of adjacent visceral organs in 19. Perioperative morbidity and mortality rates were higher in group 1 than in group 2 (P = 0·031 and P = 0·037 respectively). Additional portal vein resection was an independent predictor of morbidity (P < 0·001). Median overall survival was similar for groups 1 and 2 (14·0 versus 15·8 months; P = 0·152), and lower for group 3 (7·5 months; P = 0·028 versus group 1). CONCLUSION: In selected patients AEBR can result in overall survival comparable to that obtained with standard resection and better than that after palliative bypass. Nevertheless, AEBR is associated with significantly higher morbidity and mortality rates, counterbalancing the overall gain in survival and limiting the overall oncological benefit.

[Timing and concepts of surgical treatment of upper gastrointestinal haemorrhage]. / Die chirurgische Therapie der oberen gastrointestinalen Blutung - Konzepte und zeitliche Planung.

BACKGROUND: Upper gastrointestinal bleeding is a frequently occurring clinical scenario with a potentially serious prognosis. In spite of excellent endoscopic results, the mortality rate after an insufficient endoscopic treatment is exception-ally high (12.5-36 %). It is crucial to recognise factors in which endoscopy reaches its limitations. Until now, no uniform guidelines and concepts concerning diagnosis and treatment as well as timing of surgical interventions, in particular, have been defined. The main goal of this study is to lower the morbidity and mortality rates after upper gastrointestinal bleeding, with potential risk stratification according to the literature and our own data. PATIENTS / MATERIAL AND METHODS: In a retrospectively designed study 220 patients were evaluated with upper gastrointestinal haemorrhage, who were hospitalised as emergencies from 1999 to 2002. Only those patients were accepted in the study who were examined within 48 hours endoscopically by oesophagogastroduodenoscopy. In order to exclude bleeding complications of a preceding endoscopic therapy, those patients were excluded who had been investigated by endoscopy in the past than 8 days. RESULTS: After endoscopic evaluation of the bleed-ing activity of 33 Forrest I a / I b bleedings 5 patients and of 52 Forrest II a / II b / II c bleedings 6 patients had to undergo surgery. The haemoglobin content of conventionally treated patients was on average 10.3 mg / dL as compared to 8.4 mg / dL for the operated patients. The conventionally treated patients received an average of 3 red cell concentrates whereas the operated patients had 11 blood transfusions. The source of haemorrhage in the operated patients was located in bulbus duodeni (n = 7), cardia and fundus (n = 2) and the corpus (n = 2). CONCLUSION: The evaluation of our own patient data including the experiences of other authors shows that a risk stratification is possible and meaningful. The indication for surgery thereby -depends on different factors: the comorbidity of the patient, the haemodynamic in- / stability, the number of necessary blood transfusions and the localisation of the bleeding source.

Lack of prognostic significance of serum DNA methylation of DAPK, MGMT, and GSTPI in patients with non-small cell lung cancer.

BACKGROUND AND OBJECTIVES: To further improve the screening, diagnosis and therapy of patients with non-small cell lung cancer (NSCLC) additional diagnostic tools are desperately warranted. Aim of this study was to investigate the potential of the DNA methylation of DAPK, MGMT, and GSTPI in serum of patients with NSCLC as a prognostic molecular marker in this disease. METHODS: Seventy-six patients with NSCLC were included in this study. The analysis of DNA methylation in serum of patients was performed on pre-operative samples. Following DNA isolation and bisulfite-treatment, DNA methylation was analyzed by quantitative-methylation-specific real-time PCR with beta-actin as the internal reference gene. RESULTS: DNA methylation was detectable with following frequencies: DAPK 68.4%, MGMT 7.9%, GSTPI 0%. There were no associations between DNA methylation status and histology, tumor stage, grading or gender detectable. With a mean follow-up of 19.7 months the median survival was 26.3 months. There were no associations between the status of DNA methylation in patient's serum and prognosis detectable. CONCLUSION: The analysis of DNA methylation in serum of patients with NSCLC by quantitative-methylation-specific real-time PCR is technically feasible. Although our results suggest quantification of DNA methylation in serum not of prognostic significance in this disease, further studies are warranted to determine the future potential of this molecular approach.

[Lateral anastomosis techniques: Partington-Rochelle and V-shaped excision]. / Laterale Anastomosentechniken : Partington-Rochelle und "V-Shape-Exzision"

Characteristic symptoms of chronic pancreatitis are difficult to manage conservatively. They include severe pain and endocrine and exocrine insufficiency. Surgical treatment with simple and extended draining procedures addresses pain relief and the management of chronic pancreatitis-associated complications of adjacent organs. Following the assumption that pancreatic duct changes with intraductal hypertension are the reason for pain, simple drainage procedures have reduced pain in up to 80% of patients, with low morbidity and mortality. In case of complications involving adjacent organs with inflammatory pancreatic head tumor and stenosis of the distal bile duct, extended drainage procedures with limited pancreatic head resection according to Frey and V-shaped excision of the ventral aspect of the pancreas have been performed successfully.

Microsatellite GTn-repeat polymorphism in the promoter of heme oxygenase-1 gene is an independent predictor of tumor recurrence in male oral squamous cell carcinoma patients.

BACKGROUND: Transcriptional activity of the heme oxygenase-1 gene (HMOX-1) is modulated by a GTn-repeat promoter polymorphism. The long GTn-repeat allele has been previously reported to be associated with increased risk of oral squamous cell carcinoma (OSCC) in male areca chewer and short GTn-repeat allele has been proposed to have protective properties in OSCC patients. The aim of the present study was to correlate the GTn-repeat genotypes with clinicopathological characteristics along with clinical outcome of non-areca chewer OSCC patients. METHODS: DNA of 99 patients that underwent complete surgical resection of OSCC was analyzed for GTn-repeat polymorphism in the HMOX-1 promoter by polymerase chain reaction, capillary electrophoresis and DNA sequencing. RESULTS: Seven SS (7.1%), 51 SL (51.5%) and 41 LL (41.4%) genotypes were found. In a total of 14 (14.1%) patients, tumor recurrence (TR) was observed. There was no TR in the SS allele carriers. In SL carriers three and in LL 11 TR occurred (P = 0.009, chi-squared test). Mean relapse-free survival was 109.2 months in SL allele carriers compared with 72.3 months in LL allele carriers (P = 0.01, log-rank test). Multivariate Cox regression modeling identified GTn-repeat genotype as an independent prognostic factor (P = 0.03; relative risk (RR) 4.1; 95% CI 1.1-14.6). CONCLUSION: Presence of S allele was associated with a lower TR rate and better relapse-free survival in OSCC patients. HMOX-1 promoter polymorphism might be considered as a potential prognostic marker in OSCC patients.

Pancreatic cancer: a generalized disease--prognostic impact of cancer cell dissemination.

BACKGROUND: Pancreatic ductal adenocarcinoma is the fifth leading cause of death among all malignancies, leading to approximately 40,000 deaths each year in Europe. The annual incidence rate for all types of pancreatic cancer is approximately nine new cases per 100,000 people, ranking it as the 11th among all cancers. Stage, grade and resection margin status are currently accepted as the most accurate pathologic variables predicting survival. All classification systems fail prognostically to distinguish between different stages. Even in patients with seemingly early tumours (T1, N0), the likelihood of relapse is high. This reflects the shortcomings of the pathologic staging to sufficiently discriminate patients with a high risk to develop tumour recurrence from those that carry a lower risk. RESULTS: On the other hand, none of the currently used systems includes or takes into consideration the role of disseminated tumour cells neither in the lymph nodes nor in the bone marrow. Occult residual tumour disease is suggested when either bone marrow or lymph nodes, from which tumour relapse may originate, are affected by micrometastatic lesions undetectable by conventional histopathology. For detection, antibodies against tumour-associated targets can be used to detect individual epithelial tumour cells both in lymph nodes and in bone marrow. The clinical significance of these immunohistochemical analyses is still controversial. Various monoclonal antibodies are still in use for micrometastatic detection, thus contributing to the incongruity of data and validity of results. These assays have been rarely used in patients with pancreatic carcinoma. CONCLUSION: The presence or absence of lymph-node metastases can predict the likelihood of survival for most, if not all, patients with pancreatic ductal adenocancer and the likelihood that metastases will develop at distant sites.

Late morbidity after duodenum-preserving pancreatic head resection with bile duct reinsertion into the resection cavity.

BACKGROUND: Reinsertion of the distal common bile duct (CBD) into the pancreatic resection cavity during duodenum-preserving pancreatic head excision (DPPHE) may be an alternative option to Whipple resection or bilioenteric anastomosis when chronic pancreatitis is associated with CBD stenosis. METHODS: Outcome in 82 patients with chronic pancreatitis who underwent DPPHE with CBD reinsertion was compared with that in 432 who had DPPHE without reinsertion and 50 who had a Whipple procedure or pylorus-preserving pancreatoduodenectomy (PPPD). RESULTS: There were no deaths after DPPHE with CBD reinsertion, compared with four (0.9 per cent) after DPPHE without reinsertion and three (6 per cent) after classical resection. Overall morbidity rates were 30, 28.9 and 36 per cent respectively. Fifteen patients (18 per cent) who had DPPHE with CBD reinsertion developed a stricture at the reinsertion site, compared with a long-term stricture rate of 2.3 per cent (ten patients) after DPPHE without CBD reinsertion and 4 per cent (two patients) after PPPD/Whipple resection. CONCLUSION: Although associated with a high incidence of anastomotic stricture, reinsertion of the CBD into the resection cavity as part of DPPHE can be used to preserve duodenal passage and offers an alternative to extended resection for chronic pancreatitis.

Quality control of endoscopic ultrasound in preoperative staging of esophageal cancer.

BACKGROUND AND STUDY AIMS: Endoscopic ultrasonography (EUS) is generally established as the most sensitive diagnostic tool for the assessment of locoregional tumor stage in esophageal carcinoma. It therefore has a crucial impact on the decision whether patients should undergo surgery as primary treatment or should receive neoadjuvant therapy. This study retrospectively evaluates the accuracy of EUS in tumor and nodal staging of prospectively evaluated patients with esophageal carcinoma in relation to tumor type, tumor grading, tumor site, and the influence of dilation. PATIENTS AND METHODS: All 214 patients included in the study underwent surgery without neoadjuvant therapy and had tumor-free resection margins with no evidence of distant metastasis. EUS investigations were done at our Department of Interdisciplinary Endoscopy. EUS results were compared with the pathological findings. RESULTS: EUS correctly identified T status in 141 patients (65.9 %). The sensitivity and specificity in relation to T status were 68.1 % and 98.2 % respectively for T1, 40.9 % and 83.4 % for T2, 84.3 % and 64.6 % for T3, and 14.3 % and 98.8 % for T4. The overall diagnostic accuracy of EUS in relation to N status was 64.5 % (n = 138); sensitivity and specificity for the diagnosis of N1 were 93.8 % and 20 %, respectively. Sixty-eight (80 %) of 85 pN0-staged tumors were overstaged as uN1. Dilation had a significant influence on the accuracy of EUS staging in advanced tumors ( P = 0.02), whereas tumor grading impacted on EUS staging in early tumors ( P = 0.01). Tumor site and tumor type did not show any influence. CONCLUSIONS: Endosonographic staging of esophageal carcinoma is still unsatisfactory. An improvement in staging accuracy may be achieved by adding fine-needle aspiration biopsy (FNA) to EUS, because FNA improves N-stage accuracy, but it has no bearing on T-stage accuracy.

Endoscopic mucosal resection of early esophageal squamous cell cancer using the Duette mucosectomy kit.

BACKGROUND AND STUDY AIM: Endoscopic mucosal resection (EMR) is a less invasive alternative treatment strategy to surgery for intramucosal esophageal squamous cell carcinoma (SCC). This study described our initial experience with the newly introduced Duette Multiband Mucosectomy Kit (Cook Ireland Ltd, Limerick, Ireland) for the treatment of extensive early esophageal SCC. PATIENTS AND METHODS: Five patients with extensive early esophageal SCC, covering at least half of the circumference of the esophageal wall and measuring a mean of 2.8 cm longitudinally, underwent EMR after EUS staging. RESULTS: EMR was successfully completed in one session in five patients. Post-EMR stricture occurred in four patients but was successfully treated with bougienage. One patient did not return for follow-up after bougienage and died from ischemic heart disease 3 months later. For the remaining four patients, there was no recurrence over a mean follow up of 14.7 months. CONCLUSION: This new device obviates the need for repeated insertion of the endoscope during the process of ligation and resection and thus facilitates EMR of extensive SCC.

Pancreas-sparing duodenectomy in duodenal pathology: indications and results.

BACKGROUND/AIMS: Pancreas sparing-duodenectomy is an organ-preserving surgical procedure suitable for patients with premalignant or early malignant lesions of the duodenum. The surgical technique is challenging due to the close anatomical relationship between the pancreas and the duodenum. METHODOLOGY: All patients undergoing pancreas-sparing duodenectomy for benign or premalignant condition of the duodenum operated on between 1998 and 2001 were analyzed prospectively. The surgical technique, the hospital course, and complications are described. RESULTS: A total of four patients underwent pancreas sparing-duodenectomy. Two patients experienced an uncomplicated postoperative course. In one patient, after completing the pancreas sparing-duodenectomy, the operation was converted to a Whipple procedure after the intraoperative diagnosis of malignant disease in the fresh frozen section. One patient had a complicated postoperative course with postoperative pancreatitis requiring several reoperations. At follow-up all patients are well, free of recurrence and alive. CONCLUSIONS: Pancreas-sparing duodenectomy is a challenging surgical technique and requires excellent knowledge of the anatomy. Intraoperative fresh-frozen section is mandatory to exclude malignant disease. If performed for appropriate indications, pancreas sparing-duodenectomy offers the potential to preserve the anatomical gastrointestinal passage and the integrity of the pancreas.

Heterotopic pancreas--clinical presentation and pathology with review of the literature.

BACKGROUND/AIMS: Heterotopic pancreas is usually a silent gastrointestinal malformation, but it may become clinically evident when complicated by chronic inflammation or by growth. METHODOLOGY: We report on eleven cases of heterotopic pancreatic tissue. The cases were selected from the records of our Surgical Department and Institute of Pathology. The literature about heterotopic pancreas is reviewed. RESULTS: Nausea and vomiting (27%), epigastric pain (27%), ulceration (27%) and weight loss (18%) were the three most frequent symptoms and signs. The lesions were diagnosed as gastrointestinal tumor or ulcer by gastroduodenoscopy (36%). The other patients were diagnosed during surgery (64%). Definitive diagnosis was only achievable by pathology. Heterotopic pancreas was the reason for surgery in 36% of the cases, in another 45% diagnosis was incidental during surgery and in 18% the diagnosis was established endoscopically and surgery was not necessary. CONCLUSIONS: The diagnosis of heterotopic pancreas is rarely established, most cases remain clinically silent. In symptomatic patients diagnosis should to be secured histologically to exclude malignant disease.

[Interdisciplinary surgery of the thorax-from the general surgeon's point of view]. / Operative Interdisziplinarität - Thorax. Aus der Sicht des Allgemeinchirurgen.

Interdisciplinary professional management is the most important basic principle for successfully mastering thoracic operations including the thoracic wall and adjacent regions such as neck, axilla, mediastinal vessels, upper limb, and spine. Extended oncological resection in advanced malignant diseases, side-effects of radiotherapy and trauma explain the diversity of possible operative procedures. For technical success, the necessity of vascular grafting, reconstruction of the brachial plexus, spine surgery, cardiac surgery, plastic thoracic wall reconstruction, stabilization of the thoracic wall, modern equipment, and know-how are mandatory. We chose some show-cases which-in our opinion-might be appropriate for demonstrating interdisciplinary therapy management. Functional, oncological, and cosmetic/reconstructive aspects should be considered when approaching these cases.

[Recurrent intestinal bleeding in a patient with arterio-venous fistulas in the small bowel, limited mesenteric varicosis without portal hypertension and malrotation type I]. / Rezidivierende intestinale Blutungen bei einem Patienten mit arteriovenösen Fisteln des Dünndarms, umschriebener mesenterialer Varikosis ohne portale Hypertension sowie Typ I Malrotation.

A case of vascular malformations of the small intestine associated with malrotation Type I of the right colon is reported. Representing rare conditions, vascular malformations in the small bowel are not accessible endoscopically. Therefore, gastrointestinal haemorrhage originating from this "terra incognita" is difficult to diagnose. Our patient had a medical history of anaemia of 17 years before admitted to our hospital. After a preoperative blood pool scan had evidenced the bleeding source in the proximal jejunum, the patient underwent explorative laparotomy. The bleeding source was identified and resection of a jejunal segment was performed. Intraoperatively, malrotation type I was found. Histological examination revealed angiodysplasia extending full thickness of the intestinal wall with predominance in the submucosa and serosa. Secondary arterialisation was seen in the vessels of the serosa resembling varicosis-like lesions at gross inspection. The patient did not suffer from portal hypertension. Postoperative course was uneventful and no further bleeding occurred.

[The role of angiography in the diagnosis and therapy of gastrointestinal hemorrhage]. / Stellenwert der Angiographie in der Diagnose und Therapie gastrointestinaler Blutungen.

PURPOSE: Evaluation of angiography in the diagnosis and treatment of acute and chronic gastrointestinal bleeding. MATERIALS AND METHODS: Thirty-seven consecutive patients with clinically suspected gastrointestinal bleeding underwent selective angiography of the visceral arteries. If technically possible, patients with radiologically proven hemorrhage underwent selective embolization with microcoils. Not all angiographically detected bleeding vessels were embolized. Clinical outcome was determined from a review of the medical records. RESULTS: 37 patients underwent 43 angiographies, which demonstrated 25 bleedings considered acute and 18 considered chronic. Seventeen patients had previous intestinal surgery. In 9 of the 37 patients, 12 of the 43 (sensitivity: 28 %) hemorrhages were detected. A postoperative bleeding was found in 6 patients. With one exception, all angiographically positive cases were clinically considered to be acute. Transcatheter embolization of the bleeding vessels with microcoils was performed in 6 patients, with 3 patients having the bleeding stopped permanently and 3 patients requiring further surgical treatment. In 3 patients, embolization was not possible for technical reasons. No complications attributable to angiography were seen. CONCLUSION: Angiography should be performed in patients with spontaneous and postoperative gastrointestinal bleeding. Transcatheter embolization is an effective and safe therapeutical option in both clinical settings.

Chronic pancreatitis: etiology, pathogenesis, diagnosis, and treatment.

BACKGROUND AND AIMS: This review discusses current concepts regarding the etiology, pathogenesis, diagnosis, and treatment of chronic pancreatitis. RESULTS: Treatment of patients suffering from complications of chronic pancreatitis remains a major challenge. Continuous alcohol consumption, a disease with enormous personal and social impact, is still the leading factor in the development of chronic pancreatitis. The most distressing symptom for the patient is pain, which in many instances has already led to a considerable analgesic abuse before a specialist is even consulted. The development of an enlargement of the pancreatic head, the "pacemaker of the disease," parallels pain and potential organ complications such as common bile duct stenosis or portal hypertension. What triggers pancreatic head enlargement is still not known; in particular it is unclear what triggers growth factors to step into action. Pain is most likely due to a combination of hypertension in the organ and parenchymal alterations. Current therapeutic concepts therefore aim at alleviating pain and at management of organ complications while preserving functional tissue to best prevent exocrine and endocrine dysfunction. The ideal procedure thus seems today to be the "customized" pancreatic head resection with additional optional drainage of the pancreatic body and tail.

Attenuation of sepsis-related immunoparalysis by continuous veno-venous hemofiltration in experimental porcine pancreatitis.

OBJECTIVES: In light of evidence suggesting that hemofiltration favorably influences septic diseases by removing sepsis mediators, the impact of different modalities of continuous veno-venous hemofiltration (CVVH) on outcome and immunologic derangements in porcine pancreatogenic sepsis was evaluated. DESIGN: Randomized, controlled intervention trial. SUBJECTS: Forty-eight minipigs of either sex. INTERVENTIONS: Pancreatitis was induced by intraductal injection of sodium taurocholate (4%, 1 mL/kg body weight [BW]) and enterokinase (2 U/kg BW). Animals were allocated either to untreated controls-group 1-or to one of three treatment groups-group 2: low-volume CVVH (20 mL/kg BW), no change of hemofilters; group 3: low-volume CVVH, filters changed every 12 hrs; and group 4: high-volume CVVH (100 mL/kg BW), filters changed every 12 hrs. Survival represented the major parameter of the study. Serum cytokine levels, sepsis-related down-regulation of major histocompatibility complex II and CD14 expression on leukocytes, bacterial translocation, and endotoxemia were further parameters evaluated in the study. MEASUREMENTS AND MAIN RESULTS: High-volume CVVH combined with periodic filter change was significantly superior compared with less intensive treatment modalities (low-volume CVVH, no filter change) in sepsis protection. Long-term survival (>60 hrs) was found in 67% of group 4 and 33% of group 3 animals (p <.05), whereas in controls and group 2 no animal survived. CVVH ameliorated the initial serum tumor necrosis factor-alpha response and prevented sepsis-induced in vitro endotoxin hyporesponsiveness. Down-regulation of major histocompatibility complex II and CD14 expression on monocytes was significantly improved by CVVH. Improved oxidative burst and phagocytosis capacity in polymorphonuclear leukocytes suggested that leukocyte function was stabilized by CVVH. Also, CVVH significantly reduced bacterial translocation and endotoxemia. CONCLUSIONS: Hemofiltration reversed sepsis-induced immunoparalysis in a porcine model of bile acid-induced pancreatitis. Implications for human pancreatitis must be validated in prospective, clinical protocols.

Bradykinin B2-receptor antagonism attenuates fatal cardiocirculatory breakdown induced by severe experimental pancreatitis.

OBJECTIVES: To investigate the impact of the long-acting bradykinin B2 receptor antagonist HOE 140 (Icatibant) on survival time in a model of severe porcine pancreatitis. DESIGN: Randomized, controlled intervention trial. SUBJECTS: Thirty domestic pigs of either gender anesthetized by intravenous application of piritramide, midazolam, and pancuronium and mechanically ventilated. INTERVENTIONS: Pancreatitis was induced by an injection of sodium taurocholate (5%, 1 mL/kg body weight [BW]) and enterokinase (10 U/kg BW). Control animals (group 1, n = 10) underwent the spontaneous course of the disease. In two treatment groups, Icatibant was administered either in a low (100 nmol/kg BW; group 2, n = 10) or in a high dosage (5000 nmol/kg BW; group 3, n = 10). MEASUREMENTS AND MAIN RESULTS: Mean survival time was significantly prolonged by Icatibant (controls, 6.6 hrs; group 2, 9.8 hrs; p = .022; group 3, 10.9 hrs; p = .007). Six hours postinduction, the decline of total peripheral resistance (52% of baseline) and cardiac index (92% of baseline) in controls was significantly improved by Icatibant, both in the low (16% and 44%; p < .05) and high (6% and 45%; p < .05) dosage. The concentrations of free, nonreceptor-bound kinin in plasma 6 hrs postinduction were significantly lower in controls than in groups 2 and 3 animals (111+/-50 vs. 208+/-40 and 237+/-52 fmol/mL, respectively). Six hours postinduction, the pretreatment with Icatibant was associated with significantly higher plasma concentrations of phospholipase A2 (controls, +1194%; group 2, +2000%; group 3, +2285% of baseline values) and interleukin-1 receptor antagonist (controls, 1900+/-800; group 2, 3100+/-800; group 3, 3600+/-800 pg/mL). In contrast, the increase of urinary trypsinogen activation peptides indicating local pancreatic damage (589+/-114 nmol/L in controls) was substantially attenuated by pretreatment with Icatibant (group 2, 467+/-102, NS; 352+/-91 nmol/L in group 3; p = .022 vs. controls). Systemic inflammatory reactions, however, as quantified by C-reactive protein and the extracellularly discharged neutrophil cytosolic inhibitor leukocyte neutral proteinase inhibitor were not influenced by the bradykinin B2-receptor antagonist. CONCLUSIONS: Pretreatment with the bradykinin B2 receptor antagonist Icatibant resulted in prolonged survival time and in delayed impairment of major macrocirculatory and pulmonary variables. Icatibant resulted in elevated concentrations of free, circulating kinin. This was associated with increased concentrations of phospholipase A2 and interleukin-1 receptor antagonist, suggesting that circulating kinins strengthen the activation of some mediator cascades, the association of which with the kinin metabolism requires further experimental clarification. Other variables indicating a systemic inflammatory response (C-reactive protein, leukocyte neutral proteinase inhibitor) remained unaffected by Icatibant. Bradykinin antagonism distinctly ameliorated the local pancreatic damage, indicated by increased urinary concentrations of trypsinogen activation peptides. It is concluded that the kinin metabolism plays an important role in the pathophysiology of systemic complications after severe experimental pancreatitis.