The use of antibiotics for acute pancreatitis: is there a role?

Infections due to pancreatic necrosis and abscesses are observed in one third of patients with severe acute pancreatitis (SAP). Based on results of double-blind, randomized, placebo-controlled trials, antibiotic prophylaxis in SAP is ineffective for reducing the frequency of infected necrosis and to decrease hospital mortality. Antibiotic treatment using carbapenems and quinolones is indicated on demand in patients with SAP and multiorgan failure at admission and in those with hemodynamic shock. Patients with biliary acute pancreatitis (AP) and clinically acute cholecystitis and/or cholangitis benefit from antibiotic treatment. Patients with AP associated with bacteremia, positive bronchoalveolar lavage, and urinary tract infection should receive antibiotics. In necrotizing pancreatitis, evidence-based data do not support late use of antibiotic prophylaxis after onset. Further high-quality, randomized, controlled trials are needed to evaluate antibiotic prophylaxis in the first 24 to 48 hours after SAP onset.

Duodenum-preserving total pancreatic head resection for cystic neoplasm: a limited but cancer-preventive procedure.

BACKGROUND: Cystic neoplastic lesions of the pancreas are found in up to 10% of all pancreatic lesions. A malignant transformation of cystic neoplasia is observed in intraductal papillary mucinous tumor (IPMN) lesions in 60% and in mucinous cystic tumor (MCN) lesions in up to 30%. For cystic neoplasia located monocentrically in the pancreatic head and that do not have an association with an invasive pancreatic cancer, the duodenum-preserving total head resection has been used in recent time as a limited surgical procedure. PATIENTS: An indication to duodenum-preserving total pancreatic head resection is considered for patients who do not have clinical signs of an advanced cancer in the lesion and who have main-duct IPMN and monocentric MCN lesions. In 104 patients with cystic neoplastic lesions in the Ulm series, 32% finally had a carcinoma in situ or an advanced pancreatic cancer. The application of a duodenum-preserving total pancreatic head resection in patients with asymptomatic cystic lesion is based on the size of the tumor and the tumor relation to the pancreatic ducts. For patients who have preoperatively clinical signs of malignancy, a Kausch-Whipple type of oncologic resection is recommended. RESULTS: Duodenum-preserving total pancreatic head resection is used in several modifications. The surgical procedure is a limited pancreatic head resection which necessitates segmental resection of the peripapillary duodenum. Hospital mortality is very low; in most published series it is 0%. The long-term outcome is determined by completeness of resection for both -- benign and malignant -- entities. Careful evaluation of the frozen section results has a pivotal role for intraoperative decision making. CONCLUSION: A duodenum-preserving total pancreatic head resection is a limited surgical procedure for patients who suffer a local monocentric, cystic neoplastic lesion in the pancreatic head. Absence of an advanced pancreatic cancer and completeness of extirpation of the benign tumor determine the long-term outcome. In regards to the location of the lesion in the pancreatic head, several modifications have been applied with low hospital morbidity and mortality below 1%.

Duodenum-preserving total pancreatic head resection for cystic neoplastic lesions in the head of the pancreas.

BACKGROUND/PURPOSE: Cystic neoplastic lesions of the pancreas are now found with increasing frequency. Duodenum-preserving pancreatic head resection with segmental resection of the duodenum has been introduced for the surgical treatment of inflammatory and neoplastic lesions. We report the following data from 15 patients treated surgically for cystic neoplastic lesions of the pancreas head. METHODS: Duodenum-preserving total pancreatic head resection (DPPHRt) with segmental resection of the duodenum (SD) was performed in eight patients, five with intraductal papillary mucinous neoplasm (IPMN), two with mucinous cystic neoplasm (MCN), and one with cystic endocrine neoplasm (EN). In four patients, a subtotal pancreatic head resection was performed, but recurrence of the IPMN lesion was observed in two patients. Ten patients suffered cystadenoma, three patients had a borderline lesion, and two patients had an in-situ carcinoma. RESULTS: Eight patients had a DPPHRt with SD resection, two patients had a resection of the uncinate process including segmental resection of the inferior duodenal segment, and one patient had a duodenum-and spleen-preserving total pancreatectomy. In four patients a DPPHR with subtotal pancreatic head resection was carried out. Postoperative local complications occurred in eight patients: there was a recurrence of the IPMN lesion in the remnant pancreatic head in two patients; and there was intraabdominal bleeding in one patient, pancreatic fistula in one patient, and delay of gastric emptying in four patients. Seven patients showed signs of acute pancreatitis. Hospital mortality was 0%, and postoperative length of hospital stay was 10. 4 days (range, 8-18 days). CONCLUSIONS: Duodenum-preserving total pancreatic head resection for IPMN, MCN, serous cystadenoma (SCA), and cystic EN lesions is a safe and beneficial surgical procedure. Segmental resection of the duodenum was applied for an oncologically complete resection. In regard to long-term outcome, the procedure is, additionally, a pancreatic cancer preventive strategy.

Pancreatic cancer--low survival rates.

INTRODUCTION: Cancers of the pancreas are identified in 11 800 to 13 500 patients each year in Germany. Epidemiological studies prove smoking and chronic alcohol consumption as causes of about 30% of pancreatic cancers. METHODS: Selective literature review. RESULTS: Only patients within TNM stage I and II have after oncologic tumor extirpation a chance for long term survival. Controlled prospective clinical trials demonstrated adjuvant chemotherapy yielding an additional significant survival benefit. The 3- and 5-year-survival after R0-resection and adjuvant chemotherapy are about 30% and below 15% respectively. Using the criteria of observed 5-year-survival less than 2% of all pancreatic cancer patients are alive. After R0-resection the median survival time is between 17 and 28 months, after R1/2-resection between 8 and 22 months. DISCUSSION: Pancreatic cancer is even today for more than 95% of the patients incurable. Strategies to prevent pancreatic cancer are intended to stop smoking and chronic alcohol consumption and early surgical extirpation of cystic neoplastic lesions. For patients with established pancreatic cancer risk a follow-up protocol is discussed.

The clinical efficacy of adjuvant systemic chemotherapy with gemcitabine and NSC-631570 in advanced pancreatic cancer.

BACKGROUND/AIMS: Recently we have shown that NSC-631570 (Ukrain) is a safe and effective drug in the treatment of unresectable pancreatic cancer. The aim of this study was to determine the effectiveness of the combined treatment with Gemcitabine and NSC-631570 in the adjuvant treatment of resected advanced pancreatic cancer. METHODOLOGY: 30 patients received adjuvant chemotherapy following surgical resection for pancreatic cancer. Chemotherapy consisted of Gemcitabine according to the Burris-protocol with weekly infusions of 1000 mg/sqm. Immediately following Gemcitabine infusion 20mg of NSC-631570 were administered intravenously over 15 minutes. RESULTS: WHO grade II toxicities were observed in 53%, no WHO grade III or IV toxicities occurred. In 80% of the patients recurrence of the disease was observed. The relapse-free survival time was 21.7 months. The actuarial survival rates were 86.7% after one year, 76.6% after two years, 46.7% after three years and 23.3% after five years. The median survival time according to Kaplan-Meier regression analysis was 33.8 months. CONCLUSIONS: Adjuvant chemotherapy in advanced stages of pancreatic cancer using the combination of Gemcitabine and NSC-631570 is a safe treatment and seems to lead to a prolonged survival. Although further investigation is needed to confirm these results, the combined treatment of Gemcitabine and NSC-631570 is a promising therapy for the adjuvant treatment of resectable advanced pancreatic cancer.

Effect of early and late antibiotic treatment in experimental acute pancreatitis in rats.

BACKGROUND: The clinical course in acute necrotizing pancreatitis is mainly determined by bacterial infection of pancreatic and peripancreatic necrosis. The effect of two antibiotic regimens for early and late treatment was investigated in the taurocholate model of necrotizing pancreatitis in the rat. MATERIALS AND METHODS: Seventy male Wistar rats were divided into five pancreatitis groups (12 animals each) and a sham-operated group (10 animals). Pancreatitis was induced by intraductal infusion of 3% taurocholate under sterile conditions. Animals received two different antibiotic regimes (20 mg/kg imipenem or 20 mg/kg ciprofloxacin plus 20 mg/kg metronidazole) early at 2, 12, 20, and 28 h after induction of pancreatitis or late at 16 and 24 h after induction of pancreatitis or no antibiotics (control). Animals were examined after 30 h for pancreatic and extrapancreatic infection. RESULTS: Early and late antibiotic treatment with both regimes could significantly reduce pancreatic infection from 58 to 8-25%. However, extrapancreatic infection was only reduced by early antibiotic therapy. While quinolones also reduced bacterial counts in small and large bowel, imipenem did not. CONCLUSIONS: In our animal model of necrotizing pancreatitis, early and late treatment with ciprofloxacin/metronidazole and imipenem reduce bacterial infection of the pancreas. Extrapancreatic infection, however, is reduced significantly only by early antibiotic treatment. The effectivity of early antibiotic treatment in the clinical setting should be subject to further investigation with improved study design and sufficient patient numbers.

Systemic immune dysfunction in pancreatic cancer patients.

BACKGROUND AND AIMS: We investigated the immune status in 32 pancreatic cancer patients (PC) in comparison with healthy controls (HC). MATERIALS AND METHODS: Using flow cytometry, peripheral blood lymphocytes (PBL) were characterized by the expression of surface markers for T helper cells (CD4), T suppressor cells (CD8), B cells (CD19) and NK cells (CD56). The blastogenic response of PBL was analyzed after stimulation with concavalin A (ConA), phytohemagglutinin (PHA), pokeweed mitogen (PWM) and anti-CD3 antibodies. The serum levels of TNF-alpha, IL-1beta, IL-2, IL-10, IL-12, IL-18, IL-1RA, sIL-2R and TGF-beta were determined by ELISA. RESULTS: No differences in the distribution of peripheral immunocytes in PC were found, whereas the blastogenic response of peripheral blood lymphocytes (PBL) after stimulation with PHA or anti-CD3 antibodies was significantly decreased in PC. In PC, we found reduced serum levels of IL-2 and significantly elevated levels of TNF-alpha, TGF-beta1, IL-10, IL-2R, IL-1beta and IL-1RA. CONCLUSION: These data provide evidence for a systemic immune dysfunction in pancreatic cancer patients characterized by a shift towards a T helper cell type 2 cytokine profile, a significant elevation of substances related to T cell suppression and a reduced blastogenic response to PHA and anti-CD3 antibodies of PBL.

Increased etheno-DNA adducts in affected tissues of patients suffering from Crohn's disease, ulcerative colitis, and chronic pancreatitis.

Chronic inflammatory processes induce oxidative stress and lipid peroxidation (LPO), hereby generating DNA-reactive aldehydes such as trans-4-hydroxy-2-nonenal (HNE). Etheno-modified DNA bases are inter alia generated by reaction of DNA with HNE. Using an immunoaffinity-(32)P-postlabeling method, the authors have investigated etheno-DNA adduct levels 1,N (6)-ethenodeoxyadenosine (epsilondA) and of 3,N (4)-ethenodeoxycytidine (epsilondC) in the pancreas of chronic pancreatitis patients and in the colon of patients with inflammatory bowel disease. Both epsilondA and epsilondC levels were found to be significantly, 3 and 28 times, respectively, elevated in the inflamed pancreatic tissue. In contrast, only epsilondC was found to be increased in affected colonic mucosa of Crohn's disease (19 times) and of ulcerative colitis patients (4 times) when compared to asymptomatic tissues. In all three cancer-prone diseases, the mean epsilondC-levels in tissues were five- to ninefold higher than those of epsilondA. Differential or impaired DNA repair pathways of these adducts, known to occur by two different glycosylases are implicated. K-ras in pancreatic tumors and K-ras and p53 in colon mucosa in long-standing inflammatory bowel disease are known to be highly mutated. The conclusion is that promutagenic etheno-DNA adducts are generated as a consequence of chronic inflammation, acting as a driving force to malignancy in cancer-prone inflammatory diseases.

Influence of PMN leukocyte-mediated pancreatic damage on the systemic immune response in severe acute pancreatitis in rats.

The outcome of severe acute pancreatitis is determined by the development of the systemic inflammatory response and subsequent multiorgan dysfunction. Using the taurocholate-induced model of acute pancreatitis in rats, we investigated the relationship between early polymorphonuclear (PMN)-mediated pancreatic tissue damage and the systemic inflammatory response. The respiratory burst of PMN leukocytes was increased in animals with acute pancreatitis and was reduced by anti-ICAM-1 antibody and oxygen radical scavenger treatment after 24 hr. In acute pancreatitis a reduced number of peripheral helper T cells was evident, most likely due to L-selectin-mediated increased lymphocyte homing. After 24 hr the CD45RC(high)/CD45RC(low) ratio of helper T cells, a critical factor in T cell-mediated disease was increased due to a reduction of regulatory CD45RC(low) cells. Only the treatment with anti-ICAM-1 mAb affected these changes, indicating that immunological changes in necrotizing pancreatitis are only in part affected by early PMN leukocyte-mediated pancreatic damage.

Down-regulation of BRCA1 in chronic pancreatitis and sporadic pancreatic adenocarcinoma.

PURPOSE: BRCA1 and BRCA2 are considered to be breast cancer susceptibility genes that may also contribute to pancreatic cancer development because family studies revealed mutation carriers to have an increased risk of developing pancreatic cancer. However, as demonstrated for breast and ovarian cancer, inactivation of BRCA in sporadic diseases is based on alteration in gene expression or functional alteration. EXPERIMENTAL DESIGN: To study a potential correlation of BRCA1 and BRCA2 to chronic pancreatitis and development of sporadic pancreatic adenocarcinoma, we have analyzed the expression of these genes by quantitative PCR and performed immunohistochemical analyses in normal pancreatic tissues, chronic pancreatitis, and pancreatic cancer specimens. RESULTS: BRCA1 expression was down-regulated in chronic alcoholic pancreatitis, in particular on the RNA level. Furthermore, our data indicate suppressed BRCA1 expression in pancreatic cancer on both the RNA and protein levels. Quantitative analysis of BRCA1 protein expression demonstrated regular staining in 50% of tumor specimens tested and reduced staining in 50% of tumor specimens tested. Correlation with the clinical outcome revealed a significantly better 1-year overall survival for patients with BRCA1-regular as compared with BRCA1-reduced or BRCA1-absent tumors. In contrast, no substantial differences in BRCA2 expression were found in chronic pancreatitis and pancreatic cancer samples. CONCLUSIONS: Our data demonstrate alteration of BRCA1 expression in chronic pancreatitis and sporadic pancreatic adenocarcinoma. We, for the first time, provide evidence for a role of BRCA1 in pancreatic carcinogenesis of noninherited tumors and for clinical outcome.

Treatment of pancreatic cancer: challenge of the facts.

Adenocarcinoma of the pancreas is associated with the worst survival of any form of gastrointestinal malignancy. In spite of the progress in surgical treatment, resulting in increasing resection rates and a decrease in treatment-related morbidity and mortality, the true figures of cure are even today below 3%. The dissemination of pancreatic cancer behind the local tissue compartments restricts the short-term (< 3 years) and long-term outcome for patients who have undergone resection. By histological evaluation, less than 15% of the patients undergoing R(0) resection have a pN(0) status, more than 60% suffer from lymph angiosis carcinomatosa, and more than 50% suffer extrapancreatic nerve plexus infiltration. Hematoxylin and eosin-negative lymph nodes were found to be cancer positive when reverse transcriptase polymerase chain reaction (RT- PCR) or immunostaining was applied to the HE-negative lymph nodes. Cancer of the uncinate process has a very poor prognosis because there are no early symptoms; vessel wall involvement occurs early and frequently; a high association of liver metastasis exists as well. Surgery offers a low success rate, but it provides the only chance of cure. Ductal pancreatic cancer is diagnosed in more than 95% of the cases in an advanced stage; potentially curative resection can be performed only in about 10%-15% of these patients. Major contributions of surgery to improved treatment results are the reduction of surgical morbidity--e.g., early postoperative local and systemic complications--and a decrease of hospital mortality below 3%-5%. In most recently published prospective trials, R(0) resection has been reported to result in an increase in short-term survival beyond that recorded for patients with residual tumor. However, R(0) resection fails to improve long-term survival. In many published R(0) series, standard tissue resection of pancreatic head cancer with the Kausch-Whipple procedure failed to include remote cancer cell-positive tissues in the operative specimen; e.g., N(2)-lymph nodes, nerve plexus, and perivascular extrapancreatic and retropancreatic tissues were not excised. Cancer recurrence after so-called R(0) resection with curative intent is frequently the consequence of cancer left behind. Thus, long-term survival (> 5 years) is observed in a very small group of patients, contradicting the published 5-year actuarial survival rates of 20%-45% for resected patients. The assessment of clinical benefit from surgical or medical cancer treatment should therefore be based on several end points, not only on actuarial survival. Publication of actuarial survival figures must include the number of observed (actual) survivals, the definition of the subset of patients followed after resection, and the total number of patients in the study group; anything less is misleading. In reporting pancreatic cancer treatment trial results after oncological resections, more convincing primary end points to evaluate treatment efficacy are median survival (in months), actual survival at 1-5 years, and progression-free survival (in months). In series with multimodality treatment, clinical benefit response as well as quality of life measurements using the EORTC Quality of Life index C30 (QLQ-C30) are of importance in evaluating survival data. Adjuvant treatment improves survival after oncological resection; however, the short-term and long-term benefit after adjuvant chemotherapy in R(0) as well as in R(1)-(2) resected patients has not yet been underscored by data from controlled clinical trials. The survival benefit (median survival time) of adjuvant chemotherapy or radiochemotherapy has been demonstrated to be 6-10 months. Therefore, after oncological resection of pancreatic cancer each patient should be offered adjuvant treatment. A neoadjuvant treatment protocol for pancreatic cancer, however, has not been established.

Cyclooxygenase-2 is overexpressed in chronic pancreatitis.

INTRODUCTION: Cyclooxygenase enzymes catalyze a critical step in the conversion of arachidonic acid to prostaglandins, which are important mediators of acute and chronic inflammation. The constitutively expressed cyclooxygenase-1 (COX-1) appears to regulate many normal physiologic functions in several cell types, whereas the inducible cyclooxygenase-2 (COX-2) enzyme mediates the inflammatory response. AIMS AND METHODOLOGY: We investigated the expression of COX-2 in tissues of 35 patients with chronic pancreatitis, 6 patients with pancreatic cancer, and 5 control patients by immunohistochemical analysis and correlations to clinicopathologic features. RESULTS: We found an overexpression of COX-2 in the atrophic acinar cells (80% of patients), hyperplastic ductal cells (86% of patients), and islets cells (97% of patients) but not in normal pancreatic tissues. The COX-2 overexpression in the tissue of patients with chronic pancreatitis was significantly correlated with the frequency of acute attacks of pancreatitis. Tissue from patients who had more than five acute attacks of pancreatitis (n = 10) exhibited COX-2 immunoreactivity of a significantly higher score in atrophic acinar cells (p = 0.004). No correlation could be found with other examined clinical features such as duration of the disease, diabetes, alcohol consumption, smoking, or pain. CONCLUSION: Our results support the hypothesis that COX-2 may be involved in inflammatory responses in chronic pancreatitis and in the progression of this chronic inflammatory disease.

NSC-631570 (Ukrain) in the palliative treatment of pancreatic cancer. Results of a phase II trial.

BACKGROUND: NSC-631570 (Ukrain) is a semisynthetic compound of thiophosphoric acid and the alkaloid chelidonine from the plant Chelidonium majus. It has been used in complementary herbal medicine for more than 20 years for the treatment of benign and malignant tumors. PATIENTS/METHODS: Between August 1999 and June 2001, 90 patients with histologically proven unresectable pancreatic cancer were randomized in a monocentric, controlled, randomized study. Patients in arm A received 1000 mg gemcitabine/m2, those in arm B received 20 mg NSC-631570, and those in arm C received 1000 mg gemcitabine/m2 followed by 20 mg NSC-631570 weekly. End point of the study was overall survival. RESULTS: In all three arms therapy was well tolerated and toxicity was moderate. At the first re-evaluation in arm A 32%, in arm B 75%, and in arm C 82% showed no change or partial remission according to WHO criteria (arm A versus arm B: P<0.01, arm A versus arm C: P<0.001). Median survival according to Kaplan-Meier analysis was in arm A 5.2 months, in arm B 7.9 months, and in arm C 10.4 months (arm A versus arm B: P<0.01, arm A versus arm C: P<0.01). Actuarial survival rates after 6 months were 26%, 65% and 74% in arms A B and C, respectively (arm A versus arm B: P<0.05, arm A versus arm C P<0.01). CONCLUSION: We could show that in unresectable advanced pancreatic cancer, NSC-631570 alone and in combination with gemcitabine nearly doubled the median survival times in patients suffering from advanced pancreatic cancer.