Pancreatic surgery in the very old: face to face with a challenge of the near future.

BACKGROUND: The proportion of octogenarians requiring surgery for pancreatic disease is rapidly growing. This trend will be continued during the next decades, posing a challenge to surgeons and the health care system worldwide. This study aimed to analyze the results of pancreatic surgery in octogenarians in terms of safety and survival based on a cohort of patients at a European high-volume center. METHODS: During a 7-year period, 1,705 operations were performed, 76 in patients ≥ 80 years of age. Data on the octogenarians were retrospectively reviewed and compared to those of the whole collective and to contemporary data from the literature. Primary endpoints were mortality, morbidity, and survival. RESULTS: Overall, 80 % had a malignant disease, and resections were performed in 50 % of all cases. Mortality was 11.8 % and morbidity 72.4 %. There were significantly more medical than surgical complications: 56.6 versus 34.2 %. Pancreatic fistula occurred in 5.3 %, postoperative bleeding in 3.9 %, and delayed gastric emptying in 19.7 %. The median hospital stay was 15 days and the intensive care unit stay 2 days. Mean survival was 28.2 months and in patients with cancer 22.6 months. The 1-, 3-, and 5-year survival rates were 61.4, 31.3, and 18.8 %, respectively. CONCLUSIONS: Despite high mortality and morbidity rates, surgery remains the only chance for cure in most octogenarians with pancreatic disease. Careful patient selection is the key to success and improved long-term survival in this group, which will represent a substantial fraction of the population in the near future.

Effects of FTY720 and rapamycin on inflammation in taurocholate-induced acute pancreatitis in the rat.

OBJECTIVES: This study aimed at T-cell inhibition by immunosuppressants to reduce cell damage and improve the course of severe acute pancreatitis (SAP). METHODS: A taurocholate-induced SAP was used and 5 groups were compared: (1) rapamycin + FTY720, (2) rapamycin, (3) FTY720, (4) cortisol, and (5) control: sodium chloride. Drugs were applied intravenously at SAP induction; 6 hours later, rats were killed. Interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor α, platelet-activating factor, amylase, and lipase were measured in serum and myeloperoxidase tissue activity in pancreas, kidney, lung, liver, and spleen. Edema, inflammation, and necrosis were histologically determined in pancreas. CD4/CD8 immunohistochemistry was performed. RESULTS: Inflammation was ameliorated in all 4 treated groups. Necrosis development was suppressed by FTY720, FTY720 + rapamycin, and cortisol. IL-6 and IL-10 were significantly lower in these groups. Amylase was higher in all treatment groups compared to the controls except for the cortisol group. Tumor necrosis factor α, lipase, and myeloperoxidase activity were not affected by therapy. CD4+/CD8+ cells were significantly less in FTY720-treated pancreata. CONCLUSION: Rapamycin and FTY720 ameliorated the severity of SAP, which may be due to early suppression of helper T cells. FTY720 reduced the development of pancreatic necrosis. The combination of both immunosuppressants did not show advantage to treatment with FTY720 alone.

Protective role of endogenous melatonin in the early course of human acute pancreatitis.

Melatonin plays a protective role in experimental acute pancreatitis (AP) because of its antioxidative, antiinflammatory, and immunomodulatory effects. This study presents the first data on the dynamic changes of endogenous melatonin in the early phase of human AP. Morning (08:00 hr) serum melatonin concentrations were measured by ELISA in 75 patients with AP for the first 5 days after the onset of pain. According to the Atlanta classification, 26 patients suffered a mild AP (MAP). The other 49 developed a severe AP (SAP). Median melatonin concentrations of healthy volunteers were used as a control. Median melatonin level in healthy controls was 18.5 pg/mL. Levels of melatonin were significantly higher in the first 24 hr after onset of disease in patients with MAP compared to those with SAP, 51.2 versus 8.7 pg/mL (P = 0.01). Melatonin values were the same in MAP and SAP during the remainder of the study period. Melatonin concentrations during the first 24 hr after the onset of pain in younger patients (<35 yrs old) were significantly higher than levels in older patients (>35 yrs): 73 versus 8.7 pg/mL (P = 0.01). No correlation existed between melatonin levels and the following parameters: gender, etiology (biliary versus alcohol induced), and histological findings (edematous versus necrotizing versus infected necrosis). High endogenous melatonin serum levels in the first 24 hr after the onset of AP played a protective role and favoured a mild course of the disease in humans, especially in young patients.

Assessment of pancreatic hardness-surgeon versus durometer.

BACKGROUND: This study reports the first results of durometrically measured hardness of human pancreas and investigates its correlation to palpatory determined hardness, grade of pancreatic fibrosis, and preoperatively determined radiodensity. METHODS: Fifty-two patients with pancreatic resections were prospectively recruited. Hardness of samples from pancreatic cancer, chronic pancreatitis, and normal pancreas was measured using a durometer on a 0-100 Shore units (SU) scale. Three pancreatic surgeons palpated the pancreas and reported their assessment of hardness on a subjective 0-100 "Bochum units" (BU) scale. Radiodensity and fibrosis of pancreatic tissue were used for comparison. RESULTS: Pancreatic hardness differed significantly in normal pancreas, chronic pancreatitis, and pancreatic cancer; 30 SU, 51 SU, and 65.8 SU, respectively. Palpatory hardness of normal pancreas was 20 BU and of pancreatitis 60 BU. It correlated well to durometric readings: r(2)=0.56, P<0.00001. Fibrosis grade and radiodensity correlated neither to durometry nor to palpation. Pancreatic leak developed 4/20 (20%) patients with normal pancreas vs. 1/32 (3.1%) with chronic pancreatitis in the resection margin, P<0.05. CONCLUSIONS: Palpatory assessment of pancreatic hardness performed by experienced surgeons correlated well to durometric measurements and remains the method of choice for intraoperative decision making. Durometry was more precise and should be considered in studies on pancreatic texture and for teaching purposes. Hardness and fibrosis grade appeared to be independent characteristics of pancreatic texture.

Functional assessment of pancreatic beta-cell area in humans.

OBJECTIVE: beta-Cell mass declines progressively during the course of diabetes, and various antidiabetic treatment regimens have been suggested to modulate beta-cell mass. However, imaging methods allowing the monitoring of changes in beta-cell mass in vivo have not yet become available. We address whether pancreatic beta-cell area can be assessed by functional test of insulin secretion in humans. RESEARCH DESIGN AND METHODS: A total of 33 patients with chronic pancreatitis (n = 17), benign pancreatic adenomas (n = 13), and tumors of the ampulla of Vater (n = 3) at various stages of glucose tolerance were examined with an oral glucose load before undergoing pancreatic surgery. Indexes of insulin secretion were calculated and compared with the fractional beta-cell area of the pancreas. RESULTS: beta-Cell area was related to fasting glucose concentrations in an inverse linear fashion (r = -0.53, P = 0.0014) and to 120-min postchallenge glycemia in an inverse exponential fashion (r = -0.89). beta-Cell area was best predicted by a C-peptide-to-glucose ratio determined 15 min after the glucose drink (r = 0.72, P < 0.0001). However, a fasting C-peptide-to-glucose ratio already yielded a reasonably close correlation (r = 0.63, P < 0.0001). Homeostasis model assessment (HOMA) beta-cell function was unrelated to beta-cell area. CONCLUSIONS: Glucose control is closely related to pancreatic beta-cell area in humans. A C-peptide-to-glucose ratio after oral glucose ingestion appears to better predict beta-cell area than fasting measures, such as the HOMA index.

Bacteribilia after preoperative bile duct stenting: a prospective study.

STUDY DESIGN: A prospective analysis of intraoperative bile duct cultures in patients undergoing surgery for both, malignant or benign periampullary diseases at the Department of Surgery, St Josef Hospital, Bochum, Germany, during a period of 18 months, between January 2004 and June 2005. GOALS: The goals of the presented study were to investigate the effects of preoperative bile duct stenting on intraoperative bile duct cultures and postoperative outcome in patients undergoing pancreatic surgery. BACKGROUND: In pancreatic surgery, bile duct stenting is often aimed at improving postoperative outcome. As implantation of xenograft material in the main bile duct facilitates bacterial contamination and cholangitis, a critical evaluation of stenting is mandatory. STUDY: In all patients with a hepaticojejunostomy (n=80), a bile duct culture was collected during the operation. All patients received antibiotic prophylaxis perioperatively and a retrograde flushing of bile ducts with warm saline after bile duct resection. Fifty-one percent (41/80) patients had biliary drainage before surgery, whereas 49% (39/80) were operated without preoperative draining procedures. RESULTS: After bile duct stenting, 98% of patients had a positive bile culture, whereas only 21% of infected bile was seen in patients without drainage (P<0.001). Despite infected bile, only 2% stented patients developed acute cholangitis postoperatively, versus 13% patients in the group without stent (P=0.231). After stenting, major complications occurred in 12%, versus 8% in patients without stent (P=0.817). CONCLUSIONS: Preoperative biliary drainage leads to an almost 100% bacterial contamination of bile ducts. With hospital-adjusted antibiotic prophylaxis and retrograde flushing of bile ducts, the postoperative rate of acute cholangitis and morbidity is not elevated. A critical evaluation of benefits from preoperative biliary drainage for each patient is necessary.

Satisfactory long-term results after simultaneous resection of the esophagus, stomach and pancreas.

PURPOSE: Surgical procedures for esophageal cancer and chronic pancreatitis are demanding and still characterized by high morbidity and mortality. Cases of one-stage combined operations on the pancreas and esophagus with a long-term follow-up are rarely reported. MATERIALS AND METHODS: We present the case of a 54-year-old woman with a Barrett's carcinoma and an 8-year history of severe chronic pancreatitis complicated with multiple episodes of cholangitis and resistant to conservative treatment. RESULTS: After a successful one-stage operation consisting of esophagogastrectomy and pancreaticoduodenectomy, a 30-month disease-free follow-up with a good quality of life has been observed. CONCLUSION: Complicated surgical procedures such as one-stage multiple organ resections may offer, in selected cases, satisfactory long-term results, provided that patients are treated at a high-volume center by a multidisciplinary team.

Histopathological features of patients with chronic pancreatitis due to mutations in the PRSS1 gene: evaluation of BRAF and KRAS2 mutations.

BACKGROUND/AIMS: Hereditary pancreatitis (HP) is a rare cause of chronic pancreatitis (CP; 1%) and more than 25 mutations in the PRSS1 gene have been detected. HP patients with the p.R122H mutation have a 35% lifetime risk of developing pancreatic cancer, but the oncogenetic process remains unknown. We have investigated the histopathological features and frequency of BRAF and KRAS2 mutations in 2 patients with PRSS1 mutations (p.A121T, p.R122H) and patients with CP (n = 11). METHODS: Pancreatic tissue was stained with hematoxylin-eosin and examined by light microscopy. Mutational analysis of the BRAF (exon 5, 11) and KRAS2 (exon 1) genes was performed using PCR and direct DNA sequencing. RESULTS: Histopathological features revealed similar results in both patients, pancreata showed strong fibrosis and ducts with signs of distortion, irregular size and noticeable dilatations. We identified one BRAF mutation (p.V600E) in the p.R122H patient and two KRAS2 (p.G12D; p.G12C) mutations in CP controls. CONCLUSIONS: Our results sustain the knowledge about the clinical phenotype of patients with PRSS1 mutations who have a high risk of pancreatic cancer. Whether the histopathological picture or the BRAF mutation is specific for patients with PRSS1 mutations or plays a specific role in the tumorigenesis of patients with HP needs to be further evaluated.

The effect of synacthen on acute necrotizing pancreatitis in rats.

OBJECTIVES: This study investigates the hypothesis that an adrenocorticotropic hormone-analog therapy may ameliorate relative adrenal insufficiency in the early phase of acute necrotizing pancreatitis (NP) by boosting endogenous glucocorticoid production. METHODS: Forty Wistar rats with taurocholate-induced NP were divided into 5 groups: the first group received low-dose Synacthen (0.5 mg/kg); the second, high-dose Synacthen (5mg/kg); the third,low-dose cortisol (10 mg/kg); the fourth, high-dose cortisol (100 mg/kg); and the fifth, the control group, received no treatment. All animals were killed after 6 hours: concentrations of plasma corticosterone, interleukin 1 (IL-1), IL-6, IL-10, tumor necrosis factor alpha, amylase, and lipase in ascites, myeloperoxidase activity in the pancreas, and a histological score were evaluated. RESULTS: Corticosterone increased neither in the low-dose nor in the high-dose Synacthen group. Synacthen did not improve the early course of NP in terms of laboratory and histological results. A reduction of pancreatic necrosis and inflammation was observed in the low-dose cortisol group. CONCLUSIONS: Endogenous glucocorticoid release seemed to be at its maximum during the early stage of NP and could not be further increased by Synacthen. Low-dose exogenous cortisol ameliorated the disease. These findings support the existence of relative adrenal insufficiency in the early phase of acute NP.

Tailored resective pancreatic surgery for pediatric patients with chronic pancreatitis.

BACKGROUND: Surgical treatment for chronic pancreatitis (CP) in children comprises predominantly nonresective draining procedures. The purpose of this study was to identify indications, techniques, and results of organ-preserving resective pancreatic procedures for pediatric CP at our institution. PATIENTS AND METHODS: A retrospective chart review was performed of all children undergoing pancreatic surgery for CP over a period of 4 years. RESULTS: Overall, 6 pediatric patients (3 male, 3 female, ages 7-18 years) underwent a duodenum-preserving pancreatic head resection (3), a middle segmental pancreatic resection (2), or a distal pancreatectomy (1) for CP of different etiologies (idiopathic 2, posttraumatic 2, pancreas divisum 1, situs inversus 1). No mortality or major surgical complication occurred. Mean operative time was 294 min (207-412 min) and intraoperative blood loss was 541 mL (100-1300 mL). Postoperative hospital stay was 13 days (10-18 days). No endocrine or exocrine insufficiency occurred during follow up of 46 months (25-50 m), and pain control was improved in 5 of 6 patients. CONCLUSIONS: Tailored organ-preserving resective pancreatic surgery can be performed with low morbidity and mortality in pediatric patients with CP and not responding to conservative treatment.

Intraductal papillary mucinous neoplasms of the pancreas.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are now a well-recognized category of slowly growing tumors with a remarkably better prognosis, even when malignant, than pancreatic ductal adenocarcinoma. Their clinical and pathohistologic features have been increasingly attracting the attention of clinicians since their first description 25 years ago. Despite its burgeoning volume recently, accumulated literature devoted to IPMN still provides a low level of evidence with regard to diagnosis, treatment, and prognosis. Therefore, we performed a Medline-based systematic review of the literature aimed at clearly defining the clinicopathologic characteristics of pancreatic IPMN and determining the best currently available evidence-based principles of diagnosis and management of patients with this disease.

Corticosteroid-binding globulin: a possible early predictor of infection in acute necrotizing pancreatitis.

OBJECTIVE: Infected pancreatic necrosis is the main cause of death in patients with acute pancreatitis, and therefore its early prediction is of utmost importance. Endogenous cortisol metabolism plays a basic role both in the course of acute pancreatitis and in the process of infection. The purpose of this study was to analyze corticosteroid-binding globulin (CBG), total cortisol, calculated free cortisol and adrenocorticotropic hormone as potential early predictors in order to differentiate between infected pancreatic necrosis and sterile pancreatic necrosis in patients with acute pancreatitis. MATERIAL AND METHODS: Serum levels of CBG, total cortisol, calculated free cortisol, and plasma levels of adrenocorticotropic hormone were determined in 109 consecutive patients with acute pancreatitis. C-reactive protein was measured as the control parameter. Thirty-five patients developed necrotizing pancreatitis and 10 developed infection of the necrosis. Blood was monitored for 6 days after the onset of pain; 30 healthy individuals served as controls. RESULTS: Of all parameters only CBG showed a significant difference (p = 0.0318) in its peak levels measured in the first 48 h in patients with sterile (26.5 microg/ml, range 21.3-34.7) and infected (16.0 microg/ml, range 15.2-25.0) necrosis at a cut-off level of 16.8 microg/ml. That difference was further preserved for the first 6 days after onset of pain. CONCLUSIONS: In our group of patients, a decreased CBG level below 16.8 g/ml within the initial 48 h of acute pancreatitis was an early predictor of later infected pancreatic necrosis, with a positive predictive value of 100% and a negative predictive value of 87.5%.

Pancreatic redo procedures: to do or not to do -- this is the question.

BACKGROUND: Pancreatic redo procedures belong to the most difficult abdominal operations because of altered anatomy, significant adhesions, and the potential of recurrent disease. We report on our experience with 15 redo procedures among a series of 350 consecutive pancreatic operations. PATIENT AND METHODS: From January 1, 2004 to May 31, 2006 a total of 350 patients underwent pancreatic surgery in our department. There were 15 patients identified who had pancreatic redo surgery for benign (14) or malignant (1) disease. Perioperative parameters and outcome of 15 patients undergoing redo surgery after pancreatic resections were evaluated. RESULTS: Operative procedures included revision and redo of the pancreaticojejunostomy after resection of the pancreatic margin (6), completion pancreatectomy (3), conversion from duodenum-preserving pancreatic head resection to pylorus-preserving pancreaticoduodenectomy (3), classic pancreaticoduodenectomy after nonresective pancreatic surgery (1), redo of left-sided pancreatectomy (1), and classic pancreaticoduodenectomy after left-sided pancreatectomy (1). Histology revealed chronic pancreatitis in 14 and a mucinous adenocarcinoma of the pancreas in 1 patient. Median operative time was 335 min (235-615 min) and median intraoperative blood loss was 600 ml (300-2,800 ml). Median postoperative ICU stay was 20 h (4-113 h) and median postoperative hospital stay was 15 days (7-30 days). There was no perioperative mortality and morbidity was 33%. CONCLUSION: Pancreatic redo surgery can be performed with low morbidity and mortality. Redo surgery has a defined spectrum of indications, but to achieve good results surgery may be performed at high-volume centers.

Role of endogenous glucocorticoid metabolism in human acute pancreatitis.

OBJECTIVE: This study aimed to observe how levels of total cortisol, calculated free cortisol, corticosteroid-binding globulin, and adrenocorticotropic hormone change during the early course of human acute pancreatitis and to describe how these changes affect the development of pancreatic necrosis. DESIGN AND PATIENTS: In a total of 109 consecutive patients with acute pancreatitis (74 with edematous pancreatitis, 35 with necrotizing pancreatitis), serial daily blood monitoring of total and free cortisol, adrenocorticotropic hormone, and corticosteroid-binding globulin was done after hospital admission, up to day 6 after the onset of pain; 30 healthy individuals served as controls. MEASUREMENTS: Corticosteroid-binding globulin and total cortisol were measured by immunoassays, and free cortisol was calculated according to Coolens et al. The adrenocorticotropic hormone was measured with an enzyme-linked immunoassay. RESULTS: Initially, highly elevated levels of calculated free cortisol (median, 86.2 ng/mL; quartile ranges, 50.6-106.7 ng/mL) and total cortisol (41.2 microg/dL, 30.4-51.1 microg/dL) and depressed levels of adrenocorticotropic hormone (0.2 pg/mL, 0.1-2.0 pg/mL) and corticosteroid-binding globulin (30.6 microg/mL, 24.1-35.5 microg/mL) were observed. Further, daily measurements revealed increasing adrenocorticotropic hormone levels, whereas cortisol levels decreased. CONCLUSIONS: Although an increase in adrenocorticotropic hormone levels is suggested to increase corresponding cortisol levels, cortisol levels decreased during the development of necrotizing acute pancreatitis. This phenomenon, along with the continuously decreasing corticosteroid-binding globulin levels, brings up the hypothesis of a relative adrenal insufficiency, which favors acinar cell apoptosis and hence may trigger the development of necrosis in the initial vulnerable phase of acute pancreatitis.

A study on the activation peptide released from procarboxypeptidase B (CAPAP) and anionic trypsinogen in patients with acute abdominal disorders of non-pancreatic origin.

BACKGROUND: The activation peptide released from procarboxypeptidase B, CAPAP, is a marker of the activation of pancreatic enzymes in acute pancreatitis while anionic trypsinogen (AT) levels in urine relate to leakage of unactivated proenzymes. Data on these markers in patients suffering from severe acute abdominal disorders of non-pancreatic origin are lacking. PURPOSE: To examine levels of CAPAP and AT in serum and urine from patients with severe acute abdominal disorders of non-pancreatic origin in order to better define the diagnostic specificity of these two markers in severe acute pancreatitis in relation to other acute intra-abdominal disorders. SUBJECTS AND METHODS: The study included 54 patients with severe acute abdominal disorders of non-pancreatic origin with an APACHE II score >3. Immunoreactive CAPAP (irCAPAP) and immunoreactive AT (irAT) were measured in serum and urine using specific immunoassays. RESULTS: In urine, irCAPAP levels were mildly increased (>2 nmol/l) in 13% of the patients with severe acute abdominal diseases of non-pancreatic origin, but on no occasion did the increase approach the cutoff levels described for severe acute pancreatitis (>100 nmol/l). However, irAT levels in serum and urine were increased (>50 micro g/l) in 54% of the cases. CONCLUSION: Contrary to what is found for irAT, patients with acute abdominal pain of non-pancreatic origin rarely have markedly increased levels of irCAPAP in serum and urine.

Cefepime tissue penetration in experimental acute pancreatitis.

INTRODUCTION: Antibiotic treatment represents a cornerstone in the management of severe acute pancreatitis. However, different antibiotic substances are currently used. In this study, we analyzed penetration of cefepime into pancreatic tissue in two models of acute pancreatitis. AIMS AND METHODOLOGY: Following induction of acute pancreatitis, animals were treated with a single intravenous dose of cefepime (0.1 mg/g of body weight). At two different time points, blood and tissue samples were obtained for determination of cefepime concentration and microbiologic analysis. RESULTS: Mean pancreatic tissue concentrations +/- SEM 30 minutes after drug administration were significantly higher in animals with either mild acute pancreatitis (113 +/- 22 mg/kg) or severe acute pancreatitis (75 +/- 22 mg/kg) than in control animals (30 +/- 6 mg/kg) (p < 0.005). The minimal inhibitory concentrations (MIC90) for organisms usually isolated from infected pancreatic necrosis vary between 0.05 and 8 mg/L, which is between nine and 1,500 times lower than the mean peak concentration found in necrotic pancreatic tissue. Seven hours 30 minutes after antibiotic administration, pancreatic cefepime concentrations were still above the MIC90 in 100% and 83% of animals with mild and severe disease, respectively. The infection rate of pancreatic tissue was significantly lower after antibiotic treatment and was similar after imipenem/cilastatin or cefepime treatment. CONCLUSION: Because of its antibacterial coverage and proven tissue penetration in acute pancreatitis, cefepime should be studied in patients with severe acute pancreatitis.

Influence of contrast-enhanced computed tomography on course and outcome in patients with acute pancreatitis.

INTRODUCTION: Many of the complications in severe acute pancreatitis result from the amplifying effects of microcirculatory disruption. Contrast medium may cause significant additional reductions of capillary flow, which has been shown to aggravate acute pancreatitis in experimental studies. AIM: To investigate the role of serial contrast-enhanced computed tomography (CECT) in patients with acute pancreatitis. METHODOLOGY: A retrospective analysis evaluated 302 patients with moderate to severe acute pancreatitis. Among these patients, 264 underwent CECT within 96 hours of the onset of symptoms and again during the course, but in 38 patients no serial CECT was performed. Outcome measurement was analyzed by comparison of hospital stay and mortality rate between the two patient groups. Influences of contrast medium on severity of disease were detected by monitoring complications during the course of treatment, C-reactive protein, and APACHE II score. RESULTS: The 1-month mortality rate was less in patients with CECT (6.4% versus 15.8%, p <0.05). There were no significant differences considering the incidence of additional complications, and hospital stay was not significantly longer (29 +/- 36 versus 19 +/- 13 days). C-reactive protein and APACHE II score had similar time courses. CONCLUSION: Contrast-enhanced computed tomography remains crucial in identifying patients with acute pancreatitis at high risk to develop necrosis of the pancreas and systemic complications. Contrast medium has been found to aggravate acute pancreatitis in animal models. As compared with the patient group without being exposed to contrast medium, however, this study did not show a deterioration of acute pancreatitis by administration of contrast medium in men.