Options and limitations in applying the fistula classification by the International Study Group for Pancreatic Fistula.

BACKGROUND: Because of its retrospective character, the classification system of the International Study Group of Pancreatic Fistula (ISGPF) lacks prognostic capacity regarding fistula-related complications. This study aimed to evaluate the options and limitations of the ISGPF classification system and to identify risk factors with respect to clinical decision making. METHODS: Between 1992 and 2009, 1966 patients underwent surgery of the pancreas. All patient data were entered into a prospective clinical data management system. RESULTS: After surgery, 276 patients (14%) developed postoperative pancreatic fistula (POPF). ISGPF type A fistula was seen in 69 patients (25%), type B in 110 (39.9%), and type C in 97 (34.1%). Solely due to their death, 16 patients had to be classified as type C fistula, even though they suffered only type A or B. Compared to genuine C fistulas, we were not able to detect any significant predictors, which may allow to distinguish the development in their further clinical course. The level of drainage amylase is of no use, whereas univariate analysis identified underlying disease, type of operation, and high levels of serum amylase or bilirubin on the day of onset of POPF to be prognostic parameters for reoperation. Multivariate analysis found elevated serum C-reactive protein to be an independent factor for increased in-hospital mortality. CONCLUSIONS: The ISGPF classification system has its limitations in clinical decision making, because it does not adequately describe a large subgroup of patients. To improve clinical decision making about management of patients, it is crucial that the ISGPF classification system is merged with newer clinical data.

Multivisceral resections in pancreatic cancer: identification of risk factors.

BACKGROUND: There is an assumption that multivisceral resections (MVRs) in patients with a pancreatic malignancy are associated with higher morbidity. The oncologic benefit, however, remains controversial. METHODS: The aim was to identify risk factors for complications in cases of MVR in patients with pancreatic cancer. Of 1099 patients who underwent major pancreatic resection at our institution between January 1992 and October 2008, a total of 55 were treated with an MVR involving resection of one or more additional organs. This group was compared with 154 patients who had palliative bypass surgery and 303 patients who underwent standard pancreatic head resection. RESULTS: Multivisceral resection patients had an overall higher incidence of major surgical complications (p < 0.001). In-hospital mortality was comparable in all groups. Median survival after MVR was inferior to that after standard resection but was significantly better than that after palliative bypass. Univariate logistic regression analysis identified concomitant colon, kidney, and liver resections and any intraoperative transfusion as predictors of complications; in the multivariate analysis, only kidney resections and any intraoperative transfusion were confirmed predictors. In contrast, T status, kidney resection, resection of four or more organs, any postoperative transfusion, and intensive care unit stay of >2 days were identified as predictors of survival in the univariate Cox regression analysis; in the multivariate analysis, only the T status was confirmed. Median survival after MVR was 16 months, after palliative bypass 6 months, and after standard resection 18 months (p < 0.001). CONCLUSIONS: Multivisceral resections are technically feasible procedures with increased survival when compared to palliative bypass procedures. The incidence of postoperative complications was increased with kidney resection and when intraoperative transfusion was required.

Chronic pancreatitis complicated by cavernous transformation of the portal vein: contraindication to surgery?

BACKGROUND: A subgroup of patients with chronic pancreatitis and severe incapacitating pain develop mesentericoportal vascular complications with extrahepatic portal hypertension (EPH) and subsequent cavernous transformation. The purpose of this study was to address the question of whether a noninterventional approach regarding surgery is justified. METHODS: A total of 702 patients with chronic pancreatitis underwent major pancreatic surgery. EPH with cavernous transformation was diagnosed in 21 (3%; group C) and EPH without cavernous transformation in 60 (9%; group B). The remaining 621 patients (88%; group A) showed no evidence for extrahepatic hypertension or cavernous transformation. Prospectively collected data were analyzed with respect to perioperative parameters, outcomes, quality of life, and our previously established pain score. RESULTS: Patients in groups C and B had longer history and greater severity of pain (P = .0001). Group C had the longest operative times (P > .05) and greatest requirements of intraoperatively transfused packed red blood cells (P < .05). Morbidity was greater in group C compared with groups B and A (88% vs 55% vs 35%; P < .001). Mortality was 10% (2/21) in group C, compared with 1.3% (8/621) in group A and 0% in group B (P = .008). Quality of life as well as pain scores significantly improved postoperatively in group C, and were comparable to those in groups A and B (P < .001). CONCLUSION: Concomitant cavernous transformation in patients with chronic pancreatitis increases the operative risk significantly. Alternative treatment modalities should be evaluated thoroughly in every individual patient to offer every patient the best available treatment. Nevertheless, operative intervention is often the only treatment possible and improvements in quality of life and pain alleviation justify operative interventions.

Extended central pancreatic resection as an alternative for extended left or extended right resection for appropriate pancreatic neoplasms.

BACKGROUND: Whether patients with focal pancreatic lesions of benign or borderline pathology should be treated by extended central pancreatectomy rather than by extended classic resectional procedures, such as extended right and left resections, is controversial. METHODS: Between 1992 and 2007, 105 patients underwent operation for focal pancreatic lesions of borderline or benign neuroendocrine neoplasms, cystadenoma, intraductal papillary mucinous neoplasia (IPMN), and secondary metastasis. In all, 35 patients were subjected to extended central pancreatectomy, whereas the remaining 70 patients were treated by an extended classic right resection or an extended classic left resection. Groups were matched according to age, sex, and histopathology. RESULTS: No peri-operative mortality occurred after extended central pancreatectomy and extended classic left resection (n = 35, each). Two (6%) patients died after extended classic right resection. Overall, in-hospital morbidity was 26% after extended central pancreatectomy, 43% after extended classic right resection, and 37% after extended classic left resection. After a median follow-up of 48 months, a local recurrence rate of 17% after extended central pancreatectomy was similar to the corresponding rates of 9% after extended classic left resection and 14% after extended classic right resection. Endocrine and exocrine impairment was less pronounced after extended central pancreatectomy (6% and 9%) than after extended classic left resection (34% and 29%) and extended classic right resection (28% and 24%; P < .05). CONCLUSION: Extended central pancreatectomy for appropriate pancreatic neoplasms is associated with less peri-operative morbidity and mortality than after extended classic left and extended classic right resection. Long-term local recurrence after extended central pancreatectomy is similar to the recurrence rates after extended classic right and classic left resection. Our results suggest that appropriately selected patients will benefit from extended central pancreatectomy because of the maintenance of endocrine and exocrine function.

Subset of esophageal adenocarcinoma expresses adhesion molecule l1 in contrast to squamous cell carcinoma.

BACKGROUND: Esophageal adenocarcinoma is currently the most rapidly increasing cancer in Western populations. L1 (CD171), a neural cell adhesion molecule, has an essential function in tumor progression and has been shown to be expressed in the proliferating cells of the intestinal crypts in mice. The aim of the current study was to determine L1 expression in esophageal cancer and to evaluate whether L1 could serve as a potential marker and therapeutic target for this tumor type. MATERIALS AND METHODS: L1 expression was assessed on a tissue microarray with 257 surgically resected esophageal cancer samples by immunohistochemistry with a monoclonal antibody (Clone UJ127). L1 expression was correlated with clinicopathological data. RESULTS: L1 was detected in 22 (9%) of 257 esophageal cases, whereas 235 (91%) were L1 negative. Nineteen (86%) of the 22 L1-positive cases were adenocarcinoma. Cross table analysis showed a significant association between L1 expression and adenocarcinoma subtype (p<0.001), but not squamous cell carcinoma. CONCLUSION: L1 expression in a subgroup of esophageal cancer is specifically prevalent in adenocarcinoma. Data suggest L1 as a potential target for biological therapy in L1-positive esophageal adenocarcinoma patients.

Crossing the Rubicon: when pancreatic resection with curative intent ends in an R2 status. Impact of "desmoplastic pseudo-pancreatitis" and anatomical site of irresectability.

AIM: To analyze the impact of pancreatitis-mimicking, concomitant alterations on intraoperative assessment of curative resectability, the anatomical site of irresectability, and outcome after nonintentional R2 resection in pancreatic cancer. METHODS: Of 1,099 patients subjected to pancreatic resection for cancer, 40 (4%) underwent R2 resection (group A). The site where tumors turned out to be irresectable and the coincident presence of potentially misleading, fibro-desmoplastic alterations were analyzed. Outcome after resection was compared with 40 bypass patients matched for age, gender, histopathology, and use of additive chemotherapy (group B). RESULTS: R2 resection was due to misjudgment regarding resectability in 38 patients (95%) and to uncontrollable hemorrhage in 2 patients (5%). Group A patients had significantly longer operative times (P < 0.0001), required more blood units (P < 0.0001), and had longer hospital stay than group B patients (P = 0.049). Despite a significantly higher relaparotomy rate of 20% (n = 8) in group A versus 5% (n = 2) in group B, perioperative mortality was equal (n = 2, each). Median survival was 11.5 months in group A and 7.5 months in group B (P = 0.014). "Pancreatitis-like" lesions were assessed in 70% (n = 28/40, group A) and 25% (10/40, group B; P = 0.014). The superior mesenteric artery proximal to its jejunal branches was the most likely site of irresectability (60%), followed by its peripheral course (22.5%) and the lower aspects of the celiac trunk (17.5%). CONCLUSIONS: Concomitant "pancreatitis-like" alterations hamper the assessment of local resectability in pancreatic cancer. Although palliative resection results in elevated perioperative morbidity compared with bypass procedures, mortality is equal, while survival is prolonged.

Radical redo surgery for local rectal cancer recurrence improves overall survival: a single center experience.

BACKGROUND: To date, the survival benefit of redo surgery in locally recurrent rectal adenocarcinoma remains unclear. STUDY DESIGN: In an institutional study, operations for recurrence were retrospectively analyzed. Survival was calculated using the Kaplan-Meier plot and Cox regression analysis. RESULTS: A total of 72 patients with local recurrence were explored or resected. In 38 patients, there was synchronous distant organ recurrence. Forty-five of 72 were re-resected and in 37 of 45 cases, R0 situations were achieved. In 11 of 38 metastasized patients, both local and distant organ recurrence were successfully removed. For obtaining tumor control, resections of inner genitals, bladder, and sacral bone were necessary in 10, 4, and 11 patients, respectively. Survival was better for patients re-resected with a median overall survival of 54.9 months, as compared with 31.1 months among non-resected patients (p = 0.0047, log-rank test). Subgroup analysis revealed that a benefit of re-resection was observed to a lesser extent in synchronous local and in distant disease. Cox analysis showed that initial Dukes stage and complete resections of local recurrences were independently determining prognosis (relative risk 1.762 and 0.689, p = 0.008 and p = 0.002, respectively). CONCLUSIONS: Radical surgery for local recurrence can improve survival if complete tumor clearance is achieved, and concomitant distant tumor load should not principally preclude re-resection.

En bloc vascular resection for locally advanced pancreatic malignancies infiltrating major blood vessels: perioperative outcome and long-term survival in 136 patients.

BACKGROUND: To assess in-hospital complication rates and survival duration after en bloc vascular resection (VR) for infiltration of pancreatic malignancies in major vessels. METHODS: Between 1994 and 2005, 585 patients underwent potentially curative pancreatic resection without adjuvant chemotherapy. Four hundred forty-nine patients (77%) underwent standard oncologic resection (VR-), whereas 136 (23%) received VR (VR+). For calculation of in-hospital morbidity and mortality rates, all 136 patients who underwent VR were considered. In contrast, for survival analysis, only pancreatic adenocarcinoma patients (n = 100) were included. RESULTS: One hundred twenty-eight VR+ patients underwent portal or superior mesenteric vein resection and 13 hepatic artery (HA) or superior mesenteric artery (SMA) resection. In 5 patients, synchronous VR addressing both the mesenterico-portal axis and either the HA or SMA was performed. In-hospital morbidity and mortality rates of VR- patients (39.7%/4.0%) nearly equaled that of VR+ patients (40.3%/3.7%). From the 100 patients with pancreatic adenocarcinoma, histopathology confirmed "true" vascular invasion in 77 patients. Twenty-three patients had peritumoral inflammation, mimicking tumor invasion. Median survival was 15 months (11.2-18.8) in patients with histopathologic proven vascular invasion and 16 months (14.0-17.9) in those without (P = 0.86). Two-year survival probabilities were 36% (without) versus 34% (with vascular invasion; P = 0.9). Among VR+ patients with histopathologically evidenced vascular invasion, 19 survived longer than 30 months, and 6 were still alive 5 years after surgery. Multivariate modeling identified nodal involvement (N1) and poor grading (G3) as the only predictors of decreased survival. Evidence of vascular invasion had no adverse impact on survival. CONCLUSION: Postoperative morbidity and mortality rates after en bloc VR are comparable with "standard" pancreatectomy procedures. Median survival of 15 months in patients with vascular invasion is superior to that of patients who undergo palliative therapy and nearly equals that of patients who are not in need for VR.

Postpancreatectomy hemorrhage: diagnosis and treatment: an analysis in 1669 consecutive pancreatic resections.

BACKGROUND: To analyze clinical courses and outcome of postpancreatectomy hemorrhage (PPH) after major pancreatic surgery. SUMMARY BACKGROUND DATA: Although PPH is the most life-threatening complication following pancreatic surgery, standardized rules for its management do not exist. METHODS: Between 1992 and 2006, 1524 patients operated on for pancreatic diseases were included in a prospective database. A risk stratification of PPH according to the following parameters was performed: severity of PPH classified as mild (drop of hemoglobin concentration <3 g/dL) or severe (>3 g/dL), time of PPH occurrence (early, first to fifth postoperative day; late, after sixth day), coincident pancreatic fistula, intraluminal or extraluminal bleeding manifestation, and presence of "complex" vascular pathologies (erosions, pseudoaneurysms). Success rates of interventional endoscopy and angiography in preventing relaparotomy were analyzed as well as PPH-related overall outcome. RESULTS: Prevalence of PPH was 5.7% (n = 87) distributed almost equally among patients suffering from malignancies, borderline tumors, and focal pancreatitis (n = 47) and from chronic pancreatitis (n = 40). PPH-related overall mortality of 16% (n = 14) was closely associated with 1) the occurrence of pancreatic fistula (13 of 14); 2) vascular pathologies, ie, erosions and pseudoaneurysms (12 of 14); 3) delayed PPH occurrence (14 of 14); and 4) underlying disease with lethal PPH found only in patients with soft texture of the pancreatic remnant, while no patient with chronic pancreatitis died. Conversely, primary severity of PPH (mild vs. severe) and the kind of index operation (Whipple resection, pylorus-preserving partial pancreaticoduodenectomy, organ-preserving procedures) had no influence on outcome of PPH. Endoscopy was successful in 3 from 15 patients (20%), who had intraluminal PPH within the first or second postoperative day. "True," early extraluminal PPH had uniformly to be treated by relaparotomy. Seventeen patients had "false," early extraluminal PPH due to primarily intraluminal bleeding site from the pancreaticoenteric anastomosis with secondary disruption of the anastomosis. From 43 patients subjected to angiography, 25 underwent interventional coiling with a success rate of 80% (n = 20). Overall, relaparotomy was performed in 60 patients among whom 33 underwent surgery as first-line treatment, while 27 were relaparotomied as rescue treatment after failure of interventional endoscopy or radiology. CONCLUSION: Prognosis of PPH depends mainly on the presence of preceding pancreatic fistula. Decision making as to the indication for nonsurgical interventions should consider time of onset, presence of pancreatic fistula, vascular pathologies, and the underlying disease.

Long-term follow-up in small duct chronic pancreatitis: A plea for extended drainage by "V-shaped excision" of the anterior aspect of the pancreas.

BACKGROUND: A pancreatic duct diameter (PDD) ranging from 4 to 5 mm is regarded as "normal." The "large duct" form of chronic pancreatitis (CP) with a PDD >7 mm is considered a classic indication for drainage procedures. In contrast, in patients with so-called "small duct chronic pancreatitis" (SDP) with a PDD <3 mm extended resectional procedures and even, in terms of an "ultima ratio," total pancreatectomy are suggested. METHODS: Between 1992 and 2004, a total of 644 patients were operated on for CP. Forty-one prospectively evaluated patients with SDP underwent a new surgical technique aiming at drainage of the entire major PD (longitudinal "V-shaped excision" of the anterior aspect of the pancreas). Preoperative workup for imaging ductal anatomy included ERCP/MRCP, visualizing the PD throughout the entire gland. The interval between symptoms and therapeutic intervention varied from 12 to 120 months. Median follow-up was 83 months (range, 39-117 months). A pain score as well as a multidimensional psychometric quality-of-life questionnaire was used. RESULTS: Hospital mortality was 0%. The perioperative (30 days) morbidity was 19.6%. Postoperative, radiologic imaging showed an excellent drainage of the entire gland and the PD in all but 1 patient. Global quality-of-life index increased in median by 54% (range, 37.5%-80%). Median pain score decreased by 95%. Twenty-seven patients (73%) had complete pain relief. Sixteen patients (43%) developed diabetes, while the exocrine pancreatic function was well preserved in 29 patients (78%). CONCLUSION: "V-shaped excision" of the anterior aspect of the pancreas is a secure and effective approach for SDP, achieving significant improvement in quality of life and pain relief, hereby sparing patients from unnecessary, extended resectional procedures. The deterioration of exocrine and endocrine pancreatic functions is comparable with that observed during the natural course of the disease.

Strong prognostic value of nodal and bone marrow micro-involvement in patients with pancreatic ductal carcinoma receiving no adjuvant chemotherapy.

AIM: To study the prognostic value of adjuvant chemotherapy in patients with pancreatic, ductal adenocarcinoma. METHODS: Lymph nodes from 106 patients with resectable pancreatic ductal adenocarcinoma were systematically sampled. A total of 318 lymph nodes classified histopathologically as tumor-free were examined using sensitive immunohistochemical assays. Forty-three (41%) of the 106 patients were staged as pT((1/2)), 63 (59%) as pT((3/4)), 51 (48%) as pN(0), and 55 (52%) as pN(1). The study population included 59 (56%) patients exhibiting G((1/2)), and 47 (44%) patients with G(3) tumors. Patients received no adjuvant chemo- or radiation therapy and were followed up for a median of 12 (range: 3.5 to 139) mo. RESULTS: Immunostaining with Ber-EP4 revealed nodal microinvolvement in lymph nodes classified as "tumor free" by conventional histopathology in 73 (69%) out of the 106 patients. Twenty-nine (57%) of 51 patients staged histopathologically as pN(0) had nodal microinvolvement. The five-year survival probability for pN0-patients was 54% for those without nodal microinvolvement and 0% for those with nodal microinvolvement. Cox-regression modeling revealed the independent prognostic effect of nodal microinvolvement on recurrence-free (relative risk 2.92, P=0.005) and overall (relative risk 2.49, P=0.009) survival. CONCLUSION: The study reveals strong and independent prognostic significance of nodal microinvolvement in patients with pancreatic ductal adenocarcinoma who have received no adjuvant therapy. The addition of immunohistochemical findings to histopathology reports may help to improve risk stratification of patients with pancreatic cancer.

RAGE limits regeneration after massive liver injury by coordinated suppression of TNF-alpha and NF-kappaB.

The exquisite ability of the liver to regenerate is finite. Identification of mechanisms that limit regeneration after massive injury holds the key to expanding the limits of liver transplantation and salvaging livers and hosts overwhelmed by carcinoma and toxic insults. Receptor for advanced glycation endproducts (RAGE) is up-regulated in liver remnants selectively after massive (85%) versus partial (70%) hepatectomy, principally in mononuclear phagocyte-derived dendritic cells (MPDDCs). Blockade of RAGE, using pharmacological antagonists or transgenic mice in which a signaling-deficient RAGE mutant is expressed in cells of mononuclear phagocyte lineage, significantly increases survival after massive liver resection. In the first hours after massive resection, remnants retrieved from RAGE-blocked mice displayed increased activated NF-kappaB, principally in hepatocytes, and enhanced expression of regeneration-promoting cytokines, TNF-alpha and IL-6, and the antiinflammatory cytokine, IL-10. Hepatocyte proliferation was increased by RAGE blockade, in parallel with significantly reduced apoptosis. These data highlight central roles for RAGE and MPDDCs in modulation of cell death-promoting mechanisms in massive hepatectomy and suggest that RAGE blockade is a novel strategy to promote regeneration in the massively injured liver.

Analysis of failure in living donor liver transplantation: differential outcomes in children and adults.

Over the past decade we have reported excellent outcomes in pediatric living-donor liver transplantation (LDLT) with recipient survival exceeding 90%. Principles established in these patients were extended to LDLT in adults. To compare outcomes in donors and recipients between adult and pediatric LDLT in a single center, we reviewed patient records of 45 LDLT performed between 1/98 and 2/01: 23 adult LDLT (54 +/- 6.5 yr) and 22 pediatric LDLT (33.7 +/- 53.5 months). Preoperative liver function was worse in adults (International Normalized Ratio [INR] 1.5 +/- 0.4 vs. INR 1.2 +/- 0.5; p = 0.032). 4 adults (17%) met criteria for status 1 or 2A. Only 1 child was transplanted urgently. Analysis included descriptive statistics and Kaplan-Meier estimation. Donor mortality was 0% with 1 re-exploration, 2.4%. Median hospital stay (LOS) was 6.0 days (range, 4-12 days). Donor morbidity and LOS did not differ by sex, extent of hepatectomy, or adult and pediatric LDLT ( p = 0.49). In contrast, recipient outcomes were worse for adults. Adult 1 year graft survival was 65% (3 retransplants [ReTx], 5 deaths) vs. 91% for children (1 ReTx, 1 death) p = 0.02. Graft losses in adults were due to sepsis (n = 3), small for size (n = 2), suicide, and hepatic artery thrombosis (HAT), whereas in children graft losses were due to portal thrombosis and total parenteral nutrition (TPN) liver failure. Biliary leaks occurred in 22% of adults and 9% of children. Hepatic vein obstruction occurred in 17% of adults and in none of the children. Median LOS was comparable (adult, 16.5 days (range, 7-149 days); child, 17 days (range, 10-56 days), p = 0.2). Graft function (total bilirubin (TBili) < 5mg/dl, INR < 1.2, aspartate aminotransferase (AST) < 100 U/l) normalizing by day 4 in children and by day 14 in adults. Adults fared worse, with an array of problems not seen in children, in particular, hepatic vein obstruction and small-for-size syndrome. Biliary leaks were diagnosed later in adults and were lethal in 3 cases; this was later avoided with biliary drainage in adult recipients. Finally, use of LDLT in decompensated adults led to death in 3 of 4 patients, and should be restricted to elective use.