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Members of the Hedgehog (Hh) family of morphogens play crucial roles in development but are also involved in the progression of certain types of cancer. Despite being synthesized as hydrophobic dually lipid-modified molecules, and thus being strongly membrane-associated, Hh ligands are able to spread through tissues and act on target cells several cell diameters away. Various mechanisms that mediate Hh release have been discussed in recent years; however, little is known about dispersion of this ligand from cancer cells. Using co-culture models in conjunction with a newly developed reporter system, we were able to show that different members of the ADAM family of metalloproteinases strongly contribute to the release of endogenous bioactive Hh from pancreatic cancer cells, but that this solubilization decreases the potency of cancer cells to signal to adjacent stromal cells in direct co-culture models. These findings imply that under certain conditions, cancer-cell-tethered Hh molecules are the more potent signaling activators and that retaining Hh on the surface of cancer cells can unexpectedly increase the effective signaling range of this ligand, depending on tissue context. [ABSTRACT FROM AUTHOR]

Background: Over the years, high-volume pancreatic centers expanded their indications for pancreatoduodenectomy (PD) but with unknown impact on surgical and oncological outcome., Methods: All consecutive PDs performed between 1992-2017 in a single pancreatic center were identified from a prospectively maintained database and analyzed according to three time periods., Results: In total, 1434 patients underwent PD. Over time, more elderly patients underwent PD (P < 0.001) with increased use of vascular resection (10.4 to 16.0%, P < 0.001). In patients with cancer (n = 1049, 74.8%), the proportion pT3/T4 tumors increased from 54.3% to 70.6% over time (P < 0.001). The postoperative pancreatic fistula (16.0%), postpancreatectomy hemorrhage (8.0%) and delayed gastric emptying (31.0%) rate did not reduce over time, whereas median length of stay decreased from 16 to 12 days (P < 0.001). The overall failure-to-rescue rate (6.9%) and in-hospital mortality (2.2%) remained stable (P = 0.89 and P = 0.45). In 523 patients with pancreatic cancer (36.5%), the use of both adjuvant and neoadjuvant chemotherapy increased over time (both p<0.001), and the five-year overall survival improved from 11.0% to 17.4% (P < 0.001)., Conclusions: In a period where indications for PD expanded, with more elderly patients, more advanced cancers and increased use of vascular resections, surgical outcome remained favorable and five-year survival for pancreatic cancer improved., (Copyright © 2018 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background: The lymph node (Ln) status of patients with resectable pancreatic ductal adenocarcinoma is an important predictor of survival. The survival benefit of extended lymphadenectomy during pancreatectomy is, however, disputed, and there is no true definition of the optimal extent of the lymphadenectomy. The aim of this study was to formulate a definition for standard lymphadenectomy during pancreatectomy., Methods: During a consensus meeting of the International Study Group on Pancreatic Surgery, pancreatic surgeons formulated a consensus statement based on available literature and their experience., Results: The nomenclature of the Japanese Pancreas Society was accepted by all participants. Extended lymphadenectomy during pancreatoduodenectomy with resection of Ln's along the left side of the superior mesenteric artery (SMA) and around the celiac trunk, splenic artery, or left gastric artery showed no survival benefit compared with a standard lymphadenectomy. No level I evidence was available on prognostic impact of positive para-aortic Ln's. Consensus was reached on selectively removing suspected Ln's outside the resection area for frozen section. No consensus was reached on continuing or terminating resection in cases where these nodes were positive., Conclusion: Extended lymphadenectomy cannot be recommended. Standard lymphadenectomy for pancreatoduodenectomy should strive to resect Ln stations no. 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b, 17a, and 17b. For cancers of the body and tail of the pancreas, removal of stations 10, 11, and 18 is standard. Furthermore, lymphadenectomy is important for adequate nodal staging. Both pancreatic resection in relatively fit patients or nonresectional palliative treatment were accepted as acceptable treatment in cases of positive Ln's outside the resection plane. This consensus statement could serve as a guide for surgeons and researchers in future directives and new clinical studies., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Introduction: Operative complications after pancreatoduodenectomy can be managed by nonoperative or operative interventions. The aim of this study was to analyze the shift in management of five major complications and their success rates. An algorithm was developed according to predictors for type of intervention and failure of management., Methods: From 1992-2012, patients with pancreaticojejunostomy, hepaticojejunostomy or gastroenterostomy leakage, postpancreatectomy hemorrhage, or primary abscess after pancreatoduodenectomy were selected from a prospectively maintained database. Complications were treated by nonoperative or operative intervention Two cohorts were created according to period of index operation. Pre- and postoperative characteristics were analyzed., Results: Of 1,037 patients, 263 (25%) experienced operative complications. The incidence of pancreatic fistula increased from 11 to 18%, accompanied by a shift from operative toward nonoperative management. This was also seen in the management of late hemorrhage. Success rates of interventions remained similar for all complications. The incidence of primary abscesses decreased. Early sepsis (odds ratio [OR] 17.8, 95% confidence interval [CI] 4.9-64.4) was associated with failure of nonoperative interventions in patients with pancreatic fistula. Hemodynamic instability (OR 17.2, 95% CI 1.8-160.1) and sepsis (OR 6.7, 95% CI 2.7-16.3) were predictive for operative intervention. Failure of nonoperative intervention (HR 3.95% CI 1.3-7.1) and operative intervention (HR 6.4 95% CI 3.2-12.8) were predictors for poor survival., Conclusion: The shift towards nonoperative interventions was notable in patients suffering from pancreaticojejunostomy leakage and late hemorrhage. Anastomotic leakage, late hemorrhage, and primary abscesses can be managed nonoperatively however; hemodynamic instability and early sepsis are strong arguments to perform surgery., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background: Common anastomotic complications after pancreatoduodenectomy (PD) are leakage from the pancreaticojejunostomy or hepaticojejunostomy. Leakage from the gastroenteric anastomosis has rarely been described. We evaluated the incidence of gastroenteric leakage after PD and described its presentation, treatment, and outcome., Methods: Between 1992 and 2012, a consecutive series of 1,036 patients underwent PD in the Academic Medical Center. By use of a prospective database and medical records, we identified patients with gastroenteric leakage. Clinicopathologic data were compared with patients without gastroenteric leakage, and presentation, radiologic findings, treatment, and outcome of gastroenteric leaks were analyzed., Results: Twelve patients (1.2%) had gastroenteric leakage. Patients with gastroenteric leaks had undergone longer operative procedures, had more pancreatic fistulas and other complications, and had a significantly longer hospital stay. Median postoperative day of diagnosis was 8 (range, 2-23). Clinical signs included tender abdomen and high drain output suspicious of gastric content. Common radiologic findings were pneumoperitoneum and intra-abdominal fluid. Seven patients (58%) were treated operatively, 4 (33%) by percutaneous drainage, and 1 (8%) underwent no specific treatment duo to his poor clinical condition. This patient died in hospital, resulting in a hospital mortality of 8%., Conclusion: Gastroenteric leakage after PD is rare. Clinical presentation is not specific, unlike leakage from other sites. Drain output suspicious of gastric content may help to differentiate from pancreatic or hepatic anastomotic leakage. It may be associated with a longer duration of operation and concomitant pancreatic fistula. A good outcome depends on prompt diagnosis and is mostly achieved by operative intervention., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Objective: To evaluate the reliability of data registration in calculating the hospital standardised mortality ratio (HSMR)., Design: Retrospective, descriptive., Method: Data were collected from a research database on all patients who had undergone a partial pancreatoduodenectomy for pancreatic cancer in 2009 and 2010 at our hospital. These data were compared with information about these same patients recorded in the Dutch National Medical Registry (LMR), obtained from the medical administration department of our hospital. The differences between these 2 databases were evaluated on the basis of 3 variables: mortality, main diagnosis and secondary diagnoses (differentiated into complications and co-morbidities). Using the Charlson index, the co-morbidity score from both registries was calculated per patient., Results: A total of 118 patients had been registered in the research database. Of these patients, 103 appeared in the LMR data; 15 had not been registered in this database. There were no differences in patient characteristics or mortality (2.5%) between the registries. In the LMR, the main diagnosis of 5 patients had been incorrectly recorded. This database contained information on 136 complications and 51 co-morbidities, of which 35 comorbities had been correctly recorded. The research database contained information on 188 complications and 99 comorbidities on these same patients. In the research database, comorbidity comprised 34% of all secondary diagnoses; in the LMR, 19% (p < 0.001). The median score on the Charlson index was 0 for all patients in the LMR and 3 in the research database (p < 0.001)., Conclusion: Comorbidities in patients with pancreatic carcinoma who undergo a resection are being inadequately recorded in the LMR. This results in insufficient correction in the case mix and a low score on the Charlson index, which could result in an incorrect HSMR.

Centralization of complex upper gastrointestinal (GI) surgery and the effect on postoperative outcomes, especially mortality, has been reported extensively in the literature. In this review the highest level of evidence on the volume outcome relationship is discussed together with other important aspects that can influence postoperative outcomes. Do high-volume centers and surgeons result in better outcomes after surgery for the different upper GI surgical procedures such as esophageal, gastric, liver and pancreatic tumors? Twelve systematic reviews including four meta-analyses described the effect of hospital and/or surgeon volume on mortality. The majority of reviews (>90%) showed a lower mortality in high-volume hospitals. This correlation was also reported when analyzing the different GI procedures separately for esophageal, gastric, hepatic and pancreatic tumors. The volume discussion has limitations and therefore the relationship between hospital structure and process of care in hospitals and the outcome of surgery has also been acknowledged. Besides surgeon expertise and skills, high-intensity intensive care units, 24/7 availability of interventional radiology, effective prevention and managing of complications and adequate patient selection will influence postoperative outcomes. These forms of hospital structures and process of care might even play a more important role in surgical outcomes., (Copyright © 2012 S. Karger AG, Basel.)