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Abstract Background Greater understanding of the variance in the number of consultations per dietetic treatment will increase the transparency of dietetic healthcare. Substantial inter-practitioner variation may suggest a potential to increase efficiency and improve quality. It is not known whether inter-practitioner variation also exists in the field of dietetics. Therefore, the aims of this study are to examine inter-practitioner variation in the number of consultations per treatment and the case-mix factors that explain this variation. Methods For this observational study, data were used from the National Information Service for Allied Health Care (LiPZ). LiPZ is a Dutch registration network of allied health care professionals, including dietitians working in primary healthcare. Data were used from 6,496 patients who underwent dietetic treatment between 2006 and 2009, treated by 27 dietitians working in solo practices located throughout the Netherlands. Data collection was based on the long-term computerized registration of healthcare-related information on patients, reimbursement, treatment and health problems, using a regular software program for reimbursement. Poisson multilevel regression analyses were used to model the number of consultations and to account for the clustered structure of the data. Results After adjusting for case-mix, seven percent of the total variation in consultation sessions was due to dietitians. The mean number of consultations per treatment was 4.9 and ranged from 2.3–10.1 between dietitians. Demographic characteristics, patients’ initiative and patients’ health problems explained 28% of the inter-practitioner variation. Certain groups of patients used significantly more dietetic healthcare compared to others, i.e. older patients, females, the native Dutch, patients with a history of dietetic healthcare, patients who started the treatment on their own initiative, patients with multiple diagnoses, overweight, or binge eating disorder. Conclusions Considerable variation in number of consultations per dietetic treatment is due to dietitians. Some of this inter-practitioner variation was reduced after adjusting for case-mix. Further research is necessary to study the relation between inter-practitioner variation and the effectiveness and quality of dietetic treatment.

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all common cancers. However, divergent outcomes exist between patients, suggesting distinct underlying tumor biology. Here, we delineated this heterogeneity, compared interconnectivity between classification systems, and experimentally addressed the tumor biology that drives poor outcome. RNA-sequencing of 90 resected specimens and unsupervised classification revealed four subgroups associated with distinct outcomes. The worst-prognosis subtype was characterized by mesenchymal gene signatures. Comparative (network) analysis showed high interconnectivity with previously identified classification schemes and high robustness of the mesenchymal subtype. From species-specific transcript analysis of matching patient-derived xenografts we constructed dedicated classifiers for experimental models. Detailed assessments of tumor growth in subtyped experimental models revealed that a highly invasive growth pattern of mesenchymal subtype tumor cells is responsible for its poor outcome. Concluding, by developing a classification system tailored to experimental models, we have uncovered subtype-specific biology that should be further explored to improve treatment of a group of PDAC patients that currently has little therapeutic benefit from surgical treatment.

Background: Body composition measures may predict outcomes of cancer surgery. Whereas low muscle mass shown on preoperative computed tomography (CT) scans has been associated with worse outcomes after surgery for pancreatic cancer, less consideration has been given to low muscle attenuation, reflecting poor muscle quality. Studies relating muscle mass and muscle attenuation with outcomes for patients with periampullary, nonpancreatic cancer are lacking., Methods: Skeletal muscle mass and attenuation were assessed in 166 consecutive patients undergoing pancreatoduodenectomy (PD) for periampullary, nonpancreatic cancer at a single center between 2000 and 2012. The skeletal muscle index (SMI) was calculated from cross-sectional muscle area on preoperative CT imaging at the third lumbar vertebra level (L3) and normalized for height. The skeletal muscle attenuation index (MAI) was calculated by measuring the average Hounsfield units of the total muscle area at the L3 level. Overall survival (OS) and the rate of major postoperative complications (Clavien-Dindo ≥3) were extracted from prospectively maintained databases., Results: Low SMI was present in 78.3 % and low MAI in 48.8 % of the patients. The multivariate analysis showed lymph node metastasis [hazard ratio (HR) 1.8; 95 % confidence interval (CI) 1.1-2.9], microscopic radicality (HR 2.0; 95 % CI 1.2-3.4), and low MAI (HR 2.0; 95 % CI 1.2-3.3), but not low SMI to be significantly associated with decreased OS. Low MAI (HR 1.9; 95 % CI 1.0-3.8) was the only independent risk factor for major postoperative complications., Conclusion: Skeletal muscle quality, but not muscle mass, predicted survival and major complications after PD for periampullary, nonpancreatic cancer. Preoperative CT-derived body composition measures may stratify patients into risk categories and support shared decision making.

Introduction: In pancreatic cancer, preoperative biliary drainage (PBD) increases complications compared with surgery without PBD, demonstrated by a recent randomised controlled trial (RCT). This outcome might be related to the plastic endoprosthesis used. Metal stents may reduce the PBD-related complications risk., Methods: A prospective multicentre cohort study was performed including patients with obstructive jaundice due to pancreatic cancer, scheduled to undergo PBD before surgery. This cohort was added to the earlier RCT (ISRCTN31939699). The RCT protocol was adhered to, except PBD was performed with a fully covered self-expandable metal stent (FCSEMS). This FCSEMS cohort was compared with the RCT's plastic stent cohort. PBD-related complications were the primary outcome. Three-group comparison of overall complications including early surgery patients was performed., Results: 53 patients underwent PBD with FCSEMS compared with 102 patients treated with plastic stents. Patients' characteristics did not differ. PBD-related complication rates were 24% in the FCSEMS group vs 46% in the plastic stent group (relative risk of plastic stent use 1.9, 95% CI 1.1 to 3.2, p=0.011). Stent-related complications (occlusion and exchange) were 6% vs 31%. Surgical complications did not differ, 40% vs 47%. Overall complication rates for the FCSEMS, plastic stent and early surgery groups were 51% vs 74% vs 39%., Conclusions: For PBD in pancreatic cancer, FCSEMS yield a better outcome compared with plastic stents. Although early surgery without PBD remains the treatment of choice, FCSEMS should be preferred over plastic stents whenever PBD is indicated., Trial Registration Number: Dutch Trial Registry (NTR3142)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Recent advances in pancreatic surgery have the potential to improve outcomes for patients with pancreatic cancer. We address 3 new, trending topics in pancreatic surgery that are of relevance to the pathologist. First, increasing awareness of the prognostic impact of intraoperatively detected extraregional and regional lymph node metastases and the international consensus definition on lymph node sampling and reporting. Second, neoadjuvant chemotherapy, which is capable of changing 10% to 20% of initially unresectable, to resectable disease. Third, in patients who remain unresectable following neoadjuvant chemotherapy, local ablative therapies may change indications for treatment and improve outcomes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Large multicenter series on outcomes and predictors of survival after distal pancreatectomy (DP) for pancreatic ductal adenocarcinoma (PDAC) are scarce., Methods: Adults who underwent DP for PDAC in 17 Dutch pancreatic centers between January 2005 and September 2013 were analyzed retrospectively. The primary outcome was survival, and predictors of survival were identified using Cox regression analysis., Results: In total, 761 consecutive patients after DP were assessed, of whom 620 patients were excluded because of non-PDAC histopathology (n = 616) or a lack of data (n = 4), leaving a total of 141 patients included in the study [45 % (n = 63) male, mean age 64 years (SD = 10)]. Multivisceral resection was performed in 43 patients (30 %) and laparoscopic resection was performed in 7 patients (5 %). A major complication (Clavien-Dindo score of III or higher) occurred in 46 patients (33 %). Mean tumor size was 44 mm (SD 23), and histopathological examination showed 70 R0 resections (50 %), while 30-day and 90-day mortality was 3 and 6 %, respectively. Overall, 63 patients (45 %) received adjuvant chemotherapy. Median survival was 17 months [interquartile range (IQR) 13-21], with a median follow-up of 17 months (IQR 8-29). Cumulative survival at 1, 3 and 5 years was 64, 29, and 22 %, respectively. Independent predictors of worse postoperative survival were R1/R2 resection [hazard ratio (HR) 1.6, 95 % confidence interval (CI) 1.1-2.4], pT3/pT4 stage (HR 1.9, 95 % CI 1.3-2.9), a major complication (HR 1.7, 95 % CI 1.1-2.5), and not receiving adjuvant chemotherapy (HR 1.5, 95 % CI 1.0-2.3)., Conclusion: Survival after DP for PDAC is poor and is related to resection margin, tumor stage, surgical complications, and adjuvant chemotherapy. Further studies should assess to what extent prevention of surgical complications and more extensive use of adjuvant chemotherapy can improve survival.

Background: The upper gastrointestinal tract is home to some of most notorious cancers like esophagogastric and pancreatic cancer. Several factors contribute to the lethality of these tumors, but one that stands out for both tumor types is the strong inter- as well as intratumor heterogeneity. Unfortunately, genetic tumor models do not match this heterogeneity, and for esophageal cancer no adequate genetic models exist. To allow for an improved understanding of these diseases, tissue banks with sufficient amount of samples to cover the extent of diversity of human cancers are required. Additionally, xenograft models that faithfully mimic and span the breadth of human disease are essential to perform meaningful functional experiments., Methods: We describe here the establishment of a tissue biobank, patient derived xenografts (PDXs) and cell line models of esophagogastric and pancreatic cancer patients. Biopsy material was grafted into immunocompromised mice and PDXs were used to establish primary cell cultures to perform functional studies. Expression of Hedgehog ligands in patient tumor and matching PDX was assessed by immunohistochemical staining, and quantitative real-time PCR as well as flow cytometry was used for cultured cells. Cocultures with Hedgehog reporter cells were performed to study paracrine signaling potency. Furthermore, SHH expression was modulated in primary cultures using lentiviral mediated knockdown., Results: We have established a panel of 29 PDXs from esophagogastric and pancreatic cancers, and demonstrate that these PDXs mirror several of the (immuno)histological and biochemical characteristics of the original tumors. Derived cell lines can be genetically manipulated and used to further study tumor biology and signaling capacity. In addition, we demonstrate an active (paracrine) Hedgehog signaling mode by both tumor types, the magnitude of which has not been compared directly in previous studies., Conclusions: Our established PDXs and their matching primary cell lines retain important characteristics seen in the original tumors, and this should enable future studies to address the responses of these tumors to different treatment modalities, but also help in gaining mechanistic insight in how some tumors respond to certain regimens and others do not.

Background: Most survival studies comparing non-radical resections to bypass surgery in patients with pancreatic cancer often do not differentiate between an R1 and R2 resection. The aim of this study was to evaluate whether non-radical R1 and R2 resections have better postoperative outcomes and survival compared to a palliative bypass., Methods: A single center cohort study was performed analyzing mortality, morbidity and 1-year survival after R1 (tumor cells within 1 mm from the circumferential margin), R2 and bypass surgery in patients with pancreatic cancer. For the systematic review, studies were identified comparing R1 or R2 resections with bypass, in patients with pancreatic cancer. Postoperative outcomes were compared including the cohort study., Results: The cohort study (n=405) showed higher morbidity rates after R1 (n=191) and R2 (n=11) resections compared to bypass (52% and 73% vs. 34%, p < 0.01). In-hospital mortality did not differ (overall 1.7%). 1-year survival rates were 71%, 46% and 32% after R1, R2 resection and bypass (p=0.6 between R2 and bypass). The systematic review identified 8 studies, after including the cohort study 1535 patients were analyzed. Increased morbidity after R1-R2 resection (48%) compared to bypass (30-34%) was found. Median survival was 14-18 months after R1 resection vs. 9-13 months after bypass and 8.5-11.5 months after R2 resection vs. 7.5-10.7 months after bypass., Conclusion: An R2 resection should be avoided in patients with pancreatic cancer due to its poor prognosis. Survival benefit after an R1 resection, as compared to bypass surgery, justifies a resection despite the increased morbidity rate., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: According to some studies, the number of lymph nodes with metastases in relation to the total number of removed lymph nodes, the lymph node ratio (LNR), is one of the most powerful predictors of survival after resection in patients with pancreatic cancer. However, contradictory results have been reported, and small sample sizes of the cohorts and different definitions of a microscopic positive resection margin (R1) hamper the interpretation of data., Methods: The predictive value of LNR for 3-year survival was assessed using a Cox proportional hazards model. From 1992 to 2012, all patients with pancreatic and periampullary cancer operated on with pancreatoduodenectomy were selected from a database. Clinicopathological characteristics were analysed. Microscopic positive resection margin was defined as the microscopic presence of tumour cells within 1 mm of the margins. A nomogram was created., Results: Some 760 patients were included. Predictive factors for death in 350 patients with pancreatic ductal adenocarcinoma included in the nomogram were: R1 resection (hazard ratio (HR) 1·55, 95 per cent c.i. 1·07 to 2·25), poor tumour differentiation (HR 2·78, 1·40 to 5·52), LNR above 0·18 (HR 1·75, 1·13 to 2·70) and no adjuvant therapy (HR 1·54, 1·01 to 2·34). The C statistic was 0·658 (0·632 to 0·698), and calibration was good (Hosmer-Lemeshow χ(2)  = 5·67, P =0·773). LNR and poor tumour differentiation (HR 4·51 and 3·30 respectively) were also predictive in patients with distal common bile duct (CBD) cancer. LNR, R1 resection and jaundice were predictors of death in patients with ampullary cancer (HR 7·82, 2·68 and 1·93 respectively)., Conclusion: LNR is a common predictor of poor survival in pancreatic, distal CBD and ampullary cancer., (© 2014 BJS Society Ltd. Published by John Wiley & Sons, Ltd.)

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., (© 2015. Published by The Company of Biologists Ltd.)

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: 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.)

Background: The mortality rate due to late hemorrhage after surgery for periampullary tumors is high, especially in patients with anastomotic leakage. Patients usually require emergency intervention for late hemorrhage. In this study patients with late hemorrhage and their outcomes were analyzed. Furthermore, independent predictors for late hemorrhage, the need for emergency intervention, and type of intervention are reported., Methods: From a prospective database that includes 1,035 patients who underwent pancreatoduodenectomy for periampullary tumors between 1992 and 2012, patients with late hemorrhage (>24 h after index operation) were identified. Patient, disease-specific, and operation characteristics, type of intervention, and outcomes were analyzed. Emergency intervention was defined as surgical or radiological intervention in hemodynamically unstable patients., Results: Of the 47 patients (4.5 %) with late hemorrhage, pancreatic fistula was an independent predictor for developing late hemorrhage (OR 10.2). The mortality rate in patients with late hemorrhage was 13 % compared with 1.5 % in all patients without late hemorrhage. Twenty patients required emergency intervention; 80 % underwent primary radiological intervention and 20 % primary surgical intervention. Extraluminal location of the bleeding (OR 5.6) and occurrence of a sentinel bleed (OR 6.6) are indications for emergency intervention., Conclusion: The type of emergency intervention needed for late hemorrhage is unpredictable. Radiological intervention is preferred, but if it fails, immediate change to surgical treatment is mandatory. This can be difficult to manage but possible when both radiological and surgical interventions are in close proximity such as in a hybrid operating room and should be considered in the emergency management of patients with late hemorrhage.

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.)

Surgery in patients with obstructive jaundice caused by a tumor in the pancreatic head area is associated with a higher risk of postoperative complications. Preoperative biliary drainage was introduced in an attempt to improve the general condition and reduce morbidity and mortality. Extensive experimental studies have been performed to analyze the beneficial effect of biliary drainage and showed improvement in liver function, nutritional status, and cell-mediated immune function as well as reduction in mortality. However, despite the results seen in the experimental studies, clinical studies reported both beneficial and adverse effects, and most studies advised against routinely performing preoperative biliary drainage. To add clarity to the ongoing controversy, a recent randomized controlled trial was performed and reported more overall complications in patients with jaundice who underwent preoperative biliary drainage followed by surgery compared to those who underwent surgery alone. Many of these complications were stent related. Like most clinical studies, a plastic stent was used to initiate biliary drainage. Patients with jaundice because of a tumor in the pancreatic head area without locoregional irresectability or metastases should be candidates for early surgery. Preoperative biliary drainage should not be performed routinely. However, some selected patients might benefit from preoperative biliary drainage, in cases of severe jaundice, neoadjuvant therapy, or postponed surgery due to logistics. In these cases, the use of metal biliary stents is indicated.

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.)