Impact of expanding indications on surgical and oncological outcome in 1434 consecutive pancreatoduodenectomies.

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.

Blocking Hedgehog release from pancreatic cancer cells increases paracrine signaling potency.

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.

Outcomes of Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma in the Netherlands: A Nationwide Retrospective Analysis.

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.

Establishment of patient-derived xenograft models and cell lines for malignancies of the upper gastrointestinal tract.

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.

Emergency management in patients with late hemorrhage after pancreatoduodenectomy for a periampullary tumor.

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.

Centralization of highly complex low-volume procedures in upper gastrointestinal surgery. A summary of systematic reviews and meta-analyses.

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.

Robotic Pancreatoduodenectomy for Pancreatic Head Cancer: a Case Report of a Standardized Technique.

Robotic pancreatoduodenectomy (RPD) for pancreatic cancer is a challenging procedure. Aberrant vasculature may increase the technical difficulty. Several studies have described the safety of RPD in case of a replaced or aberrant right hepatic artery, but detailed video descriptions of the approach are lacking. This case report describes a step--by--step technical video in case of a replaced right hepatic artery. A 58-year-old woman presented with an incidental finding of a 1.7 cm pancreatic head mass. RPD was performed using the da Vinci Xi system and involves a robotic-assisted pancreatico- and hepatico-jejunostomy and open gastro-jejunostomy at the specimen extraction site. The operation time was 410 min with 220 mL of blood loss. The patient had an uncomplicated postoperative course and was discharged after 5 days. Pathology revealed a pancreatic head cancer. RPD is a feasible and safe procedure in case of a replaced hepatic artery when performed in selected patients in high-volume centers by experienced surgeons.

Unsupervised class discovery in pancreatic ductal adenocarcinoma reveals cell-intrinsic mesenchymal features and high concordance between existing classification systems.

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.

Management of Severe Pancreatic Fistula After Pancreatoduodenectomy.

Importance: Postoperative pancreatic fistula is a potentially life-threatening complication after pancreatoduodenectomy. Evidence for best management is lacking. Objective: To evaluate the clinical outcome of patients undergoing catheter drainage compared with relaparotomy as primary treatment for pancreatic fistula after pancreatoduodenectomy. Design, Setting, and Participants: A multicenter, retrospective, propensity-matched cohort study was conducted in 9 centers of the Dutch Pancreatic Cancer Group from January 1, 2005, to September 30, 2013. From a cohort of 2196 consecutive patients who underwent pancreatoduodenectomy, 309 patients with severe pancreatic fistula were included. Propensity score matching (based on sex, age, comorbidity, disease severity, and previous reinterventions) was used to minimize selection bias. Data analysis was performed from January to July 2016. Exposures: First intervention for pancreatic fistula: catheter drainage or relaparotomy. Main Outcomes and Measures: Primary end point was in-hospital mortality; secondary end points included new-onset organ failure. Results: Of the 309 patients included in the analysis, 209 (67.6%) were men, and mean (SD) age was 64.6 (10.1) years. Overall in-hospital mortality was 17.8% (55 patients): 227 patients (73.5%) underwent primary catheter drainage and 82 patients (26.5%) underwent primary relaparotomy. Primary catheter drainage was successful (ie, survival without relaparotomy) in 175 patients (77.1%). With propensity score matching, 64 patients undergoing primary relaparotomy were matched to 64 patients undergoing primary catheter drainage. Mortality was lower after catheter drainage (14.1% vs 35.9%; P = .007; risk ratio, 0.39; 95% CI, 0.20-0.76). The rate of new-onset single-organ failure (4.7% vs 20.3%; P = .007; risk ratio, 0.15; 95% CI, 0.03-0.60) and new-onset multiple-organ failure (15.6% vs 39.1%; P = .008; risk ratio, 0.40; 95% CI, 0.20-0.77) were also lower after primary catheter drainage. Conclusions and Relevance: In this propensity-matched cohort, catheter drainage as first intervention for severe pancreatic fistula after pancreatoduodenectomy was associated with a better clinical outcome, including lower mortality, compared with primary relaparotomy.

Recent Advances in Pancreatic Cancer Surgery of Relevance to the Practicing Pathologist.

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.

Shifting role of operative and nonoperative interventions in managing complications after pancreatoduodenectomy: what is the preferred intervention?

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.

Leakage of the gastroenteric anastomosis after pancreatoduodenectomy.

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.

Definition of a standard lymphadenectomy in surgery for pancreatic ductal adenocarcinoma: a consensus statement by the International Study Group on Pancreatic Surgery (ISGPS).

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.

The quandary of preresection biliary drainage for pancreatic cancer.

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.

[Reliability of the registration of data on complex patients: effects on the hospital standardised mortality ratio (HSMR) in the Netherlands]. / Betrouwbaarheid dataregistratie van complexe patiënten: invloed op het gestandaardiseerde ziekenhuissterftecijfer (HSMR).

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.