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1.  Pain sensation in pancreatic diseases is not uniform: The different facets of pancreatic pain 
AIM: To systematically characterize specific pain patterns in the most frequent pancreatic diseases.
METHODS: Pain in patients with chronic pancreatitis (n = 314), pancreatic cancer (n = 469), and other pancreatic tumors (n = 249) including mucinous (n = 20) and serous cystadenoma (n = 31), invasive (n = 37) and non-invasive intraductal papillary mucinous neoplasia (IPMN; n = 48), low stage (n = 18) and high stage neuroendocrine neoplasia (n = 44), and ampullary cancer (n = 51) was registered and correlated with clinicopathological data. Survival times were estimated by the Kaplan-Meier method. Patients alive at the follow-up time were censored. Survival curves were compared statistically using the log-rank test.
RESULTS: Forty-nine point one percent of pancreatic cancer patients revealed no pain, whereas in chronic pancreatitis only 18.3% were pain free. In contrary, moderate/severe pain was registered in 15.1% in pancreatic cancer patients that was increased in chronic pancreatitis with up to 34.2%. Serous cystadenoma was asymptomatic in most cases (58.1%), whereas 78.9% of all mucinous cystadenoma patients suffered pain. In neuroendocrine neoplasia pain was not a key clinical symptom since 64% of low stage neuroendocrine neoplasia and 59% of high stage neuroendocrine neoplasia patients were pain free. Cancer localization in the pancreatic body and patients with malignant pancreatic neoplasms were associated with more severe pain. Tumor grading and stage did not show any impact on pain. Only in pancreatic cancer, pain was directly associated with impaired survival.
CONCLUSION: Pancreatic pain depicts different patterns of abdominal pain sensation according to the respective pancreatic disorder and does not allow a unification of the term pancreatic pain.
doi:10.3748/wjg.v20.i27.9154
PMCID: PMC4112857  PMID: 25083089
Abdominal pain; Pancreatic neoplasm; Chronic pancreatitis; Intraductal papillary mucinous neoplasia; Pancreatic cancer
2.  Association of industry sponsorship and positive outcome in randomised controlled trials in general and abdominal surgery: protocol for a systematic review and empirical study 
Systematic Reviews  2014;3(1):138.
Background
Industry sponsorship has been identified as a factor correlating with positive research findings in several fields of medical science. To date, the influence of industry sponsorship in general and abdominal surgery has not been fully studied. This protocol describes the rationale and planned conduct of a systematic review to determine the association between industry sponsorship and positive outcome in randomised controlled trials in general and abdominal surgery.
Methods/design
A literature search in the Cochrane Library, MEDLINE and EMBASE and additional hand searches in relevant citations will be conducted. In order to cover all relevant areas of general and abdominal surgery, a new literature search strategy called multi-PICO search strategy (MPSS) has been developed. No language restriction will be applied. The search will be limited to publications between January 1985 and July 2014. Information on funding source, outcome, study characteristics and methodological quality will be extracted.
The association between industry sponsorship and positive outcome will be tested by a chi-squared test. A multivariate logistic regression analysis will be performed to control for possible confounders, such as number of study centres, multinational trials, methodological quality, journal impact factor and sample size.
Discussion
This study was designed to clarify whether industry-sponsored trials report more positive outcomes than non-industry trials. It will be the first study to evaluate this topic in general and abdominal surgery. The findings of this study will enable surgical societies, in particular, to give advice about cooperation with the industry and disclosure of funding source based on empirical evidence.
Systematic review registration
PROSPERO CRD42014010802
Electronic supplementary material
The online version of this article (doi:10.1186/2046-4053-3-138) contains supplementary material, which is available to authorized users.
doi:10.1186/2046-4053-3-138
PMCID: PMC4280764  PMID: 25431307
Industry bias; Industry sponsorship; General and abdominal surgery; Randomised controlled trial; Medical devices; Systematic review; Science study; Health care research
3.  A mechanistic role for the chromatin modulator, NAP1L1, in pancreatic neuroendocrine neoplasm proliferation and metastases 
Background
The chromatin remodeler NAP1L1, which is upregulated in small intestinal neuroendocrine neoplasms (NENs), has been implicated in cell cycle progression. As p57Kip2 (CDKN1C), a negative regulator of proliferation and a tumor suppressor, is controlled by members of the NAP1 family, we tested the hypothesis that NAP1L1 may have a mechanistic role in regulating pancreatic NEN proliferation through regulation of p57Kip2.
Results
NAP1L1 silencing (siRNA and shRNA/lipofectamine approach) decreased proliferation through inhibition of mechanistic (mammalian) target of rapamycin pathway proteins and their phosphorylation (p < 0.05) in the pancreatic neuroendocrine neoplasm cell line BON in vitro (p < 0.0001) and resulted in significantly smaller (p < 0.05) and lighter (p < 0.05) tumors in the orthotopic pancreatic NEN mouse model. Methylation of the p57 Kip2 promoter was decreased by NAP1L1 silencing (p < 0.05), and expression of p57Kip2 (transcript and protein) was upregulated. For methylation of the p57 Kip2 promoter, NAP1L1 bound directly to the promoter (−164 to +21, chromatin immunoprecipitation). In 43 pancreatic NEN samples (38 primaries and 5 metastasis), NAP1L1 was over-expressed in metastasis (p < 0.001), expression which was inversely correlated with p57Kip2 (p < 0.01) on mRNA and protein levels. Menin was not differentially expressed.
Conclusion
NAP1L1 is over-expressed in pancreatic neuroendocrine neoplasm metastases and epigenetically promotes cell proliferation through regulation of p57 Kip2 promoter methylation.
doi:10.1186/1756-8935-7-15
PMCID: PMC4112619  PMID: 25071868
NAP1L1; Pancreatic neuroendocrine neoplasms; pNETs; Promoter methylation; p57; Proliferation
4.  Quality of life after curative liver resection: A single center analysis 
AIM: To evaluate quality of life (QoL) after curative liver resection and identify variables associated with decreased QoL.
METHODS: From October 2001 to July 2004, 323 patients underwent liver resection. At 3-36 mo after discharge, 188 patients were disease free. QoL was assessed using the Short Form (SF)-12 Health Survey with mental and physical component scales (SF-12 MCS and PCS), supplemented with generic questions concerning pain and liver-specific items.
RESULTS: Sixty-eight percent (128/188) returned the questionnaire, which was completed in 75% (96/128) of cases. Median SF-12 PCS and MCS were 46.7 (interquartile range: 34.2-53.9) and 54.1 (42.8-58.2). Fifty percent were pain free with a median symptom score of 1.75 (1.38-2.13). PCS was higher after major hepatectomy [57% (55/96)] compared to minor resection (P = 0.0049), which represented an improved QoL. QoL was not affected by sex but by age compared to the general German population. MCS was higher after liver surgery for metastatic disease [55.9 (47.5-58.8)] compared to primary carcinoma [49.6 (36.5-55.1)] and benign disease [49.2 (37.7-56.3)] (P = 0.0317). There was no correlation between length of postoperative period and QoL. Pain, deficiencies in everyday life and a high symptom score significantly decreased MCS and PCS.
CONCLUSION: Most patients were only marginally affected even after major liver resection; however, minor complications were associated with decreased SF-12 MCS and PCS and need careful attention.
doi:10.3748/wjg.v16.i19.2388
PMCID: PMC2874143  PMID: 20480524
Quality of life; Liver resection
5.  Suppression of transforming growth factor β signalling aborts caerulein induced pancreatitis and eliminates restricted stimulation at high caerulein concentrations 
Gut  2006;56(5):685-692.
Background
Transforming growth factors βs (TGF‐βs) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF‐βs modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild‐type (FVB−/−) and transgenic mice that are heterozygous (FVB+/−) for expression of a dominant negative type II TGF‐β receptor.
Methods
After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed.
Results
The normal mouse pancreas was devoid of inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild‐type mice resulted in 6‐ and 36‐fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/− mice exhibited minimal alterations in response to caerulein with attenuated neutrophil–macrophage infiltrates. Moreover, acini from FVB+/− mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased.
Conclusion
Our findings indicate that a functional TGF‐β signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.
doi:10.1136/gut.2006.105833
PMCID: PMC1942167  PMID: 17135311
6.  Prediction of Postoperative Mortality in Liver Transplantation in the Era of MELD-Based Liver Allocation: A Multivariate Analysis 
PLoS ONE  2014;9(6):e98782.
Background and Aims
Liver transplantation is the only curative treatment for end-stage liver disease. While waiting list mortality can be predicted by the MELD-score, reliable scoring systems for the postoperative period do not exist. This study's objective was to identify risk factors that contribute to postoperative mortality.
Methods
Between December 2006 and March 2011, 429 patients underwent liver transplantation in our department. Risk factors for postoperative mortality in 266 consecutive liver transplantations were identified using univariate and multivariate analyses. Patients who were <18 years, HU-listings, and split-, living related, combined or re-transplantations were excluded from the analysis. The correlation between number of risk factors and mortality was analyzed.
Results
A labMELD ≥20, female sex, coronary heart disease, donor risk index >1.5 and donor Na+>145 mmol/L were identified to be independent predictive factors for postoperative mortality. With increasing number of these risk-factors, postoperative 90-day and 1-year mortality increased (0–1: 0 and 0%; 2: 2.9 and 17.4%; 3: 5.6 and 16.8%; 4: 22.2 and 33.3%; 5–6: 60.9 and 66.2%).
Conclusions
In this analysis, a simple score was derived that adequately identified patients at risk after liver transplantation. Opening a discussion on the inclusion of these parameters in the process of organ allocation may be a worthwhile venture.
doi:10.1371/journal.pone.0098782
PMCID: PMC4048202  PMID: 24905210
7.  Extrapulmonary sarcoidosis of liver and pancreas: A case report and review of literature 
Sarcoidosis is a chronic multisystemic granulomatous disease of unknown origin, which can involve nearly all organs. In the case of an infrequent gastrointestinal tract involvement in systemic sarcoidosis, granulomas of the liver are most commonly described while isolated pancreatic sarcoid lesions are rarely seen. We report a case of systemic sarcoidosis with exclusive extrapulmonal involvement of the liver and the pancreas in a 71-year-old white man. The diagnosis of liver involvement was confirmed by biopsy. Pancreatic surgery was needed because preoperative evaluation could not exclude pancreatic cancer and for biliary decompression. An extensive literature review of systemic sarcoidosis, focusing on reported cases with unusual presentation of sarcoidosis in the liver and the pancreas, its diagnosis, treatment, and prognosis was made.
doi:10.3748/wjg.v13.i17.2504
PMCID: PMC4146771  PMID: 17552036
Systemic; Sarcoidosis; Extrapulmonary; Liver; Pancreas
8.  Autoimmune pancreatitis associated with a large pancreatic pseudocyst 
Pancreatic cystic lesions comprise various entities with different histopathological characteristics and their differential diagnosis is often a challenge for clinicians. Autoimmune pancreatitis (AIP) is usually not considered in the differential diagnosis of cystic lesions, but often mimics the morphological aspects of pancreatic neoplasm. We report the case of a 64-year-old male patient with a cystic pancreatic head lesion (diameter 5 cm) and stenosis of the distal bile duct requiring repeated stenting. Because of the clinical presentation together with moderate elevation of serum CA19-9 and massive elevation of cyst fluid CA19-9 (122.695 U/L; normal range: < 37.0 U/L), the patient underwent explorative laparotomy and pylorus preserving partial pancreaticoduodenectomy. Histology revealed surprisingly AIP with an inflammatory pseudocyst. In conclusion, cyst fluid analysis of tumor markers and cyst fluid cytology lack high accuracy to clearly differentiate cystic pancreatic lesions. Although AIP is rarely associated with pseudocysts, the disease has to be considered in the differential diagnosis of cystic pancreatic lesions. Early examination of serum IgG, IgG4 and auto-antibodies might save these patients from unnecessary endoscopical and surgical procedures.
doi:10.3748/wjg.v12.i36.5904
PMCID: PMC4100678  PMID: 17007063
Pseudocyst; Autoimmune pancreatitis; Pancreatic cancer; Tumor marker; CEA; CA19-9
9.  CD44 standard and CD44v10 isoform expression on leukemia cells distinctly influences niche embedding of hematopoietic stem cells 
Background
A blockade of CD44 is considered a therapeutic option for the elimination of leukemia initiating cells. However, anti-panCD44 can interfere with hematopoiesis. Therefore we explored, whether a CD44 variant isoform (CD44v)-specific antibody can inhibit leukemia growth without attacking hematopoiesis. As a model we used CD44v10 transfected EL4 thymoma cells (EL4-v10).
Methods
The therapeutic efficacy of anti-panCD44 and anti-CD44v10 was evaluated after intravenous application of EL4/EL4-v10. Ex vivo and in vitro studies evaluated the impact of anti-panCD44 and anti-CD44v10 as well as of EL4 and EL4-v10 on hematopoietic stem cells (HSC) in cocultures with bone marrow stroma cells with a focus on adhesion, migration, cell cycle progression and apoptosis resistance.
Results
Intravenously injected EL4-v10 grow in bone marrow and spleen. Anti-panCD44 and, more pronounced anti-CD44v10 prolong the survival time. The higher efficacy of anti-CD44v10 compared to anti-panCD44 does not rely on stronger antibody-dependent cellular cytotoxicity or on promoting EL4-v10 apoptosis. Instead, EL4 compete with HSC niche embedding. This has consequences on quiescence and apoptosis-protecting signals provided by the stroma. Anti-panCD44, too, more efficiently affected embedding of HSC than of EL4 in the bone marrow stroma. EL4-v10, by catching osteopontin, migrated on bone marrow stroma and did not or weakly interfere with HSC adhesion. Anti-CD44v10, too, did not affect the HSC – bone marrow stroma crosstalk.
Conclusion
The therapeutic effect of anti-panCD44 and anti-CD44v10 is based on stimulation of antibody-dependent cellular cytotoxicity. The superiority of anti-CD44v10 is partly due to blocking CD44v10-stimulated osteopontin expression that could drive HSC out of the niche. However, the main reason for the superiority of anti-CD44v10 relies on neither EL4-v10 nor anti-CD44v10 severely interfering with HSC – stroma cell interactions that, on the other hand, are affected by EL4 and anti-panCD44. Anti-panCD44 disturbing HSC embedding in the osteogenic niche weakens its therapeutic effect towards EL4. Thus, as far as leukemic cells express CD44v isoforms, the therapeutic use of anti-panCD44 should be avoided in favor of CD44v-specific antibodies.
doi:10.1186/1756-8722-7-29
PMCID: PMC4022365  PMID: 24684724
Leukemia; Antibody therapy; CD44v10; Hematopoiesis; Bone marrow stroma
10.  Ruptured angiosarcoma of the liver treated by emergency catheter-directed embolization 
Angiosarcoma is a rare primary malignant neoplasm of the liver with a poor prognosis. Here, we report a case of a patient with a ruptured hepatic angiosarcoma which was treated by emergency catheter-directed embolization, followed by left-sided hemihepatectomy.
doi:10.3748/wjg.v12.i5.804
PMCID: PMC4066137  PMID: 16521200
Ruptured angiosarcoma; Liver; Embolization
11.  TIPSS for variceal hemorrhage after living related liver transplantation: A dangerous indication 
The introduction of transjugular intrahepatic portal-systemic stent-shunt (TIPSS) has been a major breakthrough in the treatment of portal hypertension, which has evolved to a large extent, into a routine procedure. A 21-year-old male patient with progressive graft fibrosis/cirrhosis requiring TIPSS for variceal hemorrhage in the esophagus due to portal hypertension was unresponsive to conventional measures two years after living related liver transplantation (LDLT). Subsequently, variceal hemorrhage was controlled, however, liver function decreased dramatically with consecutive multi organ failure. CT scan revealed substantial necrosis in the liver. The patient underwent successful “high urgent” cadaveric liver transplantation and was discharged on postoperative d 20 in a stable condition.
doi:10.3748/wjg.v12.i3.493
PMCID: PMC4066077  PMID: 16489658
Portal hypertension; Liver necrosis; Fibrosis; Cirrhosis
12.  Adjuvant therapy after resection of colorectal liver metastases: the predictive value of the MSKCC clinical risk score in the era of modern chemotherapy 
BMC Cancer  2014;14:174.
Background
Despite introduction of effective chemotherapy protocols, it has remained uncertain, if patients with colorectal cancer (CRC) liver metastases should receive adjuvant therapy. Clinical or molecular predictors may help to select patients at high risk for disease recurrence and death who obtain a survival advantage by adjuvant chemotherapy.
Methods
A total of 297 patients with potentially curative resection of CRC liver metastases were analyzed. These patients had no neoadjuvant therapy, no extrahepatic disease and negative resection margins. The primary endpoint was overall survival. Patients’ risk status was evaluated using the Memorial Sloan-Kettering Cancer Center clinical risk score (MSKCC-CRS). Multivariable analyses were performed using Cox proportional hazard models.
Results
A total of 137 (43%) patients had a MSKCC-CRS > 2. Adjuvant chemotherapy was administered to 116 (37%) patients. Patients who received adjuvant chemotherapy were of younger age (p = 0.03) with no significant difference in the presence of multiple metastases (p = 0.72) or bilobar metastases (p = 0.08). On multivariate analysis adjuvant chemotherapy was associated with improved survival in the entire cohort (Hazard ratio 0.69; 95% confidence interval 0.69–0.98). It improved survival markedly in high-risk patients with a MSKCC-CRS > 2 (HR 0.40; 95% CI 0.23–0.69), whereas it was of no benefit in patients with a MSKCC-CRS ≤ 2 (HR 0.90; 95% CI 0.57–1.43).
Conclusions
The MSKCC-CRS offers a tool to select patients for adjuvant therapy after resection of CRC liver metastases. Validation in independent patient cohorts is required.
doi:10.1186/1471-2407-14-174
PMCID: PMC4008001  PMID: 24612620
Colorectal cancer; FOLFOX; FOLFIRI; 5-FU; Leucovorin; Liver resection
13.  Stem cell Transplantation for Eradication of Minimal PAncreatic Cancer persisting after surgical Excision (STEM PACE Trial, ISRCTN47877138): study protocol for a phase II study 
BMC Cancer  2014;14:168.
Background
Pancreatic cancer is the third most common cancer related cause of death. Even in the 15% of patients who are eligible for surgical resection the outlook is dismal with less than 10% of patients surviving after 5 years. Allogeneic hematopoietic (allo-HSCT) stem cell transplantation is an established treatment capable of to providing cure in a variety of hematopoietic malignancies. Best results are achieved when the underlying neoplasm has been turned into a stage of minimal disease by chemotherapy. Allo-HSCT in advanced solid tumors including pancreatic cancer have been of limited success, however studies of allo-HSCT in solid tumors in minimal disease situations have never been performed. The aim of this trial is to provide evidence for the clinical value of allo-HSCT in pancreatic cancer put into a minimal disease status by effective surgical resection and standard adjuvant chemotherapy.
Methods/Design
The STEM PACE trial is a single center, phase II study to evaluate adjuvant allogeneic hematopoietic stem cell transplantation in pancreatic cancer after surgical resection. The study will evaluate as primary endpoint 2 year progression free survival and will generate first time state-of-the-art scientific clinical evidence if allo-HSCT is feasible and if it can provide long term disease control in patients with effectively resected pancreatic cancer. Screened eligible patients after surgical resection and standard adjuvant chemotherapy with HLA matched related stem cell donor can participate. Patients without a matched donor will be used as a historical control. Study patients will undergo standard conditioning for allo-HSCT followed by transplantation of allogeneic unmanipulated peripheral blood stem cells. The follow up of the patients will continue for 2 years. Secondary endpoints will be evaluated on 7 postintervention visits.
Discussion
The principal question addressed in this trial is whether allo-HSCT can change the unfavourable natural course of this disease. The underlying hypothesis is that allo-HSCT has the capacity to provide long-term disease control to an extent otherwise not possible in pancreatic cancer, thereby substantially improving survival of affected patients.
Trial registration
This trial has been registered: ISRCTN47877138
doi:10.1186/1471-2407-14-168
PMCID: PMC4008264  PMID: 24612467
Pancreatic cancer; Allogeneic hematopoietic stem cell transplantation; Minimal residual disease
14.  Synergistic effects of interferon-alpha in combination with chemoradiation on human pancreatic adenocarcinoma 
AIM: To determine whether IFN-α is the agent that turns a slightly effective treatment (radiochemotherapy) into a potent therapy, we tested IFN-α for its synergistic properties.
METHODS: Eight pancreatic carcinoma cell lines were treated with the single agents and combinations of these. The role of IFN-α regarding a) direct inhibitory effects; b) radio and chemosensitizing effects; c) anti-angiogenic properties and d) enhancement of immunogenicity was investigated.
RESULTS: Our results show that IFN-α has direct inhibitory properties and some synergistic influence as determined by AnnexinV/PI stain and cell count. IFN-α is also able to prevent the increase in proliferation rate and VEGF secretion of CDDP resistant cells. Having taken the results from immunogenicity experiments together, we found cells that can be influenced by IFN-α but were less susceptible against T cells. Furthermore, high expression of MHC molecules, CD118, EGF-R and Fas was predictive for a good response.
CONCLUSION: In conclusion, IFN-α has direct cytotoxic effects, acts as a radiosensitizer and circumvents tumor cell-regrowth after CDDP treatment. These mechanisms may be responsible for the good clinical outcome of CapRI.
doi:10.3748/wjg.v11.i10.1521
PMCID: PMC4305696  PMID: 15770730
Interferon-alpha; Pancreatic adenocarcinoma; Synergistic effects; Combination therapy
15.  A case of methicillin-resistant Staphylococcus aureus infection following bile duct stenting 
AIM: To present a case of methicillin-resistant Staphylococcus aureus (MRSA) infection following bile duct stenting in a patient with malignant biliary obstruction.
METHODS: A 78-year-old male patient was admitted to a community hospital with progredient painless jaundice lasting over two weeks, weight loss and sweating at night. Whether a stent should be implanted pre-operatively in jaundiced patients or whether these patients should directly undergo surgical resection, was discussed.
RESULTS: ERC and a biopsy from the papilla of Vater revealed an adenocarcinoma. In addition, a 7-Ch plastic stent was placed into the common bile duct. Persistent abdominal pain, increasing jaundice, weakness and indigestion led to the transfer of the patient to our hospital. A pylorus-preserving pancreatoduodenectomy was performed. Intraoperatively, bile leaked out of the transected choledochus and the stent was found to be dislocated in the duodenum. A smear of the bile revealed an infection with MRSA, leading to post-operative isolation of the patient.
CONCLUSION: As biliary stents can cause severe infection of the bile, the need for pre-operative placement of biliary stents should be carefully evaluated in each individual case.
doi:10.3748/wjg.v11.i9.1396
PMCID: PMC4250693  PMID: 15761984
Methicillin-resistant Staphylococcus aureus; Bile; Infection; Stent; Biliary obstruction; Malignancy; Surgery
16.  DISCOVER trial– Distal resection of the pancreas with or without coverage of the pancreatic remnant: study protocol of a randomised controlled trial 
Trials  2013;14:430.
Background
Distal pancreatectomy for benign and malignant tumours is the second most common surgical procedure on the pancreas. Postoperative pancreatic fistulas (POPF) represent the most significant clinical complication, causing prolongation of hospital stay and the need for additional diagnostic and therapeutic procedures. Although various techniques for preventing POPF have been evaluated, to date, there is no available technique that ensures closure of the pancreatic remnant.
Methods/Design
DISCOVER will aim to investigate differences in the postoperative course after a distal pancreatectomy comparing the standard surgical technique with an alternative technique that provides additional coverage of the pancreatic remnant by the falciform ligament. The primary endpoint of this trial will be the rate of POPF. As secondary endpoints, incidence of postoperative morbidity and mortality, length of hospital stay, and quality of life will be assessed.
DISCOVER is a single-centre, randomised, controlled surgical trial. For statistical analysis, a binary logistic regression model will be used. With a level of significance of 5% and a power of 80%, a sample size of 75 patients per group has been identified as necessary.
Discussion
The findings of this trial will help to evaluate the usefulness of the coverage procedure at reducing the rate of POPF. The results could influence the standard procedure for remnant closure after distal pancreatectomy.
Trial-registration
Clinical trials register (DRKS-ID: DRKS00000546)
doi:10.1186/1745-6215-14-430
PMCID: PMC3867413  PMID: 24330450
Coverage procedure; Distal pancreatectomy; Falciform ligament; Pancreatic fistula
17.  Regular three-dimensional presentations improve in the identification of surgical liver anatomy – a randomized study 
BMC Medical Education  2013;13:131.
Background
Three-dimensional (3D) presentations enhance the understanding of complex anatomical structures. However, it has been shown that two dimensional (2D) “key views” of anatomical structures may suffice in order to improve spatial understanding. The impact of real 3D images (3Dr) visible only with 3D glasses has not been examined yet. Contrary to 3Dr, regular 3D images apply techniques such as shadows and different grades of transparency to create the impression of 3D.
This randomized study aimed to define the impact of both the addition of key views to CT images (2D+) and the use of 3Dr on the identification of liver anatomy in comparison with regular 3D presentations (3D).
Methods
A computer-based teaching module (TM) was used. Medical students were randomized to three groups (2D+ or 3Dr or 3D) and asked to answer 11 anatomical questions and 4 evaluative questions. Both 3D groups had animated models of the human liver available to them which could be moved in all directions.
Results
156 medical students (57.7% female) participated in this randomized trial. Students exposed to 3Dr and 3D performed significantly better than those exposed to 2D+ (p < 0.01, ANOVA). There were no significant differences between 3D and 3Dr and no significant gender differences (p > 0.1, t-test). Students randomized to 3D and 3Dr not only had significantly better results, but they also were significantly faster in answering the 11 anatomical questions when compared to students randomized to 2D+ (p < 0.03, ANOVA). Whether or not “key views” were used had no significant impact on the number of correct answers (p > 0.3, t-test).
Conclusion
This randomized trial confirms that regular 3D visualization improve the identification of liver anatomy.
doi:10.1186/1472-6920-13-131
PMCID: PMC3848999  PMID: 24066729
18.  Phase I study evaluating the treatment of patients with locally advanced pancreatic cancer with carbon ion radiotherapy: the PHOENIX-01 trial 
BMC Cancer  2013;13:419.
Background
Treatment options for patients with locally advanced pancreatic cancer include surgery, chemotherapy as well as radiotherapy. In many cases, surgical resection is not possible, and therefore treatment alternatives have to be performed. Chemoradiation has been established as a convincing treatment alternative for locally advanced pancreatic cancer. Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 1.16 and 2.46 depending on the pancreatic cancer cell line as well as the endpoint analyzed. Japanese Data on the evaluation of carbon ion radiation therapy showed promising results for patients with pancreatic cancer.
Methods and design
The present PHOENIX-01 trial evaluates carbon ion radiotherapy using the active rasterscanning technique in patients with advanced pancreatic cancer in combination with weekly gemcitabine and adjuvant gemcitabine. Primary endpoint is toxicity, secondary endpoints are overall survival, progression-free survival and response.
Discussion
The physical and biological properties of the carbon ion beam promise to improve the therapeutic ratio in patients with pancreatic cancer: Due to the inverted dose profile dose deposition in the entry channel of the beam leads to sparing of normal tissue; the Bragg peak can be directed into the defined target volume, and the sharp dose fall-off thereafter again spares normal tissue behind the target volume. The higher RBE of carbon ions, which has been shown also for pancreatic cancer cell lines in the preclinical setting, is likely to contribute to an increase in local control, and perhaps in OS. Early data from Japanese centers have shown promising results. In conclusion, this is the first trial to evaluate actively delivered carbon ion beams in patients with locally advanced pancreatic cancer within a dose-escalation strategy.
Trial registration
NCT01795274
doi:10.1186/1471-2407-13-419
PMCID: PMC3849371  PMID: 24034562
19.  Impact of preoperative patient education on prevention of postoperative complications after major visceral surgery: study protocol for a randomized controlled trial (PEDUCAT trial) 
Trials  2013;14:271.
Background
In line with the growing number of surgical procedures being performed worldwide, postoperative complications are also increasing proportionately. Prevention of these postoperative complications is a high medical priority. Preoperative education of patients, including provision of preparatory information about the correct behavior after surgery, could improve the postoperative outcome, but the evidence for this is inconclusive. The aim of the PEDUCAT trial is to evaluate the feasibility and the impact of preoperative patient education on postoperative morbidity, mortality and quality of life in patients scheduled for elective major visceral surgery.
Methods/design
PEDUCAT is designed as a cluster-randomized controlled pilot study. The experimental group will visit a standardized preoperative seminar to learn how best to behave after surgery in addition to being given a standard information brochure, whereas the control group will only receive the information brochure. Outcome measures such as postoperative morbidity, postoperative pain, postoperative anxiety and depression, patient satisfaction, quality of life, length of hospital stay and postoperative mortality will be evaluated. Statistical analysis will be based on the intention-to-treat population. Analysis of covariance will be applied for the intervention group comparison, adjusting for age, center and quality of life before surgery. This is a pilot study to show the feasibility of the concept. Nevertheless, the planned sample size of n = 204 is large enough to show an effect with power of 90% and a significance level of 5%.
Trial registration
German Clinical Trial Register number: DRKS00004226.
doi:10.1186/1745-6215-14-271
PMCID: PMC3765330  PMID: 23978275
Patient education; Preoperative education; Postoperative complication; Prevention; Visceral surgery; Cluster randomization
20.  DiaSurg 2 trial - surgical vs. medical treatment of insulin-dependent type 2 diabetes mellitus in patients with a body mass index between 26 and 35 kg/m2: study protocol of a randomized controlled multicenter trial - DRKS00004550 
Trials  2013;14:183.
Background
Type 2 diabetes mellitus (T2DM) is a disease with high prevalence, associated with severe co-morbidities as well as being a huge burden on public health. It is known that glycemic control decreases long-term morbidity and mortality. The current standard therapy for T2DM is medical treatment. Several randomized controlled trials (RCTs) performed in obese patients showed remission of T2DM after bariatric surgery. Recent RCTs have shown bariatric procedures to produce a similar effect in non-morbidly and non-severely obese, insulin-dependent T2DM patients suggesting procedures currently used in bariatric surgery as new therapeutical approach in patients with T2DM. This study aims at investigating whether Roux-en-Y gastric bypass (RYGB) is an efficient treatment for non-severely obese T2DM patients in terms of preventing long-term complications and mortality.
Methods
The DiaSurg 2 trial is a multicenter, open randomized controlled trial comparing RYGB including standardized medical treatment if needed to exclusive standardized medical treatment of T2DM (control group). The primary endpoint is a composite time-to-event endpoint (cardiovascular death, myocardial infarction, coronary bypass, percutaneous coronary intervention, non-fatal stroke, amputation, surgery for peripheral atherosclerotic artery disease), with a follow-up period of 8 years. Insulin-dependent T2DM patients aged between 30 and 65 years will be included and randomly assigned to one of the two groups. The experimental group will receive RYGB and, if needed, standardized medical care, whereas the control group will receive exclusive standardized medical care, both according to the national treatment guidelines for T2DM. Statistical analysis is based on Cox proportional hazards regression for the intention-to-treat population. Assuming a loss to follow-up rate of 20%, 200 patients will be randomly allocated to the comparison groups. A total sample size of n = 400 is sufficient to ensure 80% power in a two-tailed significance test at alpha = 5%.
Discussion
The DiaSurg2 trial will yield long-term data (8 years) on diabetes-associated morbidity and mortality in patients with insulin-dependent T2DM receiving either RYGB or standardized medical care.
Trial registration
The trial protocol has been registered in the German Clinical Trials Register DRKS00004550.
doi:10.1186/1745-6215-14-183
PMCID: PMC3694456  PMID: 23782896
21.  Pylorus resection or pylorus preservation in partial pancreatico-duodenectomy (PROPP study): study protocol for a randomized controlled trial 
Trials  2013;14:44.
Background
Partial pancreatico-duodenectomy (PD) is the standard treatment for tumors of the pancreatic head. Today, preservation of the pylorus has been widely accepted as the surgical standard in this procedure. A common postoperative complication is the occurrence of delayed gastric emptying (DGE), which causes impairment of oral intake andpatients’ quality of life, prolongation of hospital stay and delay of further treatment (for example adjuvant chemotherapy). In a small number of two retrospective and one randomized studies, a modification by resection of the pylorus with preservation of the stomach has shown to reduce DGE incidence. The aim of the present study is to investigate the effect of pylorus resection on postoperative DGE in PD.
Methods/Design
Patients undergoing elective PD for any indication equal or older than 18 years and who have given informed consent will be included. Patients will be randomized to either PD with pylorus preservation or PD with pylorus resection and complete stomach preservation. Sample size (n = 89 patients per group) is calculated on an assumed difference in DGE incidence of 20%. Primary study endpoint is DGE within 30 days; secondary endpoints are operation time, blood loss, morbidity, mortality, hospital stay and quality of life (QoL).
Discussion
DGE is a relevant clinical problem following PD with a great impact on patients’ recovery, length of hospital stay, QoL and consecutive adjuvant therapies. As there is no causal therapy, prevention of DGE is essential to improve outcome. The technical modification of pylorus resection may offer a simple and effective method for this purpose. The present study is designed to increase the existing body of evidence and potentially change the future standard surgical procedure of PD.
Trial registration
German Clinical Trials Register DRKS00004191.
doi:10.1186/1745-6215-14-44
PMCID: PMC3599830  PMID: 23410208
Partial pancreatico-duodenectomy; Pylorus preservation; Pylorus resection; Randomized trial
22.  Chemoradiation in patients with isolated recurrent pancreatic cancer - therapeutical efficacy and probability of re-resection 
Background
In the present retrospective analysis we analysed the therapeutic outcome of a set of patients, who were treated with chemoradiation (CRT) for recurrent pancreatic cancer (RPC) in a single institution.
Patients and Methods
Forty-one patients had a history of primary resection for pancreatic cancer. In case of an unresectable recurrency patients were treated with CRT at our institution between 2002 and 2010 with a median dose of 48.4 Gy (range 39.6–54 Gy). Concurrent chemotherapy regimes included Gemcitabine (GEM) in 37/41 patients (90%) and Fluorouracil (FU) or Capecitabine (CAP) in 4/41 patients (10%). Patients were re-evaluated after CRT with computed tomography and/or explorative laparotomy. During re-resection or laparotomy 15 patients received an additional intraoperative radiotherapy (IORT) with a median dose of 15 Gy (range 12–15 Gy). Median age was 65 years (range 39–76 years) and there were 26 male and 15 female patients.
Results
The median overall survival (mOS), local control (LC) and progression-free survival (PFS) were 16.1, 13.8 and 6.9 months respectively for all patients after the first day of CRT. Re-resection was possible in five patients (12%) and a complete remission (CR) as defined by tumor-free biopsy was seen in 6 patients (15%). When re-resection could be achieved after CRT mOS was improved to 28.3 months (n = 5 patients, 95%-CI 10.2 – 46.3 months). Patients receiving IORT had a significantly improved mOS compared to no IORT (p = 0.034). Fifteen patients (37%) experienced a local tumour progression and main site of distant metastasis was the liver (11 patients, 27%).Overall treatment-related toxicity was mild, grade III hematologic toxicity was observed in 11 patients (27%).
Conclusion
In summary we observed a good therapeutic response with mild to moderate toxicity levels for CRT in RPC. Overall survival and PFS were clearly improved in case of induction of a complete remission (tumor-free biopsies) or after achieving a re-resection, thus providing a curative intended therapy even in case of disease recurrence.
doi:10.1186/1748-717X-8-27
PMCID: PMC3570445  PMID: 23369246
23.  The impact of MFG-E8 in chronic pancreatitis: potential for future immunotherapy? 
BMC Gastroenterology  2013;13:14.
Background
The glycoprotein MFG-E8 mediates phagocytic clearance of apoptotic cells and influences the pathogenesis and progression of inflammatory diseases. MFG-E8 was shown to attenuate the progression of inflammation and to improve survival in septic rats. Accumulating evidence suggests an immunomodulatory link between MFG-E8 and the pro-inflammatory chemokine fractalkine, which may determine the severity of pain, fibrosis, and inflammation in chronic pancreatitis (CP).
Methods
The expression and localization of MFG-E8 was investigated in CP (n = 62), and normal pancreas (NP; n = 34) by QRT-PCR, Western-blot and immunohistochemistry analyses. Results were correlated with mRNA expression of fractalkine, CX3CR1, and with the presence and degree of pain and fibrosis. Human pancreatic stellate cells (hPSCs) were isolated from CP tissues and evaluated for MFG-E8 mRNA expression after fractalkine stimulation.
Results
MFG-E8-mRNA was significantly overexpressed in CP and isolated hPSCs when compared to NP. Western-blot and immunohistochemistry analysis confirmed accumulation of MFG-E8 in CP, with noticeably increased MFG-E8 immunoreactivity in tubular complexes. MFG-E8 expression correlated significantly with fractalkine expression, severe fibrosis, and the presence of pain in CP patients. Stimulation of hPSCs with fractalkine led to a significant increase in MFG-E8 expression.
Conclusions
In the present study, we demonstrated for the first time that MFG-E8 is significantly up-regulated in CP patients and together with fractalkine correlated noticeably with severe fibrosis and the presence of pain. hPSCs overexpress MFG-E8 upon fractalkine stimulation in vitro, which underlines the suggested immunmodulatory link in CP and may be a key mechanism in CP fibrogenesis and pain generation. Taken together, these novel findings suggest that MFG-E8 blockade may be a promising tool for future immunotherapy in CP to attenuate both fibrosis and pain sensation.
doi:10.1186/1471-230X-13-14
PMCID: PMC3556065  PMID: 23324439
MFG-E8; Chronic pancreatitis; Fractalkine; Fibrosis; Stellate cells; Pain
24.  MEK inhibition induced downregulation of MRP1 and MRP3 expression in experimental hepatocellular carcinoma 
Background
Hepatocellular carcinoma (HCC) exhibits strong intrinsic and acquired drug resistance which is the main obstacle to chemotherapy. Overexpression of ATP binding cassette (ABC) proteins correlates with activation of mitogen activated protein kinase (MAPK) pathway in HCC. Here, we systematically investigated the inhibition of MAPK pathway and its role in regulating HCC cell growth as well as ABC proteins MRP1 and MRP3 expression.
Methods
The Raf1 kinase inhibitor (GW5074) and different MEK inhibitors (U0126 and AZD6244) were used to treat HCC cells to identify their effects on HCC cell growth and ABC proteins expression in vitro. Cell viability tests were performed after the treatment of MAPK pathway inhibitors and in combination with gemcitabine or doxorubicin. Western blot was applied to assess the changes of MAPK pathway and protein expression of MRP1 and MRP3. Flow cytometry was used to measure intracellular doxorubicin accumulation after the treatment of MEK inhibitors.
Results
Both Raf1 inhibitor (GW5074) and MEK inhibitors (U0126 and AZD6244) suppressed HCC cell growth in a dose dependent manner. Pre-treatment of MEK inhibitor U0126 or AZD6244 sensitized HCC cells to gemcitabine or doxorubicin based chemotherapy. Raf1 inhibitor GW5074 had no effect on MRP1 and MRP3 protein expression. Treatment of gemcitabine or doxorubicin activated phosphorylated ERK and induced the upregulation of MRP1 and MRP3. MEK inhibitors U0126 and AZD6244 deactivated phosphorylated ERK, decreased endogenous MRP1 expression, reversed gemcitabine or doxorubicin induced MRP1 and MRP3 upregulation, and increased the intracellular doxorubicin accumulation.
Conclusion
This study provides evidence that MEK inhibitors sensitize HCC cells to chemotherapy by increasing intracellular chemodrug accumulation. MEK inhibirors U0126 and AZD6244 reduced MRP1 as well as MRP3 expression, and may contribute partially to the sensitization. The combination of MEK inhibitor and conventional chemotherapy may offer new therapeutic option for the treatment of resistant HCC.
doi:10.1186/1475-2867-13-3
PMCID: PMC3558388  PMID: 23320839
Hepatocellular carcinoma; MEK; MRP1; MRP3; Multidrug resistance
25.  Tumor-exosomes and leukocyte activation: an ambivalent crosstalk 
Background
Tumor-exosomes being reported to suppress or promote a cancer-directed immune response, we used exosomes of the rat pancreatic adenocarcinoma BSp73ASML (ASML) to evaluate, whether and which steps in immune response induction can be affected by tumor-exosomes and how the impaired responsiveness can be circumvented.
Results
ASML-exosomes bind to and are taken up by all leukocyte subpopulations in vivo and in vitro, uptake by CD11b+ leukocytes exceeding that by T and B cells. ASML-exosomes affect leukocyte proliferation via reduced CD44v6 up-regulation and lck, ZAP70 and ERK1,2 phosphorylation, which can be compensated by dendritic cells (DC). ASML-exosomes do not support Treg. Yet, impaired activation of anti-apoptotic signals is accompanied by slightly increased apoptosis susceptibility. IgM secretion is unaffected; NK and CTL activity are strengthened, ASML-exosomes co-operating with DC in CTL activation. ASML-exosomes transiently interfere with leukocyte migration by occupying migration-promoting receptors CD44, CD49d, CD62L and CD54 during binding/internalization.
Conclusion
ASML-exosomes might well serve as adjuvant in immunotherapy as they support leukocyte effector functions and have only a minor impact on leukocyte activation, which can be overridden by DC. However, exosome-induced modulation of immune cells relies, at least in part, on exosome uptake and message transfer. This implies that depending on the individual tumor's exosome composition, exosomes may distinctly affect the immune system. Nonetheless, whether immunotherapy can profit from using tumor-exosomes as adjuvant can easily be settled beforehand in vitro.
doi:10.1186/1478-811X-10-37
PMCID: PMC3519567  PMID: 23190502
Tumor-exosomes; T cell activation; CTL; NK; Apoptosis; Leukocyte migration

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