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Background Cachexia is characterized by a negative protein and energy balance leading to loss of adipose tissue and muscle mass. Cancer cachexia negatively impacts treatment tolerability and prognosis. Supportive interventions should be initiated as early as possible. Biomarkers for early prediction of continuing weight loss during the course of disease are currently lacking. Methods In this pilot, observational, cross‐sectional, case–control study, cachectic cancer patients undergoing systemic first‐line cancer treatment were matched 2:1 with healthy controls according to age, gender and body mass index. Alterations in amino acid and energy metabolism, as indicated by acylcarnitine levels, were analysed using mass spectrometry in plasma samples (PS) and dried blood specimen (DBS). Welch's two‐sample t‐test was used for comparative analysis of metabolites between cancer patients and healthy matched controls and to identify the metabolomic profiles related to weight loss across different time points. A linear regression model was applied to correlate weight loss and single metabolites as predictor variables. Finally, metabolite pathway enrichment analyses were performed. Results Eighteen cases (14 male and 4 female) and 36 paired controls were enrolled. There was a good correlation between baseline PS and DBS of healthy controls for the levels of most amino acids but not for acylcarnitine. Amino acid levels related to cancer metabolism were significantly altered in cancer patients compared with controls in both DBS and PS for arginine, citrulline, histidine and ornithine and in DBS only for asparagine, glutamine, methylhistidine, methionine, ornithine, serine, threonine and leucine/isoleucine. Metabolite enrichment analysis in PS of cancer patients revealed histidine metabolism activation (P = 0.0025). Baseline acylcarnitine analysis in DBS was indicative for alterations of the mitochondrial carnitine shuttle, related to β‐oxidation: The ratio palmitoylcarnitine/acylcarnitine (Q2) and the ratio palmitoylcarnitine + octadecenoylcarnitine/acylcarnitine (Q3) were predictive for early weight loss (P

Introduction Pancreatic trauma (PT) involving the main pancreatic duct is rare, but represents a challenging clinical problem with relevant morbidity and mortality. It is generally classified according to the American Association for the Surgery of Trauma (AAST) and often presents as concomitant injury in blunt or penetrating abdominal trauma. Diagnosis may be delayed because of a lack of clinical or radiological manifestation. Treatment options for main pancreatic duct injuries comprise highly complex surgical procedures. Patients and Methods We retrospectively analyzed clinical data from 12 patients who underwent surgery in two tertiary centers in Germany during 2003–2016 for grade III-V PT with affection of the main pancreatic duct, according to the AAST classification. Results The median age was 23 (range: 7-44) years. In nine patients blunt abdominal trauma was the reason for PT, whereas penetrating trauma only occurred in three patients. MRI outperformed classical trauma CT imaging with regard to detection of duct involvement. Complex procedures as i.e. an emergency pancreatic head resection, distal pancreatectomy or parenchyma sparing pancreatogastrostomy were performed. Compared to elective pancreatic surgery the complication rate in the emergency setting was higher. Yet, parenchyma-sparing procedures demonstrated safety. Conclusions Often extension of diagnostics including MRI and/or ERP at an early stage is necessary to guide clinical decision-making. If, due to main duct injuries, surgical therapy for PT is required, we suggest consideration of an organ preservative pancreatogastrostomy in grade III/IV trauma of the pancreatic body or tail.

Objective We investigated the activation of pancreatic proenzymes and signs of peripancreatic inflammation in patients with clinically relevant postoperative pancreatic fistulas (POPFs). Summary background data An increase of systemic amylase concentration was associated with POPFs. This suggested parallels in the pathomechanisms between the development of POPFs and pancreatitis. Methods Trypsinogen, procathepsin B, and IL-6 concentrations as well as cathepsin B, myeloperoxidase and trypsin activities were determined throughout the first 7 postoperative days in drain fluids of 128 consecutive patients after pancreas resection. Histology and immunohistochemistry were performed in pancreatic specimens after total pancreatectomy due to complications and after placing experimental pancreatic sutures in the pancreatic tail of C57/Bl6 mice. Results Trypsin activity, cathepsin B activity and myeloperoxidase activity on the first postoperative day were elevated and predictive for clinically relevant pancreatic fistulas. Drain fluid stabilized trypsin activity and prevented the activation of the cascade of digestive enzymes. Leukocytes were the source of cathepsin B in drain fluid. Findings differed between fistulas after distal pancreatectomy and pancreatoduodenectomy. Immunohistochemistry of the pancreatic remnant revealed an inflammatory infiltrate expressing cathepsin B, independent of the presence of pancreatic fistulas. The infiltrate could be reproduced experimentally by sutures placed in the pancreatic tail of C57/Bl6 mice. Conclusions Trypsinogen activation, increased cathepsin B activity and inflammation around the pancreato-enteric anastomosis on post operative day 1 are associated with subsequent clinically relevant POPFs after pancreatoduodenectomy. The parenchymal damage seems to be induced by placing sutures in the pancreatic parenchyma during pancreatic surgery.

Zusammenfassung. Vor dem Hintergrund neuer neurobiologischer und epigenetischer Erkenntnisse erfolgt eine genauere Darstellung des (fachlich oft missverstandenen) «bio-psycho-sozialen» Schmerzverständnisses und seiner Bedeutung für das Verständnis stressinduzierter Schmerzzustände als Grundlage einer individualisierten («personenbezogenen») Schmerztherapie. Daraus werden die Konsequenzen für die Diagnostik bei stressbedingten Schmerzzuständen (z.B. Fibromyalgie-Syndrom, nicht-radikuläre Rückenschmerzen, kraniomandibuläre Dysfunktion, Spannungskopfschmerz) abgeleitet. Vor diesem Hintergrund werden die Prinzipien eines hoch wirksamen bio-psycho-sozialen Therapiekonzept skizziert.

Summary: Background: Many techniques have been developed to prevent postoperative pancreatic fistula (POPF) after distal pancreatectomy, but POPF rates remain high. The aim of our study was to analyze POPF occurrence after closure of the pancreatic remnant by different operative techniques. Methods: Between 2006 and 2017, 284 patients underwent distal pancreatectomy in our institution. For subgroup analysis the patients were divided into hand-sewn (n = 201) and stapler closure (n = 52) groups. The hand-sewn closure was performed in three different ways (fishmouth-technique, n = 27; interrupted transpancreatic U-suture technique, n = 77; common interrupted suture, n = 97). All other techniques were summarized in a separate group (n = 31). Results were gained by analysis of our prospective pancreatic database. Results: The median age was 63 (range 23–88) years. 74 of 284 patients (26%) were operated with spleen preservation (similar rates in subgroups). ASA-classes, median BMI as well as frequencies of malignant diseases, chronic pancreatitis, alcohol and nicotine abuse were also comparable in the subgroups. Neither the rates of overall POPF (fishmouth-technique 30%, common interrupted suture 40%, stapler closure 33% and interrupted U-suture 38%) nor the rates of POPF grades B and C showed significant differences in the subgroups. However is shown to be associated with pancreatic function and parenchymal texture. Conclusion: In our experience the technique of pancreatic stump closure after distal resection did not influence postoperative pancreatic fistula rate. As a consequence patient specific reasons rather than surgical techniques may be responsible for POPF formation after distal pancreatectomy. Keywords: Distal pancreatectomy, Postoperative pancreatic fistula, Hand-sewn, Stapler closure

Background Bio‐absorbable sealants are widely used to reduce the rate and severity of postoperative pancreatic fistulas after distal pancreatectomy. However, numerous clinical trials have failed to demonstrate their clinical benefit. We therefore investigated stability and bio‐compatibility of absorbable sealants in vitro and in vivo. Methods In vitro, polymerized compounds were incubated in pancreatic juice before their stability was tested. In vivo, two compounds were used to seal the pancreatic stump after distal pancreatectomy in nine pigs. Burst pressure of the pancreatic stump, surgical outcome, histology of the pancreatic stump, systemic inflammation, and drain fluid was examined. Results Products based on fibrin or collagen were unstable in the presence of active pancreatic enzymes and completely dissolved within 2 h. Sealants using chemical cross‐linking of proteins showed improved stability for 7 days. In vivo, application of polyethylenglycol‐based sealant leads to complete closure of the pancreatic duct after 5 days, while a glutaraldehyde‐based sealant prevented physiological closure of the pancreatic main duct. Conclusions Many compounds used clinically to reinforce the pancreatic stump after distal pancreatectomy are inadequate due to instability in the presence of pancreatic enzymes. While selected bio‐absorbable sealants inhibited the natural healing of the pancreatic stump, polyethylenglycol‐based sealants should be tested in further clinical trials.

Simple Summary During the last several years, gastric cancer has been extensively studied on the molecular level and distinct molecular subtypes have been defined accordingly. Here, we review the current data on targeted treatment approaches for advanced or metastatic gastric cancer based on molecular alterations or immunological features, ranging from clinically approved treatment strategies to more innovative concepts which are currently in preclinical or clinical development. Information on the translational context and methodology is also provided, holding promise for the further improved development of personalized treatment strategies in the future. Abstract Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed.

Laparoscopic resections of the pancreatic head are increasingly performed. Several studies show that they are comparable to open operations in terms of postoperative morbidity. However, since a substantial proportion of pancreatic head resections are necessary for pancreatic adenocarcinoma the oncologic safety and outcome of minimally invasive operations is of interest. In this study we evaluated oncologic outcome and survival after laparoscopically assisted pancreatic head resection for ductal adenocarcinoma.Perioperative and oncological outcome of sixty-two laparoscopically assisted pancreatic head resections for pancreatic ductal adenocarcinoma performed between 2010 and 2016 was compared to outcome of 278 open resections between 2001 and 2016 in a retrospective study. Data was continuously collected in a prospectively maintained database.Operation time was significantly longer in the laparoscopic group (477 vs. 428 min. p 0.001). Tumor size, lymph node yield and lymph node state and need of portal vein resection were comparable. There was a higher rate of free resection margins in the laparoscopic group (87% vs. 71%, p 0.01). There was no difference in postoperative mortality and morbidity. Patients with laparoscopic resection stayed in hospital significantly shorter (median 14 vs. 16 days, p 0.003). Postoperative survival after 5 years was not different in both groups.Laparoscopically assisted resection of adenocarcinoma of the pancreatic head is equal to open resection concerning oncologic outcome and actuarial survival. However, minimally invasive resection shortened the hospital stay. However, further evaluations with a longer follow up time are needed.

Carcinosarcomas are rare biphasic neoplasms with distinct malignant epithelial and mesenchymal components. Most commonly, carcinosarcomas arise in the uterus as malignant mixed müllerian tumors, but also infrequently appear in other organs such as the ovaries and breast, the prostate and urinary tract, the lungs, or in the gastrointestinal system, among others. Pancreatic carcinosarcomas are exceedingly rare; only a few cases are reported in the English literature. Their pathogenesis remains to be fully clarified. We present here the case of a pancreatic carcinosarcoma with evidence for monoclonality via determination of Kras mutational status after microdissection and suggest a common origin of the 2 tumor components. Comprehensive review of the available literature allows the conclusion that most pancreatic carcinosarcomas appear to be of monoclonal origin and seem to have arisen from a carcinoma via metaplastic transformation of 1 part or subclone of the tumor, probably by epithelial-mesenchymal transition. All reported patients were treated with surgery. Adjuvant therapy, if administered, consisted predominantly of gemcitabine. Prognosis for this neoplasm occurs to be similar or even worse compared with classic pancreatic ductal adenocarcinoma. Despite the lack of evidence-based recommendations for its treatment, resection should be performed, if possible.

BACKGROUND AND AIM: Desmoplasia is a characteristic feature and a suspected mechanism of tumor progression in pancreatic ductal adenocarcinoma (PDAC). Main constituents of the stroma involve cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM). The aim of this study was to dissect the interaction of CAFs, ECM, and PDAC cells in both an in vitro setting and a large-scale clinical cohort study. METHODS AND MATERIAL: Patients operated for PDAC were identified from our prospectively maintained clinical database. A standard pathology protocol was applied for pancreatoduodenectomy specimens also assessing CAF activation as either CAF grade 0 or CAF grade +. Interaction between a spectrum of pancreatic cancer cell lines (PCCs) and mouse embryonic fibroblasts (NIH 3T3) was assessed in a conditioned medium experimental setup. RESULTS: One hundred eleven patients operated for PDAC from 2001 to 2011 were identified. Univariate analysis disclosed CAF grade + ( P = .030), positive M status ( P 0.1 ( P = .045) to impair overall survival. Independent prognostic factors were CAF grade ( P = .050) and positive M status ( P = .002). CAF grade correlated with N status (CC = 0.206, P = .030), LNR (CC = 0.187, P = .049), tumor size (CC = −0.275, P = .003), and M status (CC = 0.190, P = .045). In the in vitro setting, paracrine effects of pancreatic cancer cell resulted in morphological activation of fibroblasts and tumor cell differentiation–dependent increase of fibroblast growth. Paracrine effects of poorly differentiated PCCs led to an upregulation of Vimentin in NIH 3T3 fibroblasts. Paracrine effects of fibroblasts on their part promoted cancer cell motility in all PCCs. As the second stromal component, fibroblast-derived ECM resulted in significantly decreased proliferation depending on density and led to upregulation of ZEB1 in poorly differentiated PCCs. CONCLUSION: In PDAC patients, positive CAF grading was identified as a negative prognostic parameter correlating with positive N status, high LNR, positive M status, and smaller tumor size. Whereas bilateral interaction of PCCs and CAFs promotes tumor progression, ECM poses PCC growth restrictions. In summary, our study discloses differential effects of stromal components and may help to interpret heterogeneous results of former studies.

In esophageal surgery, total minimally invasive techniques compete with hybrid and robot-assisted procedures. The benefit of the individual techniques for the patient remains vague. At our institution, the hybrid minimally invasive laparoscopic-thoracotomic esophagectomy (HMIE) has been routinely applied since 2013. We conducted this retrospective study to analyze the perioperative outcome. Since 2013, 60 patients were operated in HMIE technique for esophageal cancer. Each of these patients was paired according to the criteria of gender, BMI, age, tumor histology, pulmonary preexisting conditions, and a history of smoking with a patient treated by open esophagectomy (OE). Perioperative parameters were extracted from our prospectively maintained database and compared among the groups. The HMIE and OE groups were homogeneous in terms of patient- and tumor-related data. There was no difference in lymph nodes harvested (22 vs. 20, p = 0.459) and R0-resection rate (95 vs. 93%, p = 0.500). The operation time for the HMIE was significantly shorter (329 vs. 407 min, p

The aim of this study was to assess intraoperative, postoperative, and oncologic outcome in patients undergoing laparoscopic distal pancreatectomy (LDP) versus open distal pancreatectomy (ODP) for benign and malignant lesions of the pancreas. Data from patients undergoing distal pancreatic resection were extracted from the StuDoQ|Pancreas registry of the German Society for General and Visceral Surgery. After propensity score case matching, groups of LDP and ODP were compared regarding demography, comorbidities, operative details, histopathology, and perioperative outcome. At the time of data extraction, the StuDoQ|Pancreas registry included over 3000 pancreatic resections from over 50 surgical departments in Germany. Data from 353 patients undergoing ODP (n = 254) or LDP (n = 99) from September 2013 to February 2016 at 29 institutions were included in the analysis. Baseline data showed a strong selection bias in LDP patients, which disappeared after 1:1 propensity score matching. A comparison of the matched groups disclosed a significantly longer operation time, higher rate of spleen preservation, more grade A pancreatic fistula, shorter hospital stay, and increased readmissions for LDP. In the small group of patients operated for pancreatic cancer, a lower lymph node yield with a lower lymph node ratio was apparent in LDP. LDP needed more time but potential advantages include increased spleen preservation and shorter hospital stay, as well as a trend for less transfusion, ventilation, and mortality. LDP for pancreatic cancer was performed rarely and will need critical evaluation in the future. Data from a prospective randomized registry trial is needed to confirm these results.

Nodal status is a strong prognostic factor after resection of pancreatic cancer. The lymph node ratio (LNR) has been shown to be superior to the pN status in several studies. The role of log odds of the ratio between positive and negative nodes (LODDS) as a suggested new indicator of prognosis, however, has been hardly evaluated in pancreatic cancer. Prognostic factors for overall survival after resection for cancer of the pancreatic head were evaluated in 409 patients from two institutions (prospectively maintained databases). The lymph node status, LNR, and LODDS were separately analyzed and independently compared in multivariate survival analysis. The median numbers of examined and positive lymph nodes were 16 and 2, respectively. Actuarial 3- and 5-year survival rates were 29 and 16 %. All three classifications of nodal disease significantly predicted survival in the entire group (n = 409), in patients with free resection margins (n = 297), and in patients with

Pancreatoduodenectomy (PD) with superior mesenteric/portal venous resection (PVR) for pancreatic ductal adenocarcinoma (PDAC) is performed routinely in case of tumor adhesion to the superior mesenteric or portal vein. True histopathological portal vein invasion (PVI) is found in a subgroup of patients. Even though this procedure has become routine in most centers for pancreatic surgery, data on prognostic factors in this situation is limited. The aim of this study was to identify prognostic factors after PD with PVR for PDAC. Retrospective analysis was performed on the basis of a prospectively maintained database, and paraffin-embedded formalin-fixed tissue slides stained for hematoxylin-eosin were re-evaluated by two independent pathologists. Statistical analysis was conducted using MedCalc software. From 2001 to 2012, 86 cases of PD with PVR for PDAC with long-term follow-up and sufficient tissue for re-assessment were identified. Histopathological re-review disclosed PVI in 39 resection specimens and adhesion without infiltration in 47. Overall median survival in all patients was 22 months. Patients with PVI versus no PVI showed comparable baseline demographic and standard histopathological parameters; however, PVI was associated with microscopic hemangiosis (p = 0.001) and positive margin status (p = 0.001). Median survival in patients with PVI was 14 months versus 25 months in patients without PVI (p = 0.042). Only lymph node ratio and PVI were independent predictors of survival after resection. The only independent factors influencing overall survival after PD with PVR for PDAC were lymph node ratio and PVI. PVI might indicate aggressive tumor biology, but the available data remains controversial.

OBJECTIVES Ischemia/reperfusion injury (IRI) of the pancreas is a serious complication following pancreatic transplantation and hemorrhagic shock. The present study was designed to investigate the influence of the potent mammalian target of rapamycin inhibitor everolimus interfering via microvascular permeability changing key proteins hypoxia-inducible factor (HIF) and vascular endothelial growth factor on pancreatic IRI-induced microvascular disturbances. METHODS Anesthetized male Sprague-Dawley rats were assigned to 3 groups (n = 7/group): (1) sham, (2) 60-minute ischemia/reperfusion of the pancreas (I/R), and (3) I/R and everolimus (10 mg/kg BW orally). Quantification of the effective microvascular permeability (P), functional capillary density (FCD), and leukocyte-endothelial cell interaction (LEI) was performed using digital and analog intravital epifluorescence microscopy. Serum-amylase, lipase, interleukin 6, and vascular endothelial growth factor concentration were quantified using enzyme-linked immunosorbent assay. RESULTS Sham compared with I/R (P: [×10 cm/s] 0.068 ± 0.079 vs 1.516 ± 0.314; FCD: [cm/cm] 357 ± 14 vs 258 ± 13; LEI: [cells/mm] 148 ± 25 vs 349 ± 75) demonstrates a significant increase in microcirculatory damage and all previously mentioned serum parameters. Except amylase, I/R + everolimus led to a statistically significant improvement of almost all increased parameters (P: 0.434 ± 0.296, FCD: 347 ± 16, LEI: 178 ± 30). CONCLUSIONS Everolimus attenuated experimental microvascular and inflammatory IRI of the pancreas. Therefore, these results may warrant further investigation of everolimus as a therapeutic agent following clinical states with pancreatic ischemia/reperfusion.

Adeno-associated virus (AAV) vectors have gained tremendous attention as in vivo delivery systems in gene therapy for inherited monogenetic diseases. First market approvals, excellent safety data, availability of large-scale production protocols, and the possibility to tailor the vector towards optimized and cell-type specific gene transfer offers to move from (ultra) rare to common diseases. Cancer, a major health burden for which novel therapeutic options are urgently needed, represents such a target. We here provide an up-to-date overview of the strategies which are currently developed for the use of AAV vectors in cancer gene therapy and discuss the perspectives for the future translation of these pre-clinical approaches into the clinic.

The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors1. Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways1-7. Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro8. Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers., This work was supported by grants from Deutsche Forschungsgemeinschaft (DFG AL1174/5-1 to H.A. and LE3222/1-1 to M.L.), Deutsche Krebshilfe (no. 111646 and no. 111464 to H.A.; Max Eder Program no. 111273 to M.R.), the Wilhelm Sander Stiftung (2014.052.1 to H.A.) and the Fundación Asociación Española Contra el Cáncer (to B.S.).

Empirically, different strategies have evolved for the treatment of locally advanced colon cancer (surgery followed by adjuvant chemotherapy) compared to locally advanced rectal cancer (neoadjuvant radio- or radiochemotherapy followed by total mesorectal excision followed by adjuvant chemotherapy). These differences are mostly attributable to the anatomical situation which poses an increased risk of local recurrence in locally advanced rectal cancer compared to colon cancer. On the other hand, in the metastatic setting, the treatment strategies are very much the same for colon carcinomas and rectum carcinomas, and the clinical outcome is generally similar [8]. Based on differences that exist between the normal right and left colon with respect to embryonic origin (midgut vs. hindgut) and some histological features [7], the question was raised whether colon cancer can be distinguished from rectal cancer based on molecular and/or biochemical differences.

Esophageal cancers are highly aggressive tumors with poor prognosis despite some recent advances in surgical and radiochemotherapy treatment options. This study addressed the feasibility of drugs targeting epigenetic modifiers in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) cells. We tested inhibition of histone deacetylases (HDACs) by SAHA, MS-275, and FK228, inhibition of DNA methyltransferases by Azacytidine (AZA) and Decitabine (DAC), and the effect of combination treatment using both types of drugs. The drug targets, HDAC1/2/3 and DNMT1, were expressed in normal esophageal epithelium and tumor cells of ESCC or EAC tissue specimens, as well as in non-neoplastic esophageal epithelial (Het-1A), ESCC (OE21, Kyse-270, Kyse-410), and EAC (OE33, SK-GT-4) cell lines. In vitro, HDAC activity, histone acetylation, and p21 expression were similarly affected in non-neoplastic, ESCC, and EAC cell lines post inhibitor treatment. Combined MS-275/AZA treatment, however, selectively targeted esophageal cancer cell lines by inducing DNA damage, cell viability loss, and apoptosis, and by decreasing cell migration. Non-neoplastic Het-1A cells were protected against HDACi (MS-275)/AZA treatment. RNA transcriptome analyses post MS-275 and/or AZA treatment identified novel regulated candidate genes (up: BCL6, Hes2; down: FAIM, MLKL), which were specifically associated with the treatment responses of esophageal cancer cells. In summary, combined HDACi/AZA treatment is efficient and selective for the targeting of esophageal cancer cells, despite similar target expression of normal and esophageal cancer epithelium, in vitro and in human esophageal carcinomas. The precise mechanisms of action of treatment responses involve novel candidate genes regulated by HDACi/AZA in esophageal cancer cells. Together, targeting of epigenetic modifiers in esophageal cancers may represent a potential future therapeutic approach.

Therapy resistance is a major clinical problem in cancer medicine and crucial for disease relapse and progression. Therefore, the clinical need to overcome it, particularly for aggressive tumors such as pancreatic cancer, is very high. Aberrant activation of an epithelial–mesenchymal transition (EMT) and an associated cancer stem cell phenotype are considered a major cause of therapy resistance. Particularly, the EMT-activator ZEB1 was shown to confer stemness and resistance. We applied a systematic, stepwise strategy to interfere with ZEB1 function, aiming to overcome drug resistance. This led to the identification of both its target gene miR-203 as a major drug sensitizer and subsequently the class I HDAC inhibitor mocetinostat as epigenetic drug to interfere with ZEB1 function, restore miR-203 expression, repress stemness properties, and induce sensitivity against chemotherapy. Thereby, mocetinostat turned out to be more effective than other HDAC inhibitors, such as SAHA, indicating the relevance of the screening strategy. Our data encourage the application of mechanism-based combinations of selected epigenetic drugs with standard chemotherapy for the rational treatment of aggressive solid tumors, such as pancreatic cancer.

Background and Aim Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive biology and poor prognosis even after resection. Long-term survival is very rare and cannot be reliably predicted. Experimental data suggest an important role of epithelial-mesenchymal transition (EMT) in invasion and metastasis of PDAC. Tumor budding is regarded as the morphological correlate of local invasion and cancer cell dissemination. The aim of this study was to evaluate the biological and prognostic implications of EMT and tumor budding in PDAC of the pancreatic head. Methods Patients were identified from a prospectively maintained database, and baseline, operative, histopathological, and follow-up data were extracted. Serial tissue slices stained for Pan-Cytokeratin served for analysis of tumor budding, and E-Cadherin, Beta-Catenin, and Vimentin staining for analysis of EMT. Baseline, operative, standard pathology, and immunohistochemical parameters were evaluated for prediction of long-term survival (≥ 30 months) in uni- and multivariate analysis. Results Intra- and intertumoral patterns of EMT marker expression and tumor budding provide evidence of partial EMT induction at the tumor–host interface. Lymph node ratio and E-Cadherin expression in tumor buds were independent predictors of long-term survival in multivariate analysis. Conclusions Detailed immunohistochemical assessment confirms a relationship between EMT and tumor budding at the tumor–host interface. A small group of patients with favorable prognosis can be identified by combined assessment of lymph node ratio and EMT in tumor buds.

The value of extended resection (portal vein, multivisceral) in patients with pancreatic adenocarcinoma (PDAC) is not well defined. We analyzed the outcome after standard resection (standard pancreaticoduodenectomy (SPR)), additional portal vein (PV) and multivisceral (MV) resection in PDAC patients.Clinicopathologic, perioperative, and survival data of patients undergoing pancreatic head resection (PHR) for PDAC 1994-2014 were reviewed from a prospective database.Three hundred fifty nine patients had PHR for PDAC: 208 (58 %) underwent SPR, 131 (36 %) additional PV, and 20 (6 %) MV. The postoperative complication rate in MV (65 %) was slightly higher than in PV (56 %) or SPR (50 %; p = 0.32). MV patients had higher in-hospital mortality (10 %) than SPR (3.8 %) and PV (1.5 %) patients (p = 0.12). Nodal status was comparable, whereas more patients in PV and MV had final R0 resection (p = 0.02). Five-year survival was 7 % after MV versus 17 % in patients without MV (p = 0.07). Multivariate survival analysis identified resection margin, nodal disease, blood transfusions, and MV are set as independent risk factors for overall survival.Multivisceral pancreatic head resections for PDAC are associated with increased perioperative morbidity and mortality, without improving oncologic outcome. Portal vein resection can be performed safely to reach R0 resection and its survival benefits.

Background: Minimal-access video-assisted thyroidectomy (MIVAT) has now become a widespread technique in the treatment of benign thyroid disease. No studies systematically investigate risk factors for postoperative complications. The aim of our study was to investigate possible risk factors for postoperative complications in MIVAT in patients with benign disease. Methods: One-hundred eighty-nine patients who underwent MIVAT for benign disease were retrospectively identified in a prospectively-maintained institutional register of thyroid surgery. Exclusion criteria were: (1) thyroid volume>45 mL; (2) malignant disease; (3) prior neck surgery; (4) prior neck irradiation; (5) nodule size>3 cm; (6) intrathoracic component; (7) follow-up

Adipose tissue plays a pivotal role, both in the regulation of energy homeostasis and as an endocrine organ. Consequently, adipose tissue dysfunction is closely related to insulin resistance, morbid obesity, and metabolic syndrome. To study molecular mechanisms and to develop novel therapeutic strategies, techniques are required to genetically modify mature adipocytes. Here, we report on adeno-associated viral (AAV) vectors as a versatile tool to transduce human mature adipocytes in organotypic three-dimensional tissue cultures.

Modern chemotherapy (CTX) increases survival in stage IV colorectal cancer. In colorectal liver metastases (CLM), neoadjuvant (neo) CTX may increase resectability and improve survival. Due to widespread use of CTX in CLM, recent studies assessed the role of the hepatic margin after CTX, with conflicting results. We evaluated the outcome after resection of CLM in relation to CTX and hepatic resection status.Since 2000, 334 patients with first hepatic resection for isolated CLM were analyzed. Thirty-two percent had neoadjuvant chemotherapy (targeted therapy in 42%). Sixty-eight percent never had CTX before hepatectomy or longer than 6 months before resection. The results were gained by analysis of our prospective database.Positive hepatic margins occurred in 8% (independent of neoCTx). Patients after neoCTX had higher numbers of CLM (p 0.01) and a longer duration of surgery (p 0.03). After hepatectomy, 5-year survival was 45% and correlated strongly with the margin status (47% in R-0 and 21% in R-1; p 0.001). Survival also correlated with margin status in the subgroups with neoCTX (p 0.01) or without neoCTx (p 0.01). In multivariate analysis of the entire group, hepatic margin status (RR 3.2; p 0.001) and age 65 years (RR 1.6; p 0.01) were associated with poorer survival. In the subgroup of patients after neoCTX (n = 106), only the resection margin was an independent predictor of survival (p 0.001).In patients with isolated colorectal liver metastases undergoing resection, the hepatic margin status was the strongest independent prognostic factor. This effect was also present after neoadjuvant chemotherapy for CLM.

Summary Background There is substantial uncertainty regarding the optimal surgical treatment for chronic pancreatitis. Short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy. Therefore, we designed the multicentre ChroPac trial to investigate the long-term outcomes of patients with chronic pancreatitis within 24 months after surgery. Methods This randomised, controlled, double-blind, parallel-group, superiority trial was done in 18 hospitals across Europe. Patients with chronic pancreatitis who were planned for elective surgical treatment were randomly assigned to DPPHR or partial pancreatoduodenectomy with a central web-based randomisation tool. The primary endpoint was mean quality of life within 24 months after surgery, measured with the physical functioning scale of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Primary analysis included all patients who underwent one of the assigned procedures; safety analysis included all patients who underwent surgical intervention (categorised into groups as treated). Patients and outcome assessors were masked to group assignment. The trial was registered, ISRCTN38973832. Recruitment was completed on Sept 3, 2013. Findings Between Sept 10, 2009, and Sept 3, 2013, 250 patients were randomly assigned to DPPHR (n=125) or partial pancreatoduodenectomy (n=125), of whom 226 patients (115 in the DPPHR group and 111 in the partial pancreatoduodenectomy group) were analysed. No difference in quality of life was seen between the groups within 24 months after surgery (75·3 [SD 16·4] for partial pancreatoduodenectomy vs 73·0 [16·4] for DPPHR; mean difference −2·3, 95% CI −6·6 to 2·0; p=0·284). The incidence and severity of serious adverse events did not differ between the groups. 70 (64%) of 109 patients in the DPPHR group and 61 (52%) of 117 patients in the partial pancreatoduodenectomy group had at least one serious adverse event, with the most common being reoperations (for reasons other than chronic pancreatitis), gastrointestinal problems, and other surgical morbidity. Interpretation No differences in quality of life after surgery for chronic pancreatitis were seen between the interventions. Results from single-centre trials showing superiority for DPPHR were not confirmed in the multicentre setting. Funding German Research Foundation (DFG).

Solid pancreatic lesions found on imaging procedures are suspicious for malignancy and, therefore, demand immediate diagnostic evaluation and therapy. In the case of indeterminate histology, a primary resection should be considered in order to preserve the possibility of curative surgery, although rare entities may be initially disregarded. We present here the case of a 48-year-old female patient with a hypoechoic lesion of the pancreatic head, which was clearly delineated from the surrounding pancreatic tissue. The challenging diagnosis of metastatic leiomyosarcoma could only be established by considering the long-term clinical history and former histology specimens.

Laparoscopic sleeve gastrectomy (LSG) can achieve excellent weight loss, yet sleeve dilatation with concomitant weight regain proves to be a relevant issue. Hence, additional restriction might improve results after LSG. In a retrospective matched-pair analysis, 42 patients who underwent banded LSG (BLSG) using a MiniMizer® ring between January 2012 and October 2014 were analysed regarding weight loss, complications and comorbidity. Median follow-up was 3 years. Forty-two patients who had undergone conventional LSG were selected as matched pairs. Mean preoperative BMI was 54.93 ± 7.42 kg/m2 for BLSG and 53.46 ± 6.69 kg/m2 for LSG (Mann-Whitney P = 0.540). Total weight loss (%TWL) was significantly greater in the BLSG group 3 years after surgery (BLSG 38.22% ± 7.26; n = 26 vs. LSG 32.69 ± 9.47; n = 26; P = 0.0154). Ring placement had no relevant impact on new-onset reflux (Fisher’s exact test P = 1.0) but a tendency towards reflux improvement when reflux pre-existed (odds ratio 1.96). The major side effect of ring implantation was regurgitation with over 44% of patients presenting with regurgitation >1 per week (Fisher’s exact test P = 0.0019, odds ratio 18.07). BLSG is a safe procedure showing similar comorbidity to conventional LSG. However, BLSG leads to a higher rate of postoperative regurgitation. Weight loss is significantly improved 3 years after surgery. Hence, additional ring implantation might be an option for increased restriction in LSG surgery.

Pancreatoduodenectomy is the most common operative procedure performed for distal bile duct carcinoma. Data on outcome after surgery for this rare malignancy is scarce, especially from western countries. The purpose of this study is to explore the prognostic factors and outcome after pancreatoduodenectomy for distal bile duct carcinoma. Patients receiving pancreatoduodenectomy for distal bile duct carcinoma were identified from institutional databases of five German and one Russian academic centers for pancreatic surgery. Univariable and multivariable general linear model, Kaplan-Meier method, and Cox regression were used to identify prognostic factors for postoperative mortality and overall survival. N = 228 patients operated from 1994 to 2015 were included. Reoperation (OR 5.38, 95%CI 1.51–19.22, p = 0.010), grade B/C postpancreatectomy hemorrhage (OR 3.73, 95%CI 1.13–12.35, p = 0.031), grade B/C postoperative pancreatic fistula (OR 4.29, 95%CI 1.25–14.72, p = 0.038), and advanced age (OR 4.00, 95%CI 1.12–14.03, p = 0.033) were independent risk factors for in-hospital mortality in multivariable analysis. Median survival was 29 months, 5-year survival 27%. Positive resection margin (HR 2.07, 95%CI 1.29–3.33, p = 0.003), high tumor grade (HR 1.71, 95%CI 1.13–2.58, p = 0.010), lymph node (HR 1.68, 95%CI 1.13–2.51, p = 0.011), and distant metastases (HR 2.70, 95%CI 1.21–5.58, p = 0.014), as well as severe non-fatal postoperative complications (HR 1.64, 95%CI 1.04–2.58, p = 0.033) were independent negative prognostic factors for survival in multivariable analysis. Distant metastases and positive resection margin are the strongest negative prognostic factors for survival after pancreatoduodenectomy for distal bile duct carcinoma; thus, surgery with curative intent is only warranted in patients with local disease, where R0 resection is feasible.

Hospital and surgeon volume are potential factors influencing postoperative mortality and morbidity after pancreatic resection. Data on perioperative outcome of individual surgeons in different institutions, however, are scarce. We evaluated the perioperative outcome after pancreatic head resections (PHR) performed by a high-volume pancreatic surgeon in a high-volume university department and (later) in a community hospital with low prior experience in major pancreatic surgery. We compared the results after PHR were performed by a single experienced surgeon between 2001 and October 2006 in a specialized unit of a German university hospital (n = 83; group A) with the results after PHR were performed in a community hospital between November 2006 and 2011 (n = 145; group B). Before the study period (−2001), the surgeon already had a personal caseload of >200 PHR. In addition to the 228 PHR analyzed here, the surgeon also had taught further >150 PHR to residents and consulting surgeons. Comparable surgical and perioperative techniques were applied in both series (e.g., types of resection and reconstruction, abdominal drains, early enteral feeding). The data of both series were prospectively recorded in SPSS databases. The median age of the patients was lower in group A (58 vs. 66 years in B; p

To investigate the limited benefit of antibiotics in ameliorating the outcome of acute necrotizing pancreatitis, we analyzed antibiotic therapy in primarily infected necrotizing pancreatitis in mice with respect to the local pancreatic pathology as well as systemic, pancreatitis induced adverse events.Sterile pancreatic necrosis (SN) was induced by retrograde injection of 4% taurocholate in the common bile duct of Balb/c mice. Primarily infected pancreatic necrosis (IN) was induced by co-injecting 10(8) CFU/ml Escherichia coli. 10 mg/kg of moxifloxacin was administered prior to pancreatitis induction (AN). After 24 h, animals were sacrificed to examine serum as well as organs for signs of SIRS.Moxifloxacin significantly reduced bacterial count in pancreatic lysates of animals with infected pancreatic necrosis (IN 4.1·10(7) ± 2.4·10(7) vs. AN 4.9·10(4) ± 2.6·10(4) CFU/g; p 0.001). However, it did not alter pancreatic histology or pulmonary damage (Histology score: IN 23.8 ± 2.7 vs. AN 22.6 ± 1.7). Moxifloxacin reduced systemic immunoactivation (Serum IL-6: IN 330.5 ± 336.6 vs. 38.7 ± 25.5 pg/ml; p 0.001), hypoglycemia (serum glucose: IN 105.8 ± 12.7 vs. AN 155.7 ± 39.5 mg/dl; p 0.001), and serum aspartate aminotransferase (IN 606 ± 89.7 vs. AN 255 ± 52.1; p 0.05). These parameters were significantly increased in animals with necrotizing pancreatitis.In the experimental setting, initial antibiotic therapy with moxifloxacin in acute infected necrotizing pancreatitis in mice does not have a beneficial impact on pancreatic pathology or pulmonary damage. However, other systemic complications induced by infected necrosis in acute pancreatitis are reduced by the administration of moxifloxacin.

Patients who undergo surgery may develop ulnar neuropathy. Although the mechanism of ulnar neuropathy is still not clear, ulnar neuropathies are common causes of successful lawsuits against surgeons. Recently, the concept developed that endogenous patient factors can lead to postoperative peripheral neuropathies. We hypothesize that dynamic ulnar nerve dislocation at the elbow (DUNDE) may be a predisposing factor for ulnar irritation (i.e. neuropathy) in normal subjects. In a prospective investigation, patients aged 20 years and older presenting in our emergency department were asked to participate. Three physicians examined both elbows of subjects included in our study for evidence of DUNDE (through clinical and sonographic examination) and for clinical symptoms related to ulnar neuropathy. Dynamic ulnar nerve dislocation was observed in 29.3 % of examined subjects. No significant difference in its occurrence was observed in relation to gender or dominant side. Physical examination with provocation tests demonstrated significantly more positive Tinel tests and spontaneous signs of neuropathy in patients with dynamic dislocating ulnar nerves (14.7 vs. 1.1 %). Dynamic ulnar nerve dislocation may be linked to ulnar nerve irritability (i.e. ulnar neuropathy) in normal subjects without history of trauma, surgical procedure, or anesthesia. Considering the high incidence of this variant in the general population, our study supports previous investigations suggesting that many postoperative ulnar nerve deficits are traceable to chronic patient conditions. Our study suggests that dynamic ulnar nerve dislocation is a predisposing factor in the development of ulnar neuropathy in the postoperative period. (1) neuropathy should be viewed as a broad definition as signs of nerve irritation/inflammation, and independently of the pathophysiology and etiology; (2) because no specific term exists in the international anatomic nomenclature (Nomina Anatomica) to designate this variant, several synonyms have been used in the literature, leading to confusion and misleading conclusions concerning its traumatic etiologies and their consequences: (a) recurrent or habitual ulnar nerve luxation (or subluxation) [1–3]; (b) recurrent or habitual ulnar nerve dislocation [4–7]; (c) ulnar nerve instability [8]; (d) laxity of the ulnar nerve [9]; and (e) ulnar nerve hypermobility [10].

The aim of our study was the analysis of long-term sequelae of emotional parentification in childhood. Two samples (n = 500 each) were examined via the internet regarding parentification and perceived love in childhood, as well as other childhood experiences such as abuse, having been raised by a single parent and parental loss, as well as adult depressive and vegetative symptoms and pain. A questionnaire set containing 280 items was filled out. Emotional parentification in childhood, maternal as well as paternal, was found to be a strong predictor of depression in adulthood. Indicators of somatization showed associations in the same direction, but these were much weaker. Also, associations between paternal parentification and vegetative symptoms, as well as between maternal parentification and pain in adulthood could be observed. Perceived love from the father during childhood was one of the protective factors for development of various problems in adult life. The results indicate the necessity of directing more attention, both clinically and empirically, towards emotional parentification.

Postpancreatectomy hemorrhage is a rare but often severe complication after pancreatic resection. The aim of this retrospective study was to define incidence and risk factors of postpancreatectomy hemorrhage and to evaluate treatment options and outcome. Clinical data was extracted from a prospectively maintained database. Descriptive statistics, univariate and multivariate risk factor analysis by binary logistic regression were performed with SPSS software at a significance level of p = 0.05. N = 1,082 patients with pancreatic resections between 1994 and 2012 were included. Interventional angiography was successful in about half of extraluminal bleeding. A total of 78 patients (7.2 %) had postpancreatectomy hemorrhage (PPH), and 29 (2.7 %) were grade C PPH. Multivariate modeling disclosed a learning effect, age, BMI, male sex, intraoperative transfusion, portal venous and multivisceral resection, pancreatic fistula and preoperative biliary drainage as independent predictors of severe postpancreatectomy hemorrhage. High-risk histopathology, age, transfusion, pancreatic fistula, postpancreatectomy hemorrhage and pancreatojejunostomy in pancreatoduodenectomies were independent predictors of mortality. Our study identifies clinically relevant risk factors for postpancreatectomy hemorrhage and mortality. Interventional treatment of extraluminal hemorrhage is successful in about half of the cases and if unsuccessful constitutes a valuable adjunct to operative hemostasis. Based on our observations, we propose a treatment scheme for PPH. Risk factor analysis suggests appropriate patient selection especially for extended resections and pancreatogastrostomy for reconstruction in pancreatoduodenectomy.

Background: The study was done to compare treatment and long‐term outcomes of neoadjuvant chemoradiation (neoCRT) and perioperative chemotherapy (periCTX) in patients with surgically treated esophageal adenocarcinoma. Methods: An analysis of 105 patients with esophageal adenocarcinoma undergoing neoCRT (n ¼58) or periCTX (n ¼47) and esophagectomy between 2000 and 2012 was carried out. Results: The overall median survival was 5.97 years. Postoperative morbidity and in‐hospital mortality occurred in 74%/7% of the patients the neoCRT group and in 53%/0% of the patients in the periCTX group (P ¼0.03/P ¼0.08). Total or subtotal histological tumor response after neoadjuvant treatment and esophagectomy was found in 59% after neoCRT and 30% after periCTX (P

OBJECTIVE Infection of pancreatic necrosis in necrotizing pancreatitis increases the lethality of patients with acute pancreatitis. To examine mechanisms underlying this clinical observation, we developed and tested a model, in which primary infection of necrosis is achieved in taurocholate-induced pancreatitis in mice. METHODS Sterile necrosis of acute necrotizing pancreatitis was induced by retrograde injection of 4% taurocholate into the common bile duct of Balb/c mice. Primary infection of pancreatic necrosis was induced by coinjecting 10 colony-forming units of Escherichia coli. Animals were killed after 6, 12, 24, 48, and 120 hours, and pancreatic damage and pancreatitis-associated systemic inflammatory response were assessed. RESULTS Mice with pancreatic acinar cell necrosis had an increased bacterial concentration in all tissues and showed sustained bacteremia. Acute pancreatitis was induced only by coinjection of taurocholate and not by bacterial infection alone. Infection of pancreatic necrosis increased pancreatic damage and the pulmonary vascular leak. Serum glucose concentrations serving as a parameter of hepatic function were reduced in mice with infected pancreatic necrosis. CONCLUSIONS Primary infection of pancreatic necrosis with E. coli increases both pancreatic damage and pulmonary and hepatic complications in acute necrotizing pancreatitis in mice.

It has been shown that crystalloid fluid-overload promotes anastomotic instability. As physiologic anastomotic healing requires the sequential infiltration of different cells, we hypothesized this to be altered by liberal fluid regimes and performed a histomorphological analysis.36 Wistar rats were randomized into 4 groups (n=8-10 rats/group) and treated with either liberal (+) or restrictive (-) perioperative crystalline (Jonosteril = Cry) or colloidal fluid (Voluven = Col). Anastomotic samples were obtained on postoperative day 4, routinely stained and histophathologically reviewed. Anastomotic healing was assessed using a semiquantitative score, assessing inflammatory cells, anastomotic repair and collagenase activity.Overall, the crystalloid overload group (Cry (+)) showed the worst healing score (P0.01). A substantial increase of lymphocytes and macrophages was found in this group compared to the other three (P0.01). Both groups that received colloidal fluid (Col (+) and Col (-)) as well as the group that received restricted crystalloid fluid resuscitation (Cry (-)) had better intestinal healing. Collagenase activity was significantly higher in the Cry (+) group.Intraoperative infusion of high-volume crystalloid fluid leads to a pathological anastomotic inflammatory response with a marked infiltration of leukocytes and macrophages resulting in accelerated collagenolysis.

The study was done to determine long-term outcomes of surgically treated esophageal cancer and to identify trends in epidemiology, oncological therapy, and oncological prognosis over the last two decades.Overall survival in 304 patients undergoing esophagectomy was analyzed. Fifty-three percent had squamous cell carcinoma and 46 % had adenocarcinoma (AC). A total of 161 patients received neoadjuvant chemoradiation, 38 received neoadjuvant chemotherapy, and 105 were treated with surgery alone.Median survival (MS) increased significantly from 18.0 months (1988-1994) to 26.6 months (1995-2001) and to 59.3 months (2002-2011; p 0.001). The proportion of AC (22 vs 35 vs 65 %; p 0.001) and the proportion of patients treated with neoadjuvant therapy (neoT; 15.9 vs 85.3 vs 77.8 %; p 0.001) increased during the treatment period. After neoT, a beneficial outcome with a MS of 45.6 vs. 20.4 months (p = 0.003) was found. Lymph node ratio [LNR; relative risk (RR), 5.4; p 0.001], response to neoT (RR, 1.6; p 0.004), and histological subtype (RR, 1.7; p 0.003) were identified as independent parameters of survival.Since 1988, the outcome of surgically resected esophageal cancer strongly improved. Besides tumorbiological factors like histological type and LNR, the outcome is also affected by the increasing use of neoT towards favorable survival rates.

Background Therapy for systemic complications in severe necrotizing pancreatitis remains symptomatic owing to the unavailability of more specific therapeutic targets. We investigated the differential gene expression in typically affected organs in a mouse model of severe necrotizing pancreatitis. Methods Acute necrotizing pancreatitis was induced in mice by retrograde infusion of taurocholate into the common bile duct. Microarray hybridization was subsequently performed with mRNA isolated from the spleen, liver, intestine, and lungs. Additionally, quantitative real-time polymerase chain reaction was performed to confirm the microarray results. Results Severe necrotizing pancreatitis induced widespread changes in gene expression, affecting 27.20% of the genes tested in the spleen and 29.07% in the liver. Fewer genes were differentially regulated in the intestine (10.28%) and the lungs (10.75%). Only 10 genes were found to be upregulated in all 4 organs using microarray analysis. This upregulation in all organs was confirmed by quantitative real-time polymerase chain reaction for only 3 molecules. These molecules were lipocalin 2, insulin-like growth factor binding protein 1, and CD14. Additionally we observed significantly aberrant gene regulation of inter-α-trypsin inhibitor family members in several organs. Conclusions Differential gene regulation in severe necrotizing pancreatitis is far more organ specific than anticipated, with only 3 molecules uniformly regulated systemically. The inter-α-trypsin inhibitor family of molecules appears to play a crucial biologic role in the systemic inflammatory response in acute pancreatitis. Finally, owing to its regulation and function, α1-microglobulin (or bikunin) may be a suitable predictive marker of the systemic inflammatory response syndrome in acute pancreatitis.

Although advances in multimodal treatment have led to prolongation of survival in patients after resection of colorectal liver metastasis (CRC-LM), most patients develop recurrence, which is often confined to the liver. Repeat hepatic resection (RHR) may prolong survival or even provide cure in selected patients. We evaluated the perioperative and long-term outcomes after RHR for CRC-LM in a single institution series. Since 1999, 92 repeat hepatic resections (63 % wedge/segmental, 37 % hemihepatectomy or greater) for recurrent CRC-LM were performed in 80 patients. Median interval from initial liver resection to first RHR was 1.25 years. Any kind of chemotherapy (CTx) had been given in 88 % before RHR. Neoadjuvant CTx was given in 38 %. Hepatic margin-negative resection was achieved in 79 %. Mortality was 3.8 %. Overall complication rates were 53 %, including infection (17 %), operative re-intervention (12 %), and hepatic failure (5.4 %). Overall 5-year survival after first RHR was 50.3 %. Univariately, primary tumor stage, the extent of liver resection, postoperative complications, and the overall resection margin correlated with survival. By multivariate analysis, primary T stage, size of metastasis, and overall R0 resection influenced survival. Survival was not independently influenced by hepatic resection margins or (neoadjuvant) CTx. Repeat hepatic resection for recurrent CRC-LM can be performed with low mortality and acceptable morbidity. Survival after repeat hepatic resection in this selected group of patients is encouraging and comparable to results after first liver resections.

Background Mesenterico-portal vein resection (PVR) during pancreatoduodenectomy for pancreatic head cancer was established in the 1990s and can be considered a routine procedure in specialized centers today. True histopathologic portal vein invasion is predictive of poor prognosis. The aim of this study was to examine the relationship between mesenterico-portal venous tumor infiltration (PVI) and features of aggressive tumor biology. Methods Patients receiving PVR for pancreatic ductal adenocarcinoma of the pancreatic head were identified from a prospectively maintained database. Immunohistochemical staining of tumor tissue was performed for the markers of epithelial–mesenchymal transition (EMT) E-Cadherin, Vimentin and beta-Catenin. Morphology of cancer-associated fibroblasts (CAFs) was assessed as inactive or activated. Statistical calculations were performed with MedCalc software. Results In total, 41 patients could be included. Median overall survival was 25 months. PVI was found in 17 patients (41%) and was significantly associated with loss of membranous E-Cadherin in tumor buds (p = 0.020), increased Vimentin expression (p = 0.03), activated CAF morphology (p = 0.046) and margin positive resection (p = 0.005). Conclusion Our findings suggest that PVI is associated with aggressive tumor biology and disseminated growth less amenable to margin-negative resection.

Minimally invasive surgery has conquered almost all niches of abdominal surgery. Even though some surgeons have shown equal lymph node ratio and oncologic radicality for laparoscopic surgery of pancreatic cancer, oncologic surgeons still take reasonably conservative views of the use of minimally invasive techniques for the treatment of pancreatic cancer, especially if located in the head of the pancreas. Laparoscopic abdominal approaches on the other hand have a potential advantage of better visualization, decreased postoperative pain, decreased use of analgetics, and shorter hospital stay. We demonstrate in this technical surgical report the first description of a total laparoscopic pancreatoduodenectomy and reconstruction via laparoscopic pancreatogastrostomy in a 74-year-old female patient with a periampullary tumor.After pylorus-preserving pancreatoduodenectomy by superior mesenteric artery, first approach including standard lymphadenectomy, the reconstruction involved total laparoscopic end-to-side running-suture hepaticojejunostomy, double-layer running-suture antecolic pylorojejunostomy to the first jejunal loop, and pancreatogastrostomy via posterior gastrotomy secured by two anchoring and purse-string sutures.

Correct diagnosis, surgical treatment, and perioperative management of patients with esophageal carcinoma remain crucial for prognosis within multimodal treatment procedures. This study aims to achieve a consensus regarding current management strategies in esophageal cancer by questioning a panel of experts from the German Advanced Surgical Treatment Study (GAST) group, comprised of 9 centers specialized in esophageal surgery, with a combined total of >220 esophagectomies per year. The Delphi method, a systematic and interactive, evidence-based approach, was used to obtain consensus statements from the GAST group regarding ambiguities and disparities in diagnosis, patient selection, surgical technique, and perioperative management of patients with esophageal carcinoma. After four rounds of surveys, agreement was measured by Likert scales and defined as full (100% agreement), near (≥66.6% agreement), or no consensus (

BACKGROUND: Intra-abdominal hypertension (IAH) has a high prevalence among critically ill patients. It is increasingly recognised as a risk factor for poor outcome. PATIENTS / MATERIAL AND METHODS: A review of the literature including explicit management instructions was performed. We report the standardised techniques for intra-abdominal pressure (IAP) measurement as well as consensus definitions and treatment recommendations ranging from conservative measures to decompression laparotomy. RESULTS: The abdominal compartment syndrome (ACS) is defined as a sustained IAH > 20 mmHg accompanied by new organ dysfunctions. It occurs predominantly in surgical patients and is asso-ciat-ed with a poor outcome. Organ dysfunctions related to IAH mainly concern the kidneys and -respiratory system. The mechanism of action essentially is a perfusion deficit. Clinical judgement alone does not allow a valid estimate of intra-abdominal pressure. CONCLUSION: In patients at risk the IAP should be measured. In case of IAH conservative options for lowering the pressure are mandatory. Decompression laparotomy should be considered if conservative measures fail.

BackgroundPostoperative pancreatic fistula (POPF) is regarded as the most serious complication of pancreatic surgery. The preoperative risk stratification of patients by simple means is of interest in perioperative clinical management.MethodsBased on prospective data, we performed a risk factor analysis for POPF after pancreatoduodenectomy in 62 patients operated between 2006 and 2008 with special focus on clinical parameters that might serve to predict POPF. A predictive score was developed and validated in an independent second dataset of 279 patients operated between 2001 and 2010.ResultsSeveral pre- and intraoperative factors, as well as underlying pathology, showed significant univariate correlation with rate of POPF. Multivariate analysis (binary logistic regression) disclosed soft pancreatic texture (odds ratio [OR] 10.80, 95% confidence interval [CI] 1.80–62.20) and history of weight loss (OR 0.15, 95% CI 0.04–0.66) to be the only independent preoperative clinical factors influencing POPF rate. The subjective assessment of pancreatic hardness by the surgeon correlated highly with objective assessment of pancreatic fibrosis by the pathologist (r=−0.68, P

A high level of suspicion is necessary to detect postoperative sepsis in good time. It may be difficult to differentiate sepsis from normal SIRS in the postoperative setting. Early signs and symptoms include delirium and respiratory compromise. These should trigger the search for a septic focus aggressively with special attention to the original site of surgery. Key recommendations include early goal-directed resuscitation of the septic patient, administration of broad-spectrum antibiotic therapy within 1 hour of diagnosis, and source control with attention to the balance of risks and benefits of the chosen method. In cases of severe abdominal sepsis the concept of relaparotomy on-demand has become most popular.

The aim of this study was to analyze the predictive value of blood urea nitrogen (BUN) and other variables in acute necrotizing pancreatitis on hospital stay, intensive care unit (ICU) stay, and death.We retrospectively analyzed 118 consecutive case records of patients admitted with acute pancreatitis. Forty-four patients had a severe acute necrotizing pancreatitis and only those were analyzed. We compared variables on admission and in the course of the disease in association to hospital stay, ICU stay, and death.Patients with elevated BUN on admission had a significantly prolonged ICU stay (or =14 days: 32 +/- 25 mg/dL vs14 days: 15 +/- 8 mg/dL; univariate P = .007; multivariate P = .0390; odds ratio, 1.042; 95% confidence interval, 1.002-1.084). Positive and negative predictive values (PPV, NPV) were 89% and 62% with a cutoff at 33 mg/dL. The ICU stay was also significantly prolonged when BUN was elevated in the course of the disease (or =14 days: 60 +/- 33 mg/dL vs14 days: 20 +/- 8 mg/dL; P.0001; PPV 89% and NPV 77%). Mortality in patients with elevated BUN on admission was significantly increased (nonsurvivors: 39 +/- 30 vs survivors: 17 +/- 11 mg/dL; P = .028; PPV 67%, NPV 82%). Later in the course of the disease, elevated BUN was also associated with increased mortality (nonsurvivors: 69 +/- 38 mg/dL vs survivors: 27 +/- 16 mg/dL; P = .003; PPV 56% and NPV 92%).Although not as reliable as complex clinical scoring systems, BUN as a single marker is a useful routine, easy to perform, and a cheap marker to predict ICU stay and probable survival in acute necrotizing pancreatitis.