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Hepatocellular carcinoma (HCC) and pancreatic cancer (PC) belong to the most lethal malignancies worldwide. Despite advances in surgical techniques and perioperative multidisciplinary management, the prognosis of both carcinoma entities remains poor mainly because of rapid tumor progression and early dissemination with diagnosis in advanced tumor stages with poor sensitivity to current therapy regimens. Both highly heterogeneous visceral carcinomas exhibit unique somatic alterations, but share common driver genes and mutations as well. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as non-invasive biomarker in early diagnosis and prognosis. CtDNA released from necrotic or apoptotic cells of primary tumors, metastasis, and circulating tumor cells can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. In this article, we focus on clinical impact of ctDNA as potential biomarker in patients with HCC and PC.

LAPTM4B is upregulated in a wide range of cancers associated with poor prognosis. However, the clinical impact of LAPTM4B as diagnostic and prognostic marker in pancreatic ductal adenocarcinoma (PDAC) remains unknown. Thus, the aim of the present study was to investigate the expression of LAPTM4B as circulating marker in PDAC. Expression analysis of LAPTM4B-35 in pancreatic tissue and preoperative blood serum samples of 169 patients with PDAC UICC Stages I–IV (n = 98), chronic pancreatitis (n = 41), and healthy controls (n = 30) by immunohistochemistry, Western blot, and ELISA. Descriptive and explorative statistical analyses of LAPTM4B-35’s potential as diagnostic and prognostic marker in PDAC. Expression of LAPTM4B-35 was significantly increased in tumor tissue and corresponding blood serum samples of patients with PDAC (each p

Purpose Postoperative pancreatic fistula (POPF) with reported incidence rates up to 45% contributes substantially to overall morbidity. In this study, we conducted a retrospective evaluation of POPF along with its potential perioperative clinical risk factors and its effect on tumor recurrence. Methods Clinical data on patients who had received pancreatoduodenectomy (PD), distal pancreatectomy (DP), or duodenum-preserving pancreatic head resection (DPPHR) were prospectively collected between 2007 and 2016. A Picrosirius red staining score was developed to enable morphological classification of the resection margin of the pancreatic stump. The primary end point was the development of major complications. The secondary end points were overall and recurrence-free survival. Results 340 patients underwent pancreatic resection including 222 (65.3%) PD, 87 (25.6%) DP, and 31 (9.1%) DPPHR. Postoperative major complications were observed in 74 patients (21.8%). In multivariable logistic regression analysis, POPF correlated with body mass index (BMI) (p = 0.025), prolonged stay in hospital (p Conclusion Besides the known clinicopathological risk factors BMI and amylase in the drain fluid, the incidence of POPF correlates with high Picrosirius red staining score in the resection margins of the pancreatic stumps of curatively resected pancreatic ductal adenocarcinoma (PDAC). Furthermore, clinically relevant POPF seems to be a prognostic factor for tumor recurrence in PDAC.

Recently, we identified the microRNA-99 family as unfavorable prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to evaluate its value as circulating biomarker for PDAC. Tissue and corresponding preoperative blood samples of 181 patients with PDAC UICC Stages I–IV (n = 90), intraductal papillary mucinous neoplasm (IPMN, n = 11), chronic pancreatitis (n = 40), pancreatic cystadenoma (n = 20), and age-matched healthy blood serum controls (n = 20) were collected between 2014 and 2017 prospectively. Expression of microRNA-21 as confirmatory marker and the microRNA-99 family, consisting of microRNA-99a, -99b, and -100, was analyzed by qRT-PCR. Target analysis of insulin-like growth factor 1 receptor (IGF1R) was performed using tissue array immunohistochemistry and Western blotting. Expression of microRNA-99 family members was significantly increased in macrodissected tumor tissue and corresponding blood serum samples (p

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases with late diagnosis, rapid progression, high invasiveness, and early metastasis. Epithelial-to-mesenchymal transition (EMT) is a crucial step in metastasis that enables polarized immotile epithelial cells to gain fibroblast-like mesenchymal abilities such as enhanced motility. The dynamic process of EMT in PDAC with its powerful influence on disease progression and especially metastasis is of vigorous interest in biomedical research to elucidate its signaling pathways and regulation mechanisms. It is evident that epigenetics such as histone and DNA modification or noncoding RNAs such as microRNAs and long noncoding RNAs are of high importance in initiation and progress of EMT in PDAC. This review analyzes the latest research dealing with EMT and its epigenetic regulation in PDAC and summarizes its potentials in diagnostic, prognostic, and therapeutic management.

Perforations and anastomotic leakages of the upper gastrointestinal (GI) tract cause a high morbidity and mortality rate. Only limited data exist for endoscopic vacuum therapy (EVT) in the upper GI tract. Fifty-two patients (37 men and 15 women, ages 41–94 years) were treated (12/2011–12/2015) with EVT for anastomotic insufficiency secondary to esophagectomy or gastrectomy (n = 39), iatrogenic esophageal perforation (n = 9) and Boerhaave syndrome (n = 4). After diagnosis, polyurethane sponges were endoscopically positioned with a total of 390 interventions and continuous negative pressure of 125 mm of mercury (mmHg) was applied to the EVT-system. Sponges were changed endoscopically twice per week. Clinical and therapy-related data and mortality were analyzed. After 1–25 changes of the sponge at intervals of 3–5 days with a mean of 6 sponge changes and a mean duration of therapy of 22 days, the defects were healed in 94.2 % of all patients without revision surgery. In three patients (6 %), EVT failed. Two of these patients died due to hemorrhage related to EVT. Four postinterventional strictures were observed during the follow-up of up to 4 years. Esophageal wall defects of different etiology in the upper gastrointestinal tract can be treated successfully with EVT, considering that indication for EVT should be weighed carefully. EVT can be regarded as a novel life-saving therapeutic tool.

OBJECTIVES The diagnosis of pancreatic ductal adenocarcinoma (PDAC) is challenging in the setting of pancreatitis. We investigated SERPINB5 for its impact on PDAC tumor biology and its use as a diagnostic marker for PDAC in the setting of pancreatitis. METHODS Patient samples from PDAC primary tumors, PDAC lymph node metastases, and pancreatitis were investigated for SERPINB5 promoter methylation by methylation-specific polymerase chain reaction (PCR). Six PDAC cell lines were investigated in vitro and in vivo using an orthotopic mouse model to generate primary tumors and metastases. SERPINB5 mRNA expression, protein expression, and promoter methylation were determined by quantitative reverse transcriptase-PCR, methylation-specific PCR, and Western Blot. RESULTS In patient samples, detection of an unmethylated SERPINB5 promoter differentiated pancreatitis from PDAC with a sensitivity of 57% and a specificity of 95% (P < 0.001). SERPINB5 was not deregulated in primary tumors versus metastases, but primary tumors without SERPINB5 protein expression had significantly reduced viability (P = 0.02). CONCLUSIONS SERPINB5 seems to assume an oncogenic role in PDAC. In clinical samples, detection of unmethylated SERPINB5 was a specific marker for PDAC even in the context of pancreatitis and may provide the basis for a liquid biopsy option to detect PDAC.

Ranking among the most lethal tumour entities, pancreatic duct adenocarcinoma cells invade neighbouring tissue resulting in high incidence of metastasis. They are supported by tumour stroma fibroblasts which have undergone differentiation into cancer-associated fibroblasts (CAFs). Stiffness of cell substratum, cytokines, such as transforming growth factor-β (TGF-β), and stromal matrix proteins, such as laminin-332, are factors which promote CAF differentiation. In a spheroid culture system, differentiation of CAFs was analysed for laminin-332 production, laminin-binding integrin repertoire, adhesion and migration behaviour, and, in heterospheroids, for their interplay with the pancreatic duct adenocarcinoma AsPC-I cells. Our data reveal that CAFs produce laminin-332 thus contributing to its ectopic deposition within the tumour stroma. Moreover, CAF differentiation correlates with an increased expression of α3β1 integrin, the principal laminin-332-receptor. Beyond its role as novel CAF marker protein, integrin α3β1 crucially determines differentiation and maintenance of the CAF phenotype, as knock-out of the integrin α3 subunit reversed the CAF differentiated state. AsPC-I cells co-cultured in heterospheroids with integrin α3-deficient CAFs invaded less than from heterospheroids with wild-type CAFs. This study highlights the role of integrin α3β1 integrin-laminin-332 interaction of CAFs which promotes and sustains differentiation of CAFs and promotes carcinoma invasion.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most deadly cancers in Europe and the USA. There is consensus that radical tumor surgery is the only viable option for any long-term survival in patients with PDAC. So far, limited data are available regarding the routine surgical management of patients with advanced PDAC in the light of surgical guidelines.METHODS: A national survey on perioperative management of patients with PDAC and currently applied criteria on their tumor resectability in German university and community hospitals was carried out.RESULTS: With a response rate of 81.6% (231/283) a total of 95 (41.1%) participating departments practicing pancreatic surgery in Germany are certified as competence and reference centers for surgical diseases of the pancreas in 2016. More than 95% of them indicate to carry out structured and interdisciplinary therapies along with an interdisciplinary pre- and postoperative tumor board. The majority of survey respondents prefer the pylorus-preserving partial pancreatoduodenectomy (93.1%) with standard lymphadenectomy for cancer of the pancreatic head. Intraoperative histological evaluation of the resection margins is used regularly by 99% of the survey respondents. 98.7% of survey respondents carry out partial or complete vein resection, 126 respondents (54.5%) would resect tumor adjacent arteries, and 102 respondents (44.2%) would perform metastasectomy if complete PDAC resection (R0) is possible. CONCLUSION: Evidence-based and standardized pancreatic surgery is practiced by a large number of hospitals in Germany. However, a significant number of survey respondents support an extended radical tumor resection in patients with advanced PDAC even when not indicated by current clinical guidelines.

Accumulating evidence indicates that anastomotic leakages and perforations of the upper gastrointestinal tract (uGIT) can be treated successfully with endoscopic vacuum therapy (EVT). So far, no data is available regarding the long-term quality of life (QoL) after successful EVT of defects in the uGIT. We present a prospective survey on long-term Qol of 52 patients treated by EVT for defects of the uGIT. Results are compared with 63 of 221 patients treated by esophagectomy without anastomotic insufficiency (w/o EVT) between 12/2011 and 12/2015. The Gastrointestinal Quality of Life-Index (GIQLI) score was determined by a 36-item questionnaire of 25 respondents with EVT and 50 respondents w/o EVT. The response rate was 78.95% (75/95) including 25 survey respondents who were treated with EVT for anastomotic insufficiency secondary to esophagectomy or gastrectomy (n = 19), iatrogenic esophageal perforation (n = 4), and Boerhaave syndrome (n = 2) and 50 respondents with complication-free esophagectomy w/o EVT. The median follow-up was 19 months for EVT patients and 21 months for patients w/o EVT. Except for “social function” (p = 0.009) in favor for patients w/o EVT, the median GIQLI score did not differ significantly between both study groups concerning the categories ‘symptoms’, ‘emotions’, ‘physical functions’, and ‘medical treatment’ resulting in a total median GIQLI score of 83 in EVT versus 96.5 in patients w/o EVT (p = 0.185). Spearman Rho analysis revealed that a high GIQLI score correlated with a low ASA score (p

Early treatment of pancreatic ductal adenocarcinoma (PDAC) is significantly delayed due to the lack of liquid biopsy markers for early diagnosis at surgically resectable tumor stages. Recent studies suggest that microRNA-205 (miR-205) is involved in PDAC progression by post-transcriptional regulation of epithelial-to-mesenchymal transition (EMT). However, the clinical potential of miR-205 as diagnostic and prognostic marker remains undefined and its exact role in PDAC is still ambiguous. This retrospective study is a substantial contribution to this on-going scientific discussion. Expression analysis of miR-205 and its molecular targets in PDAC cell lines (n = 5), human tissue (n = 73), and blood serum samples (n = 85) by qRT-PCR, tissue microarray immunohistochemistry, and western blot. Descriptive and explorative statistical analysis of miR-205’s clinical potential for diagnosis and prognosis of PDAC. The expression of miR-205 differs more than 2000-fold (p

Background Hepatocellular carcinoma (HCC) represents the main cause of death among patients with cirrhotic liver disease, but little is known about mechanisms of cirrhosis associated carcinogenesis. We investigated the diagnostic impact of microRNA-200 (miR-200) family members as important epigenetic regulators of epithelial–mesenchymal transition (EMT) to differentiate between patients with HCC and liver cirrhosis. Methods Expression of the miR-200 family was investigated by qRT-PCR in specimens of HCC patients with and without cirrhosis. Benign specimens with and without cirrhosis served as controls. Expression of the EMT markers ZEB-1, E-cadherin and vimentin was examined using immunohistochemistry. Results MiR-200a and miR-200b were significantly downregulated in HCC (miR-200a: −40.1% (P = 0.0002); miR-200b: −52.3% (P = 0.0002)), and in HCC cirrhotic tissue (miR-200a: −40.2% (P = 0.004); miR-200b: −51.1% (P = 0.007)) compared to liver cirrhosis. Spearman's Rho analysis revealed a significant negative correlation of miR-200a and miR-200b to the expression of the mesenchymal markers Vimentin (P

Pancreatoduodenectomy in Germany is performed by a broad range of hospitals. A diversity of operative techniques is employed as no guidelines exist for intra- and perioperative management. We carried out a national survey to determine the de facto German standards for pancreatoduodenectomy, assess quality assurance measures, and identify relevant issues for further investigation.A questionnaire evaluating major outcome variables, case load, preferred surgical procedures, and perioperative management during pancreatoduodenectomy was developed and sent to 211 German hospitals performing12 pancreatoduodenectomies per year (requirement for certification as a pancreas center). Statistical analysis was carried out using the Fisher Exact, Mann-Whitney U, and Spearman tests.The final response rate was 86 % (182/211). The preferred technique and de facto German standard for pancreatoduodenectomy was pylorus-preserving pancreatoduodenectomy with pancreatojejunostomy carried out via duct-to-mucosa anastomosis with interrupted sutures using PDS 4.0. The minority of German pancreas centers were certified (18-48 %). The certification rate increased with higher capacity levels and case load (P0.05); however, significant correlations between the fistula rate and hospital case load, hospital capacity level, or hospital certification status were not seen.This study revealed a distinct variety of management strategies for pancreatic surgery and available evidence-based data was not necessarily translated into clinical practice. The limited certification rate represented a shortcoming of quality assurance. The data emphasize the need for further trials to answer the questions whether hospital certifications and omission of drains improve outcome after pancreatoduodenectomy and for the establishment of guidelines for pancreatoduodenectomy.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases with late diagnosis, rapid progression, high invasiveness, and early metastasis. Epithelial-to-mesenchymal transition (EMT) is a crucial step in metastasis that enables polarized immotile epithelial cells to gain fibroblast-like mesenchymal abilities such as enhanced motility. The dynamic process of EMT in PDAC with its powerful influence on disease progression and especially metastasis is of vigorous interest in biomedical research to elucidate its signaling pathways and regulation mechanisms. It is evident that epigenetics such as histone and DNA modification or noncoding RNAs such as microRNAs and long noncoding RNAs are of high importance in initiation and progress of EMT in PDAC. This review analyzes the latest research dealing with EMT and its epigenetic regulation in PDAC and summarizes its potentials in diagnostic, prognostic, and therapeutic management.

Adjuvant first-line gemcitabine monochemotherapy presents a standard treatment for patients with advanced pancreatic adenocarcinoma and improves overall survival in chemosensitive patients. Nonetheless, 6-month progression-free survival remains below 15%, despite interdisciplinary approaches. The success of gemcitabine treatment is disappointing and-in the absence of reliable tumor markers--challenging to quantify. Epigenetic alterations have been recently identified to take on important roles in cancer development and possibly cancer treatment. In this context, microRNAs are becoming increasingly acknowledged as useful biomarkers for classifying cancers and providing information on their chemo- and radiosensitivity. This review illustrates the potential of genetic and epigenetic markers in the prediction of chemosensitivity in pancreatic cancer patients and in the monitoring of their response rates to adjuvant therapy.

Background Pancreatic ductal adenocarcinoma (PDAC) remains a highly chemoresistant tumor entity for which no reliable molecular targets exist to predict or influence the success of chemotherapy. Recently, we identified a panel of microRNAs associated with induced gemcitabine chemoresistance in human PDAC cell lines. This clinical study evaluates these microRNAs and associated molecular markers as prognostic markers of outcome in 98 PDAC patients Union Internationale Contre le Cancer (UICC) stage II undergoing curative surgery with adjuvant gemcitabine chemotherapy. The primary end points of this study are recurrence-free survival and overall survival. Results Poor response to chemotherapy was significantly correlated to overexpression of microRNA-21 (p = 0.029), microRNA-99a (p = 0.037), microRNA-100 (p = 0.028), and microRNA-210 (p = 0.021) in tissue samples of PDAC patients UICC stage II. Upregulation of these microRNAs was associated with a significantly shorter overall survival and recurrence-free survival (p

Goals In this clinical study, we aimed to evaluate the role of circulating microRNA-200 family as a non-invasive tool to identify patients with cirrhosis-associated hepatocellular carcinoma (HCC). Background Prognosis of HCC remains poor with increasing incidence worldwide, mainly related to liver cirrhosis. So far, no reliable molecular targets exist for early detection of HCC at surgically manageable stages. Recently, we identified members of the microRNA-200 family as potential diagnostic markers of cirrhosis-associated HCC in patient tissue samples. Their value as circulating biomarkers for HCC remained undefined. Methods Blood samples and clinicopathological data of consecutive patients with liver diseases were collected prospectively. Expression of the microRNA-200 family was investigated by qRT-PCR in blood serum samples of 22 HCC patients with and without cirrhosis. Serum samples of patients with non-cancerous chronic liver cirrhosis (n = 22) and of healthy volunteers (n = 15) served as controls. Results MicroRNA-141 and microRNA-200a were significantly downregulated in blood serum of patients with HCC compared to liver cirrhosis (p

Hepatocellular carcinoma (HCC) represents the main cause of death among patients with cirrhotic liver disease, but little is known about mechanisms of cirrhosis associated carcinogenesis. We investigated the diagnostic impact of microRNA-200 (miR-200) family members as important epigenetic regulators of epithelial-mesenchymal transition (EMT) to differentiate between patients with HCC and liver cirrhosis.Expression of the miR-200 family was investigated by qRT-PCR in specimens of HCC patients with and without cirrhosis. Benign specimens with and without cirrhosis served as controls. Expression of the EMT markers ZEB-1, E-cadherin and vimentin was examined using immunohistochemistry.MiR-200a and miR-200b were significantly downregulated in HCC (miR-200a: -40.1% (P = 0.0002); miR-200b: -52.3% (P = 0.0002)), and in HCC cirrhotic tissue (miR-200a: -40.2% (P = 0.004); miR-200b: -51.1% (P = 0.007)) compared to liver cirrhosis. Spearman's Rho analysis revealed a significant negative correlation of miR-200a and miR-200b to the expression of the mesenchymal markers Vimentin (P0.007) and ZEB-1 (P0.0005) and a significant positive correlation to the epithelial marker E-cadherin (P0.0002).MiR-200 family members and their targets are significantly deregulated in HCC and liver cirrhosis. The miR-200 family is able to distinguish between cirrhotic and HCC tissue and could serve as an early marker for cirrhosis-associated HCC.

Introduction Pancreatic ductal adenocarcinoma (PDAC) is recognized for its lethality which is largely due to late clinical manifestation combined with rapid dissemination. In order to move forward the time of diagnosis, specific, sensitive and easily accessible markers are essential. MicroRNAs are an emerging class of molecules involved in tumorigenesis and metastasis. Additionally, they are disease specific and highly stable in blood, predestined to become a novel class of biomarkers. Methods 96 patients were enrolled from 2009 to 2010: PDAC: n=53, pancreatitis: n=30, healthy control: n=13. RNA was isolated from serum samples of each patient using a modified TRIzol method and artificial miRNAs were spiked in at 5nM. MicroRNA-microarray was carried out by febit GmbH (Heidelberg, Germany) for 19 PDAC, 15 pancreatitis and 8 control samples. Significantly differentially expressed miRNAs were validated by quantitative reverse transcriptase PCR in all samples. Results The following miRNAs were validated to be upregulated in PDAC vs. both pancreatitis and healthy controls: miR-190, −1246, −26a, −3152, −1265, −924, while miR-509-3-5p, −519c-5p, −501-3p, −548s-195* were downregulated. Using the validated miRNAs, PDAC was differentiated from pancreatitis with a sensitivity of 0.84 and specificity of 0.93. Conclusions This is the first investigation of circulating miRNAs as biomarkers for PDAC that has made use of microarrays to investigate global expression rather than employing qRT-PCR to focus on specific miRNAs. Thus, novel biomarker candidates have been identified. Further functional analysis of these miRNAs will uncover their significance and role in the progression of PDAC. (Supported by a grant from Foerderverein Peter Geiger e.V.).