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Importance: The prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone. Objective: To assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes. Data Sources:Literature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023. Study Selection: Two blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach. Main Outcomes and Measures: Overall and disease-free survival, postoperative morbidity, and mortality. Results:The analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperativ

Background. Preoperative FOLFIRINOX chemotherapy is increasingly administered to patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) to improve overall survival (OS). Multicenter studies reporting on the impact from the number of preoperative cycles and the use of adjuvant chemotherapy in relation to outcomes in this setting are lacking. This study aimed to assess the outcome of pancreatectomy after preoperative FOLFIRINOX, including predictors of OS.Methods. This international multicenter retrospective cohort study included patients from 31 centers in 19 European countries and the United States undergoing pancreatectomy after preoperative FOLFIRINOX chemotherapy (2012-2016). The primary end point was OS from diagnosis. Survival was assessed using Kaplan-Meier analysis and Cox regression.Results. The study included 423 patients who underwent pancreatectomy after a median of six (IQR 5-8) preoperative cycles of FOLFIRINOX. Postoperative major morbidity occurred for 88 (20.8%) patients and 90-day mortality for 12 (2.8%) patients. An R0 resection was achieved for 243 (57.4%) patients, and 259 (61.2%) patients received adjuvant chemotherapy. The median OS was 38 months (95% confidence interval [CI] 34-42 months) for BRPC and 33 months (95% CI 27-45 months) for LAPC. Overall survival was significantly associated with R0 resection (hazard ratio [HR] 1.63; 95% CI 1.20-2.20) and tumor differentiation (HR 1.43; 95% CI 1.08-1.91). Neither the number of preoperative chemotherapy cycles nor the use adjuvant chemotherapy was associated with OS.Conclusions. This international multicenter study found that pancreatectomy after FOLFIRINOX chemotherapy is associated with favorable outcomes for patients with BRPC and those with LAPC. Future studies should confirm that the number of neoadjuvant cycles and the use adjuvant chemotherapy have no relation to OS after resection.

Pancreatic stellate cells (PSCs) constitute important cells of the pancreatic microenvironment and their close interaction with cancer cells is important in pancreatic cancer. It is currently not known whether PSCs accumulate genetic alterations that contribute to tumor biology. Our aim was to analyze genetic alterations in cancer associated PSCs. PSC DNA was matched to DNA isolated from pancreatic cancer patients’ blood (n = 5) and analyzed by Next-Generation Sequencing (NGS). Bioinformatic analysis was performed using the GATK software and pathogenicity prediction scores. Sanger sequencing was carried out to verify specific genetic alterations in a larger panel of PSCs (n = 50). NGS and GATK analysis identified on average 26 single nucleotide variants in PSC DNA as compared to the matched blood DNA that could be visualized with the Integrative Genomics Viewer. The absence of PDAC driver mutations (KRAS, p53, p16/INK4a, SMAD4) confirmed that PSC isolations were not contaminated with cancer cells. After filtering the variants, using different pathogenicity scores, ten genes were identified (SERPINB2, CNTNAP4, DENND4B, DPP4, FGFBP2, MIGA2, POLE, SNRNP40, TOP2B, and ZDHHC18) in single samples and confirmed by Sanger sequencing. As a proof of concept, functional analysis using control and SERPINB2 knock-out fibroblasts revealed functional effects on growth, migration, and collagen contraction. In conclusion, PSC DNA exhibit a substantial amount of single nucleotide variants that might have functional effects potentially contributing to tumor aggressiveness.

Pancreatic stellate cells (PSCs) constitute important cells of the pancreatic microenvironment and their close interaction with cancer cells is important in pancreatic cancer. It is currently not known whether PSCs accumulate genetic alterations that contribute to tumor biology. Our aim was to analyze genetic alterations in cancer associated PSCs. PSC DNA was matched to DNA isolated from pancreatic cancer patients’ blood (n = 5) and analyzed by Next-Generation Sequencing (NGS). Bioinformatic analysis was performed using the GATK software and pathogenicity prediction scores. Sanger sequencing was carried out to verify specific genetic alterations in a larger panel of PSCs (n = 50). NGS and GATK analysis identified on average 26 single nucleotide variants in PSC DNA as compared to the matched blood DNA that could be visualized with the Integrative Genomics Viewer. The absence of PDAC driver mutations (KRAS, p53, p16/INK4a, SMAD4) confirmed that PSC isolations were not contaminated with cancer cells. After filtering the variants, using different pathogenicity scores, ten genes were identified (SERPINB2, CNTNAP4, DENND4B, DPP4, FGFBP2, MIGA2, POLE, SNRNP40, TOP2B, and ZDHHC18) in single samples and confirmed by Sanger sequencing. As a proof of concept, functional analysis using control and SERPINB2 knock-out fibroblasts revealed functional effects on growth, migration, and collagen contraction. In conclusion, PSC DNA exhibit a substantial amount of single nucleotide variants that might have functional effects potentially contributing to tumor aggressiveness.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support. Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support. Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

Hif1alpha is a key regulator of cellular adaptation and survival under hypoxia. We generated murine PDAC cells with Hif1alpha shRNA to downregulate Hif1alpha expression. The Hif1alpha depletion results in rapid tumour growth with marked hypoxia-induced cell death, which leads to a persistent tumour-sustaining inflammatory response. However, it simultaneously reduces tumour colonisation and hepatic metastases by increasing the susceptibility to anoikis induced by anchorage-independent conditions. Taken together, the role of Hif1alpha in pancreatic tumorigenesis is context-dependent., Hif1alpha spielt eine wichtige Rolle bei der Zellanpassung und des Zellüberlebens unter hypoxischen Bedingungen. In der vorliegenden Arbeit wurden murine PDAC Zellen untersucht, welche mit Hif1alpha shRNA transfiziert wurden. Dies führte zu einem raschen Tumorwachstum. Gleichzeitig verringerten sich Tumorkolonisation und Bildung von Lebermetastasen. Eine Erklärung hierfür ist die erhöhte Anfälligkeit gegenüber Anoikis. Zusammenfassend ist die Rolle von Hif1alpha in der pankreatischen Tumorgenese abhängig vom jeweiligen Zusammenhang zu betrachten und zu bewerten.

Pancreatic ductal adenocarcinoma (PDAC) cells are often exposed to the harsh microenvironment. Under this harsh microenvironment, the nutritional dependency of PDAC is found to be determined by the dominant oncogenic signal. The nutritionally stressful microenvironment selects cancer cells with locally aggressive and angiogenic phenotype; which are paradoxically deficient in remote colonisation. The loss of capacity in remote colonisation is associated with an altered expression in the extracellular matrix (ECM) proteins., Die Zellen des pankreatischen duktalen Adenokarzinoms sind oft einer sehr rauen Mikroumgebung ausgesetzt. Innerhalb dieser schlechten Mikroumgebung wird die Nährstoffabhängigkeit durch das dominant onkogene Signal bestimmt. Diese ernährungsphysiologisch anspruchsvolle Umgebung selektiert Krebszellen mit lokal aggressivem und angiogenem Phänotyp; diese sind paradoxerweise nicht fähig zur entfernten Kolonisation. Dieser Verlust der Fernkolonisation ist mit einer veränderten Expression der extrazellulären Matrix Proteine (ECM) assoziiert.

To assess outcomes among patients undergoing total pancreatectomy (TP) including predictors for complications and in-hospital mortality. Current studies on TP mostly originate from high-volume centers and span long time periods and therefore may not reflect daily practice. This prospective pan-European snapshot study included patients who underwent elective (primary or completion) TP in 43 centers in 16 European countries (June 2018-June 2019). Subgroup analysis included cut-off values for annual volume of pancreatoduodenectomies (<60 vs. ≥60). Predictors for major complications and in-hospital mortality were assessed in multivariable logistic regression. In total, 277 patients underwent TP, mostly for malignant disease (73%). Major postoperative complications occurred in 70 patients (25%). Median hospital stay was 12 days (IQR 9-18) and 40 patients were readmitted (15%). In-hospital mortality was 5% and 90-day mortality 8%. In the subgroup analysis, in-hospital mortality was lower in patients operated in centers with ≥60 pancreatoduodenectomies compared < 60 (4% vs. 10%, p = 0.046). In multivariable analysis, annual volume < 60 pancreatoduodenectomies (OR 3.78, 95%CI 1.18-12.16, p = 0.026), age (OR 1.07, 95%CI 1.01-1.14, p = 0.046), and estimated blood loss ≥2L (OR 11.89, 95%CI 2.64-53.61, p = 0.001) were associated with in-hospital mortality. ASA ≥3 (OR 2.87, 95%CI 1.56-5.26, p = 0.001) and estimated blood loss ≥2L (OR 3.52, 95%CI 1.25-9.90, p = 0.017) were associated with major complications. This pan-European prospective snapshot study found a 5% in-hospital after TP. The identified predictors for mortality, including low-volume centers, age, and increased blood loss, may be used to improve outcomes.

The data of this thesis revealed that Periostin is crucial for successful regeneration of the exocrine pancreatic compartment after caerulein-induced pancreatitis. Loss of Periostin resulted in pancreatic atrophy and lipomatosis indicating that Periostin is significantly involved in acinar cell fate decisions. Moreover, Periostin was found to promote pancreatic carcinogenesis and to be particularly required for the development of metastases in the secondary target organ. By using a focal adhesion kinase inhibitor the effects of Periostin signaling could be antagonized., Diese Arbeit zeigt, dass Periostin eine wichtige Rolle in der Regeneration des exokrinen Pankreas nach Caerulein-induzierter Pankreatitis spielt. Der Verlust von Periostin resultierte in Pankreasatrophie und Lipomatose was darauf hinweist, dass Periostin einen Einfluss auf den Differenzierungsstatus von Azinuszellen ausübt. Zudem wurden eine tumorfördernde Funktion von Periostin bei der Pankreaskarzinogenese und eine begünstigte Metastasenbildung gefunden. Durch die Inhibierung der fokalen Adhäsionskinase konnten die Effekte von Periostin aufgehoben werden.

Wt1 und Foxd1 sind zwei Transkriptionsfaktoren, die in der Organogenese der Niere beziehungsweise der Leber eine entscheidende Rolle spielen. Ziel dieser Arbeit ist es, Wt1 und Foxd1 im Pankreas nachzuweisen und die Foxd1- und Wt1-positiven Zellen zu charakterisieren. Insbesondere wurde die Bedeutung dieser mesenchymalen Zellen während der fibrotischen Reaktion bei der Pankreatitis untersucht., WT1 and Foxd1 are two transcription factors, which play a decicive role during the organogenesis of the kidney and the liver. The aim of this work is to detect WT1 and Foxd1 in the pancreas and to characterize Wt1- and Foxd1-positive cells. In particular, the significance of these mesenchymal cells during the fibrotic reaction in pancreatitis was investigated.

Diese Arbeit beschäftigt sich mit der Frage, ob Fibrose den Interferon alpha Signalweg in der Leber verändert und damit die Wirkung von therapeutisch eingesetztem Interferon alpha auf HCC-Zellen. In vitro Kokulturversuche mit HCC Zelllinien und Fibroblasten sowie histologische Untersuchungen von HCC-Patientengeweben deuten darauf hin, dass ein geringeres Therapieansprechen mit einer verminderten IFNAR1 Expression im weniger differenzierten Gewebe in Zusammenhang steht., The aim of this thesis was to investigate the influence of hepatic fibrosis on tissue resident interferon alpha signaling and additional on interferon alpha therapy on HCC cancer cells. In vitro coculture analysis with HCC cancer cells and fibroblasts and histological analysis of HCC patient tissue let us suggest that lower interferon alpha response rates are associated with lower rates of IFNAR1 in the less differentiated tissue.

Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene‐disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case–control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58–0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21–0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19–0.89, and OR = 0.73, 95%CI 0.53–1.00, respectively). Several inflammatory‐related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.

Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene‐disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case–control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58–0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21–0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19–0.89, and OR = 0.73, 95%CI 0.53–1.00, respectively). Several inflammatory‐related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.

Ein Teil der perizytären Zellpopulation im murinen Pankreas exprimiert mesenchymale Stammzellmarker. Die vorliegende Arbeit charakterisiert diese Zellen und beschreibt ihre Veränderung während einer sterilen Pankreatitis. Im postinflammatorischen Gewebe zeigt sich eine Vervielfachung der perizytären Zellen und deren mesenchymaler Marker. Darüber hinaus konnte ein Protokoll zur Isolation perizytärer Zellen aus dem murinen Pankreas entwickelt werden., A pericyte cell population in the murine pancreas expresses mesenchymal stem cell marker. This thesis characterizes these cells and starts to define their behavior during sterile inflammation. An enrichment of pericytic cells and their mesenchymal stem cell marker could be observed in the post-inflammatory tissue. Moreover a protocol to isolate pericytes from the murine pancreas was developed.

Recent studies have recognized the role of reactive oxygen species (ROS) in pancreatic inflammation and carcinogenesis. However, no in vivo animal model has been described so far. Caerulein and ethanol have been reported to induce oxidative stress in pancreatic acinar cells. Thus, we tested the efficiency of ROS-generation by combining caerulein and ethanol treatment in pancreatic inflammation and analyze themechanism in detail., Neue Studien belegen, dass reaktive Sauerstoffverbindungen (ROS) bei der Entzündung und Pankreaskarzinogenese eine wichtige Rolle spielen. Dazu wurde allerdings noch kein geeignetes Tiermodel entwickelt. Es konnte jedoch gezeigt werden, dass Caerulein und Ethanol oxidativen Stress in pankreatischenAzinuszellen auslösen kann. Daher haben wir im Tiermodel die Effektivität einer Caerulein/Ethanol Behandlung zur Induktion von ROS-generiertem Stress getestet und den Mechanismus untersucht.

Hif1alpha is a key regulator of cellular adaptation and survival under hypoxia. We generated murine PDAC cells with Hif1alpha shRNA to downregulate Hif1alpha expression. The Hif1alpha depletion results in rapid tumour growth with marked hypoxia-induced cell death, which leads to a persistent tumour-sustaining inflammatory response. However, it simultaneously reduces tumour colonisation and hepatic metastases by increasing the susceptibility to anoikis induced by anchorage-independent conditions. Taken together, the role of Hif1alpha in pancreatic tumorigenesis is context-dependent., Hif1alpha spielt eine wichtige Rolle bei der Zellanpassung und des Zellüberlebens unter hypoxischen Bedingungen. In der vorliegenden Arbeit wurden murine PDAC Zellen untersucht, welche mit Hif1alpha shRNA transfiziert wurden. Dies führte zu einem raschen Tumorwachstum. Gleichzeitig verringerten sich Tumorkolonisation und Bildung von Lebermetastasen. Eine Erklärung hierfür ist die erhöhte Anfälligkeit gegenüber Anoikis. Zusammenfassend ist die Rolle von Hif1alpha in der pankreatischen Tumorgenese abhängig vom jeweiligen Zusammenhang zu betrachten und zu bewerten.

Pancreatic ductal adenocarcinoma (PDAC) cells are often exposed to the harsh microenvironment. Under this harsh microenvironment, the nutritional dependency of PDAC is found to be determined by the dominant oncogenic signal. The nutritionally stressful microenvironment selects cancer cells with locally aggressive and angiogenic phenotype; which are paradoxically deficient in remote colonisation. The loss of capacity in remote colonisation is associated with an altered expression in the extracellular matrix (ECM) proteins., Die Zellen des pankreatischen duktalen Adenokarzinoms sind oft einer sehr rauen Mikroumgebung ausgesetzt. Innerhalb dieser schlechten Mikroumgebung wird die Nährstoffabhängigkeit durch das dominant onkogene Signal bestimmt. Diese ernährungsphysiologisch anspruchsvolle Umgebung selektiert Krebszellen mit lokal aggressivem und angiogenem Phänotyp; diese sind paradoxerweise nicht fähig zur entfernten Kolonisation. Dieser Verlust der Fernkolonisation ist mit einer veränderten Expression der extrazellulären Matrix Proteine (ECM) assoziiert.

Background: Family history (FH) of pancreatic cancer (PC) has been associated with an increased risk of PC, but little is known regarding the role of inherited/environmental factors or that of FH of other comorbidities in PC risk. We aimed to address these issues using multiple methodological approaches. Methods: Case-control study including 1431 PC cases and 1090 controls and a reconstructed-cohort study (N = 16 747) made up of their first-degree relatives (FDR). Logistic regression was used to evaluate PC risk associated with FH of cancer, diabetes, allergies, asthma, cystic fibrosis and chronic pancreatitis by relative type and number of affected relatives, by smoking status and other potential effect modifiers, and by tumour stage and location. Familial aggregation of cancer was assessed within the cohort using Cox proportional hazard regression. Results: FH of PC was associated with an increased PC risk [odds ratio (OR) = 2.68; 95% confidence interval (CI): 2.27-4.06] when compared with cancer-free FH, the risk being greater when ≥ 2 FDRs suffered PC (OR = 3.88; 95% CI: 2.96-9.73) and among current smokers (OR = 3.16; 95% CI: 2.56-5.78, interaction FHPC*smoking P-value = 0.04). PC cumulative risk by age 75 was 2.2% among FDRs of cases and 0.7% in those of controls [hazard ratio (HR) = 2.42; 95% CI: 2.16-2.71]. PC risk was significantly associated with FH of cancer (OR = 1.30; 95% CI: 1.13-1.54) and diabetes (OR = 1.24; 95% CI: 1.01-1.52), but not with FH of other diseases. Conclusions: The concordant findings using both approaches strengthen the notion that FH of cancer, PC or diabetes confers a higher PC risk. Smoking notably increases PC risk associated with FH of PC. Further evaluation of these associations should be undertaken to guide PC prevention strategies.

Background: Family history (FH) of pancreatic cancer (PC) has been associated with an increased risk of PC, but little is known regarding the role of inherited/environmental factors or that of FH of other comorbidities in PC risk. We aimed to address these issues using multiple methodological approaches. Methods: Case-control study including 1431 PC cases and 1090 controls and a reconstructed-cohort study (N = 16 747) made up of their first-degree relatives (FDR). Logistic regression was used to evaluate PC risk associated with FH of cancer, diabetes, allergies, asthma, cystic fibrosis and chronic pancreatitis by relative type and number of affected relatives, by smoking status and other potential effect modifiers, and by tumour stage and location. Familial aggregation of cancer was assessed within the cohort using Cox proportional hazard regression. Results: FH of PC was associated with an increased PC risk [odds ratio (OR) = 2.68; 95% confidence interval (CI): 2.27-4.06] when compared with cancer-free FH, the risk being greater when ≥ 2 FDRs suffered PC (OR = 3.88; 95% CI: 2.96-9.73) and among current smokers (OR = 3.16; 95% CI: 2.56-5.78, interaction FHPC*smoking P-value = 0.04). PC cumulative risk by age 75 was 2.2% among FDRs of cases and 0.7% in those of controls [hazard ratio (HR) = 2.42; 95% CI: 2.16-2.71]. PC risk was significantly associated with FH of cancer (OR = 1.30; 95% CI: 1.13-1.54) and diabetes (OR = 1.24; 95% CI: 1.01-1.52), but not with FH of other diseases. Conclusions: The concordant findings using both approaches strengthen the notion that FH of cancer, PC or diabetes confers a higher PC risk. Smoking notably increases PC risk associated with FH of PC. Further evaluation of these associations should be undertaken to guide PC prevention strategies.

Summary: Conclusions. Adaptive changes in exocrine and endocrine pancreatic function, as well as changes in pancreas size and morphology, were not observed after 4 wk of oral pancreatic enzyme application. These findings suggest that the normal pancreas does not significantly adapt—either morphologically or functionally—to a 4-wk oral application of high-dose pancreatic enzymes. Background. The control of exocrine pancreatic enzyme secretion is not completely understood. Although it has been established that exocrine pancreatic secretion is mainly regulated in the short-term by the amount of pancreatic enzymes in the proximal small intestine, it is not known whether long-term application of pancreatic enzymes causes changes in exocrine pancreatic secretion in humans. Methods. Twelve healthy male volunteers (median age 27 yr) participated in a prospective, randomized, placebo-controlled, double-blind study. Six were placed in the treatment group and six in the placebo group. Over a 4-wk period, the six subjects in the treatment group took 18 capsules of Panzytrat (20,000 units of lipase, 18,000 units of amylase, and 1000 units of protease per capsule) daily. Before (wk 0), 4 wk following pancreatic enzyme application and 2 wk afterward, a secretin-cerulein test was carried out in all subjects to study exocrine pancreatic function (trypsin, chymotrypsin, bicarbonate content, and total pancreatic fluid secretion in the duodenum). One day following the secretin-cerulein test, a standard test meal was given to all subjects to analyze endocrine pancreatic function. Additionally, before starting the treatment, once per week during treatment and 2 wk afterward, an ultrasound examination of the pancreas was carried out to see whether there was any change in pancreas size and morphology. Results. Trypsin content in the duodenal aspirates following simultaneous stimulation with secretin and cerulein after 4 wk of high-dose pancreatic enzyme application was 92% in the treatment

Trotz präoperativer Desinfektion des OP-Gebiets verbleiben partiell potentiell schädliche Hautkeime und können Wundinfektionen hervorrufen. Eine prospektive Studie der Chirurgischen Klinik und Poliklinik der TUM untersuchte die Effektivität der präoperativen Desinfektion des Bauchnabels und den Einfluss der residualen Keime auf postoperative Wundinfektionen bei Patienten mit elektiver Laparotomie. 25% der Desinfektionen waren unvollständig und von insgesamt sieben Wundinfekten wurde einer von Keimen des Bauchnabels verursacht., Skin contamination is still a risk factor for surgical site infections despite antiseptical skin washing preoperatively. Prospectively collected data of patients with planned laparotomy at the Department of Surgery, TUM, were used to determine the efficacy of preoperative antiseptical skin washing procedure of the umbilicus. Additionally the effect of remaining microbial contamination to surgical site infections was estimated. 25% of the preoperative disinfections were incomplete and one out of seven surgical site infections was caused by umbilicus contamination.

Das Adenokarzinom des Pankreas ist ein aggressiver Tumor mit einer, aufgrund unspezifischer Symptome und später Erstdiagnose, schlechten Prognose. Einzig kuratives Verfahren ist die vollständige chirurgische Resektion des Tumors im Gesunden, wobei eine Infiltration der mesentericoportalen Venen kein Ausschlusskriterium darstellt. Diese Arbeit untersucht Morbidität und Mortalität nach Pankreatektomie mit vs. ohne Venenresektion. Sie zeigt, dass eine Venenresektion eine mögliche Intervention zum Erreichen von tumorfreien Resektionsrändern darstellt, ohne erhöhte Komplikationsraten, jedoch bei tendenziell geringerem Gesamtüberleben individuell abgewogen werden muss., Pancreatic adenocarcinoma is a malignant tumour with very poor prognosis due to late initial diagnosis. Surgery is the only potentially curative therapy with the infiltration of mesentericoportal veins not being a criterion for exclusion. The present work analyses morbidity and mortality after pancreatectomy with vs. without vein resection. Our data disclose vein resection as a possibility in achieving complete tumor-free resection margins with similar complication rates but a tendency to less overall survival. Therefore, the individual situation must also be taken into account.

As a molecular chaperone, GRP94 is the most abundant glycoprotein in the endoplasmic reticulum, playing an important role in maintaining cellular homeostasis. Here, we investigated the expression and the role of GRP94 in regulating cell growth and apoptosis in pancreatic cancer cells. We found that down-regulation of GRP94 decreases apoptosis resistance in pancreatic cancer cells. Clinically, patients with high GRP94 expression show a tendency for a worsened survival., Als molekulares Chaperon ist GRP94 das Glycoprotein, das am reichlichsten in dem Endoplasmatischen Retikulum vorkommt. Es spielt eine wichtige Rolle bei der Aufrechterhaltung der zellulären Homeostase. Hier untersuchten wir die Expression und die Rolle von GRP94 bei der Regulierung des Zellwachstums und für die Apoptose in Pankreaskarzinomzellen. Unsere Ergebnisse zeigten, dass die Herunter-Regulierung von GRP94 die Apoptose-Resistenz in Pankreaskarzinomzellen verringerte. Klinisch zeigten die Patienten mit einer hohen GRP94-Expression eine Tendenz für ein schlechteres Überleben.

This study investigates the cytoskeleton protein Destrin in the context of perineural invasiveness of pancreatic cancer cells. By a previous method Destrin has been shown to be upregulated in pancreatic adenocarcinoma cancer cells with high nerve invasive potential. The upregulation of Destrin was confirmed by QRT-PCR, immunoblotting and immunohistochemistry. Silencing of Destrin by RNA interference decreased invasiveness, migration and proliferation of Panc-1 pancreatic cancer cells demonstrating Destrin might be related to neural invasiveness of pancreatic cancer cells., Das Zytoskelett-assoziierte Protein Destrin ist in hoch-nervinvasiv wachsenden Pankreaskarzinomzellen überexprimiert wie in einer vorangegangenen Arbeit gezeigt wurde. Die Überexprimierung wurde in dieser Arbeit durch verschieden Analysen bestätigt. Destrin-Supprimierung in Panc-1 Pankreaskarzinomzellen mittels RNA Interferenz zeigte eine geringere Invasivität, Migrations- und Proliferationsfähigkeit der Zellen hinweisend auf eine Bedeutung Destrin‘s für die perineurale Invasion durch Pankreaskarzinomzellen.

Das Adenokarzinom des Pankreas, dessen einziger kurativer Therapieansatz die vollständige Resektion im Gesunden darstellt, ist eine Diagnose, welche mit einer sehr schlechten Prognose einhergeht. Grund hierfür sind die unspezifischen Symptome und der späte Diagnosezeitpunkt. In dieser Arbeit werden bei Patienten mit einem resektablen duktalen Adenokarzinom des Pankreas klinische und tumorspezifische Charakteristika analysiert, um deren Einfluss auf die postoperative Prognose abzuschätzen. Als signifikante Prognosefaktoren stellen sich hierbei einige tumor- und therapiebezogene Merkmale heraus, signifikante präoperative Prognosefaktoren können nicht ermittelt werden. Vielmehr scheint es auch genetische und molekularbiologische Einflüsse auf das Outcome zu geben. Es ist somit nicht möglich, ein präoperatives Prädiktionsmodell zu entwickeln, welches zu einer sinnvollen Therapieentscheidung beiträgt., Pancreatic adenocarcinoma, which can only be cured through surgical resection, is a diagnosis with poor prognosis due to unspecific symptoms and late initial diagnosis. The current work analyzes clinical and tumor-related characteristics of patients with resectable pancreatic ductal adenocarcinoma and evaluates their influence on the postoperative outcome. Some tumor- and therapy-related characteristics appear to be significant prognostic factors, whereas no significant preoperative prognostic factors could be found. On the contrary, it also seems that there are some genetic and molecularbiological factors influencing the outcome. It is therefore not possible to create a preoperative prediction model, which can contribute to a reasonable treatment decision.

Autoimmunpankreatitis (AIP) ist eine seltene Form der chronischen Pankreatitis, von der mindestens zwei Subtypen existieren: AIP Typ I zeichnet sich durch eine starke Invasion IgG4-positiver Plasmazellen, AIP Typ II durch granulozytäre Läsionen der Gangepithelien aus. In einer Genexpressionsanalyse wurden erstmalig Th17-Zellen bei der AIP nachgewiesen. Immunhistochemische Färbungen zeigten bei der AIP Typ II periduktal signifikant mehr IL-17A/CD4-positive Zellen und neutrophile Granulozyten als bei der AIP Typ I. Diese Ergebnisse ermöglichen neue Forschungs-, und Therapiemöglichkeiten der AIP., Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis. There are at least two subtypes: AIP type I with an invasion of IgG4-positive plasma cells and AIP type II characterized by granulocyte epithelial lesions. We investigated T cell populations in AIP using a gene expression analysis. For the first time, Th17 cells could be detected in AIP tissue. Immunohistochemistry showed a significantly higher amount of IL-17A/CD4-positive cells and neutrophil granulocytes in periductal areas of AIP type II compared to type I. These results allow new scientific and therapeutic approaches.

In dieser Doktorarbeit wurde das Caerulein-Pankreatitis-Modell bei globalen TLR3-, Trif-, MyD88-, MyD88/Trif-, IFNaR- und STAT1-defizienten Mäusen angewendet. Der Schweregrad der akuten Pankreatitis wurde mittels Blutserumanalysen, histologischer Begutachtung sowie qRT-PCR-Messungen proinflammatorischer Zytokine in Pankreasgewebe gemessen. Histo-morphologisch und in den Serumanalysen konnten stärkere proinflammatorische Veränderungen nach Verlusten von Genen des Trif- und MyD88-abhängigen Signalwegs als in Wildtyp-Tieren erkannt werden., The cerulein pancreatitis model was used in global TLR3-, Trif-, MyD88-, MyD88/Trif-, IFNaR- und STAT1-deficient mice. The severity of acute pancreatitis was measured by serum analysis, histological evaluation and qRT-PCR measurements of proinflammatory cytokines in pancreatic tissue. Major proinflammatory changes were detected histologically and in serum analysis after loss of genes of the Trif- and MyD88-dependent signaling pathway compared to wildtype mice.

Das Pankreaskarzinom ist eine der fünfhäufigsten Todesursachen in westlichen Ländern. In der vorliegenden Arbeit wurde das Kinesin Motor Protein Kif20a (Kif20a) genauer charakterisiert, das in Vorversuchen eine 18- fache Überexprimierung im Tumorgewebe gegenüber Normalgewebe des Pankreas zeigte. Funktionelle Analysen konnten zeigen, dass Kif20a einen deutlichen Einfluss auf die Pankreaskarzinogenese hat. Sowohl die Proliferation, Migration als auch Motilität in Tumorzellen konnte nach Runterregulierung von Kif20a signifikant reduziert werden., Pancreatic cancer is the fifth most common cancer to cause death in western societies. In this dissertation the kinesin family member 20A (Kif20A) was analyzed, which was consistently reported to be 18- fold over- expressed in pancreatic cancer compared to normal pancreas. Different functional analyses could show, that Kif20a has an effect on pancreatic carcinogenesis. Proliferation, motility and migration could be significantly reduced, when Kif20a was silenced in pancreatic cancer cells.

Diese Arbeit beschäftigt sich mit der Frage, ob Fibrose den Interferon alpha Signalweg in der Leber verändert und damit die Wirkung von therapeutisch eingesetztem Interferon alpha auf HCC-Zellen. In vitro Kokulturversuche mit HCC Zelllinien und Fibroblasten sowie histologische Untersuchungen von HCC-Patientengeweben deuten darauf hin, dass ein geringeres Therapieansprechen mit einer verminderten IFNAR1 Expression im weniger differenzierten Gewebe in Zusammenhang steht., The aim of this thesis was to investigate the influence of hepatic fibrosis on tissue resident interferon alpha signaling and additional on interferon alpha therapy on HCC cancer cells. In vitro coculture analysis with HCC cancer cells and fibroblasts and histological analysis of HCC patient tissue let us suggest that lower interferon alpha response rates are associated with lower rates of IFNAR1 in the less differentiated tissue.

Wt1 und Foxd1 sind zwei Transkriptionsfaktoren, die in der Organogenese der Niere beziehungsweise der Leber eine entscheidende Rolle spielen. Ziel dieser Arbeit ist es, Wt1 und Foxd1 im Pankreas nachzuweisen und die Foxd1- und Wt1-positiven Zellen zu charakterisieren. Insbesondere wurde die Bedeutung dieser mesenchymalen Zellen während der fibrotischen Reaktion bei der Pankreatitis untersucht., WT1 and Foxd1 are two transcription factors, which play a decicive role during the organogenesis of the kidney and the liver. The aim of this work is to detect WT1 and Foxd1 in the pancreas and to characterize Wt1- and Foxd1-positive cells. In particular, the significance of these mesenchymal cells during the fibrotic reaction in pancreatitis was investigated.

The data of this thesis revealed that Periostin is crucial for successful regeneration of the exocrine pancreatic compartment after caerulein-induced pancreatitis. Loss of Periostin resulted in pancreatic atrophy and lipomatosis indicating that Periostin is significantly involved in acinar cell fate decisions. Moreover, Periostin was found to promote pancreatic carcinogenesis and to be particularly required for the development of metastases in the secondary target organ. By using a focal adhesion kinase inhibitor the effects of Periostin signaling could be antagonized., Diese Arbeit zeigt, dass Periostin eine wichtige Rolle in der Regeneration des exokrinen Pankreas nach Caerulein-induzierter Pankreatitis spielt. Der Verlust von Periostin resultierte in Pankreasatrophie und Lipomatose was darauf hinweist, dass Periostin einen Einfluss auf den Differenzierungsstatus von Azinuszellen ausübt. Zudem wurden eine tumorfördernde Funktion von Periostin bei der Pankreaskarzinogenese und eine begünstigte Metastasenbildung gefunden. Durch die Inhibierung der fokalen Adhäsionskinase konnten die Effekte von Periostin aufgehoben werden.

Background: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. Methods: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases. Results: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01–12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11–2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36–0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9–16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29–2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis. Conclusions: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis b

Background: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. Methods: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases. Results: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01–12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11–2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36–0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9–16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29–2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis. Conclusions: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis b

Costimulatorischen Signalwegen wurde eine Rolle bei der Antitumorimmunität zugeschrieben. Die Funktion des costimulatorischen Liganden B7-H3 (CD 276) ist bisher weitgehend ungeklärt. Wir untersuchten mit Hilfe von PCR und Immunhistochemie die Expression von B7-H3 im duktalen Adenokarzinom des Pankreas. Die Gen-Expression von B7-H3 war im duktalen Adenokarzinom des Pankreas im Vergleich zum Normalgewebe deutlich erhöht und B7-H3-Protein konnte in Adenokarzinomzellen nachgewiesen werden. Eine hohe Tumor-assoziierte B7-H3-Expression korrelierte hierbei mit einem besseren Überleben der Patienten nach Tumorresektion sowie mit einer erhöhten Anzahl von Tumor-infiltrierenden CD8+ T-Zellen. B7-H3 scheint also eine positive prognostische Rolle beim Pankreaskarzinom zu spielen., Costimulatory signaling has been implicated as a potential regulator of antitumor immunity. Since the exact role of B7-H3 (CD 276) is still elusive, we investigated its expression in pancreatic ductal adenocarcinoma using immunohistochemistry and PCR. The expression of B7-H3 is upregulated in pancreatic ductal adenocarcinoma compared to normal pancreatic tissue and was detectable by immunohistochemistry in adenocarcinoma cells. Furthermore, high tumor B7-H3 expression correlated with better postoperative survival and with the number of tumor-infiltrating CD8+ T-cells. Thus B7-H3 seems to play a positive prognostic role in pancreatic cancer.

Background: Pigment Epithelium-Derived Factor (PEDF) is a nonihibitory-member of the serine protease inhibitor gene family. Materials and Methods: The expression and localization of PEDF was assessed by quantitative-RT-PCR, immunohistochemistry, and quantitative image-analysis. Primary human pancreatic stellate cells (PSC), mouse neuroblastoma and human Schwann cells were used for functional experiments. Results: Cancer cells expressed various levels of PEDF. In cancer cell lines and in human immortalized pancreatic ductal epithelial cells, hypoxia increased PEDF-mRNA up to 132-fold. Higher expression of PEDF in cancer cells was significantly correlated with better patient survival, increased neuropathy, increased PSC activity and extracellular matrix protein production. Conclusion: PEDF increases PSC activity thereby contributing to the desmoplasia of pancreatic cancer. Increased focal PEDF expression in cancer cells correlates with neuropathic changes and better patient survival., Hintergrund: Pigment Epithelium-Derived Factor (PEDF) ist ein nichthemmendes Mitglied der Serin-Protease-Inhibitor-Gen-Familie. Material und Methoden: Die Expression und Lokalisation von PEDF wurde mit quantitativer-RT-PCR, Immunhistochemie und quantitativer Bild-Analyse bestimmt. Primäre humane pankreatische Sternzellen (PSC), murine Neuroblastom- und humane Schwann-Zellen wurden für funktionelle Experimente verwendet. Ergebnisse: Krebszellen exprimierten unterschiedliche Level an PEDF. In Krebszelllinien und in den menschlichen immortalisierten pankreatischen duktalen Epithelzellen erhöhte Hypoxie die PEDF-mRNA Expression bis um das 132-fache. Die höhere Expression von PEDF in Krebszellen korrelierte signifikant mit einer besseren Überlebensrate, mit erhöhter Neuropathie, erhöhter Aktivität der PSC und der extrazellulären Matrix Protein-Produktion. Schlussfolgerung: PEDF erhöht die PSC Aktivität und trägt damit zur Desmoplasie des Pankreaskarzinoms bei. Die gesteigerte PEDF Expression in Krebszellen korreliert mit neuropathischen Veränderungen und einer besseren Überlebensrate.

Ein Teil der perizytären Zellpopulation im murinen Pankreas exprimiert mesenchymale Stammzellmarker. Die vorliegende Arbeit charakterisiert diese Zellen und beschreibt ihre Veränderung während einer sterilen Pankreatitis. Im postinflammatorischen Gewebe zeigt sich eine Vervielfachung der perizytären Zellen und deren mesenchymaler Marker. Darüber hinaus konnte ein Protokoll zur Isolation perizytärer Zellen aus dem murinen Pankreas entwickelt werden., A pericyte cell population in the murine pancreas expresses mesenchymal stem cell marker. This thesis characterizes these cells and starts to define their behavior during sterile inflammation. An enrichment of pericytic cells and their mesenchymal stem cell marker could be observed in the post-inflammatory tissue. Moreover a protocol to isolate pericytes from the murine pancreas was developed.

Recent studies have recognized the role of reactive oxygen species (ROS) in pancreatic inflammation and carcinogenesis. However, no in vivo animal model has been described so far. Caerulein and ethanol have been reported to induce oxidative stress in pancreatic acinar cells. Thus, we tested the efficiency of ROS-generation by combining caerulein and ethanol treatment in pancreatic inflammation and analyze themechanism in detail., Neue Studien belegen, dass reaktive Sauerstoffverbindungen (ROS) bei der Entzündung und Pankreaskarzinogenese eine wichtige Rolle spielen. Dazu wurde allerdings noch kein geeignetes Tiermodel entwickelt. Es konnte jedoch gezeigt werden, dass Caerulein und Ethanol oxidativen Stress in pankreatischenAzinuszellen auslösen kann. Daher haben wir im Tiermodel die Effektivität einer Caerulein/Ethanol Behandlung zur Induktion von ROS-generiertem Stress getestet und den Mechanismus untersucht.

In recent years, multispectral optoacoustic tomography (MSOT) has emerged as a powerful pre-clinical imaging modality and offers promising prospects in clinical practice, particularly to monitor cancer development. MSOT uniquely combines high optical contrast provided by optical imaging and high resolution at deep locations delivered by acoustic imaging. Thereby, MSOT permits the non-invasive acquisition of anatomical and functional information in a single experimental data set. Important considerations to further the capabilities of MSOT are the development of probes to enhance detection sensitivity of molecular targets and the design of new hardware to improve the spatial resolution. Efficient probes are those capable of providing strong optoacoustic signals with a relative low injected dose and therefore reducing toxicity and side effects. First, optoacoustic efficiency is studied using common probes for small-animal optical imaging. Moreover, we developed an optoacoustic spectrometer for the analysis of the optoacoustic spectra of contrast agents at different concentrations in solution. Since measuring microenvironment gradients in solid tumors is important for pre-clinical and clinical research as well as development of theranostic methods, we next sought to study probes identified as efficient in tumor-bearing animals with optoacoustics. A novel mesoscopic MSOT system with enhanced resolution was then developed to examine microenvironment gradients. This mesoscopic system provides cross-sectional optoacoustic images with in-plane resolution of 50 µm and vertical resolution of 300 μm at tissue depths of about 15 mm. The system delivers superior three-dimensional images of nanoparticle distribution, heterogeneous vascular profiles and functional gradients within and around solid tumors in animal models., In den letzten Jahren hat sich die multispektrale optoakustische Tomographie (MSOT) zu einem leistungsfähigen präklinischen Bildgebungsverfahren entwickelt und bietet zudem vielversprechende Möglichkeiten in der klinischen Praxis, wie zum Beispiel das Beobachten der Entstehung von Krebs. MSOT verbindet auf einzigartige Weise den kräftigen Kontrast optischer Bildgebung mit der hohen Auflösung der Ultraschallbildgebung tief im Gewebe. Dadurch ermöglicht MSOT die Differenzierung anatomischer und funktioneller Informationen aus einem einzigen experimentellen Datensatz sowohl nicht-invasiv als auch in vivo. Wichtig für den Fortschritt der MSOT-Technologie sind die Entwicklung molekularer Sonden zur Verbesserung der Nachweisempfindlichkeit und das Design neuer Hardware zur Verbesserung der räumlichen Auflösung. Wichtige Eigenschaften effizienter molekularer Sonden sind starke optoakustische Signale bei relativ niedrigen injizierten Dosen und damit einhergehend eine geringe Toxizität und wenige Nebenwirkungen. In dieser Arbeit wird die optoakustische Effizienz gängiger Kontrastmittel der optischen Kleintierbildgebung untersucht. Dazu wurde ein optoakustisches Spektrometer zur spektralen Analyse optoakustischer Kontrastmittel verschiedener Konzentrationen in wässriger Lösung entwickelt. Da die Kenntnis von Gradienten in der Mikroumgebung von soliden Tumoren wichtig für die präklinische und klinische Forschung sowie die Entwicklung von theranostischen Methoden ist, wurden die als effizient identifizierten molekularen Sonden zudem in tumortragenden Mausmodellen untersucht. Dazu wurde ein mesoskopisches MSOT System mit verbesserter Auflösung zur in-vivo Untersuchung von Tumormikroumgebungen entwickelt. Das System erlaubt mesoskopische optoakustische Querschnittsbildgebung mit einer Auflösung von 50 µm in der Bildgebungsebene und eine vertikale Auflösung von 300 µm bei Gewebetiefen von etwa 15 mm. Das System liefert dreidimensionale Bilder der Verteilung von Nanopartikeln, hete

Trotz präoperativer Desinfektion des OP-Gebiets verbleiben partiell potentiell schädliche Hautkeime und können Wundinfektionen hervorrufen. Eine prospektive Studie der Chirurgischen Klinik und Poliklinik der TUM untersuchte die Effektivität der präoperativen Desinfektion des Bauchnabels und den Einfluss der residualen Keime auf postoperative Wundinfektionen bei Patienten mit elektiver Laparotomie. 25% der Desinfektionen waren unvollständig und von insgesamt sieben Wundinfekten wurde einer von Keimen des Bauchnabels verursacht., Skin contamination is still a risk factor for surgical site infections despite antiseptical skin washing preoperatively. Prospectively collected data of patients with planned laparotomy at the Department of Surgery, TUM, were used to determine the efficacy of preoperative antiseptical skin washing procedure of the umbilicus. Additionally the effect of remaining microbial contamination to surgical site infections was estimated. 25% of the preoperative disinfections were incomplete and one out of seven surgical site infections was caused by umbilicus contamination.

This study investigates the cytoskeleton protein Destrin in the context of perineural invasiveness of pancreatic cancer cells. By a previous method Destrin has been shown to be upregulated in pancreatic adenocarcinoma cancer cells with high nerve invasive potential. The upregulation of Destrin was confirmed by QRT-PCR, immunoblotting and immunohistochemistry. Silencing of Destrin by RNA interference decreased invasiveness, migration and proliferation of Panc-1 pancreatic cancer cells demonstrating Destrin might be related to neural invasiveness of pancreatic cancer cells., Das Zytoskelett-assoziierte Protein Destrin ist in hoch-nervinvasiv wachsenden Pankreaskarzinomzellen überexprimiert wie in einer vorangegangenen Arbeit gezeigt wurde. Die Überexprimierung wurde in dieser Arbeit durch verschieden Analysen bestätigt. Destrin-Supprimierung in Panc-1 Pankreaskarzinomzellen mittels RNA Interferenz zeigte eine geringere Invasivität, Migrations- und Proliferationsfähigkeit der Zellen hinweisend auf eine Bedeutung Destrin‘s für die perineurale Invasion durch Pankreaskarzinomzellen.

Das Adenokarzinom des Pankreas, dessen einziger kurativer Therapieansatz die vollständige Resektion im Gesunden darstellt, ist eine Diagnose, welche mit einer sehr schlechten Prognose einhergeht. Grund hierfür sind die unspezifischen Symptome und der späte Diagnosezeitpunkt. In dieser Arbeit werden bei Patienten mit einem resektablen duktalen Adenokarzinom des Pankreas klinische und tumorspezifische Charakteristika analysiert, um deren Einfluss auf die postoperative Prognose abzuschätzen. Als signifikante Prognosefaktoren stellen sich hierbei einige tumor- und therapiebezogene Merkmale heraus, signifikante präoperative Prognosefaktoren können nicht ermittelt werden. Vielmehr scheint es auch genetische und molekularbiologische Einflüsse auf das Outcome zu geben. Es ist somit nicht möglich, ein präoperatives Prädiktionsmodell zu entwickeln, welches zu einer sinnvollen Therapieentscheidung beiträgt., Pancreatic adenocarcinoma, which can only be cured through surgical resection, is a diagnosis with poor prognosis due to unspecific symptoms and late initial diagnosis. The current work analyzes clinical and tumor-related characteristics of patients with resectable pancreatic ductal adenocarcinoma and evaluates their influence on the postoperative outcome. Some tumor- and therapy-related characteristics appear to be significant prognostic factors, whereas no significant preoperative prognostic factors could be found. On the contrary, it also seems that there are some genetic and molecularbiological factors influencing the outcome. It is therefore not possible to create a preoperative prediction model, which can contribute to a reasonable treatment decision.

Expressionsanalysen an subkutanem Fettgewebe aus Laparatomiewunden zeigen ein charakteristisches Genexpressionsmuster bei Patienten, die postoperative Wundinfektionen (WI) ausbilden. Hierbei zeigten sich nicht nur eine insgesamt reduzierte metabolische Aktivität des Gewebes, sondern auch bestimmte Genkombinationen, die durch hohe Spezifität bezüglich postoperativer WI eine Rolle in der Vorhersage und Prävention von WI einnehmen könnten., Expression analysis of subcutaneous fat tissues from abdominal incisional wounds demonstrates that there is a unique gene expression signature in patients who develop incisional surgical site infections (SSI), predicting SSIs with 80% accuracy and overall indicating a locally reduced metabolic activity.

Das Adenokarzinom des Pankreas ist ein aggressiver Tumor mit einer, aufgrund unspezifischer Symptome und später Erstdiagnose, schlechten Prognose. Einzig kuratives Verfahren ist die vollständige chirurgische Resektion des Tumors im Gesunden, wobei eine Infiltration der mesentericoportalen Venen kein Ausschlusskriterium darstellt. Diese Arbeit untersucht Morbidität und Mortalität nach Pankreatektomie mit vs. ohne Venenresektion. Sie zeigt, dass eine Venenresektion eine mögliche Intervention zum Erreichen von tumorfreien Resektionsrändern darstellt, ohne erhöhte Komplikationsraten, jedoch bei tendenziell geringerem Gesamtüberleben individuell abgewogen werden muss., Pancreatic adenocarcinoma is a malignant tumour with very poor prognosis due to late initial diagnosis. Surgery is the only potentially curative therapy with the infiltration of mesentericoportal veins not being a criterion for exclusion. The present work analyses morbidity and mortality after pancreatectomy with vs. without vein resection. Our data disclose vein resection as a possibility in achieving complete tumor-free resection margins with similar complication rates but a tendency to less overall survival. Therefore, the individual situation must also be taken into account.

As a molecular chaperone, GRP94 is the most abundant glycoprotein in the endoplasmic reticulum, playing an important role in maintaining cellular homeostasis. Here, we investigated the expression and the role of GRP94 in regulating cell growth and apoptosis in pancreatic cancer cells. We found that down-regulation of GRP94 decreases apoptosis resistance in pancreatic cancer cells. Clinically, patients with high GRP94 expression show a tendency for a worsened survival., Als molekulares Chaperon ist GRP94 das Glycoprotein, das am reichlichsten in dem Endoplasmatischen Retikulum vorkommt. Es spielt eine wichtige Rolle bei der Aufrechterhaltung der zellulären Homeostase. Hier untersuchten wir die Expression und die Rolle von GRP94 bei der Regulierung des Zellwachstums und für die Apoptose in Pankreaskarzinomzellen. Unsere Ergebnisse zeigten, dass die Herunter-Regulierung von GRP94 die Apoptose-Resistenz in Pankreaskarzinomzellen verringerte. Klinisch zeigten die Patienten mit einer hohen GRP94-Expression eine Tendenz für ein schlechteres Überleben.

Für die extrem schlechte Prognose des duktalen Pankreaskarzinoms (PDA) ist vor allem die hohe Letalität durch Metastasen-assoziierte Komplikationen verantwortlich. Ziel der Arbeit war die Analyse der gewebsspezifischen Metastasierung des PDA mittels eines in vivo Selektionsmodells. Es konnte gezeigt werden, dass die Repression des Zelladhäsionsproteins E-cadherin durch Histondeacetylasen (HDACs) und den Transkriptionsfaktor Snail zur Epithelialen Mesenchymalen Transition (EMT) und Lungenmetastasierung führt. Dies weist HDACs als Zielstrukturen einer anti-metastatischen Therapie aus., Early metastasis is a hallmark of pancreatic ductal adenocarcinoma (PDA) and responsible for >90% of pancreatic cancer deaths. Using an in vivo passaging approach it was possible to analyse the process of tissue specific metastasis of PDA. It was shown that Histondeacetylases (HDACs) and the transcription factor Snail play an essential role in silencing E-cadherin during the metastatic process of PDA in vivo. These data link HDACs to the process of epithelial-mesenchymal transition (EMT) and metastasis and suggest that HDACs are promising targets for antimetastatic therapy.

Der Einsatz mechatronischer Supportsysteme soll den Operateur bei der Durchführung laparoskopischer Eingriffe unterstützen. Als wichtigster Vertreter einer neuen, zweiten Generation der Kameranachführungssysteme ist der SOLOASSIST Gegenstand der vorliegenden Untersuchung. Anhand der Untersuchungskriterien Funktionalität, Zuverlässigkeit, Handhabung, klinischer Einsatz im Modell- und Tierversuch sowie Akzeptanz bei ärztlichem und nicht-ärztlichem Operationspersonal wird der SOLOASSIST auch in Relation zu einem Vertreter der ersten Generation („AESOP“) evaluiert., The use of a mechatronical support system shall facilitate the surgeon during laparoscopic interventions. As the most important representative of a new, second generation camera control system the SOLOASSIST is the object of the present analysis. By the criteria of functionality, realibility, feasibility, clinical application in in and ex vivo experiments as well as acceptance by the medical staff the SOLOASSIST is evaluated also in relation to a representative of a first generation system (AESOP).

Pankreatische Neuritis (PN) ist ein histopath. Merkmal in chronischer Pankreatitis (CP) und im Pankreaskarzinom (PC) und ist mit neuropathischen abdominellen Schmerzen assoziiert. In dieser Arbeit wurden die Immunzelltypen in der PN immunhistochem. analysiert. Dabei zeigte sich, dass PN aus Makrophagen, CD8+ T-Lymphozyten und Mastzellen (MC) besteht. Schmerzen waren mit einer spez. Zunahme der MC in PN assoziiert. Dies deutet auf eine MC-induzierte Hypersensitivität im PC und in der CP hin., Pancreatic Neuritis (PN) is a histopath. feature of chronic pancreatitis (CP) and pancreatic carcinoma (PC) and correlates with abdominal neuropathic pain. In this dissertation immune cell subtypes composing PN were immunhistochemically quantified and correlated to the presence of pain. Here we could show that macrophages, CD8+ T-Lymphocytes and mast cells (MC) were the dominant cells in PN. Pain correlated with a specific elevation of MC in PN, suggesting MC-induced hypersensitivity in PC and CP.

Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy with an extremely poor prognosis, as shown by a 1-year survival rate of around 18% for all stages of the disease. The low survival rates associated with PDAC primarily reflect the fact that tumours progress rapidly with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. As a result, there is an urgent need to develop accurate markers of pre-invasive pancreatic neoplasms in order to facilitate prediction of cancer risk and to help diagnose the disease at an earlier stage. However, screening for early diagnosis of prostate cancer remains challenging and identifying a highly accurate, low-cost screening test for early PDAC for use in clinical practice remains an important unmet need. More effective therapies are also crucial in PDAC, since progress in identifying novel therapies has been hampered by the genetic complexity of the disease and treatment remains a major challenge. Presently, the greatest step towards improved treatment efficacy has been made in the field of palliative chemotherapy by introducing FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel. Strategies designed to raise the profile of PDAC in research and clinical practice are a further requirement in order to ensure the best treatment for patients. This article proposes a number of approaches that may help to accelerate progress in treating patients with PDAC, which, in turn, may be expected to improve the quality of life and survival for those suffering from this devastating disease., SCOPUS: ar.j, info:eu-repo/semantics/published

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and shows resistance to any therapeutic strategy used. Here we tested small-molecule inhibitors targeting chromatin regulators as possible therapeutic agents in PDAC. We show that JQ1, an inhibitor of the bromodomain and extraterminal (BET) family of proteins, suppresses PDAC development in mice by inhibiting both MYC activity and inflammatory signals. The histone deacetylase (HDAC) inhibitor SAHA synergizes with JQ1 to augment cell death and more potently suppress advanced PDAC. Finally, using a CRISPR-Cas9-based method for gene editing directly in the mouse adult pancreas, we show that de-repression of p57 (also known as KIP2 or CDKN1C) upon combined BET and HDAC inhibition is required for the induction of combination therapy-induced cell death in PDAC. SAHA is approved for human use, and molecules similar to JQ1 are being tested in clinical trials. Thus, these studies identify a promising epigenetic-based therapeutic strategy that may be rapidly implemented in fatal human tumors.