[Transanal Endoscopic Microsurgery (TEM) is a surgical option to preserve fecal continence in selected low rectal cancers]. / Die Transanale Endoskopische Mikrochirurgie (TEM) ist eine chirurgische Option zur Erhaltung der Stuhlkontinenz bei ausgewählten tiefsitzenden Rektumkarzinomen.

INTRODUCTION: Despite its existence for more than 40 years, the TEM method has not become widespread. The main reasons are the high acquisition costs, the sophisticated technology and alternative procedures (especially radical resection procedures), which provide greater oncological safety. However, avoiding major abdominal surgery with the creation of a stoma and higher complication rates can outweigh the higher risk of recurrence for some patients. We examined the results using V-TEM with reduced acquisition costs in the resection of adenomas and carcinomas and discussed its importance by literature . METHOD: From 2003 to 2019, 154 patients with 170 findings were operated by V-TEM technology. Data on the operation and follow-up were collected and analyzed retrospectively. RESULTS: The median age was 67 years, 89 patients were male and 65 female. V-TEM was performed on 79 carcinomas, 77 adenomas and 14 other findings. The complication rate was 21.2 %. R0 resection was achieved in 78.8 %. The adenoma recurrence rate was 7.3 %, the overall recurrence rate for carcinomas 11.9 %, local recurrences were observed in 6.8 %. The disease-specific survival is 100 % at 5 years and 94.2 % at ten years. DISCUSSION: The successful use of TEM in adenomas and early carcinomas is undisputed. When treating carcinomas from a T1 high risk stage using TEM, recurrence rates higher than 10 % must be expected. Better results can be achieved with radical procedures, this is why they are considered the therapy of choice in these cases. However, there are no differences in terms of survival rates and TEM offers proven better postoperative quality of life. In particular, the combination of neoadjuvant procedures with TEM delivered promising results in more advanced stages. Further studies on TEM and the possibility of lower acquisition costs through modification to V-TEM could make the method more popular in the future.

New Onset of Diabetes and Pancreatic Exocrine Insufficiency After Pancreaticoduodenectomy for Benign and Malignant Tumors: A Systematic Review and Meta-analysis of Long-term Results.

OBJECTIVE: The aim of this study was to assess the frequency and severity of new onset of diabetes mellitus (NODM) and pancreatic exocrine insufficiency (PEI) after pancreaticoduodenectomy (PD) for benign and malignant tumors. SUMMARY BACKGROUND DATA: When PD is performed on patients for benign tumors, the question of long-term metabolic dysfunctions becomes of importance. METHODS: Medline/PubMed, Embase, and Cochrane Library were searched for articles reporting results of measuring endocrine and exocrine pancreatic functions after PD. The methodological quality of 19 studies was assessed by means of the Newcastle-Ottawa scale and Moga-Score. The mean weighted overall percentages of NODM and PEI after PD were calculated with a 95% confidence interval (CI). RESULTS: Of 1295 patients, data valid-for-efficacy-analysis are based on 845 patients measuring pancreatic endocrine and on 964 patients determining exocrine functions after PD. The cumulative incidence of NODM was 40 of 275 patients (14.5%; 95% CI: 10.3-18.7) in the benign tumor group, 25 of 161 (15.5%; 95% CI: 9.9-21.2) in the malignant tumor group, and 91 of 409 patients (22.2%; 95% CI: 18.2-26.3) in the benign and malignant tumor group. Comparing the frequency of NODM after PD revealed significant differences between the groups (benign vs benign and malignant P < 0.0121; malignant vs benign and malignant P < 0.0017). Exocrine pancreatic insufficiency was found in the benign tumor group in 76 of 301 patients (25.2%; 95% CI: 20.3-30.7) and in the malignant tumor group in 80 of 163 patients (49.1%, 95% CI: 41.4-56.8) (P < 0.0001). CONCLUSION: The results of a significant increase of NODM after PD for benign and malignant tumors and a significant decrease of exocrine functions contribute to a rational weighting of metabolic long-term risks following PD.

The Indications for Laparoscopic Pancreatectomy.

BACKGROUND: Laparoscopic pancreatectomy is not yet established as a routine procedure everywhere in Germany or in other countries. Few data are available on its short- and long-term outcomes. METHODS: From 2008 onward, a working group initiated by 10 centers and currently comprising 34 centers has gathered data on all cases of laparoscopic pancreatectomy. Procedures in which laparoscopy was converted to open surgery are also included. RESULTS: The registry now contains 550 data sets representing 267 cases of benign disease, 244 malignancies, and 39 borderline tumors. The most common procedure was laparoscopic left pancreatectomy, followed by resection of the head of the pancreas and tumor enucleation. The most common intraoperative complication was hemorrhage, with a frequency of 3%. The rate of conversion to open surgery was 35%; if minilaparotomies are excluded, the conversion rate was only 16%. 39% of patients developed a pancreatic fistula after surgery (usually grade A or B, with 1.5% grade C) and 3% underwent reoperation because of postoperative hemorrhage. The procedure-related mortality was 1.3%. 91% of the patients reported only very mild postoperative pain. 6.7% newly developed diabetes mellitus after the procedure. CONCLUSION: The patient cohort in the registry consists of persons who were selected to undergo laparoscopic pancreatectomy by the participating hospital teams, and the data are thus inherently affected by selection bias. The operative procedures that they underwent reflect the current practice of laparoscopic pancreatectomy in Germany. The complication rates are similar to those of open surgery. Selection bias can be avoided only by a randomized trial.

Open Surgical versus Minimal Invasive Necrosectomy of the Pancreas-A Retrospective Multicenter Analysis of the German Pancreatitis Study Group.

BACKGROUND: Necrotising pancreatitis, and particularly infected necrosis, are still associated with high morbidity and mortality. Since 2011, a step-up approach with lower morbidity rates compared to initial open necrosectomy has been established. However, mortality and complication rates of this complex treatment are hardly studied thereafter. METHODS: The German Pancreatitis Study Group performed a multicenter, retrospective study including 220 patients with necrotising pancreatitis requiring intervention, treated at 10 hospitals in Germany between January 2008 and June 2014. Data were analysed for the primary endpoints "severe complications" and "mortality" as well as secondary endpoints including "length of hospital stay", "follow up", and predisposing or prognostic factors. RESULTS: Of all patients 13.6% were treated primarily with surgery and 86.4% underwent a step-up approach. More men (71.8%) required intervention for necrotising pancreatitis. The most frequent etiology was biliary (41.4%) followed by alcohol (29.1%). Compared to open necrosectomy, the step-up approach was associated with a lower number of severe complications (primary composite endpoint including sepsis, persistent multiorgan dysfunction syndrome (MODS) and erosion bleeding: 44.7% vs. 73.3%), lower mortality (10.5% vs. 33.3%) and lower rates of diabetes mellitus type 3c (4.7% vs. 33.3%). Low hematocrit and low blood urea nitrogen at admission as well as a history of acute pancreatitis were prognostic for less complications in necrotising pancreatitis. A combination of drainage with endoscopic necrosectomy resulted in the lowest rate of severe complications. CONCLUSION: A step-up approach starting with minimal invasive drainage techniques and endoscopic necrosectomy results in a significant reduction of morbidity and mortality in necrotising pancreatitis compared to a primarily surgical intervention.

PSP/reg inhibits cultured pancreatic stellate cell and regulates MMP/ TIMP ratio.

BACKGROUND: Pancreatic stellate cells (PSC) play a central role in fibrogenesis associated with acute and chronic pancreatitis. Pancreatic stone protein/regenerating protein (PSP/reg) belongs to a family of secretory stress proteins (SSP) that are constitutively synthesized by pancreatic acinar cells and upregulated dramatically during acute and chronic pancreatitis. Assuming a protective role of this stress protein, we investigated its effects on human PSC. MATERIAL AND METHODS: Pancreatic stellate cells were obtained by outgrowth from fibrotic human pancreas tissue. PSP/reg was expressed in the yeast Pichia pastoris and purified from medium supernatants. PSP/reg was added at concentrations of 100 ng/mL to cultured PSC. Cell proliferation was determined by bromodeoxyuridine incorporation. PSC migration was assessed by a wound healing assay. Extracellular matrix (collagen type I and fibronectin), matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) were demonstrated on protein level. RESULTS: Pancreatic stone protein/regenerating protein inhibited PSC proliferation and migration. Soluble collagen I and fibronectin were reduced after the addition of PSP/reg. PSP/reg slightly decreased the synthesis of MMP-1 and MMP-2 and strongly decreased TIMP-1 and TIMP-2 concentrations in PSC supernatants. CONCLUSIONS: Our work describes a novel aspect that in vitro PSP/reg reduces PSC activity (proliferation and migration) and stimulates fibrolysis by increasing MMP/TIMP ratio. The findings suggest that PSP/reg might have a protective function in the repair phase of acute and chronic pancreatitis by promoting resolution of fibrosis. We highlight PSP/reg as an antifibrogenic protein in pancreatic injury.

Interaction of stellate cells with pancreatic carcinoma cells.

Pancreatic cancer is characterized by its late detection, aggressive growth, intense infiltration into adjacent tissue, early metastasis, resistance to chemo- and radiotherapy and a strong "desmoplastic reaction". The dense stroma surrounding carcinoma cells is composed of fibroblasts, activated stellate cells (myofibroblast-like cells), various inflammatory cells, proliferating vascular structures, collagens and fibronectin. In particular the cellular components of the stroma produce the tumor microenvironment, which plays a critical role in tumor growth, invasion, spreading, metastasis, angiogenesis, inhibition of anoikis, and chemoresistance. Fibroblasts, myofibroblasts and activated stellate cells produce the extracellular matrix components and are thought to interact actively with tumor cells, thereby promoting cancer progression. In this review, we discuss our current understanding of the role of pancreatic stellate cells (PSC) in the desmoplastic response of pancreas cancer and the effects of PSC on tumor progression, metastasis and drug resistance. Finally we present some novel ideas for tumor therapy by interfering with the cancer cell-host interaction.

Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL).

Mechanisms leading to acute pancreatitis after a fat-enriched meal combined with excess alcohol are incompletely understood. We have studied the effects of alcohol and fat (VLDL) on pancreatic acinar cell (PAC) function, oxidative stress, and repair mechanisms by pancreatic stellate cells (PSC) leading to fibrogenesis. To do so, PAC (rat) were isolated and cultured up to 24 h. Ethanol and/or VLDL were added to PAC. We measured PAC function (amylase, lipase), injury (lactic dehydrogenase), apoptosis (TUNEL, Apo2.7, annexin V binding), oxidative stress, and lipid peroxidation (conjugated dienes, malondialdehyde, chemoluminescence); we also measured PSC proliferation (bromodeoxyuridine incorporation), matrix synthesis (immunofluorescence of collagens and fibronectin, fibronectin immunoassay), and fatty acids in PAC supernatants (gas chromatography). Within 6 h, cultured PAC degraded and hydrolyzed VLDL completely. VLDL alone (50 microg/ml) and in combination with alcohol (0.2, 0.5, and 1% vol/vol) induced PAC injury (LDL, amylase, and lipase release) within 2 h through generation of oxidative stress. Depending on the dose of VLDL and alcohol, apoptosis and/or necrosis were induced. Antioxidants (Trolox, Probucol) reduced the cytotoxic effect of alcohol and VLDL. Supernatants of alcohol/VLDL-treated PAC stimulated stellate cell proliferation and extracellular matrix synthesis. We concluded that, in the presence of lipoproteins, alcohol induces acinar cell injury. Our results provide a biochemical pathway for the clinical observation that a fat-enriched meal combined with excess alcohol consumption can induce acinar cell injury (acute pancreatitis) followed by repair mechanisms (proliferation and increased matrix synthesis in PSC).

Pancreatitis-associated protein inhibits human pancreatic stellate cell MMP-1 and -2, TIMP-1 and -2 secretion and RECK expression.

BACKGROUND/AIMS: Pancreatic stellate cells (PSCs) play a key role in fibrogenesis associated with acute and chronic pancreatitis. Pancreatitis-associated protein (PAP), an acute-phase protein, is dramatically upregulated during acute and chronic pancreatitis. Assuming a protective role of PAP, we investigated its effects on human PSCs. METHODS: PSCs were obtained by outgrowth from fibrotic human pancreas tissue. PAP was expressed in the yeast Pichia pastoris. PAP was added at 10 ng/ml to cultured PSCs. Cell proliferation was determined by bromodeoxyuridine incorporation. PSC migration was assessed by a wound healing assay. Collagen types I and III, fibronectin, matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs) and reversion-inducing cysteine-rich protein with Kazal motifs (RECK) were demonstrated on protein and mRNA level. RESULTS: PAP had no significant effect on PSC proliferation and migration. Cell-associated fibrillar collagen types I and III and fibronectin increased after addition of PAP to PSCs. PAP diminished the expression of MMP-1 and -2 and TIMP-1 and -2 and their concentrations in PSC supernatants. RECK was detected on the surface of PSCs and its expression was reduced after PAP application. CONCLUSIONS: Our data offer new insights into the biological functions of PAP, which may play an important role in wound healing response and cell-matrix interactions.

Pancreatic stellate cells--role in pancreas cancer.

BACKGROUND: Adenocarcinomas of the pancreas are characterized by a rapid progression, an early metastasis, a limited response to chemo- and radiotherapy, and an intense fibrotic reaction known as tumor desmoplasia. Carcinoma cells are surrounded by a dense stroma consisting of myofibroblast-like cells, collagens, and fibronectin. MATERIALS AND METHODS: This review describes the interaction of activated pancreatic stellate cells (myofibroblast-like cells) with tumor cells in pancreas adenocarcinomas. Our data were obtained in cell culture experiments and in in vivo investigations. RESULTS: Carcinoma cells produce soluble mediators and stimulate motility, proliferation, matrix-, and MMP synthesis of stellate cells. Vice versa-activated stellate cells release mitogens, stimulating proliferation of cancer cells. Cancer cell proliferation and resistance to apoptosis might further be induced by the microenvironment (extracellular matrix), which is primarily provided by stellate cells. A very important aspect in the interaction of stellate cells with cancer cells is the expression of EMMPRIN (extracellular matrix metalloproteinase inducer) by cancer cells, the shedding of the extracellular part of EMMPRIN by matrix metalloproteinases (MMPs), and the induction of MMPs in stellate cells by soluble EMMPRIN. In particular, the stellate cells in close proximity to tumor cells therefore express MMPs and degrade connective tissue. CONCLUSION: Through complex interactions between stellate cells and carcinoma cells, tumor progression and cancer cell invasion are accelerated. As we gain better understanding of these mechanisms, adequate therapies to reduce tumor cell invasion and cancer progression might be developed.

Pancreatic stellate cells are an important source of MMP-2 in human pancreatic cancer and accelerate tumor progression in a murine xenograft model and CAM assay.

The effect of the characteristic desmoplastic reaction of pancreatic cancer on tumor progression is largely unknown. We investigated whether pancreatic stellate cells, which are responsible for the desmoplastic reaction, support tumor progression. Immunohistology revealed that matrix metalloproteinase-2 (MMP-2), which is suggested to promote pancreatic cancer progression, is present in stellate cells adjacent to cancer cells. In vitro, stellate cells exhibited a much higher basal expression of MMP-2 compared with cancer cells. Panc1-, MiaPaCa2- and SW850-conditioned media stimulated MMP-2 release of stellate cells as detected by zymography. Cancer cells expressed and released basigin [BSG, extracellular matrix metalloproteinase inducer (EMMPRIN), CD147], a glycoprotein that is known to stimulate MMP-2 in mesenchymal cells, as detected by immunostaining, western blot and reverse transcription-polymerase chain reaction. Tumor cell-conditioned medium and BSG purified by affinity chromatography from supernatants of cancer cells, but not supernatants depleted from BSG, stimulated expression of MMP-1 and MMP-2 of stellate cells as demonstrated by western blot and zymography. Moreover, the interaction of stellate cells and cancer cells promoted the invasiveness of Panc-1 cells in the chorioallantoic membrane assay and increased the weight of tumors induced by all carcinoma cell lines in nude mice by 2.1-3.7-fold. Our findings support the assumption that the interaction of stellate cells and cancer cells promotes progression of pancreatic cancer.

Role of stellate cells in pancreatic fibrogenesis associated with acute and chronic pancreatitis.

Pancreas fibrosis is the result of a dynamic cascade of mechanisms beginning with acinar cell (AC) injury and necrosis and followed by inflammation, activation of macrophages, aggregation of platelets, release of growth factors and reactive oxygen species (ROS), activation of pancreatic stellate cells (PSC), stimulated synthesis of extracellular matrix and reduced matrix degradation. The result is a net matrix accumulation. Numerous in vivo and in vitro studies have provided strong evidence of a central role for PSC in fibrogenesis associated with acute and chronic pancreatitis. The PSC share homologies with hepatic stellate cells (HSC). In normal pancreas, the fat-storing phenotype of PSC is found in low numbers (approx. 4% of the cells) in the periacinar and interlobular space. Similar to the stellate cell-activating mechanisms in the liver, in pancreas injury PSC change their phenotype from the fat-storing to a highly active matrix-producing cell type (activated PSC). The induction of the activated phenotype of PSC has been shown to involve a number of diverse extra- and intracellular effector molecules, including inflammatory cytokines, growth factors, ethanol, acetaldehyde, and oxidative stress.

Pseudocyst treatment in chronic pancreatitis--surgical treatment of the underlying disease increases the long-term success.

BACKGROUND: For reasons of persisting controversies concerning indications for surgery, we evaluated chronic pancreatitis patients following pancreatic head resection or drainage procedure for pseudocysts located in the pancreatic head. MATERIAL AND METHODS: 206 patients (166 male, 40 female) with chronic pancreatitis and pseudocysts in the pancreatic head were operated between April 1982 and July 2001. 169 patients (82%) were treated with the duodenum-preserving pancreatic head resection, a pseudocyst-jejunostomy was performed in 37 patients (18%). RESULTS: The hospital mortality was 0.4%. The late mortality was 19% in a median follow-up of 7.3 years. The rate of patients with complete relief of pain was significantly higher after resection compared to drainage procedure in the long-term follow-up (94 vs. 75%; p = 0.003). With regard to recurrence of pseudocysts, patients had an elevated rate of reoperations following drainage procedure (13 vs. 1%; p = 0.008). The endocrine function was significantly better preserved in patients of the drainage group compared to the resection group (no diabetes 67 vs. 35%, p < 0.01). CONCLUSION: The resection has, compared to drainage procedures alone, the advantage of low recurrence rate of pseudocysts and a high rate of pain-free patients in the long-term follow-up. However, the risk of diabetes is increased in the resection group.

Transcriptome analysis of human hepatic and pancreatic stellate cells: organ-specific variations of a common transcriptional phenotype.

Pancreatic stellate cells (PSCs) are thought to be the primary source of the extensive fibrotic reaction characteristic of pancreatic cancer and chronic pancreatitis in humans. PSCs share many morphological and functional characteristics with hepatic stellate cells (HSCs), whose central role in liver fibrosis is well established. However, it has remained unclear if hepatic and pancreatic stellate cells are derived from a common cell lineage and if they are completely similar or if they possess organ-specific features. We have analysed the transcriptomes of HSCs, PSCs and skin fibroblasts to assess how the transcriptional phenotype of stellate cells differs from that of a typical fibroblast lineage cell and if there is evidence for a common stellate cell precursor. To this end, we have performed expression profiling of primary cultures of human HSCs, PSCs and skin fibroblasts using 23,000-feature 'whole genome' oligonucleotide micro-arrays. Expression data were verified using real-time PCR. The expression profiles of HSCs and PSCs displayed a great extent of similarity, clearly separating them from the fibroblasts. Predominantly extracellular and cell surface genes, but also signalling molecules, transcription factors and novel neural markers, were concordantly expressed in both stellate cell types. Despite this high degree of similarity, distinct differences in expression patterns were observed between HSCs and PSCs, reflecting organ-specific variations of the common stellate cell-specific phenotype.

Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells.

BACKGROUND & AIMS: Tumor desmoplasia is one of the representative histopathologic findings in ductal pancreatic adenocarcinoma. The aims of this study were to examine the cellular and molecular mechanisms of fibrogenesis associated with pancreatic adenocarcinomas. METHODS: Immunostainings were performed with human pancreatic adenocarcinomas (n = 27) and tumors induced in nude mice (n = 36) by subcutaneously injecting MiaPaCa2, Panc1, and SW850 with and without pancreatic stellate cells. Matrix-producing cells were isolated from pancreatic adenocarcinomas and compared with pancreatic stellate cells isolated from tissue of chronic pancreatitis. Paracrine stimulation of pancreatic stellate cells by carcinoma cells was studied regarding matrix synthesis (collagen and c-fibronectin on protein and messenger RNA level) and cell proliferation (bromodeoxyuridine incorporation). RESULTS: High numbers of desmin and alpha-smooth muscle actin-positive cells were detected in 26 of 27 pancreatic adenocarcinomas. Intense fibronectin and collagen stainings were associated with these cells. By using cytofilament stainings, gene expression profiling, and morphological examinations, the matrix-producing cells obtained by the outgrowth method from pancreatic adenocarcinomas were identified as pancreatic stellate cells. Supernatants of MiaPaCa2, Panc1, and SW850 cells stimulated proliferation and collagen type I and c-fibronectin synthesis of cultured pancreatic stellate cells. Preincubation of the carcinoma cell supernatants with neutralizing antibodies against fibroblast growth factor 2, transforming growth factor beta 1, and platelet-derived growth factor significantly reduced the stimulatory effects. Subcutaneous injection of carcinoma cells and pancreatic stellate cells induced fast-growing subcutaneous fibrotic tumors in nude mice. Morphometric analysis of carcinoma cells (cytokeratin stainings) showed a high density of carcinoma cells in these tumors. CONCLUSIONS: Pancreatic stellate cells strongly support tumor growth in the nude mouse model. The increased deposition of connective tissue in pancreatic carcinoma is the result of a paracrine stimulation of pancreatic stellate cells by carcinoma cells.

Oxygen radical production precedes alcohol-induced acute pancreatitis in rats.

INTRODUCTION: Ethanol is involved in approximately 40% of the cases of acute pancreatitis. AIMS: To investigate the influence of ethanol on the pancreatic generation of oxygen-free radicals (OFR) in alcohol-induced acute pancreatitis as one possible pathway of proenzyme activation in this disease. METHODOLOGY: In one model of acute pancreatitis, the combination of ethanol with mild stimulation of the pancreas and short-term duct obstruction leads to acute pancreatitis within 24 hours. Pancreatic tissue and blood samples were assessed for reduced (GSH) and oxidized (GSSG) glutathione, malondialdehyde, conjugated dienes (CD), and myeloperoxidase. The histologic development of the acute pancreatitis was followed between 0.5 and 24 hours. RESULTS: Ethanol systemically decreased the radical defense system (GSSG: control 0.49 +/- 0.58, ethanol 2.76 +/- 1.44, p < 0.001; GSH: control 10.13 +/- 4.45, ethanol 9.52 +/- 3.43, p < 0.05). In the pancreas, oxygen free radicals also led to membrane peroxidation (CD: control 3.70 +/- 1.67, ethanol 6.10 +/- 2.15, p < 0.05). When alcoholic pancreatitis was induced, the level of oxygen radicals further increased (GSSG: control 0.17 +/- 0.15, ethanol 0.27 +/- 0.17, p < 0.005, pancreatitis 0.42 +/- 0.29). CONCLUSIONS: Ethanol induces the generation of oxygen radicals in pancreatic acinar cells. These levels increase upon induction of alcohol-induced pancreatitis. Similar to other models of acute pancreatitis, OFRs may therefore be involved in activating the cascade of self-digestion in alcohol-induced pancreatitis.