Loss of Intestinal Alkaline Phosphatase Leads to Distinct Chronic Changes in Bone Phenotype.

BACKGROUND: The gut is becoming increasingly recognized as the source of various systemic diseases, and recently, it has been linked to bone metabolism via the so-called gut-bone axis. The microbiome and gut-derived mediators are thought to impact upon bone metabolism, and administration of probiotics has been shown to have beneficial effects in bone. The gut brush border enzyme intestinal alkaline phosphatase (IAP) plays an important role in controlling calcium absorption, inhibiting lipopolysaccharides, and other inflammatory mediators responsible for endotoxemia and appears to preserve the normal gut microbiota. Interestingly, IAP-deficient mice (AKP3-/-) also display a significant decrease in fecal Lactobacillus, the genus shown to be beneficial to bone. MATERIALS AND METHODS: IAP mRNA levels in mouse bone were measured using quantitative real-time polymerase chain reaction. Femurs of IAP-knockout (KO) and wild-type (WT) mice were analyzed by microcomputed tomography and histopathology. Serum levels of alkaline phosphatase, calcium, and phosphorus were measured. Target cell response upon exposure to serum from IAP-KO and WT mice was quantified using primary bone marrow macrophages. RESULTS: IAP was not significantly expressed in bones of WT or KO animals. IAP (alkaline phosphatase 3) expression in bone was vanishingly low compared to the duodenum (bone versus duodenum, 56.9 ± 17.7 versus 25,430.3 ± 10,884.5 relative expression, P = 0.01). Bone histology of younger IAP-KO and WT animals was indistinguishable, whereas older IAP-deficient mice showed a distinctly altered phenotype on histology and computed tomography scan. Younger KO mice did not display any abnormal levels in blood chemistry. Older IAP-KO animals showed an isolated increase in serum alkaline phosphatase levels reflecting an environment of active bone formation (IAP-WT versus IAP-KO, 80 ± 27.4 U/I versus 453 ± 107.5 U/I, P = 0.004). There was no significant difference in serum calcium or phosphorus levels between KO and WT mice. Serum from IAP-KO mice induced a significantly higher inflammatory target cell response. CONCLUSIONS: Through its multiple functions, IAP seems to play a crucial role in connecting the gut to the bone. IAP deficiency leads to chronic changes in bone formation, most likely through dysbiosis and systemic dissemination of proinflammatory mediators.

Endoscopic vacuum therapy for various defects of the upper gastrointestinal tract.

BACKGROUND: Postoperative, iatrogenic or spontaneous upper gastrointestinal defects result in significant morbidity and mortality of the patients. In the last few years, endoscopic vacuum therapy (EVT) has been recognized as a new promising method for repairing upper gastrointestinal defects of different etiology. However, probably due to insufficient data and no commercially available system for EVT of the upper gastrointestinal tract, until the end of 2014, covering of esophageal defects with self-expanding metal stents (SEMS) were still the mainstay of endoscopic therapy. The aim of this article is to review the data available about EVT for various upper gastrointestinal defects. METHODS: A selective literature search was conducted in Medline and PubMed (2007-2016), taking into account all the published case series and case reports reporting on the use of EVT in the management of upper gastrointestinal defects. RESULTS: EVT works through intracorporal application of negative pressure at the defect zone with an electronic controlled vacuum device along a polyurethane sponge drainage. This results in closure of the esophageal defect and internal drainage of the septic focus, simultaneously. Compared to stenting, EVT enables regular viewing of wound conditions with control of the septic focus and adjustment of therapy. Moreover, endoscopical negative pressure is applicable in all esophageal regions (cricopharygeal, tubular, gastroesophageal junction) and in anastomotic anatomic variants. EVT can be used solely as a definite treatment or as a complimentary therapy combined with operative revision. In total, there are published data of more than 200 patients with upper gastrointestinal defects treated with EVT, showing succes rates from 70-100%. CONCLUSION: The available data indicate that EVT is feasible, safe and effective with good short-term and long-term clinical outcomes in the damage control of upper GI-tract leaks. Still, a prospective multi-center study has to be conducted to proof the definite benefit of EVT for patients with esophageal defects.

Prognostic value of primary tumor sidedness in patients with non-metastatic IBD related CRC - Is it the exception to the rule?

BACKGROUND: Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in patients with IBD-CRC. METHODS: All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence-free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS. RESULTS: A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98). CONCLUSIONS: In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC.

Impact of Modern Drug Therapy on Surgery: Ulcerative Colitis.

BACKGROUND: The primary treatment of ulcerative colitis (UC) is conservative, and substantial therapeutic progress has been made in the past few decades. Meanwhile, biologicals have become a mainstay in the treatment for steroid-refractory UC. Despite further development of drug therapy and an increased time span to operation, a significant proportion of patients with UC require surgical intervention. Surgical intervention needs to be carried out in medically refractory cases, imminent or malignant transformation, or complications. This article discusses the impact of modern drug therapy on surgery for UC. METHODS: A selective literature search of PubMed was conducted, taking into account current studies, reviews, meta-analyses, and guidelines. Selected articles were then reviewed in detail and recommendations were drafted based on data and conclusions of the articles. RESULTS: In recent years, modern drug therapy has changed the timing, approach, and outcomes of surgery for UC. Most of the studies showed a decrease in surgery rates over time while the rate of emergency colectomies remains unchanged. So far, no convincing surgery-sparing effect of newer medications has been established, and it remains debatable if surgery rates have decreased because of improved management for UC in general or due to the introduction of biologicals. The intensified conservative therapy with increasing use of biologics has been accompanied by a trend towards performing a three-step procedure in the last decade. There is a subset of patients with complex refractory disease who most likely benefit from elective surgery as an alternative to prolonged conservative therapies after failure of first-line treatment. The majority of patients after ileal pouch-anal anastomosis can avoid hospitalizations and colitis-related medications with their associated potential adverse effects. In addition, the procedure substantially reduces UC-related symptoms and the risk for dysplasia or cancer. There is a long-term pouch success rate of >90% after 10 and 20 years of follow-up. CONCLUSION: Conservative medical therapy in the treatment of UC will continue to develop and the number of approved therapeutics will grow. Surgery should not be considered as the negative endpoint of treatment modalities but as a good alternative to a prolonged conservative therapy for some patients. In conclusion, a close cooperation between the various disciplines in the pre- and postoperative management is essential in order to optimize the timing and outcome of patients with UC.

Defining the Need for Surgery in Small-Bowel Obstruction.

BACKGROUND: Small-bowel obstruction is a frequent disorder in emergency medicine and represents a major burden for patients and health care systems worldwide. Within the past years, progress has been made regarding the management of small-bowel obstructions, including the use of contrast agent swallow as a tool in the decision-making process. OBJECTIVES: This is a prospective controlled study investigating the central role of contrast agent swallow in the diagnostic and treatment algorithm for small-bowel obstruction at a university department of surgery. Endpoints were the correct identification of patients who needed operative treatment and the accuracy of a conservative treatment decision including the analysis of dropout from this routine algorithm. METHODS: We performed a single-center analysis of 181 consecutive patients diagnosed with a small-bowel obstruction based on clinical, radiologic, and sonographic findings. Patients with clinical signs of strangulation or peritonitis underwent immediate surgery (group 1). Patients without signs of peritonitis and incomplete stop in the initial abdominal plain film were considered eligible for Gastrografin® challenge (group 2). RESULTS: Seventy-six of the 181 patients (42.0%) underwent immediate surgery. A Gastrografin® challenge was initialized in 105 of the 181 patients (58.0%). Twenty of these 105 patients (19.1%) with persisting or progressive symptoms and absence of contrast agent in the colon after 12 and 24 h subsequently underwent surgery. Here, a segmental bowel resection was necessary in 6 of these 20 patients (30.0%). In 16 out of 20 patients (80.0%) who failed the Gastrografin® challenge, a corresponding correlate in terms of a strangulation was detected intraoperatively. The Gastrografin® challenge had a specificity of 96% and a sensitivity of 100%; accuracy to predict the need for exploration was 96%. CONCLUSION: A straightforward algorithm based mainly on contrast agent swallow for patients with small-bowel obstructions enabled a timely and very accurate differentiation between patients qualifying for conservative and operative treatment.

IGF-1 induces the epithelial-mesenchymal transition via Stat5 in hepatocellular carcinoma.

It has been reported that the epithelial-mesenchymal transition (EMT) plays an important role in hepatocellular carcinoma (HCC). However, the relationship between the insulin-like growth factor-1 (IGF-1) and EMT of HCC was not fully elucidated. In the present work, we found that the expression of N-cadherin, Vimentin, Snail1, Snail2, and Twist1 was positively associated with IGF-1R expression, while E-cadherin expression was negatively associated with IGF-1 expression in human HCC samples. Furthermore, we observed that IGF-1 up-regulated the expression of N-cadherin, Vimentin, Snail1, Snail2 and Twist1, and down-regulated the expression of E-cadherin. In addition, Stat5 was induced in IGF-1-treated HepG2 and Hep3B cells, and Stat5 inhibition or siRNA significantly affected IGF-1-induced EMT in HepG2 and Hep3B cells. In conclusion, IGF-1 induces EMT of HCC via Stat5 signaling pathway. Thus, IGF-1/Stat5 can be recommended as a potential and novel therapeutic strategy for HCC patients.

PEG closure in the second attempt.

BACKGROUND AND STUDY AIMS: This case report demonstrates successful endoscopic treatment of a persistent gastrocutaneous fistula after removal of a percutaneous endoscopic gastrostomy (PEG) in a 21-year-old patient with mucoviscidosis after lung transplantation. Because the initial OTSC clip (gastric) did not close the fistula sufficiently, we had to remove it and replace it with a larger OTSC clip (colon) in a second intervention. That clip finally sufficiently closed the fistula.

Endoscopic Vacuum Therapy in Colorectal Surgery.

INTRODUCTION: Endoscopic vacuum therapy (EVT) has been established in Germany for the treatment of anastomotic leakage after rectal resection. Continuous or intermittent suction and drainage decrease bacterial contamination, secretion, and local edema promoting perfusion and granulation at the same time. However, data for use and long-term results of EVT in colorectal surgery are still scarce and are often limited by short-term follow-up. OBJECTIVES: Here, we aimed at analyzing the treatment spectrum and long-term outcome of EVT for defects of the lower gastrointestinal tract. METHODS: This is a retrospective single-center analysis of EVT for defects of the lower gastrointestinal tract of different etiology in 41 patients over a time period of 8 years (2007-2015) with a mean follow-up of 36 (2-89) months. RESULTS: In total, 426 polyurethane sponges were placed in lower GI defects of 41 patients (31 male, 10 female) with a median age of 70 years (range, 29-91). Most frequent indications for EVT were anastomotic leakage after rectal resection (n = 20), Hartmann's stump insufficiency (n = 12), and rectal perforation (n = 3). The median number of sponge insertions was six (range, 1-37) with a mean changing interval of 3 days (range, 1-5). Median time of therapy was 20 days. A successful vacuum therapy with local control of the septic focus was achieved in 18 of 20 patients (90 %) with anastomotic leakage after rectal resection and in nine of 12 patients with a Hartmann's stump insufficiency. In 15 of 19 (79 %) patients with a diverting stoma, take-down after successful treatment was possible. Median time to closure was 244 days (range, 152-488 days). CONCLUSION: To our knowledge, this retrospective observation of EVT application for rectal lesions represents the largest patient series in literature. EVT has earned its indication in complication management after colorectal surgery and can achieve a successful control of a local septic focus in the majority of patients.

Surgical Endoscopic Vacuum Therapy for Defects of the Upper Gastrointestinal Tract.

INTRODUCTION: Intraluminal therapy used in the gastrointestinal (GI) tract was first shown for anastomotic leaks after rectal resection. Since a few years vacuum sponge therapy is increasingly being recognized as a new promising method for repairing upper GI defects of different etiology. The principles of vacuum-assisted closure (VAC) therapy remain the same no matter of localization: Continuous or intermittent suction and drainage decrease bacterial contamination, secretion, and local edema. At the same time, perfusion and granulation is promoted. However, data for endoscopic vacuum therapy (EVT) of the upper intestinal tract are still scarce and consist of only a few case reports and small series with low number of patients. OBJECTIVES: Here, we present a single center experience of EVT for substantial wall defects in the upper GI tract. METHODS: Retrospective single-center analysis of EVT for various defects of the upper GI tract over a time period of 4 years (2011-2015) with a mean follow-up of 17 (2-45) months was used. If necessary, initial endoscopic sponge placement was performed in combination with open surgical revision. RESULTS: In total, 126 polyurethane sponges were placed in upper gastrointestinal defects of 21 patients with a median age of 72 years (range, 49-80). Most frequent indication for EVT was anastomotic leakage after esophageal or gastric resection (n = 11) and iatrogenic esophageal perforation (n = 8). The median number of sponge insertions was five (range, 1-14) with a mean changing interval of 3 days (range, 2-4). Median time of therapy was 15 days (range, 3-46). EVT in combination with surgery took place in nine of 21 patients (43 %). A successful vacuum therapy for upper intestinal defects with local control of the septic focus was achieved in 19 of 21 patients (90.5 %). CONCLUSION: EVT is a promising approach for postoperative, iatrogenic, or spontaneous lesions of the upper GI tract. In this series, EVT was combined with operative revision in a relevant proportion of patients.

Establishment and characterization of HROC69 - a Crohn´s related colonic carcinoma cell line and its matched patient-derived xenograft.

Colitis-associated colorectal cancer (CAC) seems to be a rather unique entity and differs in its genetic alterations, tumour formation capacities, and clinical features from sporadic colorectal carcinoma. Most descriptions about tumour biology of CAC refer to ulcerative colitis; data about Crohn´s colitis related carcinomas are scarce. The majority of patients with Crohn´s disease are under immunosuppression which generates a different environment for tumour growth. We first describe the clinical case of a fast growing CAC in a long-term immunosuppressed patient with Crohn´s disease and successful establishment and characterization of carcinoma cell lines along with their corresponding patient-derived xenograft. Subsequently, these tumor models were molecularly and functionally analysed. Beside numerous chromosomal alterations, mutations in TP53, APC, PTEN and SMAD3 were identified. The cell lines express numerous cancer testis antigens, surface molecules involved in immune evasion but low levels of HLA class I molecules. They show strong invasive but in comparison weak migratory activity. The present work is the first description of patient-derived in vitro and in vivo models for CAC from a Crohn´s disease patient. They might be valuable tools for analysis of genetic and epigenetic alterations, biomarker identification, functional testing, including response prediction, and the development of specific therapeutical strategies.

Reactivity against microsatellite instability-induced frameshift mutations in patients with inflammatory bowel disease.

AIM: To analyze the cellular immune response towards microsatellite-instability (MSI)-induced frameshift-peptides (FSPs) in patients suffering from inflammatory bowel disease (IBD) with and without thiopurine-based immunosuppressive treatment. METHODS: Frequencies of peripheral blood T cell responses of IBD patients (n = 75) against FSPs derived from 14 microsatellite-containing candidate genes were quantified by interferon-γ enzyme-linked immunospot. T cells derived from 20 healthy individuals served as controls. RESULTS: Significant T cell reactivities against MSI-induced FSPs were observed in 59 of 75 IBD patients (78.7%). This was significantly more as we could observe in 20 healthy controls (P = 0.001). Overall, the reactivity was significantly influenced by thiopurine treatment (P = 0.032) and duration of disease (P = 0.002) but not by duration or cumulative amount of thiopurine therapy (P = 0.476). Unexpected, 15 of 24 (62.5%) IBD patients without prior thiopurine treatment also showed increased FSP-specific immune responses (P = 0.001). CONCLUSION: These findings propose FSPs as potential novel class of inflammation-associated antigens and this in turn may have implications for screening, diagnosis as well as clinical management of patients suffering from IBD and other inflammatory conditions.