Do Hernias Contribute to Increased Severity of Aneurysmal Disease among Abdominal Aortic Aneurysm Patients?

BACKGROUND: Connective tissue disorders could contribute to the pathogenesis of both abdominal aortic aneurysms (AAA) and hernias. We tested the hypothesis that hernias in AAA patients contribute to increased severity of the aneurysmal disease. METHODS: A questionnaire was used to collect information from 195 AAA patients divided into four groups: (1) survivors (n = 22) of ruptured AAA, (2) patients (n = 90) after elective open repair, (3) patients (n = 43) after elective endovascular repair (EVAR), and (4) patients (n = 40) under surveillance of AAA. The control group consisted of 100 patients without AAA whose abdominal computed tomography (CT) scans were examined for the presence of hernias. Mann-Whitney U-test, Chi-squared (χ 2) test, or Fisher's exact test (as appropriate) were used for statistical analyses. Multivariate logistic regression was used to control for potential confounding variables such as sex and age. RESULTS: The prevalence of inguinal hernias was significantly higher in the AAA than the control group (25 vs. 9%, p = 0.001) and did not differ between the AAA subgroups (9, 24, 35, and 23% in subgroups 1 through 4, respectively, p = 0.15) based on univariate analysis. The prevalence of inguinal hernias did not differ (p = 0.15) between the two open surgery groups (groups 1 and 2), or when comparing all three operative procedures as a combined group to group 4 (p = 0.73). The prevalences of incisional hernias were 18 and 24% for groups 1 and 2, respectively, with no significant difference (p = 0.39). Inguinal hernia demonstrated a significant association with AAA on multivariate analysis (p = 0.006; odds ratio [OR] = 4.00; 95% confidence interval [CI] = 1.49-10.66). CONCLUSIONS: Our study confirms previous observations that patients with AAA have a high prevalence of hernias. Our results suggest that hernias do not contribute to increased severity of the aneurysmal disease.

[Advantages and future perspectives of laparoscopic liver surgery]. / Vorteile und Entwicklungspotenziale der laparoskopischen Leberchirurgie.

BACKGROUND: Laparoscopic liver surgery (LLS) is increasingly utilized worldwide due to several potential advantages over open liver surgery. OBJECTIVE: Analysis and presentation of the advantages and disadvantages of LLS in comparison to open surgery. MATERIAL AND METHODS: Analysis of clinically relevant factors of minimally invasive liver surgery in comparison to open liver surgery in the current literature. RESULTS: In addition to obvious cosmetic advantages, the current literature shows advantages regarding length of hospital stay and quality of life after LLC. In contrast to major liver resections, parenchyma-preserving resections often appear cost-neutral due a shorter postoperative hospital stay compared to conventional liver resections. In addition to particular personnel requirements, LLS also has technical prerequisites, such as a dedicated intraoperative ultrasound system. Furthermore, contrast-enhanced laparoscopic examinations are possible and ultrasound information can be fused with preoperative imaging. Virtual reality technology and 3­dimensional printing are currently under investigation to improve the intraoperative anatomical orientation of LLS. CONCLUSION: The current literature reveals significant advantages for LLS so that this procedure should be further developed in Germany in order to offer this technique to as many patients as possible.

Quality-based assessment of camera navigation skills for laparoscopic fundoplication.

Laparoscopic fundoplication is considered the gold standard surgical procedure for the treatment of symptomatic hiatus hernia. Studies on surgical performance in minimally invasive hiatus hernia repair have neglected the role of the camera assistant so far. The current study was designed to assess the applicability of the structured assessment of laparoscopic assistance skills (SALAS) score to laparoscopic fundoplication as an advanced and commonly performed laparoscopic upper GI procedure. Randomly selected laparoscopic fundoplications (n = 20) at a single institute were evaluated. Four trained reviewers independently assigned SALAS scoring based on synchronized video and voice recordings. The SALAS score (5-25 points) consists of five key aspects of laparoscopic camera navigation as previously described. Experience in camera assistance was defined as at least 100 assistances in complex laparoscopic procedures. Nine different surgical teams, consisting of five surgical residents, three fellows, and two attending physicians, were included. Experienced and inexperienced camera assistants were equally distributed (10/10). Construct validity was proven with a significant discrimination between experienced and inexperienced camera assistants for all reviewers (P < 0.05). The intraclass correlation coefficient of 0.897 demonstrates the score's low interrater variability. The total operation time decreases with increasing SALAS score, not reaching statistical significance. The applied SALAS score proves effective by discriminating between experienced and inexperienced camera assistants in an upper GI surgical procedure. This study demonstrates the applicability of the SALAS score to a more advanced laparoscopic procedure such as fundoplication enabling future investigations on the influence of camera navigation on surgical performance and operative outcome.

C-reactive Protein Levels After Esophagectomy Are Associated With Increased Surgical Trauma and Complications.

BACKGROUND: With the introduction of minimally invasive esophagectomy, postoperative complications rates have decreased. Daily laboratory tests are used to screen patients for postoperative complications. The course of inflammatory indicators after esophagectomy after different surgical approaches has not been described yet. The aim of the study was to describe the postoperative C-reactive protein (CRP) and leukocyte levels after different surgical approaches for esophagectomy and relate it to postoperative complications. METHODS: Between 2010 and 2018, 217 consecutive patients underwent thoracoabdominal esophagectomy with gastric conduit reconstruction. Blood tests to assess CRP and leukocytes were performed daily in all patients. Differences between treatment groups were analyzed with a linear mixed model. All postoperative complications were recorded in a prospective database. Prognostic factors were analyzed using multivariate logistic regression modeling. RESULTS: The study evaluated 4 different esophagectomy techniques: open (n = 57), hybrid (n = 53), totally minimally invasive (n = 52), and robot-assisted minimally invasive (n = 55). The increase of inflammatory indicators was significantly higher after open esophagectomy on the first 2 postoperative days compared with the 3 minimally invasive procedures (P < .001). Postoperative CRP values exceeding 200 mg/L on the second postoperative day and open esophagectomy were independently associated with postoperative complications. CONCLUSIONS: Open esophagectomy results in significantly higher CRP and leukocyte values compared with hybrid, minimally invasive, and robot-assisted minimally invasive esophagectomy. Open esophagectomy and a CRP increase on the second postoperative day above 200 mg/L are independent positive predictors for postoperative complications in multivariate analysis.

Minimally-invasive temporary gastric stimulation: A pilot study to predict the outcome of electronic gastric stimulation with the Enterra™ system.

INTRODUCTION: Gastroparesis (GP) is defined as delayed gastric emptying (GE) without any obstruction of the pylorus. It can be divided into idiopathic, diabetic, post surgical and rare causes. Electronic gastric stimulation (EGS) - Enterra Medtronic™ - is a part of GP therapy. Although its positive impact has been reported in open label trials, randomized controlled trials failed in demonstrating a positive outcome. The aim of this pilot study was to establish a reliable prediction for permanent gastric stimulation. PATIENTS AND PROCEDURE: 6 female patients underwent laparoscopic implantation of 2 temporary electrodes. The Enterra™ system was connected and taped to the skin. Baseline and postoperative gastroparesis cardinal symptom index (GCSI), a validated index for GP therapy, was assessed. Response to EGS was defined as a 50% decrease of baseline GCSI. RESULTS: 4 of 6 patients responded to temporary EGS. 3 of 4 responders underwent permanent implantation. 1 non-responder received a permanent Enterra™ at another institution. After a median follow up time of 9months the responder group GCSI remained low, whereas the non-responder GCSI had increased. Moreover, the health care system was saved € 30,678.03 by this test stimulation concept. CONCLUSION: Laparoscopic implantation of a temporary EGS system predicts the outcome of permanent gastric stimulation and is cost-saving.

STAT3 controls matrix metalloproteinase-1 expression in colon carcinoma cells by both direct and AP-1-mediated interaction with the MMP-1 promoter.

Aberrant activation of STAT3 in colorectal carcinoma (CRC) tissue is correlated with elevated expression of matrix metalloproteinase-1 (MMP-1). We analyzed transcriptional regulation of the human MMP-1 promoter in CRC cells by tyrosine phosphorylated (pY-) STAT3. One of six putative STAT binding elements within a 4.3 kb MMP-1 trancriptional promoter fragment showed a particular high affinity for STAT3 in vitro. However, the most profound regulatory influence on MMP-1 promoter activity resides in a proximal region relative to the transcriptional start, bearing a pair of putative binding sites for STAT3 and AP-1. Mutational analysis of the combined STAT3/AP-1 recognition element revealed that the integrity of the STAT3 binding site is necessary, but not sufficient for both DNA interaction and transcriptional regulation by activated STAT3. Instead, the adjacent AP-1 site was essential for pY-STAT3-mediated transcription on the MMP-1 promoter. DNA-protein binding assays provided strong evidence for complex formation of STAT3 and c-Jun governed by protein-protein contacts. We observed striking coincidence for concerted aberrant activation of both STAT3 and AP-1 in human colon cancer specimens. This finding supports the notion that the combination of inappropriate STAT3 and AP-1 activities drives elevated MMP-1 expression and tissue invasion in colorectal cancer and is of clinical relevance.

Cell-cell contacts induce STAT3 activity in colon carcinoma cells through an autocrine stimulation loop.

PURPOSE: Signal transducer and activator of transcription 3 (STAT3) is persistently activated in colorectal carcinoma (CRC) cells in the tumor context, but inactive in cultivated CRC cell lines. We approached mechanisms leading to STAT3 activation in CRC by mimicking "tumor-like" growth conditions and forcing cell-cell contacts of HT-29 CRC cells in culture. Further aims were to analyze in how far HT-29 cells growing in a tumorous manner spread STAT3 activity by secretion of soluble factors. METHODS: Non-adhesive growth and aggregation of HT-29 cells were achieved by cultivation on non-coated plastic surfaces. STAT3 activity was assessed by Western blot employing a phospho-STAT3-specific antibody as well as by electrophoretic mobility shift assay (EMSA). Expression changes of STAT3 target gene mmp-1 were quantified by real-time RT-PCR, Cytokine/chemokine patterns in conditioned media were characterized by cytokine arrays. RESULTS: Forced aggregation and non-adhesive growth of HT-29 CRC cells resulted in enhanced tyrosine phosphorylation of STAT3 and elevated expression of matrix metalloproteinase MMP-1. Furthermore, an activity was secreted into the medium that evoked STAT3 phosphorylation in adhesively growing HT-29 cells. The degree of activity in the conditioned medium was enhanced when wild-type STAT3 was overexpressed and reduced when a dominant variant of STAT3 was expressed in HT-29 cells. A characteristic panel of chemokines appeared in STAT3-activating conditioned medium. CONCLUSIONS: Changing cultivation conditions of the CRC cell line HT-29 toward detachment and aggregation, thus toward the situation in tumors, induces STAT3 activity and evokes an autocrine STAT3 activation loop.

Signal transducer and activator of transcription 3 activation promotes invasive growth of colon carcinomas through matrix metalloproteinase induction.

Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in colorectal carcinomas (CRCs). Here, we define the relationship between STAT3 function and the malignant properties of colon carcinoma cells. Elevated activation of STAT3 enhances invasive growth of the CRC cell lines. To address mechanisms through which STAT3 influences invasiveness, the protease mRNA expression pattern of CRC biopsies was analyzed and correlated with the STAT3 activity status. These studies revealed a striking coincidence of STAT3 activation and strong expression of matrix metalloproteinases MMP-1, -3, -7, and -9. Immunohistological examination of CRC tumor specimens showed a clear colocalization of MMP-1 and activated STAT3. Experimentally induced STAT3 activity in CRC cell lines enhanced both the level of MMP-1 mRNA and secreted MMP-1 enzymatic activity. A direct connection of STAT3 activity and transcription from the MMP-1 promoter was shown by reporter gene experiments. Moreover, high-affinity binding of STAT3 to STAT recognition elements in both the MMP-1 and MMP-3 promoter was demonstrated. Xenograft tumors arising from implantation of CRC cells into nude mice showed simultaneous appearance and colocalization of p-Y-STAT3 and MMP-1 expression. Our results link aberrant activity of STAT3 in CRC to malignant tumor progression through upregulated expression of MMPs.

Leukemia inhibitory factor triggers activation of signal transducer and activator of transcription 3, proliferation, invasiveness, and altered protease expression in choriocarcinoma cells.

Extravillous trophoblast cells resemble cancer cells with regard to their intrinsic invasiveness. They invade decidual tissue, but, unlike tumor cells, shut down their invasive properties, when they become inappropriate. Stimuli involved in the modulation of invasion, as well as their underlying signaling mechanisms require further clarification. We were especially interested in discovering signals capable of stimulating invasion in otherwise low-invasive cells involved in reproduction. Using the choriocarcinoma cell line Jeg-3 as a model, we have addressed the potential role of cytokine/growth factor-driven activation of signal transducer and activator of transcription 3 (STAT3) in this process. Jeg-3 cells were treated with various factors known to induce trophoblast proliferation, differentiation, migration, or invasiveness (insulin-like-growth-factor-II (IGF-II), hepatocyte growth factor (HGF), interleukin-6 (IL-6), and leukemia inhibitory factor (LIF)). Only LIF elicited strong tyrosine phosphorylation and specific DNA-binding activity of STAT3. It induced a significant acceleration of cell proliferation and promoted the capability of Jeg-3 cells to invade into an artificial extracellular matrix. Moreover, LIF influenced the expression pattern of proteases and protease inhibitors with potential relevance for invasiveness (downregulation of mRNA for tissue inhibitor of metalloproteinase 1 (TIMP-1) and upregulation of mRNA for caspase-4). In conjunction with earlier work, in which we found that STAT3 DNA-binding activity was increased in invasive cells (choriocarcinoma, first trimester trophoblasts) and absent in non-invasive cells (term trophoblasts), these findings suggest a connection between LIF-driven STAT3 activity and invasiveness of choriocarcinoma and trophoblast cells.

Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth.

Colorectal carcinoma (CRC) is a major cause of morbidity and mortality in Western countries. It has so far been molecularly defined mainly by alterations of the Wnt pathway. We show here for the first time that aberrant activities of the signal transducer and activator of transcription STAT3 actively contribute to this malignancy and, thus, are a potential therapeutic target for CRC. Constitutive STAT3 activity was found to be abundant in dedifferentiated cancer cells and infiltrating lymphocytes of CRC samples, but not in non-neoplastic colon epithelium. Cell lines derived from malignant colorectal tumors lost persistent STAT3 activity in culture. However, implantation of colon carcinoma cells into nude mice resulted in restoration of STAT3 activity, suggesting a role of an extracellular stimulus within the tumor microenvironment as a trigger for STAT activation. STAT3 activity in CRC cells triggered through interleukin-6 or through a constitutively active STAT3 mutant promoted cancer cell multiplication, whereas STAT3 inhibition through a dominant-negative variant impaired IL-6-driven proliferation. Blockade of STAT3 activation in CRC-derived xenograft tumors slowed down their development, arguing for a contribution of STAT3 to colorectal tumor growth.

Evidence for a correlation between trophoblast invasiveness and STAT3 activity.

PROBLEM: Extravillous trophoblast cells are capable of invading decidual tissue during early pregnancy. This property is reminiscent of cancer cells. The invasiveness of trophoblasts, however, extends only to a well-regulated limit. Signal transduction processes underlying this phenomenon are as yet poorly characterized. Many factors involved in trophoblast invasiveness are known to trigger intracellular signaling cascades in other cell types that ultimately lead to the activation of signal transducers and activators of transcription (STATs). STAT3 activity was recently found related to the malignant phenotype of different tumor cells and potentially contributes to their invasive properties. METHOD OF STUDY: We investigated the status of STAT3 activity in ex vivo trophoblast cells from first trimester and term placentae employing an electrophoretic mobility shift assay (EMSA) and compared it with that of a highly malignant choriocarcinoma cell line. RESULTS: Specific DNA binding activity of two STAT3 variants (STAT3alpha and beta) was observed in immature trophoblasts and appeared to be lost in term placentae. The malignant phenotype of choriocarcinoma cells coincides with a high degree of STAT3 activity. CONCLUSION: These results suggest a connection between STAT3 activity and trophoblast invasiveness.