Anatomy of the neural fibers at the superior mesenteric artery-a cadaver study.

PURPOSE: Most surgeons perform right-sided semicircular clearance of the superior mesenteric artery (SMA) nerve plexus for pancreatic head carcinoma, presuming a linear course of the SMA nerve fibers. The hypothesis was that the SMA nerve plexus fibers follow a non-linear course, and the goal of the present study was to assess the neural fibers distribution along the SMA. METHODS: The course of neural fibers along the retropancreatic and suprapancreatic SMA was assessed in 7 cadavers. RESULTS: In the retropancreatic course of the vessel, the main nerve cords branch and form a large number of finer nerve branches performing an anti-clockwise rotation of slightly less than 90° around the SMA. Finer nerve branches are located rather close to the vessel, while the main nerve cords are localized in the loose connective tissue of the peripheral parts of the vascular sheath. Nerve fibers around the suprapancreatic SMA run as two main nerve cords framing the artery on the right lateral-ventral and the left lateral to lateral-dorsal side. CONCLUSION: The rotation of the nerve fiber around the SMA indicates that a more radical resection of at least 180° of neural tissue around the SMA might be required to achieve tumor clearance in pancreatic cancer with perineural invasion at the uncinate margin.

Extended lymph node resection versus standard resection for pancreatic and periampullary adenocarcinoma.

BACKGROUND: Pancreatic and periampullary adenocarcinomas account for some of the most aggressive malignancies, and the leading causes of cancer-related mortalities. Partial pancreaticoduodenectomy (PD) with negative resection margins is the only potentially curative therapy. The high prevalence of lymph node metastases has led to the hypothesis that wider excision with the removal of more lymphatic tissue could result in an improvement of survival, and higher rates of negative resection margins. OBJECTIVES: To compare overall survival following standard (SLA) versus extended lymph lymphadenectomy (ELA) for pancreatic head and periampullary adenocarcinoma. We also compared secondary outcomes, such as morbidity, mortality, and tumour involvement of the resection margins between the two procedures. SEARCH METHODS: We searched CENTRAL, MEDLINE, PubMed, and Embase from 1973 to September 2020; we applied no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCT) comparing PD with SLA versus PD with ELA, including participants with pancreatic head and periampullary adenocarcinoma. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references and extracted data from study reports. We calculated pooled risk ratios (RR) for most binary outcomes except for postoperative mortality, for which we estimated a Peto odds ratio (Peto OR), and mean differences (MD) for continuous outcomes. We used a fixed-effect model in the absence of substantial heterogeneity (I² < 25%), and a random-effects model in cases of substantial heterogeneity (I² > 25%). Two review authors independently assessed risk of bias, and we used GRADE to assess the quality of the evidence for important outcomes. MAIN RESULTS: We included seven studies with 843 participants (421 ELA and 422 SLA). All seven studies included Kaplan-Meier curves for overall survival. There was little or no difference in survival between groups (log hazard ratio (log HR) 0.12, 95% confidence interval (CI) -3.06 to 3.31; P = 0.94; seven studies, 843 participants; very low-quality evidence). There was little or no difference in postoperative mortality between the groups (Peto odds ratio (OR) 1.20, 95% CI 0.51 to 2.80; seven studies, 843 participants; low-quality evidence). Operating time was probably longer for ELA (mean difference (MD) 50.13 minutes, 95% CI 19.19 to 81.06 minutes; five studies, 670 participants; moderate-quality evidence). There was substantial heterogeneity between the studies (I² = 88%; P < 0.00001). There may have been more blood loss during ELA (MD 137.43 mL, 95% CI 11.55 to 263.30 mL; two studies, 463 participants; very low-quality evidence). There was substantial heterogeneity between the studies (I² = 81%, P = 0.02). There may have been more lymph nodes retrieved during ELA (MD 11.09 nodes, 95% CI 7.16 to 15.02; five studies, 670 participants; moderate-quality evidence). There was substantial heterogeneity between the studies (I² = 81%, P < 0.00001). There was little or no difference in the incidence of positive resection margins between groups (RR 0.81, 95% CI 0.58 to 1.13; six studies, 783 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: There is no evidence of an impact on survival with extended versus standard lymph node resection. However, the operating time may have been longer and blood loss greater in the extended resection group. In conclusion, current evidence neither supports nor refutes the effect of extended lymph lymphadenectomy in people with adenocarcinoma of the head of the pancreas.

Robot-assisted versus laparoscopic single-incision cholecystectomy: results of a randomized controlled trial.

BACKGROUND: Although single-port laparoscopic cholecystectomy (SILC) is safe and effective, inherent surgeons' discomfort has prevented a large-scale adaptation of this technique. Recent advances in robotic technology suggest that da Vinci Single-Site™ cholecystectomy (dVSSC) may overcome this issue by reducing the stress load of the surgeon compared to SILC. However, evidence to objectively assess differences between the two approaches is lacking. METHODS: 60 patients [36 women, 24 men (mean age 52 years)] with benign gallbladder disease were randomly assigned to dVSSC (n = 30) or SILC (n = 30) in this single-centre, single-blinded controlled trial. The primary endpoint was surgeon's stress load. Secondary endpoints included operating time, conversion rates, additional trocar placement, blood loss, length of hospital stay, procedure costs, health-related quality of life, cosmesis and complications. Data were collected preoperatively, during the hospital stay, and at 1 and 12 months' follow-up. RESULTS: The dVSSC group showed a significant reduction of mental stress load of the surgeon compared to SILC [Subjective Mental Effort Questionnaire (SMEQ) score: median 25.0 (range 8-89) vs. 42.5 (range 13-110) points; p = 0.002] and a trend towards reduced physical stress load [Local Experienced Discomfort (LED) score: median 8 (range 2-27) vs. 12 (range 0-64) points; p = 0.088]. The length of hospital stay was longer in the SILC group [mean 3.06 (median 2; range 1-26) vs. 1.9 (median 2; range 1-4) days, p = 0.034] but overall hospital costs were higher for dVSSC [median 9734 (range 5775-16729) vs. 6900 (range 4156-99977) CHF; p = 0.001]. There were no differences in the rate of postoperative complications that required re-intervention (Dindo-Clavien grade ≥ IIIa; SILC n = 2 vs. dVSSC n = 0, p = 0.492) or other secondary endpoints. CONCLUSIONS: Da Vinci Single-Site™ cholecystectomy provides significant benefits over Single-Port Laparoscopic Cholecystectomy in terms of surgeon's stress load, matches the standards of the laparoscopic single-incision approach with regard to patients' outcomes but increases expenses. Clinicaltrials.gov registration-No.: NCT02485392.

Meta-analysis of surgical strategies in perforated left colonic diverticulitis with generalized peritonitis.

PURPOSE: Surgical strategies for perforated diverticulitis (Hinchey stages III and IV) remain controversial. This systematic review aimed to compare the outcome of primary anastomosis, Hartmann procedure and laparoscopic lavage. METHODS: A systematic literature search was conducted through Medline, Embase, Cochrane Central Register and Health Technology Assessment Database to identify randomized and non-randomized controlled trials involving patients with perforated left-sided colonic diverticulitis comparing different surgical strategies. The methodological quality of the included studies was assessed systematically (Grading of Recommendations, Assessment, Development and Evaluation) and a meta-analysis was performed. RESULTS: After screening 4090 titles and abstracts published between 1958 and January 2018, 148 were selected for full text assessment. Sixteen trials (7 RCTs, 9 non-RCTs) with 1223 patients were included. Mortality rates were not significantly different between Hartmann procedure and primary anastomosis for Hinchey III and IV, neither in the meta-analysis of three RCTs (RR 2.03 (95% CI 0.79 to 5.25); p = 0.14, moderate quality of evidence) nor in the meta-analysis of six observational studies (RR 1.53 (95% CI 0.89 to 2.65); p = 0.13, very low quality of evidence). However, stoma reversal rates were significantly higher in the primary anastomosis group (RR 0.73 (95% CI 0.58 to 0.98); p = 0.008, moderate quality of evidence). Meta-analysis of four RCTs showed no significant difference between laparoscopic lavage for Hinchey III compared to sigmoid resection neither for mortality (RR 1.07 (95% CI 0.65 to 1.76); p = 0.79, moderate quality of evidence) nor for major complications (RR 0.86 (95% CI 0.69 to 1.08); p = 0.20, moderate quality of evidence). CONCLUSIONS: This systematic review suggests similar rates of complications but higher rates of colonic restoration after primary anastomosis compared to Hartmann procedure in perforated diverticulitis with generalized peritonitis (Hinchey III and IV). Results in laparoscopic lavage for Hinchey III are not superior to primary resection. However, further studies with a careful interpretation of the meaning of re-interventions are required.

[Colorectal metastases - Current treatment strategies]. / Kolorektale Metastasen ­ Aktuelle Behandlungskonzepte.

Colorectal metastases - Current treatment strategies Abstract. In the course of their disease, more than 50 % of patients with colorectal cancer develop metastases. They are most frequently localized in the liver, followed by the peritoneum and the lungs. The therapeutic options and prognosis of colorectal metastases have improved markedly in recent years. Modern treatment concepts are multimodal and are customized for the individual patient by interdisciplinary tumour boards that follow widely recognised guidelines and norms. The recommendation of an appropriate treatment option in metastasized patients by an interdisciplinary panel of experts is of paramount importance. Besides technical possibilities, factors such as comorbidities, medical outcomes, quality of processes as well as patient-related outcome are all crucial in the decision-making process. In most patients diagnosed with distant metastases, the prognosis is determined by the extent of the liver burden. Hereby, the resection of the liver metastases is of utmost importance to improve the prognosis of a patient, since only those individuals who have successfully undergone resection have a chance for long-term disease free-survival. Whether liver metastases are resectable depends on sufficient volume and function of the future liver remnant (FLR). Manipulation of the FLR as well as upfront oncological treatment of metastases improves the resectability rates in patients with an advanced tumor load in the liver. Laparoscopic liver resection improves patient outcomes by reducing pain and results in a shortened hospital stay. Lung resection for pulmonary metastases as well as cytoreductive surgery for peritoneal metastases are important mainstays of modern personalized treatment concepts. However, results of ongoing trials are eagerly awaited to help quantify the prognostic effects of those therapies and assess their true therapeutic value.

Chronic pain and quality of life after inguinal hernia repair using the COMI-hernia score.

PURPOSE: The Core Outcome Measure Index (COMI) is a brief and multidimensional, patient-orientated outcome questionnaire that assesses chronic pain and quality of life after groin hernia repair. The primary aim of this study was to prospectively assess the COMI-hernia score, over an extended period of time in a single large cohort of patients. METHODS: Two hundred and twenty-eight male patients with inguinal hernia repair were included in the present study. Patients were recruited prospectively with an average follow-up of 3 years. RESULTS: COMI-hernia total and the COMI-hernia pain scores were significantly lower following surgery and remained unchanged over time. Young patients' age (p = 0.043), high preoperative COMI-hernia total score (p = 0.018), and bilateral hernias (p = 0.035) were identified as independent risk factors for adverse outcome after groin hernia repair. Both COMI-hernia total and the COMI-hernia pain scores significantly (p < 2.2*10-16 and p < 1.638*10-11) correlated with patient's satisfaction. CONCLUSIONS: The COMI score reflects a reliable tool to assess the outcome following groin hernia repair.

Robot-assisted single-site compared with laparoscopic single-incision cholecystectomy for benign gallbladder disease: protocol for a randomized controlled trial.

BACKGROUND: Recent advances in robotic technology suggest that the utilization of the da Vinci Single-Site™ platform for cholecystectomy is safe, feasible and results in a shorter learning curve compared to conventional single-incision laparoscopic cholecystectomy. Moreover, the robot-assisted technology has been shown to reduce the surgeon's stress load compared to standard single-incision laparoscopy in an experimental setup, suggesting an important advantage of the da Vinci platform. However, the above-mentioned observations are based solely on case series, case reports and experimental data, as high-quality clinical trials to demonstrate the benefits of the da Vinci Single-Site™ cholecystectomy have not been performed to date. METHODS: This study addresses the question whether robot-assisted Single-Site™ cholecystectomy provides significant benefits over single-incision laparoscopic cholecystectomy in terms of surgeon's stress load, while matching the standards of the conventional single-incision approach with regard to peri- and postoperative outcomes. It is designed as a single centre, single-blinded randomized controlled trial, which compares both surgical approaches with the primary endpoint surgeon's physical and mental stress load at the time of surgery. In addition, the study aims to assess secondary endpoints such as operating time, conversion rates, additional trocar placement, intra-operative blood loss, length of hospital stay, costs of procedure, health-related quality of life, cosmesis and complications. Patients as well as ward staff are blinded until the 1st postoperative year. Sample size calculation based on the results of a previously published experimental setup utilizing an estimated effect size of surgeon's comfort of 0.8 (power of 0.8, alpha-error level of 0.05, error margin of 10-15%) resulted in a number of 30 randomized patients per arm. DISCUSSION: The study is the first randomized controlled trial that compares the da Vinci Single Site™ platform to conventional laparoscopic approaches in cholecystectomy, one of the most frequently performed operations in general surgery. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (trial number: NCT02485392 ). Registered February 19, 2015.

Long-term results of endoscopic balloon dilation for treatment of colorectal anastomotic stenosis.

BACKGROUND: Despite standardized techniques, anastomotic complications after colorectal resection remain a challenging problem. Among those, anastomotic stricture is a debilitating outcome which often requires multiple interventions and which is prone to recur. The present series investigates the long-term results of endoscopic balloon dilation for stenotic colorectal anastomosis. METHODS: Consecutive patients from a single institution who presented with an anastomotic stenosis after a colorectal resection were identified using a prospective clinical database. Medical records were systematically reviewed to detail patients' outcomes. RESULTS: Over 17 years (1988-2015), 2361 consecutive patients underwent a colorectal anastomosis. Of those, 76 patients (3.2 %) suffered a symptomatic anastomotic stenosis within a median of 5 months (interquartile range (IQR) 2-13) of the index procedure. All stenoses were primarily treated by endoscopic balloon dilation. Median follow-up was 11 years (IQR 7-14). In half the patients, one to two attempts at endoscopic balloon dilation definitively relieved the stenosis. Overall, the median number of endoscopic balloon dilation required was 3 (IQR 2-3). Recurrence rates at 1 year, 3 year, and 5 year were 11, 22, and 25 %, respectively. Median time to recurrence was 12 months (IQR 3-24). Ultimately, two patients (2.6 %) underwent an operation due to failure of endoscopic treatment. All other patients (97.4 %) were treated successfully with endoscopic balloon dilation. A total of 12 patients (15.7 %) suffered a complication from endoscopic dilation. Of those, 11 were minor bleeding and one was a perforation at the level of the anastomosis. All complications were managed conservatively, and no emergency procedure was required as a consequence of attempted endoscopic balloon dilation. CONCLUSION: Endoscopic balloon dilation is a safe approach to effectively relieve an anastomotic stenosis following a colorectal resection.

Appendiceal stump closure using polymeric clips reduces intra-abdominal abscesses.

PURPOSE: Polymeric clips (hem-o-lok ligation system) are a novel alternative for securing the base of the appendix during laparoscopic appendectomy. There is a lack of systematic evaluation of polymeric clips to close the appendiceal stump with regard to postoperative intra-abdominal abscesses. The aim of this study was to compare the hem-o-lok ligation system with conventional devices. METHODS: The outcome of 813 consecutive patients, operated between 2009 and 2013 receiving laparoscopic appendectomy either with hem-o-look or endoloop for acute appendicitis, was analysed. The risk of postoperative intra-abdominal abscesses was investigated for two different techniques to close the appendiceal stump using univariate and multivariate analyses. RESULTS: Hem-o-lok clips were used in 54 % (n = 435) and endoloop sutures were applied in 46 % (n = 378) of the patients. Based on the multivariate analysis, the postoperative lack of antibiotics as well as the application of endoloop was identified as an independent predictive factor for the development of postoperative intra-abdominal abscesses. Comparing the closure techniques, the odds ratio (OR) was 0.25 (95 % CI 0.09-0.69; p < 0.008). CONCLUSION: Closure of the appendiceal stump using the non-absorbable hem-o-lok ligation system did result in a reduced rate of intra-abdominal surgical abscesses as compared to the application of endoloops.

Serotonin protects mouse liver from cholestatic injury by decreasing bile salt pool after bile duct ligation.

UNLABELLED: Obstructive cholestasis induces liver injury, postoperative complications, and mortality after surgery. Adaptive control of cholestasis, including bile salt homeostasis, is necessary for recovery and survival. Peripheral serotonin is a cytoprotective neurotransmitter also associated with liver regeneration. The effect of serotonin on cholestatic liver injury is not known. Therefore, we tested whether serotonin affects the severity of cholestatic liver injury. We induced cholestasis by ligation of the bile duct (BDL) in either wild-type (WT) mice or mice lacking peripheral serotonin (Tph1(-/-) and immune thrombocytopenic [ITP] mice). Liver injury was assessed by the levels of plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and tissue necrosis. Bile salt-regulating genes were measured by quantitative polymerase chain reaction and confirmed by western blotting and immunohistochemistry. Tph1(-/-) mice displayed higher levels of plasma AST, ALT, bile salts, and hepatic necrosis after 3 days of BDL than WT mice. Likewise, liver injury was disproportional in ITP mice. Moreover, severe cholestatic complications and mortality after prolonged BDL were increased in Tph1(-/-) mice. Despite the elevation in toxic bile salts, expression of genes involved in bile salt homeostasis and detoxification were not affected in Tph1(-/-) livers. In contrast, the bile salt reabsorption transporters Ostα and Ostß were up-regulated in the kidneys of Tph1(-/-) mice, along with a decrease in urinary bile salt excretion. Serotonin reloading of Tph1(-/-) mice reversed this phenotype, resulting in a reduction of circulating bile salts and liver injury. CONCLUSION: We propose a physiological function of serotonin is to ameliorate liver injury and stabilize the bile salt pool through adaptation of renal transporters in cholestasis.

Insulin-like growth factor II mRNA-binding protein 3 (IMP3) expression in hepatocellular carcinoma. A clinicopathological analysis with emphasis on diagnostic value.

AIMS: Patients with hepatocellular carcinoma (HCC) usually present with advanced disease and rarely qualify for curative therapy. Immunohistochemical markers that help to discriminate benign from malignant processes early, and that have prognostic significance, would be useful. Expression of the oncofetal protein insulin-like growth factor II mRNA-binding protein 3 (IMP3) in malignant cells of different tumour types correlates with reduced overall survival. METHODS AND RESULTS: Tissue microarrays (TMAs) containing 55 normal liver samples, 365 HCCs (122 with corresponding non-tumorous liver), 10 hepatocellular adenomas, 13 focal nodular hyperplasias and nine dysplastic nodules from western European patients were stained for IMP3. IMP3 was analysed in 61 core needle biopsies and findings were compared to glypican-3 and CD34. HCCs in TMAs were strongly positive for IMP3 in 18.4% of cases compared to absent expression in normal and non-tumorous liver tissue and benign liver tumours. Patients with IMP3 expression in HCCs showed significantly poorer overall survival in multivariate analysis (P = 0.044). Of the 61 core needle biopsies analysed, 32 (52.5%) of the HCCs were IMP3-positive. CONCLUSIONS: In core needle biopsies, IMP3 expression seems to be of limited use as a single marker for the diagnosis of HCC, given a sensitivity of 52%, but it may be helpful in combination with other markers.

Nuclear expression of the ubiquitin ligase seven in absentia homolog (SIAH)-1 induces proliferation and migration of liver cancer cells.

BACKGROUND & AIMS: Differential expression of tumor-relevant proteins based on aberrant proteasomal degradation may contribute to human (hepato)carcinogenesis. Recently, we identified the E3 ubiquitin ligase seven in absentia homolog (SIAH)-1 as frequently dysregulated in human hepatocellular carcinoma (HCC). We therefore systematically analyzed the expression, functional relevance, as well as possible downstream effectors of SIAH-1 in human liver carcinogenesis. METHODS: SIAH-1 expression was analyzed at the transcript and protein levels in human hepatocarcinogenesis and in HCC cells. Proliferation, apoptosis, and migration of different HCC cell lines were examined after siRNA-mediated inhibition of SIAH-1. In order to identify downstream effectors that mediate SIAH-1 effects, correlative analyses of protein expression profiles were performed. RESULTS: In HCC tissues both reduction of cytoplasmic SIAH-1 and especially its nuclear accumulation positively correlated with HCC progression. RNA interference revealed that nuclear expression of SIAH-1 predominantly supported HCC cell proliferation and migration while only moderately affecting anti-apoptosis. In de-differentiated human HCCs, nuclear SIAH-1 accumulation significantly correlated with the expression of the transcription factor far-upstream element (FUSE)-binding protein (FBP)-3. In vitro, SIAH-1 positively and indirectly regulated FBP-3 which itself primarily supported HCC cell proliferation. Indeed, high level expression of FBP-3 in human HCCs significantly correlated with reduced overall survival of patients. CONCLUSIONS: Nuclear accumulation of the E3 ubiquitin ligase SIAH-1 supports different pro-tumorigenic cellular processes associated with tumor growth and tumor cell dissemination in human hepatocarcinogenesis. It promotes HCC cell proliferation by at least partly employing the transcription factor FBP-3. Therefore, interference with SIAH-1 activity represents a promising approach to suppress HCC growth.

Serotonin promotes tumor growth in human hepatocellular cancer.

UNLABELLED: In addition to its function as a neurotransmitter and vascular active molecule, serotonin is also a mitogen for hepatocytes and promotes liver regeneration. A possible role in hepatocellular cancer has not yet been investigated. Human hepatocellular cancer cell lines Huh7 and HepG2 were used to assess the function of serotonin in these cell lines. Characteristics of autophagy were detected with transmission electron microscopy, immunoblots of microtubule-associated protein light chain 3(LC3) and p62 (sequestosome 1). Immunoblots of the mammalian target of rapamycin (mTOR) and its downstream targets p70S6K and 4E-BP1 were used to investigate signaling pathways of serotonin. Two different animal models served as principle of proof of in vitro findings. Clinical relevance of the experimental findings was evaluated with a tissue microarray from 168 patients with hepatocellular carcinoma. Serotonin promotes tumor growth and survival in starved hepatocellular carcinoma cells. During starvation hepatocellular carcinoma cells exhibited characteristics of autophagy, which disappeared in serotonin-treated cells. Rapamycin, an inhibitor of mTOR, is known to induce autophagy. Serotonin could override rapamycin by an mTOR-independent pathway and activate common downstream signals such as p70S6K and 4E-BP1. In two tumor models of the mouse, inhibition of serotonin signaling consistently impaired tumor growth. Human biopsies revealed expression of the serotonin receptor HTR2B, correlating with downstream signals, e.g., phosphorylated p70S6K and proliferation. CONCLUSION: This study provides evidence that serotonin is involved in tumor growth of hepatocellular cancer by activating downstream targets of mTOR, and therefore serotonin-related pathways might represent a new treatment strategy.

Overexpression of far upstream element binding proteins: a mechanism regulating proliferation and migration in liver cancer cells.

UNLABELLED: Microtubule-dependent effects are partly regulated by factors that coordinate polymer dynamics such as the microtubule-destabilizing protein stathmin (oncoprotein 18). In cancer cells, increased microtubule turnover affects cell morphology and cellular processes that rely on microtubule dynamics such as mitosis and migration. However, the molecular mechanisms deregulating modifiers of microtubule activity in human hepatocarcinogenesis are poorly understood. Based on profiling data of human hepatocellular carcinoma (HCC), we identified far upstream element binding proteins (FBPs) as significantly coregulated with stathmin. Coordinated overexpression of two FBP family members (FBP-1 and FBP-2) in >70% of all analyzed human HCCs significantly correlated with poor patient survival. In vitro, FBP-1 predominantly induced tumor cell proliferation, while FBP-2 primarily supported migration in different HCC cell lines. Surprisingly, reduction of FBP-2 levels was associated with elevated FBP-1 expression, suggesting a regulatory interplay of FBP family members that functionally discriminate between cell division and mobility. Expression of FBP-1 correlated with stathmin expression in HCC tissues and inhibition of FBP-1 but not of FBP-2 drastically reduced stathmin at the transcript and protein levels. In contrast, further overexpression of FBP-1 did not affect stathmin bioavailability. Accordingly, analyzing nuclear and cytoplasmic areas of HCC cells revealed that reduced FBP-1 levels affected cell morphology and were associated with a less malignant phenotype. CONCLUSION: The coordinated activation of FBP-1 and FBP-2 represents a novel and frequent pro-tumorigenic mechanism promoting proliferation (tumor growth) and motility (dissemination) of human liver cancer cells. FBPs promote tumor-relevant functions by at least partly employing the microtubule-destabilizing factor stathmin and represent a new potential target structure for HCC treatment.

Golgi phosphoprotein 2 (GOLPH2) expression in liver tumors and its value as a serum marker in hepatocellular carcinomas.

UNLABELLED: Hepatocellular carcinomas (HCCs) and bile duct carcinomas (BDCs) have a poor prognosis. Therefore, surveillance strategies including sensitive and specific serum markers for early detection are needed. Recently, Golgi Phosphoprotein 2 (GOLPH2) has been proposed as a serum marker for HCC, but GOLPH2 expression data in liver tissues was not available. Using tissue microarrays and immunohistochemistry, we semiquantitatively analyzed GOLPH2 protein expression in patients with HCC (n = 170), benign liver tumors (n = 22), BDC (n = 114) and normal liver tissue (n = 105). A newly designed sandwich enzyme-linked immunoassay (ELISA) was used to analyze GOLPH2 levels in the sera of patients with HCC (n = 62), hepatitis C virus (HCV) (n = 29), BDC (n = 10), and healthy control persons (n = 12). By immunohistochemistry 121/170 (71%) of HCC showed strong GOLPH2 expression, which was significantly associated with a higher tumor grade (P = 0.01). A total of 97/114 (85%) BDCs showed a strong GOLPH2 expression which proved to be an independent prognostic factor for overall survival (P < 0.05). Serum levels of GOLPH2 measured by ELISA were significantly elevated in patients with HCC with underlying HCV infection (median 18 mg/L, P < 0.05) and patients with BDC (median = 14.5 mg/L, P < 0.01) in comparison to healthy controls (median 4 mg/L). CONCLUSION: GOLPH2 protein is highly expressed in tissues of HCC and BDC. GOLPH2 protein levels are detectable and quantifiable in sera by ELISA. In patients with hepatitis C, serial ELISA measurements in the course of the disease appear to be a promising complementary serum marker in the surveillance of HCC. GOLPH2 should be further evaluated as a serum tumor marker in BDC on a larger scale.

Expression of the extracellular matrix protein periostin in liver tumours and bile duct carcinomas.

AIMS: To study the relevance of periostin, known to be involved in epithelial-mesenchymal transition (EMT), in hepatocellular and bile duct cancer. METHODS AND RESULTS: Immunohistochemical periostin expression was semiquantitatively analysed in normal liver tissue (n = 20), hepatocellular carcinoma (HCC; n = 91), liver-cell adenoma (n = 9), focal nodular hyperplasia (n = 13) and bile duct carcinomas (BDC; n = 116) using tissue microarrays. Normal bile ducts, gallbladder epithelium and hepatocytes showed weak cytoplasmic periostin expression. In HCC, there was strong epithelial periostin expression in 19/91 (20.9%) and strong stromal periostin expression in 10/91 cases (11%). Epithelial expression in tumour cells was significantly associated with a higher tumour grade (P < 0.05) and hepatitis B virus infection (P = 0.007). Importantly, there was no strong periostin expression in benign liver tumours. Strong stromal periostin expression was detected in 78/116 (67.2%) BDC and strong epithelial expression in 39/116 (33.6%) BDC. pT stage, differentiation grade and proliferation rate in primary BDC were independent of periostin expression. Epithelial periostin expression was associated with reduced overall survival on univariate and multivariate analysis. CONCLUSIONS: The EMT protein periostin is expressed in the stroma and epithelium of a subset of BDC and HCC. Epithelial periostin expression is a marker for malignant transformation of hepatocytes and a novel prognostic marker in BDC.

Frequent expression of the novel cancer testis antigen MAGE-C2/CT-10 in hepatocellular carcinoma.

Cancer testis (CT) antigens are attractive targets for immunotherapy in cancer patients. Immunohistochemistry was used to study the expression of the CT antigens MAGE-C2/CT-10, MAGE-C1/CT-7, GAGE, MAGE-A4 and NY-ESO-1 in 146 hepatocellular carcinomas, 13 intrahepatic cholangiocarcinomas, 37 extrahepatic cholangiocarcinomas and 32 gallbladder carcinomas. Immunopositivity was correlated with clinicopathological parameters, MHC Class 1 expression, intratumoral CD4+, CD8+ and FOXP3+ T cells and CD163+ antigen-presenting cells. Of the 146 hepatocellular carcinomas, 34% were positive for MAGE-C2/CT-10, 12% for MAGE-C1/CT-7, 11% for GAGE and 2% for NY-ESO-1, respectively. MHC Class 1 coexpression was identified in almost all CT antigen-positive tumors. The number of intratumoral FOXP3+ regulatory T cells was increased in CT antigen-positive hepatocellular carcinomas (p<0.004), suggesting inhibition of immune response in such tumors. Furthermore, MAGE-C1/CT-7 and GAGE positivity was correlated with reduced overall survival in patients with hepatocellular carcinoma (p=0.03 and 0.01, respectively). Four (13%) gallbladder carcinomas stained positive for MAGE-C2/CT-10, of which 1 tumor (3%) was also positive for NY-ESO-1 and GAGE. CT antigens were not expressed in intra- and extrahepatic cholangiocarcinomas. Our results suggest that MAGE-C2/CT-10 may be a good candidate for peptide vaccination in patients with hepatocellular carcinoma.

Appendectomy in Switzerland: how is it done?

More than 10,000 appendectomies are performed every year in Switzerland. The aim of this study was to investigate the treatment strategy for appendicitis among Swiss surgeons with particular interest in laparoscopic technique, method of appendiceal stump closure, and abdominal lavage. We performed an anonymous survey among 540 members of the Swiss Surgical Society. Technical details and differences between the surgical procedures in adults and children as well as in complicated and non-complicated appendicitis were investigated. The overall response rate was 45% (n = 243). 78% of the surgeons perform laparoscopic appendectomies in children and 95% in adult patients. Only 3% use a single incision site technique. Surgeons consider pus or stool in the abdomen (94%), an abscess (86%) or perforation of the appendix (82%), but not an inflamed appendiceal base (16%) as complicated appendicitis. 41% of surgeons use endoloops, 36% a stapling device, and 20% polymeric clips in non-complicated appendicitis for appendiceal stump closure. However, 82% of the surgeons use a stapler in complicated appendicitis. Most (76%) of surgeons do not plunge the appendiceal stump. 24% of surgeons lavage the abdomen with > 1 L of fluid independent of the intraabdominal finding. Most Swiss surgeons perform multiport laparoscopic appendectomies. Endoloops and staplers are mostly used for appendiceal stump closures in uncomplicated appendicitis, and staplers in complicated appendicitis. Only a minor part of surgeons plunge the appendiceal stump or perform routine abdominal lavage.

Impact of Sleep Deprivation on Surgical Laparoscopic Performance in Novices: A Computer-based Crossover Study.

OBJECTIVE: The 24-hour work shifts are newly permitted to first-year surgical residents in the United States. Whether surgery novices' motor activity is affected by sleep deprivation is controversial. MATERIALS AND METHODS: This study assesses sleep deprivation effects in computer-simulated laparoscopy in 20 surgical novices following 24 hours of sleep deprivation and after resting using a virtual-reality trainer. Participants were randomly assigned to perform simulator tests either well rested or sleep deprived first. RESULTS: Of 3 different tasks performed, no significant differences in total time to complete the procedure and average speed of instruments were found. Instrument path length was longer following sleep deprivation (P=0.0435) in 1 of 3 tasks. Error rates (ie, noncauterized bleedings, perforations, etc.), as well as precision, and accuracy rates showed no difference. None of the assessed participants' characteristics affected simulator performance. CONCLUSIONS: Twenty-four hours of sleep deprivation does not affect laparoscopic performance of surgical novices as assessed by computer-simulation.