Robotic-assisted esophagectomy with total mesoesophageal excision enhances R0-resection in patients with esophageal cancer: A single-center experience.

BACKGROUND: The focus of this research is to examine the growing use of robotic-assisted minimally invasive esophagectomy. Specifically, it evaluates the immediate clinical and cancer-related results of combining robotic-assisted minimally invasive esophagectomy with a systematic approach to total mesoesophageal excision, as opposed to traditional open transthoracic esophagectomy methods that do not employ a structured total mesoesophageal excision protocol. METHODS: A propensity score-matched analysis of 185 robotic-assisted minimally invasive esophagectomies and 223 open transthoracic esophagectomies after standardized Ivor Lewis esophagectomy was performed. After 1:1 nearest neighbor matching to account for confounding by covariates, outcomes of 181 robotic-assisted minimally invasive esophagectomy and 181 open transthoracic esophagectomy were compared. RESULTS: The patient characteristics showed significant differences in the age distribution and in comorbidities such as coronary heart disease, arterial hypertension, and anticoagulant intake. The R0-resection rate of robotic-assisted minimally invasive esophagectomy (96.7%) was significantly higher than open transthoracic esophagectomy (89.0%, P = .004). Thirty-day mortality and hospital mortality showed no significant differences. Postoperative pneumonia rate after robotic-assisted minimally invasive esophagectomy (12.7%) was significantly reduced (open transthoracic esophagectomy 28.7%, P < .001). Robotic-assisted minimally invasive esophagectomy had a significantly shorter intensive care unit stay (P < .001) and shorter hospital stay (P < .001). CONCLUSION: This single-center, retrospective study employing propensity score matching found that combining robotic-assisted minimally invasive esophagectomy with structured total mesoesophageal excision results in better short-term clinical and oncologic outcomes than open transthoracic esophagectomy. This finding is significant because the increased rate of R0 resection could indicate a higher likelihood of improved long-term survival. Additionally, enhanced overall postoperative recovery may contribute to better risk management in esophagectomy procedures.

The role of cytoreductive surgery and HIPEC for the treatment of primary and secondary peritoneal malignancies-experience from a tertiary care center in Germany.

PURPOSE: Peritoneal surface malignancies (PSM) are commonly known to have a dismal prognosis. Over the past decades, novel techniques such as cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and pressurized intraperitoneal aerosol chemotherapy (PIPAC) have been introduced for the treatment of PSM which could improve the overall survival and quality of life of patients with PSM. The decision to proceed with CRS and HIPEC is often challenging due the complexity of the disease, the extent of the procedure, associated side effects, and potential risks. Here, we present our experience with CRS and HIPEC to add to the ongoing discussion about eligibility criteria, technical approach, and expected outcomes and contribute to the evolution of this powerful and promising tool in the multidisciplinary treatment of patients with primary and secondary PSM. METHODS: A single-center retrospective chart review was conducted and included a total of 40 patients treated with CRS and HIPEC from April 2020 to September 2022 at the University Hospital Münster Department of Surgery. All patients had histologically confirmed primary or secondary peritoneal malignancies of various primary origins. RESULTS: Our study included 22 patients with peritoneal metastases from gastric cancer (55%), 8 with pseudomyxoma peritonei (20%), 4 with mesothelioma of the peritoneum (10%), and 6 patients with PSM originating from other primary tumor locations. Median PCI at time of cytoreduction was 4 (0-25). Completeness of cytoreduction score was 0 in 37 patients (92.5%), 1 in two patients (5%), and 2 in one patient (2.5%). Median overall survival across all patients was 3.69 years. CONCLUSION: Complete cytoreduction during CRS and HIPEC can be achieved for patients with low PCI, for patients with high PCI in low-grade malignancies, and even for patients with initially high PCI in high-grade malignancies following a significant reduction of cancer burden due to extensive preoperative treatment with PIPAC and systemic chemotherapy.

Graft-versus-host disease following liver transplantation: A systematic review of literature.

BACKGROUND: Graft-versus-host disease following liver transplantation is a serious and usually fatal complication. Data identifying the risk factors and specifying the diagnosis and treatment options of the disease are scarce and contentious. Moreover, recommendations for therapeutic approaches are similarly sparse. METHODS: A systematic review of the literature from 1988 to 2020 on graft-versus-host disease following liver transplantation was performed using the PubMed and MEDLINE databases. Medical subject headings, such as graft-versus-host disease and GvHD were used in combination with solid organ transplant, transplantation, or liver transplant. Following duplicate removal, 9298 articles were screened for suitability. A total of 238 full-text articles were analyzed for eligibility, resulting in 130 eligible articles for meta-analysis. Two hundred twenty-five patients developing graft-versus-host disease following liver transplantation reported herein were mainly published in case reports and case series. RESULTS: Graft-versus-host disease occurred with an incidence of 1.2%. 85% developed following deceased donor liver transplant and 15% following living-related donor liver transplantation. The median follow-up period following liver transplantation was 84 days (interquartile range, 45-180). The median time from liver transplantation to graft-versus-host disease onset was 30 days (interquartile range, 21-42). The main clinical features included skin rash (59%), fever (43%), diarrhea (36%), and pancytopenia (30%). The overall mortality rate was 71%. Neither univariate (HR = 0.999; 95% CI, 0.493-2.023; p = 1.0) nor multivariate Cox regression analysis revealed a significant correlation between adaptation of immunosuppression and survival probability (HR = 1.475; 95% CI, 0.659-3.303; p = 0.3). CONCLUSIONS: This systematic review suggests that an increase in immunosuppressive regimen does not yield any survival benefit in patients suffering from graft-versus-host disease following liver transplantation.

Management of intra-thoracic anastomotic leakages after esophagectomy: updated systematic review and meta-analysis of endoscopic vacuum therapy versus stenting.

Despite a significant decrease of surgery-related mortality and morbidity, anastomotic leakage still occurs in a significant number of patients after esophagectomy. The two main endoscopic treatments in case of anastomotic leakage are self-expanding metal stents (SEMS) and the endoscopic vacuum therapy (EVT). It is still under debate, if one method is superior to the other. Therefore, we performed a systematic review and meta-analysis of the existing literature to compare the effectiveness and the related morbidity of SEMS and EVT in the treatment of esophageal leakage. We systematically searched for studies comparing SEMS and EVT to treat anastomotic leak after esophageal surgery. Predefined endpoints including outcome, treatment success, endoscopy, treatment duration, re-operation rate, intensive care and hospitalization time, stricture rate, morbidity and mortality were assessed and included in the meta-analysis. Seven retrospective studies including 338 patients matched the inclusion criteria. Compared to stenting, EVT was significantly associated with higher healing (OR 2.47, 95% CI [1.30 to 4.73]), higher number of endoscopic changes (pooled median difference of 3.57 (95% CI [2.24 to 4.90]), shorter duration of treatment (pooled median difference - 11.57 days; 95% CI [- 17.45 to - 5.69]), and stricture rate (OR 0.22, 95% CI [0.08 to 0.62]). Hospitalization and intensive care unit duration, in-hospital mortality rate, rate of major and treatment related complications, of surgical revisions and of esophago-tracheal fistula failed to show significant differences between the two groups. Our analysis indicates a high potential for EVT, but because of the retrospective design of the included studies with potential biases, these results must be interpreted with caution. More robust prospective randomized trials should further investigate the potential of the two procedures.

Oestrogen Receptor Isoforms May Represent a Therapeutic Target in Oesophageal Adenocarcinoma.

Oesophageal adenocarcinoma is a rapidly increasing problem in which treatment options are limited. Previous studies have shown that oesophageal adenocarcinoma cells and tissues express oestrogen receptors (ERs) and show growth suppression and apoptosis in response to ER modulator agents such as tamoxifen. ERs are known to be expressed in a number of isoforms that act together to regulate cell growth and cell death. In this study, we used western blotting to profile the expression of ERα and ERß isoforms, and expression of the oncologically related molecules p53, HER2, and EGFR, in a panel of oesophageal adenocarcinoma cell lines. The cytotoxicity of tamoxifen in the cell lines was determined with Annexin V-FITC flow cytometry, and correlations between cytotoxicity and receptor expression were assessed using Spearman's rank-order correlation. Oesophageal adenocarcinoma cell lines showed varying cytotoxicity in response to tamoxifen. The ER species ERα90, ERα50, and ERα46, as well as p53, were positively associated with a cytotoxic response. Conversely, ERα74, ERα70, and ERß54 were associated with a lack of cytotoxic response. The ER species detected in oesophageal adenocarcinoma cells may work together to confer sensitivity to ER modulators in this disease, which could open up a new avenue for therapy in selected patients.

Merendino Resection vs. Transhiatal Gastric Conduit After Resection of the Cardia and the Gastroesophageal Junction.

BACKGROUND: Reconstruction after combined cardia resection and removal of the gastroesophageal junction can be carried out by the Merendino procedure or via a gastric conduit. This study compares postoperative complications and quality of life for both approaches. METHODS: All patients who underwent Merendino or gastric conduit reconstruction from 2011-2017 were included. Both groups were investigated regarding postoperative length of stay, complications, and gastrointestinal quality of life. RESULTS: 45 patients were identified, of which, 39 remained for analysis: 22 patients in the Merendino group and 17 patients in the gastric conduit group. The median age of patients in the gastric conduit group (71 (53-92) years) was significantly higher than in the Merendino group (58 (19-75) years), P = .0002. Hospital stay was significantly longer in the gastric conduit group (35.9 (11-82) days vs. 18.2 (7-43) days, P = .0299) and incidence of anastomotic leakage was higher (24% vs. 9%, P = .0171). General incidence of complications (Clavien-Dindo) did not vary (P = .1694). However, grade 5 complications only occurred in the Merendino group (n = 1). Evaluation of long-term outcome and quality of life showed dysphagia to only have occurred in the Merendino group (n = 3, 14%). DISCUSSION: Both approaches have advantages and disadvantages: The Merendino procedure showed reduced incidence of anastomotic leakage and shorter hospital stay but was associated with a higher in-hospital mortality rate. Discrepancies in subgroup populations as well as small patient numbers limit the interpretation of the findings. This study does however provide a first comparison of these surgical approaches and may serve as a basis for further investigation.

Minor Sphincter Sparing Surgery for Successful Closure of Perianal Fistulas in Patients with Crohn's Disease.

The purpose of this study is to demonstrate that repetitive minor surgical procedures allow for a high rate of permanent closure of perianal fistulas in patients with Crohn's disease (CD). Patients with perianal fistulizing CD (PFCD) who underwent perianal surgery at the University Hospital of Muenster between 2003 and 2018 were assessed for fistula characteristics and surgical procedures. We included 45 patients (m:f = 28:17) with a mean age of 27 years at first fistula appearance. Of these, 49% suffered from a complex fistula. An average of 4.2 (1-14) procedures were performed, abscess incisions and fistula seton drainages included. Draining setons were left in place for 5 (1-54) months, until fistula closure. Final surgical techniques were fistulotomy (31.1%), seton removal with sustained biological therapy (26.7%), Anal Fistula Plug (AFP) (17.8%), Over-The Scope-Clip proctology (OTSC) (11.1%), and mucosa advancement flap (4.4%). In 8.9% of cases, the seton was kept as permanent therapy. The time from first to last surgery was 18 (0-182) months and the median follow-up time after the last surgery was 90 (15-200) months. The recurrence rate was 15.5% after 45 (17-111) months. Recurrent fistulas healed after another 1.86 (1-2) surgical re-interventions. The final success rate was 80%. Despite biological treatment, PFCD management remains challenging. However, by repeating minor surgical interventions over a prolonged period of time, high permanent healing rates can be achieved.

Mutant p53 Mediates Sensitivity to Cancer Treatment Agents in Oesophageal Adenocarcinoma Associated with MicroRNA and SLC7A11 Expression.

TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.

Effects of therapy modifications during the last decade on the outcome of patients undergoing esophagectomy for esophageal cancer.

BACKGROUND: During the last decade, numerous therapeutic regimes were assessed to improve the outcome of patients with esophageal carcinoma. We analyzed the impact of therapy alterations, including the establishment of a standardized clinical pathway and the introduction of an interdisciplinary tumor conference on the outcome of patients undergoing esophagectomy because of esophageal cancer. METHODS: Three hundred one patients were included (204 adenocarcinoma and 97 squamous cell carcinoma) who underwent an esophagectomy between 2006 and 2015. Patients were divided into 3 groups: interval A (2006-2008), interval B (2009-2011) and interval C (2012-2015) and evaluated separately focusing on therapy management and patients' outcome. RESULTS: Over the time periods, the incidence of tumor entity of adenocarcinoma increased from 61% to 76.2% (P=0.059). Patients with an initial tumor stage uT1 increased significantly from 4% to 15.9% over the intervals (P=0.002), while positive nodal involvement remained comparable (P=0.237). Patients in the later interval suffered from greater physical impairments preoperatively, represented by a significantly increased American Society Anesthesiologists (ASA) score (P=0.023) and a reduced Karnofsky Index (P<0.001). The tumor conference was accompanied by an increasing implementation of neoadjuvant therapy (27.1% vs. 42.2%, P=0.097). After establishing the clinical pathway 30-day mortality decreased (P=0.67). Grad III anastomotic leakage decreased significantly from 6.5% to 2% (P=0.01). However, gastrointestinal (P=0.007), pulmonary complications (P<0.001) including pneumonia (P<0.001) increased. Over the past ten years both overall survival and relapse-free survival prolonged (P=0.056 and P=0.063, respectively). CONCLUSIONS: Patients' collective suffering from esophageal cancer has changed over the last decade. Continuous further developments of the therapy regimes are needed to meet the requirements of reducing perioperative mortality and extending survival time.

Economic Burden of Endoscopic Vacuum Therapy Compared to Alternative Therapy Methods in Patients with Anastomotic Leakage After Esophagectomy.

BACKGROUND: Endoscopic vacuum therapy (EVT) has become a promising option in the management of anastomotic leakage (AL) after esophagectomy. However, EVT is an effortful approach associated with multiple interventions. In this study, we conduct a comparative cost analysis for methods of management of AL. METHODS: All patients who experienced AL treated by EVT, stent, or reoperation following Ivor Lewis esophagectomy for esophageal cancer were included. Cases that were managed by more than one modality were excluded. For the remaining cases, in-patient treatment cost was collected for material, personnel, (par)enteral nutrition, intensive care, operating room, and imaging. RESULTS: 42 patients were treated as follows: EVT n = 25, stent n = 13, and reoperation n = 4. The mean duration of therapy as well as length of overall hospital stay was significantly shorter in the stent than the EVT group (30 vs. 44d, p = 0.046; 34 vs. 53d, p = 0.02). The total mean cost for stent was €33.685, and the total cost for EVT was €46.136, resulting in a delta increase of 37% for EVT vs. stent cost. 75% (€34.320, EVT), respectively, 80% (€26.900, stent) of total costs were caused by ICU stay. Mean pure costs for endoscopic management were relatively low and comparable between both groups (EVT: €1.900, stent: €1.100, p = 0.28). CONCLUSION: Management of AL represents an effortful approach that results in high overall costs. The expenses directly related to EVT and stent therapy were however comparatively low with more than 75% of costs being attributable to the ICU stay. Reduction of ICU care should be a central part of cost reduction strategies.

Short- and Long-Term Outcomes of Different Reperfusion Sequences in Liver Transplantation.

BACKGROUND Although most centers perform primary portal vein reperfusion (PV) in orthotopic liver transplantation (OLT) for historical reasons, there is so far no sound evidence as to whether this technique is superior. The present study evaluated the long-term outcome of 3 different reperfusion sequences: PV vs primary arterial (A) vs simultaneous reperfusion (SIM). MATERIAL AND METHODS All patients at our center who underwent OLT (who received a primary, whole-organ liver graft) from 2006 to 2007 were evaluated for analysis. RESULTS A total of 61 patients were found eligible (PV: 25, A: 22, SIM: 14). Twenty-one patients (35%) were still alive after the follow-up period of 12 years. Despite poorer starting conditions such as higher recipient age (59 y (SIM) vs 55 y (A) vs 50 y (PV), P=0.01) and donor age (56 y (SIM) vs 51 y (PV) vs 50 y (A), n.s.), higher MELD scores (22 vs 19 (PV) vs 17 (A), n.s.), as well as a higher number of marginal donor organs (79% (SIM) vs 36% (A/PV), P=0.02), SIM-recipients demonstrated superior outcomes. Overall survival was 8.1 y (SIM), 4.8 y (PV), and 5.9 y (A, n.s.)). None of the SIM-recipients underwent re-transplantation, while the rate was 32% in the PV-group. The 8.1 y graft survival in SIM-recipients was significantly longer than in the other 2 groups, which were 3.3 y (PV) and 5.5 y (A, P=0.013). CONCLUSIONS Although SIM-reperfused recipients were the oldest and received grafts of inferior quality, these recipients showed superior results in terms of overall patient and graft survival. Multicentric randomized controlled trials with larger study populations are required to confirm this finding.

Management of Nonmalignant Tracheo- and Bronchoesophageal Fistula after Esophagectomy.

BACKGROUND: Tracheo- or bronchoesophageal fistula (TBF) occurring after esophagectomy represent a rare but devastating complication. Management remains challenging and controversial. Therefore, the purpose of this study was to evaluate the outcome of different treatment approaches and to propose recommendations for the management of TBF. METHODS: From 2008 to 2018, 15 patients were treated because of TBF and were analyzed with respect to fistula appearance, treatment strategy (stenting, endoscopic vacuum therapy and/or surgical reintervention) and outcome. RESULTS: In each case, the fistula was small, located close to the tracheal bifurcation and associated simultaneously (n = 6, 40%) or metachronously (n = 9, 60%) with an anastomotic leakage. Latter was covered by esophageal stents in six patients which in turn resulted in occurrence of TBF at a later time in five patients. Management of TBF included conservative therapy (n = 3), stenting (n = 6), or suturing (n = 6). Ten patients underwent rethoracotomy. Treatment failure was observed in eight patients (53%). In all patients, treatment was accompanied by progressive sepsis. On the contrary, all seven patients with successful defect closure remained in good general condition. CONCLUSION: Fistula appearance was similar in all patients. Implementation of esophageal stents cannot be recommended because of possibility of TBF at a later time point. Surgery is usually required and should preferably be performed when the patient's condition has been optimized at a single-stage repair. Esophageal diversion can only be recommended in patients with persisting mediastinitis. The key element for successful treatment of TBF, however, is control over sepsis; otherwise, outcome of TBF is devastating.

MicroRNA Profiling in Oesophageal Adenocarcinoma Cell Lines and Patient Serum Samples Reveals a Role for miR-451a in Radiation Resistance.

Many patients with Oesophageal Adenocarcinoma (OAC) do not benefit from chemoradiotherapy treatment due to therapy resistance. To better understand the mechanisms involved in resistance and to find potential biomarkers, we investigated the association of microRNAs, which regulate gene expression, with the response to individual treatments, focusing on radiation. Intrinsic radiation resistance and chemotherapy drug resistance were assessed in eight OAC cell lines, and miRNA expression profiling was performed via TaqMan OpenArray qPCR. miRNAs discovered were either uniquely associated with resistance to radiation, cisplatin, or 5-FU, or were common to two or all three of the treatments. Target mRNA pathway analyses indicated several potential mechanisms of treatment resistance. miRNAs associated with the in vitro treatment responses were then investigated for association with pathologic response to neoadjuvant chemoradiotherapy (nCRT) in pre-treatment serums of patients with OAC. miR-451a was associated uniquely with resistance to radiation treatment in the cell lines, and with the response to nCRT in patient serums. Inhibition of miR-451a in the radiation resistant OAC cell line OE19 increased radiosensitivity (Survival Fraction 73% vs. 87%, p = 0.0003), and altered RNA expression. Pathway analysis of effected small non-coding RNAs and corresponding mRNA targets suggest potential mechanisms of radiation resistance in OAC.

ABO-Incompatible Living Donor Kidney Transplantation in a Human Immunodeficiency Virus-Positive Recipient From a Human Immunodeficiency Virus-Positive Donor: A Case Report.

A human immunodeficiency virus (HIV) infection is no longer an absolute contraindication for solid organ transplantation, yet such a setting is still challenging and little explored because of general reservations and medical difficulties. We describe a 51-year-old man with end-stage renal failure due to polycystic kidney disease who underwent an ABO-incompatible kidney transplantation from his 49-year-old male partner. Early postoperative course revealed an episode of suspected acute rejection, which was successfully managed with a steroid pulse. Both donor and recipient continued to have an undetectable viral load after adjusting antiretroviral medication to renal function. To the best of our knowledge, this is the first report of a successful ABO-incompatible living donor kidney transplantation from an HIV-positive donor in an HIV-positive recipient, and this case seems to be a valuable approach with favorable results.

Impact of preoperative risk factors on outcome after gastrectomy.

BACKGROUND: Gastrectomy is associated with relevant postoperative morbidity. However, outcome of surgery can be improved by careful selection of patients. The objective of the current study was therefore to identify preoperative risk factors that might impact on patients' further outcome after surgical resection. METHODS: Preoperative risk factors having respectively different surgical risk scores for major complex surgery (including Cologne Risk Score, p-/o-POSSUM, and NSQIP risk score) of patients that underwent gastrectomy for AEG II/III tumors and gastric cancer were correlated with complications according to Clavien-Dindo and outcome. Patients who underwent surgery in palliative intention were excluded from further analysis. RESULTS: Subtotal gastrectomy was performed in 23%, gastrectomy in 59%, and extended gastrectomy in 18% in a total of 139 patients (mean age: 64 years old). Thirty six percent experienced a minor complication (Dindo I-II) and 24% a major complication (Dindo III-V), which resulted in a prolonged hospital stay (p < 0.001). In-hospital mortality (=Dindo V) was 2.5%. Besides age, type of surgical procedure impacted on complications with extended gastrectomy showing the highest risk (p = 0.005). The o-POSSUM score failed to predict mortality accurately. We observed a highly positive correlation between predicted morbidity respectively mortality and occurrence of complications estimated by p-POSSUM (p = 0.005), Cologne Risk (p = 0.007), and NSQIP scores (p < 0.001). CONCLUSION: The results demonstrate a significant association between different risk scores and occurrence of complications following gastrectomy. The p-POSSUM, Cologne Risk, and NSQIP score exhibited superior performance than the o-POSSUM score. Therefore, these scores might allow identification and selection of high-risk patients and thus might be highly useful for clinical decision making.

Correction: Complex Epigenetic Regulation of Chemotherapy Resistance and Biology in Esophageal Squamous Cell Carcinoma via MicroRNAs. Int. J. Mol. Sci. 2018, 19, 499.

We would like to submit a correction to the published paper [...].

microRNAs: Key regulators of chemotherapy response and metastatic potential via complex control of target pathways in esophageal adenocarcinoma.

INTRODUCTION: Incidence of esophageal adenocarcinoma (EAC) increased significantly over the last decades. Lack of response to chemotherapy is a major problem in the treatment of this disease. This study aims to assess the biological relevance of characteristic microRNA profiles of chemotherapy resistant EAC cells with regards to response to chemotherapy and biological behavior. METHODS: We selected 3 microRNAs from characteristic microRNA profiles of resistant EAC (miR-27b-3p, miR-200b-3p, and miR-148a-3p). Expression of microRNAs was modified in 6 EAC cell lines. Effects on chemotherapy, adhesion, migration, apoptosis and cell cycle were assessed using standard assays. Target analyses were performed using Western Blot and Luciferase techniques. RESULTS: MiR-27b-3p significantly sensitized cells to 5FU and Cisplatin in 83% respectively in 33% of cell lines, miR-148a-3p in 67% respectively 33% of cases. MiR-200b-3p increased sensitivity only towards 5FU in 50% of cases. Co-transfections with miR-27b-3p/miR-148a-3p showed an additive effect on response to chemotherapy in 50% of cases. Upregulation of miR-148a-3p reduced protein expression levels of DNMT-1, MSK-1, Bcl-2 and Bim, and miR-27b upregulation led to downregulation of Sp1 and PPARy proteins implicating a potential negative post-transcriptional control via the respective microRNAs. Finally, we were able to confirm Bcl-2 for the first time as direct target of miR-148a-3p in EAC. CONCLUSION: This study demonstrates that specific microRNA profiles of chemotherapy resistant EAC in fact determine their response to chemotherapy and biological behavior. Our data further show that microRNA-mediated regulation of chemotherapy resistance is complex, and several microRNAs seem to "co-operate" at various steps within a broad number of pathways what fits very well to our recently proposed understanding of microRNA-mediated regulation as function of cellular functional complexes. These data highlight the promising potential of microRNAs to predict or monitor treatment response to chemotherapy in EAC, and to potentially modulate tumor biology in a therapeutic approach.

Complex Epigenetic Regulation of Chemotherapy Resistance and Biohlogy in Esophageal Squamous Cell Carcinoma via MicroRNAs.

BACKGROUND: Resistance towards chemotherapy is a major obstacle in the treatment of esophageal squamous cell carcinoma (ESCC). We investigated the role of specific microRNAs in chemotherapy resistance and tumor biology. METHODS: We selected three microRNAs from characteristic microRNA signatures of resistant ESCC (hsa-miR-125a-5p, hsa-miR-130a-3p, hsa-miR-1226-3p), and hsa-miR-148a-3p. Effects on chemotherapy, adhesion, migration, apoptosis and cell cycle were assessed in six ESCC cell lines. Target analyses were performed using Western blotting and luciferase techniques. RESULTS: MiR-130a-3p sensitized cells towards cisplatin in 100% of cell lines, miR-148a-3p in 83%, miR-125a-5p in 67%, miR-1226-3p in 50% (p ≤ 0.04). MiR-130a-3p sensitized 83% of cell lines towards 5-FU, miR-148a-3p/miR-125a-5p/miR-1226-3p only 33% (p ≤ 0.015). Several resistance-relevant pathways seem to be targeted on various levels. Bcl-2 was confirmed as a direct target of miR-130a-3p and miR-148a-3p, and p53 as a target of miR-125a-5p. All microRNAs decreased migration and adhesion, except miR-130a-3p, and increased apoptosis. Simultaneous manipulation of two microRNAs exhibited additive sensitizing effects towards cisplatin in 50% (miR-125a-5p/miR-148a-3p), and 75% (miR-148a-3p/miR-130a-3p) of cell lines (p ≤ 0.016) [corrected] CONCLUSION: Our data present strong evidence that specific microRNA signatures are responsible for drug resistance and aggressiveness of ESCC. Final functional readout of these complex processes appears to be more important than single microRNA-target interactions.

Effect of Continuous Motion Parameter Feedback on Laparoscopic Simulation Training: A Prospective Randomized Controlled Trial on Skill Acquisition and Retention.

OBJECTIVE: To investigate the effect of motion parameter feedback on laparoscopic basic skill acquisition and retention during a standardized box training curriculum. DESIGN: A Lap-X Hybrid laparoscopic simulator was designed to provide individual and continuous motion parameter feedback in a dry box trainer setting. In a prospective controlled trial, surgical novices were randomized into 2 groups (regular box group, n = 18, and Hybrid group, n = 18) to undergo an identical 5-day training program. In each group, 7 standardized tasks on laparoscopic basic skills were completed twice a day on 4 consecutive days in fixed pairs. Additionally, each participant performed a simulated standard laparoscopic cholecystectomy before (day 1) and after training (day 5) on a LAP Mentor II virtual reality (VR) trainer, allowing an independent control of skill progress in both groups. A follow-up assessment of skill retention was performed after 6 weeks with repetition of both the box tasks and VR cholecystectomy. SETTING: Muenster University Hospital Training Center, Muenster, Germany. PARTICIPANTS: Medical students without previous surgical experience. RESULTS: Laparoscopic skills in both groups improved significantly during the training period, measured by the overall task performance time. The 6 week follow-up showed comparable skill retention in both groups. Evaluation of the VR cholecystectomies demonstrated significant decrease of operation time (p < 0.01), path length of the left and right instrument, and the number of movements of the left and right instruments for the Hybrid group (all p < 0.001), compared to the box group. Similar results were found at the assessment of skill retention. CONCLUSION: Simulation training on both trainers enables reliable acquisition of laparoscopic basic skills. Furthermore, individual and continuous motion feedback improves laparoscopic skill enhancement significantly in several aspects. Thus, training systems with feedback of motion parameters should be considered to achieve long-term improvement of motion economy among surgical trainees.