The 3-Biomarker Classifier-A Novel and Simple Molecular Risk Score Predicting Overall Survival in Patients with Colorectal Cancer.

INTRODUCTION: Several new molecular markers in colorectal carcinomas have been discovered; however, classical histopathological predictors are still being used to predict survival in patients. We present a novel risk score, which uses molecular markers, to predict outcomes in patients with colorectal carcinoma. METHODS: The immunohistochemistry of tissue micro arrays was used to detect and quantify H2BUB1, RBM3 and Ki-67. Different intensities of staining were categorized for these markers and a score was established. A multivariate analysis was performed and survival curves were established. RESULTS: 1791 patients were evaluated, and multivariate analysis revealed that our risk score, the 3-biomarker classifier, is an independent marker to predict survival. We found a high risk-score to be associated with dismal median survival for the patients. CONCLUSIONS: A more personalized score might be able to better discriminate low- and high-risk patients and suggest adjuvant treatment compared to classical pathological staging. Our score can serve as a tool to predict outcomes in patients suffering from colorectal carcinoma.

Intraoperative Wound Irrigation for the Prevention of Surgical Site Infection After Laparotomy: A Randomized Clinical Trial by CHIR-Net.

Importance: Surgical site infections frequently occur after open abdominal surgery. Intraoperative wound irrigation as a preventive measure is a common practice worldwide, although evidence supporting this practice is lacking. Objective: To evaluate the preventive effect of intraoperative wound irrigation with polyhexanide solution. Design, Setting, and Participants: The Intraoperative Wound Irrigation to Prevent Surgical Site Infection After Laparotomy (IOWISI) trial was a multicenter, 3-armed, randomized clinical trial. Patients and outcome assessors were blinded to the intervention. The clinical trial was conducted in 12 university and general hospitals in Germany from September 2017 to December 2021 with 30-day follow-up. Adult patients undergoing laparotomy were eligible for inclusion. The main exclusion criteria were clean laparoscopic procedures and the inability to provide consent. Of 11 700 screened, 689 were included and 557 completed the trial; 689 were included in the intention-to-treat and safety analysis. Interventions: Randomization was performed online (3:3:1 allocation) to polyhexanide 0.04%, saline, or no irrigation (control) of the operative wound before closure. Main Outcome and Measures: The primary end point was surgical site infection within 30 postoperative days according to the US Centers for Disease Control and Prevention definition. Results: Among the 689 patients included, 402 were male and 287 were female. The median (range) age was 65.9 (18.5-94.9) years. Participants were randomized to either wound irrigation with polyhexanide (n = 292), saline (n = 295), or no irrigation (n = 102). The procedures were classified as clean contaminated in 92 cases (8%). The surgical site infection incidence was 11.8% overall (81 of 689), 10.6% in the polyhexanide arm (31 of 292), 12.5% in the saline arm (37 of 295), and 12.8% in the no irrigation arm (13 of 102). Irrigation with polyhexanide was not statistically superior to no irrigation or saline irrigation (hazard ratio [HR], 1.23; 95% CI, 0.64-2.36 vs HR, 1.19; 95% CI, 0.74-1.94; P = .47). The incidence of serious adverse events did not differ among the 3 groups. Conclusions and Relevance: In this study, intraoperative wound irrigation with polyhexanide solution did not reduce surgical site infection incidence in clean-contaminated open abdominal surgical procedures compared to saline or no irrigation. More clinical trials are warranted to evaluate the potential benefit in contaminated and septic procedures, including the emergency setting. Trial Registration: drks.de Identifier: DRKS00012251.

Risk Factor Analysis for Developing Major Complications Following Esophageal Surgery-A Two-Center Study.

BACKGROUND: Esophagectomy carries a high risk of morbidity and mortality compared to other major surgeries. With the aim of creating an easy-to-use clinical preoperative risk assessment tool and to validate previously described risk factors for major complications following surgery, esophagectomies at two tertiary medical centers were analyzed. METHODS: A total of 450 patients who underwent esophagectomy for esophageal carcinoma at the University Medical Centre, Hamburg, or at the Medical Center University Duisburg-Essen, Germany (January 2008 to January 2020) were retrospectively analyzed. Epidemiological and perioperative data were analyzed to identify the risk factors that impact major complication rates. The primary endpoint of this study was to determine the incidence of major complications. RESULTS: The mean age of the patients was 63 years with a bimodal distribution. There was a male predominance across the cohort (81% vs. 19%, respectively). Alcohol abuse (p = 0.0341), chronic obstructive pulmonary disease (p = 0.0264), and cardiac comorbidity (p = 0.0367) were associated with a significantly higher risk of major complications in the multivariate analysis. Neoadjuvant chemotherapy significantly reduced the risk of major postoperative complications (p < 0.0001). CONCLUSIONS: Various patient-related risk factors increased the rate of major complications following esophagectomy. Patient-tailored prehabilitation programs before esophagectomy that focus on minimizing these risk factors may lead to better surgical outcomes and should be analyzed in further studies.

Robotic-assisted repair of incisional hernia-early experiences of a university robotic hernia program and comparison with open and minimally invasive sublay technique (eMILOS).

PURPOSE: With robotic surgical devices, an innovative tool has stepped into the arena of minimally invasive hernia surgery. It combines the advantages of open (low recurrence rates and ability to perform complex procedure such as transverse abdominis release) and laparoscopic surgery (low rate of wound and mesh infections, less pain). However, a superiority to standard minimally invasive procedures has not yet been proven. We present our first experiences of robotic mesh repair of incisional hernias and a comparison of our results with open and minimally invasive sublay techniques. METHODS: A retrospective analysis of all patients who underwent robotic-assisted mesh repair (RAHR) for incisional hernia between April and November 2022 (RAHR group) and patients who underwent open sublay (Sublay group) or eMILOS hernia repair (eMILOS group) between January 2018 and November 2022 was carried out. Patients in the RAHR group were matched 1:2 to patients in the Sublay group by propensity score matching. Patient demographics, preoperative hernia characteristics and cause of hernia, intraoperative variables, and postoperative outcomes were evaluated. Furthermore, a subgroup analysis of only midline hernia was performed. RESULTS: A total of 21 patients received robotic-assisted incisional hernia repair. Procedures performed included robotic retro-muscular hernia repair (r-RMHR, 76%), with transverse abdominis release in 56% of the cases. In one patient, r-RHMR was combined with robotic inguinal hernia repair. Two patients (10%) were operated with total extraperitoneal technique (eTEP). Robotic-assisted transabdominal preperitoneal hernia repair (r-TAPP) was performed in three patients (14%). Median (range) operating time in the RAHR group was significantly longer than in the sublay and eMILOS group (291 (122-311) vs. 109.5 (48-270) min vs. 123 (100-192) min, respectively, p < 0.001). The meshes applied in the RAHR group were significantly compared to the sublay (mean (SD) 529 ± 311 cm2 vs. 356 ± 231, p = 0.037), but without a difference compared to the eMILOS group (mean (SD) 596 ± 266 cm2). Median (range) length of hospital stay in the RAHR group was significantly shorter compared to the Sublay group (3 (2-7) vs. 5 (1-9) days, p = 0.032), but not significantly different to the eMILOS group. In short term follow-up, no hernia recurrence was observed in the RAHR and eMILOS group, with 9% in the Sublay group. The subgroup analysis of midline hernia revealed very similar results. CONCLUSION: Our data show a promising outcome after robotic-assisted incisional hernia repair, but no superiority compared to the eMILOS technique. However, RAHR is a promising technique especially for complex hernia in patients with relevant risk factors, especially immunosuppression. Longer follow-up times are needed to accurately assess recurrence rates, and large prospective trials are needed to show superiority of robotic compared to standard open and minimally invasive hernia repair.

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis.

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

Failure of a Multi-Centric Clinical Trial Investigating Neoadjuvant Radio-Chemotherapy in Resectable Pancreatic Carcinoma (NEOPA-NCT01900327)-Which Lessons Are Learnt?

BACKGROUND: A significant number of clinical trials must be prematurely discontinued due to recruitment failure, and only a small fraction publish results and a failure analysis. Based on our experience on conducting the NEOPA trial on neoadjuvant radiochemotherapy for resectable and borderline resectable pancreatic carcinoma (NCT01900327-funded by the German Federal Ministry of Education and Research-BMBF), we performed an analysis of potential reasons for recruitment failure and general problems in conducting clinical trials in Germany. METHODS: Systematic analysis of environmental factors, trial history, conducting and funding in the background of the published literature. RESULTS: The recruitment failure was based on various study-specific conceptional and local environmental aspects and in peculiarities of the German surgical study culture. General reservations against a neo-adjuvant study concept combined with game changing scientific progresses during the long-lasting planning and funding phase have led to a reduced interest in the trial design and recruitment. CONCLUSIONS: Trial planning and conducting should be focused, professionalized and financed on a national basis. Individual interests must be subordinated to reach the goal to perform more relevant and successful clinical trials in Germany. Bureaucratic processes must be further fastened between a trial idea and the start of a study.

Minimally invasive intrathoracic negative-pressure therapy and flexible thoracoscopy (FlexVATS) for patients with pleural empyema.

To determine whether a new surgical method using a flexible endoscope (FlexVATS) to perform sparing debridement and apply negative-pressure therapy without extensive decortication may be an alternative treatment option for empyema. Surgical treatment of pleural empyema is associated with considerable postoperative complications and mortality rates, and alternative treatment options are being explored to improve patient outcomes. This was a prospective case series. Seventeen consecutive patients treated with FlexVATS between February 2021 and August 2022 were included in the study. Only patients for whom FlexVATS was the first therapeutic intervention for pleural empyema were included. Treatment success, defined as infection resolution, was the primary endpoint of the study. The secondary endpoints were length of hospital stay, 90-day mortality, and empyema cavity volume reduction. Patients who had previously been treated for pleural empyema by either drainage or surgery were excluded. The trial was performed as a single-centre study at a tertiary medical centre in Germany. In total, 17 patients with pleural empyema were included in the study. The median (IQR) duration of vacuum treatment was 15 days (8-35 days). Twelve of the 17 (71%) patients were successfully treated, and a significant reduction in the empyema cavity volume was observed. 41% of the dressing changes were performed outside the operating room. Compared with a historic cohort of conventionally treated patients (decortication via VATS or thoracotomy), the 90-day mortality rates tended to be lower without reaching statistical significance. Three patients (18%) died in hospital during treatment. No negative pressure-therapy-related complications were observed. FlexVATS therapy is a promising alternative therapy for both healthy and debilitated patients with pleural empyema. Larger randomised trials are required to validate this treatment option.

IL-22BP controls the progression of liver metastasis in colorectal cancer.

Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown. Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages. Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice. Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC.

Challenges in the interdisciplinary treatment of leakages after left-sided colorectal surgery: endoscopic negative pressure therapy, open-pore film drainage therapy and beyond.

PURPOSE: The treatment of anastomotic leakage after left colorectal surgery remains challenging. Since its introduction, endoscopic negative pressure therapy (ENPT) has proven to be advantageous, reducing the necessity of surgical revision. The aim of our study is to present our experience with endoscopic treatment of colorectal leakages and to identify potential factors influencing treatment outcome. METHODS: Patients who underwent endoscopic treatment of colorectal leakage were retrospectively analyzed. Primary endpoint was the healing rate and success of endoscopic therapy. RESULTS: We identified 59 patients treated with ENPT between January 2009 and December 2019. The overall closure rate was 83%, whereas only 60% of the patients were successfully treated with ENPT and 23% needed further surgery. The time between diagnosis of leakage and uptake of endoscopic treatment did not influence the closure rate, but patients with chronic fistula (> 4 weeks) showed a significantly higher reoperation rate than those with an acute fistula (94% vs 6%, p = 0.01). CONCLUSION: ENPT is a successful treatment option for colorectal leakages, which appears to be more favorable when started early. Further studies are still needed to better describe its healing potential, but it deserves an integral role in the interdisciplinary treatment of anastomotic leakages.

Intrathoracic vacuum therapy for the therapy of pleural empyema-a systematic review and analysis of the literature.

Background: Pleural empyema is a serious and potentially deadly disease leading to a significant burden on health care systems. Conservative and surgical treatment results remain poor, with high morbidity and mortality rates. Patients with pleural empyema are often multimorbid and poor candidates for surgery. Therefore, it appears sensible to explore alternative, less invasive treatment options. Recently, the well-established vacuum sponge therapy has been adopted in the treatment of pleural infections. The goal of this systematic review was to identify the existing literature and reported results of vacuum therapy for pleural empyema. Methods: A systematic search of MEDLINE and the Cochrane Database was performed independently by two reviewers using predefined criteria according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. In addition, abstracts from selected conference proceedings were screened and reference scanning of the search results was performed. Single case reports were excluded. Results: Fourteen studies met the selection criteria and were reviewed. A total of 165 patients were treated with vacuum therapy in the studies reviewed. 61.2% of the patients had pleural empyema secondary to thoracic surgery. In 71.5% of the patients, vacuum therapy was applied following open window thoracostomy (OWT). Mortality rates of 0-33% were reported for vacuum therapy after OWT and 0-9.3% for vacuum therapy without OWT. Length of hospital stay (LOHS) ranged from 44-217 days for patients after OWT and could not be analysed for vacuum therapy without OWT due to lacking data. Median treatment time was 7-14 days. Treatment related complications were rare overall. Success rates defined as infection resolution were high irrespective of previous treatment and cause of empyema. Conclusions: The current literature shows that pleural vacuum therapy is a promising, safe, and feasible treatment alternative to existing treatment modalities for pleural empyema. However, the evidence for vacuum therapy without OWT is poor, and further data, optimally prospective or randomised control trials comparing the conventional surgical approach of video-assisted thoracoscopic surgery (VATS) decortication and minimally invasive vacuum therapy, are needed.

Decreased expression of prolyl hydroxylase 1 is associated with poor prognosis in colorectal cancers.

BACKGROUND: Prolyl hydroxylase 1 (PHD1) is a prognostic marker in several cancers. AIMS AND SCOPES: This study was undertaken to elucidate the clinical relevance of PHD1 in colorectal cancer (CRC) prognosis. MATERIALS AND METHODS: We compared PHD1 expression on a tissue microarray (TMA) containing samples from 1800 CRCs with corresponding clinicopathological tumor variables and patient survival. RESULTS: While PHD1 staining was always high in benign colorectal epithelium, high PHD1 staining was detectable in only 71.8% of CRCs. Low PHD1 staining was associated with advanced tumor stage (p = 0.0101) and shortened overall survival in CRC patients (p = 0.0011). In a multivariable analysis including tumor stage, histological type and PHD1 staining revealed tumor stage and histological type (p < 0.0001 each), but also PHD1 staining (p = 0.0202) to be independent prognostic markers for CRC. CONCLUSIONS: In our cohort, loss of PHD1 expression independently identified a subset of CRC patients with poor overall survival and might, thus, be a promising prognostic marker. PHD1 targeting may even allow for specific therapeutic approaches for these patients.

RAI3 expression is not associated with clinical outcomes of patients with non-small cell lung cancer.

PURPOSE: Retinoic acid inducible protein 3 (RAI3) has been suggested as prognostic biomarker in several cancer types. The present study aimed to examine the role of RAI3 expression in non-small cell lung cancers (NSCLCs). METHODS: RAI3 protein expression was evaluated by immunohistochemistry in tissue microarray (TMA) sections from a retrospective cohort of more than 600 surgically resected NSCLCs and results were compared with clinicopathological features and follow-up data. RESULTS: While membranous RAI3 immunostaining was always strong in benign lung, strong RAI3 staining was only detectable in 14.7% of 530 interpretable NSCLCs. Within NSCLC subtypes, immunostaining intensity for RAI3 was significantly decreased in large cell lung cancers (LCLCs) and squamous cell carcinomas (SQCCs) relative to lung adenocarcinomas (LUACs) (P < 0.0001 each). However, RAI3 staining was neither associated with pathological features of NSCLCs nor with survival of patients (P = 0.6915). CONCLUSION: Our study shows that RAI3 expression was not associated with clinical outcomes of NSCLC patients and cannot be considered as prognostic marker in lung cancer patients.

A Critical Role of the IL-22-IL-22 Binding Protein Axis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) ranks among the five most common cancer entities worldwide and leads to hundred-thousands of deaths every year. Despite some groundbreaking therapeutical revelations during the last years, the overall prognosis remains poor. Although the immune system fights malignant transformations with a robust anti-tumor response, certain immune mediators have also been shown to promote cancer development. For example, interleukin (IL)-22 has been associated with HCC progression and worsened prognosis in multiple studies. However, the underlying mechanisms of the pathological role of IL-22-signaling as well as the role of its natural antagonist IL-22 binding protein (IL-22BP) in HCC remain elusive. Here, we corroborate the pathogenic role of IL-22 in HCC by taking advantage of two mouse models. Moreover, we observed a protective role of IL-22BP during liver carcinogenesis. While IL-22 was mainly produced by CD4+ T cells in HCC, IL-22BP was abundantly expressed by neutrophils during liver carcinogenesis. Hepatocytes could be identified as a major target of this pathological IL-22-signaling. Moreover, abrogation of IL-22 signaling in hepatocytes in IL22ra1flox/flox × AlbCre+ mice reduced STEAP4 expression-a known oncogene-in HCC in vivo. Likewise, STEAP4 expression correlated with IL22 levels in human HCC samples, but not in healthy liver specimens. In conclusion, these data encourage the development of therapeutical approaches that target the IL-22-IL-22BP axis in HCC.

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.

Combined endoscopic-percutaneous treatment of upper gastrointestinal enterocutaneous fistula using vacuum therapy and resorbable plug insertion (Vac-Plug).

After gastrointestinal resections, leakages can occur, persist despite conventional therapy and result in enterocutaneous fistulae. We developed a combination method using flexible endoscopic techniques to seal the enteric orifice with an absorbable plug in addition to a percutaneously and fistuloscopically guided open-pore film drainage (Vac-Plug method). We retrospectively searched our endoscopy database to identify patients treated with the outlined technique. The clinical and pathological data were assessed, the method analyzed and characterized and the technical and clinical success determined. We identified 14 patients that were treated with the Vac-Plug method (4 females, 10 males with a mean age of 56 years, range 50-74). The patients were treated over a time period of 23 days (range 4-119) in between one to thirteen interventions (mean n = 5). One patient had to be excluded due to short follow-up after successful closure. Seventy-seven percent (10/13) were successfully treated with a median follow-up of 453 days (range 35-1246) thereafter. No treatment related complications occurred during the therapy. The data of the analysis showed that the Vac-Plug therapy is safe and successful in a relevant proportion of the patients. It is easy to learn and to apply and is well tolerated. In our opinion, it is a promising addition to the armamentarium of interventional methods of these difficult to treat patients. Of course, its usefulness must be further validated in larger prospective studies.

Completion of FLOT Therapy, Regardless of Tumor Regression, Significantly Improves Overall Survival in Patients with Esophageal Adenocarcinoma.

Esophageal cancer is the eighth most common cancer worldwide, with poor prognosis and high mortality. The combination of surgery and systemic therapy provide the best chances for long-term survival. The purpose of this study was to analyze the impact of the FLOT protocol on the overall survival of patients following surgery for esophageal adenocarcinoma, with a focus on the patients who did not benefit in terms of pathological remission from the neoadjuvant therapy. A retrospective analysis of all the patients who underwent esophagectomies from 2012 to 2017 for locally advanced adenocarcinomas of the esophagus at a tertiary medical center was performed. The results show that the completion of systemic therapy, regardless of the tumor regression grading, had a significant positive impact on the overall survival. The patients with complete regression and complete systemic therapy showed the best outcomes. Anastomotic insufficiency did not negatively impact the long-term survival, while complications of the systemic therapy led to significantly reduced overall survival. We conclude that adjuvant systemic therapy should, when possible, always be completed, regardless of the tumor regression, following an esophagectomy.

CD147 expression lacks prognostic relevance in esophageal cancer.

INTRODUCTION: The role of CD147 as an important indicator of tumor prognosis remains controversially discussed in literature. We focused on the prognostic significance of CD147 expression in esophageal cancer patients. While some studies report that CD147 is an unfavorable prognostic factor in esophageal squamous cell carcinoma, others showed no significant correlation. However, only one study draws attention to the significance of CD147 in esophageal adenocarcinoma, which is one of the most rapidly increasing neoplasms in the western world. METHODS: To finally clarify the impact of CD147 as a prognostic factor, especially for esophageal adenocarcinomas, we analyzed CD147 expression in a tissue microarray of 359 esophageal adenocarcinomas and 254 esophageal squamous cell cancer specimens. For the immuno-histochemical analysis, we used a primary antibody specific for CD147. Staining intensity and proportion of positive tumor cells were scored (negative, weak, moderate, strong staining). These findings were compared to normal esophageal tissue and correlated to the histopathological tumor phenotype and survival data. RESULTS: CD147 expression was detectable in weak intensities in benign esophageal tissue (85.78%) and expressed in predominately moderate to strong intensities in esophageal cancer (88.34%). Strong CD147 immunostaining was linked to increased infiltration depth (p = 0.015) and differentiation (p = 0.016) in esophageal squamous cell cancer but revealed no significant correlation with histopathology of adenocarcinoma. Moreover, CD147 intensity was unrelated to overall survival in this collective for both subtypes of esophageal cancer. CONCLUSION: Thus, our data show that CD147 has no prognostic value, neither in esophageal adenocarcinoma nor squamous cell carcinoma.

Endoscopic vacuum therapy versus stent treatment of esophageal anastomotic leaks (ESOLEAK): study protocol for a prospective randomized phase 2 trial.

BACKGROUND: Intrathoracic anastomotic leaks represent a major complication after Ivor Lewis esophagectomy. There are two promising endoscopic treatment strategies in the case of leaks: the placement of self-expanding metal stents (SEMS) or endoscopic vacuum therapy (EVT). Up to date, there is no prospective data concerning the optimal endoscopic treatment strategy. This is a protocol description for the ESOLEAK trial, which is a first small phase 2 randomized trial evaluating the quality of life after treatment of anastomotic leaks by either SEMS placement or EVT. METHODS: This phase 2 randomized trial will be conducted at two German tertiary medical centers and include a total of 40 patients within 2 years. Adult patients with histologically confirmed esophageal cancer, who have undergone Ivor Lewis esophagectomy and show an esophagogastric anastomotic leak on endoscopy or present with typical clinical signs linked to an anastomotic leak, will be included in our study taking into consideration the exclusion criteria. After endoscopic verification of the anastomotic leak, patients will be randomized in a 1:1 ratio into two treatment groups. The intervention group will receive EVT whereas the control group will be treated with SEMS. The primary endpoint of this study is the subjective quality of life assessed by the patient using a systematic and validated questionnaire (EORTC QLQ C30, EORTC QLQ-OES18 questionnaire). Important secondary endpoints are healing rate, period of hospitalization, treatment-related complications, and overall mortality. DISCUSSION: The latest meta-analysis comparing implantation of SEMS with EVT in the treatment of esophageal anastomotic leaks suggested a higher success rate for EVT. The ESOLEAK trial is the first study comparing both treatments in a prospective manner. The aim of the trial is to find suitable endpoints for the treatment of anastomotic leaks as well as to enable an adequate sample size calculation and evaluate the feasibility of future interventional trials. Due to the exploratory design of this pilot study, the sample size is too small to answer the question, whether EVT or SEMS implantation represents the superior treatment strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03962244 . Registered on May 23, 2019. DRKS-ID DRKS00007941.

Integrin alpha-V is an important driver in pancreatic adenocarcinoma progression.

BACKGROUND: Mesothelial E- and P-selectins substantially mediate the intraperitoneal spread of Pancreatic ductal adenocarcinoma (PDA) cells in xenograft models. In the absence of selectins in the host, the integrin subunit alpha-V (ITGAV, CD51) was upregulated in the remaining metastatic deposits. Here we present the first experimental study to investigate if ITGAV plays a functional role in PDA tumor growth and progression with a particular focus on intraperitoneal carcinomatosis. METHODS: Knockdown of ITGAV was generated using an RNA interference-mediated approach in two PDA cell lines. Tumor growth, intraperitoneal and distant metastasis were analyzed in a xenograft model. Cell lines were characterized in vitro. Gene expression of the xenograft tumors was analyzed. Patient samples were histologically classified and associations to survival were evaluated. RESULTS: The knockdown of ITGAV in PDA cells strongly reduces primary tumor growth, peritoneal carcinomatosis and spontaneous pulmonary metastasis. ITGAV activates latent TGF-ß and thereby drives epithelial-mesenchymal transition. Combined depletion of ITGAV on the tumor cells and E- and P-selectins in the tumor-host synergistically almost abolishes intraperitoneal spread. Accordingly, high expression of ITGAV in PDA cells was associated with reduced survival in patients. CONCLUSION: Combined depletion of ITGAV in PDA cells and E- and P-selectins in host mice massively suppresses intraperitoneal carcinomatosis of PDA cells xenografted into immunodeficient mice, confirming the hypothesis of a partly redundant adhesion cascade of metastasizing cancer cells. Our data strongly encourage developing novel therapeutic approaches for the combined targeting of E- and P-selectins and ITGAV in PDA.