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.

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.

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.

Anti-inflammatory microenvironment of esophageal adenocarcinomas negatively impacts survival.

OBJECTIVE: Reflux promotes esophageal adenocarcinomas (EACs) creating a chronic inflammatory environment. Survival rates are low due to early local recurrences and distant metastasis. Hence, there is a need for new potential treatment options like immunotherapies. However, the inflammatory microenvironment in EACs and its impact on patient outcome remain to be fully understood. METHODS: mRNA expression levels of pro- and anti-inflammatory markers in 39 EAC patients without neoadjuvant radio-chemotherapy were measured. Data were confirmed using flow cytometric analysis of freshly resected surgical specimens. Inflammatory alterations in premalignant lesions of Barrett's esophagus were analyzed by immunohistochemistry. RESULTS: Expression levels of IL22 were reduced in EAC, while expression levels of FOXP3, IL10 and CTLA4 were increased. Flow cytometry demonstrated a strong infiltration of CD4+ T cells with a reduction in CD4+ T cells producing IL-22 or IL-17A. We also observed an increase in CD4+CD127lowFOXP3+ cells producing IL-10. Accumulation of FOXP3+ T cells occurred prior to malignant changes. High expression of IL10 and low expression of IL22 in EAC were associated with reduced overall survival. Moreover, increased expression of IL10, CTLA4 and PD1 in the unaltered esophageal mucosa distant to the EAC was also linked with an unfavorable prognosis. CONCLUSION: EAC shows an anti-inflammatory environment, which strongly affects patient survival. The microscopically unaltered peritumoral tissue shows a similar anti-inflammatory pattern indicating an immunological field effect, which might contribute to early local recurrences despite radical resection. These data suggest that using checkpoint inhibitors targeting anti-inflammatory T cells would be a promising therapeutic strategy in EAC.

Endoscopic vacuum therapy versus stenting for postoperative esophago-enteric anastomotic leakage: systematic review and meta-analysis.

BACKGROUND: Esophageal anastomotic leakage still represents a challenging complication after esophageal surgery. Endoscopically placed self-expandable metal stents (SEMS) are the treatment of choice, but since the introduction of endoscopic vacuum therapy (EVT) for esophageal leakage 10 years ago, increasing evidence has demonstrated that EVT might be a superior alternative. Therefore, we performed a systematic review and meta-analysis to compare the effectiveness and related morbidity of SEMS and EVT in the treatment of esophageal leak. METHODS: We systematically searched for studies comparing SEMS and EVT to treat anastomotic leakage after esophageal surgery. Predefined end points including outcome, treatment success, endoscopy, treatment duration, hospitalization time, morbidity, and mortality were assessed and included in the meta-analysis. RESULTS: Five retrospective studies including 274 patients matched the inclusion criteria. Compared with stenting, EVT was significantly associated with a higher rate of leak closure (odds ratio [OR] 3.14, 95 % confidence interval [CI] 1.23 to 7.98), more endoscopic device changes (pooled median difference of 3.09; 95 %CI 1.54 to 4.64]), a shorter duration of treatment (pooled median difference -11.90 days; 95 %CI -18.59 to -5.21 days), and a lower mortality rate (OR 0.39, 95 %CI 0.18 to 0.83). There were no significant differences in short-term and major complications. CONCLUSIONS: Owing to the retrospective quality of the studies with potential biases, the results of the meta-analysis must be interpreted with caution. However, the analysis indicates the potential benefit of EVT, which should be further investigated with standardized and prospectively collected data.

Improved colorectal anastomotic leakage healing by transanal rinsing treatment after endoscopic vacuum therapy using a novel patient-applied rinsing catheter.

PURPOSE: Anastomotic or stump leakage is a common and serious complication of colorectal surgery. The objective of this study was to retrospectively investigate the clinical use and potential benefit of transanal rinsing treatment (TRT) using an innovative rinsing catheter (RC) after treatment with endoscopic vacuum therapy (EVT). METHODS: Patients with leakage after low colorectal surgery who had been treated with EVT were retrospectively analyzed. A subset of patients was trained to perform TRT with a specially developed RC. We investigated the rate of complete healing of the leakage, septic complications, failure of the therapy, surgical revisions, ostomy closure rate, and complications related to endoscopic therapy. RESULTS: Between February 2007 and January 2014, 98 patients with local complications after low colorectal surgery, treated with EVT, were identified. Eighty-nine patients were analyzed (the treatment of nine patients was stopped due to medical or technical problems): 31 patients were treated with EVT only (EVT group) and 58 patients with EVT followed by TRT (EVT/TRT group). Complete healing of the leakage was significantly better in the EVT/TRT group [84% vs. 58% (p < 0.009)], and significantly fewer septic complications needing surgical revision were detected [3% vs. 11% (p = 0.001)]. No significant differences regarding endoscopy-related complications and ostomy closure were found between EVT and EVT/TRT patients. CONCLUSIONS: The use of patient-administered TRT with an innovative, customized RC after EVT is technically feasible and reliable and significantly improves therapeutic results. Further prospective trials with larger patient groups are needed to validate the results of our study.

Surgical Management of Non-Malignant Esophageal Perforations: A Single-Center Analysis Over a 15-Year Period.

PURPOSE: Esophageal perforations are associated with high morbidity and mortality. Different nonoperative and operative treatment options have been proposed. This study focuses on the impact of different surgical treatments in nonmalignant esophageal perforations and tries to identify predictors of mortality in a single tertiary center over a 15-year period. METHODS: From 2002 to 2017, patients with surgically managed esophageal perforation were identified from our database. Patients with esophageal malignancies were excluded. Etiology, clinical data, treatment, and outcome were analyzed. A multivariate logistic regression analysis was performed to investigate the impact on mortality. RESULTS: A total of 72 patients were identified. The majority of perforations were iatrogenic (54.2%) followed by Boerhaave's syndrome (23.6%). Most ruptures were found in the distal third of the esophagus (59.7%) measuring <3 cm (61.1%). Patients were treated with exploration and drainage (8.3%), primary suture and patch reinforcement (36.1%), resection and restoration of continuity (25.0%), or resection without restoration of continuity (30.6%). Delayed therapy significantly correlated with sepsis (p < 0.0001) and mortality (p = 0.032). A correlation between an increasing perforation length with sepsis (p = 0.012) was observed. A higher Perforation Severity Score (PSS; OR 4.430; 95% CI 1.143-17.174; p = 0.031) and a higher American Society of Anesthesiologists (ASA) score (OR 2.923; 95% CI 1.011-8.448; p = 0.048) were associated with mortality in multivariate analysis. CONCLUSION: Esophageal perforations are associated with high mortality, and larger ruptures are associated with worse outcome. Rapid diagnosis and treatment are crucial for patient survival. Hence, PSS and ASA score help to identify high-risk patients. The advantage of surgical management lies in the rapid control of the septic focus in an already critically ill patient. Though, the kind of surgical technique needs to be adjusted to the individual situation.

Activated leukocyte cell adhesion molecule (CD166): an "inert" cancer stem cell marker for non-small cell lung cancer?

Recently, the activated leukocyte cell adhesion molecule (CD166) was identified as an "inert" cancer stem cell (CSC) marker for non-small cell lung cancer (NSCLC). Few data exist regarding the clinical relevance of CD166 expression in NSCLC. We evaluated the expression of CD166 using immunohistochemistry in a large cohort of NSCLC patients (n = 1,910) on a tissue microarray basis. Expression was inversely associated with tumor size and lymph node status. Grading slightly failed to be significantly inversely associated, and survival analysis revealed no significant survival benefit of CD166-positive patients. Due to the results of this study, the theory of CD166 as a CSC marker for NSCLC must be questioned. The association of CD166 with smaller tumors and no nodal metastases does not make it a typical CSC marker. Further studies are required to investigate the functional role of CD166 in NSCLC.

Resection margin clearance in pancreatic cancer after implementation of the Leeds Pathology Protocol (LEEPP): clinically relevant or just academic?

BACKGROUND AND OBJECTIVES: The aim of this study was to assess the overall survival (OS) after R0/R1 resections in patients with pancreatic ductal adenocarcinoma (PDAC) of the pancreatic head after implementation of a standardized histopathologic protocol (Leeds Pathology Protocol, LEEPP). METHODS: One hundred and twenty-five patients underwent surgical resection because of PDAC of the pancreatic head. Patients were histopathologically examined according to a standardized protocol. Their oncologic outcome and clinicopathologic data were compared with those of a patient group before implementation of the LEEPP (n = 116). RESULTS: The R1 rate increased significantly from 13 to 52 %. There was no significant difference in OS between R0 and R1 resections. The median OS in patients with a tumor clearance of less than 2 mm from the resection margin was 15.1 months (12.1-18.1 months) versus 22.2 months (7.8-36.7 months) (P = 0.046). Multivariate analysis revealed a margin clearance or 2 mm and more as an independent prognosticator for OS. CONCLUSIONS: With applying the LEEPP, there was still no significant correlation between the R-status and OS in patients with PDAC. However, since a margin clearance of 2 mm or more is a predictive factor for OS, the R1 definition might have to be adapted in PDAC.

Sequential neoadjuvant chemoradiotherapy (CRT) followed by curative surgery vs. primary surgery alone for resectable, non-metastasized pancreatic adenocarcinoma: NEOPA- a randomized multicenter phase III study (NCT01900327, DRKS00003893, ISRCTN82191749).

BACKGROUND: Median OS after surgery in curative intent for non-metastasized pancreas cancer ranges under study conditions from 17.9 months to 23.6 months. Tumor recurrence occurs locally, at distant sites (liver, peritoneum, lungs), or both. Observational and autopsy series report local recurrence rates of up to 87% even after potentially "curative" R0 resection. To achieve better local control, neoadjuvant CRT has been suggested for preoperative tumour downsizing, to elevate the likelihood of curative, margin-negative R0 resection and to increase the OS rate. However, controlled, randomized trials addressing the impact of neoadjuvant CRT survival do not exist. METHODS/DESIGN: The underlying hypothesis of this randomized, two-armed, open-label, multicenter, phase III trial is that neoadjuvant CRT increases the three-year overall survival by 12% compared to patients undergoing upfront surgery for resectable pancreatic cancer. A rigorous, standardized technique of histopathologically handling Whipple specimens will be applied at all participating centers. Overall, 410 patients (n=205 in each study arm) will be enrolled in the trial, taking into regard an expected drop out rate of 7% and allocated either to receive neoadjuvant CRT prior to surgery or to undergo surgery alone. Circumferential resection margin status, i.e. R0 and R1 rates, respectively, surgical resectability rate, local and distant disease-free and global survival, and first site of tumor recurrence constitute further essential endpoints of the trial. DISCUSSION: For the first time, the NEOPA study investigates the impact of neoadjuvant CRT on survival of resectable pancreas head cancer in a prospectively randomized manner. The results of the study have the potential to change substantially the treatment regimen of pancreas cancer. TRIAL REGISTRATION: Clinical Trial gov: NCT01900327, DRKS00003893, ISRCTN82191749.

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.

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.

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.

CXCR7 expression in esophageal cancer.

BACKGROUND: The chemokine CXCL12 and its receptor CXCR4 play a major role in tumor invasion, proliferation and metastasis in different malignant diseases, including esophageal carcinoma, amongst others. CXCR7 was recently identified as a novel alternate receptor for CXCL12. The aim of this study was to evaluate the prognostic impact of expression of chemokine receptor CXCR7 in patients with esophageal carcinoma (EC). METHODS: Expression of CXCR7 in primary tumors, lymph nodes and distant metastases of 299 patients with EC was evaluated by immunohistochemistry on a tissue microarray and compared with clinical and histopathological data. RESULTS: In esophageal cancer sections, CXCR7-specific reactivity was apparent in 45% of the squamous cell carcinomas (ESCC), but only occasionally in adenocarcinomas. No correlation between CXCR4 and CXCR7 expression was evident. We correlated expression with clinical and histopathological characteristics, but could not find any association. CONCLUSIONS: Contrary to the other known CXCL12 receptor, CXCR4, CXCR7 is expressed in ESCC only, underlining the divergent mechanisms and backgrounds of EAC and ESCC. The results of the study do not indicate a significant functional role for CXCR7 in EAC or ESCC of the esophagus. However, its variable expression in the main two main types of EC needs to be further investigated.

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.

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.

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.

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.

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.