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.

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.

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.

Decreased Frequency of Intestinal CD39+ γδ+ T Cells With Tissue-Resident Memory Phenotype in Inflammatory Bowel Disease.

The ectoenzymes CD39 and CD73 play a major role in controlling tissue inflammation by regulating the balance between adenosine triphosphate (ATP) and adenosine. Still, little is known about the role of these two enzymes and ATP and its metabolites in the pathophysiology of inflammatory bowel disease (IBD). We isolated mononuclear cells from peripheral blood and lamina propria of the large intestine of patients diagnosed with IBD and of healthy volunteers. We then comprehensively analyzed the CD39 and CD73 expression patterns together with markers of activation (HLA-DR, CD38), differentiation (CCR7, CD45RA) and tissue-residency (CD69, CD103, CD49a) on CD4+, CD8+, γδ+ T cells and mucosa-associated invariant T cells using flow cytometry. CD39 expression levels of γδ+ and CD8+ T cells in lamina propria lymphocytes (LPL) were much higher compared to peripheral blood mononuclear cells. Moreover, the frequency of CD39+ CD4+ and CD8+, but not γδ+ LPL positively correlated with T-cell activation. The frequency of CD39+ cells among tissue-resident memory LPL (Trm) was higher compared to non-Trm for all subsets, confirming that CD39 is a marker for the tissue-resident memory phenotype. γδ+ Trm also showed a distinct cytokine profile upon stimulation - the frequency of IFN-γ+ and IL-17A+ cells was significantly lower in γδ+ Trm compared to non-Trm. Interestingly, we observed a decreased frequency of CD39+ γδ+ T cells in IBD patients compared to healthy controls (p = 0.0049). Prospective studies need to elucidate the exact role of this novel CD39+ γδ+ T-cell population with tissue-resident memory phenotype and its possible contribution to the pathogenesis of IBD and other inflammatory disorders.

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.

Alterations of the bile microbiome in primary sclerosing cholangitis.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) display an altered colonic microbiome compared with healthy controls. However, little is known on the bile duct microbiome and its interplay with bile acid metabolism in PSC. METHODS: Patients with PSC (n=43) and controls without sclerosing cholangitis (n=22) requiring endoscopic retrograde cholangiography were included prospectively. Leading indications in controls were sporadic choledocholithiasis and papillary adenoma. A total of 260 biospecimens were collected from the oral cavity, duodenal fluid and mucosa and ductal bile. Microbiomes of the upper alimentary tract and ductal bile were profiled by sequencing the 16S-rRNA-encoding gene (V1-V2). Bile fluid bile acid composition was measured by high-performance liquid chromatography mass spectrometry and validated in an external cohort (n=20). RESULTS: The bile fluid harboured a diverse microbiome that was distinct from the oral cavity, the duodenal fluid and duodenal mucosa communities. The upper alimentary tract microbiome differed between PSC patients and controls. However, the strongest differences between PSC patients and controls were observed in the ductal bile fluid, including reduced biodiversity (Shannon entropy, p=0.0127) and increase of pathogen Enterococcus faecalis (FDR=4.18×10-5) in PSC. Enterococcus abundance in ductal bile was strongly correlated with concentration of the noxious secondary bile acid taurolithocholic acid (r=0.60, p=0.0021). CONCLUSION: PSC is characterised by an altered microbiome of the upper alimentary tract and bile ducts. Biliary dysbiosis is linked with increased concentrations of the proinflammatory and potentially cancerogenic agent taurolithocholic acid.

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.

Comparison of the integrin α4ß7 expression pattern of memory T cell subsets in HIV infection and ulcerative colitis.

Anti-α4ß7 therapy with vedolizumab (VDZ) has been suggested as possible immune intervention in HIV. Relatively little is known about the α4ß7-integrin (α4ß7) expression of different T-cell subsets in different anatomical compartments of healthy individuals, patients with HIV or inflammatory bowel disease (IBD). Surface expression of α4ß7 as well as the frequency of activation, homing and exhaustion markers of T cells were assessed by multicolour flow cytometry in healthy volunteers (n = 15) compared to HIV infected patients (n = 52) or patients diagnosed with ulcerative colitis (UC) (n = 14), 6 of whom treated with vedolizumab. In addition, lymph nodal cells (n = 6), gut-derived cells of healthy volunteers (n = 5) and patients with UC (n = 6) were analysed. Additionally, we studied longitudinal PBMC samples of an HIV patient who was treated with vedolizumab for concomitant UC. Overall, only minor variations of the frequency of α4ß7 on total CD4+ T cells were detectable regardless of the disease status or (VDZ) treatment status in peripheral blood and the studied tissues. Peripheral α4ß7+ CD4+ T cells of healthy individuals and patients with UC showed a higher activation status and were more frequently CCR5+ than their α4ß7- counterparts. Also, the frequency of α4ß7+ cells was significantly lower in peripheral blood CD4+ effector memory T cells of HIV-infected compared to healthy individuals and this reduced frequency did not recover in HIV patients on ART. Conversely, the frequency of peripheral blood naïve α4ß7+ CD4+ T cells was significantly reduced under VDZ treatment. The results of the current study will contribute to the understanding of the dynamics of α4ß7 expression pattern on T cells in HIV and UC and will be useful for future studies investigating VDZ as possible HIV cure strategy.

Assessment of endoscopic Doppler to guide hemostasis in high risk peptic ulcer bleeding.

INTRODUCTION: Rebleeding or emergency surgery in failed endoscopic therapy of peptic ulcer bleeding are associated with high rates of morbidity and mortality. The clinical benefit of an endoscopic Doppler (ED) examination prior to endoscopic injection therapy was evaluated in high risk ulcer patients for rebleeding episode. Standard injection therapy (non-Doppler (ND)) was compared with targeted injection therapy after examination of the supplying vessel in the ulcer base by the ED. MATERIALS AND METHODS: Sixty patients with peptic ulcer bleeding (Forrest Ia-IIa; Rockall score of 5 or higher) were included in the study. Patients were assigned to ED or ND group with conventional therapy by chance. In the ND group injection was directed by the visual aspect of the ulcer, whereas in ED therapy was directed by ED. RESULTS: Thirty-five patients were allocated to the ED group, and 25 to the ND group, respectively. No significant differences in patient or ulcer characteristics were observed regarding ulcer size, localization, Forrest classification or endoscopic treatment. Recurrent bleeding was observed in 7/35 (20%) in the ED group and in 13/25 (52%) of patients in the ND group (p = .013). Fewer ED patients needed surgery for rebleeding (1/35 vs. 6/25; p = .017). Bleeding related, but not all-cause mortality was significantly lower in the ED group (1/35 vs. 6/25, p = .017). DISCUSSION: In this comparative analysis, use of ED to guide hemostatic therapy was associated with a significant reduction in recurrence of bleeding, surgical intervention and bleeding associated mortality.

EUS Needle Identification Comparison and Evaluation study (with videos).

BACKGROUND AND AIMS: EUS-guided FNA or biopsy sampling is widely practiced. Optimal sonographic visualization of the needle is critical for image-guided interventions. Of the several commercially available needles, bench-top testing and direct comparison of these needles have not been done to reveal their inherent echogenicity. The aims are to provide bench-top data that can be used to guide clinical applications and to promote future device research and development. METHODS: Descriptive bench-top testing and comparison of 8 commonly used EUS-FNA needles (all size 22 gauge): SonoTip Pro Control (Medi-Globe); Expect Slimline (Boston Scientific); EchoTip, EchoTip Ultra, EchoTip ProCore High Definition (Cook Medical); ClearView (Conmed); EZ Shot 2 (Olympus); and BNX (Beacon Endoscopic), and 2 new prototype needles, SonoCoat (Medi-Globe), coated by echogenic polymers made by Encapson. Blinded evaluation of standardized and unedited videos by 43 EUS endoscopists and 17 radiologists specialized in GI US examination who were unfamiliar with EUS needle devices. RESULTS: There was no significant difference in the ratings and rankings of these needles between endosonographers and radiologists. Overall, 1 prototype needle was rated as the best, ranking 10% to 40% higher than all other needles (P < .01). Among the commercially available needles, the EchoTip Ultra needle and the ClearView needle were top choices. The EZ Shot 2 needle was ranked statistically lower than other needles (30%-75% worse, P < .001). CONCLUSIONS: All FNA needles have their inherent and different echogenicities, and these differences are similarly recognized by EUS endoscopists and radiologists. Needles with polymeric coating from the entire shaft to the needle tip may offer better echogenicity.

Pre-study protocol MagPEP: a multicentre randomized controlled trial of magnesium sulphate in the prevention of post-ERCP pancreatitis.

BACKGROUND: Acute pancreatitis is the most common complication of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP). In spite of continuing research, no pharmacologic agent capable of effectively reducing the incidence of ERCP-induced pancreatitis has found its way into clinical practise. A number of experimental studies suggest that intrapancreatic calcium concentrations play an important role in the initiation of intracellular protease activation, an initiating step in the course of acute pancreatitis. Magnesium can act as a calcium-antagonist and counteracts effects in calcium signalling. It can thereby attenuate the intracellular activation of proteolytic digestive enzymes in the pancreas and reduces the severity of experimental pancreatitis when administered either intravenously or as a food supplement. METHODS: We designed a randomized, double-blind, placebo-controlled phase III study to test whether the administration of intravenous magnesium sulphate before and after ERCP reduces the incidence and the severity of post-ERCP pancreatitis. A total of 502 adult patients with a medical indication for ERCP are to be randomized to receive either 4930 mg magnesium sulphate (= 20 mmol magnesium) or placebo 60 min before and 6 hours after ERCP. The incidence of clinical post-ERCP pancreatitis, hyperlipasemia, pain levels, use of analgetics and length of hospital stay will be evaluated. CONCLUSIONS: If magnesium sulphate is found to be effective in preventing post-ERCP pancreatitis, this inexpensive agent with limited adverse effects could be used as a routine pharmacological prophylaxis. TRIAL REGISTRATION: Current Controlled Trials ISRCTN46556454.