Perioperative Enhanced Recovery Concepts Significantly Improve Postoperative Outcome in Patients with Crohn`s Disease.

BACKGROUND AND AIMS: Despite recent advancements in medical and surgical techniques in patients suffering from Crohn`s Disease (CD), postoperative morbidity remains relevant due to a long-standing, non-curable disease burden. As demonstrated for oncological patients, perioperative enhanced recovery concepts provide great potential to improve postoperative outcome. However, robust evidence about the effect of perioperative enhanced recovery concepts in the specific cohort of CD patients is lacking. METHODS: In a prospective single-center study, all patients receiving ileocecal resection due to CD between 2020 and 2023 were included. A specific perioperative enhanced recovery concept (ERC) was implemented and patients were divided into two groups (before and after implementation). The primary outcome focused on postoperative complications as measured by the Comprehensive Complication Index (CCI), secondary endpoints were severe complications, length of hospital stay, and rates of re-admission. RESULTS: 83 patients were analyzed of which 33 patients participated in the enhanced recovery program (postERC). While patient characteristics were comparable between both groups, ERC resulted in significantly decreased rates of overall and severe postoperative complications (CCI: 21.4 versus 8.4, p=0.0036; Clavien Dindo >2: 38% versus 3.1%, p=0.0002). Additionally, postERC-patients were earlier ready for discharge (6.5 days versus 5 days, p=0.001) and rates of re-admission were significantly lower (20% versus 3.1%, p=0.03). In a multivariate analysis, the recovery concept was identified as independent factor to reduce severe postoperative complications (p=0.019). CONCLUSION: A specific perioperative enhanced recovery concept significantly improves the postoperative outcome of patients suffering from Crohn`s Disease.

Nationwide volume-outcome relationship concerning in-hospital mortality and failure-to-rescue in surgery of sigmoid diverticulitis.

PURPOSE: A correlation between the hospital volume and outcome is described for multiple entities of oncological surgery. To date, this has not been analyzed for the surgical treatment of sigmoid diverticulitis. The aim of this study was to explore the impact of the annual caseload per hospital of colon resection on the postoperative incidence of complications, failure to rescue, and mortality in patients with diverticulitis. METHODS: Patients receiving colorectal resection independent from the diagnosis from 2012 to 2017 were selected from a German nationwide administrative dataset. The hospitals were grouped into five equal caseload quintiles (Q1-Q5 in ascending caseload order). The outcome analysis was focused on patients receiving surgery for sigmoid diverticulitis. RESULTS: In total, 662,706 left-sided colon resections were recorded between 2012 and 2017. Of these, 156,462 resections were performed due to sigmoid diverticulitis and were included in the analysis. The overall in-house mortality rate was 3.5%, ranging from 3.8% in Q1 (mean of 9.5 procedures per year) to 3.1% in Q5 (mean 62.8 procedures per year; p < 0.001). Q5 hospitals revealed a risk-adjusted odds ratio of 0.85 (95% CI 0.78-0.94; p < 0.001) for in-hospital mortality compared to Q1 during multivariable logistic regression analysis. High-volume centers showed overall lower complication rates, whereas the failure-to-rescue did not differ significantly. CONCLUSION: Surgical treatment of sigmoid diverticulitis in high-volume colorectal centers shows lower postoperative mortality rates and fewer postoperative complications.

Group 2 innate lymphoid cells constrain type 3/17 lymphocytes in shared stromal niches to restrict liver fibrosis.

Group 2 innate lymphoid cells (ILC2s) cooperate with adaptive Th2 cells as key organizers of tissue type 2 immune responses, while a spectrum of innate and adaptive lymphocytes coordinate early type 3/17 immunity. Both type 2 and type 3/17 lymphocyte associated cytokines are linked to tissue fibrosis, but how their dynamic and spatial topographies may direct beneficial or pathologic organ remodelling is unclear. Here we used volumetric imaging in models of liver fibrosis, finding accumulation of periportal and fibrotic tract IL-5 + lymphocytes, predominantly ILC2s, in close proximity to expanded type 3/17 lymphocytes and IL-33 high niche fibroblasts. Ablation of IL-5 + lymphocytes worsened carbon tetrachloride-and bile duct ligation-induced liver fibrosis with increased niche IL-17A + type 3/17 lymphocytes, predominantly γδ T cells. In contrast, concurrent ablation of IL-5 + and IL-17A + lymphocytes reduced this progressive liver fibrosis, suggesting a cross-regulation of type 2 and type 3 lymphocytes at specialized fibroblast niches that tunes hepatic fibrosis.

Anti-HLA-A2-CAR Tregs prolong vascularized mouse heterotopic heart allograft survival.

Alloantigen-specific regulatory T cell (Treg) therapy is a promising approach for suppressing alloimmune responses and minimizing immunosuppression after solid organ transplantation. Chimeric antigen receptor (CAR) targeting donor alloantigens can confer donor reactivity to Tregs. However, CAR Treg therapy has not been evaluated in vascularized transplant or multi-MHC mismatched models. Here, we evaluated the ability of CAR Tregs targeting HLA-A2 (A2-CAR) to prolong the survival of heterotopic heart transplants in mice. After verifying the in vitro activation, proliferation, and enhanced suppressive function of A2-CAR Tregs in the presence of A2-antigen, we analyzed the in vivo function of Tregs in C57BL/6 (B6) mice receiving A2-expressing heart allografts. A2-CAR Treg infusion increased the median survival of grafts from B6.HLA-A2 transgenic donors from 23 to 99 days, whereas median survival with polyclonal Treg infusion was 35 days. In a more stringent model of haplo-mismatched hearts from BALB/cxB6.HLA-A2 F1 donors, A2-CAR Tregs slightly increased median graft survival from 11 to 14 days, which was further extended to >100 days when combined with a 9-day course of rapamycin treatment. These findings demonstrate the efficacy of CAR Tregs, alone or in combination with immunosuppressive agents, toward protecting vascularized grafts in fully immunocompetent recipients.

Bile acid-sensitive tuft cells regulate biliary neutrophil influx.

Inflammation and dysfunction of the extrahepatic biliary tree are common causes of human pathology, including gallstones and cholangiocarcinoma. Despite this, we know little about the local regulation of biliary inflammation. Tuft cells, rare sensory epithelial cells, are particularly prevalent in the mucosa of the gallbladder and extrahepatic bile ducts. Here, we show that biliary tuft cells express a core genetic tuft cell program in addition to a tissue-specific gene signature and, in contrast to small intestinal tuft cells, decreased postnatally, coincident with maturation of bile acid production. Manipulation of enterohepatic bile acid recirculation revealed that tuft cell abundance is negatively regulated by bile acids, including in a model of obstructive cholestasis in which inflammatory infiltration of the biliary tree correlated with loss of tuft cells. Unexpectedly, tuft cell-deficient mice spontaneously displayed an increased gallbladder epithelial inflammatory gene signature accompanied by neutrophil infiltration that was modulated by the microbiome. We propose that biliary tuft cells function as bile acid-sensitive negative regulators of inflammation in biliary tissues and serve to limit inflammation under homeostatic conditions.

CD28 Superagonist D665-mediated activation of mouse regulatory T cells maintains their phenotype without loss of suppressive quality.

Regulatory T cells (Tregs) maintain immune homeostasis by regulating the activation of other immune cells. Preclinical studies show that the infusion of Tregs can promote immunological tolerance to allografts and prevent or cure multiple autoimmune diseases. However, Treg therapy is limited by high numbers of cells required to induce tolerance. In this study, we aimed at improving the in vitro expansion of sort purified mouse Tregs using the CD28 Superagonist (CD28-SA) D665 and comparing it to the conventional expansion using anti-CD3/anti-CD28 Dynabeads®. CD28-SA-stimulated Tregs expanded more than Dynabead®-stimulated Tregs while maintaining their phenotype by expressing the same level of CD4, CD25 and Foxp3. CD28-SA-expanded Tregs produced comparable amounts of IL-10 and TGFß while showing a slightly superior suppressive capacity compared to Dynabead®-stimulated Tregs. Thus, stimulating murine Tregs with the CD28-SA is a promising alternative since it maintains their suppressive capacity without altering their phenotype and yields a higher fold expansion within 14 days.

Successful surgical closure of infected abdominal wounds following preconditioning with negative pressure wound therapy.

PURPOSE: Traditionally, previous wound infection was considered a contraindication to secondary skin closure; however, several case reports describe successful secondary wound closure of wounds "preconditioned" with negative pressure wound therapy (NPWT). Although this has been increasingly applied in daily practice, a systematic analysis of its feasibility has not been published thus far. The aim of this study was to evaluate secondary skin closure in previously infected abdominal wounds following treatment with NPWT. METHODS: Single-center retrospective analysis of patients with infected abdominal wounds treated with NPWT followed by either secondary skin closure referenced to a group receiving open wound therapy. Endpoints were wound closure rate, wound complications (such as recurrent infection or hernia), and perioperative data (such as duration of NPWT or hospitalization parameters). RESULTS: One hundred ninety-eight patients during 2013-2016 received a secondary skin closure after NPWT and were analyzed and referenced to 67 patients in the same period with open wound treatment after NPWT. No significant difference in BMI, chronic immunosuppressive medication, or tobacco use was found between both groups. The mean duration of hospital stay was 30 days with a comparable duration in both patient groups (29 versus 33 days, p = 0.35). Interestingly, only 7.7% of patients after secondary skin closure developed recurrent surgical site infection and in over 80% of patients were discharged with closed wounds requiring only minimal outpatient wound care. CONCLUSION: Surgical skin closure following NPWT of infected abdominal wounds is a good and safe alternative to open wound treatment. It prevents lengthy outpatient wound therapy and is expected to result in a higher quality of life for patients and reduce health care costs.

Laparoscopic appendectomy versus antibiotic treatment for acute appendicitis-a systematic review.

BACKGROUND: Over the last years, laparoscopic appendectomy has progressively replaced open appendectomy and become the current gold standard treatment for suspected, uncomplicated appendicitis. At the same time, though, it is an ongoing discussion that antibiotic therapy can be an equivalent treatment for patients with uncomplicated appendicitis. The aim of this systematic review was to determine the safety and efficacy of antibiotic therapy and compare it to the laparoscopic appendectomy for acute, uncomplicated appendicitis. METHODS: The PubMed database, Embase database, and Cochrane library were scanned for studies comparing laparoscopic appendectomy with antibiotic treatment. Two independent reviewers performed the study selection and data extraction. The primary endpoint was defined as successful treatment of appendicitis. Secondary endpoints were pain intensity, duration of hospitalization, absence from work, and incidence of complications. RESULTS: No studies were found that exclusively compared laparoscopic appendectomy with antibiotic treatment for acute, uncomplicated appendicitis. CONCLUSIONS: To date, there are no studies comparing antibiotic treatment to laparoscopic appendectomy for patients with acute uncomplicated appendicitis, thus emphasizing the lack of evidence and need for further investigation.

CAR-Tregs as a Strategy for Inducing Graft Tolerance.

PURPOSE OF THE REVIEW: The adoptive transfer of alloantigen-specific regulatory T cells (Tregs) following organ transplantation is an emerging treatment paradigm that may induce tolerance and reduce the risk for graft rejection. In particular, redirecting Treg specificity via expression of synthetic chimeric antigen receptors (CARs) has demonstrated therapeutic promise in several preclinical studies. In this review, we highlight recent progress and remaining barriers to the clinical translation of CAR-Treg therapies. RECENT FINDINGS: CAR Tregs targeting human leukocyte antigen (HLA)-A2 showed antigen-specific in vitro activation and superior in vivo protective function relative to polyclonal Tregs. Adoptively transferred anti-HLA-A2 CAR Tregs prolonged the survival of HLA-A2-positive grafts in humanized mouse models. SUMMARY: Donor HLA molecules are attractive candidate antigens to target with CAR Tregs in transplantation due to mismatched HLA only expressed on the transplanted organ. The feasibility of this approach has been demonstrated by several independent groups in recent years. However, substantial challenges in CAR design and preclinical modeling must be more extensively addressed prior to clinical application.