Treatment with the 5-Lipoxygenase Antagonist Zileuton Protects Mice from Postoperative Ileus.

INTRODUCTION: Previous work of our group showed that lipoxygenase (LOX) pathways become activated upon surgical manipulation of the bowel wall and revealed a beneficial immune modulating role of the LOX-derived anti-inflammatory mediator protectin DX in postoperative ileus (POI). While we found a particular role of 12/15-LOX in the anti-inflammatory LOX action during POI, the role of 5-LOX, which produces the pro-inflammatory leukotriene B4 (LTB4), remained unknown. The purpose of this study was to investigate the role of 5-LOX within the pathogenesis of POI in a mouse model. METHODS: POI was induced by intestinal manipulation (IM) of the small bowel in C57BL/6, 5-LOX-/-, and CX3CR1GFP/+. Mice were either treated with a vehicle or with the synthetic 5-LOX antagonist zileuton or were left untreated. Cellular localization of 5-LOX and LTB4 release were visualized by immunofluorescence or ELISA, respectively. POI severity was quantified by gastrointestinal transit (GIT) and leukocyte extravasation into the muscularis externa (ME) by immunohistochemistry. RESULTS: 5-LOX expression was detected 24 h after IM within infiltrating leukocytes in the ME. LTB4 levels increased during POI in wild type but not in 5-LOX-/- after IM. POI was ameliorated in 5-LOX-/- as shown by decreased leukocyte numbers and normalized GIT. Zileuton normalized the postoperative GIT and reduced the numbers of infiltrating leukocytes into the ME. DISCUSSION/CONCLUSION: Our data demonstrate that 5-LOX and its metabolite LTB4 play a crucial role in POI. Genetic deficiency of 5-LOX and pharmacological antagonism by zileuton protected mice from POI. 5-LOX antagonism might be a promising target for prevention of POI in surgical patients.

[Incidental finding of an intestinally differentiated adenocarcinoma in a tailgut cyst after robotic-assisted resection]. / Zufallsbefund eines intestinal differenzierten Adenokarzinoms in einer Tailgut Zyste nach robotisch-assistierter Resektion.

Due to pelvic symptoms, a diagnostic sectional imaging was initiated in a 52-year-old female patient. This revealed a cystic, retrorectal mass, suspected to be a tailgut cyst. Due to the symptoms and the unclear dignity after several frustrating endosonographic punctures, a robotic-assisted resection of the cystic Tumor was performed after careful interdisciplinary consultation.The histological examination confirmed the diagnosis of a tailgut cyst but also revealed parts of an intestinally differentiated adenocarcinoma.Due to the unclear metastatic behaviour, robotic-assisted low anterior resection with total mesorectal excision was performed as oncological resection, similar to rectal carcinomas. No residuals or lymph node metastases were detectable in the histological examination, so that follow- up monitoring was recommended.Retrorectal tumours are an extremely rare entity, worldwide only 28 cases of an intestinally differentiated carcinoma in a tailgut cyst have been described so far. Since there are no clear recommendations in the literature regarding the diagnostic or therapeutic procedure, we would like to discuss a possible algorithm in case of a proven retrorectal mass in our case study.

Active smokers show ameliorated delayed gastric emptying after pancreatoduodenectomy.

BACKGROUND: Delayed gastric emptying (DGE) is the most common complication following pancreatoduodenectomy (PD). The data about active smoking in relation to gastric motility have been inconsistent and specifically the effect of smoking on gastric emptying after PD has not yet been investigated in detail. METHODS: 295 patients at our department underwent PD between January 2009 and December 2019. Patients were analyzed in relation to demographic factors, diagnosis, pre-existing conditions, intraoperative characteristics, hospital stay, mortality and postoperative complications with special emphasis on DGE. All complications were classified according to the definitions of the International Study Group on Pancreatic Surgery. RESULTS: 274 patients were included in the study and analyzed regarding their smoking habits (non or former smokers, n = 88, 32.1% vs. active smokers, n = 186, 68.6%). Excluded were patients for whom no information about their smoking habits was available (n = 3), patients who had had gastric resection before (n = 4) and patients with prolonged postoperative resumption to normal diet independently from DGE (long-term ventilation > 7 days, fasting due to pancreatic fistula) (n = 14). Smokers were younger than non-smokers (61 vs. 69 years, p ≤ 0.001) and mainly male (73% male vs. 27% female). Smoking patients showed significantly more pre-existing pulmonary conditions (19% vs. 8%, p = 0.002) and alcohol abuse (48% vs. 23%, p ≤ 0.001). We observe more blood loss in smokers (800 [500-1237.5] vs. 600 [400-1000], p = 0.039), however administration of erythrocyte concentrates did not differ between both groups (0 [0-2] vs. 0 [0-2], p = 0.501). 58 out of 88 smokers (66%) and 147 out of 186 of non-smokers (79%) showed malign tumors (p = 0.019). 35 out of 88 active smokers (40%) and 98 out of 188 non- or former smokers (53%) developed DGE after surgery (p = 0.046) and smokers tolerated solid food intake more quickly than non-smokers (postoperative day (POD7 vs. POD10, p = 0.004). Active smokers were less at risk to develop DGE (p = 0.051) whereas patients with pulmonary preexisting conditions were at higher risk for developing DGE (p = 0.011). CONCLUSIONS: Our data show that DGE occurs less common in active smokers and they tolerate solid food intake more quickly than non-smokers. Further observation studies and randomized, controlled multicentre studies without the deleterious effect of smoking, for instance by administration of a nicotine patch, are needed to examine if this effect is due to nicotine administration.

Microbiota-dependent presence of murine enteric glial cells requires myeloid differentiation primary response protein 88 signaling.

Enteric glial cells (EGCs) were shown to maintain the barrier integrity and immune homeostasis of the bowel. Postnatally, EGCs develop from progenitor cells located in the myenteric plexus and are continuously replenished through adulthood. Both, murine EGC development and replenishment were shown to depend on the microbiome. The underlying mechanisms are still unknown, and we hypothesized that the myeloid differentiation primary response protein 88 (Myd88) or toll-like receptor signaling pathways may be involved. Adult and neonatal C57BL/6 wild-type (wt) and Myd88-/- mice were housed under specific pathogen-free (SPF) or germ-free (GF) conditions. GF mice were further conventionalized by gavaging stools from, and cohousing with, SPF mice having intact microbiomes. The small bowels were harvested at various time points, and immunohistochemistry and qPCR analysis of EGC markers in the muscularis externa and mucosa were performed. In wt mice, after conventionalization, the glial cell-specific markers, glial fibrillary acidic protein (GFAP) and S100 calcium-binding protein ß (S100ß), were upregulated in the mucosa and muscularis externa. In Myd88-/- mice, this upregulation did not occur. Importantly, GFAP (only in the mucosa) and S100ß (in both the mucosa and muscularis externa) were significantly reduced in conventionalized Myd88-/- mice compared with the conventionalized wt mice. In neonatal mice, the gene expressions of GFAP and S100ß increased between the day of birth (P0) and postnatal day 15 (P15) in the mucosa and muscularis externa of both wt and Myd88-/- mice. Notably, in the mucosa but not the muscularis externa, at P15, the gene expressions of GFAP and S100ß were significantly reduced in Myd88-/-. Our data demonstrated that postnatal development and replenishment of EGCs require intestinal microbiota and depend on Myd88. The specific upstream mechanisms may involve toll-like-receptor recognition of the microbiota and will be the subject of further research.

Clinically Relevant Pancreatic Fistula after Pancreaticoduodenectomy: How We Do It.

(1) Background: This study's goals were to investigate possible risk factors for clinically relevant postoperative pancreatic fistula (POPF) grade B/C according to the updated definitions of the International Study Group of Pancreatic Surgery and to analyze possible treatment strategies; (2) Methods: Between 2017 and 2021, 200 patients were analyzed regarding the development of POPF grade B/C with an emphasis on postoperative outcome and treatment strategies; (3) Results: POPF grade B/C was observed in 39 patients (19.5%). These patients were younger, mainly male, had fewer comorbidities and showed a higher body mass index. Also, they had lower CA-19 levels, a smaller tumor size and softer pancreatic parenchyma. They experienced a worse outcome without affecting the overall mortality rate (10% vs. 6%, p = 0.481), however, this lead to a prolonged postoperative stay (28 (32-36) d vs. 20 (15-28) d, p ≤ 0.001). The majority of patients with POPF grade B/C were able to receive conservative treatment, followed by drainage placement, endoscopic vacuum-assisted therapy (EVT) and surgery. Conservative treatment resulted in a shorter length of the postoperative stay (24 (22-28) d vs. 34 (26-43) d, p = 0.012); (4) Conclusions: Patients developing POPF grade B/C had a worse outcome; however, this did not affect the overall mortality rate. The majority of the patients were able to receive conservative treatment, resulting in a shorter length of their hospital stay.

Obesity Does Not Influence Delayed Gastric Emptying Following Pancreatoduodenectomy.

Background: The data about obesity on postoperative outcome after pancreatoduodenectomy (PD) are inconsistent, specifically in relation to gastric motility and delayed gastric emptying (DGE). Methods: Two hundred and eleven patients were included in the study and patients were retrospectively analyzed in respect to pre-existing obesity (obese patients having a body mass index (BMI) ≥ 30 kg/m2 vs. non-obese patients having a BMI < 30 kg/m2, n = 34, 16% vs. n = 177, 84%) in relation to demographic factors, comorbidities, intraoperative characteristics, mortality and postoperative complications with special emphasis on DGE. Results: Obese patients were more likely to develop clinically relevant pancreatic fistula grade B/C (p = 0.008) and intraabdominal abscess formations (p = 0.017). However, clinically relevant DGE grade B/C did not differ (p = 0.231) and, specifically, first day of solid food intake (p = 0.195), duration of intraoperative administered nasogastric tube (NGT) (p = 0.708), rate of re-insertion of NGT (0.123), total length of NGT (p = 0.471) or the need for parenteral nutrition (p = 0.815) were equally distributed. Moreover, mortality (p = 1.000) did not differ between the two groups. Conclusions: Obese patients do not show a higher mortality rate and are not at higher risk to develop DGE. We thus show that in our study, PD is feasible in the obese patient in regard to postoperative outcome with special emphasis on DGE.

Delayed Gastric Emptying Does Not Influence Cancer-Specific Survival after Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Delayed gastric emptying (DGE) remains the most frequent complication following pancreatoduodenectomy (PD). The present study investigates the influence of delayed gastric emptying on cancer-specific survival after PD. METHODS: We included 267 patients who underwent PD between 2014 and 2021. They were analyzed regarding demographic factors, pre- and perioperative characteristics, surgical complications, and long-term survival. RESULTS: Patients with a higher Charlson Comorbidity Index (CCI) or pre-existing pulmonary disease suffered significantly more from DGE. When experiencing PPH, a prolonged hospital stay, or major overall complications (Clavien-Dindo °III-V) were more common in the DGE group. Tumor size over 3 cm negatively affected survival. CONCLUSIONS: DGE has no influence on long-term survival in PDAC patients, although it prolongs hospital stay.

Operative Re-Intervention following Pancreatoduodenectomy: What Has Changed over the Last Decades.

Background: To investigate changes over the last decades in the management of postoperative complications following pancreatoduodenectomy (PD) with special emphasis on reoperations, their indications, and outcomes. Methods: 409 patients who underwent PD between 2008 and 2021 were retrospectively analyzed with respect to their need for reoperations (reoperation, n = 81, 19.8% vs. no reoperation, n = 328, 80.2%). The cohort was then compared to a second cohort comprising patients who underwent PD between 1989 and 2007 (n = 285). Results: 81 patients (19.8%) underwent reoperation. The main cause of reoperation was the dehiscence of pancreatogastrostomy (22.2%). Reoperation was associated with a longer duration of the index operation, more blood loss, and more erythrocyte concentrates being transfused. Patients who underwent reoperation showed more postoperative complications and a higher mortality rate (25% vs. 2%, p < 0.001). Compared to the earlier cohort, the observed increase in reoperations did not lead to increased mortality (5% vs. 6%, p = 353). Conclusions: The main cause for reoperation has changed over the last decades and was the dehiscence of pancreatogastrostomy. Associated with a leakage of pancreatic fluid and clinically relevant PF, it remains the most devastating complication following PD. Strategies for prevention and treatment, e.g., by endoscopic vacuum-assisted-closure therapy are of utmost importance.

Chronic Liver Disease Increases Mortality Following Pancreatoduodenectomy.

According to the International Study Group of Pancreatic Surgery (ISGPS), data about the impact of pre-existing liver pathologies on delayed gastric emptying (DGE) after pancreatoduodenectomy (PD) according to the definitions of the International Study Group of Pancreatic Surgery (ISGPS) are lacking. We therefore investigated the impact of DGE after PD according to ISGPS in patients with liver cirrhosis (LC) and advanced liver fibrosis (LF). Patients were analyzed with respect to pre-existing liver pathologies (LC and advanced LF, n = 15, 6% vs. no liver pathologies, n = 240, 94%) in relation to demographic factors, comorbidities, intraoperative characteristics, mortality and postoperative complications, with special emphasis on DGE. DGE was equally distributed (DGE grade A, p = 1.000; B, p = 0.396; C, p = 0.607). Particularly, the first day of solid food intake (p = 0.901), the duration of intraoperative administered nasogastric tube (NGT) (p = 0.812), the rate of re-insertion of NGT (p = 0.072), and the need for parenteral nutrition (p = 0.643) did not differ. However, patients with LC and advanced LF showed a higher ASA (American Society of Anesthesiologists) score (p = 0.016), intraoperatively received more erythrocyte transfusions (p = 0.029), stayed longer in the intensive care unit (p = 0.010) and showed more intraabdominal abscess formation (p = 0.006). Moreover, we did observe a higher mortality rate amongst patients with pre-existing liver diseases (p = 0.021), and reoperation was a risk factor for higher mortality (p ≤ 0.001) in the multivariate analysis. In our study, we could not detect a difference with respect to DGE classified by ISGPS; however, we did observe a higher mortality rate amongst these patients and thus, they should be critically evaluated for PD.

A Population of Radio-Resistant Macrophages in the Deep Myenteric Plexus Contributes to Postoperative Ileus Via Toll-Like Receptor 3 Signaling.

Postoperative ileus (POI) is triggered by an innate immune response in the muscularis externa (ME) and is accompanied by bacterial translocation. Bacteria can trigger an innate immune response via toll-like receptor (TLR) activation, but the latter's contribution to POI has been disproved for several TLRs, including TLR2 and TLR4. Herein we investigated the role of double-stranded RNA detection via TLR3 and TIR-domain-containing adapter-inducing interferon-ß (TRIF) signaling pathway in POI. POI was induced by small bowel intestinal manipulation in wt, TRIF-/-, TLR3-/-, type I interferon receptor-/- and interferon-ß reporter mice, all on C57BL/6 background, and POI severity was quantified by gene expression analysis, gastrointestinal transit and leukocyte extravasation into the ME. TRIF/TLR3 deficiency reduced postoperative ME inflammation and prevented POI. With bone marrow transplantation, RNA-sequencing, flow cytometry and immunohistochemistry we revealed a distinct TLR3-expressing radio-resistant MHCIIhiCX3CR1- IBA-1+ resident macrophage population within the deep myenteric plexus. TLR3 deficiency in these cells, but not in MHCIIhiCX3CR1+ macrophages, reduced cytokine expression in POI. While this might not be an exclusive macrophage-privileged pathway, the TLR3/TRIF axis contributes to proinflammatory cytokine production in MHCIIhiCX3CR1- IBA-1+ macrophages during POI. Deficiency in TLR3/TRIF protects mice from POI. These data suggest that TLR3 antagonism may prevent POI in humans.

FTY720-Induced Lymphopenia Does Not Aggravate Mortality in a Murine Model of Polymicrobial Abdominal Sepsis.

BACKGROUND: FTY720 is an immunosuppressive molecule licensed for the treatment of chronic relapsing multiple sclerosis (MS). It attenuates the adaptive immune response by sequestering T cells within secondary lymphoid organs via its action as functional antagonist of sphingosine-1-phasphate. To date, it is unknown whether FTY-induced lymphopenia puts MS patients at increased risk for severe forms of postoperative infectious complications such as abdominal sepsis. OBJECTIVES: To determine the effect of FTY720-induced lymphopenia on survival to sepsis secondary to postoperative intraabdominal infections in a murine model of polymicrobial sepsis. METHODS: Detailed analysis of cellular dynamics in secondary lymphoid organs and of cytokine profiles was performed in FTY720-treated or placebo-treated C57BL/6 mice after induction of colon ascendens stent peritonitis (CASP). Furthermore, survival analysis was performed in FTY720-treated and placebo-treated animals in severe CASP. Fifty percent of each group were treated with broad spectrum antibiotics. RESULTS: FTY720 treatment resulted in remodeling of cell populations present in the peripheral blood, the peritoneal cavity, and the spleen after CASP induction. Both lymphoid and myeloid cell lines were affected. However, survival in lymphopenic FTY720-treated animals was similar to placebo-treated mice following CASP. Antibiotic treatment increases survival in untreated as well as FTY720-treated animals to a similar extent. DISCUSSION: Our data demonstrate that inhibition of T-cell migration and induction of peripheral lymphopenia did not affect survival in a model of severe murine sepsis. The presence of reduced T- and B-cell numbers in the peripheral blood during a septic challenge did not negatively affect sepsis mortality in our model of severe abdominal sepsis. The absence of increased mortality under FTY720 treatment in the CASP model suggests that FTY720 treatment will probably not result in increased mortality in MS patients suffering from sepsis.