European Society of Coloproctology: Guidelines for diagnosis and treatment of cryptoglandular anal fistula.

AIM: The primary aim of the European Society of Coloproctology (ESCP) Guideline Development Group (GDG) was to produce high-quality, evidence-based guidelines for the management of cryptoglandular anal fistula with input from a multidisciplinary group and using transparent, reproducible methodology. METHODS: Previously published methodology in guideline development by the ESCP has been replicated in this project. The guideline development process followed the requirements of the AGREE-S tool kit. Six phases can be identified in the methodology. Phase one sets the scope of the guideline, which addresses the diagnostic and therapeutic management of perianal abscess and cryptoglandular anal fistula in adult patients presenting to secondary care. The target population for this guideline are healthcare practitioners in secondary care and patients interested in understanding the clinical evidence available for various surgical interventions for anal fistula. Phase two involved formulation of the GDG. The GDG consisted of 21 coloproctologists, three research fellows, a radiologist and a methodologist. Stakeholders were chosen for their clinical and academic involvement in the management of anal fistula as well as being representative of the geographical variation among the ESCP membership. Five patients were recruited from patient groups to review the draft guideline. These patients attended two virtual meetings to discuss the evidence and suggest amendments. In phase three, patient/population, intervention, comparison and outcomes questions were formulated by the GDG. The GDG ratified 250 questions and chose 45 for inclusion in the guideline. In phase four, critical and important outcomes were confirmed for inclusion. Important outcomes were pain and wound healing. Critical outcomes were fistula healing, fistula recurrence and incontinence. These outcomes formed part of the inclusion criteria for the literature search. In phase five, a literature search was performed of MEDLINE (Ovid), PubMed, Embase (Ovid) and the Cochrane Database of Systematic Reviews by eight teams of the GDG. Data were extracted and submitted for review by the GDG in a draft guideline. The most recent systematic reviews were prioritized for inclusion. Studies published since the most recent systematic review were included in our analysis by conducting a new meta-analysis using Review manager. In phase six, recommendations were formulated, using grading of recommendations, assessment, development, and evaluations, in three virtual meetings of the GDG. RESULTS: In seven sections covering the diagnostic and therapeutic management of perianal abscess and cryptoglandular anal fistula, there are 42 recommendations. CONCLUSION: This is an up-to-date international guideline on the management of cryptoglandular anal fistula using methodology prescribed by the AGREE enterprise.

Strikingly conserved gene expression changes of polyamine regulating enzymes among various forms of acute and chronic kidney injury.

The polyamines spermidine and spermine and their common precursor molecule putrescine are involved in tissue injury and repair. Here, we test the hypothesis that impaired polyamine homeostasis contributes to various kidney pathologies in mice during experimental models of ischemia-reperfusion, transplantation, rhabdomyolysis, cyclosporine treatment, arterial hypertension, diabetes, unilateral ureteral obstruction, high oxalate feeding, and adenine-induced injuries. We found a remarkably similar pattern in most kidney pathologies with reduced expression of enzymes involved in polyamine synthesis together with increased expression of polyamine degrading enzymes. Transcript levels of amine oxidase copper-containing 1 (Aoc1), an enzyme which catalyzes the breakdown of putrescine, were barely detectable by in situ mRNA hybridization in healthy kidneys. Aoc1 was highly expressed upon various experimental kidney injuries resulting in a significant reduction of kidney putrescine content. Kidney levels of spermine were also significantly reduced, whereas spermidine was increased in response to ischemia-reperfusion injury. Increased Aoc1 expression in injured kidneys was mainly accounted for by an Aoc1 isoform that harbors 22 additional amino acids at its N-terminus and shows increased secretion. Mice with germline deletion of Aoc1 and injured kidneys showed no decrease of kidney putrescine content; although they displayed no overt phenotype, they had fewer tubular casts upon ischemia-reperfusion injury. Hyperosmotic stress stimulated AOC1 expression at the transcriptional and post-transcription levels in metanephric explants and kidney cell lines. AOC1 expression was also significantly enhanced after kidney transplantation in humans. These data demonstrate that the kidneys respond to various forms of injury with down-regulation of polyamine synthesis and activation of the polyamine breakdown pathway. Thus, an imbalance in kidney polyamines may contribute to various etiologies of kidney injury.

Benchmarks in colorectal surgery: multinational study to define quality thresholds in high and low anterior resection.

BACKGROUND: Benchmark comparisons in surgery allow identification of gaps in the quality of care provided. The aim of this study was to determine quality thresholds for high (HAR) and low (LAR) anterior resections in colorectal cancer surgery by applying the concept of benchmarking. METHODS: This 5-year multinational retrospective study included patients who underwent anterior resection for cancer in 19 high-volume centres on five continents. Benchmarks were defined for 11 relevant postoperative variables at discharge, 3 months, and 6 months (for LAR). Benchmarks were calculated for two separate cohorts: patients without (ideal) and those with (non-ideal) outcome-relevant co-morbidities. Benchmark cut-offs were defined as the 75th percentile of each centre's median value. RESULTS: A total of 3903 patients who underwent HAR and 3726 who had LAR for cancer were analysed. After 3 months' follow-up, the mortality benchmark in HAR for ideal and non-ideal patients was 0.0 versus 3.0 per cent, and in LAR it was 0.0 versus 2.2 per cent. Benchmark results for anastomotic leakage were 5.0 versus 6.9 per cent for HAR, and 13.6 versus 11.8 per cent for LAR. The overall morbidity benchmark in HAR was a Comprehensive Complication Index (CCI®) score of 8.6 versus 14.7, and that for LAR was CCI® score 11.9 versus 18.3. CONCLUSION: Regular comparison of individual-surgeon or -unit outcome data against benchmark thresholds may identify gaps in care quality that can improve patient outcome.

Reduced port versus open right hemicolectomy for colorectal cancer: a retrospective comparison study of two centers.

PURPOSE: The concept of complete mesocolic excision (CME) in right-sided colorectal cancer is well known for open and laparoscopic surgery. The aim of this study was to evaluate and compare perioperative and oncological outcomes of reduced port and open surgery for right-sided colorectal cancer. METHODS: One hundred forty-one patients received elective surgery for right-sided colonic cancer between January 2015 and December 2019 and were included in a retrospective database. RESULTS: We observed longer operation time in the RP-CME group (145 min vs. 119.43 min, p<0.01). Hospital stay (8 days vs. 14 days, p<0.01) and time to first intestinal passage (42 h. vs. 59 h, p<0.01) were significantly shorter in the reduced port group. Postoperative complications were more likely to be observed in the O-CME group (7.2% vs. 14.1%, p=0.28); anastomotic leakage rate was low in both groups (1.8% vs. 2.4%, p=1.00). Specimen scores (score 1= good: 93.8% vs. 91.7%, p=1.00) and average number of retrieved lymph nodes were comparable (24 vs. 23 p=0.69). In O-CME patients, we observed more advanced tumor stages (UICC III: 21.4% vs. 45.9%, p<0.01). CONCLUSION: To our knowledge, this is the first study comparing reduced port to open surgery for right-sided colorectal cancer. We could demonstrate that this technique is feasible for oncological right hemicolectomy with observation of shorter hospital stay and lower morbidity rates compared to open surgery. The oncological outcome did not differ in the present study.

Damage control strategy in perforated diverticulitis with generalized peritonitis.

BACKGROUND: The best treatment for perforated colonic diverticulitis with generalized peritonitis is still under debate. Concurrent strategies are resection with primary anastomosis (PRA) with or without diverting ileostomy (DI), Hartmann's procedure (HP), laparoscopic lavage (LL) and damage control surgery (DCS). This review intends to systematically analyze the current literature on DCS. METHODS: DCS consists of two stages. Emergency surgery: limited resection of the diseased colon, oral and aboral closure, lavage, vacuum-assisted abdominal closure. Second look surgery after 24-48 h: definite reconstruction with colorectal anastomosis (-/ + DI) or HP after adequate resuscitation. The review was conducted in accordance to the PRISMA-P Statement. PubMed/MEDLINE, Cochrane central register of controlled trials (CENTRAL) and EMBASE were searched using the following term: (Damage control surgery) AND (Diverticulitis OR Diverticulum OR Peritonitis). RESULTS: Eight retrospective studies including 256 patients met the inclusion criteria. No randomized trial was available. 67% of the included patients had purulent, 30% feculent peritonitis. In 3% Hinchey stage II diverticulitis was found. In 49% the Mannheim peritonitis index (MPI) was greater than 26. Colorectal anastomosis was constructed during the course of the second surgery in 73%. In 15% of the latter DI was applied. The remaining 27% received HP. Postoperative mortality was 9%, morbidity 31% respectively. The anastomotic leak rate was 13%. 55% of patients were discharged without a stoma. CONCLUSION: DCS is a safe technique for the treatment of acute perforated diverticulitis with generalized peritonitis, allowing a high rate of colorectal anastomosis and stoma-free hospital discharge in more than half of the patients.

Prospectively Randomized Controlled Trial on Damage Control Surgery for Perforated Diverticulitis with Generalized Peritonitis.

INTRODUCTION: Damage control surgery (DCS) with abdominal negative pressure therapy and delayed anastomosis creation in patients with perforated diverticulitis and generalized peritonitis was established at our Institution in 2006 and has been published. The concept was adopted in other hospitals and published as a case series. This is the first prospectively controlled randomized study comparing DCS and conventional treatment (Group C) in this setting. METHODS: All consecutive patients from 2013 to 2018 with indication for surgery were screened and randomized to Group DCS or Group C. The primary outcome was the rate of reconstructed bowel at discharge and at 6 month. Informed consent was obtained. The trial was approved by the local ethics committee and registered at CinicalTrials.gov: NCT04034407. RESULTS: A total of 56 patients were screened; 41 patients gave informed consent to participate and ultimately 21 patients (9 female) with intraoperatively confirmed Hinchey III (n = 14, 67%) or IV (n = 7, 33%), and a median (range) age of 66 (42-92), Mannheim Peritonitis Index of 25 (12-37) and Charlson Comorbidity Index of 3 (0-10) were intraoperatively randomized and treated as Group DCS (n = 13) or Group C (n = 8). Per protocol analysis: A primary anastomosis without ileostomy (PA) was performed in 92% (11/12) patients in Group DCS at the second-look operation, one patient died before second look, and one underwent a Hartmann procedure (HP). In Group C 63% (5/8) patients received a PA and 38% (3/8) patients a HP. Two patients in Group C, but none in Group DCS experienced anastomotic leakage (AI). ICU and hospital stay was median (range) 2 (1-10) and 17.5 (12-43) in DCS and 2 (1-62) and 22 (13-65) days in group C. In Group DCS 8% (1/12) patients was discharged with a stoma versus 57% (4/7) in Group C (p = 0.038, n.s., α = 0.025); one patient died before discharge. The odds ratio (95% confidence interval) for discharge with a stoma is 0.068 (0.005-0.861). Intent to treat analysis: A PA was performed in 90% (9/10) of patients randomized to DCS, one patient died before the second look, and one patient received a HP. In group C, 70% (7/10) were treated with PA and 30% (3/10) with HP. 29% (2/7) experienced AI treated with protective ileostomy. In group DCS, 9% (1/11) were discharged with a stoma versus 40% (4/10) in group C (p = 0.14, n.s.). The odds ratio for discharge with a stoma is 0.139 (0.012-1.608). CONCLUSION: This is the first prospectively randomized controlled study showing that damage control surgery in perforated diverticulitis Hinchey III and IV enhances reconstruction of bowel continuity and can reduce the stoma rate at discharge.

How to reduce anastomotic leakage in colorectal surgery-report from German expert meeting.

AIMS: Anastomotic leakage is one of the most worrisome complications in colorectal surgery. An expert meeting was organized to discuss and find a consensus on various aspects of the surgical management of colorectal disease with a possible impact on anastomotic leakage. METHODS: A three-step Delphi-method was used to find consensus recommendations. RESULTS: Strong consensus was achieved for the use of mechanical bowel preparation and oral antibiotics prior to colorectal resections, the abundance of non-selective NSAIDs, the preoperative treatment of severe iron deficiency anemia, and for attempting to improve the patients' general performance in the case of frailty. Concerning technical aspects of rectal resection, there was a strong consensus in regard to routinely mobilizing the splenic flexure, to dividing the inferior mesenteric vein, and to using air leak tests to check anastomotic integrity. There was also a strong consensus on not to oversew the stapled anastomoses routinely, to use protective ileostomies for low rectal and intersphincteric, but not for high-rectal anastomoses. Furthermore, a consensus was reached in regard to using CT-scans with rectal contrast enema to evaluate suspected anastomotic leakage as well as measuring C-reactive protein routinely to monitor the postoperative course after colorectal resections. No consensus was found concerning the indication and technique for testing bowel perfusion, the routine use of endoscopy to check the integrity of the anastomosis, the placement of transanal drains for rectal anastomoses and the management of anastomotic leakage with peritonitis. CONCLUSION: Consensus could be found for several practice details in the perioperative management in colorectal surgery that might have an influence on anastomotic leakage.

Gender comparison of clinical, histopathological, therapeutic and outcome factors in 185,967 colon cancer patients.

INTRODUCTION: Colorectal carcinomas represent the third most common cause of cancer-related deaths in Germany. Although the incidence is significantly higher in men compared with women and gender is a well-established crucial factor for outcome in other diseases, detailed gender comparisons for colon cancer are lacking. METHODS: This retrospective population-based cohort study included all patients diagnosed with colon cancer in Germany between 2000 and 2016 who were included in the common dataset of colorectal cancer patients from the quality conference of the German Cancer Society. We compared clinical, histopathological, and therapeutic characteristics as well as overall and recurrence-free survival. RESULTS: A total of 185,967 patients were included in the study, of which 85,685 were female (46.1%) and 100,282 were male (53.9%). The proportion of women diagnosed with colon cancer decreased from 2000 to 2016 (f: 26.6 to 40.1%; m: 24.9 to 41.9%; p < 0.001), and the proportion of very old patients was especially high in women (f: 27.3%; m: 15.6%; p < 0.001). The localization in women was more right-sided (f: 45.0%, m: 36.7%; p < 0.001), and women had a higher tumor grading and a higher UICC stage (especially stage III nodal-positive) at diagnosis of primary colon cancer (UICC III: f: 22.7%, m: 21.0%; p < 0.001). We could detect a significantly better overall (hazard ratio: 0.853, lower 95%: 0.841, upper 95%: 0.864; p < 0.001) and recurrence-free survival (hazard ratio: 0.857, lower 95%: 0.845, upper 95%: 0.868; p < 0.001) in women compared with men, even though women received chemotherapy less frequently compared with men (f: 26.1%, m: 28.1%; p < 0.001). CONCLUSION: We could detect several variables that differed significantly between men and women regarding clinical, histopathological, therapeutic, and outcome factors. We believe that it is crucial to consider gender as a key factor in the diagnosis and treatment of colon cancer. Sex-specific diagnostic tools could lead to an earlier diagnosis of colon cancer in women, and ways to increase the rate of chemotherapy in women should be evaluated. Furthermore, we recommend stratifying randomized trials by gender.

Surgical workflow for fully navigated high sacral amputation in sacral chordoma.

The method of choice for treatment of sacral chordomas is en bloc tumor removal via sacrectomy or sacral amputation in varying degrees depending on the initial tumor extent. Besides local tumor control, the preservation of neurological function is equally important to minimize postoperative bladder and bowel dysfunction. Removal of sacral tumors is complicated by the complex regional anatomy of the pelvis and the surrounding visceral and retroperitoneal structures. We aim to describe the surgical workflow for a fully navigated high sacral amputation facilitated by integration of an intraoperative computed tomography (iCT)-based spinal navigation system. An iCT-based spinal navigation system (AIRO® CT scanner, Brainlab AG, Feldkirchen, Germany) was used to perform intraoperative navigation with an image-guidance system and infrared tracking camera (BrainLab CurveTM, Brainlab AG, Feldkirchen, Germany) in combination with the spinal navigation set by Brainlab (Brainlab AG, Feldkirchen, Germany) to perform a fully navigated high sacral amputation. We demonstrate the successful implementation of iCT-based spinal navigation during high sacral amputation and the key advantages of this technique throughout the surgery. iCT-based spinal navigation is a useful complementing technique for en bloc high sacral amputations that renders the surgery safer and more accurate.

Recent Advances and the Potential for Clinical Use of Autofluorescence Detection of Extra-Ophthalmic Tissues.

The autofluorescence (AF) characteristics of endogenous fluorophores allow the label-free assessment and visualization of cells and tissues of the human body. While AF imaging (AFI) is well-established in ophthalmology, its clinical applications are steadily expanding to other disciplines. This review summarizes clinical advances of AF techniques published during the past decade. A systematic search of the MEDLINE database and Cochrane Library databases was performed to identify clinical AF studies in extra-ophthalmic tissues. In total, 1097 articles were identified, of which 113 from internal medicine, surgery, oral medicine, and dermatology were reviewed. While comparable technological standards exist in diabetology and cardiology, in all other disciplines, comparability between studies is limited due to the number of differing AF techniques and non-standardized imaging and data analysis. Clear evidence was found for skin AF as a surrogate for blood glucose homeostasis or cardiovascular risk grading. In thyroid surgery, foremost, less experienced surgeons may benefit from the AF-guided intraoperative separation of parathyroid from thyroid tissue. There is a growing interest in AF techniques in clinical disciplines, and promising advances have been made during the past decade. However, further research and development are mandatory to overcome the existing limitations and to maximize the clinical benefits.

Surgical Quality Assurance in COLOR III: Standardization and Competency Assessment in a Randomized Controlled Trial.

OBJECTIVE: The aim of this study was to develop an objective and reliable surgical quality assurance system (SQA) for COLOR III, an international multicenter randomized controlled trial (RCT) comparing transanal total mesorectal excision (TaTME) with laparoscopic approach for rectal cancer. BACKGROUND OF SUMMARY DATA: SQA influences outcome measures in RCTs such as lymph nodes harvest, in-hospital mortality, and locoregional cancer recurrence. However, levels of SQA are variable. METHOD: Hierarchical task analysis of TaTME was performed. A 4-round Delphi methodology was applied for standardization of TaTME steps. Semistructured interviews were conducted in round 1 to identify key steps and tasks, which were rated as mandatory, optional, or prohibited in rounds 2 to 4 using questionnaires. Competency assessment tool (CAT) was developed and its content validity was examined by expert surgeons. Twenty unedited videos were assessed to test reliability using generalizability theory. RESULTS: Eighty-three of 101 surgical tasks identified reached 70% agreement (26 mandatory, 56 optional, and 1 prohibited). An operative guide of standardized TaTME was created. CAT is matrix of 9 steps and 4 performance qualities: exposure, execution, adverse event, and end-product. The overall G-coefficient was 0.883. Inter-rater and interitem reliability were 0.883 and 0.986. To enter COLOR III, 2 unedited TaTME and 1 laparoscopic TME videos were submitted and assessed by 2 independent assessors using CAT. CONCLUSION: We described an iterative approach to develop an objective SQA within multicenter RCT. This approach provided standardization, the development of reliable and valid CAT, and the criteria for trial entry and monitoring surgical performance during the trial.

Safety of extraperitoneal rectal resection and ileo- or colorectal anastomosis without loop ileostomy in patients with peritoneal metastases treated with CRS and HIPEC.

AIM: Extraperitoneal rectal resection combined with complete peritonectomy of the pelvis in patients with peritoneal metastases is associated with a high rate of morbidity and mortality due to anastomotic leakage (AL). Therefore, many centers tend to perform loop ileostomy to reduce the clinical impact of AL. The aim of this study was to analyze the need for protective stoma creation in this patient group to avoid major complications and mortality in the case of AL. METHOD: We analyzed 53 patients who underwent extraperitoneal rectal resection from 409 consecutive patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) at our department between January 1997 and December 2016. RESULTS: Mean age of the patients was 56.7 (SD 12.2) years and the mean Peritoneal Cancer Index was 24.6 (SD 12.0). Complete cytoreduction was achieved in 33 patients (62.3%). Six patients received an ileostomy or a colostomy, 5 of 6 with permanent intention. One patient (2.1%) developed AL postoperatively. Overall, 21 patients (39.6%) developed surgical complications, while 41 (77.3%) developed medical complications. The mortality rate was 7.5% (n = 4). In total, 26 patients (49.1%) developed Clavien-Dindo class-III/IV complications. CONCLUSIONS: These results demonstrate the safety of colorectal anastomosis in combination with HIPEC in the absence of loop ileostomy. Loop ileostomy may be omitted for patients with low risk for AL in experienced centers with adequate post-operative care, possibilities for post-operative assessment and radiological intervention to avoid stoma related complications and increase the quality of life of patients with peritoneal metastases. This article is protected by copyright. All rights reserved.

Inferior graft survival of hepatitis B core positive grafts is not influenced by post-transplant hepatitis B infection in liver recipients--5-year single-center experience.

Nonoptimal liver grafts, and among them organs from anti-HBc+ donors, are increasingly used for liver transplantation. In this retrospective study including 1065 adult liver transplantations performed between 1977 and 2012, we analyzed long-term patient and graft survival and occurrence of HBV infection. A total of 52 (5.1%) patients received an anti-HBc+ graft. The 10-year graft and patient survival of these recipients were 50.9% and 59.0% compared to 72.0% and 76.5% (P = 0.001; P = 0.004) of patients receiving anti-HBc- grafts, respectively. Cox regression model showed that high urgency allocation (P = 0.003), recipient age (P = 0.027), anti-HCV+ recipients (P = 0.005), and anti-HBc+ organs (P = 0.048) are associated with decreased graft survival. Thirteen of 52 (25.0%) patients receiving anti-HBc+ grafts developed post-transplant HBV infection within a mean of 2.8 years. In this study, antiviral prophylaxis did not have significant impact on HBV infection, but long-term survival (P = 0.008). Development of post-transplant HBV infection did not affect adjusted 10-year graft survival (100% vs. 100%; P = 1). Anti-HBc+ liver grafts can be transplanted with reasonable but inferior long-term patient and graft survival. The inferior graft survival is not, however, related with post-transplant HBV infection as long as early diagnosis and treatment take place.

Diverticulitis in immunosuppressed patients: A fatal outcome requiring a new approach?

BACKGROUND: Diagnosis and treatment of diverticulitis in immunosuppressed patients are more challenging than in immunocompetent patients, as maintenance immunosuppressive therapies may mask symptoms or impair the patient's ability to counteract the local and systemic infective sequelae of diverticulitis. The purpose of this study was to compare the in-hospital mortality and morbidity due to diverticulitis in immunosuppressed and immunocompetent patients and identify risk factors for lethal outcomes. METHODS: This retrospective study included consecutive in-patients who received treatment for colonic diverticulitis at our institution between April 2008 and April 2014. Patients were divided into immunocompetent and immunosuppressed groups. Primary end points were mortality and morbidity during treatment. Risk factors for death were evaluated. RESULTS: Of the 227 patients included, 15 (6.6%) were on immunosuppressive therapy for solid organ transplantation, autoimmune disease, or cerebral metastasis. Thirteen of them experienced colonic perforation and showed higher morbidity (p = 0.039). Immunosuppressed patients showed longer stays in hospital (27.6 v. 14.5 d, p = 0.016) and in the intensive care unit (9.8 v. 1.1 d, p < 0.001), a higher rate of emergency operations (66% v. 29.2%, p = 0.004), and higher in-hospital mortality (20% v. 4.7%, p = 0.045). Age, perforated diverticulitis with diffuse peritonitis, emergency operation, C-reactive protein > 20 mg/dL, and immunosuppressive therapy were significant predictors of death. Age (hazard ratio [HR] 2.57, p = 0.008) and emergency operation (HR 3.03, p = 0.003) remained significant after multivariate analysis. CONCLUSION: Morbidity and mortality due to sigmoid diverticulitis is significantly higher in immunosuppressed patients. Early diagnosis and treatment considering elective sigmoid resection for patients with former episodes of diverticulitis who are wait-listed for transplant is crucial to prevent death.

BACKGROUND: Le diagnostic et le traitement des diverticulites sont plus délicats chez les patients immunosupprimés que chez les patients immunocompétents, étant donné que les thérapies immunosuppressives d'entretien peuvent masquer les symptômes ou réduire la capacité du patient à lutter contre les infections locales ou systémiques pouvant découler de la diverticulite. La présente étude avait pour but de comparer les taux de mortalité et de morbidité en milieu hospitalier associés à la diverticulite chez des patients immunosupprimés et immunocompétents et de cerner les facteurs de risque de décès. METHODS: Cette étude rétrospective portait sur des patients traités consécutivement pour une diverticulite du côlon hospitalisés dans notre établissement entre avril 2008 et avril 2014. Les patients ont été divisés en 2 groupes : immunocompétents et immunosupprimés. Les résultats primaires à l'étude étaient la mortalité et la morbidité pendant le traitement, et nous avons évalué les facteurs de risque de décès. RESULTS: Parmi les 227 patients retenus, 15 (6,6 %) suivaient une thérapie immunosuppressive en raison d'une greffe d'organe plein, d'une maladie auto-immune ou de métastases cérébrales. Parmi eux, 13 ont subi une perforation du côlon et présentaient un taux de morbidité supérieur (p = 0,039). Les patients immunosupprimés sont restés plus longtemps à l'hôpital (27,6 j c. 14,5 j, p = 0,016) et à l'unité de soins intensifs (9,8 j c. 1,1 j, p < 0,001), et présentaient des taux supérieurs d'intervention d'urgence (66 % c. 29,2 %, p = 0,004) et de mortalité pendant l'hospitalisation (20 % c. 4,7 %, p = 0,045). L'âge, une diverticulite perforée avec péritonite diffuse, une opération d'urgence, un résultat de protéine C réactive > 20 mg/dL et une thérapie immunosuppressive étaient des prédicteurs de décès significatifs. L'âge (rapport de risque [RR] 2,57, p = 0,008) et une opération d'urgence (RR 3,03, p = 0,003) sont demeurés significatifs après l'exécution d'une analyse multivariée. CONCLUSION: Les taux de morbidité et de mortalité attribuables à une diverticulite du sigmoïde sont significativement plus élevés chez les patients immunosupprimés que chez les autres patients. Afin de prévenir les décès, il est essentiel de diagnostiquer et de traiter rapidement, possiblement par résection du sigmoïde, les patients ayant déjà souffert de diverticulite qui sont sur une liste d'attente pour une greffe.

The role of lipocalin-2 in liver regeneration.

BACKGROUND & AIMS: Various immune mediators such as interleukin-6 (IL-6) have been implicated in the process of liver regeneration. Lipocalin-2 (LCN2) has been recently characterized as a prototypic immune mediator produced by various cell types being involved mainly in host defence. In addition, numerous studies have demonstrated its clinical value as a biomarker. This study aimed at defining the role of LCN2 in liver regeneration. METHODS: We studied LCN2 expression in wild-type mice in a model of partial hepatectomy (PH). Furthermore, we evaluated liver regeneration after PH in LCN-deficient mice compared to littermate controls. Serum levels of LCN2 were assessed in a small group of patients undergoing hepatic resection. RESULTS: LCN2 is dramatically induced in livers and sera of wild-type mice after PH, whereas liver LCN2-receptor expression was decreased. Sham operations did not affect hepatic and serum LCN2 expression. Although LCN2-deficient mice exhibited increased baseline liver expression indices, LCN2-deficient mice did not differ from wild-type mice with respect to hepatic proliferation suggesting that this molecule is not involved in hepatic repair. Only serum IL-1ß levels were slightly lower in LCN(-/-) mice, whereas IL-6 serum levels did not differ between various tested animal groups. In humans undergoing hepatic resection, LCN2 levels increased significantly within 24 h following surgery. CONCLUSIONS: LCN2, although massively induced in mice after PH, is not relevant in murine hepatic regeneration. Further, human studies have to define whether LCN2 could evolve as biomarker after liver surgery.

Biopsychronology: live confocal imaging of biopsies to assess organ function.

Prolonged ischemia (I) times caused by organ procurement and transport are main contributors to a decrease in organ function, which is further enhanced during reperfusion (R). This combined damage, referred to as ischemia-reperfusion injury (IRI), is a main contributor to delayed graft function, which leads to costly and lengthy follow-up treatments or even organ loss. Methods to monitor the status of a graft prior to transplantation are therefore highly desirable to optimize the clinical outcome. Here, we propose the use of fine needle biopsies, which are analyzed by real-time live confocal microscopy. Such a combination provides information about the functional and structural integrity of an organ within a few minutes. To confirm the feasibility of this approach, we obtained fine needle biopsies from rodent kidneys and exposed them to various stress conditions. Following the addition of a range of live stains, biopsies were monitored for mitochondrial function, cell viability, and tissue integrity using confocal live cell imaging. Our data demonstrate that this procedure requires minimal time for sample preparation and data acquisition and is well suitable to record organ damage resulting from unphysiological stress.

Bilirubin rinse of the graft ameliorates ischemia reperfusion injury in heart transplantation.

Ischemia and reperfusion contribute to substantial organ damage in transplantation. Clinically feasible measures for the prevention thereof are scarce. We tested whether rinsing rodent hearts with the antioxidant bilirubin ameliorates ischemia reperfusion injury (IRI). Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDevP), rate per pressure product (RPP), coronary flow, maximum (+dP/dt) and minimum (-dP/dt) rate of contraction were analyzed in Lewis rat hearts rinsed with bilirubin prior to reperfusion on a Langendorff apparatus after 12 h of cold ischemia. In vivo, isogenic C57Bl/6 mouse hearts rinsed with bilirubin were transplanted after 12 h of cold ischemia. Cardiac function and apoptosis were assessed 24 h after reperfusion. Heart lysates recovered 15 min after reperfusion were probed for the total and the phosphorylated forms of extracellular signal-related protein kinases (ERK), JNK, p38-MAPK, and Akt. In isolated perfused hearts, bilirubin rinse resulted in significantly lower LVEDP and improved LVDevP, RPP, coronary flow, +dP/dt and -dP/dt. In vivo, after reperfusion, all mitogen-activated protein kinases (MAPKs) were suppressed significantly by bilirubin pretreatment. Bilirubin rinse improved cardiac scores (3.4 ± 0.5 vs. 2.0 ± 1.0 in controls, P < 0.05) and significantly suppressed apoptosis. Ex vivo administration of bilirubin to heart grafts prior reperfusion ameliorates IRI and provides a simple and effective tool to ameliorate outcome in heart transplantation.

Up-regulation of neutrophil gelatinase-associated lipocalin in colorectal cancer predicts poor patient survival.

BACKGROUND: Lipocalin-2 (Lcn-2) is expressed in human neutrophils and epithelial cells, particularly in the presence of inflammation or cancer. It was shown to be highly expressed in various human cancers. Increased protein levels were associated with decreased survival of patients with breast or gastric cancer. The main focus of this work was to analyze the implication of Lcn-2 up-regulation in the genesis of colon cancer. METHODS: Expression of Lcn-2 was analyzed in colorectal carcinoma cell lines, paired colorectal carcinoma tissues, and regular mucosa by Western blot analysis. Lcn-2 immunohistochemical staining was performed in 192 colorectal carcinoma resection specimens and correlated with clinicopathologic parameters. RESULTS: Western blot analysis of colorectal carcinoma tissues demonstrated Lcn-2 overexpression in carcinomas as compared with regular mucosa. Immunohistochemical staining revealed Lcn-2 expression in 179 (93.2%) colorectal carcinoma tissues. Intense immunoreactivity was significantly correlated with metastasis (p = 0.042) and UICC stage (p = 0.027). Survival analysis according to the Kaplan-Meier method revealed a significant association between Lcn-2 overexpressing tumors and overall survival (p < 0.001) and disease-free survival (p < 0.001). CONCLUSIONS: Our data provide evidence that Lcn-2 expression is up-regulated with tumor progression and was found to be a predictor of overall survival.

Lipocalin-2 as mediator of chemokine expression and granulocyte infiltration during ischemia and reperfusion.

Lipocalin-2 (Lcn2) expression contributes to ischemia and reperfusion injury (IRI) by enhancing pro-inflammatory responses. The aim of this work was to elucidate the regulation of Lcn2 during hypoxia and its effects on the expression of key chemokines and adhesion molecules. Lcn2 wt and Lcn2(-/-) mice were used in a heterotopic heart transplantation model. Quantitative RT-PCR was applied for chemokine gene expression analysis. Reporter gene studies were used to elucidate the regulation of the Lcn2 promoter by hypoxia. HIF-1ß expression led to a 2.4-fold induction of the Lcn2 promoter. Apart from an earlier onset of granulocyte infiltration in the Lcn2 wt setting after 2 h of reperfusion compared with the Lcn2(-/-) setting (P < 0.013), exogenous application of recombinant Lcn2 revealed a trend toward increase of granulocyte infiltration. Analyzed chemokines were expressed significantly higher in the Lcn2 wt setting at 2 h of reperfusion (P ≤ 0.05). The number of apoptotic cells observed in Lcn2(-/-) grafts was significantly higher than in the Lcn2 wt setting. Our results indicate that Lcn2 affects granulocyte infiltration in the reperfused graft by modulating the expression of chemokines, their receptors and the apoptotic rate.