Quality of Recovery and Innate Immune Homeostasis in Patients Undergoing Low-pressure Versus Standard-pressure Pneumoperitoneum During Laparoscopic Colorectal Surgery (RECOVER): A Randomized Controlled Trial.

OBJECTIVE: To study the effects of intra-abdominal pressure on the quality of recovery and innate cytokine production capacity after laparoscopic colorectal surgery within the enhanced recovery after surgery program. BACKGROUND: There is increasing evidence for the safety and advantages of low-pressure pneumoperitoneum facilitated by deep neuromuscular blockade (NMB). Nonetheless, there is a weak understanding of the relationship between clinical outcomes, surgical injury, postoperative immune dysfunction, and infectious complications. METHODS: Randomized controlled trial of 178 patients treated at standard-pressure pneumoperitoneum (12 mm Hg) with moderate NMB (train-of-four 1-2) or low pressure (8 mm Hg) facilitated by deep NMB (posttetanic count 1-2). The primary outcome was the quality of recovery (Quality of Recovery 40 questionnaire) on a postoperative day 1 (POD1). The primary outcome of the immune substudy (n=100) was ex vivo tumor necrosis factor α production capacity upon endotoxin stimulation on POD1. RESULTS: Quality of Recovery 40 score on POD1 was significantly higher at 167 versus 159 [mean difference (MD): 8.3 points; 95% confidence interval (CI): 2.5, 14.1; P =0.005] and the decline in cytokine production capacity was significantly less for tumor necrosis factor α and interleukin-6 (MD: -172 pg/mL; 95% CI: -316, -27; P =0.021 and MD: -1282 pg/mL; 95% CI: -2505, -59; P =0.040, respectively) for patients operated at low pressure. Low pressure was associated with reduced surgical site hypoxia and inflammation markers and circulating damage-associated molecular patterns, with a less impaired early postoperative ex vivo cytokine production capacity. At low pressure, patients reported lower acute pain scores and developed significantly less 30-day infectious complications. CONCLUSIONS: Low intra-abdominal pressure during laparoscopic colorectal surgery is safe, improves the postoperative quality of recovery and preserves innate immune homeostasis, and forms a valuable addition to future enhanced recovery after surgery programs.

Long-term clinical experience with laparoscopic ventral hernia repair using a ParietexTM composite mesh in severely obese and non-severe obese patients: a single center cohort study.

Background: The treatment of incisional and ventral hernias is associated with significant complications and recurrences, especially in severely obese patients. Recent studies have shown a reduced rate of surgical site infections and length of hospital stay in severely obese patients undergoing a laparoscopic ventral hernia repair.Aim: This study aims to describe the clinical experience in terms of efficacy and safety with laparoscopic ventral hernia repair using the ParietexTM Composite mesh (Covidien Sofradim Production, Trevoux, France) in severely obese patients (body mass index ≥35) compared with non-severe obese patients in a seven-year single-center cohort.Material and methods: All patients with a primary ventral or incisional hernia admitted to our hospital from 2006 until December 2012 who underwent a laparoscopic repair with the Parietex Composite mesh were included in this study. Pain scores using a numeric rating were collected prospectively 24-48 hours postoperatively. Patient data were retrospectively collected.Results: A total number of 210 patients were included; 173 with a BMI <35 and 37 with a BMI ≥35. Mean follow-up was 31 months. No statistically significant differences were found with regard to operation time, hospital stay, use of analgesics and postoperative complications. The long-term follow up recurrence rate in non-severely obese patients was 13% compared to 16% in severely obese patients (p = .60).Conclusion: Laparoscopic ventral and incisional hernia repair using the Parietex Composite mesh is feasible and safe in severely obese patients compared to non-severely obese patients.

Cecal volvulus caused by a large uterine leiomyoma.

INTRODUCTION: Cecal volvulus is a relatively uncommon encountered clinical condition. PRESENTATION OF CASE: A 48-year-old patient known with a large uterine leiomyoma, presented with progressive abdominal pain since one week. An abdominal computed tomography scan revealed a very large leiomyoma of the uterus, severely distended loops of the small bowel with a caliber change and a suggested 'whirl sign' of the mesenteric vessels. A laparotomy was performed, showing a very large uterus as well as torsion of the mesentery of the cecum with a sharp demarcated area of necrosis of the right hemicolon. DISCUSSION: Cecal volvulus due to a large uterine mass is a rare encountered clinical entity. The suggested mechanism might be the same mechanism causing cecal volvulus during pregnancy; the enlarged uterus raisingout the mobile cecum out of the pelvis. Obstruction may occur from kinking of the colon at a fixed point. CONCLUSION: This case demonstrates that uterine leiomyoma can be a cause of a cecal volvulus, leading to severe intestinal strangulation.

Infliximab exerts no direct hepatotoxic effect on HepG2 cells in vitro.

BACKGROUND: Infliximab-induced hepatotoxicity is reported in several case studies involving patients with inflammatory bowel disease (IBD) and a direct hepatotoxic effect has been proposed. OBJECTIVE: The aim of this study was to determine the direct in vitro toxicity of infliximab. As a proof of principle the in vitro toxicity of thiopurines and methotrexate was also determined. METHODS: Cell survival curves and the half maximal inhibitory concentrations (IC(50)) were obtained after 24, 48 and 72 h of incubation in HepG2 cells with the IBD drugs azathioprine, 6-mercaptopurine, 6-thioguanine, methotrexate or infliximab by using the WST-1 cytotoxicity assay. RESULTS: No in vitro hepatotoxicity in HepG2 cells was seen with infliximab, while concentration-dependent cytotoxicity was observed when HepG2 cells were incubated with increasing concentrations of azathioprine, 6-mercaptopurine and 6-thioguanine. CONCLUSION: Infliximab alone or given in combination with azathioprine showed no direct hepatotoxic effect in vitro, indicating that the postulated direct hepatotoxicity of infliximab is unlikely.

A functional polymorphism in UGT1A1 related to hyperbilirubinemia is associated with a decreased risk for Crohn's disease.

BACKGROUND: An imbalance between the production of reactive oxygen species (ROS) and their capturing by antioxidants results in oxidative stress, this may play an important role in the pathogenesis of inflammatory bowel disease (IBD). Since bilirubin is an important endogenous antioxidant, increased levels of bilirubin may protect against IBD. UDP-glucuronosyltransferase 1A1 (UGT1A1) is the only enzyme involved in the conjugation of bilirubin and the common UGT1A1*28 allele in the UGT1A1 gene, which is strongly associated with Gilbert's syndrome in Caucasians, results in elevated plasma bilirubin levels. AIMS: To test the hypothesis that the UGT1A1*28 allele is associated with lower disease susceptibility to, and disease behavior within, IBD. In addition, a possible altered risk for developing IBD-drug related side-effects was explored. METHODOLOGY: Genomic DNA of 751 patients with IBD (209 patients with ulcerative colitis and 542 patients with Crohn's disease) and 930 healthy controls was genotyped for the UGT1A1*28 promoter polymorphism, and genotype distribution was compared between patients and controls. Genotype phenotype interactions were also investigated. RESULTS: Patients with Crohn's disease significantly less often bear the UGT1A1*28 homozygous genotype compared to the control group, with an odds ratio of 0.64, 95% CI: 0.42-0.98. The ulcerative colitis group showed no significant differences compared to controls. CONCLUSION: The homozygous state of the UGT1A1*28 polymorphism, associated with higher serum bilirubin levels, may be protective for the development of Crohn's disease, suggesting that the anti-oxidant capacity of bilirubin may play a part.

Appropriate infliximab infusion dosage and monitoring: results of a panel meeting of rheumatologists, dermatologists and gastroenterologists.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Infliximab is an effective treatment for rheumatoid arthritis, ankylosing spondylitis, Crohn's disease (both adult and paediatric), ulcerative colitis, psoriatic arthritis and plaque psoriasis and national and international guidelines have been developed for each indication. WHAT THIS STUDY ADDS: This study is the first study which compared current international, national and local guidelines from the medical specialties involved in the treatment with infliximab on the following topics: indication, dosage, synergy and monitoring of vital signs. AIMS: Infliximab, an anti-TNF biologic agent, is currently indicated and reimbursed for rheumatoid arthritis, ankylosing spondylitis, Crohn's disease (both adult and paediatric), ulcerative colitis, psoriatic arthritis and plaque psoriasis. Development of national and international guidelines for rheumatology, gastroenterology and dermatology, was mostly based on clinical studies and expert opinion. The aim of this study was to compare available guidelines and local protocols for rheumatology, dermatology and gastroenterology, regarding dosage of infliximab, synergy of infliximab with concomitant medication and monitoring of vital signs during infliximab administration, for achieving optimal care. METHODS: Current international, national and local guidelines on the use of infliximab were reviewed and compared, differences and shortcomings were identified, and optimal treatment schedules discussed during a meeting (July 2008) of clinical experts and researchers from three departments of a Dutch university hospital. RESULTS: Recommended dosages of infliximab are not equal for different indications. Loss of response to infliximab is a common problem encountered within the three medical specialties, but indications for adjustments in treatment schedules are lacking in all of the guidelines. Monitoring of vital signs (blood pressure, pulse, temperature) during infusion with infliximab is common practice and recommended by some guidelines. Routine measurement of vital signs is not of any value in predicting or recognizing acute infusion reactions, in our experience, and this is confirmed by literature on inflammatory bowel disease. CONCLUSION: Different indications encompass different dosing schedules. National and internal guidelines do not provide advice regarding loss of response. Routine measurement of vital signs during infusion is not valuable in detecting acute infusion reactions and should only be performed in case of an acute infusion reaction. These topics need to be studied in future studies and covered in future guidelines.

The functional -765G→C polymorphism of the COX-2 gene may reduce the risk of developing crohn's disease.

BACKGROUND: Cyclooxygenase-2 (COX-2) is a key enzyme involved in the conversion of arachidonic acid into prostaglandins. COX-2 is mainly induced at sites of inflammation in response to proinflammatory cytokines such as interleukin-1α/ß, interferon-γ and tumor necrosis factor-α produced by inflammatory cells. AIM: The aim of this study was to investigate the possible modulating effect of the functional COX-2 polymorphisms -1195 A→G and -765G→C on the risk for development of inflammatory bowel disease (IBD) in a Dutch population. METHODS: Genomic DNA of 525 patients with Crohn's disease (CD), 211 patients with ulcerative colitis (UC) and 973 healthy controls was genotyped for the -1195 A→G (rs689466) and -765G→C (rs20417) polymorphisms. Distribution of genotypes in patients and controls were compared and genotype-phenotype interactions were investigated. RESULTS: The genotype distribution of the -1195A→G polymorphism was not different between the patients with CD or UC and the control group. The -765GG genotype was more prevalent in CD patients compared to controls with an OR of 1.33 (95%CI 1.04-1.69, p<0.05). The -765GC and -765CC genotype carriers showed a tendency to be less frequent in patients with CD compared to controls, with ORs of 0.78 (95%CI: 0.61-1.00) and 0.49 (95%CI 0.22-1.08), respectively. Combining homozygous and heterozygous patients with the -765C allele showed a reduced risk for developing CD, with an OR of 0.75 (95%CI: 0.59-0.96). In the context of this, the G(-1195)G(-765)/A(-1195)C(-765) diplotype was significantly less common in patients with CD compared to controls, with an OR of 0.62 (95%CI: 0.39-0.98). For UC however, such an effect was not observed. No correlation was found between COX-2 diplotypes and clinical characteristics of IBD. CONCLUSIONS: The -765G→C polymorphism was associated with a reduced risk for developing Crohn's disease in a Dutch population.

Genetic association analysis of the functional c.714T>G polymorphism and mucosal expression of dectin-1 in inflammatory bowel disease.

BACKGROUND: Dectin-1 is a pattern recognition receptor (PRR) expressed by myeloid cells that specifically recognizes beta-1,3 glucan, a polysaccharide and major component of the fungal cell wall. Upon activation, dectin-1 signaling converges, similar to NOD2, on the adaptor molecule CARD9 which is associated with inflammatory bowel disease (IBD). An early stop codon polymorphism (c.714T>G) in DECTIN-1 results in a loss-of-function (p.Y238X) and impaired cytokine responses, including TNF-alpha, interleukin (IL)-1beta and IL-17 upon in vitro stimulation with Candida albicans or beta-glucan. The aim of the present study was to test the hypothesis that the DECTIN-1 c.714T>G (p.Y238X) polymorphism is associated with lower disease susceptibility or severity in IBD and to investigate the level of dectin-1 expression in inflamed and non-inflamed colon tissue of IBD patients. METHODOLOGY: Paraffin embedded tissue samples from non-inflamed and inflamed colon of IBD patients and from diverticulitis patients were immunohistochemically stained for dectin-1 and related to CD68 macrophage staining. Genomic DNA of IBD patients (778 patients with Crohn's disease and 759 patients with ulcerative colitis) and healthy controls (n = 772) was genotyped for the c.714T>G polymorphism and genotype-phenotype interactions were investigated. PRINCIPAL FINDINGS: Increased expression of dectin-1 was observed in actively inflamed colon tissue, as compared to non-inflamed tissue of the same patients. Also an increase in dectin-1 expression was apparent in diverticulitis tissue. No statistically significant difference in DECTIN-1 c.714T>G allele frequencies was observed between IBD patients and healthy controls. Furthermore, no differences in clinical characteristics could be observed related to DECTIN-1 genotype, neither alone, nor stratified for NOD2 genotype. CONCLUSIONS: Our data demonstrate that dectin-1 expression is elevated on macrophages, neutrophils, and other immune cells involved in the inflammatory reaction in IBD. The DECTIN-1 c.714T>G polymorphism however, is not a major susceptibility factor for developing IBD.

Serious events with infliximab in patients with inflammatory bowel disease: a 9-year cohort study in the Netherlands.

BACKGROUND: The tumour necrosis factor-alpha inhibitor infliximab is incorporated in the treatment guidelines for patients with inflammatory bowel disease (IBD). However, concerns about serious adverse events such as infections, malignancies and death do exist. OBJECTIVE: To evaluate the occurrence of serious events of infliximab during 9 years in a single-centre cohort of patients with IBD. METHODS: Consecutive patients (>18 years) with a proven diagnosis of IBD who started treatment for IBD with infliximab at our referral centre in the Netherlands, from June 1999 to October 2007, were included. Infusion data were collected prospectively and medical records were reviewed retrospectively. All serious events were recorded and scored in the following categories: events leading to hospitalization, infections, malignancies and death. Severity and relationship to the use of infliximab were assessed for every serious event. RESULTS: 147 patients (33% male, mean age at first infusion 38 years, standard deviation = 12) received a total number of 1924 infusions (median per patient = 10, range 1-70). A total of 89 patients (61%) were hospitalized during follow-up, involving a total of 300 hospitalizations. Of these, 60 hospitalizations (20%) were considered at least possibly related to the use of infliximab. In 21 hospitalizations, the occurrence of a serious infection was considered at least possibly related to infliximab. Of all hospitalized patients, 70 patients (79%) underwent 139 surgical procedures, of which 70 surgeries (50%) were gastrointestinal related. Nine patients (6%) developed malignancies during follow-up: four colorectal carcinomas, one carcinoid tumour with another primary signet-ring cell carcinoma of the small bowel, one breast cancer, two skin cancers and one superficial melanoma. During follow-up, eight patients (5%) died: six as a result of malignancies, one patient as a result of a complication of short bowel syndrome and one patient due to unknown reasons. Patients who developed malignancies tended to have a longer disease duration than those who did not. CONCLUSION: Clinicians prescribing biological therapies should be aware of the development of serious events in their patients. Thorough follow-up of all patients during treatment with infliximab is warranted. If infliximab is considered in patients with IBD not responding to conventional treatment, efforts to exclude other possible underlying causes for worsening of symptoms should be made. Careful prescribing and monitoring during follow-up remains necessary.