Andreas D. Rink

Antibodies Against Tumor Necrosis Factor (TNF) Induce T-Cell Apoptosis in Patients With Inflammatory Bowel Diseases via TNF Receptor 2 and Intestinal CD14+ Macrophages

BACKGROUND & AIMS The anti-tumor necrosis factor (TNF) antibodies infliximab, adalimumab, and certolizumab pegol have proven clinical efficacy in Crohns disease. Here, we assessed the effects of anti-TNF antibodies on apoptosis in inflammatory bowel disease (IBD). METHODS CD14(+) macrophages and CD4(+) T cells were isolated from peripheral blood and lamina propria mononuclear cells from patients with IBD and control patients. Cell surface markers and apoptosis were assessed by immunohistology and fluorescence-activated cell sorting techniques. RESULTS Lamina propria CD14(+) macrophages showed significantly more frequent and higher membrane-bound TNF (mTNF) expression than CD4(+) T cells in IBD, whereas mTNF-dependent signaling proteins such as TNF receptor (TNFR) 2, TNFR-associated factor (TRAF) 2, and nuclear factor κB were induced in IBD mucosal CD4(+) T cells. Most anti-TNF antibodies did not induce T-cell apoptosis in purified peripheral or mucosal CD4(+) T cells. However, in contrast to etanercept, administration of all clinically effective anti-TNF antibodies resulted in a significant induction of T-cell apoptosis in IBD when lamina propria CD4(+) T cells expressing TNFR2(+) were cocultured with mTNF(+) CD14(+) intestinal macrophages. In contrast, no effects in control patients were noted. T-cell apoptosis in IBD occurred in vivo after treatment with adalimumab and infliximab, was critically dependent on TNFR2 signaling, and could be prevented via interleukin-6 signal transduction. Blockade of interleukin-6R signaling augmented anti-TNF-induced T-cell apoptosis in IBD. CONCLUSIONS Clinically effective anti-TNF antibodies are able to induce T-cell apoptosis in IBD only when mucosal TNFR2(+) T cells are cocultured with mTNF-expressing CD14(+) macrophages. The finding that anti-TNF antibodies induce apoptosis indirectly by targeting the mTNF/TNFR2 pathway may have important implications for the development of new therapeutic strategies in IBD.

Achalasia—If Surgical Treatment Fails: Analysis of Remedial Surgery

IntroductionHeller myotomy leads to good–excellent long-term results in 90% of patients with achalasia and thereby has evolved to the “first-line” therapy. Failure of surgical treatment, however, remains an urgent problem which has been discussed controversially recently.Materials and MethodsA systematic review of the literature was performed to analyze the long-term results of failures after Heller’s operation with emphasis on treatment by remedial myotomy.DiscussionOther reinterventions and their causes after failure of surgical treatment in patients with achalasia are discussed.

Pharmacokinetics and Tissue Penetration of Moxifloxacin in Intervention Therapy for Intra-Abdominal Abscess

AbstractBackground and objective: Intra-abdominal abscesses are usually polymicrobial and involve a variety of aerobic and anaerobic organisms. Thus, in addition to adequate drainage, empirical coverage with broad-spectrum antimicrobials is central to the management of such abscesses and an understanding of pharmacokinetic properties can be valuable when selecting antimicrobial agents. The present study examined the penetration of the fluoroquinolone antimicrobial moxifloxacin into abdominal abscess fluid in patients with an intra-abdominal abscess. Methods: This was a non-randomized, open-label, single-centre trial. Eight patients with CT or ultrasound evidence of a localized intra-abdominal abscess requiring interventional drainage without signs of generalized peritonitis were considered suitable candidates for pharmacokinetic analysis. Each patient received a single dose of moxifloxacin 400 mg by intravenous infusion. Paired samples of blood and abscess fluid were collected over 24 hours for pharmacokinetic analysis. Results: Following intravenous infusion, moxifloxacin penetrated and accumulated in intra-abdominal abscess fluid. The abscess fluid/plasma concentration ratio increased continuously from 0.083 (95% CI 0.047, 0.147) at 2 hours after administration to 1.66 (95% CI 0.935, 2.946) at 24 hours; concentrations in abscess fluid tended to exceed those in plasma after 12–24 hours. Half-life and mean residence time were longer in abscess fluid than in plasma, suggesting that moxifloxacin accumulates in abscess fluid. The abscess fluid/plasma concentration ratio continued to increase throughout the 24-hour sampling period, indicating that equilibrium between plasma and abscess fluid was not reached during this time. High intersubject variability for total moxifloxacin concentrations in intra-abdominal abscess fluid was noted, suggesting that abscess wall permeability is likely to be the parameter most strongly influencing moxifloxacin pharmacokinetics in abscess fluid. Comparison of the study results with data obtained from other in vitro studies suggested that abscess fluid concentrations above the minimum inhibitory concentrations for pathogens commonly isolated in intra-abdominal infections were maintained for approximately 8 hours after administration in this study. Conclusions: Moxifloxacin penetrates intra-abdominal abscesses after interventional drainage. Based on the pharmacokinetic data, moxifloxacin is a good candidate therapy for use in patients with intra-abdominal abscesses undergoing CT-guided percutaneous drainage and may also prove valuable in the general systemic management of intra-abdominal abscesses in the future.

Does Mesorectal Preservation Protect the Ileoanal Anastomosis after Restorative Proctocolectomy

Background and aimsThe technique of rectal dissection during restorative proctocolectomy might influence the rate of septic complications. The aim of this study was to analyze the morbidity of restorative proctocolectomy in a consecutive series of patients who had rectal dissection with complete preservation of the mesorectum.Patients and methodsOne hundred thirty-one patients who had restorative proctocolectomy for chronic inflammatory bowel disease with handsewn ileopouch-anal anastomosis (IPAA) and preservation of the mesorectal tissue were analyzed by chart reviews and a follow-up investigation at a median of 85 (14–169) months after surgery.ResultsOnly one of 131 patients had a leak from the IPAA, and one patient had a pelvic abscess without evidence of leakage, resulting in 1.5% local septic complications. All other complications including the pouch failure rate (7.6%) and the incidence of both fistula (6.4%) and pouchitis (47.9%) were comparable to the data from the literature.ConclusionThe low incidence of local septic complications in this series might at least in part result from the preservation of the mesorectum. As most studies do not specify the technique of rectal dissection, this theory cannot be verified by an analysis of the literature and needs further approval by a randomized trial.

Differences in ano‐neorectal physiology of ileoanal and coloanal reconstructions for restorative proctectomy

Objective  Restorative proctectomy with straight coloanal anastomosis (CAA) and restorative proctocolectomy with ilealpouch‐anal anastomosis (IPAA) are options for maintaining bowel integrity after rectal resection. The aim of this study was to compare clinical function and anorectal physiology in patients treated with CAA and IPAA.

Beneficial effect of H2-agonism and H1-antagonism in rat endotoxic shock.

Although histamine release is generally considered harmful in endotoxic shock, several data exist to doubt this view. Own previous studies in rats let us assume a possible beneficial effect only with H1−antagonists, however a detrimental effect on survival with H2−antagonists. Consequently H1− and H2−agonists and antagonists were studied to prove the hypothesis of a beneficial H2−agonistic and H1−antagonistic effect. Two randomized studies were performed in a standardized rat endotoxic shock model (45 mg of Escherichia coli endotoxin/kg body weight (b.w.)). In both, methylprednisolone (50 mg/kg b.w.) and saline were used as positive and negative controls, respectively. Study I compared the effects of H1− and H2−agonists (betahistine, .1 mg/kg/h, and impromidine, 100 μg/kg/h) with H1− and H2−antagonists (astemizole and famotidine both 1 mg/kg b.w.; 20 rats/dose). Study II was performed to estimate the dose-response relationship of a new, highly potent H2−agonist with additional H1−antagonistic features (BU-E 75: .01, .1, 1.0, 10, and 100 μg/kg/h; 20 rats/dose). Animals receiving impromidine or BU-E 75 all received omeprazole (1 μol/kg b.w.) to suppress gastric acid secretion. In study I impromidine significantly increased the survival-time and -course compared to famotidine treated animals (p = .01 and p < .05). Study II showed a positive dose-response relationship of BU-E 75 with an increase in survival rates from 30% (.01 μg/kg/h) to 70% (100 μg/kg/h). These data strongly support the hypothesis of a beneficial effect of H2−agonism and H1−antagonism on survival parameters in rat endotoxic shock.

Laparoscopic-Assisted or Laparoscopic-Facilitated Sigmoidectomy for Diverticular Disease? A Prospective Randomized Trial on Postoperative Pain and Analgesic Consumption

PURPOSE: Laparoscopic-assisted sigmoidectomy is an attractive but sometimes challenging operative technique for the treatment of diverticulitis of the sigmoid colon. The aim of this study was to compare, with respect to early postoperative analgesic demand and postoperative pain, laparoscopic-assisted sigmoidectomy with a laparoscopic-facilitated technique. In the laparascopic-facilitated technique, the sigmoid colon is removed conventionally via a cosmetically inconspicuous incision after prior laparoscopic mobilization. PATIENTS AND METHODS: Patients subjected to elective sigmoidectomy for diverticulitis were randomized to either laparoscopic-assisted or laparoscopic-facilitated sigmoidectomy. All patients had piritramide-based, patient-controlled analgesia. The cumulative postoperative consumption over 96 hours was defined as the primary end point. Postoperative pain, fatigue, pulmonary function, and resumption of bowel function were secondary endpoints. RESULTS: Forty-five patients were randomized according to the protocol to laparoscopic-assisted sigmoidectomy (n = 22) or laparoscopic-facilitated sigmoidectomy (n = 23). The analgesic consumption between the two groups was equivalent (61.3 (9–171) mg piritramide/96 hours vs. 64.3 (18–150) mg piritramide/96 hours; P = 0.827). Patients with laparoscopic-assisted sigmoidectomy had lower pain levels on Day one and Day two. Cumulative pain levels over 96 hours and over the whole 7-day observation period, however, were not significantly different, although postoperative fatigue and pulmonary function were significantly different. Duration of surgery was slightly shorter for laparoscopic-assisted sigmoidectomy (127 (47–200) vs. 135 (60–239) minutes; P = 0.28), but recovery of bowel activity was faster after laparoscopic-facilitated surgery. There was no significant difference in morbidity. CONCLUSION: Overall, the postoperative outcome was roughly equivalent after both techniques of laparoscopic sigmoidectomy. Therefore, laparoscopic-facilitated sigmoidectomy could be considered as an alternative to laparoscopic-assisted sigmoidectomy in technically difficult cases of diverticulitis subjected to laparoscopic surgery.

Technische Aspekte der laparoskopischen Heller-Myotomie bei der Achalasie

Minimally invasive surgery has influenced the treatment of achalasia more than that of any other gastrointestinal disorder. Laparoscopic Heller myotomy has thus evolved to the first-line therapy in patients with achalasia and led to a significant change in the treatment algorithm of this disorder. The aim of this article is to present technical aspects and pitfalls of Heller myotomy with combined antirefluxplasty. After injection of 0.9% NaCl into the muscularis and submucosa of the distal esophagus and proximal fundus, whereby the submucosal layer can be easily separated from the mucosa, myotomy of the longitudinal and circular musculature is performed up to 6-7 cm proximally to the esophagogastric junction and completed distally by 1.5-2 cm onto the fundus. We prefer the 180 degrees anterior semifundoplication according to Dor as antirefluxplasty, which is sutured in a two-rowed manner into the two sites of the myotomy. The pitfalls are incomplete myotomy, especially at its distal, fundic site, with consecutive persistence or recurrence of symptoms, as well as occult mucosal perforations, which can be detected by intraoperative endoscopy.

Lymph node harvest in single incision laparoscopic surgery for colorectal malignancy

Single incision laparoscopic surgery (SILS) has not been sufficiently evaluated with respect to its oncological equivalence to conventional laparoscopic or open surgery.

The colon J-pouch as a cause of evacuation disorders after rectal resection: myth or fact

BackgroundColon J-pouch (JCP) reconstructions result in a better functional outcome than straight coloanal anastomosis (SCA) in terms of continence and frequency of defecation after rectal resection but might be associated with more evacuation difficulties. In order to evaluate this hypothesis, we systematically reviewed the literature to collect data on evacuation disorders after rectal resection in randomized or otherwise comparative trials.Materials and methodsRandomized controlled trials and comparative trials evaluating CJP versus SCA, latero-terminal anastomosis (LTA), and transverse coloplasty pouch (TCP) were ascertained by methodical search using Medline, Embase, and PubMed. Pooled estimates of outcomes were calculated for early-, intermediate-, and long-term follow-up. Primary meta-analysis outcomes were sensation of incomplete evacuation, prolonged evacuation, use of laxatives, use of enemas and suppositories, and stool fragmentation.ResultsWhen compared to SCA, CJP was associated with significantly less “prolongation of evacuation” but more “use of laxatives” in the intermediate-term follow-up, while both less “sensation of incomplete evacuation” and less “fragmentation” was found after CJP in the long-term. When compared to TCP, CJP was associated with significantly less fragmentation in the intermediate-term follow-up.ConclusionsEvacuation disorders are a unique problem of low anterior resection and are not specifically related to the colon J-pouch.