Wolfgang H. Schraut

Infliximab Prevents Crohn's Disease Recurrence After Ileal Resection

BACKGROUND & AIMS Crohns disease commonly recurs after intestinal resection. We evaluated whether the administration of infliximab after resective intestinal surgery for Crohns disease reduces postoperative recurrence. METHODS We randomly assigned 24 patients with Crohns disease who had undergone ileocolonic resection to receive intravenous infliximab (5 mg/kg), administered within 4 weeks of surgery and continued for 1 year, or placebo. The primary end point was the proportion of patients with endoscopic recurrence at 1 year. Secondary end points were clinical recurrence and remission and histologic recurrence. RESULTS The rate of endoscopic recurrence at 1 year was significantly lower in the infliximab group (1 of 11 patients; 9.1%) compared with the placebo group (11 of 13 patients; 84.6%) (P = .0006). There was a nonsignificant higher proportion of patients in clinical remission in the infliximab group (8 of 10; 80.0%) compared with the placebo group (7 of 13; 53.8%) (P = .38). The histologic recurrence rate at 1 year was significantly lower in the infliximab group (3 of 11 patients; 27.3%) compared with the placebo group (11 of 13 patients; 84.6%) (P = .01). The occurrence of adverse events was similar between the placebo and infliximab groups, and none occurred in the immediate postoperative period. CONCLUSIONS Administration of infliximab after intestinal resective surgery was effective at preventing endoscopic and histologic recurrence of Crohns disease.

Role of inducible nitric oxide synthase in postoperative intestinal smooth muscle dysfunction in rodents

BACKGROUND & AIMS We have shown that intestinal manipulation leads to a significant inhibition of circular muscle contraction. We hypothesized that the inflammatory mediator inducible nitric oxide (NO) plays a role in surgically induced ileus. METHODS Rats and inducible NO synthase (iNOS) knockout and wild-type mice underwent a simple intestinal manipulation. Reverse-transcription polymerase chain reaction and immunohistochemistry were used to detect and localize iNOS expression. Nitrite and NO production were measured in muscularis cultures. Spontaneous and bethanechol-stimulated jejunal circular muscle contractions were measured in an organ bath. RESULTS Intestinal manipulation resulted in significant iNOS messenger RNA induction in mucosa and muscularis. Immunohistochemistry localized iNOS in phagocytes within the muscularis. Nitrite and NO production increased 59.8-fold 24 hours after manipulation. L-n(6)-(1-iminoethyl) lysine (L-NIL) inhibited this response. In control rats, selective iNOS inhibition did not increase spontaneous muscle activity, but after manipulation L-NIL significantly improved spontaneous activity. iNOS knockout mice showed a significant 81% decrease in neutrophil infiltration into the muscularis after intestinal manipulation compared with wild-types. Contractile activity was normal in knockout mice after intestinal manipulation. CONCLUSIONS These results show that leukocyte-derived inducible NO inhibits gastrointestinal motility after manipulation and plays an essential role in the initiation of intestinal inflammation.

Intra-Abdominal Activation of a Local Inflammatory Response Within the Human Muscularis Externa During Laparotomy

ObjectiveTo investigate the initiation of a complex inflammatory response within the human intestinal muscularis intraoperatively so as to determine the clinical applicability of the inflammatory hypothesis of postoperative ileus. Summary Background DataMild intestinal manipulation in rodents initiates the activation of transcription factors, upregulates proinflammatory cytokines, and increases the release of kinetically active mediators (nitric oxide and prostaglandins), all of which results in the recruitment of leukocytes and a suppression in motility (i.e., postoperative ileus). MethodsHuman small bowel specimens were harvested during abdominal procedures at various times after laparotomy. Histochemical and immunohistochemical techniques were applied to intestinal muscularis whole-mounts. Reverse transcriptase–polymerase chain reaction (RT-PCR) was performed for interleukin (IL)-6, IL-1&bgr;, tumor necrosis factor (TNF)-&agr;, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Signal transducers and activators of transcription (STAT) protein phosphorylation was determined by electromobility shift assay. Organ bath experiments were performed on jejunal circular smooth muscle strips. GW274150C and DFU were used in vitro as iNOS and COX-2 inhibitors. ResultsNormal human muscularis externa contained numerous macrophages that expressed increased lymphocyte function associated antigen-1 (LFA-1) immunoreactivity as a function of intraoperative time. RT-PCR demonstrated a time-dependent induction of IL-6, IL-1&bgr;, TNF-&agr;, iNOS, and COX-2 mRNAs within muscularis extracts after incision. Mediators were localized to macrophages with STAT protein activation in protein extracts demonstrating local IL-6 functional activity. DFU alone or in combination with GW274150C increased circular muscle contractility. Specimens harvested after reoperation developed leukocytic infiltrates and displayed diminished in vitro muscle contractility. ConclusionsThese human data demonstrate that surgical trauma is followed by resident muscularis macrophage activation and the upregulation, release, and functional activity of proinflammatory cytokines and kinetically active mediators.

Biphasic response to gut manipulation and temporal correlation of cellular infiltrates and muscle dysfunction in rat

BACKGROUND Surgical manipulation of the intestine results in the massive movement of leukocytes into the intestinal muscularis at 24 hours. This is associated with muscle inhibition. The aim of this study was to temporally associate leukocyte extravasation with ileus after surgical manipulation. METHODS Rats underwent a simple manipulation of the small bowel and were killed at various times (0, 0.25, 0.5, 1, 3, 6, 12, and 24 hours) postoperatively. Jejunal circular-muscle contractile activity was assessed in a standard organ bath. Both extravasating and resident leukocytes were immunohistochemically stained in muscularis whole mounts. RESULTS Contractile activity was significantly reduced immediately after surgery, but rapidly returned to control levels at 3 hours. After recovery, muscle function decreased at 12 and 24 hours (41% and 81%, respectively). The resident muscularis macrophage network demonstrated cellular activation 1 hour postoperatively. The number of leukocytes increased over time (neutrophils, 67.5-fold; monocytes, 98.2-fold; and mast cells, 47-fold at 24 hours). CONCLUSIONS The functional results demonstrate a biphasic response in the suppression of muscle activity after surgical manipulation. Regression analysis (r2 = 0.998) of the temporal development of leukocyte infiltration and the protracted phase of muscle inhibition provides evidence for a correlation between cellular inflammation and postoperative dysmotility.

Pathogenesis of pancreatic sepsis

Although pancreatic sepsis is the most common cause of major morbidity and mortality associated with acute pancreatitis, the pathogenesis of such infections is unknown. Since intraperitoneal foci of inflammation are known to promote bacterial translocation, we hypothesized that acute pancreatitis promotes bacterial translocation that leads to infection of the inflamed pancreas and peripancreatic tissues. Non-lethal acute pancreatitis was induced in rats, and the translocation of live bacteria to the pancreas, mesenteric lymph nodes, liver, and spleen was determined. The presence of orally fed fluorescent beads, sensitive inert markers of translocation, was also determined in the pancreas and mesenteric lymph nodes. Live bacteria were recovered from 33% of the pancreata of rats with acute pancreatitis but from none of the control rats. Beads were visualized in 91% of the pancreata of rats with acute pancreatitis but in none of the pancreata from control rats. Beads were not visualized in the mesenteric lymph nodes of rats with acute pancreatitis, suggesting a transperitoneal route of migration. We conclude that acute pancreatitis promotes bacterial translocation leading to transperitoneal infection of the pancreas. These results support the use of selective decontamination of the gut and peritoneal lavage for the prevention of pancreatic infections in acute pancreatitis.

Comparison of laparoscopic versus open repair of paraesophageal hernia

BACKGROUND Recent reports suggest that laparoscopic paraesophageal hernia repair (LPHR) is feasible, but no direct comparisons with the standard open paraesophageal hernia repair (OPHR) have been reported. The purpose of this study was to compare the short-term outcome of LPHR versus OPHR at a single institution. METHODS The operative and postoperative courses of 95 consecutive patients undergoing open or laparoscopic repair of a paraesophageal hernia (PEH) were retrospectively reviewed, and outcomes of LPHR versus OPHR were compared. RESULTS PEH was associated with advanced age and significant comorbidity. Although the operative time was increased for LPHR, there was a significant reduction in blood loss, intensive care unit stay, ileus, hospital stay, and overall morbidity associated with LPHR compared with OPHR. CONCLUSIONS PEH is associated with significant comorbidity that increases the operative risk. Short-term outcomes for LPHR are superior to OPHR, suggesting that the laparoscopic approach is the preferred approach to paraesophageal hernia repair.

Leukocytes of the intestinal muscularis: their phenotype and isolation.

The basal presence of immunologically potent cells within the intestinal muscularis externa and their functional significance is unclear. Our aim was to investigate the basal distribution of various leukocyte populations within the rat jejunal muscularis. In addition, we sought to immunohistochemically phenotype the muscularis macrophage in jejunal whole‐mounts, isolate these cells in primary culture, and investigate their ontogenesis. Macrophages form a regularly distributed network that expresses major histocompatibility complex class II, CD14 receptors, and a low level of CD11/ CD18. The macrophages are activated by dissection and are present in fetal animals. Enriched macrophage cultures show a normal resident phenotype and remain present for weeks in dissociated muscularis cultures. The results also demonstrate the presence of neutrophils, monocytes, mast cells, and lymphocytes within the muscularis and suggest that the dense network of muscularis macrophages may be a potent resident trigger for inflammation in response to tissue injury or bacterial translocation. J. Leukoc. Biol. 63: 683–691; 1998.

Small bowel allografts: sequence of histologic changes in acute and chronic rejection

Using a rat model of accessory small bowel transplantation, the histologic sequence of both acute and chronic rejection in intestinal allograft rejection has been defined. Histologically, all allografts were normal for the first 5 postoperative days. Allografts with caval venous drainage were subject to acute rejection. By 6 to 7 days postoperatively, plasma cells and lymphocytes infiltrated the lamina propria of these grafts (phase I). By 8 to 9 days postoperatively, the cellular infiltration intensified and was associated with villous blunting and scattered epithelial sloughing (phase II). By the 10th day, complete mucosal destruction developed, with heavy transmural infiltration by lymphocytes, plasma cells, and polymorphonuclear leukocytes (phase III). This histologic end point of acute graft rejection was accompanied by death of the host. Grafts with portal venous drainage underwent a similar, although less rapid, sequence of histologic changes (phase I 6 to 9 days, phase II 10 to 13 days, phase III 13 or more days) resulting in graft fibrosis and encapsulation. Some variability was seen among different areas of a given circumferential cross section taken from grafts in phases I and II. Studying circumferential cross sections allowed correct classification into the appropriate phases.

Current status of small-bowel transplantation

Patients who have lost such a large portion of their small bowel that they permanently require total parenteral nutrition for survival would greatly benefit by receiving a small-intestinal transplant. Over the past two decades, many experimental studies have delineated the specific problems surrounding small-bowel transplantation and provided strategies for their control. Control of rejection, the most difficult problem, may be achieved with a combination of cyclosporine, azathioprine, prednisone, antithymocyte globulin, and monoclonal antibodies. The threat of graft-versus-host disease originating from the allogeneic lymphatic tissues in the allograft is abolished by in vitro x-irradiation of the cold, nonperfused graft with 1000 rads. Monitoring of the intestinal allograft is possible with the combination of a function test (maltose absorption, glucose absorption, or any other function test) and repeated graft biopsy. Effective short-term preservation of small-bowel segments for up to 18 h is possible by intravascular flushing with a balanced electrolyte solution containing 3% fructose and by subsequent hypothermic storage. Clinical small-bowel transplantation is certainly not an imminent therapeutic tool. However, clinical trials in highly selected patients could be envisioned on the basis of our present understanding of small-bowel transplantation and of transplantation biology in general, and in view of the clinical successes achieved with duodenal grafts transplanted in conjunction with pancreatic grafts.

Depth of invasion, location, and size of cancer of the anus dictate operative treatment

Review of 47 patients with carcinoma of the anus demonstrated that perianal squamous cell carcinoma (16 patients) occurred as a small, in situ/microinvasive lesion more often than did squamous/cloacogenic carcinoma of the anal canal (31 patients). Metastatic lymph node involvement was associated only with anal‐canal lesions (13 of 31 patients). When survival time was examined as a function of tumor extent (depth of invasion, size), however, the prognosis was the same for both types of lesions. Grouping of the anal‐canal lesions into those of the squamous cell and the cloacogenic variety did not demonstrate any differences in outcome. Local excision was successful in each instance for in situ/microinvasive tumors (all were 2 cm or less in diameter), but failed for invasive lesions, even if they were small. Abdominoperineal resection for invasive (26 patients) and for larger microinvasive lesions (three patients) was followed by a 59% five‐ to ten‐year survival. When lesions with lymph node involvement were excluded, the survival rates for perianal (80%) and anal‐canal carcinoma (82%) were similar. The addition of hypogastric lymph node dissection to abdominoperineal resection is indicated for invasive anal‐canal carcinomas; we attribute the long‐term survival of three patients with hypogastric‐node involvement to this extended procedure. The presence of metastatic deposits in inguinal lymph nodes was a grave prognostic sign; all six patients with this finding died within five years. The study concludes that the operative treatment of anal carcinoma can be based on the size and, in particular, the depth of invasion of the lesion and that the histologic type is of limited significance. If local excision is considered, its choice must be guided, for technical reasons, by the location and size of the tumor.