[Role of anastomotic configuration in ileocolic resection for Crohn's disease]. / Ruolo della configurazione anastomotica nella resezione ileocolica per malattia di Crohn.

Crohn's disease is characterised by a high incidence of perianastomotic recurrence after ileocolic resection. The influence of the anastomotic configuration on the incidence of reoperation was evaluated in patients undergoing resection for Crohn's disease. In our Institution, from 1993 to 2007, 308 consecutive patients affected by ileocolic Crohn's disease were submitted to 343 ileocolic resections or right colectomies. In 292 cases (85.1%), an antiperistaltic side-to-side (or functional end-to-end) anastomosis was performed, with an 80 mm linear stapler in 190 cases, a 100 mm linear stapler in 79, and a hand-sewn anastomosis in 23. The other hand-sewn anastomotic configurations were: 30 (8.8%) side-to-side isoperistaltic, 15 (4.3%) end-to-side and 6 (1.8%) end-to-end. The overall morbidity was 7.3%, with two postoperative deaths (0.6%) with no significant differences between groups. There were 38 overall recurrences (11%). In the side-to-side antiperistaltic group, the rate of recurrence was 8.2%, significantly lower than the recurrence rates observed in the other anastomoses (26.9%, p = 0.002), especially side-to-side isoperistaltic anastomosis (33.3%, p = 0.001). Early recurrences (< 1-year) were 2.6%, without significant differences between groups. There was a higher trend for end-to-end anastomosis (16.6%). In the side-to-side antiperistaltic group the morbidity was higher in the large mechanical anastomoses (100 mm length), but the recurrence rate was lower in this group as compared to the 80 mm anastomoses (1.2% vs. 12.1%, p = 0.006). Our non-randomised study suggests a better trend for the wide side-to-side antiperistaltic technique in terms of recurrence rate. These observations need further investigation with randomised controlled trials to compare the different anastomotic procedures.

Does stapled functional end-to-end anastomosis affect recurrence of Crohn's disease after ileocolonic resection?

BACKGROUND/AIMS: Crohn's disease is characterized by a high incidence of perianastomotic recurrence after ileocolonic resection. The influence of anastomotic configuration on the incidence of reoperation was evaluated in patients undergoing resection for Crohn's disease. METHODOLOGY: 106 patients affected by ileocolonic Crohn's disease were divided in two groups: group I with a hand-sewn end-to-side or side-to-side isoperistaltic anastomosis (30 patients) and group II with functional end-to-end anastomosis made with linear staplers (76 patients). RESULTS: The morbidity was 4.7%: 3 complications and a postoperative death occurred in group I and two complications occurred in group II. There were 5 recurrences (16.7%) in the hand-sewn group and 2 recurrences (2.6%) in the stapled group, with a recurrence rate of 3.54 and 0.92, respectively. CONCLUSIONS: Our non-randomized study suggests a better trend toward the functional stapled technique, in terms of recurrence rate. These observations need further investigation with randomized controlled trials, to compare the two different anastomotic procedures.

Postoperative chemoradiotherapy in rectal cancer. Late results of a pilot study.

BACKGROUND/AIMS: It has recently been proven that postoperative radiotherapy combined with fluorouracil showed an increase of survival and local control in patients with rectal cancer. However, hematological and intestinal toxicity also increased. Experimental and clinical studies showed an increased radiation effect with an acceptable toxicity by delivering drug via a continuous intravenous infusion. METHODOLOGY: From 1988 to 1998, 80 patients radically operated on for stages B2-C rectal cancer were irradiated with 3 fractions of 100 cGy per day to a total dose of 5,600 cGy. 34 out of these 80 patients underwent postoperative radiotherapy alone and 46 received radiotherapy combined with concomitant protracted infusion of fluorouracil at doses of 250 mg/m2 per day. RESULTS: After a median follow-up of 54 months, the 5-year overall and disease-free survival were 59% and 54%, respectively, in the combined modality group, as compared to 42% and 34%, respectively, in the radiation alone group. The differences were not significant, but the incidence of local relapse and patients' survival showed a better trend for combined approach. CONCLUSIONS: The data from international literature are in favor of a combined approach, both in preoperative and postoperative treatment of advanced rectal cancer. Adjuvant therapy must be re-evaluated in trials using total mesorectal excision as the standard operative technique.

[Anastomosis dehiscence in anterior resection of the rectum with total excision of the mesorectum]. / Deiscenze anastomotiche nelle resezioni anteriori del retto con escissione totale del mesoretto.

Anterior rectal resection with total mesorectal excision is currently regarded as the operation of choice in patients with neoplasms of the extraperitoneal rectum. This operation is associated with a significant incidence of anastomotic dehiscence. Some authors, therefore, advise the execution of a protective stoma. From 1987 to 2000, 241 patients with rectal neoplasma were submitted to radical surgery: 183 to anterior rectal resection (extraperitoneal neoplasms in 129 cases and intraperitoneal neoplasms in 54) and 58 to a Miles operation. The total incidence of anastomotic complications was 8.1% (15 patients). In 12 cases (6.5%) a clinical dehiscence was observed, while in 3 patients (1.6%) an asymptomatic fistula was present. In the patients with symptomatic dehiscence a colostomy was performed in 5 cases (42%), while in 7 cases (58%) a conservative approach was adopted (total parenteral nutrition and antibiotic therapy), with complete healing of the fistula. The incidence of anastomotic complications was 9.3% in extraperitoneal neoplasms and 5.6% in intraperitoneal localizations. In relation to the anastomotic technique adopted, the incidence of dehiscences was 25% after 8 Knight-Griffen anastomoses, 16% after 12 manual anastomoses and 7.3% after 163 end-to-end mechanical anastomoses (P = NS). The percentage of anastomotic complications was greater in the period from 1995 to 1997, compared to the period from 1987 to 1994 (12.6% vs 3.8%, P = NS), due to the routine execution of rectal resection in conjunction with total mesorectal excision, particularly at the beginning of the experience, in 1995. In the last 36 cases from 1998 on the incidence of anastomotic complications was reduced to 8.3%, after the learning phase. No related mortality was observed. On the basis of our experience and the evidence reported in the international literature we do not think the execution of a protective stoma is justified after low and ultra-low colorectal anastomosis, except in selected cases.

Postoperative chemoradiotherapy in rectal cancer. Long-term results of a pilot study.

It has recently been proven that postoperative radiotherapy combined with fluorouracil affords an increase in survival and local control in patients with rectal cancer. However, haematological and intestinal toxicity also increase. Experimental and clinical studies have shown an increased effect of radiation with an acceptable toxicity by delivering the drug via continuous intravenous infusion. From 1988 to 1998, 80 patients radically operated on for stage B2-C rectal cancer were irradiated with 3 fractions of 100 cGy per day up to a total dose of 5,600 cGy; 34 of these patients underwent postoperative radiotherapy alone and 46 received radiotherapy combined with concomitant protracted infusion of fluorouracil at doses of 250 mg/m2 per day. After a median follow-up of 60 months, the 5-year overall and disease-free survival rates were 59% and 54%, respectively, in the combined modality group, as compared to 42% and 34%, respectively, in the radiation alone group. The differences were non-significant, but the incidence of local relapse and patient survival showed better trends with the combined approach. The international literature data are in favour of a combined approach in both the preoperative and postoperative treatment of advanced rectal cancer. Adjuvant therapy needs to be re-assessed in trials using total mesorectal excision as the standard operative technique.

Adenocarcinoma below stapled ileoanal anastomosis after restorative proctocolectomy for ulcerative colitis.

A case of adenocarcinoma arising in a 39-year-old patient after restorative proctocolectomy is reported. The patient underwent an ileal pouch-anal anastomosis with double-stapled technique for severe ulcerative colitis 18 years earlier, without evidence of associated neoplasm or dysplasia in operative specimen. After endoscopic diagnosis of adenocarcinoma, the patient was submitted to excision of the pouch and permanent ileostomy, followed by combined radiotherapy and chemotherapy. Pathology showed an AJCC stage III moderately differentiated mucinous adenocarcinoma. The patient died 24 months after the operation, due to cancer progression. There are 50 reported cases in the indexed medical literature of carcinoma arisen after ileal pouch-anal anastomosis for ulcerative colitis. Twenty-five out of these arose after mucosectomy and hand-sewn anastomosis, and 25 after stapling technique. Furthermore, in 48% of the patients, dysplasia or cancer was already present at the time of the colectomy. The increase of reported cases suggests a routine long-term endoscopic surveillance in patients with long-standing ileal pouches, especially in presence of dysplasia or cancer in the proctocolectomy specimen.

Biliodigestive anastomosis with circular mechanical device after pancreatoduodenectomy: our experience.

The authors describe the technique to perform a mechanical biliodigestive anastomosis after pancreatoduodenectomy that could be able to reduce the time of surgical intervention and the major systemic postoperative complication especially in elderly patients. Pancreaticoduodenectomy (PD) is considered to be the most effective procedure for the treatment of tumors of the pancreatic head and periampullary tumors. Postoperative morbidity remains high, reaching 40-50% in some series. Leakage and stricture of hepaticojejunal anastomosis have a special significance and occur in 2.5-5% of cases. The usefulness of mechanical staplers is well established in gastric and colorectal surgery, but their use in creating biliodigestive anastomosis is still a very controversial application. In the last 2 years (Nov 2008-Nov 2010), seven patients who underwent PD and presented at the time of operation, a main bile duct (MBD) greater of 20 mm, received a mechanical biliodigestive anastomosis with surgical stapler. All the patients were postoperatively controlled with an ultrasonography at 3 and 6 months, and a cholangio MRI at 1 year from operation. The follow up of the seven patients ranged from 3 to 18 months. Six patients are still alive and free of oncologic disease. One patient presented a single episode of cholangitis with a significant reduction of caliber of the biliodigestive anastomosis. The remaining five patients showed a good caliber of hepaticojejunal anastomosis. The authors suggest this procedure as a safe, feasible, more rapid and easier technique than traditional suture for bilioenteric anastomosis, when a suitable caliber of MBD allows to perform it.

Video-assisted versus open ileocolic resection in primary Crohn's disease: a comparative case-matched study.

Despite the technical difficulties, laparoscopic ileocolic resection for Crohn's disease (CD) has become widely accepted in recent years, due to its potential benefits. There are numerous reports concerning the use of laparoscopy in successfully treating CD, including two randomized trials and few comparative studies. For the most part, these reports outline use of laparoscopic approach in primary distal ileal or ileocolic disease, with a careful selection of the patients. The purpose of this comparative case-control study was to point out potential advantages and disadvantages in short- and long-term outcomes of the laparoscopic approach compared with the open one. From January 1999 to January 2004, 200 patients were admitted in our Surgical Unit for complicated primary CD. 100 patients (group 1) underwent a laparoscopic ileocolic resection, 100 patients (group 2), with alike demographic and clinical characteristics, underwent the same procedure using a traditional approach. The incidence of perforative disease was 32 and 40% in groups 1 and 2, respectively. Average operative time was 140 min (range 90-245 min) in the video-assisted group and 98 min (range 65-255 min) in group 2 (P < 0.05). Postoperative morbidity was 6 and 8% in groups 1 and 2, respectively (P = NS). Recovery of peristalsis occurred within 2-3 days in group 1 and 3-4 days in group 2 (P = NS). Median postoperative hospitalization was 7 days (range 5-18 days) in group 1 and 9 days (range 7-22 days) in control group (P < 0.05). The overall rate of surgical relapse of CD was 8 and 13% in groups 1 and 2, respectively (P = NS), at a mean follow-up of 52 and 60 months, respectively. The 1-year surgical recurrence rate was similar (3%) for the two groups. In conclusions, in spite of the technical difficulties, video-assisted surgery for CD offers advantages over laparotomy, including less postoperative pain, reduced postoperative hospital stay, less disability of the patient, and better cosmetic results. Potential advantages are: easier approach for re-resection, lower rate of postoperative adhesions and bowel obstruction, and lower rate of wound complications.

Interferon-gamma-expressing cells are a major source of interleukin-21 in inflammatory bowel diseases.

BACKGROUND: We previously demonstrated that in inflammatory bowel disease (IBD) there is enhanced production of interleukin (IL)-21, a cytokine that activates multiple pathways that sustain mucosal inflammation. However, the phenotype of IL-21-producing cells in IBD, and the cytokine(s) they coproduce, is not known. We here characterized the cell source of IL-21 and determined which factors regulate IL-21 in the human gut. METHODS: Cytokines were analyzed in CD4+ T intestinal lamina propria lymphocytes (T-LPL) isolated from IBD patients and controls by flow cytometry. Moreover, IL-21 was evaluated in mucosal T follicular cells (TFH). To assess the involvement of IL-12 and IL-23 in the production of IL-21, T-LPL were activated in the presence or absence of IL-12 or IL-23. RESULTS: The proportion of IL-21-producing CD4+ T-LPL was increased in IBD compared to controls. The majority of IL-21-producing T-LPL coexpressed interferon (IFN)-gamma, and to a lesser extent IL-4 or IL-17A. Activation of CD4+ T-LPL with IL-12 but not IL-23 enhanced the fraction of cells coexpressing IL-21 and IFN-gamma. TFH cells in LPL were identified by CXCR5 expression and expressed IL-21 both in IBD and controls; however, the fraction of IL-21-positive TFH cells was higher in Crohn's disease than in ulcerative colitis and controls. Treatment of CD4+ T-LPL with IL-12 enhanced the frequency of CXCR5+ IL-21-producing TFH cells. CONCLUSIONS: These findings indicate that in IBD IL-21 is mostly produced by CD4+ T-LPL coexpressing IFN-gamma, reinforcing the concept that distinct subsets of T cells can produce IL-21.

Accumulation of dysfunctional effector CD8+ T cells in the liver of patients with chronic HCV infection.

BACKGROUND/AIMS: Hepatitis C virus (HCV) causes a chronic infection that can lead to fibrosis and carcinoma. Immune responses mediated by cytotoxic T lymphocytes (CTLs) could be involved in viral clearance or persistence, and therefore in determining the course of the disease. METHODS: Intrahepatic and peripheral blood CD8+T cells were obtained from 32 HCV-chronically infected patients and analysed by flow-cytometry for surface markers of differentiation, IFNgamma and TNFalpha production, degranulation capacity and perforin content, after CD3 triggering. Results were compared with those obtained from 13 patients with a non-viral liver disease. RESULTS: Intrahepatic CD8+T cells of HCV-infected patients, despite their phenotype of pre-terminally and terminally differentiated effectors (CCR7-CD45RA-/+), are poorly responsive to T cell receptor (TCR)-mediated stimulation compared with those obtained from uninfected subjects. This defect correlates with the severity of fibrosis, is more pronounced in patients with ALT<1.5xN than with ALT>1.5xNU/ml, and is not evident after mitogen stimulation. CONCLUSIONS: The present study describes the accumulation of hypo-responsive CD8+T cells in the liver of patients with chronic HCV infection. Understanding the mechanisms underlying this impairment may be helpful in the design of innovative strategies for HCV treatment.

Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease.

BACKGROUND & AIMS: T-helper (Th)1 cells play a central role in the pathogenesis of tissue damage in Crohn's disease (CD). Interleukin (IL)-12/STAT4 signaling promotes Th1 cell commitment in CD, but other cytokines are needed to maintain activated Th1 cells in the mucosa. In this study, we examined the expression and role of IL-21, a T-cell-derived cytokine of the IL-2 family; in tissues and cells isolated from patients with inflammatory bowel disease. METHODS: IL-21 was examined by Western blotting in whole mucosa and lamina propria mononuclear cells (LPMCs) from patients with CD, ulcerative colitis (UC), and controls. We also examined the effects of exogenous IL-12 on IL-21 production, as well as the effects of blocking IL-21 with an IL-21-receptor Ig fusion protein. Interferon (IFN)-gamma was measured in the culture supernatants by enzyme-linked immunosorbent assay, and phosphorylated STAT4 and T-bet were examined by Western blotting. RESULTS: IL-21 was detected in all samples, but its expression was higher at the site of disease in CD in comparison with UC and controls. Enhanced IL-21 was seen in both ileal and colonic CD and in fibrostenosing and nonfibrostenosing disease. IL-12 enhanced IL-21 in normal lamina propria lymphocytes through an IFN-gamma-independent mechanism, and blocking IL-12 in CD LPMCs decreased anti-CD3-stimulated IL-21 expression. Neutralization of IL-21 in CD LPMC cultures decreased phosphorylated STAT4 and T-bet expression, thereby inhibiting IFN-gamma production. CONCLUSIONS: Our data suggest that IL-21 contributes to the ongoing Th1 mucosal response in CD.

A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gut inflammation.

Immunologically mediated tissue damage in the gut is associated with increased production of proinflammatory cytokines, which activate the transcription factor NF-kappaB in a variety of different cell types. The mechanisms/factors that negatively regulate NF-kappaB in the human gut and the pathways leading to the sustained NF-kappaB activation in gut inflammation remain to be identified. Pretreatment of normal human intestinal lamina propria mononuclear cells (LPMC) with transforming growth factor-beta1 (TGF-beta1) resulted in a marked suppression of TNF-alpha-induced NF-kappaB p65 accumulation in the nucleus, NF-kappaB binding DNA activity, and NF-kappaB-dependent gene activation. TGF-beta1 also increased IkappaBalpha transcripts and protein in normal LPMC. In marked contrast, treatment of LPMC from patients with inflammatory bowel disease with TGF-beta1 did not reduce TNF-induced NF-kappaB activation due to the overexpression of Smad7. Indeed inhibiting Smad7 by specific antisense oligonucleotides increased IkappaBalpha expression and reduced NF-kappaB p65 accumulation in the nucleus. This effect was due to endogenous TGF-beta1. TGF-beta1 directly stimulated IkappaBalpha promoter transcriptional activity in gut fibroblasts in vitro, and overexpression of Smad7 blocked this effect. These data show that TGF-beta1 is a negative regulator of NF-kappaB activation in the gut and that Smad7 maintains high NF-kappaB activity in gut inflammation by blocking TGF-beta1 signaling.