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.
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.
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.
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.
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.
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)-γ 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-γ–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-γ production.
Conclusions
Our data suggest that IL-21 contributes to the ongoing Th1 mucosal response in CD.
Immunologically mediated tissue damage in the gut is associated with increased production of proinflammatory cytokines, which activate the transcription factor NF-κB in a variety of different cell ...types. The mechanisms/factors that negatively regulate NF-κB in the human gut and the pathways leading to the sustained NF-κB activation in gut inflammation remain to be identified. Pretreatment of normal human intestinal lamina propria mononuclear cells (LPMC) with transforming growth factor-β1 (TGF-β1) resulted in a marked suppression of TNF-α–induced NF-κB p65 accumulation in the nucleus, NF-κB binding DNA activity, and NF-κB-dependent gene activation. TGF-β1 also increased IκBα transcripts and protein in normal LPMC. In marked contrast, treatment of LPMC from patients with inflammatory bowel disease with TGF-β1 did not reduce TNF-induced NF-κB activation due to the overexpression of Smad7. Indeed inhibiting Smad7 by specific antisense oligonucleotides increased IκBα expression and reduced NF-κB p65 accumulation in the nucleus. This effect was due to endogenous TGF-β1. TGF-β1 directly stimulated IκBα promoter transcriptional activity in gut fibroblasts in vitro, and overexpression of Smad7 blocked this effect. These data show that TGF-β1 is a negative regulator of NF-κB activation in the gut and that Smad7 maintains high NF-κB activity in gut inflammation by blocking TGF-β1 signaling.
Background & Aims: Normal human lamina propria lymphocytes manifest increased unstimulated apoptosis compared with peripheral lymphocytes, which are enhanced after stimulation via the CD2 activation ...pathway. This activation-induced apoptosis down-regulates cell expansion and cytokine production. In previous studies, it was shown that lamina propria T cells from patients with Crohn's disease and ulcerative colitis manifest abnormal proliferation and cytokine production. It was therefore of interest to determine if such cells also showed abnormal patterns of apoptosis.
Methods: Apoptosis was evaluated by propidium iodide staining of cells followed by flow cytometric analysis. Fas expression and Bcl-2 levels in cells were evaluated by immunofluorescence.
Results: Lamina propria lymphocytes from patients with Crohn's disease and ulcerative colitis as well as from 2 patients with diverticulitis showed defective CD2 pathway–induced apoptosis. Studies of the mechanisms of this defect focusing on cells from patients with Crohn's disease showed that Crohn's disease lamina propria lymphocytes from inflamed tissues express the same amount of cell surface Fas but are less sensitive to Fas-mediated apoptosis than control cells. In addition, lamina propria lymphocytes from inflamed Crohn's disease tissues manifest increased expression of Bcl-2 after CD2 pathway stimulation and elevated Bcl-2 levels in cultures of unstimulated T cells.
Conclusions: T cells isolated from areas of inflammation in Crohn's disease, ulcerative colitis, and other inflammatory states manifest decreased CD2 pathway–induced apoptosis. Studies of cells from inflamed Crohn's disease tissue indicate that this defect is accompanied by elevated Bcl-2 levels. These changes are probably caused by the chronic inflammation and may aggravate the underlying disease processes that are present.
GASTROENTEROLOGY 1999;116:557-565
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.
Background and purpose: This study analyses and compares the results of local regional control, distant metastases and survival in two series of patients irradiated from 1986 to 1992 in our radiation ...oncology centre following quadrantectomy or tumourectomy for early stage breast cancer.
Materials and methods: The quadrantectomy group consisted of 152 women, 109 (72%) with T1 and 43 (28%) with T2 tumours. Axillary nodes in this group were positive in 51 (33%) patients. The tumourectomy group included 123 women, 71 (58%) with T1 and 52 (42%) with T2 tumours. Positive axillary nodes were found in 56 (46%) of these patients. All quadrantectomy and tumourectomy patients received a dose of 50 Gy in 5 weeks to the whole breast, followed by a 10–16 Gy electron boost. Node positive patients in the tumourectomy group also received 50 Gy to the axillary apex and supraclavicular region. In both surgical groups, node positive premenopausal and postmenopausal patients received adjuvant CMF or tamoxifen therapy, respectively.
Results: After a median follow-up of 58 months, 89% of women in the tumourectomy group and 87% in the quadrantectomy group were alive and 80 and 73%, respectively, were free of disease. Breast and nodal failures were detected in 4.9 and 0.8% of cases, respectively, in the tumourectomy group, as compared to 5.9 and 3.3% of cases, respectively, in the quadrantectomy group. Distant relapses were observed in 16 and 18% of patients in the former and latter groups, respectively. Actuarial overall and disease-free survival was similar in the two series, with 5-year rates of 90 and 72%, respectively, in the tumourectomy group, and of 91 and 78%, respectively, in the quadrantectomy group. The differences in survival are not statistically different.
Conclusions: Our findings show that tumourectomy and quadrantectomy, followed by adequate radiotherapy, provide comparable results in terms of local-regional control and survival.
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.
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).
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.
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.
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.
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, IFNγ and TNFα production, degranulation capacity and perforin content, after CD3 triggering. Results were compared with those obtained from 13 patients with a non-viral liver disease.
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<1.5×N than with ALT>1.5×N
U/ml, and is not evident after mitogen stimulation.
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.
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