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PubMed1995

Restorative proctocolectomy without diverting ileostomy.

PURPOSE: Restorative proctocolectomy (RPC) by abdominal colectomy and ileal pouch-anal anastomosis (IPAA) in the setting of chronic ulcerative colitis (CUC) and familial adenomatous polyposis (FAP) has gained widespread popularity among surgeons and patients. Traditionally, temporary loop ileostomy has been established proximal to the ileal pouch in an effort to mitigate the effects of any suture line complications that may occur. This study compares functional results and complications encountered after RPC with mucosectomy with and without temporary ileostomy. METHODS: One hundred forty-three consecutive patients with either CUC or FAP underwent RPC including mucosectomy and ileal "J" reservoir. Proximal loop ileostomy was performed in 69 patients, and ileostomy was omitted in 74. Ileostomy was omitted if the patient was taking no immunosuppressives and less than 20 mg of prednisone daily in the month preceding surgery, the anastomosis was absolutely tension-free, and blood supply to the pouch was excellent. RESULTS: There were no perioperative deaths. There were two instances of pelvic abscess, one in the diverted group and one in the nondiverted group. Occurrence of IPAA suture line dehiscence was not significantly different between the two groups (ileostomy, 4/69 (6 percent), vs. no ileostomy, 6/74 (8 percent); P > 0.05). Comparison of 129 patients with colitis with and without diversion also failed to demonstrate a significant difference with regard to IPAA suture line dehiscence (ileostomy, 4/69 (6 percent) vs. 4/60 (7 percent); P > 0.05). Frequency of bowel movements and continence were the same in both groups and were comparable with results obtained without mucosectomy. Mean hospital stay at time of RPC for the nondiverted group was significantly longer (12 days vs. 10 days; P = 0.0004). Significantly fewer patients without an ileostomy were hospitalized for partial intestinal obstruction (ileostomy, 13/69 (19 percent), vs. no ileostomy, 3/74 (4 percent); P = 0.02), and significantly fewer required enterolysis (ileostomy, 7/69 (10 percent), vs. no ileostomy, 1/74 (1 percent); P = 0.04). On average, patients without an ileostomy spent significantly fewer total days in the hospital (17 vs. 24; P = 0.002). CONCLUSION: Restorative proctocolectomy with mucosectomy and without ileostomy is the procedure of choice for selected patients with FAP and CUC. Septic complications and functional results are similar to those seen in patients managed with a stoma. Anastomotic leakage, when it occurs, can be safely managed in most cases without surgery. RPC without ileostomy results in significantly fewer episodes of intestinal obstruction, fewer instances of re-exploration, and fewer total days in the hospital.

Abscess↗
PubMed2004

Raltitrexed increases tumorigenesis as a single agent yet exhibits anti-tumor synergy with 5-fluorouracil in ApcMin/+ mice.

The thymidylate synthase (TS) inhibitors raltitrexed (RTX) and 5-fluorouracil (FUra) have shown promising anti-tumor activity in preclinical and clinical settings for the treatment of colorectal cancer. Though the effects of these two agents have been reasonably well-characterized in cell lines, knowledge of their modes of action in vivo is limited. Here, we utilize the Apc(Min/+) mouse, an animal model of intestinal tumorigenesis, to study the effects of RTX treatment alone and in combination with FUra. Rather surprisingly, RTX monotherapy resulted in a dose dependent 4-10-fold increase in tumor number. The majority of these adenomas (74-95%) were rather small (i.e., less than 1 mm in diameter) and exhibited loss of heterozygosity at the Apc locus, suggesting an increase in mutational events leading to tumor development. RTX augmented BrdU-labeling of crypt epithelial cells, and retarded the movement of these cells along the crypt-villus axis. Co-administration of FUra and RTX resulted in a significant reduction in tumor number compared to mice treated with either RTX or FUra alone (P < 0.0001). In addition, FUra abrogated the RTX-mediated increase in BrdU labeling. In all, the results show that RTX increases tumor burden in the Apc(Min/+) mouse, yet enhances the anti-tumor effect of FUra. This is the first illustration of in vivo synergy of RTX and FUra in a genetically predisposed animal model. Possible mechanisms underlying the current observations are discussed.

Adenoma↗
PubMed2001

Total colectomy and straight ileo-anal soave endorectal pull-through: personal experience with 42 cases.

During the period from 1974 to June 2000 we used the straight ileo-anal Soave pull-through to treat 42 patients (24 affected by total colonic aganglionosis [TCA], 10 with ulcerative colitis and 8 with familial polyposis). The aim of this paper is to show that this operation, associated with total colectomy, is highly recommended, causing a lower number of complications when compared to the various "reservoir" techniques. The mean age of the 24 patients with TCA at the time of the pull-through was 2.8 years; in the ulcerative colitis group, it was 14.3 years and in the familial polyposis group 27.2 years. We always used an ileo-anal deferred anastomosis and never performed temporary loop-diverting ileostomy at the time of the pull-through. In the TCA patients we had no immediate or long-term serious post-operative complications: ileal adaptation, after a frequency of 10 - 12 liquid stools a day, showed a gradual, constant and in some cases amazing improvement in all children. Two years after surgery, the mean stool frequency was 3.6 per 24 hours with no significant differences between the 3 main groups; only 4 children still presented with occasional soiling. After pull-through, all children showed normal growth curves in the long term. There was no malabsorption, no serious electrolyte imbalance, no perianal excoriation, no strictures or intestinal obstruction; their quality of life was considered more than satisfactory by the children's families. We have no direct experience with the various ileal "reservoir" techniques for ulcerative colitis and ileal polyposis nor with colon-sparing operations for TCA; as reported in the literature, all these surgical procedures seem to have a higher number of complications such as pelvic sepsis, pouchitis, enterocolitis, etc. compared with our series; we therefore confirm that total colectomy with the straight ileo-anal Soave pull-through is our treatment of choice, as it is simpler to perform and has fewer short- and long-term complications.

Adolescent↗
PubMed1989

Electron microscopic studies of endocrine hyperplasia in duodenal adenomas in familial adenomatous polyposis.

Electron microscopical studies on endocrine cell hyperplasia of duodenal adenomas from five patients with familial adenomatous polyposis were performed. All the endocrine cell types normally found in the duodenal mucosa were identified. A constant feature was proliferation of duodenal-enterochromaffin cells but an increase in the number of all other endocrine cell types apart from pyloric-gastrin cells and somatostatin cells, was also observed. Certain types of intestinal endocrine cells (the intestinal enterochromaffin cell and the glicentin cell) are rare cells in the normal duodenal mucosa. The finding of these cells may indicate increased biological aggressivity.

Adenoma↗
PubMed2001

Carcinogenesis of cancer of the papilla and ampulla: pathophysiological facts and molecular biological mechanisms.

BACKGROUND: Ampullary cancer has one of the highest resectability rates and best prognoses among neoplasms arising in the periampullary region. DISCUSSION: Early diagnosis due to early symptoms can partially explain the better prognosis as compared to other cancers of the periampullary region, but biologic factors should also be taken in account. In the past few years, the molecular mechanisms underlying this disease have been investigated and alterations of genes that regulate different cell functions have been described. Mutations of K-ras and of the tumor suppressor genes APC, p16 and p53 indicate a major disturbance in cell cycle regulation. CONCLUSIONS: If the molecular profile of ampullary cancer is examined in terms of rate and type of molecular changes, it seems to be more similar to intestinal than to pancreatic cancer. Furthermore, the fact that many ampullary carcinomas arise from adenomas and the frequent finding of ampullary tumors in patients affected by polyposis syndromes also suggest that ampullary and colon cancers share common molecular mechanisms of carcinogenesis.

Ampulla of Vater↗
PubMed2000

Functional outcome of stapled ileal pouch-anal canal anastomosis versus handsewn pouch-anal anastomosis.

This study was conducted to determine whether stapled ileal pouch-anal canal anastomosis (IACA) preserving the anal transitional zone (ATZ) or hand-sewn ileal pouch-anal anastomosis with mucosectomy (IPAA) is more beneficial in achieving disease eradication and better postoperative function. IACA was performed in 10 patients with ulcerative colitis (UC) and 10 patients with familial adenomatous polyposis (FAP), 15 of whom were examined proctoscopically. IPAA was performed in 4 patients with UC and 8 patients with FAP. The mean maximum resting pressure (MRP) was 55 mmHg in the IACA group and 34 mmHg in the IPAA group (P < 0.01). The anorectal inhibitory reflex was positive in 18 patients (90%) from the IACA group and 5 (42%) from the IPAA group (P < 0.05). The pre- and postoperative MRPs were 61 mmHg and 55 mmHg, respectively, in the IACA group vs 63 mmHg and 34 mmHg, respectively, in the IPAA group (P < 0.01). Whereas 16 (80%) of the 20 IACA patients could discriminate feces from gas, only 4 (33%) of the 12 IPAA patients could (P < 0.05). The mean observation period was 2.3 years, the mean length of the columnar cuff was 2.8 cm, and no case of dysplasia or adenoma was seen. Postoperative function is more favorable following IACA than following IPAA, both physiologically and symptomatically. However, long-term surveillance of the residual mucosa is necessary before making a final recommendation.

Adenomatous Polyposis Coli↗
PubMed1996

Familial segregation in the occurrence and severity of periampullary neoplasms in familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) patients often develop periampullary adenomas that may progress to periampullary cancer, a common cause of death in this population. The risk of periampullary cancer in FAP is unclear, and variables that predict the occurrence and severity of periampullary tumors are not well understood. The specific aim of this study was to determine whether the risk of periampullary neoplasia segregates in specific FAP families. MATERIALS AND METHODS: A total of 144 FAP patients from 74 families were either screened by gastroduodenoscopy (n = 132) or information was obtained from surgical or autopsy reports (n = 12). The severity of periampullary neoplasia was recorded for each patient and graded based on maximum polyp size and histology. Linear regression was used to determine the significance of a number of variables with respect to periampullary neoplasia. A blood sample was available from at least one member of 50 unrelated families and used to detect germline mutations in codons 686 through 1693 of the adenomatous polyposis coli (APC) gene. RESULTS: Statistically significant familial segregation was found for the incidence and severity of periampullary neoplasia (P < 0.02). Age was also a statistically significant variable (P < 0.01). No correlation was observed between specific APC germline mutations and periampullary polyp frequency and severity. CONCLUSIONS: The occurrence and severity of periampullary neoplasms in patients with FAP segregates in families. This familial association may be related to as yet unidentified modifier genes or perhaps common environmental factors. These results should prove useful in developing upper gastrointestinal screening protocols for FAP patients at risk for periampullary neoplasia.

Adenoma↗
PubMed1997

Cell proliferation of the duodenal mucosa in patients affected by familial adenomatous polyposis.

BACKGROUND & AIMS: Patients affected by familial adenomatous polyposis (FAP) are at increased risk of developing duodenal adenomas. In this study, cell proliferation of duodenal mucosa was analyzed to detect kinetic abnormalities related to cancer risk. METHODS: Duodenal biopsy specimens were collected in three groups of patients: group A, 9 hospital controls; group B, 14 patients with FAP without duodenal adenomas; and group C, 6 patients with FAP and duodenal adenomas. Proliferative cell nuclear antigen was assessed through immunohistochemistry. The main labeling parameters were (1) overall labeling index (LI) and (2) LI in the upper 40% of the crypts. RESULTS: Overall LI in groups B and C was higher than in group A (both P < 0.01). LI in group C was also significantly higher than in group B (P < 0.01). Similarly, the upper 40% LI was higher in groups B and C than in group A (both P < 0.01). This value was higher in group C than in group B (P < 0.05). CONCLUSIONS: These data suggest the presence of cell kinetics abnormalities in FAP and the existence of two subgroups of patients with FAP at different risks of duodenal neoplasia. These abnormalities could be used as an intermediate biomarker for chemoprevention studies of duodenal cancer in FAP.

Adenomatous Polyposis Coli↗
PubMed1998

Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.

Juvenile polyps are present in a number of Mendelian disorders, sometimes in association only with gastrointestinal cancer [juvenile polyposis syndrome (JPS)] and sometimes as part of known syndromes (Cowden, Gorlin and Banayan-Zonana) in association with developmental abnormalities, dysmorphic features or extra-intestinal tumours. Recently, a gene for JPS was mapped to 18q21.1 and the candidate gene DPC4 (SMAD4) was shown to carry frameshift mutations in some JPS families. We have analysed eight JPS families for linkage to DPC4. Overall, there was no evidence for linkage to DPC4; linkage could be excluded in two of the eight pedigrees and was unlikely in two others. We then tested these eight families and a further 13 familial and sporadic JPS cases for germline mutations in DPC4. Just one germline DPC4 mutation was found (in a familial JPS patient from a pedigree unsuitable for linkage analysis). Like all three previously reported germline mutations, this variant occurred towards the C-terminus of the DPC4 protein. However, our patient's mutation is a missense change (R361C); somatic missense mutations in DPC4 have been reported previously in tumours. We therefore confirm DPC4 as a cause of JPS, but show that there is considerable remaining, uncharacterized genetic heterogeneity in this disease.

DNA-Binding Proteins↗
PubMed1996

Clinical enteroscopy.

We prospectively evaluated the diagnostic yield of push enteroscopy using either the Olympus SIF 10-LY fiberscope or the SIF-100 video enteroscope in 120 patients suspected of having small-bowel pathology. Insertion beyond the ligament of Treitz, checked by fluoroscopy, ranged from 30 to 150 cm (median 100). The source of bleeding was identified in 25 (41%) of 61 patients referred for gastrointestinal bleeding of obscure origin; vascular malformations were the most common finding, followed by neoplasias. Of 16 patients with inherited polyposis syndromes, multiple distal duodenal or jejunal hamartomas were diagnosed in five of six with Peutz-Jeghers syndrome and multiple duodenal or jejunal adenomas in six of 10 with familial adenomatous polyposis. Overall, isolated vascular malformations were successfully cauterized in three patients, and polypectomy was performed in 12 patients. Endoscopic and histological alterations, in both duodenum and jejunum, were found in 16 of 43 patients with diarrhea and/or malabsorption of unclear origin. The remaining 27 had normal duodenal and jejunal mucosal appearances; six had abnormal histological findings only in the jejunum and one both in the duodenum and in the jejunum. If we take jejunal histology as diagnostic, the sensitivity of duodenal histology was 74% and the specificity was 100%. We conclude that push enteroscopy provides useful diagnostic information and has therapeutic capabilities in patients with small-bowel pathology.

Adenomatous Polyposis Coli↗
PubMed2005

The ileo neo rectal anastomosis (INRA) in patients with familial adenomatous polyposis: clinical results at two years.

BACKGROUND: Ileo neo rectal anastomosis (INRA) is a promising alternative for patients with familial adenomatous polyposis (FAP) to restorative proctocolectomy with its morbidity and unpredictable functional outcome to colectomy with ileo rectal anastomosis (IRA) with the continuing risk of rectal cancer. The aims of the present study were to evaluate the function of the neorectum, to assess the morbidity and complications of the operation and to determine the incidence of neorectal polyps. METHODS: Data of all patients having INRA, including bowel function and complications, were prospectively recorded. The reservoir capacity was determined repeatedly by physiologic tests. The anal sphincter complex was assessed by manometry and ultrasound examination. Evaluation of the neorectal mucosa was performed by endoscopy. RESULTS: Six patients underwent the INRA procedure for FAP. Median defaecation frequency two years postoperatively was 5.5/24 h (range 4-7) including 1/night (range 0-2). Endoscopic examination showed normal mucosa and no evidence of polyp formation in all patients. CONCLUSION: INRA affords a good functional reservoir and is accompanied by few reservoir-related complications. At a minimum follow up period of two years, no growth of polyps in the neorectum occurred.

Adenoma↗
PubMed2003

Genetic testing for polyposis: practical and ethical aspects.

The three autosomal dominant inherited polyposis syndromes, familial adenomatous polyposis, juvenile polyposis, and Peutz-Jeghers polyposis predispose to colorectal cancer as does hereditary non-polyposis colorectal cancer syndrome. Uncovering the genetic background of these four cancer traits provides the possibility for genetic testing of the family members of an affected patient. Before testing identification of the underlying family specific pathogenic mutation is mandatory. This is possible in about 60% to 95% of families. Endoscopic surveillance can be safely discontinued in mutation negative family members and surveillance or prophylactic surgery can be targeted to mutation positive members alone. Testing requires genetic counselling and written informed consent to prevent misunderstanding and to minimise untoward effects such as anxiety. Permanent surveillance and adequate prophylactic treatment for all mutation positive subjects and families is best ensured in national or regional polyposis registries with the capacity to take care of long term follow up from generation to generation.

Adenomatous Polyposis Coli↗
PubMed1997

Significance of apoptosis in the process of tumorigenesis in colorectal mucosa and adenomas in FAP patients.

The relation between proliferation and apoptosis was studied in colorectal mucosal biopsies (N = 41), tubular adenomas (TA) (N = 104) and tubulovillous adenomas (TVA) (N = 34) from 37 FAP patients. Proliferative activity was determined by cell cycle distribution analysis. In addition, transcriptional capacity was determined by chromatin in situ testing. For both, DNA flow cytometry was used. Cycling cells were identified by immunohistochemical staining with monoclonal antibody Ki67. The existence of subdiploid apoptotic cells was derived from DNA and/or DNA/protein patterns. In a follow-up group, the mucosa is characterised by a balance between proliferation (S % + G2M % = 19) and apoptotic cells (% = 17). The percentage of Ki67 positive cells (16%) corresponds to the percentages mentioned above. In TA, the amount of apoptotic cells remains unaltered, in TVA it decreases to 8%. At the same time, the percentage of Ki67 positive cells increases significantly in both TA and TVA (39%, 42%). With patients who underwent surgery due to clinical signs without histological evidence for malignancy, apoptotic cells in TA continue to decrease significantly (9%), without any changes in cycling cells. Only in the carcinoma-bearing bowel, cycling cells increase to 52%. Here, the percentage of apoptotic cells in TVA reaches the lowest level (5%). A connection between proliferation and apoptosis was observed in mucosa and TVA. The process of tumorigenesis is characterised by a stepwise increase in resistance to apoptosis followed by an increase in cycling cells.

Adenoma↗