Background The conventional ileostomy can be avoided. Many attempts have been performed. The first successful solution was the continent ileostomy- Kock pouch. The high rate of complications and revisions some experienced forced surgeon to try to restore the continence by the mechanism of the anus involving an ileal pouch. Both procedures afterwards documented excellent functional outcome, but the complication rates were not negligible and the long-term failure rate were increasing. Different surgical refinements were done and the risk factors for complications and failures were investigated as experience and materials increased. Restoring of the integrity of anal function and the succsess of the ileal pouch-anal anastomosis shadowed the practise of the forerunner: the continent ileostomy reservoir. This latter procedure was more demanding and seemed in the first year of ileal pouchanal anastomosis era to have significant more complications and revisional surgery. The worldwide adoption of the pelvic pouch decreased the need for the continent ileostomy and a vicious circle evolved. Today only few centres perform the procedure. Patients who are not suitable for ileal anal-pouch anastomosis are seldom offered the possibility of having a continent ileostomy. Aims The aims of the study was to investigate surgical load, complications and long-term functional outcome and to define factors which affect these subjects in patients operated with ileal pouch-anal anastomosis, continent ileostomy or both in one single surgical department during the same period and without any institutional learning curve, and furthermore, to compare and contrast the two options. Material and methods From 1984 to 2005(7) 304 (315) patients were operated with IPAA at St. Olavs Hospital (earlier: Regional Hospital of Trondheim). From 1983 to 2002(7) 50 (65) patients had a continent ileostomy constructed. This was an observational study in the scope of surveillance and quality assurance. All patients were offered a planed regularly annual outpatient clinic follow up programme including a prospective standardised interview on clinical outcome. This was a supplement to clinical investigation with endoscopy and consecutive documentation of complications and other factors affecting the patients’ health. Data were recorded in the medical chart. In this system, all patients had recorded dataset. However, the intervals between data recordings differ and the intervals increased by time. All inpatients data were included. Standard descriptive statistical analysis and simple associations were undertaken. Handling longitudinal data with limited cases, varying time intervals was done in a Times Series Cross Sectional data model, analysed, and adjusted for several factors affecting functional outcome. Multivariable analysis was done. Results The estimated failure rate at 20 years was 11.4% for ileal pouch-anal anastomosis and 11.6% for continent ileostomy. Salvage procedures rates were 31% vs. 38%, respectively (p=0.06). The salvage procedures in IPAA included local procedures and redoes with laparotomy. Salvage procedures in CI were related to the function of the nipple valve, mainly nipple valve sliding and less frequent stenosis or fistulas. Complications rates were high. In pelvic pouch surgery, half of the patients would need re-operations in 20 years. Ten percentages had early anastomotic separation without septic complications. Four percentages had early pelvic septic complications. Fistulas and sepsis at the anastomotic site were the main severe complications, often leading to pouch failure. Closing of the loop ileostomy was accompanied with complications in six percentages. In the patients (48) who did not have a covering stoma the overall complications rate did not differ from those with a loop ileostomy, although nine needed a secondary stoma. Covering stoma seems to postpone anastomotic complications. Handsewn anastomosis had more strictures, but otherwise the complications rates were similar to stapled anastomosis. Patients having the diagnosis changed to Crohn`s diseases had more complications and higher failure rate. Early anastomotic complications were associated with long-term complications. In patients with continent ileostomy the nipple valve sliding is the main cause of revision. One third needed revision once or several times. At 20 years follow-up, half of the patients would need surgery due to complications. Although many patients with CI need several revisions, all patients were continent at the last follow up with a stable intubation frequency of 3 – 5 per 24 hour. The failure of the pelvic pouch is the end of severe complications. Two third of the failures had the pouch excision or permanent ileostomy with the pouch in situ. One third underwent a conversion to CI, with equal surgical and functional outcome as other patients with CI. In IPAA, bowel movements at day were between 5-6 at day and 0-1 at night. The rates of more or less frequent incontinence were about 10%, and 41% and 55% had reported soling at day and night respectively. The long-term functional outcome did not deteriorate with time: ie. observational time, as an independent factor did not influence outcome. Factors influencing the outcome were found but the impact of gender, age, protective stoma, hand-sewn anastomosis and early complications were negligible. Pouchitis did significantly influence functional outcome negatively, but did not create deterioration over time. Estimated pouchitis rate in IPAA was 43% for more than 20 years. The onset of the first pouchitis appears mostly in the 5-6 first years after surgery. The crude rate was 35% and 6% of the patients had chronic pouchitis. Severe/chronic pouchitis was associated with primary sclerosing cholangitis, but not with pyoderma gangrenousum or diagnosed joint affections. Idiopathic pouchitis were absent among patients with familial adenomatous polyposis. In continent ileostomy the rate of pouchitis was 26%. Conclusion The complications in both the pelvic pouch surgery and the surgery of continent ileostomy are considerable. Although not similar the surgical load are in the same order of magnitude. For the continent ileostomy revisional surgery are to be expected. The failure rate of both procedures are high and in long-term similar. The long-term functional outcome are however stabile and excellent. The failed pelvic pouch can be converted to a continent ileostomy in selected and motivated patients. The entity of pouchitis is conflicting and has to be divided into several different entities both on clinical, constitutional and other differentiating features. Patients with PSC should be informed of a possible higher risk of severe and chronic pouchitis after IPAA.

The ω-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA), in the free fatty acid (FFA) form, has been demonstrated,to reduce adenoma number and size in patients with familial adenomatous polyposis. However, the mechanistic basis of the antineoplastic activity of EPA in the colorectum remains unclear. We tested the hypothesis that EPAFFA negatively modulates synthesis of and signaling by prostaglandin (PG) E2 in human colorectal cancer (CRC) cells.,EPA-FFA induced apoptosis of cyclooxygenase (COX)-2-positive human HCA-7 CRC cells in vitro. EPA-FFA in cell,culture medium was incorporated rapidly into phospholipid membranes of HCA-7 human CRC cells and acted as,a substrate for COX-2, leading to reduced synthesis of PGE2 and generation of PGE3. Alone, PGE3 bound and activated,the PGE2 EP4 receptor but with reduced affinity and efficacy compared with its "natural" ligand PGE2. However,,in the presence of PGE2, PGE3 acted as an antagonist of EP4 receptor-dependent 3',5' cyclic adenosine,monophosphate induction in naturally EP4 receptor-positive LoVo human CRC cells and of resistance to apoptosis,in HT-29-EP4 human CRC cells overexpressing the EP4 receptor. We conclude that EPA-FFA drives a COX-2dependent "PGE2-to-PGE3 switch" in human CRC cells and that PGE3 acts as a partial agonist at the PGE2 EP4 receptor.

In severe cases of ulcerative colitis (UC) unresponsive to current treatment options, patients require a complete proctocolectomy, or surgical removal of the colon. Ileal pouch anal anastomosis (IPAA) has become the preferred surgical technique for patients who require surgery, as this method restores rectal function. This procedure is also used to treat colorectal cancers such as adenocarcinoma and familial adenomatous polyposis (FAP). The surgery involves an abdominal colectomy with the construction of an ileal pouch created from folded tissue recovered from the ileal portion of the small intestine. Up to 50% of patients who require IPAA surgery experience an episode of pouchitis, a non-specific inflammation of the constructed ileal pouch with unknown etiology. Several hypotheses have been proposed regarding the pathogenesis of pouchitis. Current theories include bacterial overgrowth due to fecal stasis, microbial imbalance (dysbiosis), immune alteration, genetic susceptibility, metaplasia, ischemic complications of surgery, a recurrence of UC, or even a novel form of inflammatory bowel disease. The efficacy of antibiotics and probiotics in treating pouchitis and maintaining remission underscores the importance of gut microbiota in the development of this condition. In the study, we aimed to characterize the intestinal bacterial communities that inhabit IPAA pouches of both UC and FAP patients, in an effort to investigate the hypothesis that bacterial dysbiosis is involved in the pathogenesis of pouchitis. Mucosal biopsy and stool samples were analyzed from patients with UC and pouchitis (UCP), healthy UC controls (HUC) and healthy pouches with a background of FAP (FAP). Samples were examined through analysis of terminal restriction fragment length polymorphisms (TRF) and DNA sequencing. The data presented here demonstrate that a microbial imbalance exists in pouchitis, as bacterial communities in pouchitis differ significantly from healthy UC pouches and pouches constructed for FAP. Both methods identified potential groups of organisms that may play a role in the development of pouchitis, including decreases in protective Lactobacillus and Bacteroides and increases in mucin-degrading Clostridium and Akkermansia. A better understanding of the factors driving the pathogenesis of pouchitis will not only benefit patients with this disease, but also lead to a better understanding of the complex relationship that exists between the human host and the diverse community of organisms that inhabit the gastrointestinal tract.

Familial adenomatous polyposis (FAP) is a condition caused by germline mutations in tumor suppressor gene APC, inherited in autosomal dominant manner. Patients with FAP develop hundreds to thousands of adenomatous colorectal polyps with extremely high risk of malignant reversal into adenocarcinoma of colon and/or rectum. The aim of this thesis is to re-analyze a cohort of highly suspected FAP probands from years 1993-2004 whose diagnosis previously failed to be confirmed by at that time commonly used methods of molecular diagnostics. Next generation sequencing on MiSeq and NextSeq platforms (Illumina®) was performed on 78 samples of probands' DNA, isolated from peripheral blood, using gene panel CZECANCA version 1.2 (Czech Cancer Panel for Clinical Application). The panel enables sequencing of exons and exon-intron junctions of 226 genes linked to hereditary cancer predispositions, newly also including the diagnostically important promoter 1B region of APC. Pathogenic variant in the APC gene was detected in 18 % of re-analyzed probands, 11 % of probands carry pathogenic variants in other genes associated with colorectal polyps. Additional 13 % of probands are carriers of a variants of unknown clinical significance. NGS gene panel CZECANCA enabled diagnosis confirmation or re-evaluation of 22 FAP...

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Epidemiological, experimental, and clinical observations provide support for a colorectal cancer chemopreventive role for aspirin. We have evaluated the effects of aspirin on proliferation biomarkers in normal-risk and high-risk human subjects for colorectal cancer. Colorectal biopsies were obtained at baseline and at 24h after 28 daily doses of 81mg of aspirin from 13 high-risk and 15 normal-risk subjects for colorectal cancer. We evaluated aspirin's effects on proliferating cell nuclear antigen (PCNA) immunohistochemistry and epithelial mucin histochemistry using the lectin, Amaranthus caudatus agglutinin (ACA) in crypt sections from rectal biopsies. The baseline whole crypt PCNA LIs differed significantly between normal-risk and high-risk subjects. PCNA LIs are not affected by 28 days of aspirin at 81mg daily. ACA LIs are decreased by 28 days of aspirin at 81mg daily in both normal-risk and high-risk subjects. Aspirin's effects on ACA LIs may have mechanistic and biological implications that deserve further attention. PCNA and ACA LIs are not useful as proliferation biomarkers for aspirin's chemopreventive activity in morphologically normal human colorectal mucosa.