Complication Of Ulcerative Colitis Research Articles

Systematic Review of Cuff and Pouch Cancer in Patients with Ileal Pelvic Pouch for Ulcerative Colitis

Ileal pouch-anal anastomosis (IPAA) is the procedure of choice for refractory or complicated ulcerative colitis (UC). Since 1990, pouch-related adenocarcinomas have been described. The aim of this study was to review the literature to evaluate the burden of this complication, seeking for risk factors, prevention, and ideal management. We performed a systematic review of the literature to identify all described pouch-related adenocarcinoma in patients operated on with IPAA for UC. Studies were thoroughly evaluated to select authentic de novo pouch carcinomas. Some authors were contacted for additional information. Data of patients were pooled. Meta-analyses of suitable studies were attempted to identify risk factors. Thirty-four articles reported on 49 patients (2:1, male:female) who developed unequivocal pouch-related adenocarcinoma, 14 (28.6%) and 33 (67.3%) arising from the pouch and anorectal mucosa, respectively. Origin was not reported in 2 (4%). Pooled cumulative incidence of pouch-related adenocarcinoma was 0.33% (95% confidence interval [CI], 0.31-0.34) 50 years after the diagnosis and 0.35% (95% CI, 0.34-0.36) 20 years after IPAA. Primary pouch cancer incidence was below 0.02% 20 years after IPAA. Neoplasia on colectomy specimen was the strongest risk factor (odds ratio, 8.8; 95% CI, 4.61-16.80). Mucosectomy did not abolish the risk of subsequent cancer but avoiding it increased 8 times the risk of cancer arising from the residual anorectal mucosa (odds ratio, 8; 95% CI, 1.3-48.7; P = 0.02). Surveillance is currently performed yearly starting 10 years since diagnosis, but cancers escaping this pathway are reported. In patients receiving mucosectomy, a 5-year delay for surveillance could be proposed. Pouch-related adenocarcinomas are rare. Diagnosis of Crohn's disease in the long term may further decrease the rates in UC. Presumed evolution from dysplasia might offer a time window for cancer prevention. Abdominoperineal excision should be recommended for pouch-related adenocarcinomas.

DNA methylation of microRNA-124a is a potential risk marker of colitis-associated cancer in patients with ulcerative colitis.

Colitis-associated cancer (CAC) is the serious complication of ulcerative colitis (UC), and molecular markers to evaluate the individual risk are required. MicroRNA-124a (miR - 124a) is known to have tumor-suppressive function and be methylation-silenced during exposure to chronic inflammation. We analyzed whether higher methylation levels of miR-124a genes correlated with the higher epidemiologic risk of CAC development in UC patients. Forty UC patients without CAC, four patients with CAC or dysplasia, eight sporadic colorectal cancer (S-CRC) patients, and 12 healthy volunteers (HV) were studied. Methylation status of miR-124a genes (miR-124a-1, -2, and -3) was analyzed by methylation-specific polymerase chain reaction (MSP), and methylation levels were quantified by real-time MSP. Expression of cyclin-dependent kinase 6 (CDK6), a target of miR-124a, was analyzed by immunohistochemistry. Three miR-124a genes were methylated in all neoplastic tissues (CAC, dysplasia, and S-CRC), and CDK6 was highly expressed in those tissues. Regarding disease extent, mean methylation levels of miR-124a-3 in HV, non-pancolitis, and pancolitis were 2.0, 5.3, and 12.3%, respectively, and were significantly higher in pancolitis than in HV (p < 0.01). Regarding disease duration, mean methylation levels in short-term and long-standing UC patients were 2.5 and 13.2%, respectively. Long-standing UC patients had significantly higher methylation levels than HV (p < 0.01). Moreover, UC patients with both pancolitis and long-standing had 7.4-fold higher methylation levels than those without these risk factors. MiR-124a genes are methylated during carcinogenesis in UC patients. The methylation level of miR-124a-3 is a promising marker for estimating individual risk for CAC.

Alicaforsen: An Emerging Therapeutic Agent for Ulcerative Colitis and Refractory Pouchitis

Pouchitis is a relatively common complication that develops following ileal pouch-anal anastomosis in patients with complicated ulcerative colitis (UC). Both pouchitis and UC share similarities in their development, as well as in the mechanisms involving mediators of the inflammatory process. In the recent years, the discovery and investigation of biological therapies have led to advancement in the management of these disorders, and the continuation of research on this novel area holds strong implications for a future reduction in the use of invasive surgical procedures. Alicaforsen represents one of these emerging therapeutic agents, and has demonstrated promising results in both preclinical and clinical settings. This article reviews the therapeutic effects of alicaforsen for the management of UC and refractory pouchitis, with special emphasis on the mechanism of action of this therapeutic agent and the clinical studies asserting its effectiveness. Gastroenterology Research. 2014;7(2):51-55 doi: http://dx.doi.org/10.14740/gr599w

P-215 Biomarkers of Neoplasm in Ulcerative-Colitis

Colorectal cancer (CRC) remains a serious complication in ulcerative colitis (UC). Biomarkers that identify patients at greatest risk for this outcome could increase the effectiveness of current surveillance methods. Our previous work compared single nucleotide polymorphisms (SNP) and methylation between UC patients who developed CRC (UC-CRC) and UC patients who did not develop CRC (UC-controls). In that work, we studied methylation in DNA extracted from tissue obtained not only in the cancer section, but also from the non-adjacent, non-neoplastic tissue. These initial studies yielded both a potential “risk” SNP in the tumor necrosis factor alpha gene (TNFα) plus 3 markers with significant alterations in methylation status, RUNX3, MINT1 and COX2. The aims of the current study were to: 1.) validate methylation markers in earlier neoplasms (low-grade dysplasia, LGD), 2.) determine if TNFα is a marker of “risk” to develop any neoplasm and 3.) determine if these markers were associated with a LGD-non-progressor phenotype. We identified/reviewed 200 UC-LGD patients for potential inclusion. After chart review and histological confirmation, 162 were selected for testing. For each sample, formalin-fixed, paraffin-embedded sections were cut both from the dysplastic area (LGD-DYS) as well as a non-adjacent, non-neoplastic area (LGD-NAN). DNA was extracted using a modified Gentra protocol and 500 ng bisulfite treated using the EZ DNA Methylation Gold Kit (Zymo Research). TNFα genotyping was completed using TaqMan assay (Applied Biosystems). Methylation testing for RUNX3, MINT1 and COX2 was done using MS-PCR as previously described by our group. Comparisons were made between LGD-NAN, UC-controls (prior data) and UC-CRC cases (prior data). LGD-NAN results were also combined with UC-CRC data and compared to UC-controls. The subset of LGD patients who did not progress to CRC in long-term follow up (LGD-NP) was compared to UC-CRC and UC-control data. Statistical analysis was completed using JMP. Table 1 summarizes the Validation (A) and the Non-progressive LGD (B) analyses. P-values and sample numbers for each comparison are provided. •Validation of methylation as a marker for concurrent neoplasm in non-adjacent mucosa: RUNX3, MINT1 and COX2 have altered methylation compared to UC-controls, even in patients with early neoplasm in the form of LGD. • TNFα-308 is associated with neoplasm in UC: Comparisons between UC-controls and any neoplasm were significant. Comparisons within neoplastic groups (UC-CRC, LGD-DYS and LGD-NP) were not significant. • Methylation in non-progressor LGD: The only variation between UC-controls and LGD-NP-NAN was methylation status of COX2, with LGD-NP-NAN more likely to be unmethylated than UC-controls. In comparisons between LGD-NP and UC-CRC (either NAN or DYS), COX2 was not significant but both RUNX3 and MINT1 were. Results in Table1A confirm our previous findings that TNFα-308 (G>A) is a risk SNP and that this methylation panel can be used to increase standard surveillance sensitivity. Although the sample set is small, the data for LGD-NP suggest that altered methylation patterns may be informative in guiding treatment of LGD. In addition, the alteration of COX2 between LGD-NP-NAN and UC-controls may suggest a possible target for chemoprevention.

Complications and functional outcomes of restorative proctocolectomy for ulcerative colitis in the elderly

BackgroundRestorative proctocolectomy with ileopouch-anal anastomosis (IPAA) is the treatment of choice for intractable or complicated ulcerative colitis (UC). Debate exists concerning outcomes of IPAA in the elderly and literature data are scarce. We report our experience of IPAA in older population.MethodsWe gathered data on a prospective database of patients undergoing IPAA for UC over 70 years of age in our Unit from January 1990 through January 2010. Patients were compared with randomly selected younger controls on a 1:3 ratio. Patients underwent IPAA in 2 or 3 stages. Demographical data, disease characteristics, comorbidities, concomitant medications, peri-operative management, intra- and post-operative complications were analyzed. Function and quality of life were assessed by clinical visit and Inflammatory Bowel Disease Questionnaire 1 and 3 years after ileostomy takedown.ResultsTwenty-seven elderly patients underwent IPAA for UC in the study period; these were compared with 81 younger controls. The former had more comorbidities and higher ASA score. All patients underwent loop-ileostomy closure. There were no differences between groups concerning the rate of major complications, but elderly patients more frequently had nuisances due to stoma output. Younger patients experienced significantly more episodes of small bowel obstruction. No significant differences in bowel control and health-related quality of life was observed, except for an higher rate of elderly patients taking antidiarrhoeals at 1-year follow-up; this observation was not confirmed at 3-year follow-up. A minimal decrease in continence was observed, but this did not affect overall satisfaction.ConclusionsIPAA can be safely offered to selected elderly UC patients who are strongly motivated and with no clinical disturbances of continence. In experienced hands no differences are likely to be expected concerning complications, quality of life and function. Results are stable with time and comparable to those of younger patients.

Adalimumab Therapy Is Associated With Reduced Risk of Hospitalization in Patients With Ulcerative Colitis

Adalimumab is effective for induction and maintenance of remission in patients with moderate to severe ulcerative colitis (UC). We assessed whether adalimumab, in addition to standard UC therapy, reduced the risk for hospitalization (from all causes, from complications of UC, or from complications of UC or the drugs used to treat it) and colectomy in patients with moderate to severe UC compared with placebo. Data were combined from patients that received induction therapy (a 160-mg dose followed by an 80-mg dose of adalimumab) or placebo in 2 trials (ULTRA 1 and ULTRA 2; n = 963). The risks of hospitalization and colectomy were compared between groups using unadjusted rates during the 8-week induction period, and patient-year-adjusted rates during 52 weeks. Statistical differences between groups were determined using the χ(2) method and Z score normal approximations. Numbers of hospitalizations were compared using Poisson regression with time offset. Significant reductions in risk of all-cause, UC-related, and UC- or drug-related hospitalizations (by 40%, 50%, and 47%, respectively; P < .05 for all comparisons) were observed within the first 8 weeks of adalimumab therapy compared with placebo. Significantly lower incidence rates for all-cause (0.18 vs 0.26; P = .03), UC-related (0.12 vs 0.22; P = .002), and UC- or drug-related (0.14 vs 0.24; P = .005) hospitalizations were observed during 52 weeks of adalimumab therapy compared with placebo. Rates of colectomy did not differ significantly between patients given adalimumab vs placebo. In patients with moderate to severe UC, the addition of adalimumab to standard of care treatment reduced the number of hospitalizations for any cause, as well as for UC-related and UC- or drug-related complications, compared with placebo. ClinicalTrials.gov numbers, NCT00385736 and NCT00408629.

Tu1908 DNA Methylation Level of Mir-124a Could Be Individual Risk Marker of Colitis-Associated Cancer in Ulcerative Colitis

OBJECTIVE: Colitis-associated cancer (CAC) is the most serious complication of ulcerative colitis (UC). Recent studies have recommended that surveillance intervals should be tailored with individual risk, and useful molecular markers focusing on high-risk patients for CAC are needed. This study evaluated the usefulness of quantification of miR-124a methylation as a risk marker of CAC development. METHODS: Twelve healthy volunteers (HV), 40 UC patients without CAC, and 4 patients with CAC or dysplasia were recruited. DNAmethylation levels of miR-124a, a tumor-suppressive microRNA, were quantified in the colorectal mucosa of UC patients, and analyzed the association with major risk factors, disease extent and duration. The methylation statuses of miR-124a genes (miR-124a-1, -2, and -3) in colorectal mucosa and tumor tissue were analyzed by methylation-specific polymerase chain reaction (MSP), and their methylation levels were quantified by real-time MSP. Expression of cyclindependent kinase 6 (CDK6), a target of miR-124a, was analyzed by immunohistochemistry. RESULTS: All three miR-124a genes were methylated, and CDK6 was expressed in all CAC and dysplasia. Mean methylation levels of miR-124a-3 in HV, non-pancolitis, and pancolitis patients were 2.0%, 5.3%, and 12.3%, respectively, and were significantly higher in pancolitis patients than in HV (p,0.01). As for disease duration, mean methylation levels in patients with short-term and longstanding duration were 2.5%, and 13.2%, respectively. Patients with longstanding duration had significantly higher methylation levels than HV (p ,0.01). Moreover, UC patients with both pancolitis and longstanding duration had 7.4-fold higher methylation levels than those without two risk factors. CONCLUSIONS: MiR-124a genes are methylated during carcinogenesis in UC patients, and their methylation levels correlate with risk factors for CAC development. Therefore they could be novel markers for estimating individual risk of CAC.

Infliximab administration prior to surgery does not increase surgical site infections in patients with ulcerative colitis

The high incidence of infectious complications in ulcerative colitis (UC) is generally recognized to be due to several factors related to a compromised host. In our previous study, a high dose of corticosteroid was shown to be a risk factor for surgical site infection (SSI). Recently, infliximab (IFX) has been used for refractory UC. In this study, the effect of IFX on the occurrence of infectious postoperative complications for UC was evaluated, because it remains controversial. A total of 196 UC patients who underwent laparotomy between January 2010 and September 2012 were included. Possible factors related to complications were analyzed to identify significant predictors. Twenty-two patients had IFX before surgery. The overall incidence of SSI was 47/196 (24.0%). The incidence of infections, including SSI and other infections, was 69/196 (35.2%). On multivariate analysis, national nosocomial infection surveillance (NNIS) risk index ≥2 (p<0.01) and preoperative prednisolone dose ≥0.2 mg/kg/day (p = 0.01) were identified as independent risk factors for overall SSI; NNIS risk index ≥2 (p <0.01) and duration from onset of UC ≥6.3years (p = 0.045) were identified as independent risk factors for incisional SSI; contaminated wound class (p <0.01), preoperative hospital stay ≥6days (p = 0.048), severe/fulminant disease activity (p = 0.04), and pancolitis (p = 0.02) were identified as independent risk factors for organ/space SSI; and contaminated wound (p < 0.01), severe/fulminant disease activity (p = 0.02), and age at surgery ≥43years (p = 0.047) were identified as independent risk factors for total infectious complications. IFX administration was not associated with infectious complications for UC surgery.

Letter: seeking oesophageal eosinophilia among unselected patients ‐ looking for a needle in a haystack?

1. Yamamoto T, Shiraki M. Letter: pre-operative anti-TNF-a and post-operative complications in ulcerative colitis. Aliment Pharmacol Ther 2012; 36: 210–1. 2. Yang Z, Wu Q, Wu K, Fan D. Meta-analysis: pre-operative infliximab treatment and short-term post-operative complications in patients with ulcerative colitis. Aliment Pharmacol Ther 2010; 31: 486–92. 3. Norg ard BM, Nielsen J, Qvist N, Gradel KO, de Muckadell OB, Kjeldsen J. Pre-operative use of anti-TNF-a agents and the risk of post-operative complications in patients with ulcerative colitis – a nationwide cohort study. Aliment Pharmacol Ther 2012; 35: 1301–9. 4. Norg ard BM, Nielsen J, Qvist N, Gradel KO. Schaffalitzky de Muckadell OB, Kjeldsen J. Pre-operative use of anti-TNF-a agents and the risk of post-operative complications in patients with Crohn’s disease – a nationwide cohort study. Aliment Pharmacol Ther 2013; 37: 214–24. 5. Cornillie F, Shealy D, D’Haens G, et al. Infliximab induces potent anti-inflammatory and local immunomodulatory activity but no systemic immune suppression in patients with Crohn’s disease. Aliment Pharmacol Ther 2001; 15: 463–73. 6. Yang Z, Wu Q, Wang F, Wu K, Fan D. Meta-analysis: effect of preoperative infliximab use on early postoperative complications in patients with ulcerative colitis undergoing abdominal surgery. Aliment Pharmacol Ther 2012; 36: 922–8.

Avellis syndrome as presenting manifestation of ulcerative colitis

We described a 41-year-old woman presenting with subacute onset of left hemihypesthesia, left facial palsy, dysphagia and dysgeusia. A cranial T2-weighted magnetic resonance imaging revealed bilateral inhomogeneous medullary hyperintensities. The clinical manifestations conformed to Avellis syndrome, and were linked to the diagnosis of ulcerative colitis which was proved by serological findings and pathological evidence on rectosigmoid mucosa. She recovered favorably under conservative medical treatment with complete remission over one month of follow-up. Brainstem syndromes are rarely associated with neurological complications of ulcerative colitis and can be the presenting manifestation beyond gastrointestinal symptoms.

Infliximab for the treatment of pouchitis

Pouchitis is not a rare complication that develops after an ileal-pouch anastomosis, performed after colectomy in patients refractory to treatment or with complicated ulcerative colitis. This condition may become chronic and unresponsive to medical therapies, including corticosteroids, antibiotics and probiotics. The advent of biological therapies (tumor necrosis factor-α inhibitors) has changed the course of these complications. In particular, in these cases, infliximab (IFX) may represent a safe and effective therapy in order to avoid the subsequent operation for a permanent ileostomy. This article reviews the therapeutic effects of one of the most widely used anti-tumor necrosis factor-α molecules, IFX, for the treatment of complicated pouchitis (refractory to conventional treatment and/or fistulizing).

Rectosigmoid stump washout as an alternative to permanent mucous fistula in patients undergoing subtotal colectomy for ulcerative colitis in emergency settings

BackgroundRestorative proctocolectomy with ileopouch-anal anastomosis (IPAA) is the treatment of choice for intractable or complicated ulcerative colitis(UC). Elderly patients often present with acute colitis requiring emergent subtotal colectomy(SC). Frail patients are at risk of developing septic complications related to the closed rectosigmoidal stump, often requiring formation of a second stoma to be reversed at the time of completion proctectomy. This carries nuisance to such exhausted patients. We propose a simple and inexpensive trick to avoid the need for creating a mucous fistula.MethodsIPAA was performed as a 3-stage procedure in emergency settings. The rectosigmoidal stump was closed and placed subcutaneously; skin was closed over it. After SC, if patients showed signs of stump-related pelvic sepsis, a lavage of the rectal stump with povidone iodine solution and with saline was carried out as a rescue treatment aiming to avoid the need of opening the rectal stump to drain sepsis.ResultsThirty-five patients underwent SC for UC between 1987 and 2012. The skin was closed over the closed stump in the 20. Seven patients out of these 20 experienced early stump-related septic complication. In five cases, we were able to avoid opening of the rectal stump, and a second stoma was unnecessary. After opening the closed stump in the remaining ones, a prompt improving of symptoms was observed.ConclusionsRectal washout was well tolerated and avoided a second stoma in five out of seven patients, with better quality of life and body perception after IPAA surgery. This is relevant when dealing with geriatric patients, needing to completely recover before undergoing completion proctectomy.

Indian Society of Gastroenterology consensus on ulcerative colitis

In 2010, the Indian Society of Gastroenterology's Task Force on Inflammatory Bowel Diseases undertook an exercise to produce consensus statements on ulcerative colitis. This consensus, produced through a modified Delphi process, reflects our current understanding of the definition, diagnostic work up, treatment and complications of ulcerative colitis. The consensus statements are intended to serve as a reference point for teaching, clinical practice, and research in India.

Risk factors for complications after total colectomy in ulcerative colitis

Ulcerative colitis can be cured by total proctocolectomy. The aim of this study was to investigate the risk factors for colectomy-related complications in ulcerative colitis patients. All patients with ulcerative colitis who underwent total colectomy at Seoul National University Hospital from 1990 to 2009 were identified through a surgical database. Their demographic and clinical characteristics were reviewed retrospectively. They were followed for a mean of 6.2 years, and risk factors affecting the development of complications were analyzed. A total of 85 ulcerative colitis patients (M:F = 35:50) were enrolled and analyzed. Eighty (94.1%) patients received total proctocolectomy with ileal pouch-anal anastomosis. Thirty-nine (45.9%) patients had readmitted (95 hospitalizations) and 23 (27.1%) underwent further surgical procedures (44 operations) due to complications. Multivariate analysis showed that female gender (odds ratio [OR], 2.99; p=0.046), delayed surgery (OR, 3.45; p=0.03), and postoperative pathological diagnosis of dysplasia/cancer (OR, 4.22; p=0.03) were the risk factors for complication-related rehospitalization. Pouchitis (OR, 6.31; p=0.007) and frequent previous ulcerative colitis flare-up (OR, 1.39; p=0.023) were the risk factors for complication-related reoperation. Female gender, delayed surgery, pathological diagnosis of dysplasia/cancer, pouchitis, and frequent previous flare-up are the risk factors for postoperative complications.

A Rare Complication of Ulcerative Colitis: ST Elevation Myocardial Infarction

Purpose: A 44-year-old female presented to the emergency room (ER) with sudden onset substernal chest pain. The patient had no known cardiac risk factors. She had a history of Ulcerative Colitis (UC), which had been in remission until two days prior to the presentation, when she started having abdominal pain and bloody diarrhea. This episode was similar to her prior exacerbations but she was currently not on any treatment. The physical exam was only remarkable for mild diffuse tenderness in the abdomen. The EKG done in the ER showed ST segment elevations in leads II, III and aVF and the lab work was significant for elevated cardiac enzymes (Troponin I-25 ng/ml). The patient underwent an urgent cardiac catheterization which revealed total occlusion of the right coronary artery. The artery could not be stented due to the presence of extensive thrombus and even though, thrombectomy was attempted, it was not successful. The decision was made to manage the patient medically and she was started on a beta blocker, ACE inhibitor and statin for acute MI and mesalamine for Ulcerative colitis exacerbation. Aspirin and Clopidogrel were held in the light of bloody diarrhea but it was decided to start intravenous heparin. The patient responded well to the treatment. The hematocrit remained stable and there were no further episodes of bleeding. She was eventually discharged in a stable condition. Ulcerative colitis is frequently associated with many extra-intestinal manifestations, mostly in the form of dermatological, hepatobiliary or ocular involvement but cardiac involvement is rare. It usually manifests as either pericarditis with or without myocardial involvement or conduction abnormalities. Myocardial infarction, as seen in our patient, is an extremely rare complication of Ulcerative colitis. The hypercoagulable state in UC is postulated to be due to increased levels of platelets, prothrombin fragment, fibrinogen, homocysteine and reduced levels of anticoagulants. These alterations in the coagulation cascade can result in deep venous thrombosis, pulmonary embolism, atrial thrombi and rarely coronary artery thrombosis. Interestingly, intravenous heparin has been suggested as a treatment for UC exacerbation along with standard therapy, with no increase in the incidence of bleeding. The exact mechanism by which heparin ameliorates the exacerbation is still unclear but it makes it particularly beneficial in the setting of a MI. We would like to conclude that physicians should be aware of this rare complication of Ulcerative colitis and it is important to recognize chest pain during UC exacerbation as it can indicate an impending Myocardial Infarction.

Impending megacolon: small bowel distension as a predictor of toxic megacolon in ulcerative colitis

We have read with great interest the recent excellent review by Di Sabatino et al. [1] on ulcerative colitis (UC). We fully agree with their description that toxic megacolon is a life-threatening complication in severe UC, and that a standard plain X-ray study is useful to evaluate the degree of intestinal distension. In clinical settings, delay of surgery sometimes bears a poor prognosis when patients may not fulfill the clinical criteria for toxic megacolon by Jalan et al. [2] or definitive colonic dilatation. We recently experienced a case of ‘impending’ megacolon in a patient with UC, highlighting small bowel distension as a predictor of toxic megacolon. A 27-year-old man with UC presented with sudden onset of severe abdominal pain after 5 weeks’ duration of relapse with hematochezia. He had experienced multiple relapses of pancolitis and was being treated with 750 mg of oral mesalazine three times a day for over 6 years since the first presentation of colitis. On examination, the temperature was 37.6 C. Abdominal examination revealed a distended and tender abdomen with marked rebound and hypoactive bowel sounds. The clinical activity index was elevated up to 19. Laboratory tests showed an increased white blood cell count of 17,400/lL and a C-reactive protein of 8.36 mg/dL. A supine abdominal X-ray study (Fig. 1) showed a notable dilatation of the small intestine with a maximum internal diameter exceeding 4 cm (arrows) as well as indistinct colonic distension (arrowheads). He was diagnosed as having impending megacolon of UC, and therefore underwent subtotal colectomy with end ileostomy. Histopathological examination revealed severe transmural inflammation of the colon. He had an uneventful post-surgical course. Toxic megacolon, a life-threatening complication of UC and diverse colitis, is defined as nonobstructive hypotonic dilatation of the colon, classically exceeding 5.5 cm in diameter in the transverse colon on supine abdominal X-ray [3]. The pathogenesis for megacolon seems to be the excessive colonic production of inflammatory mediators that inhibit colonic motility and nitric oxide, as the key nonadrenergic, noncholinergic neurotransmitter induces colonic muscle relaxation. Recent studies indicate that the finding of persistent small bowel distension on plain abdominal radiograph characterizes a subgroup of patients at high risk for the development of toxic megacolon and multiorgan dysfunction, termed ‘impending’ megacolon [4, 5]. Gaseous distension in the uninflamed stomach and small intestine may precede colonic dilatation presumably due to the increased release of the above inflammatory mediators. The distension can result from the activation of extrinsic intestine–intestinal inhibitory reflexes, which induce paralytic ileus [5]. In conclusion, although the clinical entity of ‘impending’ megacolon has not been established yet, we highlight small bowel distension as a reliable predictor of toxic megacolon, called ‘impending’ A. Hokama (&) K. Kishimoto J. Fujita Department of Infectious, Respiratory and Digestive Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan e-mail: hokama-a@med.u-ryukyu.ac.jp

Letter: surgery for ulcerative colitis mostly follows anti‐TNF drugs ‐ a new ‘therapeutic package’?

We read with interest Nørgård et al. article ‘Pre-operative use of anti-TNF-α agents and the risk of post-operative complications in patients with ulcerative colitis – a nationwide cohort study’.1 This is a very interesting study, with a good design and including a high number of patients. The results confirm the feelings of most gastroenterologists about the absence of more post-operative complications in ulcerative colitis (UC) patients who received anti-TNF before a colectomy. Undoubtedly, these results will help in the future when we -gastroenterologists- have to ‘convince’ surgeons, classically more sceptical in this issue due to the results of previous studies.2, 3 What we find rather interesting in the article is the progressive increase in the use of anti-TNFs before colectomy, with nearly 90% of patients treated with these drugs in the last 3 years. Anti-TNF indications in UC are progressively increasing; nowadays they are not only used for steroid-refractory UC 4 but also for some patients after ciclosporin failure.5 Anti-TNF drugs are commonly used in steroid-dependent UC patients after thiopurines failure,6, 7 and if in this indication anti-TNFs do not work, the next step should be colectomy.8 We think that in the near future most UC patients who are going to be colectomised, perhaps with the exception of those having a very severe flare or those having high-grade dysplasia, could have previously been treated with anti-TNF drugs. Nevertheless, in a slightly more distant future, the increased use of anti-TNF drugs before colectomy may not be as beneficial. It is known that about 30% of UC patients who undergo a colectomy will develop pouchitis.9 In recent years, anti-TNF drugs have been more commonly used for the treatment of chronic refractory pouchitis, but in a recent Spanish (GETECCU) multicenter study we have observed that patients who had received infliximab before colectomy, when treated for chronic refractory pouchitis with the same drug, had a poorer response and developed more adverse events.10 Declaration of personal and funding interests: None.

Letter: pre-operative anti-TNF-α and post-operative complications in ulcerative colitis

We read with interest the article by Nørgård et al.1 The authors examined the impact of pre-operative use of anti-tumour necrosis factor-alpha (TNF-α) agents on post-operative complications after colectomy for ulcerative colitis (UC). Patients (n = 1226) were classified according to use of anti-TNF-α agents within the 12 weeks prior to surgery. They found that pre-operative use of anti-TNF-α agents did not increase the risk of post-operative complications (within 30 and 60 days after surgery). A meta-analysis has reported that pre-operative infliximab use increases short-term post-operative complications in UC.2 In the studies included in this meta-analysis, most patients received combined therapy (glucocorticosteroids, ciclosporin A or other immunomodulators) with infliximab prior to surgery. In addition, not all the studies clarified the duration between last infliximab infusion and surgery. Some patients had received their last infusion more than 12 weeks before. A sustained biological effect of infliximab beyond 12 weeks seems unlikely.3 Furthermore, the number of patients in each study was relatively small. The nationwide study by Nørgård et al.1 provides reassuring results after pre-operative use of anti-TNF-α agents in UC patients. In this study,1 the majority of patients underwent colectomy and ileostomy. Few patients had construction of ileal pouch-anal anastomosis (IPAA). From the results in this study,1 we conclude that anti-TNF-α agents do not increase the risk of complications after colectomy without IPAA. However, most surgeons would like to know whether anti-TNF-α agents increase the risk of pouch-related complications after IPAA. If the risk is significantly increased, surgeons should avoid construction of IPAA at the first colectomy for UC. Further studies evaluating the impact of anti-TNF-α agents on the risk of pouch-related complication after IPAA are warranted. Declaration of personal and funding interests: None.

P002 The potential role of IL-33 in inflammatory-associated gut fibrosis: Induction of pro-fibrogenic gene expression and myofibroblast hypertrophy

Background: The pathogenesis of human ulcerative colitis (UC) is characterized by the presence of IL-13-producing Natural Killer T cells (NKT cells). One major complication of UC is the development of colitis-associated colorectal cancer. In these studies we determined the role of alternatively activated “M2 macrophages” in a new mouse model of colitis-associated carcinogenesis. Further, we verified these results through immunological analysis of surgical specimens obtained from patients with UC-associated colon cancer. Methods: Studies were performed using a mouse model for colitis-associated carcinogenesis based on chronic Oxazolonecolitis in combination with an initial i.p. azoxymethane (AOM) injection in female BALB/c mice. We observed chronic intestinal inflammation lasting for 12 weeks in mice repeatedly administered Oxazolone. Surgical specimens with UC-associated colon cancer were analyzed by flow cytometry and immunohistochemistry. Results: We could show that Oxazolone-colitis was mediated by colonic alpha-galactosyl-ceramide+CD1+ NKT-cells producing IL-13 and therefore resembles the immunological characteristics of human UC. Colon cancer development in this model was dependent on F4/80+CD11bhighGr1low macrophages producing IL-6 and EGF. Those cells inherited phenotypic characteristics of IL-13-stimulated alternativelyactivated “M2 macrophages”. To elucidate the importance of these “M2 macrophages”, we conducted bone marrow chimera studies and demonstrated that innate immune signaling through MyD88 in “M2 macrophages” is the key event for the production of tumor supporting factors like IL-6 and EGF. In surgical specimens obtained from patients with UC-associated colon cancer we verified those experimental findings. We consistently found a dense accumulation of IL-13-producing NKT cells inside the tumors. In addition, in this IL-13-dominated tumor micromilieu CD14+ and CD68+ antigen-presenting cells accumulated intensively and those antigen-presenting cells demonstrated an alternatively activated “M2 phenotype” by the expression of CD163 and CD205. Conclusions: We could demonstrate that in an experimental UC model, as well as in human UC, pathogenic IL-13producing NKT cells accumulate in the tumor micromilieu of UC-associated colon cancers. This immunologic situation inside the tumor microenvironment of mice and men induces tumor promoting M2 macrophages. Therefore M2 macrophages represent a potential target for future therapeutic strategies.

Rare and New Extraintestinal Complication of Ulcerative Colitis: Nasal Septal Perforation

Rare and New Extraintestinal Complication of Ulcerative Colitis: Nasal Septal Perforation