 improved outcomes in colon and rectal surgery Although TPMT testing is helpful in avoiding early, profound bone marrow suppression, it should not take the place of careful monitoring of full blood counts throughout the duration of treat- ment on AZA/6-MP. If the patient is a slow metabolizer, clinical decision on treatment dose with consideration for lower dosing and closer follow-up must be made, while those that are deficient should not be treated due to bone marrow toxicity. Patients who are found to be nonresponders are suggested to have metabolite testing. The utility of measuring the 6-MP metabolites 6-TGN and 6-MMP has been debated in the literature and even referred to as the “metabolite controversy”. According to expert opinion, it would seem reasonable to recommend checking 6-TGN/6-MMP metabolites when patients are not achieving therapeutic efficacy despite adequate weight-based dosing to ascertain noncompliance or metabolism favoring 6-MMP.(59) Methotrexate has also been shown to be effective in CD for both treating active disease (66) and maintaining remission (67). However, like AZA/6-MP, its slow onset of action limits its use in induction therapy. Nausea is a common side effect of methotrexate, but more serious concerns over opportunistic infections, hypersen- sitivity pneumonitis, and hepatotoxicity add to the factors limiting its use as a first line immunomodulator in treatment of CD. Although some data have suggested a beneficial effect of high- dose cyclosporine in active luminal CD (68), the benefit was not durable (69). An open-label trial of 16 patients with fistulizing dis- ease found that cyclosporine treatment resulted in 88% response and 44% complete closure.(70) However, a comprehensive review of the literature has shown that 39 patients with fistulizing disease who were treated with cyclosporine had 82% relapse rate in absence of oral cyclosporine.(71) Therefore, cyclosporine is not recom- mended for use in luminal CD and its use in fistulizing disease with subsequent maintenance therapy on AZA/6-MP is debatable. (72) Cyclosporine has several serious side effects including renal failure, seizures, and opportunistic infections. Biologic Response Modifiers In 1998, the FDA approved use of Infliximab for use in treatment of moderate to severely active CD and patients with fistulizing Crohn’s disease, who have had inadequate response to conventional ther- apy. In fact, it is the first drug to gain FDA approval for treatment of CD. Prior to the late 1990s, patients who had failed response to first-line therapies or were steroid-dependent had few nonsurgical options. The mechanism of action of biologic response modifiers in CD is through the interaction of the interleukins and cytokines. Neutrophils from patients with colitis (e.g., CD, ulcerative colitis, and infectious colitis) all produce significantly more IL-1 and TNF than neutrophils from healthy controls.(73) Infliximab is a chimeric IgG-1 monoclonal antibody com- prised of 75% human and 25% murine sequences, which has a high specificity for and affinity to tumor necrosis factor (TNF)-α. The pivotal trial for assessing the efficacy of Infliximab in CD in 1997 showed 33% rate of remission and 81% overall symptom improvement in patients who had been resistant to conventional treatment.(74) However, up to 40% of patients do not respond to treatment initially. The standard dose of Infliximab at 5 mg/ kg of body weight given as infusion every 8 weeks can sustain remission for up to 1 year in only 30% of initial responders. This is likely due to a combination of loss of efficacy and intolerable side effects. Infliximab also has modest steroid-sparing efficacy where at week 54, about 3 times as many patients (29% vs 9%) on Infliximab versus placebo had discontinued treatment with corticosteroids while maintaining clinical remission.(75) The efficacy of regularly scheduled treatment versus episodic treatment with Infliximab for patients with CD was compared in a posthoc analysis of the ACCENT I trial in 2004.(76) It was shown that regularly scheduled treatment resulted in a higher proportion of patients in remission at weeks 10, 14, 22, and 46 compared with the episodic treatment group. Patients were also found to have improved mucosal healing, less likelihood of hav- ing antibodies to Infliximab, fewer Crohn’s-related hospitaliza- tions, and fewer surgeries if on regularly scheduled treatment. Infliximab therapy causes antibody formation in up to 61% of patients and they correlate with increased risk of transfusion reactions as well as decline in efficacy.(77) Concomitant use of AZA/6-MP has been shown to reduce rate of antibodies to Infliximab (ATI), although currently there is no prospective trial comparing remission and response rates in patients concomi- tantly using AZA/6-MP and Infliximab.(78–80) Infliximab is also effective in closure of perianal enterocutane- ous and rectovaginal fistulas and maintaining fistula closure. Two prospective, randomized, placebo-controlled trials have shown closure rate of 55% at week 4 and maintenance of closure in 39% of patients respectively.(81, 82) In February 2007, Adalimumab gained FDA approval for the treatment of moderate to severe CD. Adalimumab is a fully human recombinant immunoglobulin G1 (IgG1) monoclonal antibody that binds with high affinity and specificity to human soluble TNF. Its efficacy is similar to Infliximab except that there is currently not enough evidence to comment on its value in fistulizing dis- ease.(83) However, certain features make it more attractive for use in clinical practice. It is thought that Adalimumab may be less immunogenic because it is a fully human antibody. Indeed, some evidence does exist for inducing remission in those who cannot tolerate Infliximab or have disease activity despite receiv- ing Infliximab therapy.(84) Another advantage is that it is admin- istered as a subcutaneous injection whereas Infliximab must be given as an infusion. Main side effects of Infliximab and Adalimumab include infec- tions, infusion reactions, serum-sickness-like reactions and a pos- sible increased risk of lymphoma. A tuberculin skin test should be done before initiating therapy, as reactivation of latent tuberculosis is a potential complication. Prevention of Postoperative Recurrence Approximately 75% of patients with CD require surgery within the first 20 years after symptom onset.(85, 86) Several studies have shown that, 1-year postresection, the endoscopic recurrence rate is near 73% with clinical relapse rate of 50% in 5 years.(87, 88) Increased risk of recurrence is associated with the following prog- nostic variables at the time of surgery: female gender, perianal dis- ease, smoking, use of 5-ASA, jejunal site, ileal and ileocolonic site, and Nod2/Card15 gene variants. Severity of endoscopic recur- rence at the neoterminal ileum within 1 year of surgery was found to be the most powerful predictor of symptomatic recurrence.(89)  surgery for crohn's disease Most studies of postoperative recurrence of CD have found that endoscopic findings predate clinical relapse. Management options to prevent postoperative recurrence vary and depend on the patient. The first line treatment, despite mar- ginal efficacy, has been mesalamine. Most studies only demon- strate a modest relative risk reduction in recurrence rates when compared to placebo. A recent meta-analysis showed an abso- lute risk reduction of 10% in postoperative patients at 2 years. (90) The largest benefit was found in pts with ileitis and pro- longed disease duration. The number needed to treat (NNT) to prevent one relapse was found to be 10 patients.(91) Whether or not this is a clinically relevant finding and the financial cost and effort spent in taking these medications merit their use is highly debatable. Azathioprine and 6-MP have both been used exten- sively in the postoperative patient, but data is limited and shows only modest efficacy for prevention of recurrence. The general consensus is that larger blinded controlled trials are warranted. A randomized, prospective, multicenter, placebo-controlled, dou- ble-blind, double-dummy trial done in 2004 by Hanauer showed relapse rates of 50% with 6-MP (50 mg), 58% with mesalamine (3 g), and 77% with placebo.(92) There were several shortcomings in this study, including the use of a suboptimal fixed dose of 6-MP, a high drop-out rate, higher clinical vs endoscopic relapse rate, and lack of a validated, reproducible clinical index used to judge clinical relapse. A prospective, open-label, randomized study of 142 patients who received AZA (2 mg/kg/day) or mesalamine (3 g/day) for 24 months found AZA effective in preventing relapse in those patients who had undergone previous intestinal resection.(93) Shortcomings of this study included open label bias. Currently, AZA/6-MP use is recommended for postoperative prophylaxis in those patients who are deemed to have high risk of recurrence or in those for whom recurrence would have substantially harmful effects. The use of antibiotics has been long debated in the prevention of recurrence in the postoperative Crohn’s patient. There are no large controlled trials that show clear effectiveness of the use of antibiotics in postoperative Crohn’s patients beyond 1 year. One large trial on metronidazole has shown a 4% clinical recurrence rate in the treat- ment group versus 25% in placebo group at 1 year, 52% endoscopic recurrence versus 75% in the placebo group at 3 months, and no significant difference in clinical recurrence rate at 2 or 3 years.(94) Another trial of Ornidazole showed an 8% clinical recurrence versus 38% with placebo at 1 year, but no significant difference at 2 or 3 years.(95) These agents may be considered for prevention of post- operative recurrence but their utility beyond 1 year and potential for considerable side effects in long- term use limit their clinical utility. The last group that has shown possible effectiveness in post- operative Crohn’s patients is the biologic response modifiers, but these have yet to be adequately studied in this setting. A nonran- domized, open-label, single-center experience involving 7 patients who received Infliximab with methotrexate has demonstrated no endoscopic or clinical recurrence at 2 years.(96) Adalimumab has not been studied in this respect. Multicenter, randomized, con- trolled studies are needed to further define the role of Anti-TNF agents in postoperative recurrence of CD. Treatments that have been shown to be ineffective in the pre- vention of postoperative recurrence are systemic corticosteroids, budesonide, probiotics, and interleukin-10. Nutritional Therapy There is no proof that any food or substance is responsible for causing the initial episode or recurrence of CD.(97) The biggest challenge in patients with CD is restoration and maintenance of weight, particularly in the presence of sepsis and/or obstruction. SURGICAL TREATMENT Indication Table 32.2 summarizes the indications for surgical treatment of a CD.(98) Surgical management of CD has changed considerably dur- ing the past as a result of numerous advances in medical therapy. Regardless of these developments, patients with CD will undergo a surgical procedure in up to 80% of the cases.(99) Patients often come to the surgeons office with worsening symptoms, a compli- cation, or as steroid-dependent. Failure of medical therapy or complications of medical therapy • Surgery may be indicated if the medication cannot control inflammation and its symptoms, or if the medication causes significant intolerable or inducible side effects. Symptoms that can be an indication for surgery includes diarrhea, anemia, pain, weight loss, sepsis, and obstruction. Most patients are either ste- roid-dependent or steroid-resistent (100) by the time of surgical consultation. In addition, pancreatitis from GRMP, osteoporosis from steroids, and leucopenia from infliximab are all potential reasons for surgery to be recommended. Acute and chronic disease complications • Although rates are decreasing, up to 20% of procedures are still performed to treat acute complications.(101) Among the indica- tions is toxic megacolon, obstruction, hemorrhage, perforation with or without peritonitis, and abscess. Perforation According to the Viena classification, intestinal perforation is a penetrating disease. The penetrating disease behavior is defined by the occurrence of intraabdominal or perianal fistulas, inflam- matory masses or abscesses, or perianal ulcers at any time in the course of disease. Neither postoperative intraabdominal compli- cations nor perianal skintags constitute evidence of penetrating disease.(102) Penetration of the bowel wall often presents not as an acute abdomen but as an indolent process related to fistuliza- tion. Diffuse peritonitis due to perforation is a rare but recognized complication of Crohn’s disease. Perianal disease manifestations include perianal pain and drainage from large skin tags, anal Table 32.2 Indications for Surgery in Crohn’s Disease. Failure of medical management Complications of Medical Management Obstruction Inflammatory mass Sepsis Free perforation/sepsis Fistulae/abscess Hemorrhage/anemia Dysplasia/carcinoma Growth retardation  improved outcomes in colon and rectal surgery fissures, perirectal abscesses, and anorectal fistulae. Emergency surgical therapy for a perforation behavior includes: free perfora- tion, intraabdominal abscess or masses with sepsis, and intestinal obstruction. In Crohn’s disease, free perforation is a rare but severe com- plication occurring in 1% to 3% of cases.(103) Free perforation in the absence of a megacolon should alert for the suspicion of CD. It can occur anywhere in the gastro-intestinal tract, from the stomach through the colon; a distal stricture might exist and make the perforation possible. Other etiologies for perforation include the presence of malignancy, and of endoscopic proce- dures. Frequently, the perforations are sealed. Gastro-duodenum perforations are best treated by debridement and primary suture. For jejuno-ileal perforations, resection and primary anastomosis are best if feasible and conditions favorable. Factors associated with postoperative complications include abscess, enterocutane- ous fistulae, steroid-dependence, and albumin <2 g/L. If one or more of the risk factors is present, a diversion is suggested.(104) Colonic perforation in Crohn’s colitis, often seen in the setting of toxic colitis, usually requires subtotal colectomy with rectal preservation and end ileostomy. If the etiology is not toxic coli- tis, a segmental resection and fecal diversion might be an option. (105) A postcolonoscopic perforation must be managed regard- ing the absence or presence of CD at the site of perforation and elsewhere in the colon. If the perforation occurs in a diseased seg- ment, the segment along with the perforation is reseated to allow reconstruction with or without fecal diversion depending upon the factors mentioned above.(104) If perforation occurs during a follow-up for surveillance, resection or primary repair may be feasible. Abscess Between 10–30% of patients with CD may present with intraab- dominal abscesses. Abscesses can develop because of a local sealed perforation, in association with a fistula, or postoperatively because of intraabdominal contamination or anastomotic leakage. Yamaguchi et al. found that almost 50% of the abscess were due to an anastomosis (surgical anastomosis and peristomal) (106), Preoperative percutaneous transcutaneous drainage and admin- istration of antibiotics is preferable if possible. Otherwise, surgery with resection of the disease site is necessary. Perianal CD Perianal Crohn’s Disease (PCD) occurs in 5–25% of CD patients and can be associated with active disease in the proximal gas- trointestinal tract or colon in about one-third to one-half of patients. It is often associated with colonic and rectal inflamma- tion. Perianal manifestations include cutaneous (tag and ulcer- ations), anal canal lesions (fissures, ulcers, stenosis), and septic (abscess, fistulas) (Figure 32.3). The purpose of surgical treatment in PCD is to improve quality of life and offer effective palliation, and therefore is reserved for patients who develop perianal complications of the disease or are unresponsive to aggressive medical therapy. The surgical treat- ment of PCD can be divided into two main categories: urgent and emergent treatment (to control perineal sepsis); and elective (to treat sequelae such as perianal fistulas and anal strictures).(107) Prompt and definitive surgical incision and drainage is required in all patients suspected of having acute abscesses. These lesions will not spontaneously resolve and delays can lead to uncontrolled sepsis with necrotizing infections, sphincter impairment and anal stenosis. If a fistula is identified a noncut- ting Seton (nonabsorbable suture) is inserted through the fistula tract to ensure continuous drainage, leading to the resolution of the perianal sepsis. Primary fistulotomy should be avoided. Premature removal of the seton increases the incidence of recur- rent perianal sepsis. If the abscess is superficial, the procedure may be completed under anesthesia. It is important to mini- mize trauma or additional injuries so that the incision must be as close as possible to the anal verge. Excision of skin edge or latex mushroom catheter placement can be utilized to obtain adequate drainage. Fistulotomy can be safely performed on simple (low) fistulas which do not include any significant portion of the external anal sphincter, in patients without active proctitis, well-controlled proximal luminal disease and adequate continence. Endorectal advancement flap is a surgical technique that repairs perineal fistulas with the preservation of anal sphincter function. The principal idea of this procedure is to surgically close the internal opening of the fistula using a flap made of rec- tal wall, allowing the healing of the fistula from inside out. The reported success rate of endorectal advancement flap in patients with Crohn’s perianal fistulas ranges from 25 to 100% in different series, with an average success of approximately 50–60%.(108) Elective surgery for PCD may include procedures for nonfistulous complications such as dilation of anorectal strictures. Most com- monly, however, patients with PCD will require surgery to repair perianal and rectovaginal fistulas not responsive to medical ther- apy, which may include fistulotomy, fibrin glue injection, transanal endorectal flap advancement, and gracilis muscle interposition. Fibrin Glue is a technically simple procedure for the treatment of perianal fistulas and it is associated with low risk and early return to normal activity. Fibrin glue is a blood by-product that uses the activation of thrombin to form a fibrinclot, mechanically sealing the Figure 32.3 Typical perianal Crohn’s Disease with associated fistulas and scars from prior surgery (Picture taken by Badma Bashankaev, M.D., Cleveland Clinic Florida).  surgery for crohn's disease fistula tract. Series using fibrin glue for perianal fistulas of mixed eti- ologies have yielded success rates of approximately 30–70%.(109) Gracilis transposition can be an option in patients after proc- tocolectomy or others types of CD related fistulas in whom other options may have failed before proctocolectomy.(110) Occasionally, temporary diverting colostomy or ileostomy is required to control symptoms, and in extremely severe cases resistant to both medi- cal and surgical therapy, proctectomy or proctocolectomy may be required. The PCD score developed by Wexner et al. can be very helpful in selecting therapeutic alternatives and in prognostication.(111) The PCD Activity Index analyzes 6 features in PCD: abscess, fistula, fissure and/or ulcer, stenosis, and incontinence. Obstruction Gastrointestinal obstruction usually results from acute active inflammation superimposed on a stenotic segment. Mass effect from an adjacent phlegmon or abscess is not an uncommon sce- nario. Malignancy must be excluded in CD strictures involving the colon. Yamazaki et al. noted a 6.8% malignancy rate in 132 patients with colonic Crohn’s disease complicated by stricture.(112) Although traditionally by-pass without vagotomy was consid- ered the best option for gastro-duodenal obstruction stricture- plasty has become acceptable.(113) Complete or near-complete intestinal obstruction unrespon- sive to medical therapy requires surgical correction. Depending on location, this treatment involves either resection or strictureplasty. (114) If malignancy is present or suspected, a resection is obviously indicated following standard oncologic principles. Bleeding Whereas mild gastrointestinal bleeding is a common manifes- tation of inflammatory bowel disease, severe bleeding is a rare phenomenon. CD has been reported to be an established source of gastrointestinal hemorrhage, in 0.9% to 2.5% of patients with this disease.(115) CD bleeding is often from a localized source. This is caused by erosion of a blood vessel within multiple deep ulcerations that extend into bowel wall. The small bowel is the site of bleeding in 65% of cases, whereas the colon was involved in 12%, and in 23% the site could not be identified. It is important to exclude a gastroduodenal source before bowel resection. Angiography is often performed to identify and possibly treat the bleeding site by selective or superselective angiographic infusion of vasopressin.(116) Embolization should be the initial treatment of choice in CD in an attempt to avoid surgical resec- tion. Cirocco et al. (115) reported that surgical resection offered excellent palliation, with low mortality (3%) and a low rebleed- ing rate (3.5%). Surgery is indicated in those patients who fail to show improvement of bleeding after 4 to 6 units of blood, have recurrent hemorrhage, or have other indications to resect diseased bowel.(114) A bowel preparation is contraindicated, and the aim is to remove the patient from life threatening hemorrhage. Toxic Megacolon Toxic megacolon is a potentially lethal complication which has gradually decreased in incidence because of earlier recognition and intensive management of severe colitis. A possible mechanism is that mucosal inflammation sequentially leads to the release of inflammatory mediators and bacterial products, increased nitric oxide syntheses, generation of excessive nitric oxide, and colonic dilation. Toxic megacolon affects all ages and both genders. Signs and symptoms of acute colitis that are frequently resistant to therapy are often present for at least 1 week before the onset of acute dilatation. Severe bloody diarrhea is the most common pre- senting symptom, while improvement of diarrhea usually occurs because of the onset of megacolon. Other futures include malaise and abdominal pain and distention.(117) Up to 47% of patients require surgery due to failure in medical therapy. Factors affecting mortality are age (>40), gender (female), and presence of colonic perforation. The overall mortality rate is 16%.(118) Although the frequencies of performed emergency surgery have decreased, improved medical treatment has lead to higher rates of elective operations. Siassi et al. published a 33 years expe- rience, and prospectively found that the rates of elective sur- gery rose from 69.5% (1970 to 1980) to 81.4% (1981–1991) and 80.9% (1992–2002) (101). This change might reflect the changes in disease location. Combined large/small bowel resections such as ileocecal resections increased from 27.5% (1970–1980) to 41.9% (1981–1991) and 67.1% (1992–2002) (101), as CD limited to this region that is unresponsive to medical management is best treated by ileocolectomy and anastomosis (119). Similar results were found by Reissman et al. with a 59% rate of ileocolectomy and anastomosis.(120) SPECIFIC CONSIDERATIONS IN SURGICAL TECHNIQUES FOR CD PATIENT The philosophy behind surgical intervention in Crohn’s disease rests on the fact that Crohn’s disease is currently incurable and potentially involves the entire intestine, and that surgery relieve only the complications. Strictureplasty Over one-third of patients with CD will develop an intestinal stricture and the great majority of these will require at least one surgical procedure. The initial view was that strictureplasty should only be undertaken for recurrent disease and in patients who have had previous multiple resections. The potential benefits of any surgery include symptom relief, improved nutritional sta- tus, and reduced dependence on medication. The most obvious advantage of strictureplasty over resection is that the development of short bowel syndrome can be avoided. All jejunoileal strictures and most duodenal strictures are able to strictureplasty.(121) The procedure can also be undertaken in patients with symptomatic anastomotic strictures. Table 32.3 shows current indications for strictureplasty and contraindications.(122) There are two main types of operation used. The Heineke– Mikulicz procedure is used for strictures of up to 10 cm in length. For strictures up to 25 cm long, the Finney procedure (a side to side amastomosis) is done. Most of the others methods of strictureplasty are generally derivations of one of the above methods, or a combi- nation of both. In 2000, Tichansky et al. published a meta-analysis that showed that Heineke-Mikulicz technique is most often used for Crohn’s strictureplasty. However, the outcome revealed that the Finney strictureplasty may reduce the reoperation rate.(123) 2 improved outcomes in colon and rectal surgery Stricture biopsy The morbidity rate ranges from 10.2–13%, with fistula forma- tion as the most frequent complication.(123) Strictureplasty has been found to be a safe and efficacious procedure for small bowel Crohn’s disease.(124) Resection The most common surgery is ileocolic resection (Figure 32.4a, 32.4b, 32.4c), usually undertaken for medical therapy failure, fistula, obstruction, mass, perforation, or malignancy. The development of malignancy increased to 4 to 20 times of the average population. As previously mentioned, strictureplasty site should be evaluated for intraoperative biopsy and resection, the only procedure which should be considered in the setting of carcinoma. Over the past two decades, laparoscopic resection has demonstrated clear superiority over laparotomy relative to postoperative recovery, cost, morbidity, cosmesis, and long-term bowel obstruction.(125–128) Regardless of the technique of resection performed, the anas- tomosis should be between two and of grossly normal bowel. Histologic disease free margins and further resection add no ben- efit and may predispose to the onset of short bowel syndrome. Bemelman et al. (129) showed that medical therapy was able to prevent surgery in one third of the cases of CD in the terminal ileum. Patients who probably will fail medical therapy are those with stenosis, extraintestinal manifestation, or known history of CD for more than 5 years. Some patients might undergo resection if the obstruction is contra-indicated to have strictureplasty. Many studies compare the outcomes between medical therapy and conventional laparoscopic procedure. A meta-analysis done in 2007 showed 14 studies with 881 patients. The operative time for laparoscopic surgery was longer, but morbidity was lower.(130) The Surgical treatment for large bowel Crohn’s disease has included total proctocolectomy, segmental colectomy or colec- tomy with ileorectal anastomosis (IRA), depending on severity and disease distribution. Conventional proctocolectomy is reserved for those patients with anorectal involvement, but in the 50% of patients with large bowel Crohn’s disease with rectal sparing, Table 32.3 Current indication for strictureplasty and contraindications. Indication Previous extensive (>100 cm) resections of small bowel Short bowel syndrome Duodenal strictures Rapid recurrence of disease with obstruction Strictures at previous anastomotic sites, particularly ileorectal or ileocolic Fibrotic strictures within diffuse involvement of the small bowel Small bowel stricture (active or nonactive disease) Contra indications Perforation of the small bowel, with or without peritonitis Serum albumin <2.0 g dl Fistula or phlegmonous inflammation at intended strictureplasty site Likelihood of tension on closure of strictureplasty Intended strictureplasty site next to segment requiring resection Presence of malignancy Figure 32.4 (A)Terminal ileal strictures are the most common cause for surgery (Picture taken by Wang Hao, M.D., Cleveland Clinic Florida). (B) The best surgical option for stricturing terminal ileal disease is often an ileocolic resection (Picture taken by Wang Hao, M.D., Cleveland Clinic Florida). (C) The length of the narrowing in the small bowel varies. (Picture taken by Wang Hao, M.D., Cleveland Clinic Florida) (A) (B) (C)  surgery for crohn's disease Figure 32.5 (A) After an ileocolic resection, the recurrence is most commoly at the anastomotic site (arrow) (Picture taken by Jorge Canedo, M.D., Cleveland Clinic Florida). (B) A 15 cm stricture; also note the creeping fat (Picture taken by Jorge Canedo, M.D., Cleveland Clinic Florida). (C) Small bowel resection and anastomosis. (Picture taken by Jorge Canedo, M.D., Cleveland Clinic Florida). (D) Note the thick fibrotic stricture (Picture taken by Jorge Canedo, M.D., Cleveland Clinic Florida) (A) (B) (D)(C) resection diminishes over time, especially from more than 20 years after the first resection.(133) Bypass Bypass surgery enjoyed popularity many decades ago, at the begin- ning of CD surgery, when complication rates for resection were high. However, it fell out of use due to high rates of recurrence, great metabolic changes, higher risk of malignancy, and higher rates of postoperative complications.(104) Bypass surgery is currently undertaken for duodenal stricture, although fecal diversion may have a long dysfunctional segment. Diversion without resection may be indicated in very selective situations, like severe perianal disease.(134) POSTOPERATIVE RECURRENCE AFTER SURGERY Rates for recurrence after resection are up to 73% after 1 year, although only 20% of patients have symptoms. After 3 years, recurrence has been noted in 85% of patients, with symptoms present in only 34%. The site of recurrence is usually the anasto- mosis site.(135) segmental resection or colectomy with an ileorectal anastomosis has been used. A meta-analysis done in 2005 comparing segmental ver- sus subtotal ⁄ total colectomy concluded that both procedures were equally effective as treatment options for colonic Crohn’s disease, however, patients in the SC group exhibited recurrence earlier than those in the IRA group.(131) The choice of operation is dependent on the extent of colonic disease. Better outcomes are expected for IRA in patients with two or more colonic segments involved. A meta-analysis done in 2007 compared the end-to-end anas- tomisis to other configurations (132) and found that end-to-end anastomosis after resection for Crohn’s disease may be associated with increased anastomotic leak rates. Side-to-side anastomosis may lead to fewer anastomotic leaks and overall postoperative com- plications, a shorter hospital stay, and a perianastomotic recurrence rate comparable to end-to-end anastomosis. Further randomized, controlled trials should be performed for confirmation Resection is contra-indicated in duodenum stricture, due the high risk of the procedure. In order to avoid short small bowel syndrome, the resection should include macroscopic intestinal disease. It is known that activity of CD necessitating intestinal  improved outcomes in colon and rectal surgery Reoperation for recurrence rates after strictureplasty is between 24–26% after 5 years. Medical therapy may have a great value in lowering rates of recurrence. Smoking significantly increases the risk of recurrence after surgery for CD, especially in women, and it is dose-dependent. Another feature that influences recurrence after surgery is a short duration of disease before surgery. The site of the disease also affects recurrence rates, as small bowel and ileocolic disease have higher rates of recurrence (Figure 32.5a, 32.5b, 32.5c, 32.5d). Perforation is associated with a higher rate of recurrence in patients who have had a colonic resection.(136) Gender, family history of CD, blood transfusion, length of resection, presence of granuloma in the specimen, and postoperative compli- cations do not correlate with recurrence. QUALITY OF LIFE AFTER SURGERY: Patients who undergo surgical treatment for CD experience improve- ment in Health-related Quality of Life (HRQL) up to 1 year after surgery. Most of the studies focus on assessment of quality of life for ileocolic resection, the most common procedure. Controversies exist as to whether there is actually improvement or not in a long term fol- low-up for these patients. Thaler et al. (137) concluded that HRQL actually reduces in patients with CD in a long-term follow-up, no matter whether the surgery was open or laparoscopic compared to a normal control population. And recurrence was the most important factor adversely affecting quality of life. Casellas et al. (138) analyzed the impact of previous surgery for complicated or refractory CD on HRQOL. The results indi- cated that patients with active CD have a serious impairment in HRQOL and patients with a history of previous surgical bowel resection are not different from patients who have never had surgery, as long as those patients remain in clinical remission. REFERENCES 1. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis. A pathological and Clinical entity. JAMA 1932; 99: 1323–9. 2. Lockhart-Mummery HE, Morson BC. Crohn’s disease (regional enteritis) of the large intestine and its distinction from ulcerative colitis. Gut 1960; 1: 87–105. 3. Vermeire S, Rutgeerts P. Chapter 54: Crohn’s Disease in the … edition of Diseases of the Gut and Liver. 4. Heresbach D, Alexandre JL, Bretagne JF. ABERMAD ((Association Bretonne d’Etude et de Recherche sur les Maladies de l’Appareil Digestif). Crohn’s disease in the over- 60 age group: a population based study. Eur J Gastroenterol Hepatol 2004; 16(7): 657–64. 5. Andres PG, Fridman LS. Epidemiology and the natural course of inflammatory bowel disease. Gastroenterology Clin North Am 1999; 28(2): 255–81. 6. Loftus EV Jr, Snadborn WJ. Epidemiology of inflammatory bowel disease. Gastroenterol clin North Am 2002; 31: 1–20. 7. Nikolaus S, Schreiber S. Diagnostics of inflamatory bowel disease. Gastroenterology 2007; 133(5): 1670–89. 8. Gasche C, Lomer MCE, Cavill I. Weiss, G. Iron, anaemia, and inflammatory bowel diseases. Gut 2004; 53(8): 1190–7. 9. Vermeire S, Van Assche G, Rutgeerts P. Laboratory markers in IBD: useful, magic, or unnecessary toys? Gut 2006; 55(3): 426–33. 10. Denis MA, Reenaers C, Fontaine F, Belaïche J, Louis E. Assessment of endoscopic activity index and biological inflamatory markers in clinical active Crohn’s disease with normal c-reative protein serum level. Inflamm Bowel Dis 2007; 13(9): 1100–5. 11. Papp M, Norman GL, Altorjay I, Lakatos PL. Utility of sero- logical markers in inflammatory bowel diseases: Gadget or magic? World J Gastroenterol 2007; 13(14): 2028–36. 12. Ferrante M, Henckaerts L, Joossens M et al. New serological markers in inflammatory bowel disease are associated with complicated disease behaviour. Gut 2007; 56(10): 1394–403. 13. D’Incà R, Dal Pont E, Di Leo V. Calprotectin and lactoferrin in the assessment of intestinal inflammation and organic disease. Int J Colorectal Dis 2007; 22: 429–37. 14. Gionchetti P. Imaging of the small bowel in Crohn’s disease: a review of old and new techniques. World J Gastroenterol 2007; 13(24): 3279–87. 15. Antes G. Barium examinations of the small intestine and the colon in inflammatory bowel disease. Radiologe 2003; 43(1): 9–16. 16. Lemberg DA, Clarkson CM, Bohane TD, Day AS. Role of esophagogastroduodenoscopy in the initial assessment of children with inflammatory bowel disease. J Gastroenterol Hepatology 2005; 20: 1696–700. 17. Isaacs KL. Upper gastrointestinal tract endoscopy in inflam- matory bowel disease. Gastrointest Endosc Clin N Am 2002; 12: 451–62. 18. Nahon S, Bouhnik Y, Lavergne-Slove A et al. Colonoscopy accurately predicts the anatomical severity of colonic Crohn’s disease attacks: correlation with findings from colectomy specimens. Am J Gastroenterol 2002; 97(12): 3102–7. 19. Gan SI, Beck PL. A new look at toxic megacolon: an update and review of incidence, etiology, pathogenesis, and man- agement. AJG 2003; 98(11): 2363–71. 20. Minderhoud IM, Samson M, Oldenburg B. What predicts mucosal inflamation in Crohn’s disease patients? Inflamm Bowel Dis 2007; 13(12): 1567–72. 21. Parente F, Grecoa S, Moltenia M, Anderlonic A, Porroa GP. Imaging inflammatory bowel disease using bowel ultra- sound. Eur J Gastroenterol Hepatol 2005; 17: 283–291. 22. Parente F, Maconi G, Bollani S et al. Bowel ultrasound in assessment of Crohn’s disease and detection of related small bowel strictures. A prospective comparative study versus X-ray andintraoperative findings. Gut 2002; 50: 490–5. 23. Maconi G, Sampietro G, Parente F et al. Contrast radiol- ogy, computer tomography and ultrasonography in detect- ing septic abdominal complications of Crohn’s disease. Am J Gastroenterol 2003; 98: 1545–55. 24. Maconi G, Ardizzone S, Greco S et al. Transperineal ultra- sound in the detection of perianal and rectovaginal fistulae in Crohn’s disease. Am J Gastroenterol 2007; 102(10): 2214–9. 25. Schlottmanna K, Kratzerb W, Schölmericha J. Doppler ultrasound and intravenous contrast agents in gastrointes- tinal tract disorders: current role and future implications. Eur J Gastroenterol Hepatol 2005; 17(3): 263–75. 26. Turetsschek K, Gasche C. Current status and new imaging trends in IBD. In: Bernstein CN, eds. The Inflammatory  surgery for crohn's disease Bowel Disease Yearbook. London: Remedica Publishing, 2003:129–45. 27. Rajesh A, Maglint DDT. Multislice CT enteroclysis: tech- nique and clinical applications. Clin Radiol 2006; 61, 31–9. 28. Andersen K, Vogt C, Blondin D et al. Multi-detector CT colonography in inflammatory bowel disease: prospective analysis of CT-findings to high-resolution video colonos- copy. Eur J Radiol 2006; 8: 140–6. 29. Carrascosa P, Castiglioni R, Capunãy C, López EM, Carrascosa J. CT colonoscopy in inflammatory bowel disease. Abdom Imaging 2007; 32: 596–601. 30. Schwartz DA, Wiersema M, Dudiak KM et al. A comparison of endoscopic ultrasound, magnetic resonance imaging, and exam under anesthesia for evaluation of Crohn’s perianal fistulas. Gastroenterology 2001; 121: 1064–72. 31. Schwartz DA, White CM, Paul E et al. Crohn’s perianal fistulas. Inflamm Bowel Dis 2005; 11: 727–32. 32. Masselli G, Brizi GM, Parrella et al. Crohn disease: magnetic resonance enteroclysis. Abdom Imaging 2004; 29: 326–34. 33. Koh DM, Miao Y, Chinn RJ et al. MR Imaging evaluation of the activity in Crohn’s disease. AJR Am J Roentgenol 2001; 177: 1325–32. 34. Van Assche G, Vanbeckevoort D, Bielen D et al. Magnetic reso- nance imaging of the effects of infliximab on perianal fistuliz- ing Crohn’s disease. Am J Gastroenterol 2003; 98(2): 332–9. 35. Yamamoto H, Kito H. Double-balloon endoscopy. Curr Opin Gastroenterol 2005; 21: 573–7. 36. Oshitani N, Yukawa T, Yamagami H et al. Evaluation of deep small bowel involvement by double-balloon enteroscopy in Crohn’s disease. Am J Gastroenterol 2006; 101(7): 1484–9. 37. Pohl J, May A, Nachbar L, Ell C. Diagnostic and therapeu- tic yield of push-and-pull enteroscopy for symptomatic small bowel Crohn’s disease strictures. Eur J Gastroenterol Hepatol 2007; 19(7): 529–34. 38. Albert JG, Martiny F, Krummenerl A et al. Diagnosis of small bowel Crohn’s disease: a prospective comparison of capsule endoscopy with magnetic resonance imaging and fluoroscopic enteroclysis. Gut 2005; 54(12): 1721–7. 39. Park CH, Kim JO, Choi M et al. Utility of capsule endoscopy for the classification of Crohn’s disease: a multicenter study in Korea. Dig Dis Sci 2007; 52(6): 1405–9. 40. Spada C, Shah SK, Riccioni MEl et al. Video capsule endos- copy in patients with known of suspected small bowel stricture previously tested with the dissolving patency capsule. J Clin Gastroenterol 2007; 41(6): 576–82. 41. Neurath MF, Vehling D, Schunk K et al. Noninvasive assessment of Crohn’s disease activity: a comparison of 18 F-fluorodeoxyglucose positron emission tomography, hydromagnetic resonance imaging, and granulocyte scin- tigraphy with labeled antibodies. Am J Gastroenterol 2002; 97(8): 1978–85. 42. Annovazzi A, Biancone L, Caviglia R et al. 99mTc-inter- leukin-2 and 99mTc-HMPAO granulocyte scintigraphy in patients with inactive Crohn’s disease. Eur J Nucl Med 2003; 30: 374–82. 43. Almer S, Granerus G; Ström M et al. Leukocyte scintigraphy compared to intraoperative small bowel enteroscopy and laparotomy findings in Crohn’s disease. Inflamm Bowel Dis 2007; 13: 164–74. 44. Saibeni S, Rondonotti E, Iozzelli A et al. Imaging of the small bowel in Crohn’s disease: a review of old and new techniques. World J Gastroenterol 2007; 13(24): 3279–87. 45. MacKalski BA, Bernstein CN. New diagnostic imaging tools for inflammatory bowel disease. Gut 2006; 55: 733–41. 46. Bergman R, Parkes M. Systematic review: the use of mesala- zine in inflammatory bowel disease. Aliment Pharmacol Ther 2006; 23(7): 841–55. 47. Nielsen OH, Munck LK. Drug insight: aminosalicylates for the treatment of IBD. Nat Clin Pract Gastroenterol Hepatol 2007; 4(3): 160–70. 48. Sandborn WJ, Feagan BG, Lichtenstein GR. Medical manage- ment of mild to moderate Crohn’s disease: evidence-based treatment algorithms for induction and maintenance of remission. Aliment Pharmacol Ther 2007; 26(7): 987–1003. 49. Qureshi AI, Cohen RD. Mesalamine delivery systems: do they really make much difference? Adv Drug Deliv Rev 2005; 57(2): 281–302. 50. Morikawa K, Watabe H, Araake M. Morikawa S.Modulatory effect of antibiotics on cytokine production by human monocytes in vitro. Antimicrob Agents Chemother 1996; 40(6): 1366–70. 51. Xu G, Fujita J, Negayama K et al. Effect of macrolide antibi- otics on macrophage functions. Microbiol Immunol 1996; 40(7): 473–9. 52. Caprilli R, Gassull MA, Escher JC et al. European Crohn’s and Colitis Organisation. European evidence based consen- sus on the diagnosis and management of Crohn’s disease: special situations. Gut 2006; 55(Suppl 1): i36–58. 53. Summers RW, Switz DM, Sessions JT et al. National co- operative Crohn’s disease study group: results of drug treat- ment. Gastroenterology 1979; 77: 847–69. 54. Malchow H, Ewe K, Brandes JW et al. European co-operative Crohn’s disease study (ECCDS): results of drug treatment. Gastroenterology 1984; 86: 249–66. 55. Irving PM, Gearry RB, Sparrow MP, Gibson PR. Review article: appropriate use of corticosteroids in Crohn’s disease. Aliment Pharmacol Ther 2007; 26(3): 313–29. 56. Steinhart AH, Ewe K, Griffiths AM, Modigliani R, Thomsen OO. Corticosteroids for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev 2003; (4): CD000301. 57. Kane SV, Schoenfeld P, Sandborn WJ et al. The effective- ness of budesonide therapy for Crohn’s disease. Aliment Pharmacol Ther 2002; 16: 1509–17. 58. Sandborn WJ, Löfberg R, Feagan BG et al. Budesonide for maintenance of remission in patients with Crohn’s disease in medically induced remission: a predetermined pooled anal- ysis of four randomized, double-blind, placebo- controlled trials. Am J Gastroenterol 2005; 100(8): 1780–7. 59. Siegel CA, Sands BE. Review article: practical management of inflammatory bowel disease patients taking immuno- modulators. Aliment Pharmacol Ther 2005; 22(1): 1–16. 60. Present DH, Korelitz BI, Wisch N et al. Treatment of Crohn’s disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980; 302(18): 981–7.  improved outcomes in colon and rectal surgery 61. Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med 1995; 123(2): 132–42. 62. Osterman MT, Kundu R, Lichtenstein GR, Lewis JD. Association of 6-thioguanine nucleotide levels and inflamma- tory bowel disease activity: a meta-analysis. Gastroenterology 2006; 130(4): 1047–53. 63. Weinshilboum RM, Sladek SL. Mercaptopurine pharma- cogenetics: Monogenic inheritance of erythrocyte thio- purine methyltransferase activity. Am J Hum Genet 1980; 32: 651–62. 64. Black AJ, McLeod HL, Capell HA et al. Thiopurine meth- yltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med 1998; 129(9): 716–8. 65. Gisbert JP, Nino P, Rodrigo L, Cara C, Guijarro LG. Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long- term follow-up study of 394 patients. Am J Gastroenterol 2006; 101(12): 2769–76. 66. Feagan BG, Rochon J, Fedorak RN et al. Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators. N Engl J Med 1995; 332: 292–7. 67. Feagan BG, Fedorak RN, Irvine EJ et al. A comparison of methotrexate with placebo for the maintenance of remis- sion in Crohn’s disease. North American Crohn’s Study Group Investigators. N Engl J Med 2000; 342: 1627–32. 68. Brynskov J, Freund L, Rasmussen SN et al. A placebo- controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn’s disease. N Engl J Med 1989; 321: 845–50. 69. Brynskov J, Freund L, Norby Rasmussen S et al. Final report on a placebo-controlled, double-blind, randomized, mul- ticentre trial of cyclosporin treatment in active chronic Crohn’s disease. Scand J Gastroenterol 1991; 26: 689–95. 70. Present DH, Lichtiger S. Efficacy of cyclosporine in treatment of fistula of Crohn’s disease. Dig Dis Sci 1994; 39: 374–80. 71. McDonald JW, Feagan BG, Jewell D et al. Cyclosporine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2005; 2: CD000297. 72. Judge TA, Lichtenstein GR. Treatment of fistulizing Crohn’s disease. Gastroenterol Clin North Am 2004; 33: 421–54, xi–xii. 73. Nikolaus S, Bauditz J, Gionchetti P et al. Increased secretion of pro-inflammatory cytokines by circulating polymorpho- nuclear neutrophils and regulation by interleukin-10 during intestinal inflammation. Gut 1998; 42: 470–6. 74. Targan SR, Hanauer SB, van Deventer SJ et al. A short- term study of chimeric monoclonal antibody cA2 to tumor necrosis factor _ for Crohn’s disease. Crohn’s Disease cA2 Study Group. N Engl J Med 1997; 337: 1029–35. 75. Hanauer SB, Feagan BG, Lichtenstein GR et al. Maintenance Infliximab for Crohn’s disease: the ACCENT I randomized trial. Lancet 2002; 359: 1541–9. 76. Rutgeerts P, Feagan BG, Lichtenstein GR et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease. Gastroenterology 2004; 126: 402–13. 77. Baert F, Noman M, Vermeire S et al. Influence of immuno- genicity on the long-term efficacy of Infliximab in Crohn’s disease. N Engl J Med 2003; 348: 601–8. 78. Hanauer SB, Feagan BG, Lichtenstein GR et al. ACCENT I Study Group. Maintenance Infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002; 359: 1541–9. 79. Baert F, Noman M, Vermeire S et al. Influence of immuno- genicity on the long-term efficacy of Infliximab in Crohn’s disease. N Engl J Med 2003; 348: 601–8. 80. Farrell RJ, Alsahli M, Jeen YT et al. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial. Gastroenterology 2003; 124(4): 917–24. 81. Present DH, Rutgeerts P, Targan S et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999; 340: 1398–405. 82. Sands BE, Anderson FH, Bernstein CN et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med 2004; 350: 876–85. 83. Hanauer SB, Sandborn WJ, Rutgeerts P et al. Human anti- tumor necrosis factor monoclonal antibody (Adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology 2006; 130: 323–33. 84. Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel JF, Panaccione R et al. Adalimumab induction therapy for Crohn disease previously treated with Infliximab. A randomized trial. Ann Intern Med 2007; 146: 829–38. 85. Becker JM. Surgical therapy for Ulcerative Colitis and Crohns Disease. Gastroentero Clinic North Am 1999; 28: 371–390, viii–ix. 86. Mekhjian HS, Switz DM, Watts HD et al: National Cooperative Crohns Disease Study: Factors determining recurrence of Crohns disease after surgery. Gastroenterology 1979; 77: 907–13. 87. Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn’s disease. Ann Surg 2000; 231: 38–45. 88. Rutgeerts P, Geboes K, Vantrappen G et al. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990; 99: 956–63. 89. Caprilli R, Corrao G, Taddei G et al: Prognostic factors for postoperative recurrence of Crohn’s disease. Gruppo Italiano per lo Studio del Colon e del Retto (GISC). Dis Colon Rectum 1996; 39: 335–41. 90. Cammà C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn’s disease: a metaanaly- sis adjusted for confounding variables. Gastroenterology 1997; 113: 1465–73. 91. Cottone M, Camma C. Mesalamine and relapse prevention in Crohn’s disease. Gastroenterology 2000; 119: 597. 92. Hanauer SB, Korelitz BI, Rutgeerts P et al. Present DH. Postoperative maintenance of Crohn’s disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial. Gastroenterology 2004; 127(3): 723–9. 93. Ardizzone S, Maconi G, Sampietro GM et al. Azathioprine and mesalamine for prevention of relapse after conservative surgery for Crohn’s disease. Gastroenterology 2004; 127(3): 730–40.  surgery for crohn's disease 94. Rutgeerts P, Hiele M, Geboes K et al. Controlled trial of metronidazole treatment for prevention of Crohn’s recur- rence after ileal resection. Gastroenterology 1995; 108(6): 1617–21. 95. Rutgeerts P, Van Assche G, Vermeire S et al. Ornidazole for prophylaxis of postoperative Crohn’s disease recurrence: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2005; 128(4): 856–61. 96. Sorrentino D, Terrosu G, Avellini C, Maiero S. Infliximab with low-dose methotrexate for prevention of postsurgical recurrence of ileocolonic Crohn disease. Arch Intern Med 2007; 167(16): 1804–7. 97. Kotze LMS. Crohn’s Disease. In: Dantas W, Koltze LMS, eds. Condutas em gastroenterologia 1st Ed. Editora Revinter, Rio de Janeiro-RJ, 2004: 216–38. 98. Fishera A, Fabrizio M. Surgical Treatment of Crohn’s Disease. J Gastrointest Surg 2007; 11: 791–803. 99. Hancock L, Windsor AC, Mortensen NJ. Inflammatory bowel disease: the view of the surgeon. Colorectal disease 2006; 8 (suppl 1): 10–4. 100. Diziki A, Galbfach P. Crohn’s disease when to operate? Acta Chir Iugosl 2004; 51(2): 61–8. 101. Siassi M, Weiger A, Hohenberger W, Kessler H. Changes in surgical therapy for Crohn’s disease over 33 years: a prospec- tive longitudinal study. Int J Colorectal Dis 2007; 22: 319–24. 102. Gasche C, Scholmerich J, Brynskov J et al. A simple classi- fication of Crohn’s disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 2000; 6(1): 8–15. 103. Bundred NJ, Dixon JM, Lumsden AB, Gilmour HM, Davies GC. Free perforation in Crohn’s colitis: a ten year review. Dis Colon Rectum 1985; 28: 35–7. 104. Keighley MRB. Surgical Management of Crohn’s Disease in the Small Bowel (Chapter 55). In: Surgery of the Anus, Rectum and Colon, eds. Keighley MRB, Williams NS. 1st Edtion in Brasil. Editora Manole Ltda, São Paulo-SP, 1998: 1608–50. 105. Mahadevan U, Young-Fadok T. Crohn’s Disease of the colon. In: Diseases of the Colon, eds. Wexner SD, Stollman N. Informa Healthcare USA, Inc. New York-NY, 2007: 625–46. 106. Yamaguchi A, Matsui T, Sakurai T et al. The clinical charac- teristics and outcome of intraabdominal abscess in Crohn’s disease. J Gastroenterol 2004; 39(5): 441–8. 107. Khaikin M, Chowers Y, Zmora O. Perianal Crohn’s Disease. IMAJ 2007; 9: 163–8. 108. Kodner IJ, Mazor A, Shemesh EI et al. Endorectal advance- ment flap repair of rectovaginal and other complicated anorectal fistulas. Surgery 1993; 114: 682–90. 109. O’connor L, Champagne BJ, Ferguson MA et al. Efficacy of anal fistula plug in closure of Crohn’s anorectal fistulas. Dis Colon Rectum 2006; 49: 1569–73. 110. Rius J, Nessim A, Nogueras JJ, Wexner SD. Gracilis transpo- sition in complicated perianal fistula and unhealed perineal wounds in Crohn’s disease. Eur J Surg 2000; 166: 218–22. 111. Pikarsy AJ, Gervaz P, Wexner SD. Perianal Crohn disease: a new scoring system to evaluate and predict outcome of surgical intervention. Arch Surg 2002; 137: 774–7. 112. Yamazaki Y, Ribeiro MB, Sachar DB, Aufses AH Jr, Greenstein AJ. Malignant strictures in Crohn’s disease. Am J Gastroenterol 1991; 86: 882–5. 113. Takesue Y, Yokoyama T, Akagi S et al. Strictureplasty for short duodenal stenosis in Crohn’s disease. J Gastroenterol 2000; 35: 929–32. 114. Berg DF, Bahadursingh AM, Kaminski DL, Longo WE. Acute surgical emergencies in inflammatory bowel disease. Am J Surg 2002; 184: 45–51. 115. Cirocco WC, Reilly JC, Rusin LC. Life-threatening hemor- rhage and exsanguination from Crohn’s disease. Report of four cases. Dis Colon Rectum 1995; 38: 85–95. 116. Kazama Y, Watanabe T, Akahane M et al. Crohn’s disease with life-threatening hemorrhage from terminal ileum: successful control by superselective arterial embolization. J Gastroenterol 2005; 40: 1155–7. 117. Ng SC, Kamm MA. Fulminant Crohn’s colitis: when only an antibody will do. Inflamm Bowel Dis 2007; 13(8): 971–4. 118. Greenstein AJ, Sachar DB, Gibas A et al. Outcome of toxic dilatation in ulcerative colitis and Crohn’s colitis. J Clin Gastroenterol 1985; 7(2): 137–43. 119. Hamel CT, Hildebrandt U, Weiss EG, Feifelz G, Wexner SD. Laparoscopic surgery for inflammatory bowel disease: Ileocolic resection vs subtotal colectomy. Surg Endosc 2001; 15: 642–5. 120. Reissman P, Salky BA, Pfeifer J et al. Laparoscopic surgery in the management of inflammatory bowel disease. Am J Surg 1996; 171(1): 47–51. 121. Roy P, Kumar D. Strictureplasty. Br J Surg 2004; 91: 1428–37. 122. Roy P, Kumar D. Strictureplasty for active Crohn’s disease. Int J Colorectal Dis 2006; 21: 427–32. 123. Tichansky D, Cagir B, Yoo E, Marcus SM, Fry RD. Strictureplasty for Crohn’s disease: meta-analysis. Dis Colon Rectum 2000; 43: 911–9. 124. Fernhead NS, Chowdhury R, Box B et al. Long-term follow-up of strictureplasty for Crohn’s disease. Br J Surg 2006; 93(4): 475–82. 125. Wexner SD, Johansen OB. Laparoscopic bowel resection: advantages and limitations. Ann Med 1992; 24: 105–10. 126. Schmitt SL, Cohen SM, Wexner SD, Nogueras JJ, Jagelman DG. Does laparoscopic-assisted ilealpouch anal anastomo- sis reduce the length of hospitalization? Int J Colorectal Dis 1994; 9: 134–7. 127. Fichera A, Peng SL, Elisseou NM, Rubin MA, Hurst RD. Laparoscopy or conventional open surgery for patients with ileocolonic Crohn’s disease? A prospective study. Surgery 2007; 142(4): 566–71. 128. Tan JJ, Tjandra JJ. Laparoscopic surgery for Crohn’s disease: a meta-analysis. Dis Colon Rectum 2007; 50: 576–85. 129. Bemelman WA, Ivenski M, van Hogezand RA et al. How effective is extensive nonsurgical treatment of patients with clinically active Crohn’s disease of the terminla ileum in preventing surgery? Dig Surg 2001; 18: 56–60. 130. Tekkis PP, Purkayastha S, Lanitis S et al. A comparison of segmental vs subtotal/total colectomyfor colonic Crohn’s disease: a meta-analysis. Colorectal Dis 2006; 8: 82–90. 131. Simillis C, Pukayastha S, Yamamoto T et al. A meta-anal- ysis comparing conventional end-to-end anastomosis vs. . D’Incà R, Dal Pont E, Di Leo V. Calprotectin and lactoferrin in the assessment of intestinal inflammation and organic disease. Int J Colorectal Dis 2007; 22: 429–37. 14. Gionchetti P. Imaging. clinically relevant finding and the financial cost and effort spent in taking these medications merit their use is highly debatable. Azathioprine and 6-MP have both been used exten- sively in.  improved outcomes in colon and rectal surgery Although TPMT testing is helpful in avoiding early, profound bone marrow suppression, it should not take the place of careful monitoring of