Lisa S. Poritz

Remicade does not abolish the need for surgery in fistulizing Crohn's disease.

AbstractPURPOSE: Tumor necrosis factor antagonist therapy in the form of infliximab has been shown to promote significant healing in fistulizing Crohn’s disease and therefore is often considered as a possible alternative to surgery. Our aim was to evaluate the role of infliximab in supplanting surgery for fistulizing Crohn’s disease. METHODS: We performed a retrospective chart review of all adult patients who received infliximab for fistulizing Crohn’s disease at one institution between September 1998 and October 2000. RESULTS: Twenty-six patients (14 male; mean age, 38 years; range, 19–80 years) received a mean of three (range, one to six) doses of infliximab (5 mg/kg) with the intent to cure fistulizing Crohn’s disease. Nine patients (35 percent) had perianal, 6 (23 percent) enterocutaneous, 3 (12 percent) rectovaginal, 4 (15 percent) peristomal, and 4 (15 percent) intra-abdominal fistulas. Nineteen (73 percent) of the patients had had prior surgery for Crohn’ s disease. Six patients (23 percent) had a complete response to infliximab with fistula closure, 12 (46 percent) had a partial response, and 8 (31 percent) had no response to infliximab. Fourteen (54 percent) patients still required surgery for their fistulizing Crohn’s disease after infliximab therapy (10 bowel resections, 4 perianal procedures), whereas half (6/12) of the patients treated with infliximab who still had open fistulas after treatment declined surgical intervention. Five of six patients with fistula closure on infliximab had perianal or rectovaginal fistulas. None of the patients with either enterocutaneous or peristomal fistulas were healed with infliximab. CONCLUSIONS: Although it was associated with a 61 percent complete or partial response rate, infliximab therapy did not supplant the need for surgical intervention in the majority of our patients with fistulizing Crohn’s disease. Seventy-three percent of the patients either required surgery or still had open fistulas after infliximab therapy. Infliximab was much more effective in treating perianal disease than abdominal enterocutaneous disease.

Dehydration Is the Most Common Indication for Readmission After Diverting Ileostomy Creation

BACKGROUND: Early readmission after discharge from the hospital is an undesirable outcome. Ileostomies are commonly used to prevent symptomatic anastomotic complications in colorectal resections. OBJECTIVE: The aim of this study was to identify factors predictive of readmission after colectomy/proctectomy and diverting loop ileostomy. DESIGN: This study is a retrospective review. PATIENTS: Patients were included who underwent colon and rectal resections with ileostomy at our institution. Sex, age, type of disease, comorbidities, elective vs urgent procedure, type of ileostomy, operative method, steroid use, ASA score, and the use of diuretics were evaluated as potential factors for readmission. MAIN OUTCOME MEASURES: The primary outcomes measured were the need for readmission and the presence of dehydration (ostomy output ≥1500 mL over 24 hours and a blood urea nitrogen/creatinine level ≥20, or physical findings of dehydration). RESULTS: Six hundred three loop ileostomies were created mostly in white (95.3%), male (55.6%) patients undergoing colon or rectal resections. IBD was the most common indication at 50.9%, with rectal cancer at 16.1%, and other at 31.0%. The 60-day readmission rate was 16.9% (n = 102) with the most common cause dehydration (n = 44, 43.1%). Regression analysis demonstrated that the laparoscopic approach (p = 0.02), lack of epidural anesthesia (p = 0.004), preoperative use of steroids (p = 0.04), and postoperative use of diuretics (p = 0.0001) were highly predictive for readmission. Furthermore, regression analysis for readmission for dehydration identified the use of postoperative diuretics as the sole risk factor (p = 0.0001). LIMITATIONS: This study is limited by the retrospective analysis of data, and it does not capture patients that were treated at home or in clinic. CONCLUSION: Readmission after colon or rectal resection with diverting loop ileostomy was high at 16.9%. Dehydration was the major cause for readmission. Patients receiving diuretics are at increased risk for readmission for dehydration. High-risk patients should be treated more cautiously as inpatients and closely monitored in the outpatient setting to help reduce dehydration and readmission.

Tumor necrosis factor alpha disrupts tight junction assembly

BACKGROUND We have previously shown an increase in intestinal permeability and a corresponding decrease in the expression of tight junction (TJ) proteins in the in testines of patients with Crohns disease (CD). Tumor necrosis factor-alpha (TNFalpha) has been implicated in the inflammatory process of CD and its suppression has therapeutic benefit. ZO-1, occludin, and the claudins are key proteins in the TJ. HYPOTHESIS TNFalpha disrupts the TJ. METHODS MDCK cells were incubated with TNFalpha (0-100 ng/ml) for 5 days. Qualitative evaluation of the TJ was done with monoclonal antibody to ZO-1 detected by an immunofluorescence. Duplicate cells were lysed and ZO-1, occludin, and claudin-1 amount determined by western blot. RESULTS Immunofluorescent staining of MDCK cells for ZO-1 showed TJ structural disruption with increasing amount of TNFalpha characterized by fragmented staining of ZO-1. There were no significant differences in quantitation of ZO-1 or occludin in the MDCK cells for all TNFalpha concentrations. There was a significant decrease in the amount of claudin-1 with increasing concentration of TNFalpha. CONCLUSIONS (1) MDCK TJs are qualitatively disrupted by TNFalpha. (2) This disruption is not because of a decrease in cell number, lack of cell layer confluency, or a decrease in the amount of ZO-1 or occludin. (3) The amount of claudin-1 present in the cell is decreased with increasing amounts of TNFalpha suggesting that the lack of claudin-1 may cause a relocation of ZO-1 away from the TJ. (4) This rearrangement may play a role in the increased intestinal permeability seen in CD and other diseases.

Identification of disease-associated DNA methylation in intestinal tissues from patients with inflammatory bowel disease

Lin Z, Hegarty JP, Cappel JA, Yu W, Chen X, Faber P, Wang Y, Kelly AA, Poritz LS, Peterson BZ, Schreiber S, Fan J‐B, Koltun WA. Identification of disease‐associated DNA methylation in intestinal tissues from patients with inflammatory bowel disease.

Extended follow-up of patients treated with cytotoxic chemotherapy for intra-abdominal desmoid tumors.

BACKGROUND: Cytotoxic chemotherapy can achieve a good initial response in inoperable desmoid tumors that have caused progressive obstruction of the gastrointestinal and urinary tracts and have caused unrelenting pain. METHODS: We have reviewed 8 patients (3 male) with desmoid tumors and familial adenomatous polyposis who underwent cytotoxic chemotherapy for inoperable gastrointestinal obstruction and/or uncontrolled pain. They were treated with doxorubicin and dacarbazine followed by carboplatin and dacarbazine. RESULTS: Follow-up after cytotoxic chemotherapy in the 7 patients for whom it was available was a mean of 42 (range 24–54) months. Two patients achieved complete remission after therapy. Four patients achieved a partial remission after completing all or some of the chemotherapy regimen; of these, three remained in stable remission, whereas the other was lost to follow-up. There were two recurrences that required further therapy; one of these patients was treated with further chemotherapy, which induced a second remission, and the other was treated with pelvic exenteration and has subsequently died. CONCLUSIONS: Most patients had a substantial response to cytotoxic chemotherapy; however, two patients required additional therapy 24 and 30 months after cytotoxic chemotherapy, respectively. Cytotoxic chemotherapy is effective in producing short-term and long-term remission in these difficult patients.

Factors affecting surgical risk in elderly patients with inflammatory bowel disease

The operative treatment of elderly patients with inflammatory bowel disease (IBD) has often been avoided in favor of medical management because of a perceived increase in surgical risk. This study sought to define the following in the elderly IBD patient population: (1) the risk of surgical management and (2) those factors affecting risk. Thirty patients with IBD, aged 60 years or more, who were surgically managed by a single surgeon over a 10-year period, were retrospectively matched to 75 patients with IBD who were less than 60 years of age; patients were matched according to sex, date of surgery, and type of surgery performed. Regression analysis using generalized estimating equation methodology to account for the matched clusters of patients was performed to evaluate the effect of age group on the complication rate, operating room time, and length of hospital stay. Presence of comorbid conditions, surgical indications, prior surgery for IBD, and the use of immunosuppressive medications were studied in multivariate models, adjusting for age group. By means of univariate analysis, the odds of complications in elderly IBD patients were shown to be statistically higher than the odds seen in younger patients (47% vs. 20%, P= 0.01). Also observed in the elderly group were a longer length of hospital stay (11.5 days vs. 7.1 days, P = 0.001) and longer operating room time (249 minutes vs. 212 minutes, P= 0.02). Multivariate analysis revealed that the effect of age remained statistically significant, even when adjusted for potential confounding variables such as comorbidity, medications, date of diagnosis of IBD, and indications for surgery. The complication outcome was significantly associated with the surgical indication, with obstruction, fistula, and bleeding having increased odds of complications as compared with other indications (odds ratio = 1.7 vs. 4.2 vs. 7.2, respectively, P= 0.02). The length of hospital stay similarly was significantly associated with the surgical indication (fistula, 10.5 days vs. bleeding, 9.8 days vs. obstruction, 7.4 days vs. other, 9.3 days; P= 0.04) and a history of prior surgery. A significant interaction for length of hospital stay was present between age group and prior surgery status (with prior surgery: old, 18 days vs. young, 6.4 days, P= 0.0001; without prior surgery: old, 9.5 days vs. young 7.3 days, P= 0.10). Elderly patients with IBD have an increased rate of postoperative complications along with an increased length of hospital stay and increased operating room time. This effect of age persists when adjusted for comorbidity and immuno-suppressive therapy. Complications are most dependent on surgical indications, with obstruction being the least and bleeding the worst predictive factors. The longest hospital stay is associated with patients who require surgery for fistulous disease and patients who have undergone previous surgery. The fact that the higher complication rate seen in older patients with IBD is associated with disease-defined surgical indications suggests that IBD in elderly patients may be more aggressive than what is observed in younger individuals.

Management of peristomal pyoderma gangrenosum.

BACKGROUND Pyoderma gangrenosum (PG) occurs in about 1% to 5% of patients with inflammatory bowel disease (IBD). Peristomal pyoderma gangrenosum (PPG) is particularly difficult to manage. STUDY DESIGN A retrospective chart review was performed on all patients with IBD in whom PPG developed from 1997 to 2007 at the Milton S Hershey Medical Center. RESULTS Sixteen patients (11 women) were identified. Seven had Crohns disease (CD), seven had ulcerative colitis (UC), and two had indeterminate colitis. Six patients underwent total proctocolectomy, six patients had total abdominal colectomy (TAC), and four patients had diverting loop stomas. PPG occurred an average of 18.4+/-7.5 months after stoma creation. Twelve patients had active IBD when PPG developed. Two patients had stoma revisions and both had recurrence of the PPG with the new stoma. Medical therapy was successful in eight patients. Five patients had their stomas closed, with active PPG, and all five resolved their lesions. In four of five, surgical management was altered because of PPG (one early stoma closure, two ileal pouches without stomas, one ileal pouch with high body mass index). Of the seven and six patients treated with cyclosporine or infliximab, respectively, there were only two successes with each. CONCLUSIONS PPG is more common in the presence of active IBD. Surgical closure of the stoma was successful in resolving PPG in all patients. Cure rate of PPG was poor with cyclosporine and only marginally better with infliximab. Medical treatment of PPG is imperfect, and the best therapy is stoma closure when possible.

Risk Factors for Surgical Site Infections after Colorectal Resection in Diabetic Patients

BACKGROUND Surgical site infections (SSIs) are a well known complication of gastrointestinal surgery and associated with an increased morbidity, mortality and overall cost. Diabetes mellitus (DM) is a risk factor for SSI. However, there is no clear consensus as to which other risk factors play a significant role. The goal of this study was to identify risk factors associated with SSI in patients with DM undergoing colorectal resection. STUDY DESIGN A retrospective review was conducted of DM patients who underwent colorectal resection from June 2000 to June 2009 at Milton S Hershey Medical Center, Division of Colorectal Surgery. Individual measures were analyzed using chi-square, t-test, and Mann-Whitney U tests, and statistical significance was confirmed using a multiple logistical regression model. RESULTS There were 183 DM patients included in the study, 28 (15%) of whom developed SSI. Glucose levels were significantly higher in the SSI group for each time interval, 0 to 6 hours (211 mg/dL, p = 0.03), 0 to 48 hours (176 mg/dL, p = 0.001), and 48 to 96 hours (167 mg/dL, p = 0.012) postoperatively. Other measures significantly associated with SSI included the use of drains (p = 0.05) and the use of prophylactic antibiotics for more than 24 hours (p = 0.02). Body mass index and stoma creation approached statistical significance (p = 0.08, 0.07, respectively). The type of hypoglycemic regimen, immunosuppression, and emergency surgery were not associated with an increased rate of SSI. CONCLUSIONS Higher than normal glucose control at all postoperative time intervals was associated with SSI. The majority of glucose levels were below the American Diabetes Association recommended level of 200 mg/dL, but patients still developed SSI. Type of perioperative glucose control did not affect the incidence of SSI. These data suggest that DM patients undergoing colectomy should have glucose tightly controlled, avoid placement of drains, and receive antibiotics for less than 24 hours.

Cytomegalovirus enteritis: a highly lethal condition requiring early detection and intervention.

Cytomegalovirus infection causing symptomatic enteritis is most usually associated with immunosuppressed transplant patients or patients positive for human immunodeficiency virus. Most reports studying this illness are small and do not clearly define the risk factors or mortality rates. METHODS: The present study retrospectively reviewed the charts of 67 patients with biopsy-proven cytomegalovirus enteritis (esophageal, gastric, small bowel, and colonic) to define and to investigate factors that influence survival. Patients were classified into four groups based on underlying medical condition: 1) patients positive for human immunodeficiency virus; 2) transplant patients receiving immunosuppressive medications; 3) immunosuppressed nontransplant patients; and 4) otherwise healthy individuals. Mortality rates based on underlying medical condition, location of intestinal cytomegalovirus infection, cytomegalovirus therapy, age, and average days to institution of treatment were defined and statistically assessed. RESULTS: Mortality was significantly greater in the normal patient group (80 percent) than in the transplant (21 percent), other immunosuppressed (44 percent), or human immunodeficiency virus-positive (75 percent) groups (P=0.0006, Cochran-Mantel-Haenszel statistics). There was no difference in mortality based on intestinal location of disease or treatment modality (surgery, medical therapy, or both). Cohorts of patients older than 65 years had a statistically higher mortality ratevs. those younger than 65 years old (68vs. 38 percent;P=0.05, Cochran-Mantel-Haenszel statistics). Statistically increased mortality was also associated with increased time from hospital admission to institution of cytomegalovirus treatment, whether therapy was medication alone or medication and surgery (P < 0.05, exact Wilcoxons test). CONCLUSIONS: 1) Lethal cytomegalovirus enteritis can arise in patient populations not typically identified as being at risk for this disorder, including normal individuals. 2) Mortality in cytomegalovirus enteritis is adversely associated with age older than 65 years and increased time to institution of therapy but is not affected by anatomic site of infection or particular form of treatment. Paradoxically, in this study, normal patients had the highest mortality, which we attribute to a low index of suspicion and relatively late institution of therapy.

NOD2/CARD15 Mutations Correlate With Severe Pouchitis After Ileal Pouch-Anal Anastomosis

PURPOSE: Pouchitis and Crohns-like complications can plague patients after IPAA. NOD2 is an intracellular sensor for bacterial cell wall peptidoglycan. NOD2 mutations compromise host response to enteric bacteria and are increased in Crohns disease. We hypothesize that IPAA patients with complications (Crohns disease-like/pouchitis) have a higher rate of NOD2 mutations compared with asymptomatic IPAA patients. METHODS: Patients were retrospectively subclassified into the following groups: 1) IPAA with Crohns-like complications (n = 28, perianal fistula, pouch inlet stricture/upstream small-bowel disease, or biopsies showing granulomata) occurring at least 6 months after ileostomy closure; 2) IPAA with mild pouchitis (n = 33, ≤3 episodes/y for 2 consecutive years); 3) IPAA with severe pouchitis (n = 9, ≥4 episodes/y for 2 consecutive years or need for continuous antibiotics); 4) IPAA without complications or pouchitis (n = 37); 5) patients with Crohns disease with colitis undergoing total proctocolectomy/ileostomy (n = 11); and 6) healthy controls (n = 269). The 3 NOD2 single-nucleotide polymorphism mutations (rs2066844, rs2066845, and rs2066847) previously identified as associated with Crohns disease were genotyped using polymerase chain reaction. Groups were compared by use of &khgr;2 with Yates continuity correction. RESULTS: NOD2 mutations were found in 8.5% of healthy controls. NOD2 mutations were significantly higher in the severe pouchitis group (67%) compared with both asymptomatic IPAA (5.4%, P < .001) and IPAA with Crohns disease-like complications (14.3%, P = .008) groups. CONCLUSIONS: 1) Asymptomatic IPAA patients have a low incidence of NOD2 mutations not significantly different from patients with mild pouchitis or healthy controls. 2) Patients with severe pouchitis had the highest incidence of NOD2 mutations, suggesting that this group may have a compromised host defense mechanism to enteric bacteria. 3) Patients with Crohns-like complications after IPAA have a significantly lower incidence of NOD2 mutations than patients with severe pouchitis, suggesting a different genetic makeup in these 2 patient groups. Preoperative assessment of NOD2 in the equivocal IPAA candidate may predict severe pouchitis and might assist in preoperative surgical decision making.