Perforating Crohn's disease: conservative and surgical treatment.

Surgery is a part of the clinical history of patients with Crohn's disease (CD) since nearly all the patients receive at least one surgical procedure. The main indication for surgery is obstruction, but 50-60% of patients present a concomitant perforating disease at surgery, and 10% of patients have a primary indication for abscess or fistula. Generally, fistulas are classified on an anatomical basis, indicating the site of origin followed by the target (i.e. ileocolic, ileovesical, etc.). Enteroenteric fistulas are frequently asymptomatic and are not always considered an indication for surgery. However, in case of bypass with severe malnutrition or bacterial overgrowth (i.e. duodenal involvement), surgery is the only option. Enterovesical, enteroureteral and enterobiliary fistulas, due to their potential for septic complications, are a definite indication for surgery. Enterogenital fistulas have an indication mainly for their impact on the quality of life. Enterocutaneous fistulas are, in most cases, a late surgical complication, and the indication and timing for treatment are due to their output volume. Abscesses may be present alone or in association with enteric fistulas. The initial approach is conservative, and a percutaneous drainage should be a good treatment or a bridge to elective surgery. Since a modern surgical approach to CD has to be minimally invasive and highly conservative whenever possible, the presence of perforating disease should be well characterized in order to plan a laparoscopic approach and to reduce the amount of resected bowel, in case combining resection and strictureplasty. Perforating CD necessitates a multidisciplinary approach involving, behind the gastroenterologist and the surgeon, the radiologist, the urologist, the gynecologist and the nutritionist in order to obtain the best tailored treatment.

Watchful Waiting After Radiological Guided Drainage of Intra-abdominal Abscess in Patients With Crohn's Disease Might Be Associated With Increased Rates of Stoma Construction.

Background: Management of spontaneous intra-abdominal abscess (IAA) in patients with Crohn's disease (CD) with radiologically guided percutaneous drainage (PD) was debated. Methods: This is a secondary analysis from a multicenter, retrospective cohort study of all the patients with CD who underwent PD followed by surgery at 19 international tertiary centers. Results: Seventeen patients (4.8%) who did not undergo surgery after PD were compared to those who had PD followed by surgical intervention 335/352 (95.2%). Patients who had PD without surgery were those with longer disease duration, more frequently had previous surgery for CD (laparotomies/laparoscopies), enteric fistula, on steroid treatment before and continue to have it after PD. Patients who had PD without subsequent surgical resection had a higher risk of stoma construction at later stages 8/17 (47.1%) versus 90/326 (27.6%) (P < .01). Patients with PD with no subsequent surgery had numerically higher rates of abscess recurrence 5/17 (29.4%) compared to those who had PD followed by surgery 45/335 (13.4%) the difference was not statistically significant (P = .07). Conclusions: Even with the low number of patients enrolled in this study who had PD of IAA without subsequent surgery, the findings indicate a markedly worse prognosis in terms of recurrence, length of stay, readmission, and stoma construction. Watchful waiting after PD to treat patients with spontaneous IAA might be indicated in selected patients with poor health status or poor prognostic factors.

Surgical site infections caused by multi-drug resistant organisms: a case-control study in general surgery.

Multi-drug resistant organisms (MDR-Os) are emerging as a significant cause of surgical site infections (SSI), but clinical outcomes and risk factors associated to MDR-Os-SSI have been poorly investigated in general surgery. Aims were to investigate risk factors, clinical outcomes and costs of care of multi-drug resistant organisms (MDR-Os-SSI) in general surgery. From January 2018 to December 2019, all the consecutive, unselected patients affected by MDR-O SSI were prospectively evaluated. In the same period, patients with non-MDR-O SSI and without SSI, matched for clinical and surgical data were used as control groups. Risk factors for infection, clinical outcome, and costs of care were compared by univariate and multivariate analysis. Among 3494 patients operated on during the study period, 47 presented an MDR-O SSI. Two control groups of 47 patients with non-MDR-O SSI and without SSI were identified. MDR-Os SSI were caused by poly-microbial etiology, meanly related to Gram negative Enterobacteriales. MDR-Os-SSI were related to major postoperative complications. At univariate analysis, iterative surgery, open abdomen, intensive care, hospital stay, and use of aggressive and expensive therapies were associated to MDR-Os-SSI. At multivariate analysis, only iterative surgery and the need of total parenteral and immune-nutrition were significantly associated to MDR-Os-SSI. The extra-cost of MDR-Os-SSI treatment was 150% in comparison to uncomplicated patients. MDR-Os SSI seems to be associated with major postoperative complications and reoperative surgery, they are demanding in terms of clinical workload and costs of care, they are rare but increasing, and difficult to prevent with current strategies.

Repeated surgery for recurrent Crohn's disease: does the outcome keep worsening operation after operation? A comparative study of 1224 consecutive procedures.

Complicated Crohn's disease (CD) will require surgical treatment during patients' lifetime, with a considerable recurrence rate requiring additional surgery. The present study is a retrospective analysis of a prospectively maintained database in an IBD Tertiary Centre that included all the consecutive, unselected patients undergoing surgery for CD between 1993 and 2019. Patients treated with small bowel resections, colonic resections, conventional and non-conventional strictureplasties were considered. The aim was to evaluate morbidity and long-term recurrence of repeated surgery. Among the population included, the following procedures were performed: 713 (58.2%) primary surgery (group S1), 325 (26.5%) first recurrence (group S2), and 186 (15.3%) multiple recurrences (group S3). Patients undergoing repeat surgery were older (p < 0.0001) and had a longer disease duration (p < 0.0001), extended disease (p = 0.0001), shorter time frame to first surgery (p < 0.0001), nutritional impairment (p < 0.0001), and a history of aggressive medical therapy (p = 0.04). Patients undergoing surgery for recurrences required higher complexity level surgery, with more conservative approaches (p = 0.0004) and a higher ostomy number (p = 0.06). Recurrent patients had higher short bowel syndrome rate (p < 0.0001), higher minor (p = 0.04) but not major (p = 0.2) postoperative complications rate. The 10-year surgical recurrence rate was 18% for group S1, 27% for S2, and 48% for S3, with significant differences at the log-rank test. Repeated surgery for complicated CD was associated with an increased rate of minor, but not major complications, requiring high-risk surgery, with a major ostomy rate and short bowel syndrome, and is associated with an increased long-term surgical recurrence, even on strictureplasty sites.

Has the Removing of the Mesentery during Ileo-Colic Resection an Impact on Post-Operative Complications and Recurrence in Crohn's Disease? Results from the Resection of the Mesentery Study (Remedy).

Some evidence suggests a reduction in clinical and surgical recurrence after mesenteric resection in Crohn's Disease (CD). The aim of the REsection of the MEsentery StuDY (Remedy) was to assess whether mesenteric removal during surgery for ileocolic CD has an impact in terms of postoperative complications, endoscopic and ultrasonographic recurrences, and long-term surgical recurrence. Among the 326 patients undergoing primary resection between 2009 and 2019 in two referral centers, in 204 (62%) the mesentery was resected (Group A) and in 122 (38%) it was retained (Group B). Median follow-up was 4.7 ± 3 years. Groups were similar in the peri-operative course. Endoscopic and ultrasonographic recurrences were 44.6% and 40.4% in Group A, and 46.7% and 41.2% in Group B, respectively, without statistically significant differences. The five-year time-to-event estimates, compared with the Log-rank test, were 3% and 4% for normal or thickened mesentery (p = 0.6), 2.8% and 4% for resection or sparing of the mesentery (p = 0.6), and 1.7% and 5.4% in patients treated with biological or immunosuppressants versus other adjuvant therapy (p = 0.02). In Cox's model, perforating behavior was a risk factor, and biological or immunosuppressant adjuvant therapy protective for surgical recurrence. The resection of the mesentery does not seem to reduce endoscopic and ultrasonographic recurrences, and the five-year recurrence rate.

Prevalence and significance of mesentery thickening and lymph nodes enlargement in Crohn's disease.

BACKGROUND: Mesentery thickening and enlarged lymphnodes are typical findings of Crohn's disease (CD), but their role is unknown. Aim of the present study was to evaluate their prevalence and significance on postoperative complications and long-term surgical recurrence after CD surgery. METHODS: 1272 consecutive, unselected patients were retrospectively reviewed, divided into 4 groups based on the presence or absence of a thickened mesentery and enlarged lymphnodes, and stratified for primary or recurrent surgical procedure. In all patients but those treated with strictureplasty the mesentery and lymphnodes were removed. Patients' characteristics, peri-operative findings, and long-term recurrence were compared by univariate and multivariate analysis. RESULTS: Thickened mesentery and enlarged lymphnodes were not present in all cases, were typical of ileal location and penetrating behaviour, had a constant decrease over recurrences, were independent of either pre-operative medical therapy or surgical approach, did not increase the duration of surgery and complications, presented similar 20-years recurrence rate to normal mesentery and lymphnodes. Lymphopathy was associated to a worst nutritional status during disease recurrences. At multivariate analysis, age, location, and behaviour, but not mesenteric characteristics, were related to an increased risk of surgical recurrence. CONCLUSIONS: This study provides new information on mesentery and lymphnodes in CD patients. Further studies are needed to clarify the appropriate surgical approach.

Segmental Versus Total Colectomy for Crohn's Disease in the Biologic Era: Results From The SCOTCH International, Multicentric Study.

BACKGROUND: The extent of resection in colonic Crohn's disease [cCD] is still a topic of debate, depending on the number of locations, the risk of recurrence and permanent stoma, and the role of medical therapy. METHODS: The Segmental COlecTomy for CroHn's disease [SCOTCH] international study is a retrospective analysis on six tertiary centre prospective databases, comprising all consecutive, unselected patients operated on between 2000 and 2019 with segmental colectomy [SC] or total colectomy [TC] for cCD. The primary aim was long-term surgical recurrence. Secondary aims were perioperative complications, stoma formation and predictors of recurrence. RESULTS: Among 687 patients, SC was performed in 285 [41.5%] and TC in 402 [58.5%]. Mean age at diagnosis and surgery, disease duration, and follow-up were 30 ±â€…15.8, 40.4 ±â€…15.4, 10.4 ±â€…8.6 and 7.1 ±â€…5.2 years respectively. Isolated cCD, inflammatory pattern, perianal CD, younger age, longer disease duration and preoperative maximal therapy were more frequent in TC, while SC presented more small bowel locations and perforating disease, required fewer 90-day re-admissions, and fewer temporary and definitive stomas. Morbidity and mortality were similar. The 15-year surgical recurrence was 44% in TC and 27% in SC [p = 0.006]. In patients with one to three diseased segments, recurrence risk was related to the omission of biological therapy (hazard ratio [HR] 5.6), the number of segments [HR 2.5], perianal disease [HR 1.9] and paediatric diagnosis [HR 2.8]. CONCLUSION: When technically feasible, SC is safe and reduces temporary and permanent stoma. Young age, number of locations and perianal disease adversely affect, but postoperative biological therapy significantly reduces, the long-term surgical recurrence.

Strictureplasties performed by laparoscopic approach for complicated Crohn's disease. A prospective, observational, cohort study.

BACKGROUND: Laparoscopy is considered the best surgical approach for Crohn's Disease (CD), and strictureplasty a reliable alternative to intestinal resection. Nevertheless, their association has never been evaluated. AIM: To investigate feasibility and safety of conventional (SP) and non-conventional (NCSP) strictureplasties, using laparoscopy, for complicated CD. METHODS: Starting January 2008, a prospective cohort study was performed, in consecutive, unselected patients, undergoing primary surgery for CD (Group-A). The residential database (CD-CARD) was used for the retrospective extraction of control patients (Group-B). Univariate and multi-variate analysis of pre-operative characteristics, intra-operative findings, morbidity, and intra-abdominal septic complications (IASCs) was performed. RESULTS: Between January 2008 and December 2019, 331 patients received 162 SPs, 138 NCSPs, and 373 resections (Group-A). From the CD-CARD, 227 control patients received 159 SPs, 117 NCSPs, and 271 resections (Group-B) (ns). Preoperatively, Group-A presented batter nutritional status and received more biological therapies, Group-B more steroids. Group-A presented less abdominal abscesses, planned ostomies, minor complications, shorter operating time and hospitalization than Group-B, but similar major complications, IASCs and anastomotic leaks. IASCs were related to older age, elevated inflammatory indices, and preoperative treatment with high-risk drugs. CONCLUSIONS: SP and NCSP are feasible by laparoscopy, with low morbidity rate, confirming the advantages of both minimally invasive and conservative surgery.

Circulating Fibroblast Activation Protein as Potential Biomarker in Patients With Inflammatory Bowel Disease.

A major concern in the management of Inflammatory Bowel Disease (IBD) is the absence of accurate and specific biomarkers to drive diagnosis and monitor disease status timely and non-invasively. Fibroblast activation protein (FAP) represents a hallmark of IBD bowel strictures, being overexpressed in stenotic intestinal myofibroblasts. The present study aimed at evaluating the potential of circulating FAP (cFAP) as an accessible blood biomarker of IBD. Quantitative determination of cFAP was performed by enzyme-linked immunosorbent assay on plasma samples prospectively collected from patients with IBD and control subjects. A discrimination model was established on a training set of 50% patients and validated on independent samples. Results showed that cFAP concentration was reduced in patients with IBD when compared to controls (p < 0.0001). Age, sex, smoking, disease location and behavior, disease duration and therapy were not associated with cFAP. The sensitivity and specificity of cFAP in discriminating IBD from controls were 70 and 84%, respectively, based on the optimal cutoff (57.6 ng mL-1, AUC = 0.78). Predictions on the test set had 57% sensitivity, 65% specificity, and 61% accuracy. There was no strong correlation between cFAP and routine inflammatory markers in the patients' population. A subgroup analysis was performed on patients with Crohn's disease undergoing surgery and revealed that cFAP correlates with endoscopic mucosal healing. In conclusion, cFAP deserves attention as a promising blood biomarker to triage patients with suspected IBD. Moreover, it might function as a biomarker of post-operative remission in patients with Crohn's disease.

Inflammatory Bowel Disease patients requiring surgery can be treated in referral centres regardless of the COVID-19 status of the hospital: results of a multicentric European study during the first COVID-19 outbreak (COVIBD-Surg).

Outcomes of inflammatory bowel disease (IBD) patients requiring surgery during the outbreak of Coronavirus disease 19 (COVID-19) are unknown. Aim of this study was to analyse the outcomes depending on the COVID-19 status of the centre. Patients undergoing surgery in six COVID-19 treatment and one COVID-free hospitals (five countries) during the first COVID-19 peak were included. Variables associated with risk of moderate-to-severe complications were identified using logistic regression analysis. A total of 91 patients with Crohn's disease (54, 59.3%) or ulcerative colitis (37, 40.7%), 66 (72.5%) had surgery in one of the COVID-19-treatment hospitals, while 25 (27.5%) in the COVID-19-free centre. More COVID-19-treatment patients required urgent surgery (48.4% vs. 24%, p = 0.035), did not discontinue biologic therapy (15.1% vs. 0%, p = 0.039), underwent surgery without a SARS-CoV-2 test (19.7% vs. 0%, p = 0.0033), and required intensive care admission (10.6% vs. 0%, p = 0.032). Three patients (4.6%) had a SARS-CoV-2 infection postoperatively. Postoperative complications were associated with the use of steroids at surgery (Odds ratio [OR] = 4.10, 95% CI 1.14-15.3, p = 0.03), presence of comorbidities (OR = 3.33, 95% CI 1.08-11, p = 0.035), and Crohn's disease (vs. ulcerative colitis, OR = 3.82, 95% CI 1.14-15.4, p = 0.028). IBD patients can undergo surgery regardless of the COVID-19 status of the referral centre. The risk of SARS-CoV-2 infection should be taken into account.

Risk factors for locally advanced cancer associated with ulcerative colitis: Results of a retrospective multicentric study in the era of biologics.

BACKGROUND: Patients affected by ulcerative colitis (UC) are more likely to develop colorectal cancer, and are often diagnosed with lymph node involvement (N+) at surgery. AIM: To identify the risk factors for N+ cancer in UC patients. METHODS: Patients undergoing surgery from 2001 to 2018 in six European tertiary centres were included. N+ patients were compared to the control group (N-) for clinical variables. The evaluation of risk factors for N+ was assessed using univariate and multivariable logistic regression analyses. RESULTS: A total of 130 patients were included. Median duration of disease was 21 years (1-52). Forty patients (30.8%) were N+ at surgery. Eighteen (13.8%) developed cancer within 10 years from the onset of UC. Younger age at surgery (Odds ratio -OR- 0.96, p = 0.042), left colon location (OR 2.44, p = 0.045) and the presence of stricture (OR 5.07, p = 0.002) were associated with N+. CONCLUSION: Location in the left colon, presence of strictures and younger age strongly correlated with a higher risk of N+ cancer, which could develop before the starting point of surveillance. Duration, extension and severity of disease were not associated with N+. These results should be considered in the evaluation of risk of advanced cancer in UC patients.

Prospective study of long-term results and prognostic factors after conservative surgery for small bowel Crohn's disease.

BACKGROUND & AIMS: Several bowel-sparing techniques have been proposed for treating patients with CD, but there have been no prospective studies analyzing risk factors and long-term outcome. We prospectively evaluated safety and long-term efficacy of conservative surgery for patients with complicated CD. METHODS: From 1993-2007, 393 of 502 consecutive patients underwent surgery for complicated CD of the small bowel. Those with colonic involvement were excluded. The Student t test, chi(2) test, Kaplan-Meier estimates, and Cox proportional hazard model were used to analyze postoperative complications and long-term outcome. RESULTS: A total of 865 jejunoileal segments underwent 318 small bowel resections and 367 strictureplasties (either classic or nonconventional). There were no deaths; the complication rate was 5.6%, and the cumulative 10-year recurrence rate was 35%. None of the prognostic factors were correlated with postoperative complications. Younger age, an upper jejunoileal location, stricturing behavior, and small-bowel wall thickening 12 months after surgery showed hazard ratios of 2.4 (95% confidence interval [CI], 1-5.4; P = .03), 2.5 (95% CI, 1.3-4.7; P = .004), 2.2 (95% CI, 1.1-4.1; P = .01), and 4.5 (95% CI, 2.3-8.6; P = .000), respectively. Immunomodulator therapy failed to reduce long-term surgical recurrence. CONCLUSIONS: Young patients with extended and stricturing disease are at high risk for disease recurrence after surgery. Bowel wall thickening was a reliable prognostic factor for these patients. Conservative surgery is safe and effective in treating patients with jejunoileal CD and should be considered as the first-line surgical treatment, preventing the risk of short bowel syndrome caused by repeated resections.

Minimally invasive surgery and stoma-related complications after restorative proctocolectomy for ulcerative colitis. A two-centre comparison with open approach.

BACKGROUND: Although the creation of a stoma reduces the risk of septic pouch complications following ileal pouch-anal anastomosis (IPAA), the stoma itself and its reversal can give rise to substantial morbidity during the two- or three-stage concept. Aim of study is to compare stoma-related complications in Ulcerative Colitis patients undergoing laparoscopic versus open IPAA. METHODS: We collected data on 250 IPAA patients from two Italian Centres between 2005 and 2015. We compared perioperative and postoperative events in 150 open vs 100 laparoscopic IPAA. We performed a case-matched analysis based on baseline differences among groups to compare the rate of mechanical complications. RESULTS: There were no significant differences between open and laparoscopic IPAA in overall stoma complications (complications during ileostomy: 11.3% vs 12%,p = 0.8; early complications: 10% vs 8%,p = 0.5; late complications: 12.6% vs 6%,p = 0.08). The case-matched analysis found a slightly reduced incidence of obstructive complications at any stage with laparoscopy. CONCLUSIONS: Overall stoma related complications do not seem to be reduced by minimally-invasive approach itself, but patients might experience less mechanical problems with laparoscopy without conversion.

Monocyte-derived dendritic cells from Crohn patients show differential NOD2/CARD15-dependent immune responses to bacteria.

BACKGROUND: Three common mutations in the NOD2/CARD15 gene are strongly associated with Crohn's disease (CD). NOD2 is an intracellular receptor of muramyl dipeptide (MDP), a component of peptidoglycan present in the cell wall of gram-positive (G+) and gram-negative (G-) bacteria. METHODS: We generated monocyte-derived dendritic cells (MoDCs) from CD patients mutated or not for CARD15 (n = 53) or from healthy donors (n = 12) and analyzed their activation in response to live Salmonella typhimurium as a model of pathogenic G- bacteria. RESULTS: MoDCs carrying the L1007fs mutation, although phenotypically activated by bacteria, produced a significantly reduced amount of tested cytokines. MoDCs carrying R702W or compound G908R/R702W NOD2 mutations displayed an increased basal level of IL-8 release. After a bacterial encounter, these cells were phenotypically activated and produced levels of cytokines similar to healthy controls. Interestingly, although L1007fs/WT mutations conferred reduced production of cytokines, including IL-12, these cells were perfectly capable of inducing T-cell polarization toward the Th1 phenotype. CONCLUSIONS: NOD2 mutations affect the basal characteristics of MoDCs and their response to G- bacteria differently. MoDCs could be involved in CD onset because they have defects in releasing inflammatory cytokines and in polarizing T-cell responses.

Inhibition of Fibroblast Activation Protein Restores a Balanced Extracellular Matrix and Reduces Fibrosis in Crohn's Disease Strictures Ex Vivo.

Background: Crohn's disease (CD) is a chronic bowel inflammation that ultimately leads to fibrosis, for which medical therapy is currently unavailable. Fibrotic strictures in CD are characterized by excessive extracellular matrix (ECM) deposition, altered balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), and overexpression of fibroblast activation protein (FAP), a marker of active fibroblasts. Here we investigated the role of FAP-targeted therapy in ECM remodeling in CD strictures ex vivo. Methods: Bowel specimens were obtained from stenotic and nonstenotic ileal segments from 30 patients with fibrostenotic CD undergoing surgery. FAP expression was evaluated in isolated mucosal myofibroblasts by immunoblotting and flow cytometry. Bowel tissue cultures were treated with anti-FAP antibody, and soluble collagen, TIMP-1, and MMPs were measured in tissue culture supernatants by immunoblotting. Anti-FAP-treated myofibroblasts were analyzed for TIMP-1 expression by immunoblotting, for migratory potential by wound healing assay, and for apoptosis by Annexin V staining. Results: Myofibroblasts from stenotic CD mucosa showed upregulation of FAP expression when compared with nonstenotic mucosa. Treatment of stenotic tissues with anti-FAP antibody induced a dose-dependent decrease in collagen production, particularly affecting type I collagen. The treatment also reduced TIMP-1 production in CD strictures, without altering MMP-3 and MMP-12 secretion. Accordingly, anti-FAP treatment inhibited TIMP-1 expression in stenotic CD myofibroblasts and enhanced myofibroblast migration without affecting survival. Conclusions: FAP inhibition reduced type I collagen and TIMP-1 production by CD strictures ex vivo without compromising uninvolved bowel areas. These results suggest that targeting FAP could reconstitute ECM homeostasis in fibrostenotic CD.