Introduction

Small bowel fibrostenotic strictures are common in patients with Crohn’s disease (CD). No global consensus recommendations on definitions, diagnosis and clinical management are available.

Aims & Methods

Several systematic reviews followed by a RAND/University of California Los Angeles appropriateness study on the definitions, diagnosis and clinical management of fibrostenosing CD in clinical practice were performed. A panel of 27 global experts and a patient representative were convened. They assessed a total of 152 candidate items. The items were subsequently evaluated for appropriateness.

Results

No accurate predictive biomarkers are available for naïve or anastomotic fibrostenosing strictures. Accurate diagnosis of fibrostenosing CD requires cross-sectional imaging which should evaluate bowel wall thickness, luminal narrowing and prestenotic dilatation. A potential inflammatory component should be assessed. Abdominal cross-sectional imaging was considered necessary prior to any treatment decision. The panel proposed an approach to medical, endoscopic, and surgical therapies. Technical characteristics for endoscopic balloon dilation and follow up strategies after successful dilation therapy were identified. Appropriateness, types and performance of different surgical approaches in various settings were evaluated.

Conclusion

This global consensus provides clinical guidance for the diagnostic and therapeutic management of patients with fibrostenotic CD.

Introduction

Ozanimod (OZA) is approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis. A previous phase 1 study of single dose OZA 0.23 mg showed a 31%–33% reduction of CC112273, the predominant active metabolite (MET) of OZA, in mild or moderate hepatic impaired participants (ppts) vs healthy ppts. That study was designed prior to identification of the 2 major METs of OZA (CC112273; CC1084037). Due to their slow accumulation and elimination, a new multiple dose study was designed with a long sampling schedule.

Aims & Methods

This multicenter, open-label phase 1 study (NCT04639115) evaluated the effect of mild (Child-Pugh [C-P] score 5–6) or moderate (C-P score 7–9) hepatic impairment on the multiple-dose pharmacokinetics (PK) of OZA and its 2 major active METs. Eligible ppts with hepatic impairment without active hepatitis were enrolled into the mild or moderate hepatic impairment groups (8 ppts each) based on their C-P scores. Ppts with normal hepatic function were matched to hepatic-impaired ppts by sex, age, weight, and smoking status. All ppts received once-daily OZA for 8 d in accordance with dose titration: 0.23 mg on Days (D) 1–4, 0.46 mg on D5–7, and 0.92 mg thereafter. Serial PK samples were collected on D1, D5, and D8, and additionally on D10, D12, and D15, and up to D72. Analysis of variance (ANOVA) fitted to the natural log-transformed PK parameters with hepatic function group as the fixed effect and the matching pair as a random effect was used to compare PK parameters between groups. Safety was assessed.

Results

All dosed ppts (N=26) completed the study. Each hepatic impairment group had 8 ppts; 10 ppts were in the normal hepatic function group, of whom 6 matched both mild and moderate hepatic-impaired ppts. Of the 16 hepatic-impaired ppts, 13 had documented hepatic cirrhosis. No clinically meaningful differences in total and unbound PK parameters for OZA and its major METs were observed between healthy and hepatic-impaired ppts on D1, D5, or D8 (dose titration) (Table). The unbound area under the plasma concentration-time curve from D8, time 0 to the time of last quantifiable concentration (AUC_0-last) (up to 64 d after the D8 dose) of both METs increased ~2-fold in both mild and moderate hepatic-impaired ppts (Table). Although steady state for both METs was not achieved by D8, AUC_0-last is a reasonable predictor of exposure at steady state. No correlation was observed between PK parameters for OZA or its major METs and measures of hepatic function (C-P score, serum albumin, and prothrombin time). No laboratory results (ie, absolute lymphocyte count), vital signs, physical examination, or 12-lead ECG results were reported as treatment-emergent adverse events.

Conclusion

Due to the lack of OZA PK differences between hepatic-impaired and healthy ppts during dose titration and the 2-fold increase of AUC_0-last of both METs in hepatic-impaired ppts, a dose adjustment of OZA 0.92 mg once every other day is recommended in patients with mild or moderate hepatic impairment after completing the standard 1-week dose titration.

Disclosure

This study was funded by Bristol Myers Squibb, Princeton, NJ, USA.
PZ, FH, KY, SW, MS, GT, BM, and DT: employees and/or shareholders of Bristol Myers Squibb.

Introduction

Inflammatory bowel disease (IBD) commonly affects female patients of reproductive age, making the interaction between fertility, pregnancy and IBD an important issue in disease management. The effect of disease activity on the outcome of pregnancy and its impact on neonatal growth is a field of intense research. Close follow-up of pregnant IBD patients by a multidisciplinary team improves maternal and neonatal outcomes.

Aims & Methods

Α national retrospective study of pregnancies in women with IBD between 2010-2020 was carried out in 22 IBD reference centers in Greece. Patient characteristics such as disease profile, type of treatment, and disease activity during gestation were analyzed in correlation to the method of delivery, pregnancy outcomes, as well as breastfeeding and offspring health.

Results

Two-hundred and twenty-three pregnancies in 175 IBD patients were registered in the study. 122 with Crohn’s disease (CD). Median age during diagnosis was 25.6 years (12-44) with median disease duration of 7.4 years (0-23). One-hundred and twenty-nine patients (58%) were recorded during their first pregnancy. Early pregnancy termination was reported by 48 patients (22%). Pregnancy as a result of in vitro fertilization (IVF) occurred in 15 cases (6.7%). At the beginning of gestation 165 patients (74%) were under treatment: 48 with anti-TNF agents (29%), 43 with azathioprine (26%), 101 with 5-aminosalicylic acid formulations (61%) and 12 with steroids (7%). We recorded 49 cases of IBD flares (22%) during pregnancy. Two-thirds of them (n=30) were in remission at the onset of the pregnancy. Almost half of them (n=22) required corticosteroid treatment. Patients with ulcerative colitis (UC) were in greater risk of disease flare during pregnancy (p<0.001). All but 3 pregnancies (99.1%) resulted in uncomplicated delivery. In 147 cases (67.1%) cesarean delivery was performed. Two late fetal deaths (0.9%) were reported, both in patients with continuously active disease since the beginning of pregnancy. After delivery, 75 patients (34%) presented with a disease flare, which was associated with active disease at the beginning of pregnancy (p <0.001).
Table 1. Demographics and characteristics of the cohort

Conclusion

The majority of female, Greek IBD patients, had a favorable pregnancy outcome. Active inflammation during gestation and UC diagnosis were associated with a negative impact on pregnancy outcomes. The results of this study are in favor of the continuation of IBD treatment during pregnancy.
This study was funded by a research grant 2020EOMIFNEmp1 from the Hellenic Group for the Study of IBD (EOMIFNE)

Introduction

Emergency surgery (ES) is associated with higher morbidity and mortality for acute left colonic malignant obstruction. Since the first application of self-expandable metallic stent (SEMS), the technique has been popularly applied as “bridge to surgery (BTS)”. The short-term clinical outcomes and long-term oncologic prognosis remain controversial.

Aims & Methods

This retrospective study aimed to compare the performance for managing acute left colonic malignant obstruction by ES or BTS. The medical records were collected from May 2015 to December 2019 in two tertiary hospitals in Eastern China. Patients were followed up after surgery every 6 months for 3 years and once a year afterwards. Clinical success was defined as resumption of intestinal function for 30 days without morbidity or mortality after surgical procedure. All demographics, intervention procedures and follow-up were analyzed for short-term and long-term outcomes. Risk factors for long-term survival were discussed as well.

Results

A total of 136 patients were eligible for the study, 67 in BTS group and 69 in ES group. No significant differences concerning demographics were found, including age, sex, body-mass index (BMI), symptoms, coexisting disorders, laboratory tests, preoperative radiotherapy or chemotherapy, previous history of abdominal surgery, cancer location, obstructive degree and TNM stage. Technical success of SEMS insertion was achieved in 64 patients (95.5%). The interval from SEMS placement to elective surgery was 16 days. Minor perforation was detected on 4 patients during the elective surgery, while no symptomatic complaint was recorded.
BTS group showed better short-term performance, including less intraoperative decompressive intervention (85.1% vs. 69.6%, p=0.045), more complete decompression (64.2% vs. 27.5%, p＜0.001), more primary anastomosis (65.7% vs. 17.4%, p＜0.001), less temporary and permanent stoma (34.3% vs. 82.6%, 13.4% vs. 58.7%, both p＜0.001), less intensive care unit requirement (10.4% vs. 27.5%, p=0.011), less intraoperative complications (3.0% vs. 13.0%, p=0.031) and reduced 30-day mortality (0 vs. 8.7%, p=0.028). Longer hospitalization was observed in the BTS group (21.7±13.3 days vs. 14.9±7.6 days, p＜0.001). Postoperative hospitalization and total cost were comparable between the two groups. No significant difference was observed about clinical success (73.1% vs. 63.8%, p=0.240), overall mortality (53.7% vs. 64.4%, p=0.247) or long-term survival (52.0 months vs. 35.0 months, p=0.121). TNM stage Ⅳ, permanent stoma and postoperative complication were the independent risk factors for long-term survival.

Table.1 Operation related characteristics

Conclusion

SEMS served as a safe and effective bridge to elective surgery for acute left colonic malignant obstruction, without adverse effect on long-term survival. It significantly improved short-term outcomes by reducing perioperative complication, 30-day mortality and stoma. More prospective studies are necessary for further evaluating the clinical values of SEMS, and weighing its benefits against potential complications.

References

1. Manfredi S, Sabbagh C, Vanbiervliet G, et al. Place of colorectal stents in therapeutic management of malignant large bowel obstructions. Endoscopy. 2014;46:546-552.
2. Frago R, Ramirez E, Millan M, et al. Current management of acute malignant large bowel obstruction: a systematic review. Am J Surg. 2014;207:127-138.
3. Arezzo A, Passera R, Lo Secco G, et al. Stent as bridge to surgery for left-sided malignant colonic obstruction reduces adverse events and stoma rate compared with emergency surgery: results of a systematic review and meta-analysis of randomized controlled trials. Gastrointest Endosc. 2017;86:416-426.
4. van Hooft JE, van Halsema EE, Vanbiervliet G, et al. Self-expandable metal stents for obstructing colonic and extracolonic cancer: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Gastrointest Endosc. 2014;80:747-761 e741-775.
5. Pisano MA-O, Zorcolo L, Merli C, et al. 2017 WSES guidelines on colon and rectal cancer emergencies: obstruction and perforation. 2017.
6. Kawachi J, Kashiwagi H, Shimoyama R, et al. Comparison of efficacies of the self-expandable metallic stent versus transanal drainage tube and emergency surgery for malignant left-sided colon obstruction. Asian J Surg. 2018;41:498-505.

Introduction

In Crohn’s disease (CD) a symptomatic luminal stricture occurs in up to 20% of patients at the diagnosis and in more than 50% during lifetime (1,2). Endoscopic balloon dilatation (EBD) or surgical procedures are the currently available treatments (3,4). However, a considerable percentage of patients often require further surgery for post-operative CD recurrence (5). A consequent increased burden of short bowel syndrome is warranted. The combination of biological therapy with EBD could potentially reduce this risk.

Aims & Methods

The aim of our study was to evaluate the efficacy of EBD combined with biologic therapy in symptomatic gastrointestinal strictures in CD’s patients. We conducted a retrospective study including consecutive CD patients who underwent EBD for low bowel strictures from December 2015 until November 2022 at our tertiary IBD Center. Clinical strictures recurrence, needs for steroids and for surgery due to CD stenosis relapse were the primary outcomes evaluated during a follow-up period of six and twelve months. Chi-square and univariate statistical analyses were used when appropriate.

Results

A total of 52 patients treated with EBD with an overall number of 55 strictures were included. In the study population, 14 patients (27%) were smoker, the mean age was of 46,8 (18-77) years; the median of disease duration was 9 (0-42) years. Thirty-nine patients (75%) were in active treatment with biologic therapy at the moment of EBD. Twenty-three patients (44%) underwent EBD for anastomotic stricture, 8 (15%) for ileal stricture, 11 (21%) for ileocecal valve stricture, 5 (6%) for anal stricture and 4 (8%) for colic stricture. Three patients (6%) underwent EBD for multifocal bowel stenosis. Twenty-two (42%) patients had increased CRP value, 40 patients (77%) had evidence of moderate or severe endoscopic disease activity and 42 (81%) patients showed ulcerative lesions at stricture site. EBD was performed by 8-10, 12-15 or 15-18 mm dilation balloon. Technical success was reported in 60% of procedures and no adverse events were registered.
After 6 months from EBD, at univariate analysis, active smoke resulted a risk factor for clinical stricture recurrence (OR 10,25; IC 1,350 to 135,4; p value = 0,022) and for subsequent surgery (OR 10,25; IC 1,350 to 135,4; p value = 0,022). Moreover, increased CRP at the time of dilatation resulted a risk factor for need of steroids (OR 14,63; IC 2,69 to 71,50; p value = 0,0006). Concomitant biologic therapy and presence of ulcerative lesions did not show significative correlation with considered outcomes.
After 12 months from EBD, concomitant biologic therapy resulted a protective factor for prevention of surgery (OR 0,061; IC 0,005 to 0,502; p value = 0,0047), while anastomotic strictures were associated with a lower risk of sub-occlusion events than ileal stenosis (OR 0,07; IC 0,005 to 0,651; p value = 0,015). Increased CRP at the time of EBD, ulcerative lesions at the stricture site and active smoke were not significantly correlated with the considered outcome.

Conclusion

Our results suggest that in patients with CD undergoing EBD for bowel CD stricture, concomitant biological therapy reduces the risk of surgery for CD stenosis recurrence. Further prospective and controlled studies are underway to confirm these observations.

References

1. Rieder F Managing Intestinal Fibrosis in Patients With Inflammatory Bowel Disease. Gastroenterology &amp; hepatology. 2018. February; 14(2):120–122
2. Yoo JH, Holubar S, Rieder F. Fibrostenotic strictures in Crohn’s disease. Intest Res. 2020;0.
3. Paine E, Shen B. Endoscopic therapy in inflammatory bowel diseases (with videos). Gastrointest Endosc 2013;78:819–35.
4. Hassan C, Zullo A, De Francesco V, Ierardi E, Giustini M, Pitidis A, Taggi F, Winn S, Morini S. Systematic review:
Endoscopic dilatation in Crohn's disease. Aliment Pharmacol Ther. 2007 Dec;26(11-12):1457-64
5. Olaison G, Smedh K, Sjödahl R. Natural course of Crohn’s disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms. Gut 1992;33:331–5.

Introduction

Insulinomas are rare, functioning neuroendocrine neoplasms that cause non-ketotic hypoglycemia due to hyperinsulinism. Surgery is considered the gold-standard treatment, although endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) has been recently described as a less invasive, efficient therapeutic option for these tumors. In this study, we aim to compare post-procedural outcomes of surgical resection versus EUS-RFA for pancreatic insulinomas.

Aims & Methods

All patients who underwent surgical resection or EUS-RFA for pancreatic insulinoma in our Institution were included in the study, and data from all procedures were retrospectively recorded and statistically analyzed. EUS-RFA was indicated for all subjects either unfit for surgery or unwilling to undergo surgical treatment. Patients’ baseline characteristics, location, size of insulinomas, procedural time, and intra- and postoperative outcomes were compared.

Results

From April 2012 to July 2022, 11 and 10 patients with pancreatic insulinoma underwent surgical resection and EUS-RFA, respectively. The median age was 65.5 (51-84) and 37 years (28-72, p<0.001) for the EUS-RFA and surgery cohorts, respectively. As a whole, 15 (71.4%) out of 21 were female. The median tumor size was 15mm (8-30) for the surgical group and 11mm (8-19) for the EUS-RFA group (p=0.17). The majority of the insulinomas were located in the pancreatic body (28.6%) and tail (28.6%), with no statistical difference between the two groups (p=0.16). Operative time was significantly longer in the surgical population (280min, 120-372) as compared to the endoscopic one (28min,18-40, p<0.001). Clinical success, defined as the normalization of glucose blood levels, was reached in all cases. The complication rate was significantly higher in the surgical group compared to the endoscopic group (7-63.6% vs 1-10%, p=0.01). Specifically, 7 patients in the surgical cohort developed a pancreatic fistula while one patient in the EUS-RFA population had self-limiting bleeding after the procedure. One patient of the surgical cohort underwent reoperation for an infected abdominal fluid collection.

Table 1. Characteristics of patients classified by treatments.

Conclusion

As compared to surgical resection, EUS-RFA for pancreatic insulinomas may be considered a safe and efficient treatment option with a shorter operative time and a lower rate of related complications. Prospective comparative studies are needed to ascertain the role of EUS-RFA as a treatment of choice for selected patients with pancreatic insulinoma.

References

Fahmawi Y, Mehta A, Abdalhadi H et al. Efficacy and safety of endoscopic ultrasound-guided radiofrequency ablation for management of pancreatic lesions: a systematic review and meta-analysis. Transl Gastroenterol Hepatol. 2022 Jul 25;7:30.
Zhao YP, Zhan HX, Zhang TP et al. Surgical management of patients with insulinomas: Result of 292 cases in a single institution. J Surg Oncol. 2011 Feb;103(2):169-74.