Introduction

Background and objectives: Small intestinal neuroendocrine tumours (SI-NETs) are slow growing but have often metastasized at the time of diagnosis. Most patients are operated either with the intention of curation or to prolonged survival. Improved surgical resection, more comprehensive oncological treatment as well as earlier diagnoses may improve survival, but only few studies have examined survival trends. In this study we aimed to examine the trend in overall survival in patients diagnosed with SI-NETs.

Aims & Methods

Patients with a histological and / or imaging-based diagnosis of SI-NET in Central Norway from 2005 to 2021 were identified. Patient, disease and treatment characteristics including histological grade (G), European Neuroendocrine Tumour Society (ENETS) stage, surgical and oncological treatment types and survival were retrospectively recorded. The cohort was divided in those diagnosed in period one (June 2005-November 2012) and period two (November 2012-December 2021), with 121 patients in each sub-cohort. Overall survival was analyzed using the Kaplan Meier method and a Cox multivariate analysis was performed to identify factors independently associated with survival.

Results

The 242 patients had a median age 70 (17-91) years at diagnosis or surgery and 55.8% were males. The majority of patients underwent surgery (n=205, 84.7%) which was considered curative in 137 (66.8%) patients. Median estimated overall survival was 10.1 years (95% CI 8.5-11.7) and the median overall survival for localized, regional and distant disease stage was 10.6 years (95% CI 7.9-13.2), 11.0 years (95% CI 8.8-13.2) and 7.1 years (3.4-10.8), p=0.005, respectively.
Patients diagnosed in period one had a median survival of 9.0 years (95% CI 6.4-11.7), while median survival for period two was significantly longer and was not reached, p = 0.014. Five year survival for period one was vs. period two was 63.5% and 83.5%. The Kaplan-Meier curves for period one and two separated the first year after diagnosis and the difference persisted. For resected patients the median survival was 9.6 years (95% CI 8.4-10.9) in period one, whereas median survival was not reached for period two, p = 0.008. The ENETs disease stage did not differ between period one and two, but a higher proportion had carcinoid heart disease in period one (7.4% vs. 1.7%, p=0.031). A higher proportion of patients who underwent SI-NET resection were considered tumour free after surgery in period two than in period one (74.3% vs 59.6%, p=0.027). There was also a higher proportion of patients with resection of multiple primary SI-NETs in period two (37.6% vs. 24.0%, p=0.049), which was explained by a higher proportion of multifocal tumours being resected during elective surgery (42.9% vs. 21.1%, p 0.005). There was also a higher number of retrieved lymph nodes in period two (p=0.014). Similar proportions of patients received somatostatin analogues, PRRT or transarterial embolization of liver metastases in period one vs. period two. In a Cox proportional hazard regression model age at diagnosis, ENETS stage, tumour resection and diagnosis before November 2012 were independently associated with overall survival, whereas sex and tumour grade were not.

Conclusion

Survival of patients with SI-NET improved over the study period and this seemed related to lower mortality the first year after diagnosis. Disease stage or oncological treatment did not change, but several factors associated with surgical quality improved during the study period.

Introduction

As the therapeutic armamentarium for inflammatory bowel diseases (IBD) is rapidly expanding, it is of increasing importance to optimize treatment sequencing. However, head-to-head trials comparing efficacy of vedolizumab (VDZ) in bio-naïve versus bio-experienced patients are scarce.

Aims & Methods

Aim: To compare the effectiveness of VDZ in bio-naïve versus bio-experienced patients with IBD in a real world setting.
Methods: A retrospective monocentric study was performed in IBD patients treated with VDZ at a Belgian University Hospital, from January 2018 to June 2021 with follow-up until December 2021. Primary endpoints considering efficacy after induction and after 1 year of therapy were: clinical response (CRp) and remission (CRm), biochemical response (BRp) and remission (BRm) and endoscopic response (ERp) and remission (ERm). Secondary endpoint was treatment survival during follow-up. For assessment of risk factors influencing efficacy and treatment survival, a multivariate logistic regression and Cox regression model (CRM) were applied.

Results

A total of 84 patients were treated with VDZ, 42 bio-naïve and 42 bio-experienced. At baseline, significantly more bio-experienced patients had prior intestinal resection (IR) (40.5% (17/42) vs. 16.7% (7/42), P=0.016), used an immunomodulator (IMM) (35.7% (15/42) vs. 16.7% (7/42), P=0.047) and had a longer disease duration (12.5 vs. 3.5 years, P<0.001). Bio-naïve patients had more moderate to severe comorbidities (21.4% (9/42) vs. 2.4% (1/42), P=0.007). After VDZ induction, CRp rate was higher in bio-naïve patients (60.9% (39/42) vs 39.1% (25/42), P<0.001). Multiple logistic regression analyses revealed that bio-naïve patients had a higher chance reaching CRp (aOR 14.69, 95%CI [3.12-69.14], P<0.001)(table). CRm was reached in 35.7% bio-naïve and 19% bio-experienced patients (P=0.087). No significant difference in BRp (P=0.932) or BRm (P=0.730) rate was found . A significantly higher ERp rate was seen in bio-naïve patients (90.3% (28/31) vs. 66.7% (18/27), P=0.027). Multiple logistic regression analyses showed a trend towards higher ERp rate in bio-naïve patients (aOR 4.65, [0.99-21.84], P= 0.051)(table). No significant difference was seen for ERm (32.3 % (10/31) vs. 11.1% (3/27), P=0.054). After 1 year of VDZ, CRp was significantly higher in bio-naïve patients (82.9% (34/41) vs. 62.5% (25/40), P=0.039). Multiple logistic regression analyses showed no significant difference between both groups. Univariate analyses showed significantly higher CRm rate in bio-naïve patients (70.7% (29/41) vs. 37.5% (15/40), P=0.003). After adjustment for age, disease duration, IMM use and prior IR, this difference was no longer significant. Patients without prior IR had significantly higher odds of reaching CRm (aOR 4.33,[1.13-16.59], P=0.032). No significant difference was seen for BRp (P=0.443) and BRm (P=0.313), nor for ERp (P=0.184) or ERm (P=0.061) in univariate analyses. Cox regression analysis showed significantly longer treatment survival in bio-naïve patients (aHR 2.32, [1.03-5.23], P=0.043).

Conclusion

In this tertiary real-world cohort of patients treated with VDZ, overall, a better efficacy was seen in bio-naïve compared to bio-experienced patients.

Disclosure

No conflict of interest

Introduction

Interleukin 33 (IL-33) is a pro-inflammatory cytokine that has been implicated in the pathophysiology of inflammatory bowel disease (IBD), ulcerative colitis (UC) in particular. IL-33 as a cytokine and an alarmin might evoke systemic inflammation, which could have ramifications for the functioning of the central nervous system, contributing to mood and sleep disorders. Disruptions in IL-33 concentration are well known to occur in the course of numerous psychiatric disorders as well as obstructive sleep apnea, a condition characterized by chronic low-grade inflammation and sleep fragmentation. To date, however, this protein has not been studied in relation to insomnia or poor sleep quality, frequently comorbid to chronic inflammatory and psychiatric diseases.

Aims & Methods

The study aimed to compare serum IL-33 concentrations of IBD patients and healthy controls as well as evaluate the association between the expression level of this interleukin, depression, sleep quality, and insomnia. IBD patients (n=81) and healthy controls (HC=44) were recruited. Harvey-Bradshaw index or partial Mayo were applied in the assessment of clinical disease activity for Crohn’s disease (CD) or UC respectively. Venous blood samples as well as questionnaires: Beck Depression Inventory (BDI), Epworth sleepiness scale (ESS), Athens Insomnia Scale (AIS), and Pittsburgh Sleep Quality Index (PSQI) were collected. Human IL-33 High Sensitivity Magnetic Luminex Performance Assay was used for the analysis of serum IL-33 protein concentration according to the manufacturer’s protocol. Fluorescence measurements were taken with MAGPIX, Luminex. The study has been funded by National Science Centre, Poland (2018/31/N/NZ5/03715).

Results

No differences were noted regarding IL-33 concentrations, sleep, or psychological variables between IBD patients and HC, except for sleep efficiency, which was higher in HC (p=0.004). Only in the IBD group, a positive correlation between IL-33 concentration and BDI, PSQI, and AIS (R=0.521, p=0.003; R=0.458, p=0.01; R=0.40, p=0.03), as well as negative one with sleep efficiency (R=-0.475, p=0.008) was noted. IBD individuals with high scores on ESS or PSQI (ESS>10, PSQI>5) had elevated IL-33 serum level compared to IBD patients without sleep problems (IL-33 concentration [pg/ml]: 53.385 (30.070-313.020) vs 18.795 (11.790-26.175), P=0.01 for PSQI; 270.900 (156.225-438.680) vs 21.840 (11.870-47.720), P=0.006 for ESS). IL-33 concentrations and questionnaire scores were comparable in patients with different disease activity. As for IBD types, in the CD, but not the UC group, IL-33 was positively correlated with the severity of depression symptoms and poor sleep quality (R=0.581, p=0.02; R=0.531, p=0.03) and negatively with sleep efficiency (R=-0.667, p=0.005).

Conclusion

IL-33 might be associated with mood and sleep disorders in IBD. It could exert its effect by promoting systemic and neuroinflammation, thus negatively affecting the well-being of IBD patients. Further research on the subject of changes in mental health of IBD patients in the context of anti-inflammatory or immunosuppressive treatment would be valuable.

Introduction

IL-33/ST2 axis and gut microbiota are important factors in the pathogenesis of IBD with a potential reciprocal influence. IL-33/ST2 axis controls the mucosal healing process during intestinal inflammation. Restorative proctocolectomy with ileal pouch-anal anastomosis is a surgical procedure in patients with ulcerative colitis (UC) refractory to medical therapies. Pouchitis, the most common complication, is the inflammation of the pouch with a controversial etiology.

Aims & Methods

We aimed to explore the potential role of IL-33/ST2 and gut microbiota axis in the inflammatory process of pouchitis.
30 UC patients with ileal pouch-anal anastomosis were enrolled. After clinical, endoscopic and histological assessment 18 showed pouchitis and 12 a normal pouch. Mucosal samples were collected from the afferent ileal loop and from the pouch and processed for cytokines assessment, histological evaluation and gut microbiota analyses. Multiplex analysis for inflammatory and regulatory cytokines was performed. ELISA and western blot were run to assess IL-33/ST2 protein levels and to evaluate protein isoforms, respectively. IHC was done to evaluate mucosal IL-33/ST2 expression and localization. Microbiota was analyzed by 16S ribosomal RNA gene amplicon pyrosequencing. Pouchitis Disease Activity Index and Pouchitis Histological Score were calculated, and CRP and fecal calprotectin were obtained for each patient. Multivariate analyses were run to generate transcriptional interaction networks and identify biomarkers for patients with inflamed pouches.

Results

IL-1Ra, IL-6, IL-8, IL-17, IP-10, MCP-1, MIP-1a, MIP-1b resulted increased in inflamed pouch vs. normal pouch. No differences were registered between samples obtained from the afferent ileal loop. In pouchitis, IL-7 resulted reduced in the inflamed pouch vs. the afferent ileal loop. In pouchitis, IL-33 and ST2 protein levels were reduced in the pouch vs. the afferent ileal loop and resulted overall decreased vs. patients with normal pouch indicating a potential IL-33/ST2-mediated defective healing process. Full-length, bioactive IL33, ST2L and sST2 were expressed in all experimental groups; the cleaved, less active form of IL33 was increased in only patients with pouchitis. IHC confirmed these observations. IL-33 and ST2 staining was less intense within the inflamed and ulcerated mucosa of pouchitis patients compared to normal pouch, and in close proximity to areas of re-epithelialization. An overall decreased biodiversity in patients with pouchitis vs. patients with normal pouch (both at pouch and afferent ileal loop level) was shown. Lower levels of Verrucomicrobia and increased abundance of Actinobacteria were recorded in inflamed pouch vs normal pouch. In pouchitis, the afferent ileal loop and the pouch showed significantly decreased levels of Akkermansia muciniphila and augmented abundance of Collinsella vs. samples obtained from patients with normal pouch. In pouchitis, multivariate analyses evidenced a significant inverse correlation between Collinsella e Collinsella aereofaciens abundance and ST2 levels.

Conclusion

In patients with pouchitis vs patients with normal pouch divergent inflammatory molecular pathways and microbial populations distinctly characterize the pouch and the afferent ileal loop. Overall, our results suggest a potential role for IL-33/ST2 and gut microbiota axis in driving the gut mucosal wound healing in patients with ileal pouch-anal anastomosis. Further studies are underway to determine mechanisms of action that support these findings.

Introduction

Insulin-like growth factor binding protein 3 (IGFBP3) signals through the death receptor TMEM219 to modulate survival of target cells; inhibition of this signaling has been associated with a rescue of intestinal stem cell death.

Aims & Methods

Here we report the screening, generation, and characterization of fully human IgG monoclonal antibodies (mAbs) through phage display or by hybridoma technology, that block IGFBP3 or TMEM219. We used in vitro large crypts organoids (mini-guts) generated by crypts obtained from healthy subjects and from patients with inflammatory bowel disease to test the effect of the mAbs on the regenerative potentials. Expression of intestinal stem cell markers and apoptotic markers by RT-PCR was also analyzed.

Results

Both anti-IGFBP3 and anti-TMEM219 mAbs showed high affinity binding with the target antigens and potent effects in protecting self-renewal ability of intestinal stem cells in in vitro relevant assays. Among all the mAbs tested, anti-TMEM219 mAbs generated by phage display, particularly Ent001, showed the highest score in displacing the IGFBP3/TMEM219 binding and in rescuing ISC expression and function in IGFBP3-cultured human mini-guts obtained from healthy donors. In human in vitro proof-of-concept studies, in which we generated mini-guts from patients with immune-mediated intestinal disease such as Crohn’s disease, Ent001 successfully restored mini-guts growth and ISC markers’ expression, while expression of the proapoptotic IGFBP3-related factor Caspase 8 was downregulated.

Conclusion

Ent001 may represent a novel IGFBP3/TMEM219 inhibitor to be further tested and developed in in vivo models and in clinical studies as a novel therapeutic in human diseases.

Disclosure

P.F. and F.D. hold a patent on IGFBP3/TMEM219 axis. V.M., M.N., F.C. are employees of Enthera S.r.l.

Introduction

Patients diagnosed with inflammatory bowel disease (IBD) may have damage in different parts of the gut. The development of this disease involves an intricate interaction between a host with genetic susceptibility, environmental factors, an imbalanced immune response, and intestinal microbiota. Several studies have revealed discrepancies in the composition of gut microbiota between IBD patients and healthy individuals, especially concerning microbial diversity and relative abundance of specific bacteria. Nonetheless, previous research typically involves patients who have undergone immunosuppressive treatment, potentially altering the microbiota and affecting the integrity of study findings.

Aims & Methods

The aim of this study was to elucidate the differences in the microbiota of newly diagnosed patients with Crohn’s disease (CD) and ulcerative colitis (UC) compared to healthy controls (HC), based on the location of the affected area. Stool samples were obtained from IBD patients who had not yet initiated treatment for the disease, and from HC. Each sample underwent shotgun metagenomic sequencing, followed by bioinformatic analysis using the Cutadapt, Kraken2, and Bracken programs. Shannon index (α-diversity) and Bray-Curtis dissimilarity (β-diversity) were used as tests of within-species diversity and within-group diversity, respectively.

Results

We included 103 patients with CD, 144 with UC and 49 HC. Patients with CD, which have been classified depending on disease location (ileal, colonic and ileocolonic), showed lower α-diversity compared to HC in each subgroup, showing the lowest index in those with ileocolonic location. In UC patients, divided according to disease extension (proctitis, left-sided colitis and extensive colitis), those with extensive involvement, exhibited the lowest α-diversity compared to HC and other groups. β-diversity in CD patients revealed the highest differences between the comparisons ileal vs ileocolonic and colonic vs ileocolonic, suggesting that patients with ileocolonic pattern showed a more different microbiota profile compared to the other groups studied; however, there were no differences in UC patients. Examination of taxonomic abundance revealed a decrease in Phocaeicola coprocola and several species of Adlercreutzia, and an increase in Shigella flexneri, in CD patients, compared to HC. In UC patients, an increase in Toxoplasma gondii and Gemella morbillorum was observed in all three extension subgroups compared to HC. However, several species of Adlercreutzia and Alistipes were decreased in patients with extensive colitis compared to HC.

Conclusion

Our data suggest that newly diagnosed CD and UC patients showed relevant differences in the microbiota depending on the location of the disease, with a reduction in beneficial genus such as Adlercreutzia and Alistipes, and an increase in pathogenic species.

Introduction

Chronic inflammatory bowel disease (IBD) is an early onset disease most often between the 2nd and 3rd decade, a second peak of incidence between 50 and 70 years old has been recognized.

Aims & Methods

The aim of our study was to describe the prevalence of elderly patients in IBD as well as the epidemiological, evolutionary and therapeutic profiles of these patients. Then, we compared the evolution of their IBD to younger patients.
We conducted a retrospective, descriptive, comparative study including patients hospitalized for IBD over a 9-year period [January 2011-January 2020]. Patients with less than 2 years of follow-up were excluded. We defined the elderly patients group, or group 1, as patients in whom IBD was diagnosed at an age ≥ 60 years. Group 2 represented younger patients.

Results

Of the 452 patients included, 6.8% (n=31) were elderly patients.
We first described this group of patients. The mean age was 64 years with extremes ranging from 60 to 80 years. The sex ratio M/F=1.6. Fourteen were smokers and 9 were occasional drinkers. For the history, 6 patients were diabetic, 7 had hypertension, and 2 were dyslipidemic. Only one patient had an associated autoimmune disease such as ALS-like syndrome. Fourteen patients had a BMI > 25kg/m². Sixteen patients had Crohn's disease (CD) and 15 had ulcerative colitis (UC). UC was of pancolic location in 7 patients, left in 3 and distal in 5 of them. For CD, it was mainly a colonic localization (n=6) and an inflammatory phenotype (n=9). A phenotypic progression was noted in only one patient, from stenosing phenotype to fistulizing phenotype. Twelve patients had extra-intestinal manifestations, exclusively rheumatological. Severe acute colitis was noted in 10 patients. Corticosteroids were used in 61% of the patients with a good response in 87% of them. Immunosuppressive therapy was used in 9 patients. Thiopurines were used in 100% of cases. Treatment with an anti-TNF α was indicated in 3 patients. Eight patients underwent surgery. These were mainly ileo-caecal resections (n=6).
After comparison, we found that patients in group 1 were significantly more overweight and obese compared to group 2 (45.2 vs 23%, p=0.006). The proportion of UC was significantly higher in group 1 (p=0.001). For patients with CD, there were significantly more ano-perineal manifestations in group 2 (p=0.015), however, the proportion of upper GI tract involvement was equivalent in both groups (p=1). The rate of surgical intervention was comparable in both groups (p=0,9). Nevertheless, the rate of use of immunosuppressive therapy was higher in group 2 (30% vs. 60%, p=0.045). Similarly for the rate of use of anti-TNF α therapy which was 9.6% and 33% in group 1 and 2 respectively (p=0.009).

Conclusion

In our study, we showed that elderly IBD has a mild disease course compared to younger patients. We found significantly lower rate of initiation of IBD medications in elderly patients.