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

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.

Introduction

The introduction of biological drugs has led to great expectations and growing optimism in the possibility that this new therapeutic strategy could favourably change the natural history of Inflammatory Bowel Disease (IBD) and in particular that it could lead to a significant reduction in surgery in the short and long term. The evaluation of the incidence of intestinal resection after the introduction of biological therapy is very complex and subject to several potential bias, the most prominent being the shift in IBD management over the last few decades.

Aims & Methods

This study aims to assess the impact of biological versus conventional therapy on surgery-free survival time (from the diagnosis to the first bowel resection) and on the overall risk of surgery in patients with Crohn’s disease (CD) who were never with the surgical option.
This is a retrospective, double-arm study including CD patients treated with either biological or conventional therapy (mesalamine, immunomodulators, antibiotics, or steroids). All CD patients admitted at the GI Unit of the S. Salvatore Hospital (L’Aquila, Italy) and treated with biological therapy since 1998 were included in the biological arm. Data concerning the CD patients receiving a conventional therapy were retrospectively collected from our database. These patients were divided into a pre-1998 and post-1998 group (pre and post biologic era, respectively). Our primary outcome was the evaluation of the surgery-free survival since CD diagnosis to the first bowel resection. Surgery-free time and event incidence rates were calculated and compared among all groups, both in the original population and in the propensity-matched population.

Results

203 CD patients (49 biological, 93 conventional post-1998, 61 conventional pre-1998) were included in the study. Kaplan-Mayer survivorship estimate shows that patients in the biological arm had a longer surgery-free survival compared to those in the conventional arm (p=0.03). However, after propensity matching analysis, no significant difference was found in surgery-free survival (p=0.3). A sub-group analysis showed shorter surgery-free survival in patients on conventional therapy in the pre-biologic era only (p=0.02) while no significative difference was found between the biologic and conventional post-biologic groups (p=0.15).

Conclusion

This study shows that the introduction of biological therapy had only a slight impact on the occurrence of surgery in CD patients over a long observation period. Despite the milder disease, patients in the conventional group in the biologic era had the same surgery-free survival compared to patients in biological therapy. Nevertheless, biological therapy appears to delay the first intestinal resection. However, the cumulative incidence of first intestinal resection between patients who underwent biological or conventional therapy ends up being similar considering a very long period.

Disclosure

None

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

​​​​​Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-associated mortality in developed countries with a 5-year survival rate of less than 10%. Despite extensive research, there is still a lack of reliable biomarkers for early disease detection and pathophysiology. Therefore, the minute delineation of intimate molecular mechanisms involved in the intratumoral interplay between different compartments of PDAC became of paramount importance. DKK3 (Dickkopf-3), one of the main modulators of Wnt signaling, is a rather unique protein: in PDAC, suppression of DKK3 in a Trp53-deficient context negatively impacts tumor progression and prolongs survival. We previously identified DKK3 as a novel factor for organ regeneration during pancreatitis and, through state-of-the-art investigations involving a in vivo models, delineated a direct, previously unknown link between DKK3 and the canonical-Wnt- and Hedgehog-signaling. This, and given that pancreatitis renders as a risk factor for pancreatic cancer, prompted us to investigate the potential role of DKK3 in PDAC development.

Aims & Methods

To investigate the role of DKK3 in PDAC progression, we employed cutting-edge in vivo, in vitro, and ex vivo experimental settings at different stages of KRAS-driven tumorigenesis (from early dysplasia to cancer stage). In line, a KRAS-driven PDAC mouse model (LSL-KrasG12D/+; Ptf1aCre/+) harboring wildtype Dkk3 allele (KC), heterozygous Dkk3 deletion (DKC) or homozygous Dkk3 deletion (DDKC) was involved. To specifically examine stage-specific roles of DKK3, we characterized the mice at different stages, from development of early dysplasia (10 weeks) until invasive PDAC (36 weeks). To dissect the DKK3 compartment-specific role at early and late stages within the epithelial compartment, functional assays were conducted on acinar and tumor cells respectively. Comprehensive co-culture systems employing stellate and tumor cells were utilized to characterize the intratumoral heterogeneity traits.

Results

The phenotyping of mice revealed that DKCs and DDKCs animals displayed significantly more acinar-to-ductal metaplasia (ADM) and precursor lesions from 10 weeks onward. These lesions translated in a substantial PDAC invasiveness at 36 weeks, and negatively impacted the survival and metastasis at end stage. Additionally, the loss of DKK3 positively correlated with a higher fibrotic content, a key characteristic of PDAC tumorigenesis. In line, ex vivo ADM assays demonstrated a significantly increased capacity of DKK3-null acinar cells to form ductal structures. Additionally, functional assays employing knockout tumor cells revealed higher mesenchymal marker expression such as Vimentin and N cadherin, increased invasion and migration compared to KC, in line with increased metastasis at the end stage. Furthermore, DDKC tumor cells were able to redraft the fibroblast compartment and thus, to give rise to more myofibroblasts that could likely contribute to the tumor aggressiveness at the end stages.

Conclusion

Overall, we show a multifaceted role of DKK3 in pancreatic cancer progression, and especially highlight its tumor-restraining capability within the epithelial compartment as a moderator of early tumor initiating events. This could potentially enable DKK3 to rise as a novel stage-specific biomarker for early PDAC detection.