Introduction

Luminal stenoses with variable degrees of inflammatory and fibrotic components are commonly observed in patients with Crohn’s disease (CD) and may require medical, endoscopic, or surgical management.¹ Upadacitinib (UPA), an oral, reversible Janus kinase inhibitor, demonstrated efficacy in 3 randomized, controlled, double-blind studies, and is approved for the treatment of moderately to severely active CD.^2-6 We conducted a post hoc analysis of these studies to evaluate the efficacy of UPA in patients with baseline (BL) luminal stenoses.

Aims & Methods

Patients in induction studies U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836) were randomized 2:1 to receive UPA 45 mg (UPA45) or placebo (PBO) once daily (QD) for 12 weeks. Patients with clinical response were re-randomized 1:1:1 in the U-ENDURE maintenance study (NCT03345823) to receive UPA 30 mg (UPA30), UPA 15 mg (UPA15), or PBO QD for 52 weeks. The presence, location, degree of patency, and number of luminal stenoses were assessed by Simple Endoscopic Score for CD (SES-CD) narrowing component (range 0–3; patients with symptomatic stenosis were excluded). Resolution of BL stenosis and achievement of clinical remission and endoscopic response were assessed at week 12 of induction and week 52 of maintenance.

Results

One-third of patients (33.0% [337/1021]) had stenoses at induction BL (UPA45: 34.1% [230/674]; PBO: 30.8% [107/347]). BL demographics and disease characteristics were generally similar in patients with or without stenoses. BL stenoses occurred most frequently in the ileum (161 stenoses) followed by the right colon, transverse colon, sigmoid and left colon, and rectum (116, 39, 53, and 33 stenoses, respectively). At week 12, resolution rates of BL stenosis were nominally greater in the sigmoid and left colon and numerically greater in the ileum, transverse colon, and rectum among patients receiving UPA45 vs PBO (Table). UPA45 showed nominally greater efficacy compared with PBO in achieving clinical remission and endoscopic response in patients with or without BL stenoses (Table). Of the 502 patients in the maintenance population, 35.3% (n = 177) had stenoses at induction BL (UPA30: 34.5% [58/168]; UPA15: 35.6% [60/169]; PBO: 35.8% [59/165]). Narrowing was most frequent in the ileum (82 stenoses) followed by the right colon, transverse colon, sigmoid and left colon, and rectum (56, 21, 27, and 20 stenoses, respectively). By week 52, resolution rates of BL stenosis were nominally greater in the sigmoid and left colon and numerically greater in the ileum, right colon, transverse colon, and rectum among patients receiving UPA30 vs PBO (Table). Numerically greater rates of right colon, sigmoid and left colon, and rectum stenosis resolution occurred among patients receiving UPA15 vs PBO (Table). Nominally or numerically greater proportions of patients, with or without BL stenoses, achieved clinical remission and endoscopic response at week 52 with UPA30 and UPA15 vs PBO (Table).

Conclusion

Among patients with moderately to severely active CD, UPA induction and maintenance treatment improved the narrowing component of BL luminal stenoses, and clinical and endoscopic outcomes for patients with or without stenoses.

References

1. Bettenworth D, et al. Gut. 2019;68:1115–1126.
2. Loftus E, et al. United European Gastroenterol J. 2022;10(S8):103.
3. Colombel JF, et al. Gastroenterology. 2022;162(7):S-1394.
4. Panés J, et al. Am J Gastroenterol. 2022;117:S10.
5. RINVOQ. Summary of Product Characteristics. AbbVie Deutschland GmbH & Co. KG; 2023. Accessed 24 April 2023. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf
6. RINVOQ. Summary of Product Characteristics. AbbVie Inc.; 2023. Accessed 27 March 2023. https://www.medicines.org.uk/emc/product/12830/smpc.

Disclosure

WR has served as a speaker and/or consultant and/or an advisory member for AbbVie, Amgen, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Bioclinica, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celgene, Celltrion, Eli Lilly, Falk Pharma GmbH, Ferring, Janssen, Galapagos Medice, Gatehouse Bio Inc., Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Landos Biopharma, Medahead, MedImmune, Microbiotica, Mitsubishi Tanabe Pharma Corporation, MSD, Roche, Novartis, OMass, Otsuka, Parexel, Periconsulting, Pharmacosmos, Pfizer, Pharmacosmos, Protagonist, Provention, Quell Therapeutics, Sandoz, Seres Therapeutics, Setpointmedical, Shire, Sigmoid, Sublimity, Takeda, Teva Pharma, Therakos, Theravance, and Zealand; and has received research funding from AbbVie, Janssen, MSD, Sandoz, Sanofi, and Takeda.
RA has served as a speaker or consultant, or received research grants from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Falk Foundation, Ferring, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Kliniksa, Lilly, MSD Sharp & Dohme, Novartis, Pandion Therapeutics, Pfizer, Roche Pharma, Samsung Bioepsis, Takeda Pharma, Tillotts Pharma, and Viatris.
VJ has received consulting/advisory board fees from AbbVie, Alimentiv Inc, Arena Pharmaceuticals, Asieris, Bristol-Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Galapagos, GSK, Genentech, Gilead, Janssen, Lilly, Merck, Mylan, Pandion, Pendopharm, Pfizer, Reistone Biopharma, Roche, Sandoz, Takeda, and Topivert; and speaker fees from, AbbVie, Ferring, Galapagos, Janssen, Pfizer, Shire, and Takeda.
JP has received financial support for research from AbbVie and Pfizer; lecture fees from AbbVie, Ferring, Janssen, and Takeda; and consultancy fees from AbbVie, Arena Pharmaceuticals, Athos, Boehringer Ingelheim, Celltrion, Ferring, Galapagos, Genentech, GSK, Janssen, Mirum, Morphic, Origo, Pandion, Pfizer, Protagonist, Revolo, Robarts, Roche, Takeda, Theravance, and Wassermann.
EVL has received consultancy honoraria from AbbVie, Alvotech, Amgen, Arena, Avalo Therapeutics, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iota Biosciences, Iterative Scopes, Janssen, Morphic, Ono Pharma, Pfizer, Protagonist, Scipher Medicine, Sun Pharma, Surrozen, Takeda, and UCB; and has received research support from AbbVie, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Gossamer Bio, Janssen, Pfizer, Receptos, Robarts Clinical Trials, Takeda, Theravance, and UCB.
SH reports no disclosures.
MTA has received consulting fees from Arena AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Celsius, Eli Lilly Pharmaceuticals, Gilead, Janssen, Microba, Pfizer, Prometheus Biosciences, UCB Biopharma, WebMD Global, and Focus Medical.
FR has received consulting/advisory board fees from Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, Astra Zeneca, Boehringer-Ingelheim, Celgene/BMS, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Janssen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, UCB, Ysios, and 89Bio.
VPR, EM, ED, SIA, and AG are employees or contractors of AbbVie and may own stock and/or options.
JFC has received research grants from AbbVie, Janssen, and Takeda; payment for lectures from AbbVie, Amgen, Ferring, Shire, and Takeda; consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enterome, Ferring, Genentech, Janssen, Medimmune, Merck, Novartis, Pfizer, Protagonist Therapeutics, Sandoz, Second Genome, Seres Therapeutics, Shire, Takeda, Theradiag, and Theravance; and holds stock options in Genfit and Intestinal Biotech Development.
Funding
AbbVie Inc. funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and authors thank all the trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Tracy Wetter, PhD, and Akua Adu-Boahene, MD, MPH, of JB Ashtin, and funded by AbbVie.

Introduction

Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) can demonstrate microvascularization of the tumors. However, most images acquired from CEH-EUS are interpreted subjectively without quantification by time-intensity curves (TICs) analysis.

Aims & Methods

In this study, we used handcrafted software to quantify CEH-EUS images for objective interpretation of tumor microvascularization to make differential diagnosis of pancreatic tumors feasible.
We analyzed the videos of CEH-EUS for pancreatic tumors from the patients in National Taiwan University Hospital and Far Eastern Memorial Hospital. The convex-type echoendoscope (GF-UCT260; Olympus, Tokyo, Japan) equipped with ultrasound (US) systems (EU-ME2) was used for the procedures. The second generation of US contrast agent with Sonazoid (GE Healthcare, Milwaukee,Wisc), which contains perfluorobutane microbubbles with a median diameter of 2–3 μm, was administered bolus and intravenously with a dosage of 0.015 ml encapsulated gas per kilogram body weight. The videos were recorded in AVI formats with 30 frames/second.
The algorithm for getting TICs includes the following steps:
(1) Circling the region of interest(ROI) in the B-mode
(2) Performing speckle tracking of the ROI in the B-mode
(3) Simultaneously obtaining the intensity of ROI (the mean pixel values in the ROI) in the corresponding contrast-enhanced harmonic image
(4) Outputting TICs after subtracting the baseline intensity (defined as mean TIC in the first 10 s for eliminating the different baseline intensities caused by other settings).
(5) Outputting histogram of pixel values and excel file containing all pixel values from the frame with the highest mean pixel value automatically.
(6) Calculating the standard variance of (5) to represent the heterogeneity inside the ROI.
The speckling tracking composes of searching and matching processes. We used full search for the searching process and normalization cross-correlation for the matching process. By using the hardware of CPU with Intel i7-8750H and GPU with Nvidia GTX 1050 Ti, the computation time was 0.7 ms/frame.

Results

The detailed results were shown in Table 1. We collected 10 and 7 videos of CEH-EUS for pancreatic tumors from NTUH and FEMH respectively in this study. Among them, 9 were diagnosed of pancreatic ductal adenocarcinoma (PDAC), 6 were pancreatic neuroendocrine tumors (PNET), and 2 were autoimmune pancreatitis (AIP). The TICs were obtained through our proposed model. Briefly, there were no significant differences in times to peak, the mean peak intensity, the in-slope tangent and standard deviation of pixel value in ROI (from the frame with the highest mean pixel value) among PDAC, PNET, and AIP. However, there was significant difference in the mean peak intensities of PDAC and non-PDAC (37.88 vs 63.12, p=.031).

Table 1.The results from three kinds of pancreatic tumors based on the proposed model

Conclusion

In this study, there were no significant differences in times to peak, the mean peak intensity, and SD of pixel value in ROI (from the frame with the highest mean pixel value) among PDAC, PNET, and AIP, however there was significant difference in the mean peak intensity between PDAC and non-PDAC group. A study with larger test number is needed in the future for further application.

Disclosure

We have no conflicts of interest to disclose.

Introduction

Current endoscopic ultrasound technologies (EUS) are suboptimal in the assessment of pancreatic cystic lesions (PCLs). We developed a new through-the-needle brush, the "loop brush", to improve the cellular yield, and thereby sensitivity, of EUS fine needle aspiration (EUS-FNA) of pancreatic cysts.

Aims & Methods

We aim to evaluate the "loop brush" safety, robustness, and efficacy.
We performed an in-vivo randomized controlled trial in pigs using artificial cysts. In one group, the loop brush was deployed through a 22G EUS-FNA needle into the cysts. In the control group, cystic punction was performed with standard EUS-FNA. Loop brushes were visually inspected post-procedure. Cytological assessment, cell counting, and hemoglobin analysis were performed in samples from both groups.

Results

Artificial cysts (n=114) were punctured in six pigs, 57 in each group. Neither adverse events nor significant device malfunction occurred during loop brushing. Samples collected with the brush had non-detectable concentrations of hemoglobin in 72% (41/57) of cases, and 26% (16/57) had less than 0.6 g/dL, with no significant difference to the controls (p=0.32). Brushing cell counts were associated with significantly increased cell counts (11.7× median difference, p<.0001). Cytological smears
were diagnostic in 77% of cases in the brushing group, while 54% in the control group (p=0.01, Fisher’s exact test; p=0.006, Chi-square test).

Conclusion

The new loop brush procedure appears to be safe, causing neither significant bleeding nor device malfunction. Samples obtained with the loop brush were suitable for cytological analysis and showed significantly higher cell yield than controls. Further clinical studies are warranted.

References

DOI: 10.1053/j.gastro.2020.10.007
DOI: 10.1186/s12916-018-1215-3
DOI: 10.3389/fonc.2021.688377
DOI: 10.1136/gutjnl-2016-313127
DOI: 10.1038/ajg.2018.14
Mohamed, E.; et al. Role of radiological imaging in the diagnosis andcharacterization of pancreatic cystic lesions: a systematic review. Pancreas 2018, 47, 1055–1064.
Cazacu, I. M.; et al. A quarter cen- tury of EUS-FNA: Progress,milestones, and future directions. Endoscopic ultrasound 2018, 7, 141
DOI: 10.1038/s41598-021-81065-2
doi: 10.4103/eus.eus_93_17
Shirley, L. A.; et al. Routine cyst fluid cytology is not indicated in the evaluation of pancreatic cystic lesions. Journal of Gastrointestinal Surgery 2016, 20, 1581–1585.
Muniraj, T.; et al. Devices for endoscopic ultrasound-guided tissue acquisition. Techniques in Gastrointestinal Endoscopy 2018, 20, 2–9.
Balaban, V. D.; et al. EUS- through-the-needlemicrobiopsy forceps in pancreatic cystic lesions: A systematic review. Endoscopic Ultrasound 2021, 10, 19.
Marques, F.; et al. A loop-shaped minimally invasive brush for improved cytology sampling of pancreatic cysts during EUS-FNA. Medical Devices & Sensors 2021, 4, e10165.
doi: 10.1177/0271678X20943823.
doi: 10.3748/wjg.v18.i34.4659
DOI: 10.3748/wjg.v27.i26.4194

Disclosure

FM, WW, UA, NR, and FBS have patent applications for the brush technology and are co- founders of Lucky LoopMedical AB, a company commercializing technology for improved sampling in EUS-FNA. UA has received a research grant from Boston Scientific and is a consultant to Boston Scientific, Medtronic, and Ambu. IS declares no conflict ofinterest.

Clinical Case Summary

A 40-year-old male came to our emergency department referring worsening jaundice, mental status deterioration, epigastric pain and anorexia over the past week. Four weeks earlier he presented odynophagia, myalgias, and hand pruritus but didn’t seek medical attention.
Patient’s clinical background included cognitive impairment due to peripartum anoxia and type 2 Diabetes Mellitus. At admission, he had elevated liver enzymes (R value=2,7), coagulopathy (INR 1.3), pancreatic enzymes >3 times the upper normal level and hyperbilirubinemia (mostly conjugated).
The CT-scan revealed pancreatic tail globosity, diffuse abdominal and retroperitoneal peri-centimetric lymph nodes and excluded biliary lithiasis.
After common causes of acute hepatitis and pancreatitis were ruled out, and since patient was at risk of acute liver failure despite supportive treatment, a liver biopsy was performed. Autoimmune hepatitis, drug-induced liver injury or lymphoproliferative disease were held as potential differentials. Hepatitis E Virus (HEV) RNA was then found and genotyped in the serum (genotype 3). HEV infection was assumed as the cause for both hepatitis and pancreatitis. Histological pattern was inconclusive and epidemiological source wasn’t found.

HEV infection paradigm has changed and is now considered an endemic zoonotic infection in most high-income countries (Portuguese seroprevalence is 16.3%)¹. Infection occurs due to ingestion of undercooked pig or boar meat and should be suspected in every acute hepatitis, mostly with a cholestatic pattern.
The setting of acute HEV hepatitis complicated with acute pancreatitis (AP) is uncommon². AP usually starts after a median of 10 days of jaundice onset³. Literature only reports association between AP and HEV caused by genotype 1 from Southeast Asia^{3 4}, and genotype 3 was only related to gallstone-related pancreatitis, according to current knowledge⁵. This might be the first form of HEV genotype 3 infection with hepatitis and pancreatitis.

References

1. Nascimento MSJ, Pereira SS, Teixeira J, et al. A nationwide serosurvey of hepatitis E virus antibodies in the general population of Portugal. Eur J Public Health 2018;28(4):720-24. doi: 10.1093/eurpub/ckx213 [published Online First: 2017/12/14]
2. Debnath P, Datta AK, Chakraborty U, et al. Acute viral hepatitis E complicated with acute pancreatitis in an immunocompetent adult. BMJ Case Rep 2021;14(2) doi: 10.1136/bcr-2020-239684 [published Online First: 2021/02/06]
3. Haffar S, Bazerbachi F, Garg S, et al. Frequency and prognosis of acute pancreatitis associated with acute hepatitis E: A systematic review. Pancreatology 2015;15(4):321-6. doi: 10.1016/j.pan.2015.05.460 [published Online First: 2015/06/08]
4. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol 2018;68(6):1256-71. doi: 10.1016/j.jhep.2018.03.005 [published Online First: 2018/04/04]
5. Karlsson M, Norder H, Bergstrom M, et al. Hepatitis E virus genotype 3 is associated with gallstone-related disease. Scand J Gastroenterol 2019;54(10):1269-73. doi: 10.1080/00365521.2019.1666163 [published Online First: 20190925]

Introduction

Irritable bowel syndrome (IBS) is a bothersome condition with long term pain and bowel symptoms and the most common cause of referral to gastroenterologists in the United Kingdom. Despite this, IBS is poorly understood as a clinical entity. Furthermore, IBS has numerous comorbidities but the full spectrum of these and how they relate to IBS has not been studied.

Aims & Methods

Using clustering analysis on the UK Biobank dataset, an adult cohort (age > 40 years), we aimed to define the top co-morbidities associated with IBS and develop a machine learning model to predict IBS. Co-morbidities in patients based on ICD-10 Summary Diagnosis codes 2 years prior to and 2 years following diagnosis with IBS were assessed and clusters defined. These were compared with a control group of non-IBS patients. Several machine learning algorithms (K-Means, Linear Discriminant Analysis, Gaussian Mixture Models) were compared for accuracy.

Results

Amongst 18000 total adults (aged over 40), 8168 patients coded for IBS, 75% of whom were female. The top ten comorbidities (Table 1) found in IBS patients included diverticular disease, hypertension, hernia, haemorrhoids, osteoarthritis, asthma, gastro-oesophageal reflux disease without oesophagitis, history of psychoactive substance abuse, hypercholesterolaemia, and cholelithiasis. K-Means achieved the highest accuracy (83%) for predicting IBS based on the co-morbidity profile.

Conclusion

Most clusters identified contained obesity, hypercholesterolemia, and hypertension, indicating a possible link with metabolic syndrome. Asthma and allergies suggest a possible cohort of IBS patients with atopy. Further research is needed to establish these links. In clinical practice, this could help both in predicting development of IBS, and also identify the cohorts of IBS on which certain therapies are more likely to work.

References

Drossman, D. A., Camilleri, M., Mayer, E. A., & Whitehead, W. E. (2002). AGA technical review on irritable bowel syndrome. Gastroenterology, 123(6), 2108-2131. doi:10.1053/gast.2002.37095
Snyder, N. (2023, 10 Feb 2023). Irritable bowel syndrome. BMJ Best Practice. Retrieved from https://bestpractice.bmj.com/topics/en-gb/122
Staller, K., Olén, O., Söderling, J., Roelstraete, B., Törnblom, H., Khalili, H., . . . Ludvigsson, J. F. (2021). Diagnostic yield of endoscopy in irritable bowel syndrome: A nationwide prevalence study 1987-2016. Eur J Intern Med, 94, 85-92. doi:10.1016/j.ejim.2021.08.001

Introduction

Mucinous cysts of the pancreas are known precursors of pancreatic ductal adenocarcinoma. International guidelines for management and surveillance of pancreatic cysts advise surgical resection of high-risk lesions - mucinous cystic neoplasms (MCNs) and main duct intraductal papillary neoplasms (IPMNs), especially in those with worrisome clinicopathological stigmata. For low-risk cysts, lifelong radiographic surveillance is the standard approach, which can be psychologically distressing for patients and burdensome for healthcare systems. Endoscopic ultrasound (EUS)-guided radiofrequency ablation (RFA) of high-risk cystic lesions of the pancreas is increasingly being used as a minimally invasive alternative in patients who are unfit for or who decline surgery (1). We assessed the safety and efficacy of EUS-guided RFA in the management of low-risk cystic lesions of the pancreas.

Aims & Methods

68 patients (29M, 39F; mean age 63, range 33-82 years) with low-risk mucinous cystic neoplasms of the pancreas (branch-duct IPMN/mucinous cystadenomas, 0.7-4cm in size) were recruited for treatment by EUS-RFA. The primary endpoint was change in size of the pancreatic cyst on cross-sectional imaging (MRI) at one year after treatment (efficacy). Secondary endpoints included progression following treatment, procedure related morbidity and local complication rate (safety).

Results

68 patients were recruited of whom 55 completed RFA ablation of their cyst. Anatomical concerns (i.e., blood vessel, main duct proximity) precluded RFA in 12 patients. 18/55 patients (33%) underwent a second ablation. Follow up imaging data were available for 46 (84%) patients and showed a <20% reduction in cyst size in 18 patients, 20-49% in 4 patients, 50-79% in 5 and 80-100% size reduction in 18 patients. For one patient, doubling in cyst size was recorded at the 12-month follow-up. Excluding one case of scope-induced small bowel perforation (Clavien-Dindo; ClvD grade 3), other adverse events were mild (ClvD 0-2) and expected (transient abdominal pain, bloating, sore throat, nausea/vomiting). One patient experienced a self-limiting, post procedure grand mal seizure on a background of epilepsy.

Conclusion

​EUS-RFA was well tolerated in most cases. Our data indicate that the procedure is relatively safe. The response ranged from a <20% reduction in size to complete cyst resolution.

References

1. Papaefthymiou A, Johnson GJ, Maida M, Gkolfakis P, Ramai D, Facciorusso A, Arvanitakis M, Ney A, Fusai GK, Saftoiu A, Tabacelia D, Phillpotts S, Chapman MH, Webster GJ, Pereira SP. Performance and safety of EUS-ablation techniques for pancreatic cystic lesions: a systematic review and meta-analysis. Cancers 2023 [in press].

Disclosure

No conflict of interest