Clinical Case Summary

We here report the case of a 26-year-old woman with panenteric non-stricturing and non-penetrating Crohn's disease since the age of 10. She was initially treated with Infliximab and Azathioprine when, in 2009, the onset of histologically proven oral granulomatosis led to discontinuation of this therapy and beginning of Thalidomide, stopped the following year due to a convulsive episode. Subsequent treatments with Adalimumab and Methotrexate were discontinued due to primary failure. Furthermore, they did not prove benefit on the oral ulcers. In 2014, 10 mg/Kg Infliximab was resumed until 2017, when it was again stopped due to suspicion of a secondary vasculitis. Due to the lack of a clear diagnosis, this therapy was resumed following the recurrence of intestinal and oral symptoms, leading to resolution of the granulomatosis. In 2021, two hospitalizations occurred due to fever, right-sided pain, hyperchromic urine, recurrence of oral ulcers, and antibiotic and corticosteroid therapy were started, without clear benefit on the oral ulcers. Given the positivity for anti-DNA antibodies and presence of proteinuria, due to suspicion of "lupus-like" connective tissue disorder secondary to therapy and immunocomplex-induced glomerulonephritis, Infliximab was discontinued. Subsequently, in March 2022, Ustekinumab 90 mg q8w in combination with Azathioprine was started; however, despite adding topical therapy with Cyclosporine and Budesonide followed by systemic steroids, the benefit on oral ulcers was scarce. In 2023, due to secondary loss of response to Ustekinumab, compassionate induction therapy with 45 mg/day Upadacitinib was started, fully effective on the oral ulcers. At the end of the 12 week-induction, upon transitioning to a maintenance dosage of 30 mg/day, the effect on the oral disease was maintained but, due to the recurrence of Crohn’s disease following multidisciplinary evaluation, Vedolizumab dual-targeted therapy was started, leading to complete clinical benefit.

References

Gordon H et al. ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease. J Crohns Colitis. 2024 Jan 27;18(1):1-37. doi: 10.1093/ecco-jcc/jjad108. PMID: 37351850.
Loftus EV Jr et al. Upadacitinib Induction and Maintenance Therapy for Crohn's Disease. N Engl J Med. 2023 May 25;388(21):1966-1980. doi: 10.1056/NEJMoa2212728. PMID: 37224198.

Phillips F et al. Orofacial Granulomatosis Associated with Crohn's Disease: a Multicentre Case Series. J Crohns Colitis. 2022 Mar 14;16(3):430-435. doi: 10.1093/ecco-jcc/jjab158. PMID: 34498037.
O'Neill ID, Scully C. Biologics in oral medicine: oral Crohn's disease and orofacial granulomatosis. Oral Dis. 2012 Oct;18(7):633-8. doi: 10.1111/j.1601-0825.2012.01918.x. Epub 2012 Mar 15. PMID: 22420719.

Introduction

The efficacy and safety of upadacitinib (UPA), an oral, reversible Janus kinase (JAK) inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD),^1.2 has been demonstrated in two phase 3 induction studies (U-EXCEL, NCT03345849³; U-EXCEED, NCT03345836⁴) and a phase 3 maintenance study (U-ENDURE, NCT03345823⁵). An association between shorter disease duration and improved outcomes has been shown in post hoc analyses of clinical trial data with other advanced CD therapies.^6,7 We therefore conducted a post hoc analysis of data from these phase 3 UPA studies to assess the potential impact of CD duration on UPA efficacy.

Aims & Methods

Patients in the induction studies were randomized 2:1 to receive UPA 45 mg (UPA45) or placebo (PBO) once daily for 12 weeks.^2,3 Patients achieving clinical response per stool frequency and/or abdominal pain score (SF/APS) criteria were re-randomized 1:1:1 in the maintenance study to UPA 30 mg (UPA30), UPA 15 mg (UPA15), or PBO once-daily for 52 weeks.⁴ Efficacy was evaluated in patient subgroups stratified by CD duration at baseline (< 2 years, 2–5 years, >5–10 years, and >10 years). Endpoints evaluated at week 12 (induction) and week 52 (maintenance) included achievement of clinical remission (per average daily very soft/liquid SF/APS and per Crohn’s Disease Activity Index [CDAI]), normalization of fecal calprotectin and high-sensitivity C-reactive protein levels for patients with elevated baseline levels, endoscopic response, endoscopic remission, and mucosal healing.

Results

Baseline patient and disease characteristics were generally similar across CD duration subgroups during induction (N = 1021). UPA45 demonstrated nominally greater improvement vs PBO in efficacy endpoints across most CD duration subgroups at week 12 (Table). UPA45-treated patients with a shorter disease duration had numerically greater endoscopic improvement vs patients with longer disease duration, and nominally greater endoscopic improvement vs patients receiving PBO at week 12 (Table). Further, the clinical remission rate per CDAI at week 12 was numerically higher with UPA45 vs PBO in patients with CD duration < 2 years, and was nominally higher vs PBO in other CD duration subgroups (Table). Consistent with induction outcomes, UPA30 and UPA15 demonstrated nominally or numerically greater improvement in efficacy endpoints vs PBO regardless of disease duration at week 52 (Table); there was also a general trend towards greater improvements in efficacy outcomes in patients with a shorter disease duration.
​Table. Efficacy Outcomes by Baseline CD Duration During Induction and Maintenance Studies

Endpoint by CD duration at baseline, % (n/N)	Induction, Week 12 (U-EXCEL and U-EXCEED, pooled)		Maintenance, Week 52 (U-ENDURE)
	UPA 45 mg QD n = 674	PBO n = 347	UPA 30 mg QD n = 168	UPA 15 mg QD n = 169	PBO n = 165
Clinical remission per SF/APSa < 2 y 2–5 y > 5–10 y > 10 y	51.0 (52/102)** 58.4 (78/133)*** 50.6 (85/168)*** 34.0 (92/271)***	25.5 (14/55) 23.6 (17/72) 19.5 (16/82) 11.6 (16/138)	50.0 (10/20) 58.5 (24/41)*** 49.0 (25/51)** 33.9 (19/56)**	51.9 (14/27) 39.3 (11/28)** 28.6 (12/42) 31.9 (23/72)**	31.6 (6/19) 10.5 (4/38) 15.8 (6/38) 11.1 (8/70)
Clinical remission per CDAIb < 2 y 2–5 y > 5–10 y > 10 y	46.1 (47/102) 49.6 (66/133)** 48.0 (81/168)** 38.8 (105/271)***	36.4 (20/55) 27.8 (20/72) 29.3 (24/82) 16.8 (23/138)	50.0 (10/20)* 61.0 (25/41)*** 49.0 (25/51)*** 35.7 (20/56)**	55.6 (15/27)** 35.7 (10/28) 28.6 (12/42) 36.1 (26/72)**	15.8 (3/19) 15.8 (6/38) 13.2 (5/38) 15.6 (11/70)
FCP normalizationc < 2 y 2–5 y > 5–10 y > 10 y	40.8 (31/76)*** 38.1 (40/105)*** 28.5 (35/123)** 34.9 (66/189)***	7.3 (3/41) 7.3 (4/55) 9.7 (6/62) 8.1 (8/99)	33.3 (5/15)* 37.8 (14/37)*** 31.4 (11/35)*** 34.3 (12/35)***	36.4 (8/22)* 20.8 (5/24)* 20.6 (7/34)** 22.2 (12/54)**	0 (0/13) 0 (0/28) 0 (0/32) 2.0 (1/50)
hs-CRP normalizationd < 2 y 2–5 y > 5–10 y > 10 y	53.6 (37/69)*** 57.6 (53/92)*** 49.6 (60/121)*** 46.1 (70/152)***	9.1 (3/33) 4.3 (2/47) 11.3 (6/53) 7.7 (6/78)	38.9 (7/18) 59.4 (19/32)*** 20.6 (7/34)** 46.7 (14/30)***	70.0 (14/20)** 23.8 (5/21)** 21.2 (7/33)** 26.1 (12/46)*	12.5 (1/8) 0 (0/27) 0 (0/31) 5.3 (2/38)
Endoscopic responsee < 2 y 2–5 y > 5–10 y > 10 y	61.8 (63/102)*** 48.1 (64/133)*** 36.4 (61/168)*** 30.7 (83/271)***	14.5 (8/55) 11.1 (8/72) 7.3 (6/82) 5.1 (7/138)	45.0 (9/20) 53.7 (22/41)*** 41.2 (21/51)*** 27.5 (15/56)***	53.1 (14/27)* 17.9 (5/28) 21.4 (9/42)* 25.4 (18/72)***	21.1 (4/19) 10.5 (4/38) 2.6 (1/38) 4.3 (3/70)
Endoscopic remissionf < 2 y 2–5 y > 5–10 y > 10 y	40.2 (41/102)*** 26.3 (35/133)*** 26.8 (45/168)*** 15.5 (42/271)***	10.9 (6/55) 5.6 (4/72) 4.9 (4/82) 2.2 (3/138)	40.0 (8/20) 39.0 (16/41)*** 21.6 (11/51)** 23.3 (13/56)**	30.1 (8/27) 10.7 (3/28) 19.0 (8/42)** 18.1 (13/72)*	21.1 (4/19) 2.6 (1/38) 0 (0/38) 5.8 (4/70)
Mucosal healingg < 2 y 2–5 y > 5–10 y > 10 y	37.3 (38/102)*** 23.4 (31/133)*** 19.2 (32/167)*** 15.0 (40/269)***	7.3 (4/55) 2.8 (2/71) 3.7 (3/82) 0 (0/137)	35.0 (7/20) 34.1 (14/41)*** 17.6 (9/51)* 18.2 (10/56)*	22.3 (6/27) 14.3 (4/28)* 14.6 (6/41) 8.7 (6/71)	10.5 (2/19) 0 (0/38) 2.6 (1/38) 4.4 (3/69)
APS, abdominal pain score; CD, Crohn’s disease; CDAI, Crohn’s disease activity index; FCP, fecal calprotectin; hs-CRP, high-sensitivity C-reactive protein; PBO, placebo; QD, once daily; SES-CD, Simple Endoscopic Score for Crohn’s Disease; SF, stool frequency; UPA, upadacitinib; y, years. aAverage daily SF ≤ 2.8 and average daily APS ≤ 1.0, and both not greater than baseline. bCDAI < 150. cFCP normalization to ≤ 250 mg/kg among patients with elevated baseline levels. dhs-CRP normalization to ≤ 5 mg/L, among patients with elevated baseline levels. eDecrease in SES-CD > 50% from baseline (or for patient with a baseline SES-CD of 4, ³ 2-point reduction from baseline) . fSES-CD ≤ 4 and ³ 2-point reduction from baseline and no subscore > 1 in any individual variable. gSES-CD ulcerated surface subscore of 0. *P ≤ .05; **P ≤ .01; ***P ≤ .001 vs PBO. All P-values are nominal and not multiplicity adjusted.

Conclusion

Regardless of disease duration, UPA demonstrated positive clinical and endoscopic outcomes in patients with moderately to severely active CD. Achievement of endoscopic endpoints was numerically higher in patients with shorter vs longer duration of CD, suggesting initiation of UPA earlier in the disease course may lead to better outcomes for patients.

References

1. 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
2. RINVOQ. Summary of Product Characteristics. AbbVie Inc.; 2023. Accessed 27 March 2023. https://www.medicines.org.uk/emc/product/12830/smpc.
3. Loftus E, et al. United European Gastroenterol J. 2022;10(S8):103.
4. Colombel J-F, et al. Gastroenterology. 2022;162(7):S-1394.
5. Panés J, et al. Am J Gastroenterol. 2022;117:S10.
6. Faleck DM, et al. Clin Gastroenterol Hepatol. 2019;17(12):2497–2505.
7. Peyrin-Biroulet L, et al. J Crohn's Colitis. 2022;16(Suppl 1):i045–i048.

Disclosure

RCU has served as an advisory board member or consultant for AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, and Takeda; received research support from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly, and Pfizer; and is funded by a National Institutes of Health (NIH) K23 Career Development Award K23KD111995-01A1.
LP-B has received personal fees from AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Enterome, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Hikma, InDex Pharmaceuticals, Inotrem, Janssen, Lilly, MSD, Mylan, Nestle, Norgine, Oppilan Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Pharmacosmos, Roche, Samsung Bioepis, Sandoz, Sterna, Sublimity Therapeutics, Takeda, Theravance, Tillots, and Vifor; research grants from AbbVie, Fresenius Kabi, MSD, and Takeda; and stock options from CTMA.
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.
EJL has received research grants from Janssen, Pfizer, and Takeda; educational grants from AbbVie, Janssen, MSD, and Takeda; speaker fees from AbbVie, Falk, Ferring, Hospira, Janssen, MSD, Pfizer, and Takeda; served on advisory boards for AbbVie, Arena, Celgene, Ferring, Galapagos, Gilead, Hospira, Janssen, MSD, Pfizer, and Takeda; and served as a consultant for AbbVie.
MF has received financial support for research from AbbVie, Amgen, Biogen, EG, Janssen, Pfizer, Takeda and Viatris; consultancy fees from AbbVie, Agomab Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, Medtronic, MSD, Pfizer, Regeneron, Samsung Bioepis, Sandoz, Takeda, and Thermo Fisher Scientific; and speaker fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Falk, Ferring, Janssen-Cilag, Lamepro, MSD, Pfizer, Sandoz, Takeda, Truvion Healthcare and Viatris.
TM has received grants and honoraria from EA Pharma, AbbVie, Pfizer, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Nippon Kayaku Co., and Zeria Pharmaceutical Co; honoraria from Kyorin Pharmaceutical Co., JIMRO Co., Nichi-lko Pharmaceutical Co., and Takeda; and grants from Daiichi-Sankyo.
CD, APL, VPR, ED, SIA, and AG are employees or contractors of AbbVie, and may own AbbVie stock and/or stock options.
RP has received consultancy and/or speaking honoraria from Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB.
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

Conventional therapy is recommended for the treatment of mild-to-moderate ulcerative colitis (UC); however, patients (pts) are often unable to maintain durable responses and may be suboptimally treated with the overuse of corticosteroids (CS). Some studies on advanced therapies have reported pts achieving CS-free remission, which may benefit pts with UC. This study characterizes CS overuse and the associated economic burden.

Aims & Methods

Data were extracted from the IBM MarketScan Commercial and Medicare Supplemental Databases (January 1, 2014–March 31, 2021) for pts (age ≥18 years) with ≥2 UC diagnoses (≥90 days apart) who received first-line (1L) conventional therapy and had continuous enrollment for 6 months before and 4 years after treatment initiation, respectively. Conventional therapy included aminosalicylates (5-ASA), immunomodulators (IM), CS monotherapy, and CS combination therapy. CS overuse was identified if pts had an episode of receiving CS for a continuous period of >90 days or ≥2 episodes within 1 year. For pts with CS overuse, the index date was defined as the earlier of the 91st day of a CS episode or the initiation date of the second CS episode within 1 year. For pts without CS overuse, the index date was defined as 12 months after the initiation of 1L conventional therapy. All-cause healthcare resource use (HCRU) and costs incurred in terms of per pt per year (PPPY) were evaluated for pts with and without CS overuse at baseline (6 months before the index date) and during the follow-up period (from the index date to the end of 4 years after initiation of 1L).

Results

Overall, 4004 pts were included. Of these, 1820 (45.5%) pts had CS overuse. Median time from 1L treatment initiation to CS overuse was 9.4 (interquartile range, 4.5–23.0) months. Pts with CS overuse were less likely to receive mesalamine monotherapy in 1L (28.1% vs 56.7%) (Table). For pts with and without CS overuse, the baseline mean PPPY medical costs were $15,942 and $5964 (P<0.001), and total mean drug costs were $6051 and $6970, respectively (P<0.001). During the follow-up period, pts with CS overuse had higher inpatient (24.6% vs 14.2%; P<0.001) and emergency room visits (59.0% vs 50.5%; P<0.001) than those without; for pts with and without CS overuse, total mean medical costs were $10,418 and $4922 (P<0.001), and total mean drug costs were $9951 and $5923 (P<0.001), respectively.

Table. Pt characteristics and treatment use

	Pts with CS overuse (N=1820)	Pts without CS overuse (N=2184)
Age, mean ± standard deviation, years	47.7 ± 13.1	46.4 ± 12.5
Female, n (%)	1040 (57.1)	1171 (53.6)
Conventional therapies received in 1L, n (%)
Mesalamine	511 (28.1)	1239 (56.7)
CS	780 (42.9)	393 (18.0)
CS + mesalamine	359 (19.7)	244 (11.2)
IM	10 (0.5)	36 (1.6)
IM + mesalamine	4 (0.2)	22 (1.0)
Other regimensa	156 (8.6)	250 (11.4)

​^aBalsalazide monotherapy, olsalazine monotherapy, and combinations of CS, IM, and 5-ASA.

Conclusion

Approximately half of pts with UC had overused CS while being treated with conventional therapies. In these pts, all-cause HCRU during follow-up, and costs at baseline (except for drug costs) and during follow-up were significantly higher compared with those without CS overuse, suggesting a need for other more effective therapies to be considered for the treatment of these pts. Pts with UC currently treated with prolonged CS courses may benefit from early use of advanced therapies, which are associated with the induction of CS-free remission.

Disclosure

SNH received consulting fees from AbbVie, Bristol Myers Squibb, Janssen, and Takeda. DP is an employee and shareholder of Bristol Myers Squibb. KAB, XN, and SG are employees of the Analysis Group, which received funding for the current research from Bristol Myers Squibb.

Introduction

Pancreatic cancer has remained one of the most serious malignancies and is still a leading cause of cancer-related deaths worldwide. Great attention has been paid to the relationship between diabetes mellitus and pancreatic cancer. At the time of diagnosis of pancreatic cancer, impaired glucose metabolism has been reported to be present in variable rates according to particular studies (ref.).

Aims & Methods

Aims: The aim of our study was to analyse mutual association of pancreatic cancer and diabetes mellitus in the whole population of the Czech Republic within a 5-year period.
Methods: Based on the individual population data from the Czech National Cancer Registry, the incidence of pancreatic cancer in 2017-2021 was estimated. Another data source, the National Registry of Reimbursed Health Services that collects data from health insurance companies, was used to estimate people recently diagnosed with diabetes mellitus. For the purpose of this study, diagnosis of new-onset of diabetes mellitus was defined as the time of the first prescription of any antidiabetic drug (subgroup of patients with prediabetes treated with metformin was included). Patients with diabetes treated with diet only were not included. Subsequently, people diagnosed with pancreatic cancer in 2021 were retrospectively followed up to see if they had been diagnosed with diabetes mellitus in the last 5 years (or earlier) before diagnosis of pancreatic cancer.

Results

There were 310,427 new cases of diabetes mellitus identified within the period 2017 - 2021. Over this period, an average of 2,448 people were diagnosed with pancreatic cancer per year (23.1 / 100,000 population). In 2021, 2,064 patients > 60 years were diagnosed with pancreatic cancer. New onset of diabetes mellitus was recorded in 12.2% three years before the diagnosis of pancreatic cancer and four or five years before this diagnosis in another 5.2%. If we focus only on the 60-74 age group, the proportion was 13.8% and 5.8 %, respectively. Mutual association of diabetes mellitus and pancreatic cancer is displayed in the Table 1.

Table 1
Mutual association of diabetes mellitus and pancreatic cancer within the period 2017-2021

Time of diagnosis of diabetes mellitus (DM)	Age: 39 years and younger	Age: 40-59-year old	Age: 60-74-year old	Age: 75 years and older	TOTAL
DM diagnosed within 1 year prior to cancer diagnosis	0 (0.0%)	29 (9.4%)	82 (7.1%)	54 (5.9%)	165 (6.9%)
DM diagnosed within 2 years prior to cancer diagnosis	1 (5.6%)	5 (1.6%)	44 (3.8%)	11 (1.2%)	61 (2.6%)
DM diagnosed within 3 years prior to cancer diagnosis	1 (5.6%)	5 (1.6%)	33 (2.9%)	27 (3.0%)	66 (2.8%)
DM diagnosed within 4 years prior to cancer diagnosis	0 (0.0%)	5 (1.6%)	29 (2.5%)	18 (2.0%)	52 (2.2%)
DM diagnosed within 5 years prior to cancer diagnosis	0 (0.0%)	7 (2.3%)	38 (3.3%)	22 (2.4%)	67 (2.8%)
DM diagnosed 6 or more years prior to cancer diagnosis	2 (11.1%)	47 (15.2%)	389 (33.7%)	392 (43.1%)	830 (34.7%)
DM diagnosed after the cancer diagnosis	0 (0.0%)	9 (2.9%)	40 (3.5%)	17 (1.9%)	66 (2.8%)
DM not diagnosed	14 (77.8%)	203 (65.5%)	500 (43.3%)	368 (40.5%)	1,085 (45.4%)
TOTAL NUMBER OF PATIENTS DIAGNOSED WITH PANCREATIC CANCER (2021)	18 (100.0%)	310 (100.0%)	1,155 (100.0%)	909 (100.0%)	2,392 (100.0%)

Conclusion

Incidence of pancreatic cancer in the Czech Republic belongs to the highest ones in Europe. New-onset of diabetes mellitus precedes the diagnosis of pancreatic cancer in nearly 20 % of cases within a 5-year period. These findings lead to considerations of the introduction of an early detection programme for pancreatic cancer in the Czech Republic based on new-onset of diabetes mellitus and possible other risk factors.

References

Cancers (Basel) 2023; 15(14): 3669

Introduction

Esophageal reflux burden can be quantified using acid exposure time (AET), mean nocturnal baseline impedance (MNBI) and numbers of reflux episodes (RE), each of which has identified thresholds for physiologic, borderline and pathologic reflux evidence. Alternate parameters such as reflux-symptom association on ambulatory reflux monitoring, hiatus hernia on high resolution manometry, and advanced esophagitis grade on endoscopy escalate confidence for reflux. Each of these parameters has varying importance in determining conclusive evidence of gastroesophageal reflux disease (GERD).

Aims & Methods

Our aim was to determine if a novel reflux score (the Lyon Score) designed to quantify reflux burden can phenotype reflux syndromes and predict treatment outcome from medical or surgical anti-reflux therapy. Scores and ranges were assigned a priori to thresholds for each metric based on available research, the Lyon Consensus and ROME phenotypes (Table). An existing database of endoscopy-negative patients with typical reflux symptoms (heartburn, regurgitation, chest pain) evaluated off therapy for persisting reflux symptoms were reviewed from two centers (one each in Europe and US). Included patients were required to have completed high resolution manometry (Medtronic, Duluth, GA) and ambulatory pH-impedance monitoring (Diversatek, Boulder, CO) off antisecretory therapy. Symptom response was assessed using change in global symptom scores from validated symptom questionnaires over follow-up; a 50% reduction in global symptoms constituted a response to anti-reflux therapy, both medical management and anti-reflux surgery. Receiver operating characteristics (ROC) analysis determined performance of the scoring system in predicting overall response as well as within each distinct syndrome, and principal component analysis identified predictors of response within the scoring system.

Results

Data from 281 patients (median age 53 yr, 57.7% female) was analyzed, 71.9% with heartburn, 13.9% with regurgitation and 14.3% with chest pain. The median Lyon score was 4.0 (IQR 1.5-8.0, range 0.0-16.0). On ROC analysis, the Lyon score demonstrated an AUC of 0.816 in predicting 50% symptom improvement (p=0.026), with an optimal Lyon score threshold of 3.75 (sensitivity 81.2%, specificity 74.1%). The Lyon score performed better than any of the individual components of the score, and only AET (AUC 0.770, p=0.029), MNBI (AUC 0.747, p=0.030) and RE (AUC 0.728, p=0.030) approached the combined score. Using the Lyon score, patients were successfully phenotyped into distinct syndromes (Table), whereby proportions of patients with 50% response from anti-reflux therapy progressively increased across phenotypes with increasing reflux evidence: idiopathic heartburn: 6.1%, isolated permeability defect: 18.2%, reflux hypersensitivity: 27.7%, borderline GERD: 55.9%, conclusive GERD 76.6%, severe GERD 76.9% (Table, p<0.001 across groups). On principal component analysis, AET, MNBI and RE all demonstrated high values within the component matrix (≥0.80 for each), suggesting that each of these primary metrics carries independent weight in driving response to anti-reflux therapy.

Phenotype, score range	No GERD* (0-0.5)	Isolated permeability defect (0.5-2.0)	Reflux hypersensitivity (1.0-3.0)	Inconclusive or borderline GERD (≥3.0)	Conclusive GERD (≥5.0)	Severe GERD (≥10.0)
EGD	Normal: 0 LA A: 0.5	Normal-0 LA A: 0.5	Normal-0 LA A: 0.5	Normal- 0 LA A: 0.5	LA B: 5	LA C/D: 10
AET	< 4.0%: 0	< 4.0%: 0	< 4.0%: 0	4-6%: 2	>6.0%: 5	>10%: 10
RE (number)	<40: 0	<40: 0 40-80: 1	<40: 0 40-80:1	<40: 0 40-80: 1 >80: 2	<40: 0 40-80: 1 >80: 2	<40: 0 40-80: 1 >80: 2
MNBI (ohms)	>2500: 0	<1500: 1	<1500:1 1500-2499: 0.5 >2500: 0	<1500: 1 1500-2499 0.5 >2500- 0	< 1500: 1 1500-2499: 0.5 >2500: 0	<1500: 1 1500-2499: 0.5 >2500: 0
RSA	Negative: 0	Negative: 0	Positive:1	NA	Negative: 0 Positive: 1	Negative:0 Positive: 1
Hiatus Hernia	Negative: 0	Negative: 0	Negative: 0 <3 cm: 1 ≥3 cm: 2	Negative-0 <3 cm: 1 ≥3 cm: 2	Negative: 0 <3 cm: 1 ≥3 cm: 2	Negative: 0 <3 cm: 1 ≥3 cm: 2
Median score (IQR)	0.0 (0.0-0.0)	2.0 (1.0-2.0)	1.4 (0.5-2.3)	4.3 (2.8-4.7)	6.5 (5.5-8.0)	14.0 (12.0-15.0)
50% response**	3/49 (6.1%)	4/22 (18.2%)	13/47 (27.7%)	19/34 (55.9%)	59/77 (76.6%)	40/52 (76.9%)

GERD: gastroesophageal reflux disease; EGD: esophagogastroduodenoscopy; LA: Los Angeles grades (A/B/C/D); AET: acid exposure time; RE: reflux episodes: MNBI: mean nocturnal baseline impedance: RSA: reflux symptom association; IQR: interquartile range
*idiopathic heartburn, presumed esophageal chest pain; **improvement with medical or surgical anti-reflux therapy;

Conclusion

The novel Lyon score segregates reflux phenotypes, and identifies likelihood of symptom response from anti-reflux therapy. Prospective validation of the Lyon score is warranted.

Introduction

Endoscopic ultrasound-guided fine needles biopsy (EUS-FNB) is nowadays considered mandatory for the assessment of solid pancreatic lesions (SPLs) in the neoadjuvant era. Even if most recent guidelines suggest that not less than 3 passes are sufficient to obtain adequate histological characterization, the right number of needle passes with the newest generation of FNB needles remains a topic of debate. In our study we aim to evaluate if less than 3 passes are enough to ensure high rates of confirmed histological diagnosis with the newest generation of FNB cutting needles.

Aims & Methods

Consecutive patients with SPLs requiring tissue sampling through EUS-FNB were enrolled in our study between October 2022 and March 2023. Tissue sampling was performed by the same expert endoscopist through a new 22G needle with asymmetric three-prong tip with the slow-pull technique and fanning when possible. The number of needle passes was determined by the macroscopic onsite evaluation (MOSE), and samples, coming from different passes, were divided into different test tubes. Our endpoints were diagnostic accuracy, positive core procurement yield and sample quality considering each test tube separetely.

Results

53 lesions (of which 75% pancreatic ductal adenocarcinoma) were sampled with an average size of 31 mm (SD=12mm). Sampling was performed with 2 or 3 passes, according to MOSE. Regarding the first needle pass, diagnostic accuracy was 97% (51 confirmed histological diagnosis) which reached 98% considering the second needle pass. Sample adequacy reached approximately 99%. Positive core procurement and tissue quality were >95% in all test tubes. No major adverse events were detected.

Conclusion

In patients with SPLs, the newest generation of histology needles for EUS-FNB could ensure a high diagnostic accuracy with only one needle pass, becoming extremely relevant in terms of time-saving, cost-effectiveness and safety, especially in high volume centers. Due to the limited number of patients additional data are needed.

Introduction

There is controversy about the management of low-risk pT1 CRCs resected in piecemeal, due to impossibility in assessing margins and potential suboptimal histological risk stratification in a fragmented and cauterized specimen.

Aims & Methods

Aims:To compare en bloc and piecemeal resected low-risk pT1CRC in terms of overall survival (OS) and metastasis free survival (MFS).
Materials and Methods: Low risk pT1 CRCs (no poor differentiation and no lymphovascular invasion) either piecemeal or en bloc resected were selected from two combined European multicenter cohorts (EpiT1 Consortium and Dutch pT1CRC study group). The exclusion criteria were primary surgical treatment, incomplete local resection, lack of information on type of resection , lack of follow-up of at least 2 years. The outcomes studied were metastasis free survival(MFS) and overal survival(OS). Cox regression analysis was performed adjusting for rectal location, size, and pedunculated morphology.

Results

Results: 3918/7043 patients with a pT1 CRC met the inclusion criteria: 822 (21%) resected in piecemeal and 3096 (79%) resected en bloc (Table 1). After local treatment, 46.6% in the piecemeal group received completion oncological surgery and 26.6% in the en bloc group. Adjusted 5-yrs MFS was lower for the piecemeal resected pT1 CRCs (94.6% (95%CI) vs. en bloc 97.4% (95%CI);p=0.001). Within the piecemeal resected pT1CRC group, the adjusted 5-yrs MFS did not differ between the group which underwent completion surgery versus the group who received only surveillance. (93.7%(95%CI) vs 96.3% (95%CI), p=0.08). Patients with a pT1 CRC resected in piecemeal followed by secondary surgery showed more endoluminal recurrence than en bloc resected pT1 CRCs followed by surveillance (10.8% VS 1.6%, p<0.00), higher proportion of distant metastasis (13/381 (3.4%) vs 14/730 (1.9%), p = 0.04) despite a similar 5-yrs MFS (96.3% vs 97.8%, p=0.08).

TABLE 1. Baseline characteristics of the patients (Multivariate analysis)

Variable	Piecemeal (N = 822)	En bloc (N = 3096 )	P
Age, median+SD	66.88 + 9.7	66.59 + 9.4	0.46
Female Sex, n (%)	317 (38.6)	1168 (37.7)	0.66
ASA Classification ,n (%) I-II III-IV	N=795 636 (80.0) 159 (20.0)	N=2971 2399 (80.7) 572 (19.3)	0.63
Polyp size, mm, DE	28.04+13.23	18.93+10.32	<0.001
Location, n (%) Rectum No rectum	N=818 284(34.7) 534 (65.3)	N=3079 816 (26.5) 2263(73.5)	<0.001
Morphology Not Pedunculated Pedunculated	N=789 516 (65.4%) 273 (34.6%)	N=3002 1263 (42.1%) 1739 (57.9)	<0.001
Treatment Surveillance Oncological surgery	N=822 441(53.6%) 381 (46.4%)	N=3096 2366 (76.4%) 730 (26.6%)	<0.001

Conclusion

Conclusions: Even after secondary surgery Piecemeal resected pT1 CRC have a worse outcome than en bloc resected pT1 CRCs with surveillance . This is probably due to suboptimal histological risk stratification in a fragmented and cauterized specimen.