Introduction

KRAS, TP53, CDKN2A, and SMAD4 have been the main driver mutations in pancreatic ductal adenocarcinoma (PDAC). Studies on the clinical significance and treatment response to 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) regimen in terms of the presence of these mutations remain inconclusive.

Aims & Methods

This study analyzed patients diagnosed with pancreatic adenocarcinoma using a targeted next-generation sequencing platform at two tertiary referral hospitals from January 2016 to March 2022. Patients receiving FOLFIRINOX chemotherapy as the initial treatment were retrospectively investigated.

Results

The analysis included 100 patients. KRAS mutation was identified in 92 (92.0%) patients, followed by TP53, CDKN2A, and SMAD4 in 63 (63.0%), 18 (18.0%), and 17 (17.0%) patients, respectively. The TP53 wild type group demonstrated longer overall survival (OS) than the TP53 mutated group (median OS: 29 months vs. 19 months, p = 0.03), and TP53 served as a prognostic factor for survival (hazard ratio = 1.74, 95% confidence interval: 1.00–3.00, p = 0.048). The difference in OS according to TP53 mutation was intensified in localized pancreatic adenocarcinoma (37 months vs. 19 months, p = 0.01). The TP53 wild type group demonstrated a higher objective response rate to FOLFIRINOX chemotherapy than the TP53 mutation group in localized pancreatic adenocarcinoma (50.0% vs. 17.6%, p = 0.024).

Conclusion

PDAC patients with wild type TP53 demonstrated longer OS than those with TP53 mutation, and this trend was intensified in patients with localized disease. This result may be due to an impaired response to FOLFIRINOX chemotherapy in patients with TP53 mutation.

Introduction

Incidence of sporadic ductal pancreatic adenocarcinoma (PDAC) in the Czech Republic is the third highest in Europe (23.1/100,000 population). New-onset diabetes mellitus with weight loss (> 5% within < 6 months) in patients over sixty can be an early sign of PDAC. New-onset diabetes mellitus was recorded in 12.2% subjects three years prior to the diagnosis of PDAC (in the 60-74+ age group:13.8%) in the Czech Republic in the period 2017-2021 [ref. 1].

Aims & Methods

The aim of this study was to evaluate the standardized incidence ratio (SIR) of PDAC in patients with diabetes mellitus with and without previous history of any other malignancy within a 12-year period.
Methods: The analysis was based on individual population data from the Czech National Registry of Reimbursed Health Services, the National Cancer Registry, and the Death Certificate Information System in the period 2010 - 2021. Patients were divided into two groups: the first one included subjects with diabetes mellitus who had a history of any malignancy prior to the diagnosis of diabetes (follow-up 865,956 person-years); the second cohort consisted of people with diabetes mellitus who had no history of malignancy prior to the diagnosis of diabetes (7,971,090 person-years). The calculated person-years at risk were stratified by sex, age and time periods (2010-2013; 2014-2017; 2018-2021). Subgroup analyses were performed considering follow-up and age at diagnosis of diabetes. The first report of any antidiabetic drug (ATC group A10) was the determinant for the diagnosis of diabetes mellitus in a particular individual. SIR was calculated as the ratio of observed to expected (estimated from incidence in the general population) cases of PDAC.

Results

Selected SIRs stratified according to age and follow-up are displayed in Table 1.
A significantly higher risk of PDAC in diabetes mellitus with a history of previous malignant diseases (compared to the general population) was found for the following: head and neck cancer (SIR 2.54), gastric cancer (2.12), colorectal cancer (1.38), laryngeal cancer (2,51), malignant melanoma (1.65), breast cancer (1.61), cervical cancer (2.22), uterine cancer (1.72), prostate cancer (1.59), testicular cancer (3.1), kidney cancer (1.75), urinary bladder cancer (1.74), thyroid cancer (2.13), Hodgkin lymphoma (2.74), non-Hodgkin lymphoma (2.15) and leukaemias (1.93).

Table 1
Risk of PDAC in diabetes mellitus

Conclusion

Risk of PDAC in patients with diabetes mellitus was higher in subjects with a history of various malignant diseases compared to those with no previous history of any malignancy. Particular attention should be paid to new-onset diabetes (diagnosis made within one last year). History of a malignancy, as an important risk factor for PDAC, should be taken into account when surveilling patients with diabetes mellitus.

Funding: Research projects MO1012 (DZVRO) and MH CZ-DRO (UHHK, 00179906).

References

Ref. 1: UEG Journal 2024; 12 (Suppl S8): 565.

Disclosure

There is conflict of interest.

Introduction

Budesonide orodispersible tablet (BOT) is the only approved topical steroid available in Europe for the induction and maintenance of remission in patients with eosinophilic esophagitis (EoE). Available randomized controlled trials have demonstrated that, following induction of histological remission with BOT 1mg twice daily (bid), patients can be maintained in remission with BOT 0.5mg bid. It is currently unknown whether a dose of 1mg once daily (od) has comparable efficacy to 0.5mg bid.

Aims & Methods

In this prospective study conducted at two tertiary referral centers for EoE, we enrolled consecutive patients with EoE undergoing clinical, endoscopic, and histologic re-assessment while on maintenance treatment for EoE with BOT 0.5mg bid or BOT 1mg od. All included patients had achieved histological remission (i.e., <15 eosinophils/high-power field, eos/HPF) following induction of remission with BOT 1mg bid. At the end of the induction of remission period (T0), all patients were assessed using the dysphagia symptom questionnaire (DSQ), the EoE endoscopic reference score (EREFS), and peak eosinophil counts (PEC). At re-assessment while on maintenance treatment (T1), all patients underwent 1) assessment of dysphagia and adaptive behaviors with the DSQ and the Pisa EoE Adaptation Questionnaire v1.0 (PiEAQ). Clinical remission was defined as DSQ not increasing >30% compared to T0. 2) upper endoscopy (EGDS) with assessment of EREFS score and at least six esophageal biopsies, and 3) histological assessment using the EoE Histology Scoring System (EoEHSS). In addition, a comprehensive global assessment of clinical, endoscopic, and histologic findings was performed using the validated index of severity for EoE (I-SEE score). Kruskal-Wallis Rank Sum Test and Pearson’s Chi-squared were used for comparisons. Significance threshold was p<0.05.

Results

Fifty-six patients were included (46 males and 10 females). Following histological remission with BOT 1mg bid, 28 (50%) initiated maintenance treatment with BOT 1mg od and 28 (50%) with BOT 0.5 bid. At the end of induction of remission (T0), the two groups had achieved similar outcomes, with comparable median DSQ [0 (0-28) vs 0 (0-28)], EREFS [1 (0-2) vs 1 (0-1)], and PEC [1 (0-7) vs 1.5 (0-4)] (all p>0.3) (Table 1). At the end of the maintenance treatment (T1), the two groups had been taking maintenance treatment for a comparable duration [20 weeks (12 – 36) vs 20 weeks (12 – 32; p=0.7). Persistent histological and clinical remission at T1 was present in 86% of BOT 1mg od versus 93% of BOT 0.5 bid (p=0.7). In addition, EREFS scores were comparable between groups at T1 [1 (0-2) vs 1 (0-2), p=0.8]. Similarly, the EoEHSS stage and grade was comparable between groups, as was the PiEAQ score [1.5 (0.75-2) vs 0.5 (0-2); p=0.06], and the I-SEE score [ 3 (2-4) vs 3 (2-4); p=0.5] (Table 2).

Conclusion

Persistent clinical endoscopic, and histological remission was maintained in most patients treated either with BOT 1mg od or BOT 0.5mg bid for a median of 20 weeks, indicating that the total daily dose of BOT 1mg may be more important that the frequency of administration, at least in the short term.

Disclosure

Speaker or Consultancy for Apogee Therapeutics, Alfasigma, Dr Falk Pharma, Sanofi, Malesci, JB Pharmaceuticals

Introduction

Acute pancreatitis (AP) is associated with an intense catabolic, local-regional and systemic inflammatory state, which can lead to changes in body composition, with prognostic implications.

Aims & Methods

Aims: To evaluate the body composition by anthropometry, bioelectrical impedance analysis (BIA) and computed tomography (CT) and its influence in AP severity, endocrine insufficiency (EnPI-AP), pancreatic exocrine (EPI-AP) and post-pancreatic enzyme replacement therapy (PERT).
Methods: Prospective longitudinal study of consecutive adult patients diagnosed with first AP episode. EPI-AP patients were randomized to receive PERT (4000IU/meal+20000IU/snack) vs. placebo (clinicaltrials.gov:NCT05480241). Body composition was assessed using anthropometry, BIA (InBody 570) and CT (cross-sectional areas L1/L3). Obesity was diagnosed for body mass index (BMI)≥30Kg/m², waist-to-hip ratio (WHR)>0.9(men)/0.85(women) and percentage total fat mass (TFM)>20%(men)/28%(women). Visceral obesity was defined by abdominal circumference (AC)>94(men)/80(women)cm, visceral fat area (VFA)≥100cm² and visceral/subcutaneous fat ratio (VSFR)≥0.4. Sarcopenia was diagnosed by skeletal muscle mass (SMM)<20(men)/15(women)Kg, SMM index (SMMi)<7.0/5.5Kg/m² and skeletal muscle area index (SMAi)<41(men)/38.5(women)cm². The three methods were correlated using spearman test and Bland-Altman plots.

Results

A total of 105 patients (65.7%(n=69) males; mean age:63.8±17.1yo) were enrolled and followed-up. AP was moderately-severe/severe in 32.4%/16.2%. EPI-AP and EnPI-AP occurred in 47.6%(n=50) and 17.1%(n=18). EPI-AP was persistent (≥6months after AP diagnosis) in 58%. After 6-month post-randomization, 44%(n=11/25) under PERT and 40%(n=10/25) under placebo resolved EPI-AP (p=0.598).
Obesity was diagnosed in 19.0%(n=20) by BMI, 97.1%(n=102)/72.4%(n=76) by WHR in antropometry/BIA, and 57.1%(n=60) by TFM. Visceral obesity was diagnosed in 78.1%(n=82) by AC, in 41.9%(n=44)/ 97.2%(n=103) by VFM in BIA/CT and in 90.5%(n=95) by VSFR. Sarcopenia was diagnosed in 1.0%(n=1) by MMS.
Considering outcomes, moderately-severe/severe AP was strongly associated with WHR by BIA (OR=10.2; p=0.034) and VFA by BIA (OR=1.08; p=0.029) and CT (OR=1.003; p=0.038). EPI-AP was statically associated with WHR by BIA (OR=11.6; p=0.048) and SMMi by BIA (OR=77.4; p=0.048) and TFM (OR=2.3; p=0.048). Severe EPI-AP was strongly associated with VSFR (OR=20;95%CI; p=0.048) and SMMi by BIA (OR=23.2; p=0.003) and CT (OR=2.3; p=0.041). SMMi by BIA (OR=14.1; p=0.030) and CT (OR=1.6; p=0.031) predicted EnPI-AP.
For obesity, TFM by BIA had a strong correlation with BMI (r=0.61; p<0.001) and a weak correlation with WHR by anthropometry (r=0.37; p<0.001). Regarding visceral obesity, VFA by BIA was weakly correlated with WHR by anthropometry (r=0.29; p=0.004) and VFA by CT (r=0.20; p=0.045). For sarcopenia, SMM by BIA was strongly correlated with SMM by CT (r=0.78; p<0.001).
In EPI-AP patients, a significant decrease of WHR (t(52)=2.262; p=0.028) and TFM (t(53)=1.695; p=0.046) by BIA was observed after 6months of PERT.

Conclusion

Body composition is significantly changed in AP, with >2/3 of patients with obesity, especially the visceral component. Obesity, including visceral obesity, correlates with AP severity. Obesity, including visceral obesity and sarcopenia are correlated with the EPI-AP and its severity, while sarcopenia is correlated with EnPI-AP. PERT has led to a significant reduction in obesity markers. Body composition assessment by BIA (TFM, VFA and SMM) and CT (VFA and SMM) were of clinical value and comparable.

References

1. Kim J, Kim S-s, Hwang HK, Kang CM, Kim KS, Kim SH. Body composition assessment using bioelectrical impedance analysis and computed tomography in patients who underwent pancreatoduodenectomy in Korea: a before and after study. Ann Nutr Metab 2023;15(3):72-80.
2. Wang S, Wang M, Jiang L, Zhao X. Low skeletal muscle quality extracted from CT is associated with poor outcomes in severe acute pancreatitis patients. Eur J Radiol 2024;170:111215.
3. Zhou Y, Hao N, Duan Z, Kong M, Xu M, Zhang D, et al. Assessment of acute pancreatitis severity and prognosis with CT-measured body composition. Int J Gen Med 2021;14:3971-3980.
4. Chaigneau T, Morello R, Vannier E, Musikas M, Piquet M-A, Vupont B. Impact of sarcopenic obesity on predicting the severity of acute pancreatitis. Did Liver Dis 2023;55(7):926-932.

Introduction

The diagnosis of Coeliac Disease (CD) in adults still continues to rely heavily on duodenal histology, in spite of several studies demonstrating a positive predictive value (PPV) of 100% for Marsh 3 histology when anti-tissue transglutaminase (TTG) exceeds 10x upper limit of normal. The majority of these studies come from tertiary centres and the slow uptake of the non biopsy approach may be as a result of limited data on the histological outcome of positive serology originating in the primary care setting.

Aims & Methods

To determine the PPV of primary care-based TTG testing with concurrent anti-endomysial antibody (EMA) positivity for histological diagnosis of CD.
The immunology lab in our institution performs reflex EMA testing on all newly positive and newly borderline positive TTG samples from the West of Ireland (TTG≥5U/ml Celikey by Phadia). Over a 6 year period (2018-2023), 1,361 index TTG positive samples also proved positive when tested for EMA. Following electronic medical record review, we excluded all samples from patients who were <16 years old, had a previous diagnosis of CD made elsewhere, lacked biopsy data, or had biopsies that predated the serological test. Patients who had their coeliac serology testing requested by any hospital-based physician were also excluded to ensure that only patients identified by primary care-based screening were included in the outcome analysis. In this manner, 335 adult patients who had serology screening performed by their primary care physician were eligible for further analysis. These eligible patients were then stratified by TTG levels ( ≤20, 21-69, and ≥70 U/ml). PPV was calculated for each stratum. Logistic regression assessed the relationship between TTG values and biopsy results. Additional analyses examined influence of interval between serology and biopsy.

Results

Chi-square analysis confirmed significant association between TTG levels and biopsy results (p<0.00001). For each 10 U/ml increase in TTG, odds of positive biopsy increased by 18% (OR 1.18, 95% CI: 1.10-1.26). For TTG 21-69 U/ml, PPV declined with longer serology-to-biopsy intervals: 100% for ≤47 days versus 45.2% for >203 days. High TTG values maintained excellent PPV regardless of interval. Long-term follow-up of initially biopsy-negative patients revealed subsequent CD diagnosis in 19/40 (47.5%) in the low titre group, 11/30 (36.7%) in the intermediate group, and 7/11 (63.6%) in the high titre group.

Conclusion

TTG titre significantly predicts biopsy-confirmed CD, with TTG ≥70 U/ml having 90.4% PPV. The predictive value of intermediate TTG diminishes with increasing interval between serology and biopsy. A substantial portion of initially biopsy-negative patients across all TTG strata were subsequently diagnosed with CD during follow-up. These findings support TTG in risk-stratifying CD patients, suggest prompt biopsies for intermediate TTG values, and highlight the importance of long-term monitoring even in patients with negative initial biopsies.

References

1. Husby S, et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54(1):136-60.
2. Penny HA, et al. Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts. Gut. 2021;70(5):876-883.

Introduction

Avoidant/restrictive eating is common in people with neurogastroenterology disorders including functional dyspepsia (FD). There is debate on whether avoidant/restrictive food intake disorder (ARFID) is an expected response to severe symptoms or simply a common comorbid disorder. To address this, among adults with FD, we aimed to contrast those with and without ARFID on FD symptoms, quality of life, psychosocial factors, nutrient tolerance, and gut transit.

Aims & Methods

Adults with Rome-IV confirmed FD and healthy controls (HC) from an ongoing study participated. ARFID diagnosis was assigned based on a semi-structured DSM-5 diagnostic interview. Surveys: Patient Assessment of GI Disorders Symptom Severity Index (PAGI-SYM), Short Form Nepean Dyspepsia Inventory (SF-NDI), Nine-Item ARFID Screen (NIAS), Fear of Food Questionnaire (FFQ), Visceral Sensitivity Index (VSI), and Hospital Anxiety/Depression Scale (HADS). Nutrient Drink Test (NDT) measured gastric tolerance—liquid nutrient ingestion at 30mL/minute until subject reported unbearable fullness. Wireless Motility Capsule (WMC) measured gut transit. Height/weight was measured for body mass index (BMI).

Results

Sample (80% female, M_age=37.1±14.4y) included 37 FD+ARFID, 14 FD only, and 18 HC. Groups did not significantly differ in sex or age. Adjusted pairwise comparisons showed small (r=.1-.2) non-significant differences between FD and FD+ARFID on FD symptoms by PAGI-SYM and SF-NDI (Table 1). However, FD+ARFID had significantly worse scores compared to FD with medium effects (r=.3-.4) on: FD-related quality of life by SF-NDI, Fear of Food by NIAS-Fear and FFQ, GI-anxiety by VSI, and anxiety by HADS. FD+ARFID vs FD also had small differences (rs=.2) on: feeling more bothered by FD symptoms on SF-NDI, worse depression by HADS, lower BMI, and less NDT consumption. Compared to HC, FD and FD+ARFID had significantly worse survey scores with large effects for FD+ARFID (r=.6-.8) and medium effects for FD vs HC (r=.3-4). For the NDT, FD+ARFID consumed significantly less than HC with large effect (r=.6) but with a trend medium effect for FD consuming less than HC (r=.3). Groups did not significantly differ in WMC transit times.

Conclusion

Our findings suggest ARFID, when present in FD, does not reflect a response to more severe FD symptoms. Thus, ARFID is a legitimate secondary condition in FD. ARFID may reflect more profoundly altered distress around symptoms (e.g., fear of symptoms, anxiety sensitivity) and greater negative impacts (e.g., FD-related quality of life, lower liquid nutrient tolerance).

Introduction

Diabetes is a known risk factor for pancreatic cancer (PC), potentially mediated by mechanisms such as hyperinsulinemia, insulin resistance, chronic inflammation, and hyperglycemia. Prediabetes shared many of these pathophysiological features; however, its association with PC remains inconclusive.

Aims & Methods

We aimed to evaluate the association between prediabetes and risk of PC and to determine whether changes in glycemic status modify the subsequent PC risk. This retrospective cohort study used data from a territory-wide electronic healthcare database. Adults (≥18 years) with at least one hemoglobin A1c (HbA1c) or fasting glucose (FG) measurement between January 2007 and December 2022 were included. Baseline glycemic status was classified as: (1) normoglycemia (HbA1c <5.7% or FG <5.6 mmol/L), (2) prediabetes (HbA1c 5.7-6.4% or FG 5.6-6.9 mmol/L), or (3) diabetes (HbA1c ≥6.5% or FG ≥7 mmol/L). The index date was the date of first recorded HbA1c or FG. Patients were followed until PC, pancreatectomy, death, or study end date (December 31, 2022). Exclusion criteria included prior PC, immunoglobulin G4-related disease, and type 1 diabetes. To minimize reverse causality between diabetes and PC, individuals with PC diagnosed within two years of the index date or with less than two years of follow-up were excluded. The primary outcome was incident PC. Covariates included demographic factors, body mass index, smoking status, alcohol use disease, metabolic and cardiovascular comorbidities, diabetes-related complications, and concomitant medications (including aspirin, non-steroidal anti-inflammatory drugs [NSAIDs] statins, and antidiabetic agents). Adjusted hazard ratios (aHRs) were estimated using multivariable Cox regression. Among individuals with normoglycemia or prediabetes at baseline, glycemic trajectories over the first 2 years were categorized as: (1) persistent normoglycemia, (2) reversion from prediabetes to normoglycemia, (3) persistent prediabetes, and (4) progression from prediabetes to diabetes, with PC risk evaluated accordingly.

Results

A total of 1,977,149 individuals were included (median age:55.3 [IQR:45.0-65.0] years; 44.5% male), with 1,295,290 (65.5%) classified as normoglycemia, 469,236 (23.7%) as prediabetes, and 212,623 (10.8%) as diabetes at baseline. Over a median follow-up of 8.8 (IQR:5.4-11.6) years, PC developed in 1,419 (1.26/10,000 person-years) normoglycemic, 859 (2.19/10,000 person-years) prediabetic, and 551 (2.92/10,000 person-years) diabetic individuals. The 14-year cumulative PC incidence among three groups was shown in Figure 1 (log-rank P <0.001). Compared with normoglycemia, prediabetes and diabetes were associated with 27% (aHR:1.27; 95%CI:1.17-1.39) and 56% (aHR:1.56; 95%CI:1.40-1.75) higher PC risk, respectively. Each 1% increase in HbA1c was associated with an 11% increased risk (aHR:1.11; 95%CI:1.07–1.15). At year 2, of those with prediabetes at baseline, 68,268 (14.5%) progressed to diabetes, 81,122 (17.3%) reverted to normoglycemia, and 319,846 (68.2%) remained prediabetic. Among normoglycemics, 81,122 (6.3%) remained persistently normoglycemic. Compared with persistent normoglycemia, PC risk was higher in persistent prediabetes (aHR:1.37; 95%CI:1.22-1.53) and prediabetes progressing to diabetes (aHR:2.22; 95%CI:1.91-2.59), but not in those reverting to normoglycemia (aHR:1.17; 95%CI:0.96-1.42).

Conclusion

Prediabetes was independently associated with an increased risk of PC compared with normoglycemia. Early intervention to revert prediabetes to normoglycemia may be a modifiable oncopreventive strategy to reduce PC risk.