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

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.

Introduction

The rising number of patients with intraductal papillary mucinous neoplasms (IPMNs) in countries with aging populations in the near future is predictable considering that the incidence of pancreatic cystic tumors is positively correlated with patient age and that IPMNs occur most frequently among multifocal pancreatic cystic tumors. Although the majority of IPMNs detected incidentally through various imaging tests have a tumor diameter ≤10 mm and are thus deemed low-risk for carcinogenesis, the possibility of malignant transformation persists. Thus, such IPMNs are subject to periodic follow-up diagnostic imaging. Therefore, an appropriate surveillance system must be established to effectively and efficiently identify cases of IPMN-related malignant transformation, which develops only in few IPMN cases, under the constraints of limited national healthcare funding.

Aims & Methods

In the current study, we analyzed the clinical background observed at initial patient presentation that affect long-term prognosis and tried to narrow the population for whom continued evaluation is inevitable. The study included 1645 patients with IPMNs (776 men and 869 women) treated at our hospital since 2010. We examined the types and timing of medical intervention (surgical resection or pancreatic carcinogenesis) selected mainly in terms of worrisome features (WF) as advocated by the international guidelines (Pancreatology, 2024:24;255–70) for IPMN treatment. Statistical analysis was performed using the chi-square test, log-rank test, and Cox proportional hazards model, with statistical significance set at α = 0.05.

Results

During the entire observation period, 123 patients (7.5%) had IPMN-derived carcinoma (IPMN-DC), whereas 41 patients (2.5%) had concomitant pancreatic ductal adenocarcinoma (PDAC), which required medical intervention. The proportion of cases with c-Stage I, II, III, and IV (UICC 8th edition) at the time of diagnosis were 52.0%, 43.9%, 0.8%, and 3.3%, respectively, for IPMN-DC and 39.0%, 31.7%, 9.8%, and 19.5%, respectively for PDAC. A significantly higher proportion of PDAC cases were diagnosed with an advanced disease stage that developed earlier in time. Factors with significantly shorter time for IPMN-DC medical intervention were: maximum cyst diameter ≥30 mm, non-branched type, main pancreatic duct diameter ≥5 mm, and septal nodal structure for IPMN-DC. For PDAC, these factors were maximum cyst diameter ≥30 mm, main duct type, main pancreatic duct diameter ≥5 mm, septal nodal structure, cyst enlargement (≥2.5 mm/year), and abnormally high levels of CA19-9. Both groups could be significantly stratified by the number of WFs. However, the difference was more distinct in IPMN-DC, whereas <1% (9/1190) medical intervention from the group with 0 WFs was noted in PDAC. Relative risk (hazard ratio, HR) analysis of WF in which proportional hazard was maintained revealed that the presence of septal nodular structure (HR 5.2), maximum cyst diameter ≥30 mm (HR 3.3), and main pancreatic duct diameter ≥5 mm (HR 2.6) were significant factors for IPMN-DC, whereas abnormally high CA19-9 levels (HR 5.0) and septal nodular structure (HR 4.8) were significant for PDAC. Conversely, a significantly higher percentage of patients who exhibited these factors at initial presentation also later developed IPMN-DC or PDAC.

Conclusion

Ten percent of IPMN cases will develop IPMN-DC or PDAC, thereby requiring careful follow-up, especially in cases with septal nodules, abnormally high CA19-9 levels, and cysts with a maximum diameter of ≥30 mm.

Clinical Case Summary

A female patient (born 1974) presented with chronic diarrhea (up to 16 times/day, including nocturnal episodes), bloating, periumbilical pain, fatigue, general weakness, and 10 kg weight loss. Since childhood, the patient had been under observation for chronic iron-deficiency anemia of unknown origin without prior gastrointestinal evaluation. Symptoms progressively worsened over two years due to the lack of therapeutic effect at the outpatient stage, leading to hospitalization in July 2022. Histology revealed total duodenal villous atrophy (celiac disease: Marsh 3C, Corazza-Villanacci B2; 30-40 IELs/100 epithelial cells) and lymphocytic microscopic colitis (MC) of the colon (60-70 IELs/100 epithelial cells). Other examinations (abdominal CT, enterography, stool analysis) were normal; labs showed mild iron-deficiency anemia, with protein markers within normal ranges. She was diagnosed with celiac disease combined with lymphocytic MC. A gluten-free diet, iron supplementation, and budesonide (9 mg/day for 3 months) were initiated, leading to clinical improvement. However, diarrhea recurred (up to 10 times/day) one month after stopping budesonide, despite adherence to the gluten-free diet. Duodenal histology improved (Marsh I, IELs ≤20/100 cells), confirming dietary effectiveness for celiac disease. Colonic histology showed ongoing lymphocytic MC activity (25-30 IELs/100 cells). The relapse was attributed to persistent MC. A prolonged regimen of budesonide (9 mg/day for 3 months, tapering to 6 mg/day for 6 months) was prescribed. This clinical case of celiac disease combined with lymphocytic MC demonstrates that significant improvement in small intestine structure can be achieved with a gluten-free diet and prolonged budesonide therapy. However, the recurrent diarrheal syndrome in this case was associated with the persistent course of MC. Literature emphasizes increased MC prevalence in celiac patients, reinforcing the need for timely recognition and combined therapy.

References

1. Miehlke S., Guagnozzi D., Zabana Y., Tontini G.E., Kanstrup Fiehn A.M., Wildt S., Bohr J., Bonderup O., Bouma G., D’Amato M., Heiberg Engel P.J., Fernandez-Banares F., Macaigne G., Hjortswang H., Hultgren-Hörnquist E., Koulaouzidis A., Kupcinskas J., Landolfi S., Latella G., Lucendo A., Lyutakov I., Madisch A., Magro F., Marlicz W., Mihaly E., Munck L.K., Ostvik A.E., Patai Á.V., Penchev P., Skonieczna-Żydecka K., Verhaegh B., Münch A. European guidelines on microscopic colitis: United European Gastroenterology and European Microscopic Colitis Group statements and recommendations. United European Gastroenterol J. 2021 Feb 22;9(1):13–37. doi: 10.1177/2050640620951905. Epub ahead of print. PMID: 33619914; PMCID: PMC8259259.

2. Calabrese C., Gionchetti P., Liguori G., Areni A., Fornarini G.S., Campieri M., Rizzello F. Clinical course of microscopic colitis in a single-center cohort study. J Crohns Colitis. 2011 Jun;5(3):218-21. doi: 10.1016/j.crohns.2011.01.004. Epub 2011 Feb 18. PMID: 21575884.

3. Microscopic Colitis: A Concise Review for Clinicians. June Tome MD, Amrit K. Kamboj MD, Darrell S. Pardi MD MS. DOI: https://doi.org/10.1016/j.mayocp.2021.03.022.

4. Tome M.D., Kamboj A.K., Pardi D.S. Microscopic Colitis: A Concise Review for Clinicians. Mayo Clinic Proceedings. 2021;96(5):1212-1222. DOI: https://doi.org/10.1016/j.mayocp.2021.03.022.

Introduction

Besides stage, age and CA19-9 there is limited knowledge on “patient-related factors” associated with chemotherapy response for Pancreatic Ductal Adenocarcinoma (PDAC) patients. Smoking worsens chemotherapy response in other tumours and seems to promote tumor progression in PDAC preclinical models, but data in human PDAC are scanty.

Aims & Methods

PDAC patients were prospectively enrolled at diagnosis with exposome and clinical data registered, and tumors sampled for research purpose during Endoscopic Ultrasound (EUS). Patients were then followed-up to register chemotherapy treatment [whether Folfirinox (F), Abraxane-gemcitabine (AG) or a combination of cisplatin, abraxane, capecitabine and gemcitabine (PAXG)] and evaluate disease control rate (DCR) at 6-months (DCR-6), Progression-Free-Survival (PFS) and Overall-Survival (OS). We also explored transcriptomic signatures associated with smoking on a subset of EUS-acquired PDAC samples undergoing RNA-sequencing, with differential gene expression (DGE) analysis and pathways analysis performed. Furthermore, in vitro analyses with PDAC cell lines CAPAN-1 were treated with Folfirinox or gemcitabine with/without the nicotine compound 4-(Methylnitrosoamino)-1-(3-pyridinyl)-1-butanone to evaluate in vitro effects.

Results

326 patients treated with chemotherapy of interest were analyzed. Median age was 65, with 51.5% being males. Disease’s resectability at diagnosis was 10.4% resectable, 37.7% borderline-resectable, 26.9.% locally-advanced, 24.8% metastatic. AG was used in 42.3% of patients, PAXG in 25.7%, Folfirinox in 31.9%. DCR-6 was 57.9% in current smokers vs 70.4% in never-/ex-smokers (p=0.05). Current smoking was associated with a lack of DCR-6 at adjusted multivariable analysis (OR=1.99; 95%CI:1.1-3.5; p=0.01). At subgroup analysis, this was confirmed only for Folfirinox patients, with DCR-6 being 46.2% for current smokers vs 75.6% for non-current smokers(p=0.007). Current smokers had a significantly shorter PFS (5 vs 13 months; HR:1.79; 95%CI:1.13-3.21; p=0.01) and OS (24 vs 34; HR 1.93; 95%CI: 1-3.67; p=0.04) compared to non-smokers at adjusted multivariable analysis.
At transcriptomic analysis on a subset of 84 patients, current smokers were more prevalent in patients developing the more aggressive basal-like subtype (50% vs 15%; p=0.03), had lower expression of the classical marker GATA6 (3.27 vs 3.92; p=0.03) as also different activated pathways such as activated MAPK signalling, Axon guidance, Hypoxia and epithelial-mesenchymal-transition signalling among the others.
At in vitro experiments, for cell survival analysis, CAPAN-1 PDAC cells showed a significant reduced response to Folfirinox treatment when treated in combination with nicotin compounds, which was not observed for gemcitabine alone or in combination.

Conclusion

Collectively, our results consistently point towards a deleterious effect of smoking on response to Folfirinox regimen. Clinical data show that current smoking is a predictive factor for lower DCR-6, shorter PFS and OS; transcriptomic analyses show different gene expressions between smokers and non-smokers, with a transition toward reduced expression of classical phenotype and activation of inflammatory and pro-mesenchimal pathways. In vitro experiments support the negative effect of smoking on the response to Folfirinox. Smoking should be considered as a covariate to be investigated when choosing chemotherapy regimens in patients with PDAC, and patients should be discouraged to continue smoking.