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

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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

Pain is the hallmark and most disabling symptom of chronic calcific pancreatitis (CCP), often severe and significantly impairing patients' quality of life. Its pathophysiology involves increased intraductal pressure, chronic inflammation, and neuropathic changes.

Aims & Methods

This study aimed to assess the prevalence of pain in CCP and to identify factors associated with its occurrence and severity.
This was a retrospective analytical study including patients followed for CCP. We collected data on disease duration, etiology, clinical manifestations, complications, analgesic treatments (AT), and symptom evolution under treatment. Pain intensity and impact on quality of life were assessed using the Izbicki Score (IS), which categorizes pain as mild (0–20), moderate (21–40), severe (41–60), or very severe (>60). Incomplete records that prevented IS calculation were excluded. Data were entered and analyzed using SPSS software, with statistical significance set at p < 0.05.

Results

We included 22 patients (14 men and 8 women), with a mean age of 55.6 years [27–80 years]. The most common symptoms were epigastric pain (n=18), weight loss (n=13), and chronic diarrhea (n=6). The mean delay between symptom onset and diagnosis was 25 months [1–120 months]. Etiologies included hyperparathyroidism (n=6), alcohol use (n=2), pancreas divisum (n=2), autoimmune causes (n=2), and were undetermined in 10 cases. The IS ranged from 0 to 93.75, with a mean of 40.22. Eight patients had an IS >40. Morphine was required in four cases; paracetamol was prescribed for 12 patients, and tramadol for two. Endoscopic treatment was indicated in three cases, while one patient underwent a Wirsungojejunostomy.
In univariate analysis, alcohol consumption was significantly associated with the occurrence of epigastric pain (p=0.01). Smoking and alcohol use were both linked to a higher IS (>50) (p=0.04). Smoking cessation was associated with a better analgesic response (p=0.04). Morphine use was significantly more frequent among alcoholic patients (p=0.01), and their treatment response was often unfavorable (p=0.02).

Conclusion

In our cohort, 80% of patients with CCP experienced pain, which was severe to very severe in nearly half the cases. Pain intensity was significantly associated with tobacco and alcohol consumption, while cessation improved treatment response. These findings underscore the importance of therapeutic education focused on smoking and alcohol cessation, in addition to analgesic management, to slow disease progression and improve pain control.

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.

Introduction

Cognitive Behavioral Therapy (CBT) is an evidence-based treatment for Irritable Bowel Syndrome (IBS), demonstrating long-term improvements in symptoms and quality of life (QOL). However, its implementation is hindered by the complexity of treatment protocols, high time and financial costs, and limited accessibility in Japan.

Aims & Methods

This study aimed to develop a smartphone-based CBT application and evaluate its effectiveness in alleviating IBS symptoms.
Adults aged 18 or older who met the Rome IV criteria for IBS and scored ≥110 on the Japanese version of the IBS Symptom Severity Index (IBSSI-J) were enrolled. Twenty-six participants were randomly assigned to either the intervention group (n = 14) or the waiting-list control group (n = 12). Outcome measures included the IBSSI-J, Japanese versions of the IBS-QOL (IBS-QOL-J), Pain Catastrophizing Scale (PCS-J), and Visceral Sensitivity Index (VSI-J). A two-way ANOVA was conducted with group (intervention vs. control) and time (pre, mid, post, follow-up 1) as independent variables.
The intervention group used the app for 5–10 minutes daily over two months. The app included three components: psychoeducation, cognitive restructuring, and exposure. Psychoeducation consisted of educational materials and follow-up quizzes. Cognitive restructuring used gamified multiple-choice content (135 items), replacing conventional thought records. Exposure involved users creating individual anxiety hierarchies and recording their thoughts before and after exercises. The app visualized anxiety changes and progress via graphs.

Table 1.
Intervention module of the application

Results

Eleven participants in the intervention group and eight in the control group completed the program. Significant group × time interactions were observed for all outcome measures. For the IBSSI-J, the interaction was significant (F(3, 51) = 4.41, p < .001), with the intervention group showing greater improvement at mid-point (F(1, 17) = 5.54, p = .03, η² = .25). For the IBS-QOL-J, a significant interaction was found (F(3, 51) = 8.00, p < .001), with improvement evident at follow-up 1 (F(1, 17) = 6.65, p = .02, η² = .28). For the PCS-J, the interaction was significant (F(3, 51) = 3.83, p = .02), with improvements at post (F(1, 17) = 9.26, p = .01, η² = .35) and follow-up 1 (F(1, 17) = 5.83, p = .03, η² = .26). For the VSI-J, the interaction also reached significance (F(3, 51) = 3.32, p = .05).

Conclusion

The CBT-based app was effective in reducing IBS symptom severity. Its effects persisted after the intervention and extended to improvements in QOL, visceral anxiety, and pain catastrophizing—psychological factors associated with the maintenance and exacerbation of IBS. It is assumed that the cognitive restructuring component of the app facilitated cognitive diversification among participants. By empirically challenging the plausibility of these diversified cognitions through behavioral experiments in the form of exposure tasks, participants were able to further develop more adaptive thoughts. This process is considered to have contributed to the improvement of symptoms and enhancement of QOL. This digital approach may offer a viable solution to current barriers in CBT access.

Introduction

The rise in obesity rates has triggered a surge in associated health issues, with metabolic syndrome (MS) affecting approximately 25% of populations in Western countries. Severe acute pancreatitis (AP) is associated with mortality rates as high as 50%. Prior research has linked components of MS to heightened complications and mortality in cases of AP.

Aims & Methods

This meta-analysis aims to elucidate potential risk factors and their combined effects on the outcomes of AP. We performed a systematic search of PubMed, Embase, and the Cochrane Library until November 1, 2023, identifying studies based on specified criteria. We investigated the influence of MS and its components (obesity, hypertension, diabetes mellitus, and hypertriglyceridemia) on AP outcomes, calculating pooled odds ratios (OR) with 95% confidence intervals (CIs). The study protocol was registered with PROSPERO under the identifier CRD42023471092.

Results

From an initial 15,904 records, 93 studies were included in the analysis. Overweight and obesity emerged as significant risk factors for complications (local OR: 2.677, 95%CI: 1.421-5.044; systemic OR: 2.404, 95%CI: 1.481-3.901) and the severity of AP (BMI≥30 kg/m², OR: 3.058, 95%CI: 1.369-6.829). Elevated triglyceride levels were linked to ICU admissions (OR: 2.546, 95%CI: 1.529-4.237) and severe AP (OR: 2.372, 95%CI: 1.275-4.413); hypertension correlated with increased mortality (OR: 2.135, 95%CI: 1.870-2.437), while diabetes was associated with higher odds of ICU admission (OR: 1.645, 95%CI: 1.358-1.992) and severe AP (OR: 1.49, 95%CI: 1.09-2.03). Our findings suggest that MS may elevate the likelihood of severe AP (OR=1.398, 95%CI: 0.918-2.129).

Conclusion

The individual components of metabolic syndrome are significant risk factors for complications, severity, and mortality related to acute pancreatitis. It is imperative to prioritize lifestyle counseling, education, and effective management for patients dealing with obesity.