Introduction

​​​​​Pancreatic cancer (PC) has one of the poorest prognoses among malignancies. Early detection, particularly of stage 0 or stage 1 disease, is crucial to improving survival outcomes. However, conventional screening strategies based solely on family history or symptoms—as commonly practiced in Western countries—have shown limited sensitivity for early-stage PC. In Japan, more comprehensive approaches are being developed.

Aims & Methods

Low-grade relevant (LGR) factor	High-grade relevant (HGR) factor
・sporadic family history ・diabetes mellitus ・diabetes mellitus worsening ・stomach/back symptoms ・weight loss ・elevated serum pancreatic enzyme ・heavy alcohol consumption ・smoking history ・obesity	・familial PC ・hereditary PC syndrome/pancreatitis ・new-onset diabetes mellitus ・jaundice ・elevated serum tumor biomarkers ・chronic pancreatitis ・pancreatic cyst ・main pancreatic duct dilation
Score positive; 3 points or more	Score positive; 1 point or more

This nationwide, multicenter prospective study aimed to evaluate the utility of a novel scoring system for early PC detection among hospital outpatients. From August 2019 to May 2024, all outpatients presenting with symptoms, risk factors, subtle imaging abnormalities of the pancreas, or requesting pancreatobiliary screening at the Department of Gastroenterology in hospitals participating in the Early Pancreatic Cancer Screening Study (EPSS) were considered for inclusion. Consecutive patients who had no pancreatic tumors suspected by any imaging modalities were examined, no prior history of endoscopic ultrasound (EUS) examination for pancreatic disease, and/or no referrals from other hospitals specifically for PC diagnosis were prospectively enrolled. The system comprised low- and high-grade relevant (LGR/HGR) factors referring to both risk factors and diagnostic indicators, including symptoms and subtle imaging abnormalities associated with PC. Patients were classified as score-positive if they had ≥3 LGR or ≥1 HGR factor(s). Diagnostic yield for stage 0/1 and all-stage PC was compared between score-positive and score-negative groups. Diagnostic performance was also evaluated against previous large-scale Japanese data and Western screening methods based on family/genetic risk or symptoms. The sample size was determined based on a previous large-scale PC screening study in Japan.

Results

Of 3,287 patients, 2,531 were score-positive and 756 were score-negative. PC was diagnosed in 283 patients (8.6%), including 67 with stage 0/1 disease. The detection rate of stage 0/1 PC was significantly higher in score-positive than in score-negative patients (2.6% vs. 0.7%, P=.001). Compared to a previous Japanese study (0.78%), this study showed a significantly higher detection rate (P<.001). The sensitivity of the scoring system for stage 0/1 PC was 93.1%, significantly outperforming Western-style approaches (12.5% for family/genetic risk and 50.0% for symptom-based screening; both P<.001), while maintaining comparable accuracy. Even combining family/genetic risk and symptoms, sensitivity remained lower than that of the scoring system (56.9%, P<.001). For all-stage PC, both the accuracy and sensitivity of the diagnosis based on the scoring system were significantly higher than those based on family/genetic risk, symptom, or the combination of symptom and family/genetic risk (P = .030, .004, .002 for accuracy; and all P <.001 for sensitivity, respectively). Among the 283 PC cases, 23.7% were stage 0/1, 15.9% were ≤10 mm, and 45.6% underwent surgical resection. Multivariate logistic analysis identified older age, worsening diabetes, and MPD dilation as significant independent predictors of stage 0/1 PC.

Conclusion

The scoring system demonstrated superior sensitivity and comparable accuracy to traditional screening strategies for detecting early-stage PC. Its use in outpatient settings may facilitate earlier diagnosis and intervention, thereby improving resectability and prognosis.

References

Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol 2021;18:493-502.
Hanada K, Okazaki A, Hirano N, et al. Diagnostic strategies for early pancreatic cancer. J Gastroenterol 2015;50:147-54.
Sagami R, Hayasaka K, Ujihara T, et al. Role of EUS combined with a newly modified scoring system to detect pancreatic high-grade precancerous lesions. Endosc Ultrasound 2022.

Introduction

Inflammatory bowel disease (IBD) is a growing global health problem with increasing prevalence. Current therapeutic strategies for IBD are mainly aimed at modulating the dysregulated immune activity in the intestinal mucosa. Targeting the JAK/STAT signalling pathway has been shown to be highly effective in ulcerative colitis, but not in Crohn's disease (CD), where efficacy was found to be insufficient in the initiation phase of a clinical trial [1]. Failure of the therapeutic response in Crohn’s disease may be influenced by the unique immune microenvironments in the small and large intestine and their characteristic cytokine profiles and immune cell compositions.

Aims & Methods

To gain deeper insight into region-specific efficacy in the inflamed ileum versus colon, this study investigates the immunomodulatory effects of filgotinib, a Jak1 inhibitor, using precision-cut intestinal slices (PCIS) from patients with Crohn's diseases. PCIS are viable, ultra-thin human tissue slices that retain the original intestinal architecture ex vivo and contain important cell types, including resident immune cells.
PCIS were prepared from resected ileal and colonic tissue of CD patients. The slices were cultured ex vivo and stimulated with concanavalin A or anti-CD3/CD28 antibodies to induce T cell-driven inflammatory responses. Filgotinib (1-100 µM) was applied to assess the immunomodulatory effects of JAK1 inhibition following Concanavalin A preactivation. To exclude treatment-related toxicity, cellular integrity was evaluated using an LDH release assay. Tissue morphology was examined by H&E staining and immunofluorescence. The immune response was assessed by multiplex ELISA of 20 cytokines.

Results

After filgotinib treatment, primary tissue slices from the ileum and colon of CD patients remained viable. Regional morphological characteristics of ileum and colon tissue were preserved after ex vivo cultivation, with prominent villi and smaller crypts in the ileum, and larger, more frequent crypts and flattened villi in the colon. Compared to non-CD tissue slices, Crohn’s disease-related changes, such as immune cell accumulation, were also observed in CD tissue slices ex vivo. Upon T cell-specific stimulation with anti-CD3/CD28 antibodies, region-specific immune reactivity was observed. Colonic PCIS showed an increased release of IL-2 (~3-fold), IL-10 (~2‑fold) and TRAIL (~4-fold) compared to ileal PCIS, indicating a stronger involvement of Th and regulatory T cells in the colon. In contrast, ileal PCIS showed higher levels of MIP-3α (2-fold) and granzyme A (~8-fold) after stimulation, suggesting increased cytotoxic T cell activity in this region. Filgotinib treatment showed region-specific differences in its ability to modulate cytokine release in PCIS of CD patients. In colonic PCIS, filgotinib reduced the induced secretion of Th17-associated cytokines such as IL-17F and IL-22 by up to 95%, whereas in ileal PCIS it showed no effect on the same cytokines.

Conclusion

In conclusion, filgotinib exhibited more potent anti‑inflammatory effect on Th17 cells in the colon, and a markedly reduced efficacy in the ileum. This study demonstrates for the first time that precision-cut intestinal slices can be used to predict region-specific drug response in inflamed intestinal tissue ex vivo, underscoring the critical importance of region-specific immune profiling in IBD and highlight the limited efficacy of JAK1 inhibition in ileum. This ex vivo, patient-derived model represents a valuable platform for evaluating localised treatment efficacy and advancing personalised therapeutic strategies in IBD.

References

[1] Rogler G. Efficacy of JAK inhibitors in Crohn's Disease. J Crohns Colitis. 2020 Aug 1;14(Supplement_2):S746-S754. doi: 10.1093/ecco-jcc/jjz186