Pancreatic Ductal Adenocarcinoma

This systems-level framework provides mechanistic rationale for clinical investigation of intratumoral S. boulardii as adjuvant PDAC therapy. The online version contains supplementary material available at 10.1007/s40203-026-00685-6.

Patients in the high-risk group exhibited characteristics associated with worse outcomes, including KRAS mutations, chemoresistance, an immunosuppressive microenvironment and reduced responsiveness to immunotherapy. The present study establishes HRH1 as a novel therapeutic target in PDAC and proposes the repurposing of fexofenadine as a promising strategy to disrupt the oncogenic HRH1-YAP1 feedback loop.

This may explain why PARP7i were more effective as monotherapy in PANC-1 cells, promoting NK cell activation. These findings support further evaluation of PARP7i in PDAC in combination with radiotherapy or as monotherapy, depending on the immunosuppressive effects of radiation.

P1/2, N=222, Not yet recruiting, Genfleet Therapeutics (Shanghai) Inc.

P2, N=19, Active, not recruiting, Georgetown University | Recruiting --> Active, not recruiting | N=54 --> 19

It underscores the importance of maintaining diagnostic vigilance in patients with hereditary cancer syndromes and supports an aggressive, multidisciplinary approach, including neoadjuvant therapy, even in cases initially presumed to represent locally advanced PDAC. Recognition of such atypical presentations is essential not only for optimising management but also for reinforcing the central role of tumour biology in guiding diagnosis, therapeutic decision-making, and future research in hereditary malignancies.

Finally, we summarize current challenges-including limited accessibility, resistance mechanisms, and toxicities-and outline future directions, such as novel biomarkers, liquid biopsy for real-time resistance monitoring, and innovative adaptive trial designs. This review highlights the evolution of DDR-targeted therapy in pancreatic cancer toward personalized, combination-based precision medicine.

In localized PDAC, KRAS-mutant ctDNA detected by NGS or ddPCR was associated with worse survival. ddPCR identified additional patients missed by NGS. Integrating ddPCR with NGS ctDNA measures may improve perioperative risk stratification, though validation is needed before clinical implementation.

Morphometric and immunofluorescence analyses further showed increased 53BP1⁺Ki67⁺ nuclei and nuclear atypia in MGCs, indicating ongoing proliferation despite DNA damage. Together, these data identify MGCs of macrophage origin as an immune cell state shaped by hypoxia and stress signaling, associated with aggressive tumor phenotypes, and potentially exploitable as an immune classifier in PDAC.

These findings demonstrate that plasma proteomics provides discriminatory molecular insights and supports the development of population-relevant biomarker panels. While several candidate proteins show promise for inclusion in multianalyte panels, further validation in larger cohorts is necessary to establish their diagnostic and translational utility for early detection, risk stratification, and improved differential diagnosis of PDAC.

In addition, CLDN1-high tumors exhibited activation of epithelial-mesenchymal transition, HIPPO signaling, and immune-related pathways, together with increased stromal and immune cell infiltration. Collectively, our findings identify CLDN1 as a marker of a biologically distinct and clinically aggressive pNET subset characterized by dedifferentiation, lineage plasticity, and tumor microenvironment remodeling, supporting further evaluation of CLDN1 as a candidate prognostic biomarker and potential therapeutic target in pNETs.

Despite apparently favorable pathological staging and adjuvant FOLFIRINOX chemotherapy, the patient developed early biochemical progression with rapidly rising carbohydrate antigen 19-9 (CA 19-9) levels, followed by widespread metastatic dissemination involving the liver, lung, spine, skeletal muscle, and multiple visceral sites...This case highlights the limitations of anatomical staging in PDAC and emphasizes the prognostic importance of tumor biology, including KRAS mutation status, lymphovascular invasion, and perineural invasion. It also demonstrates the potential limitations of CA 19-9 as a solitary marker of treatment response in biologically aggressive disease.