Understanding futility in pancreaticoduodenectomy: Insights from a national cohort.

BACKGROUND AND OBJECTIVES: Pancreaticoduodenectomy (PD), the only surgical option for right-sided pancreatic ductal adenocarcinoma (PDAC), carries significant morbidity. Not all patients may be deriving a survival benefit from this operation. We sought to identify the rate of futile PD and its associated factors in a large national cohort. METHODS: We performed a retrospective analysis using the National Cancer Database (2004-2020), including all patients who underwent PD for non-metastatic PDAC. The primary outcome was operative futility, which was defined as death within 12 months of diagnosis despite PD. Multivariable regression was used to identify factors associated with futility. We performed a subgroup analysis on patients who received neoadjuvant systemic therapy. RESULTS: Data from 66 326 patients were analyzed, and 16 772 (25.3%) underwent PD that met criteria for futility. Macroscopically positive margins (odds ratio [OR]: 2.87; 95% confidence interval [CI]: 2.36-3.48), poor tumor differentiation (OR: 2.44; 95% CI: 2.25-2.65), and N2 nodal stage (OR: 2.09; 95% CI: 1.98-2.20) were associated with the greatest odds of futility. Meanwhile, receipt of any systemic therapy (OR: 0.33; 95% CI: 0.31-0.34), receipt of any radiation (OR: 0.60; 95% CI: 0.57-0.63), and receipt of neoadjuvant systemic therapy (OR: 0.62; 95% CI: 0.57-0.66) were associated with the lowest odds of futility. In the neoadjuvant subgroup, a longer diagnosis-to-surgery interval was associated with lower odds of futility. CONCLUSION: PD was futile in about one quarter of patients. Futility was associated with higher age and worse tumor biology. Receipt of neoadjuvant therapy resulted in fewer futile operations.

Circadian disruption, clock genes, and metabolic health.

A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene (CLOCK), brain and muscle ARNT-Like 1 gene (BMAL1), period (PER), and cyptochrome (CRY), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential mechanistic links between circadian disruption and altered clock gene expression contributions to metabolic health-related pathologies. Findings have important implications for the treatment, prevention, and control of metabolic pathologies underlying leading causes of death and disability, including diabetes, cardiovascular disease, and cancer.

Nanodrug-bacteria conjugates-mediated oncogenic collagen depletion enhances immune checkpoint blockade therapy against pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) cancer cells specifically produce abnormal oncogenic collagen to bind with integrin α3ß1 receptor and activate the downstream focal adhesion kinase (FAK), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, this promotes immunosuppression and tumor proliferation and restricts the response rate of clinical cancer immunotherapies. METHODS: Here, by leveraging the hypoxia tropism and excellent motility of the probiotic Escherichia coli strain Nissle 1917 (ECN), we developed nanodrug-bacteria conjugates to penetrate the extracellular matrix (ECM) and shuttle the surface-conjugated protein cages composed of collagenases and anti-programmed death-ligand 1 (PD-L1) antibodies to PDAC tumor parenchyma. FINDINGS: We found the oncogenic collagen expression in human pancreatic cancer patients and demonstrated its interaction with integrin α3ß1. We proved that reactive oxygen species (ROS) in the microenvironment of PDAC triggered collagenase release to degrade oncogenic collagen and block integrin α3ß1-FAK signaling pathway, thus overcoming the immunosuppression and synergizing with anti-PD-L1 immunotherapy. CONCLUSIONS: Collectively, our study highlights the significance of oncogenic collagen in PDAC immunotherapy, and consequently, we developed a therapeutic strategy that can deplete oncogenic collagen to synergize with immune checkpoint blockade for enhanced PDAC treatment efficacy. FUNDING: This work was supported by the University of Wisconsin Carbone Cancer Center Research Collaborative and Pancreas Cancer Research Task Force, UWCCC Transdisciplinary Cancer Immunology-Immunotherapy Pilot Project, and the start-up package from the University of Wisconsin-Madison (to Q.H.).

Aryl Hydrocarbon Receptor Knockout Accelerates PanIN Formation and Fibro-Inflammation in a Mutant Kras -Driven Pancreatic Cancer Model.

OBJECTIVES: The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the development of several cancers and can be targeted for therapeutic effect. However, its involvement in the pathogenesis of PDAC remains unclear. To address this gap, we evaluated the role of AHR in the development of PDAC precancerous lesions in vivo . MATERIALS AND METHODS: We created a global AHR-null, mutant Kras -driven PDAC mouse model (A -/- KC) and evaluated the changes in PDAC precursor lesion formation (PanIN-1, 2, and 3) and associated fibro-inflammation between KC and A -/- KC at 5 months of age. We then examined the changes in the immune microenvironment followed by single-cell RNA-sequencing analysis to evaluate concomitant transcriptomic changes. RESULTS: We identified a significant increase in PanIN-1 lesion formation and PanIN-1 associated fibro-inflammatory infiltrate in A -/- KC versus KC mice. This was associated with significant changes in the adaptive immune system, particularly a decrease in the CD4+/CD8+ T-cell ratio, as well as a decrease in the T-regulatory/Th17 T-cell ratio suggesting unregulated inflammation. CONCLUSIONS: These findings show the loss of AHR results in heightened Kras -induced PanIN formation, through modulation of immune cells within the pancreatic tumor microenvironment.