Introduction

Patients with new onset diabetes (NODM) have a higher risk of pancreatic cancer (PAC) development. We aimed to (1) compare the incidence of PAC among NODM and non-DM patients and (2) develop a risk prediction model for incident PAC within 1 year after diagnosis of DM.

Aims & Methods

We included adult patients who were newly diagnosed with type 2 DM (i.e. NODM group) or had any clinical consultation without a diagnosis of DM (i.e. non-DM group) between 2008 and 2015 from a territory-wide electronic healthcare database in Asia. Patients with type 1 DM or prior history of PAC were excluded. Each patient was followed from the diagnosis date of DM (or first consultation in non-DM group) till PAC development, death or 1 year. The incidence rate of PAC was calculated under Poisson distribution and compared between NODM and non-DM groups. The NODM cohort with complete data was further randomly split in a ratio of 7:3 into a training set (to develop the prediction model) and a validation set, respectively. Logistic regression with forward stepwise selection was conducted to identify the potential predictors of PAC. Model performance against the validation set was assessed by the area under receiver operating characteristic curve (AUC).

Results

Among 4,002,826 patients identified, 261,046 (6.5%) of whom had NODM. The incidence of PAC at 1 year was 11.68 per 10,000 persons (95% CI: 10.41-13.07) for NODM group and 1.82 per 10,000 persons (95% CI: 1.68-1.96) for non-DM group, with an incidence rate ratio of 6.43 (95% CI: 5.60-7.37). To develop a prediction model for PAC at 1 year, 19,210 NODM patients (28 PAC cases) were included, of whom 13,447 (18 PAC cases) were in the training set and 5,763 (10 PAC cases) in the validation set. After forward stepwise selection, the final prediction model included age, baseline body mass index (BMI), BMI change in 1 year, baseline blood glucose, prescription of anti-diabetic medications (oral drugs or insulin) and high-density lipoprotein cholesterol (HDL-C) change in previous 1 year. NODM patients who were older (OR: 1.06, 95% CI: 1.01, 1.11), had higher baseline blood glucose (OR: 1.01, 95% CI: 1.00, 1.01), were prescribed anti-diabetic medications at baseline (OR: 3.40, 95% CI: 1.92, 9.70), had larger drop in BMI (OR: 1.24, 95% CI: 1.05, 1.45) and HDL-C (OR: 3.28, 95% CI: 1.33, 8.09) in previous year were more likely to be diagnosed with PAC (Table 1). Using the validation set, the model showed an AUC of 0.89 (95% CI:0.81-0.96) with a sensitivity of 90.0% and specificity of 72.3%. The number-needed-to-screen (NNS) to identify one PAC case among all NODM and high-risk NODM patients was 763 and 234, respectively.
Table 1: The final model for 1-year risk prediction of pancreatic cancer using logistic regression with forward stepwise.

Conclusion

Patients with NODM had 6.4-times higher risk of developing PAC within 1 year than patients without DM, and our new prediction model may help to identify high risk patients.

Introduction

During severe acute pancreatitis (SAP), large amounts of reactive oxygen species (ROS) are produced in the abdominal cavity, which can directly damage abdominal organs and be absorbed into the blood, causing systemic inflammatory response syndrome and multiple organ dysfunction. Molecular hydrogen (H₂) can target to eliminate harmful ROS such as hydroxyl radical ^[1]. When severe inflammatory damage occurs in the pancreas, microthrombosis are widely produced, and the antioxidant effect is difficult to be fully exerted if H₂ is administered through circulation.

Aims & Methods

We have developed hydrogen-loaded nanoparticles (nano hydrogen) to bring H₂ into direct contact with the pancreas by intraperitoneal administration, providing a new strategy for the anti-inflammatory treatment of SAP. In this study, we investigated the pathophysiological mechanisms by which nano hydrogen ameliorates SAP.
In vivo, SAP was established by retrograde injection of sodium taurocholate through the rat pancreatic duct. Nano hydrogen (37.5 mg/kg) was injected intraperitoneally in the SAP + nano hydrogen group. The survival rate was calculated. Pathological scoring was performed. Neutrophil and macrophage infiltration, ultrastructural changes of acinar cells and vascular endothelial cells, and microthrombosis of pancreatic tissue were detected. In vitro, intracellular ROS of AR42J cells were measured using hydroxyphenyl fluorescein solution. Human umbilical vein endothelial cells (HUVECs) were stimulated with TNF-α, and nano hydrogen was used for intervention. RNA-seq was performed on rat pancreatic tissue and HUVEC samples. The expression of VCAM-1, ICAM-1 and NF-κB p65 in HUVECs was compared. β-galactosidase staining and markers of cellular senescence such as phosphorylated γ-H₂A.X, p53, p21, and p16 were detected. The opening of the mitochondrial permeability transition pore (MPTP) and mitochondrial membrane potential of HUVECs were assessed.

Results

After intraperitoneal administration of nano hydrogen into SAP rats, the survival rate increased by 66%, and the pathological score of pancreas dramatically decreased (p < 0.01). The neutrophil infiltration was significantly reduced (p < 0.01), and the ultrastructure of acinar cells and vascular endothelial cells was significantly improved. The pancreatic tissue of SAP rats had a large number of microthrombi, which were significantly reduced by nano hydrogen. Pancreatic vascular endothelial cells in SAP rats expressed p21.
Nano hydrogen significantly downregulated the dominant transcriptional events in SAP pancreas, such as leukocyte chemotaxis and migration and oxidative stress, and also significantly reduced the production of ROS in the acinar cells and the expression of VCAM-1, ICAM-1 and phosphorylated p65 after TNF-α stimulation of HUVECs (p < 0.01). RNA-seq analysis of HUVECs indicated that TNF-α induced cellular senescence, confirmed by positive β-galactosidase staining and significantly increased expression of phosphorylated γ-H₂A.X, total p53, phosphorylated p53, p21 (p < 0.05) and p16 (p < 0.01). MPTP opened and mitochondrial membrane potential disappeared in TNF-α-stimulated HUVECs. Nano hydrogen significantly attenuated the abovementioned manifestation.

Conclusion

Nano hydrogen can effectively eliminate ROS brought to the pancreas by neutrophil infiltration and etc., and improve vascular endothelial cell function, thus significantly improving pathological damage such as pancreatic necrosis, which has important translational value for clinical treatment.

References

1. Ohsawa I, Ishikawa M, Takahashi K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med, 2007, 13(6): 688-694.