Clinicopathological and survival data of 138 PDAC patients who underwent radical pancreatoduodenectomy(R0) in our center from January 2015 to December 2020 was retrospectively collected. We comprehensively evaluated the prognostic value of both tumor characteristics (e.g. pathological stage) and indicators of pathophysiological changes of cancer-hosts (e.g. hypercoagulation, cachexia),building an integrated nomogram model based on the results of multivariate analysis. This model has considerable predictive performance (internally verified) and is able to provide individualized survival probability prediction at certain time points (1, 2, 3 years) according to the patient's clinicopathological profile.
In PDAC, the lymphatic invasion is one of the hallmarks of tumor aggressiveness and has an adverse prognostic significance. The number of regional lymph node metastasis comprises of a major part of the latest TNM classification (8th edition).While tumor grade, or tumor cell differentiation, is another long-established prognostic indicator after resection of PDAC [19–21]. Wasif et.al  reported that adding tumor grade(well-differentiated and moderately differentiated tumors were classified as low-grade,poorly differentiated and undifferentiated tumors as high-grade) to AJCC staging system resulted in a significantly improved prognostic stratification, which was further validated by Rochefort et al. The same tumor grading criteria were used in our study, and high-tumor grade were identified as an independent risk factor for poor prognosis along with N2 of AJCC8th staging and vessel carcinoma embolus (VCE), another well-acknowledged sign of cancer aggressiveness.
Platelet and fibrinogen are characteristic markers of PDAC-induced hypercoagulable state, which can promote cancer progression and are associated with poor prognosis. For one thing, long duration of thrombocytosis and high plasma fibrinogen level were major risk factors for thrombosis[23, 24], and symptomatic VTE was a major cause of cancer-related death. More importantly, increasing evidence have shown that the collaboration of platelet and fibrinogen plays critical role in promoting cancer hematogenous metastasis. Tight adherence to platelets can guard circulating tumor cells (CTCs) against shear stresses in blood stream, making it easier to form thrombus and promote their arrest at the vascular endothelium, while fibrinogen acts as a “bridge” in this process, enhancing the sustained adherence and survival of individual tumor cell emboli in the vasculature of target organs[27–29]. Meanwhile, tumor cell adhesion leads to platelet activation and the release of a soluble factors including transforming growth factor-β (TGF-β), which could impair cytotoxicity and proliferation of natural killer (NK) cell and T cells[30–32],thus further protecting CTCs from immune surveillance/elimination. In addition, fibrinogen also participates in tumor extracellular matrix (ECM) forming and angiogenesis, promotes epithelial-mesenchymal transition (EMT) and affects tumor infiltration of immune cells. The result of our study that high level of platelet-to-lymphocyte ratio and fibrinogen are independent risk factors for poor survival just provided another proof for their synergistic effect on cancer progression.
Cachexia caused by cancer-induced metabolic perturbation significantly worsens the patients’ quality of life (QoL), increases the risk of complications such as anemia and infection, and aggravates the body's immunosuppression and chemotherapy resistance, which is closely associated with about 33% of PDAC deaths. In addition to the mechanical compression of the tumor and the loss of pancreatic exocrine function, the tumor-induced systemic inflammatory response and related cytokines such as TNF-α, IL-1 and IL-6 also plays key role by inducing excessive catabolism of fat and muscle. A major definition of cachexia is involuntary weight loss greater than 5% of the usual body weight or more than 2% in those with a BMI at baseline minor than 20 kg/m2, over six months) ,which is also the diagnostic criteria our study took. PNI, an emerging prognostic biomarker for PDAC, generally reflects nutrition status of patients and is closely related with cachexia[37–39].The occurrence of cachexia and low PNI(<40.5) were significantly corelated with poorer survival in univariate analysis, but intriguingly they were not identified as independent risk factor in multivariate analysis, but anemia was. This finding may suggest that comparing to weight loss and hypoalbuminemia, anemia is the downstream factor of malnutrition affecting patients’ survival.
The ratio of the serum aspartate transaminase to alanine transaminase(AST/ALT) was first proposed by De Ritis et.al in 1957, since then it has been accepted as De Ritis ratio(DRR). In recent years, DRR has received extensive attention as a potential biomarker for prognosis of malignancies, rising DRR was proven to be associated with poor survival outcomes of a variety of cancers[40–42]. There have been several hypotheses on the association of DRR with cancer. For one thing, AST plays a central role in glycolysis, which is the main energy supply mode for most cancer cells. For another, cancer-induced oxidative stress and inflammation could damage hepatocytes and intracellular mitochondria in particular, thus resulting in a higher level of AST release relative to ALT. Therefore, higher levels of DRR may generally reflect higher tumor proliferative activity and malignant behavior. Ridel et.al found that for patients with pancreatic cancer treated with first-line nab-paclitaxel and gemcitabine, high AST/ALT ratio was significantly associated with low objective response rate and higher relative risk of progression/death [HR:1.38, 95% CI: 1.06–1.80, p = 0.017]. However, the prognostic effect of DRR for resectable PDAC has not previously been studied. In our study cohort, DRR > 1.1 has been proved to be an independent risk factor of poor survival for PDAC patients undergoing radical pancreatoduodenectomy, this ground-breaking discovery deserves further study by clinical and laboratory trials.
There are a few limitations attached to this study: For one thing, this was a retrospective study performed in single center and the size of samples is relative limited therefore, verifications from multi-institution cohorts are still necessary. The other is that some promising biomarkers such as cytokines and D-dimer may not have been incorporated because of the absence of numbers or observations, which limits the predicting performance in a way.