High Systemic Immune Inflammation Index Is Associated With Low Skeletal Muscle Quantity in Resectable Pancreatic Ductal Adenocarcinoma.

Background and Aims: Failing immune surveillance in pancreatic ductal adenocarcinoma (PDAC) is related to poor prognosis. PDAC is also characterized by its substantial alterations to patients' body composition. Therefore, we investigated associations between the host systemic immune inflammation response and body composition in patients with resected PDAC. Methods: Patients who underwent a pancreatectomy for PDAC between 2004 and 2016 in two tertiary referral centers were included. Skeletal muscle mass quantity and muscle attenuation, as well as subcutaneous and visceral adipose tissue at the time of diagnosis, were determined by CT imaging measured transversely at the third lumbar vertebra level. Baseline clinicopathological characteristics, laboratory values including the systemic immune inflammation index (SIII), postoperative, and survival outcomes were collected. Results: A total of 415 patients were included, and low skeletal muscle mass quantity was found in 273 (65.7%) patients. Of the body composition indices, only low skeletal muscle mass quantity was independently associated with a high (≥900) SIII (OR 7.37, 95% CI 2.31-23.5, p=0.001). The SIII was independently associated with disease-free survival (HR 1.86, 95% CI 1.12-3.04), and cancer-specific survival (HR 2.21, 95% CI 1.33-3.67). None of the body composition indices were associated with survival outcomes. Conclusion: This study showed a strong association between preoperative low skeletal muscle mass quantity and elevated host systemic immune inflammation in patients with resected PDAC. Understanding how systemic inflammation may contribute to changes in body composition or whether reversing these changes may affect the host systemic immune inflammation response could expose new therapeutic possibilities for improving patients' survival outcomes.

Spatial genomics reveals a high number and specific location of B cells in the pancreatic ductal adenocarcinoma microenvironment of long-term survivors.

Background and aim: Only 10% of pancreatic ductal adenocarcinoma (PDAC) patients survive longer than five years. Factors underlining long-term survivorship in PDAC are not well understood. Therefore, we aimed to identify the key players in the tumor immune microenvironment (TIME) associated with long-term survivorship in PDAC patients. Methods: The immune-related gene expression profiles of resected PDAC tumors of patients who survived and remained recurrence-free of disease for ≥36 months (long-term survivors, n=10) were compared to patients who had survived ≤6 months (short-term survivors, n=10) due to tumor recurrence. Validation was performed by the spatial protein expression profile of immune cells using the GeoMx™ Digital Spatial Profiler. An independent cohort of samples consisting of 12 long-term survivors and 10 short-term survivors, was used for additional validation. The independent validation was performed by combining qualitative immunohistochemistry and quantitative protein expression profiling. Results: B cells were found to be significantly increased in the TIME of long-term survivors by gene expression profiling (p=0.018). The high tumor infiltration of B cells was confirmed by spatial protein profiling in the discovery and the validation cohorts (p=0.002 and p=0.01, respectively). The higher number of infiltrated B cells was found mainly in the stromal compartments of PDAC samples and was exclusively found within tumor cells in long-term survivors. Conclusion: This is the first comprehensive study that connects the immune landscape of gene expression profiles and protein spatial infiltration with the survivorship of PDAC patients. We found a higher number and a specific location of B cells in TIME of long-term survivors which emphasizes the importance of B cells and B cell-based therapy for future personalized immunotherapy in PDAC patients.

Rintatolimod Induces Antiviral Activities in Human Pancreatic Cancer Cells: Opening for an Anti-COVID-19 Opportunity in Cancer Patients?

Severe acute respiratory virus-2 (SARS-CoV-2) has spread globally leading to a devastating loss of life. Large registry studies have begun to shed light on the epidemiological and clinical vulnerabilities of cancer patients who succumb to or endure poor outcomes of SARS-CoV-2. Specific treatment for COVID-19 infections in cancer patients is lacking while the demand for treatment is increasing. Therefore, we explored the effect of Rintatolimod (Ampligen®) (AIM ImmunoTech, Ocala, FL, USA), a Toll-like receptor 3 (TLR3) agonist, to treat uninfected human pancreatic cancer cells (HPACs). The direct effect of Rintatolimod was measured by targeted gene expression profiling and by proteomics measurements. Our results show that Rintatolimod induces an antiviral effect in HPACs by inducing RNase-L-dependent and independent pathways of the innate immune system. Treatment with Rintatolimod activated the interferon signaling pathway, leading to the overexpression of several cytokines and chemokines in epithelial cells. Furthermore, Rintatolimod treatment increased the expression of angiogenesis-related genes without promoting fibrosis, which is the main cause of death in patients with COVID-19. We conclude that Rintatolimod could be considered an early additional treatment option for cancer patients who are infected with SARS-CoV-2 to prevent the complicated severity of the disease.

The Systemic-immune-inflammation Index Independently Predicts Survival and Recurrence in Resectable Pancreatic Cancer and its Prognostic Value Depends on Bilirubin Levels: A Retrospective Multicenter Cohort Study.

OBJECTIVE: Our aim was to determine the prognostic significance of the systemic-immune-inflammation index (SIII) in patients with resectable pancreatic cancer, using cancer-specific survival as the primary outcome. BACKGROUND: Pancreatic cancer is associated with a dysfunctional immune system and poor prognosis. We examined the prognostic significance of the SIII in patients with resectable pancreatic ductal adenocarcinoma (PDAC) and the effects of bilirubin on this index. METHODS: We retrospectively assessed all pancreatic resections performed between 2004 and 2015 at 4 tertiary referral centers to identify pathologically confirmed PDAC patients. Baseline clinicopathologic characteristics, preoperative laboratory values such as absolute neutrophil, lymphocyte, and platelet counts, C-reactive protein, albumin, bilirubin, and CA19-9 levels, and also follow-up information, were collected. The associations of the calculated inflammatory indices with outcome were both internally and externally validated. RESULTS: In all, 590 patients with resectable PDAC were included. The discovery and validation cohort included 170 and 420 patients, respectively. SIII >900 [hazard ratio (HR) 2.32, 95% confidence interval (CI) 1.55-3.48], lymph node ratio (HR 3.75, 95% CI 2.08-6.76), and CA19.9 >200 kU/L (HR 1.62, 95% CI 1.07-2.46) were identified as independent predictors of cancer-specific survival. Separate model analysis confirmed that preoperative SIII contributed significantly to prognostication. However, SIII appeared to lose its prognostic significance in patients with bilirubin levels above 200 µmol/L. CONCLUSIONS: SIII is an independent predictor of cancer-specific survival and recurrence in patients with resectable PDAC. SIII may lose its prognostic significance in patients with high bilirubin levels. Properly designed prospective studies are needed to further confirm this hypothesis.