Exhausted Tumor-infiltrating CD39+CD103+ CD8+ T Cells Unveil Potential for Increased Survival in Human Pancreatic Cancer.

In pancreatic ductal adenocarcinoma, the infiltration of CD8+ T cells within the tumor microenvironment correlates with a favorable prognosis. However, a significant proportion of tumor-infiltrating T cells become trapped within the desmoplastic stroma and lack tumor reactivity. Here, we explored different T-cell subsets in pancreatic tumors and adjacent tissues. We identified a subset of CD8+ T cells, double positive (DP) for CD39 and CD103 in pancreatic tumors, which has recently been described to display tumor reactivity in other types of solid tumors. Interestingly, DP CD8+ T cells preferentially accumulated in central tumor tissues compared with paired peripheral tumor and adjacent non-tumor tissues. Consistent with an antigen encounter, DP CD8+ T cells demonstrated higher proliferative rates and displayed an exhausted phenotype, characterized by elevated expression of PD-1 and TIM-3, compared with CD39-CD103- CD8+ T cells. In addition, DP CD8+ T cells exhibited higher expression levels of the tissue trafficking receptors CCR5 and CXCR6, while displaying lower levels of CXCR3 and CXCR4. Importantly, a high proportion of DP CD8+ T cells is associated with increased patient survival. These findings suggest that DP CD8+ T cells with a phenotype reminiscent of that of tumor-reactive T cells are present in pancreatic tumors. The abundance of DP CD8+ T cells could potentially aid in selecting patients for pancreatic cancer immunotherapy trials. SIGNIFICANCE: Patients with pancreatic cancer with a high proportion of CD39+CD103+ CD8+ T cells exhibiting a tumor-reactive phenotype have improved survival rates, suggesting their potential utility in selecting candidates for immunotherapy trials.

Plasma thymidine kinase activity as a prognostic biomarker in pancreatic ductal adenocarcinoma: a single-center prospective study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) patients might benefit from a biomarker to more precisely prognosticate their overall survival to make more informed treatment and surveillance decisions. The aim of the study was to assess the circulating biomarker Thymidine kinase (TK) activity in samples from patients with PDAC to improve prognostic precision. MATERIAL AND METHODS: Using the sensitive TK activity (TKa) assay DiviTum®, serum samples from 60 PDAC patients were analyzed. RESULTS: Median TKa value for patients with PDAC was 931 Du/L. TK activity <931 and CA19-9 < 37 was prognostic for a longer survival, compared to patients with any or both TK activity >931 and CA19-9 > 37, with median 41.3 vs 8.6 months from sample to death (p < 0.001), and 3-year survival was 55.6% vs 8.9% (p < 0.001). Hazard ratio was 2.81 if any or both of TK or CA19-9 were above the cut-off value (p < 0.05).TKa in combination with CA19-9 outperforms each marker individually for prediction of survival. Overall survival is longer in patients with both TKa <931 Du/L and CA19-9 < 37. Further studies of TKa levels at different disease stages and correlation to outcome is warranted to find the full potential clinical usage of the TKa marker in PDAC.

Painless chronic pancreatitis: experiences from a high-volume center.

INTRODUCTION: Although abdominal pain is the most prevalent and disabling symptom in patients with chronic pancreatitis (CP), there are also patients who have painless CP. PATIENTS AND METHODS: We performed a retrospective analysis of patients with a diagnosis of CP. A total of 279 patients with definite CP with completed demographic and clinical data were included in the final analysis. RESULTS: There were 75 (26.9%) patients with painless CP. These patients had a significantly higher mean age at diagnosis, 61.7 years, than the 52.5 years of patients with pain (p < 0.001). Painless and painful CP had similar rates of diabetes mellitus (DM) (28.4% vs. 31.6%) and pancreatic exocrine insufficiency (PEI) (50.0% vs. 52.3%). Painless CP had lower rates of alcoholic etiology, 36.0%, than the 52.5% in painful CP (p < 0.05). Patients older than 55 at the time of CP diagnosis were associated with painless CP with an adjusted odds ratio (aOR) of 3.27 [95% confidence interval (CI): 1.62-6.60]. Alcoholic etiologies were not associated with painless CP, aOR of 0.51 (95% CI: 0.25-0.91). CONCLUSION: Patients with painless CP had a significantly higher mean age than patients with painful CP and increased aOR for those older than 55 at CP diagnosis. Painless and painful CP patients had similar rates of DM and PEI, confirming the necessity of routine follow up in all patients with CP.

Paraduodenal pancreatitis - problem in the groove.

BACKGROUND: Paraduodenal pancreatitis (PDP) is a particular form of chronic pancreatitis (CP) occurring in and around the duodenal wall. Despite its low prevalence, this rare condition presents a significant challenge in clinical practice. METHODS: We retrospectively analysed the electronic medical charts of all patients with a diagnosis of chronic pancreatitis and identified those with PDP, between January 1999 and December 2020. RESULTS: There were 35 patients diagnosed with PDP (86% males and 14% females); median age of 56 ± 11 (range 38-80). Alcohol overconsumption was reported in 81% and smoking in 90% of patients. Abdominal pain was the leading symptom (71%), followed by weight loss, nausea and vomiting, jaundice, and diarrhoea. In 23 patients (66%), recurrent acute pancreatitis attacks were noted. Focal duodenal wall thickening was present in 34 patients (97%), cystic lesions in 80%, pancreatic duct dilatation in 54% and common bile duct dilatation in 46%. Endoscopic treatment was performed on nine patients (26%) and five patients (14%) underwent surgery. Complete symptom relief was reported in 12 patients (34%), partial symptom relief in three (9%), there was no improvement in five (14%), data were not available in three (9%) and 12 (34%) patients died before data analysis. CONCLUSIONS: PDP is a rare form of pancreatitis, most commonly occurring in the 5th or 6th decade of life, with a predominance in males and patients with a history of smoking and high alcohol consumption. Focal thickening and cystic lesions of the duodenal wall are the most common imaging findings, followed by pancreatic duct and common bile duct dilatation. A minority of patients requires surgery.

Low Bone Mineral Density and Risk for Osteoporotic Fractures in Patients with Chronic Pancreatitis.

Introduction: Chronic pancreatitis (CP) can lead to malnutrition, an established risk factor for low bone mineral density (BMD) and fractures. This study aims to determine the prevalence of low BMD, assess fracture incidence and explore risk factors for fractures in patients with CP. Patients and methods: We performed a retrospective analysis of all patients treated for CP at Karolinska University Hospital between January 1999 and December 2020. Electronic medical records were retrieved to assess demographic, laboratory and clinical data. Patients subjected to dual-energy X-ray absorptiometry (DXA) were categorised as either low BMD or normal BMD. We investigated whether the rate of fractures, defined by chart review, differed between these groups using Cox regression, adjusting the model for age, sex and body mass index (BMI). Additional within-group survival analysis was conducted to identify potential risk factors. Results: DXA was performed in 23% of patients with definite CP. Some 118 patients were included in the final analysis. Low BMD was present in 63 (53.4%) patients. Mean age at CP diagnosis in the total cohort was 53.1 years and was significantly lower in patients with normal BMD than in patients with low BMD (45.5 vs. 59.8, p < 0.001). Significant differences were observed in smoking status and disease aetiology, i.e., a higher proportion of patients with low BMD were current or former smokers, with nicotine or alcohol being a more common cause of CP (p < 0.05). Total follow-up time was 898 person-years. Fractures were found in 33 (28.0%) patients: in 5 of 55 patients (16.7%) with normal DXA and in 28 of 63 patients (44.4%) with low BMD (adjusted hazard ratio = 3.4, 95% confidence interval (CI) = 1.2-9.6). Patients with at least 3 months of consecutive pancreatic enzyme replacement therapy (PERT) or vitamin D treatment had a longer median time to fracture after CP diagnosis. Conclusion: DXA was only performed in 23% of patients with definite CP in this study, indicating a low adherence to current European guidelines. A low BMD was found in 53.4% of patients with CP, and 44% of the patients with a low BMD experienced a fracture during follow-up. Moreover, the fracture rate in patients with low BMD increased compared to those with normal BMD.

Vascular Complications in Patients with Chronic Pancreatitis.

INTRODUCTION: Chronic pancreatitis (CP) is a long-standing progressive inflammation of the pancreas, which can lead to a variety of vascular complications, such as splanchnic venous thrombosis (VT) and arterial pseudoaneurysm (PA). There is a lack of studies on vascular complications in Scandinavian countries. METHODS: We performed a retrospective analysis of medical records of patients with CP identified from the Karolinska University Hospital database between 2003 and 2018. A total of 394 patients with definite CP were included in the study. RESULTS: There were 33 patients with vascular complications, with a median age of 62 (IQR 55-72) years. The cumulative incidence of vascular events was 3.2% at 5 years. Thirty patients had isolated VT, whereas three patients had PA (7.6% and 0.8%, respectively). Isolated splenic vein thrombosis was most common (53.3%), followed by a combination with other splanchnic veins. PA was found in the splenic artery in two patients and in the left gastric artery in one patient. Varices were present in three (10%) patients; variceal bleeding was not recorded. All patients had asymptomatic splanchnic VT, most with chronic VT with developed collaterals (83.3% had abdominal collateral vessels). Nearly two-thirds of patients with VT (63.3%) received no treatment, whereas 11 (36.6%) were treated with anticoagulants. Pseudocysts and alcoholic etiology of CP are risk factors for vascular complications. CONCLUSIONS: The cumulative incidence of vascular complications was 3.2% at 5 years. Splanchnic VT is more common than PA. Patients were asymptomatic with no variceal bleeding, explained by well-developed collateral vessels and strong study inclusion criteria.