Integrating plasma protein-centric multi-omics to identify potential therapeutic targets for pancreatic cancer.

BACKGROUND: Deciphering the role of plasma proteins in pancreatic cancer (PC) susceptibility can aid in identifying novel targets for diagnosis and treatment. METHODS: We examined the relationship between genetically determined levels of plasma proteins and PC through a systemic proteome-wide Mendelian randomization (MR) analysis utilizing cis-pQTLs from multiple centers. Rigorous sensitivity analyses, colocalization, reverse MR, replications with varying instrumental variable selections and additional datasets, as well as subsequent meta-analysis, were utilized to confirm the robustness of significant findings. The causative effect of corresponding protein-coding genes' expression and their expression pattern in single-cell types were then investigated. Enrichment analysis, between-protein interaction and causation, knock-out mice models, and mediation analysis with established PC risk factors were applied to indicate the pathogenetic pathways. These candidate targets were ultimately prioritized upon druggability and potential side effects predicted by a phenome-wide MR. RESULTS: Twenty-one PC-related circulating proteins were identified in the exploratory phase with no evidence for horizontal pleiotropy or reverse causation. Of these, 11 were confirmed in a meta-analysis integrating external validations. The causality at a transcription level was repeated for neutrophil elastase, hydroxyacylglutathione hydrolase, lipase member N, protein disulfide-isomerase A5, xyloside xylosyltransferase 1. The carbohydrate sulfotransferase 11 and histo-blood group ABO system transferase exhibited high-support genetic colocalization evidence and were found to affect PC carcinogenesis partially through modulating body mass index and type 2 diabetes, respectively. Approved drugs have been established for eight candidate targets, which could potentially be repurposed for PC therapies. The phenome-wide investigation revealed 12 proteins associated with 51 non-PC traits, and interference on protein disulfide-isomerase A5 and cystatin-D would increase the risk of other malignancies. CONCLUSIONS: By employing comprehensive methodologies, this study demonstrated a genetic predisposition linking 21 circulating proteins to PC risk. Our findings shed new light on the PC etiology and highlighted potential targets as priorities for future efforts in early diagnosis and therapeutic strategies of PC.

Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) shows a remarkable predilection for liver metastasis. Pro-oncogenic secretome delivery and trafficking via exosomes are crucial for pre-metastatic microenvironment formation and metastasis. This study aimed to explore the underlying mechanisms of how PDAC-derived exosomes (Pex) modulate the liver microenvironment and promote metastasis. DESIGN: C57BL/6 mice were 'educated' by tail vein Pex injection. The intrasplenic injection liver metastasis and PDAC orthotopic transplantation models were used to evaluate liver metastasis. Stable cell lines CD44v6 (CD44 variant isoform 6) or C1QBP (complement C1q binding protein) knockdown or overexpression was established using lentivirus transfection or gateway systems. A total of 142 patients with PDAC in Huashan Hospital were retrospectively enrolled. Prognosis and liver metastasis were predicted using Kaplan-Meier survival curves and logistic regression models. RESULTS: Pex tail vein injection induced the deposition of liver fibrotic extracellular matrix, which promoted PDAC liver metastasis. Specifically, the exosomal CD44v6/C1QBP complex was delivered to the plasma membrane of hepatic satellite cells (HSCs), leading to phosphorylation of insulin-like growth factor 1 signalling molecules, which resulted in HSC activation and liver fibrosis. Expression of Pex CD44v6 and C1QBP in PDAC patients with liver metastasis was significantly higher than in PDAC patients without liver metastasis, and simultaneous high expression of exosomal CD44v6 and C1QBP correlated with a worse prognosis and a higher risk of postoperative PDAC liver metastasis. CONCLUSION: The Pex-derived CD44v6/C1QBP complex is essential for the formation of a fibrotic liver microenvironment and PDAC liver metastasis. Highly expressed exosomal CD44v6 and C1QBP are promising biomarkers for predicting prognosis and liver metastasis in patients with PDAC.

The construction and analysis of a ferroptosis-related gene prognostic signature for pancreatic cancer.

Ferroptosis is a regulated cell death nexus linking metabolism, redox biology and diseases including cancer. The aim of the present study was to identify a ferroptosis-related gene prognostic signature for pancreatic cancer (PCa) by systematic analysis of transcriptional profiles from Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). Altogether 14 ferroptosis-relevant genes with potential prognostic values were identified, based on which a risk score formula was constructed. According to the risk scores, we classified the patients into a high- and a low-risk score group. It was verified in Gene Expression Omnibus (GEO) and ICGC (International Cancer Genome Consortium) datasets. The Kaplan-Meier survival curves demonstrated that patients with lower risk scores had significantly favorable overall survival (OS) (P < 0.0001). The area under the receiver operating curve (ROC) for 12, 18 and 24 months was about 0.8 in all patients. The result of immune status analysis revealed that the signature significantly associated with the immune infiltration and immune checkpoint blockade (ICB) proteins. In addition, we used quantitative real time PCR (q-rtPCR) and Human Protein Atlas (HPA) to validate the expression of the key genes. Collectively, the signature is valuable for survival prediction of PCa patients. As the signature also has relevance with the immune characteristics, it may help improve the efficacy of personalized immunotherapy.

Controlling Nutritional Status score is superior to Prognostic Nutritional Index score in predicting survival and complications in pancreatic ductal adenocarcinoma: a Chinese propensity score matching study.

Preoperative nutritional status plays an important role in predicting postoperative outcomes. Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) are good tools to assess patients' nutritional status. They have been used in predicting outcomes in various malignancies, but few studies have focused on pancreatic adenocarcinoma (PDAC) patients. Totally, 306 PDAC patients were enrolled. The propensity score matching (PSM) method was introduced to eliminate the baseline inequivalence. Patients with different PNI (or CONUT) scores showed inequivalence baseline characteristics, and patients with compromised nutritional status were related with a more advanced tumour stage. After PSM, the baseline characteristics were well balanced. Both low PNI (≤45) and high CONUT (≥3) were independent risk factors for poor overall survival (P < 0·05), and the result remained the same after PSM. Survival analysis demonstrated both patients with low PNI and high CONUT score were associated with poorer survival, and the result remained the same after PSM. The results of AUC indicated that CONUT might have a higher sensitivity and specificity in predicting complications and survival. Preoperative low PNI (≤45) and high CONUT (≥3) scores might be reliable predictors of prognosis and surgical complications in PDAC patients. Compared with PNI, CONUT might be more effective.

Partial pancreatic tail preserving subtotal pancreatectomy for pancreatic cancer: Improving glycemic control and quality of life without compromising oncological outcomes.

BACKGROUND: Total pancreatectomy (TP) is usually considered a therapeutic option for pancreatic cancer in which Whipple surgery and distal pancreatectomy are undesirable, but brittle diabetes and poor quality of life (QoL) remain major concerns. A subset of patients who underwent TP even died due to severe hypoglycemia. For pancreatic cancer involving the pancreatic head and proximal body but without invasion to the pancreatic tail, we performed partial pancreatic tail preserving subtotal pancreatectomy (PPTP-SP) in selected patients, in order to improve postoperative glycemic control and QoL without compromising oncological outcomes. AIM: To evaluate the efficacy of PPTP-SP for patients with pancreatic cancer. METHODS: We retrospectively reviewed 56 patients with pancreatic ductal adenocarcinoma who underwent PPTP-SP (n = 18) or TP (n = 38) at our institution from May 2014 to January 2019. Clinical outcomes were compared between the two groups, with an emphasis on oncological outcomes, postoperative glycemic control, and QoL. QoL was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 and EORTC PAN26). All patients were followed until May 2019 or until death. RESULTS: A total of 56 consecutive patients were enrolled in this study. Perioperative outcomes, recurrence-free survival, and overall survival were comparable between the two groups. No patients in the PPTP-SP group developed cancer recurrence in the pancreatic tail stump or splenic hilum, or a clinical pancreatic fistula. Patients who underwent PPTP-SP had significantly better glycemic control, based on their higher rate of insulin-independence (P = 0.014), lower hemoglobin A1c (HbA1c) level (P = 0.046), lower daily insulin dosage (P < 0.001), and less frequent hypoglycemic episodes (P < 0.001). Global health was similar in the two groups, but patients who underwent PPTP-SP had better functional status (P = 0.036), milder symptoms (P = 0.013), less severe diet restriction (P = 0.011), and higher confidence regarding future life (P = 0.035). CONCLUSION: For pancreatic cancer involving the pancreatic head and proximal body, PPTP-SP achieves perioperative and oncological outcomes comparable to TP in selected patients while significantly improving long-term glycemic control and QoL.

Pancreatoduodenectomy with portal vein resection favors the survival time of patients with pancreatic ductal adenocarcinoma: A propensity score matching analysis.

Portal vein (PV) involvement is common in patients with pancreatic ductal adenocarcinoma (PDAC). To the best of our knowledge, pancreatectomy combined with PV resection (PVR) is the only radical therapy for patients with PV involvement. However, there remains a debate on whether patients with PV involvement could benefit from PVR or not. The present study aimed to compare the survival outcomes between patients receiving pancreatoduodenectomy (PD) with PVR and those receiving PD alone. A total of 377 patients with PDAC were enrolled, 138 patients with PV involvement were placed in the PVR group, while the other 239 patients were in the non-PVR group. To reduce selection bias and estimate the causal effect, 123 pairs of propensity score matched (PSM) patients were selected and compared for the survival outcomes. Before PSM, the survival of patients in the PVR group was worse compared with those in the non-PVR group (mean survival, 25.1 vs. 29.3 months; P=0.038). After balancing the baseline characteristics using the PSM method, the significant survival difference between the two groups was insignificant (mean survival, 25.9 vs. 31.2 months; P=0.364). Tumor stage, body mass index, serum albumin, R1 resection, lymph node metastasis, carbohydrate antigen (CA)125 and CA19-9 were significant independent prognostic factors. The incidence of serious postoperative complications was similar between the two groups. PVR is safe and effective for patients with PDAC. Patients with PV involvement could achieve the similar survival outcome as patients without PV involvement, through radical resection combined with PVR, without increasing the risk of serious complications.

Delaying surgery after preoperative biliary drainage does not increase surgical morbidity after pancreaticoduodenectomy.

BACKGROUND: The effects of the time interval from preoperative biliary drainage to pancreaticoduodenectomy on morbidity and mortality have not been established, but a recent multicenter study found that an interval greater than 4 weeks resulted in fewer major complications. We investigated whether delaying pancreaticoduodenectomy after preoperative biliary drainage led to improved postoperative morbidity and mortality. METHODS: Patients who underwent elective open pancreaticoduodenectomy between January 2009 and December 2016 were retrospectively analyzed. They were divided into a short duration group (time interval to surgery <4 weeks) and a delaying surgery group (time interval to surgery ≥4 weeks). An unstented control group (no stent group) was added. Perioperative characteristics and surgical outcomes were compared. RESULTS: Of 603 patients who underwent pancreaticoduodenectomy, 183 (30.3%) had preoperative biliary drainage, 110 patients (18.2%) in the short duration group and 73 (12.1%) in the delaying surgery group. The median interval between preoperative biliary drainage and pancreaticoduodenectomy was 3 weeks (interquartile range, 2-3) for the former group and 6 weeks (interquartile range, 5-7) for the latter. With the exception of wound infection, which was significantly higher in the short duration group than in the controls (8.2% vs 1.7%, P = .002) but not significantly increased compared with the delaying surgery group (8.2% vs 4.1%, P = .368), other complications were comparable among the 3 groups. Subgroup analyses in the intermediate- and high-risk cohort based on either original or alternative Fistula Risk Score showed similar outcomes. Univariate and multivariate analyses showed that short stent duration and female sex were independent factors associated with wound infection. CONCLUSION: A time interval between preoperative biliary drainage and resection greater than 4 weeks does not have a negative impact on short-term surgical outcomes. This finding indicates the relative safety of postponing surgery, if necessary, for preoperative treatment, optimization, or preparation.

Portal vein resection and reconstruction with artificial blood vessels is safe and feasible for pancreatic ductal adenocarcinoma patients with portal vein involvement: Chinese center experience.

Evidence shows that portal vein resection (PVR) increase the resectability but does little benefit to overall survival in all pancreatic ductal adenocarcinoma (PDAC) patients. But for patients with portal vein involvement, PVR is the only radical choice. But whether the PDAC patients with portal vein involvement would benefit from radical pancreaticoduodenectomy with PVR or not is controversial. All 204 PDAC patients with portal vein involvement were enrolled in this study [PVR group, n=106; surgical bypass (SB) group, n=52; chemotherapy group, n=46]. Overall survival and prognostic factors were analyzed among three groups. Moreover, a literature review of 13 studies were also conducted. Among 3 groups, patients in PVR group achieved a significant longer survival (median survival: PVR group, 22.83 months; SB group, 7.26 months; chemotherapy group, 10.64 months). Therapy choice [hazard ratio (HR) =1.593, 95% confidence interval (CI) 1.323 to 1.918, P<0.001], body mass index (HR=0.772, 95% CI 0.559 to 0.994, P=0.044) and carbohydrateantigen 19-9 (HR=1.325, 95% CI 1.064 to 1.651, P=0.012) were independent prognostic factors which significantly affected overall survival. Pancreaticoduodenectomy combined with PVR and reconstruct with artificial blood vessels is a safe and an appropriate therapy choice for resectable PDAC patients with portal vein involvement.