Discussion on gemcitabine combined with targeted drugs in the treatment of pancreatic cancer

Pancreatic cancer is a malignant tumor with poor prognosis. The treatment of pancreatic cancer depends on the tumor stage and type, and includes local treatment (surgery, radiotherapy and ablation intervention) and systemic therapy (chemotherapy, targeted therapy and immunotherapy). We read with great interest the review “Effective combinations of anti-cancer and targeted drugs for pancreatic cancer treatment” published on World J Gastroenterol and intended to share some of our perspectives in pancreatic cancer treatment. This review presents the therapeutic effects of the combination of gemcitabine and targeted drugs, which gives us a deeper insight into the combination treatments for pancreatic cancer.     

Serum cytokine profiles in patients with pancreatic cancer and chronic pancreatitis

BackgroundChronic pancreatitis (CP) may cause tumor-like lesions, creating a challenge in distinguishing between CP and pancreatic ductal adenocarcinoma (PDAC) in a patient. Given that invasive surgery is a standard cancer treatment, we aimed to examine whether a noninvasive diagnostic tool utilizing serum cytokines could safely differentiate between PDAC and CP.MethodsA pre-operative serum panel comprising 48 inflammatory cytokines, CA19-9, and C-reactive protein (CRP) was analyzed, consisting of 231 patients, 186 with stage I–III PDAC and 45 with CP. We excluded PDAC patients who underwent neoadjuvant therapy and those CP patients with other active malignancies. The laboratory variables most associated with PDAC diagnosis were assessed using logistic regression and selected using the lasso method.ResultsThe cytokines CTACK, GRO-α, and β-NGF were selected alongside CA19-9 and CRP for our differential diagnostic model. The area under the curve (AUC) for our differential diagnostic model was 0.809 (95% confidence interval [CI] 0.738–0.880), compared with 0.791 (95% CI 0.728–0.854) for CA19-9 alone (not significant).ConclusionsWe found that inflammatory cytokines CTACK, GRO-α, and β-NGF alongside CA19-9 and CRP may help distinguish PDAC from CP.     

The impact of intra- and postoperative fluid balance in pancreatic surgery - A retrospective cohort study

Background/objectivesThe aim of this study was to evaluate the impact of perioperative fluid administration in pancreatic surgery.MethodsPatients who underwent pancreatic resections were identified from our institution's prospectively maintained database. Fluid balances were recorded intraoperatively and at 24hr postoperatively. Patients were stratified into tertiles of fluid administration (low, medium, high). Adjusted multivariable analysis was performed and outcome measures were postoperative complications.ResultsA total of 211 patients were included from 2012 to 2017. Complication rates were POPF(B/C) 19.4%, DGE(B/C) 14.7%, PPH(C) 10.0% and CDC ≥ IIIb 26.1%. In multivariable analysis, high perioperative fluid balance was an independent risk factor associated with POPF (OR = 10.5, 95%CI 2.7–40.7, p = .001), CDC (OR = 2.5, 95%CI 1.2–5.3, p < .002), DGE (OR = 2.3, 95%CI 1.0–5.2, p = .017), PPH (OR = 6.7 95%CI 2.2–20.0, p = .038) and reoperation (OR = 3.1, 95%CI 1.6–6.2, p = .006). In multivariable analysis with intraoperative and postoperative fluid balances as separate predictors, intraoperative (OR = 2,5, 95%CI 1.2–5.5, p = .04) and postoperative fluid balance (OR = 2.5, 95%CI 1.2–5.5, p = .02) were predictors of POPF. Postoperative fluid balance was the only predictor for mortality (OR = 4.5, 95%CI 1.0–18.9, p = .041) and predictor for CDC (OR = 2.0, 95%CI 1.0–4.0, p = .043) and OHS days (OR = 6.9, 95%CI 0.03–13.7, p = .038).ConclusionsHigh postoperative fluid balance in particular is associated with postoperative morbidity. Maintaining a fluid-restrictive strategy postoperatively should be recommended for patients undergoing pancreatic surgery.     

Dynamics of intestinal and intratumoral microbiome signatures in genetically engineered mice and human pancreatic ductal adenocarcinoma

BackgroundEmerging evidence has recently revealed a prominent role of the microbiome in pancreatic ductal adenocarcinoma (PDAC). However, while most observations were made in patients, mouse models still require a precise characterization of their disease-related microbiome to employ them for mechanistic and interventional preclinical studies.MethodsTo investigate the fecal and tumoral microbiome of LSL-Kras^G12D/+;LSL-Trp53^R172H/+;Pdx-1-Cre (KPC) and control (CTRL) mice, Oxford Nanopore sequencing was applied. Feces were collected from 10 KPC mice and 10 CTRLs at 3 timepoints (6 weeks, 12 weeks, and when tumor-bearing (KPC) or 6 months (CTRL), respectively). Metagenomic sequencing was performed on feces DNA. KPC tumor and healthy pancreas DNA samples were subjected to 16S rRNA gene sequencing. Bacterial marker components were detected in KPC tumor tissue over time by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC).ResultsMurine fecal samples showed a significantly different microbiome compared to age-matched healthy CTRLs regarding beta diversity (p = 0.001, R2 = 0.2–0.25 for Bray-Curtis). Adjusted human PDAC classifiers predicted disease status from feces of KPC mice achieving area under the receiver operating characteristic (AUROC) values of 80%. Furthermore, KPC tumors harbored significantly more bacterial components than healthy pancreas. Also the microbial composition differs significantly between KPC tumors and healthy pancreas tissue (p = 0.042 for Bray-Curtis). Microbiota found highly abundant in human PDAC samples were considerably more abundant in KPC tumors as compared to healthy pancreas samples (p-value <0.001).ConclusionKPC fecal samples show similarities with the microbial composition of stool samples from human PDAC patients.     

Exosomes in ascites from patients with human pancreatic cancer enhance remote metastasis partially through endothelial-mesenchymal transition

BackgroundDespite advances in multidisciplinary treatment, the prognosis of pancreatic cancer remains poor. Since distant metastasis defines prognosis, elucidation of the mechanism of metastasis is important for improving survival. Exosomes are extracellular secretory vesicles and are responsible for intercellular communication. In this study, we investigated whether exosomes secreted by human pancreatic cancer cells are involved in promoting distant metastasis of cancer and the mechanism that underlies the promotion of metastasis.MethodsExosomes were isolated from ascites of a patient with pancreatic cancer and a patient with liver cirrhosis as a control. Three days after the administration of exosomes to nude mice, GFP-labeled human pancreatic cancer cells were injected via the spleen or tail vein, and then the liver and lungs were histologically analyzed. To elucidate the mechanism, vascular permeability was estimated using FITC-dextran in place of pancreatic cancer cells in vivo and human umbilical vascular endothelial cells (HUVECs) were used to analyze vascular permeability and the induction of endothelial-mesenchymal transition (EndMT) in vitro.ResultsDistant metastasis and vascular permeability were significantly enhanced in mice treated with exosomes from pancreatic cancer patients in comparison to exosomes from a control patient in vivo. In addition, exosomes from pancreatic cancer patients significantly enhanced vascular permeability and the induction of EndMT in HUVECs in vitro.ConclusionExosomes derived from pancreatic cancer cells form a pre-metastatic niche and promote the extravasation and colonization of pancreatic cancer cells to remote organs, partially through endothelial-mesenchymal transition.     

Machine learning versus regression for prediction of sporadic pancreatic cancer

Background/objectivesThere is currently no widely accepted approach to identify patients at increased risk for sporadic pancreatic cancer (PC). We aimed to compare the performance of two machine-learning models with a regression-based model in predicting pancreatic ductal adenocarcinoma (PDAC), the most common form of PC.MethodsThis retrospective cohort study consisted of patients 50–84 years of age enrolled in either Kaiser Permanente Southern California (KPSC, model training, internal validation) or the Veterans Affairs (VA, external testing) between 2008 and 2017. The performance of random survival forests (RSF) and eXtreme gradient boosting (XGB) models were compared to that of COX proportional hazards regression (COX). Heterogeneity of the three models were assessed.ResultsThe KPSC and the VA cohorts consisted of 1.8 and 2.7 million patients with 1792 and 4582 incident PDAC cases within 18 months, respectively. Predictors selected into all three models included age, abdominal pain, weight change, and glycated hemoglobin (A1c). Additionally, RSF selected change in alanine transaminase (ALT), whereas the XGB and COX selected the rate of change in ALT. The COX model appeared to have lower AUC (KPSC: 0.737, 95% CI 0.710-0.764; VA: 0.706, 0.699-0.714), compared to those of RSF (KPSC: 0.767, 0.744-0.791; VA: 0.731, 0.724-0.739) and XGB (KPSC: 0.779, 0.755-0.802; VA: 0.742, 0.735-0.750). Among patients with top 5% predicted risk from all three models (N = 29,663), 117 developed PDAC, of which RSF, XGB and COX captured 84 (9 unique), 87 (4 unique), 87 (19 unique) cases, respectively.ConclusionsThe three models complement each other, but each has unique contributions.     

Uncoupling protein 2 deficiency of non-cancerous tissues inhibits the progression of pancreatic cancer in mice

Background: Pancreatic ductal adenocarcinoma(PDAC) is a disease of the elderly mostly because its development from preneoplastic lesions depends on the accumulation of gene mutations and epigenetic alterations over time. How aging of non-cancerous tissues of the host affects tumor progression, however, remains largely unknown. Methods: We took advantage of a model of accelerated aging, uncoupling protein 2-deficient( Ucp2 knockout, Ucp2 KO) mice, to investigate the growth of orthotopically trans...     

替吉奥联合吉西他滨治疗晚期胰腺癌 35例观察

目的 探究替吉奥联合吉西他滨对晚期胰腺癌病人客观缓解率(ORR)、血清糖抗原242(CA242)、糖抗原199(CA199)及癌胚抗原(CEA)水平及卡氏功能状态量表(KPS)评分的影响.方法 选取内蒙古自治区人民医院2017年3月至2018年9月收治的晚期胰腺癌病人70例,按照随机数字表法分为研究组和对照组各35例.研究组给予替吉奥+吉西他滨联合治疗,对照组给予单一药物吉西他滨治疗.观察两组治疗后ORR及治疗前后血清CA242、CA199、CEA水平、KPS评分变化,并对比两组治疗方案安全性及治疗后1年生存情况.结果 研究组病人治疗后ORR和临床控制率(DCR)分别为42.86％(15/35)、82.86％(29/35),均明显高于对照组20.00％(7/35)、60.00％(21/35),两组比较差异有统计学意义(P<0.05);治疗后,两组病人血清CA242、CA199及CEA水平均比治疗前显著降低,且研究组血清CA242、CA199及CEA水平[(26.34±8.54)U/mL、(87.62±25.67)U/mL、(7.23±2.11)μg/L]明显低于对照组[(40.63±12.21)U/mL、(126.24±32.33)U/mL、(14.12±3.67)μg/L](P<0.05);治疗后,研究组病人KPS评分均比治疗前明显升高,且治疗后研究组KPS评分(85.52±14.44)分显著高于对照组(78.45±12.88)分(P<0.05).结论 替吉奥联合吉西他滨一线治疗晚期胰腺癌临床有效率及控制率都高于单一吉西他滨治疗,且在保证安全情况下,还可尽快纠正血清CA242、CA199及CEA水平,提高病人生活质量.