The evolution and heterogeneity of neutrophils in cancers: origins, subsets, functions, orchestrations and clinical applications.

Neutrophils, the most prevalent innate immune cells in humans, have garnered significant attention in recent years due to their involvement in cancer progression. This comprehensive review aimed to elucidate the important roles and underlying mechanisms of neutrophils in cancer from the perspective of their whole life cycle, tracking them from development in the bone marrow to circulation and finally to the tumor microenvironment (TME). Based on an understanding of their heterogeneity, we described the relationship between abnormal neutrophils and clinical manifestations in cancer. Specifically, we explored the function, origin, and polarization of neutrophils within the TME. Furthermore, we also undertook an extensive analysis of the intricate relationship between neutrophils and clinical management, including neutrophil-based clinical treatment strategies. In conclusion, we firmly assert that directing future research endeavors towards comprehending the remarkable heterogeneity exhibited by neutrophils is of paramount importance.

Is surgical resection justified for pancreatic ductal adenocarcinoma with distant abdominal organ metastasis? A position paper by experts in pancreatic surgery at the Joint Meeting of the International Association of Pancreatology (IAP) & the Japan Pancreas Society (JPS) 2022 in Kyoto.

Pancreatic ductal adenocarcinoma (PDAC) is a typical refractory malignancy, and many patients have distant organ metastases at diagnosis, such as liver metastasis and peritoneal dissemination. The standard treatment for unresectable PDAC with distant organ metastasis (UR-M) is chemotherapy, but the prognosis remained poor. However, with recent dramatic developments in chemotherapy, the prognosis has gradually improved, and some patients have experienced marked shrinkage or disappearance of their metastatic lesions. With this trend, attempts have been made to resect a small number of metastases (so-called oligometastases) in combination with the primary tumor or to resect the primary and metastatic tumor in patients with a favorable response to anti-cancer treatment after a certain period of time (so-called conversion surgery). An international consensus meeting on surgical treatment for UR-M PDAC was held during the Joint Congress of the 26th Meeting of the International Association of Pancreatology (IAP) and the 53rd Annual Meeting of the Japan Pancreas Society (JPS) in Kyoto in July 2022. The presenters showed their indications for and results of surgical treatment for UR-M PDAC and discussed their advantages and disadvantages with the experts. Although these reports were limited to a small number of patients, findings suggest that these surgical treatments for patients with UR-M PDAC who have had a significant response to chemotherapy may contribute to a prognosis of prolonged survival. We hope that this article summarizing the discussion and agreements at the meeting will serve as the basis for future trials and guidelines.

Application of ultrasound shear wave elastography in pre-operative and quantitative prediction of clinically relevant post-operative pancreatic fistula after pancreatectomy: a prospective study for the investigation of risk evaluation model.

OBJECTIVES: The aim of this study was to modify recognized clinically relevant post-operative pancreatic fistula (CR-POPF) risk evaluation models with quantitative ultrasound shear wave elastography (SWE) values and identified clinical parameters to improve the objectivity and reliability of the prediction. METHODS: Two prospective, successive cohorts were initially designed for the establishment of CR-POPF risk evaluation model and the internal validation. Patients who scheduled to receive pancreatectomy were enrolled. Virtual touch tissue imaging and quantification (VTIQ)-SWE was used to quantify pancreatic stiffness. CR-POPF was diagnosed according to 2016 International Study Group of Pancreatic Fistula standard. Recognized peri-operative risk factors of CR-POPF were analyzed, and the independent variables selected from multivariate logistic regression were used to build the prediction model. RESULTS: Finally, the CR-POPF risk evaluation model was built in a group of 143 patients (cohort 1). CR-POPF occurred in 52/143 (36%) patients. Constructed from SWE values and other identified clinical parameters, the model achieved an area under the receiver operating characteristic curve of 0.866, with sensitivity, specificity, and likelihood ratio of 71.2%, 80.2%, and 3.597 in predicting CR-POPF. Decision curve of modified model revealed a better clinical benefit compared to the previous clinical prediction models. The models were then examined via internal validation in a separate collection of 72 patients (cohort 2). CONCLUSIONS: Risk evaluation model based on SWE and clinical parameters is a potential non-invasive way to pre-operatively, objectively predict CR-POPF after pancreatectomy. CLINICAL RELEVANCE STATEMENT: Our modified model based on ultrasound shear wave elastography may provide an easy access in pre-operative and quantitative evaluating the risk of CR-POPF following pancreatectomy and improve the objectivity and reliability of the prediction compared to previous clinical models. KEY POINTS: • Modified prediction model based on ultrasound shear wave elastography (SWE) provides an easy access for clinicians to pre-operatively, objectively evaluate the risk of clinically relevant post-operative pancreatic fistula (CR-POPF) following pancreatectomy. • Prospective study with validation showed that the modified model provides better diagnostic efficacy and clinical benefits compared to previous clinical models in predicting CR-POPF. • Peri-operative management of CR-POPF high-risk patients becomes more possible.

NEDD8-Activating Enzyme Inhibitor MLN4924 Inhibits Both the Tumor Stroma and Angiogenesis in Pancreatic Cancer via Gli1 and REDD1.

PURPOSE: Pancreatic cancer is characterized by a dense desmoplasia stroma, which hinders efficient drug delivery and plays a critical role in tumor progression and metastasis. MLN4924 is a first-in-class NEDD8-activating enzyme inhibitor that exhibits anti-tumor activities toward pancreatic cancer, and given the comprehensive effects that MLN4924 could have, we ask what impact MLN4924 would have on the stroma of pancreatic cancer and its underlying mechanisms. METHODS: Primary pancreatic stellate cells (PSCs) and human HMEC-1 cells were treated with MLN4924 in vitro. The proliferation and extracellular matrix protein levels of PSCs were tested, and their relationship with transcription factor Gli1 in PSCs was investigated. The angiogenic phenotypes of HMEC-1 cells were evaluated using capillary-like tube formation assay, and their relationship with REDD1 in HMEC-1 cells was investigated. RESULTS: In this study, we found that MLN4924 inhibited the proliferation of pancreatic stellate cells and their secretion of collagen and CXCL-1, and the collagen secretion inhibiting effect of MLN4924 was related with transcription factor Gli1. MLN4924 inhibited multiple angiogenic phenotypes of HMEC-1 cells, and mTOR agonist partially relieved the inhibition of MLN4924 on HEMCs. MLN4924 increased the expression of REDD1 and REDD1 knockdown promoted the angiogenic phenotypes of HMEC-1 cells. CONCLUSIONS: Our study suggests that MLN4924 inhibits both the tumor stroma and angiogenesis in pancreatic cancer, and the inhibition effect is related with Gli1 in pancreatic stellate cells and REDD1 in vascular endothelial cells, respectively.

Baseline radiologic features as predictors of efficacy in patients with pancreatic neuroendocrine tumors with liver metastases receiving surufatinib.

Objective: Currently, pre-treatment prediction of patients with pancreatic neuroendocrine tumors with liver metastases (PNELM) receiving surufatinib treatment was unsatisfying. Our objective was to examine the association between radiological characteristics and efficacy/prognosis. Methods: We enrolled patients with liver metastases in the phase III, SANET-p trial (NCT02589821) and obtained contrast-enhanced computed tomography (CECT) images. Qualitative and quantitative parameters including hepatic tumor margins, lesion volumes, enhancement pattern, localization types, and enhancement ratios were evaluated. The progression-free survival (PFS) and hazard ratio (HR) were calculated using Cox's proportional hazard model. Efficacy was analyzed by logistic-regression models. Results: Among 152 patients who had baseline CECT assessments and were included in this analysis, the surufatinib group showed statistically superior efficacy in terms of median PFS compared to placebo across various qualitative and quantitative parameters. In the multivariable analysis of patients receiving surufatinib (N=100), those with higher arterial phase standardized enhancement ratio-peri-lesion (ASER-peri) exhibited longer PFS [HR=0.039; 95% confidence interval (95% CI): 0.003-0.483; P=0.012]. Furthermore, patients with a high enhancement pattern experienced an improvement in the objective response ratio [31.3% vs. 14.7%, odds ratio (OR)=3.488; 95% CI: 1.024-11.875; P=0.046], and well-defined tumor margins were associated with a higher disease control rate (DCR) (89.3% vs. 68.2%, OR=4.535; 95% CI: 1.285-16.011; P=0.019) compared to poorly-defined margins. Conclusions: These pre-treatment radiological features, namely high ASER-peri, high enhancement pattern, and well-defined tumor margins, have the potential to serve as predictive markers of efficacy in patients with PNELM receiving surufatinib.

Basal microvilli define the metabolic capacity and lethal phenotype of pancreatic cancer.

Apical microvilli of polarized epithelial cells govern the absorption of metabolites and the transport of fluid in tissues. Previously, we reported that tall and dense basal microvilli present on the endothelial cells of pancreatic cancers, a lethal malignancy with a high metabolism and unusual hypomicrovascularity, contain nutrient trafficking vesicles and glucose; their length and density were related to the glucose uptake of pancreatic cancers in a small-scale analysis. However, the implications of basal microvilli on pancreatic cancers are unknown. Here, we evaluated the clinical implications of basal microvilli in 106 pancreatic cancers. We found that basal microvilli are a dominant change in pancreatic cancers. The presence of longer and denser basal microvilli on the microvessels in pancreatic cancer tissues positively correlated with increased glucose uptake and higher metastatic (or invasive) and proliferative potentials of neoplastic cells and vice versa. Clinically, postoperative patients with longer and denser basal microvilli were more prone to unfavorable pathological characteristics and dismal prognoses. They were even more refractory to adjuvant therapy than those with shorter and thinner basal microvilli were. Our findings show that basal microvilli define the metabolic capacity and lethal phenotype of pancreatic cancers. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

DIAPH3 promotes pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects.

Pancreatic cancer is a highly malignant tumour of the digestive tract which is difficult to diagnose and treat. Approximately 90% of cases arise from ductal adenocarcinoma of the glandular epithelium. The morbidity and mortality of the disease have increased significantly in recent years. Its 5-year survival rate is <1% and has one of the worst prognoses amongst malignant tumours. Pancreatic cancer has a low rate of early-stage diagnosis, high surgical mortality and low cure rate. Selenium compounds produced by selenoamino acid metabolism may promote a large amount of oxidative stress and subsequent unfolded reactions and endoplasmic reticulum stress by consuming the NADPH in cells, and eventually lead to apoptosis, necrosis or necrotic cell death. In this study, we first identified DIAPH3 as a highly expressed protein in the tissues of patients with pancreatic cancer, and confirmed that DIAPH3 promoted the proliferation, anchorage-independent growth and invasion of pancreatic cancer cells using overexpression and interference experiments. Secondly, bioinformatics data mining showed that the potential proteins interacted with DIAPH3 were involved in selenoamino acid metabolism regulation. Selenium may be incorporated into selenoprotein synthesis such as TrxR1 and GPX4, which direct reduction of hydroperoxides or resist ferroptosis, respectively. Our following validation confirmed that DIAPH3 promoted selenium content and interacted with the selenoprotein RPL6, a ribosome protein subunit involved in selenoamino acid metabolism. In addition, we verified that DIAPH3 could down-regulate cellular ROS level via up-regulating TrxR1 expression. Finally, nude mice xenograft model experimental results demonstrate DIAPH3 knock down could decrease tumour growth and TrxR1 expression and ROS levels in vivo. Collectively, our observations indicate DIAPH3 could promote pancreatic cancer progression by activating selenoprotein TrxR1-mediated antioxidant effects.

Chemokine C-C motif ligand 21 synergized with programmed death-ligand 1 blockade restrains tumor growth.

Programmed death-ligand 1 (PD-L1) blockade has revolutionized the prognosis of several cancers, but shows a weak effect on pancreatic cancer (PC) due to poor effective immune infiltration. Chemokine C-C motif ligand 21 (CCL21), a chemokine promoting T cell immunity by recruiting and colocalizing dendritic cells (DCs) and T cells, serves as a potential antitumor agent in many cancers. However, its antitumor response and mechanism combined with PD-L1 blockade in PC remain unclear. In our study, we found CCL21 played an important role in leukocyte chemotaxis, inflammatory response, and positive regulation of PI3K-AKT signaling in PC using Metascape and gene set enrichment analysis. The CCL21 level was verified to be positively correlated with infiltration of CD8+ T cells by the CIBERSORT algorithm, but no significant difference in survival was observed in either The Cancer Genome Atlas or the International Cancer Genome Consortium cohort when stratified by CCL21 expression. Additionally, we found the growth rate of allograft tumors was reduced and T cell infiltration was increased, but tumor PD-L1 abundance elevated simultaneously in the CCL21-overexpressed tumors. Then, CCL21 was further verified to increase tumor PD-L1 level through the AKT-glycogen synthase kinase-3ß axis in human PC cells, which partly impaired the antitumor T cell immunity. Finally, the combination of CCL21 and PD-L1 blockade showed superior synergistic tumor suppression in vitro and in vivo. Together, our findings suggested that CCL21 in combination with PD-L1 blockade might be an efficient and promising option for the treatment of PC.

Grading Solid Pseudopapillary Tumors of the Pancreas: the Fudan Prognostic Index.

BACKGROUND: Ki-67 has been shown to predict outcome of patients with solid pseudopapillary tumor of the pancreas (SPTP) but has not been incorporated into a formal classification system to predict recurrence-free survival (RFS). METHODS: This is a retrospective cohort study of patients with histologically confirmed diagnosis of SPTP who had at least 1 year of follow-up at two tertiary academic centers. Survival data were assessed by Kaplan-Meier method and multivariable Cox regression model. Prognostic performance was compared among various systems. RESULTS: A total of 193 consecutive patients were included, ranging in age from 12 to 70 years (median 33 years). Seven patients (3.6%) developed tumor recurrence. The 3-, 5-, and 10-year RFS rates were estimated at 96.9%, 96.1%, and 94.8%, respectively. For the AJCC staging system, patients with stage I had similar prognosis to those with stage II. For the ENETS staging system, patients with stage I to III had similar prognosis. Grade based on Ki-67 was superior to both the AJCC and ENETS systems for predicting survival. Multivariate analysis revealed that large tumor size [> 10 cm; hazard ratio (HR), 6.177 95% confidence interval (CI), 1.289-29.603; P = 0.023] and Ki-67 (HR, 17.199 95% CI, 4.001-73.930; P < 0.001) were independent predictors for RFS. The Fudan Prognostic Index based on the combination of Ki-67 and tumor size showed excellent discrimination for RFS and was more accurate and informative than other grading/staging systems. CONCLUSION: The Fudan Prognostic Index better predicts RFS compared with either Ki-67 alone or the current AJCC and ENETS TNM-based staging systems.

Prediction of pancreatic fistula after pancreatectomy by virtual touch tissue imaging and quantification (VTIQ) technology.

OBJECTIVES: The aim of this study was to quantitatively evaluate the stiffness of pancreatic parenchyma and solid focal pancreatic lesions (FPLs) by virtual touch tissue imaging and quantification (VTIQ) technique and to investigate the potential usefulness of VTIQ method in the prediction of post-operative pancreatic fistula (POPF) after pancreatectomy. METHODS: In this prospective study, patients who scheduled to undergo pancreatectomy were initially enrolled and received VTIQ assessment within one week before surgery. VTIQ elastography (Siemens ACUSON Sequoia, 5C-1 transducer) was used to measure the shear wave velocity (SWV) value of FPLs and the body part pancreatic parenchyma. The palpation stiffness of pancreas was qualitatively evaluated during operation by surgeons. POPF was finally diagnosed and graded through a three-weeks post-operative follow-up according to international study group of pancreatic fistula (ISGPF). SWV values were compared between POPF positive and negative group. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic efficacy of SWV value in predicting POPF. RESULTS: From December 2020 to June 2021, 44 patients were finally enrolled in this study, among which, 26 patients were identified to develop POPF after pancreatectomy. The SWV value of pancreatic parenchyma in POPF positive group was significantly lower than that in POPF negative group (P = 0.001). However, there was no significant difference in palpation stiffness between the two groups (P = 0.124). Besides, neither the SWV value of FPL nor the SWV ratio between FPL to surrounding pancreatic parenchyma differ significantly between POPF positive and negative group (P > 0.05). Taking SWV value of pancreatic parenchyma >1.10 m/s as a cut-off value for predicting POPF, area under the receiver operating characteristic curve (AUROC) was 0.864 with 72.2% sensitivity, 92.3% specificity, 86.7% positive predictive value (PPV) and 82.8% negative predictive value (NPV), respectively. CONCLUSIONS: VTIQ technique might be a potential non-invasive imaging method to predict POPF before pancreatectomy in future clinical practice.

Prognostic value of preoperative glucose to lymphocyte ratio in patients with resected pancreatic cancer.

BACKGROUND: Inflammatory factors and fasting blood glucose were verified to be associated with the prognosis of pancreatic ductal adenocarcinoma. The goal of this study is to confirm the prognostic role of preoperative blood glucose to lymphocyte ratio for patients with resected pancreatic ductal adenocarcinoma. METHODS: A total of 259 pancreatic ductal adenocarcinoma patients were enrolled and randomly divided into training cohort and validation cohort. The training cohort was used to generate an optimal cutoff value and the validation cohort was used to further validate the model. RESULTS: A total of 259 patients were incorporated in this study and randomly divided into the training cohort (n = 130, 1/2 of 259) and the validation cohort (129, 1/2 of 259). The optimal cutoff value of glucose to lymphocyte ratio was calculated to be 3.47 for overall survival. Cox regression analysis found that preoperative blood glucose to lymphocyte ratio was independent risk factor (p = 0.040) for overall survival. Prognostic values of glucose to lymphocyte ratio on overall survival were observed in younger male patients with pancreatic body and tail cancer, American Joint Committee on Cancer 8th N1 stage, without microvascular and peripancreatic fat invasion, and Carbohydrate antigen 19-9 higher than 200 U/ml. A prognostic prediction model of overall survival was designed and presented in nomogram. CONCLUSION: Preoperative blood glucose to lymphocyte ratio is an independent biomarker to predict the overall survival for pancreatic ductal adenocarcinoma patients who underwent curative resection.

Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. METHODS: SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821. FINDINGS: Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3-19·4) in the surufatinib group and 11·1 months (5·7-35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5-13·8) for surufatinib versus 3·7 months (2·8-5·6) for placebo (hazard ratio 0·49, 95% CI 0·32-0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. INTERPRETATION: Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. FUNDING: Hutchison MediPharma.

CD73 acts as a prognostic biomarker and promotes progression and immune escape in pancreatic cancer.

CD73 is a glycosylphosphatidylinositol (GPI)-anchored protein that attenuates tumour immunity via cooperating with CD39 to generate immunosuppressive adenosine. Therefore, CD73 blockade has been incorporated into clinical trials for cancers based on preclinical efficacy. However, the biological role and underlying mechanism of CD73 in pancreatic cancer (PC) microenvironment and its prognostic impact have not been comprehensively studied. In this article, we found that the expression of CD73 was up-regulated in PC tissues and patients with higher CD73 expression had poorer overall survival (OS) and disease-free survival (DFS) in multiple publicly available databases. Higher CD73 expression was significantly associated with its reduced methylation, and only the hypomethylation of CpG site at cg23172664 was obviously correlated with poorer OS. Then, Metascape analysis and GSEA showed that CD73 may play an important role in PC progression and immune regulations. Notably, CD73 was verified to be negatively correlated with infiltrating levels of CD8+ T cells and γδ+ T cells in both TCGA and GEO cohorts via the CIBERSORT algorithm. In addition, patients with higher CD73 expression also tended to have higher PD-L1 expression and tumour mutation load. It seemed that CD73 might be a promising biomarker for the response to the anti-PD-1/PD-L1 treatment in PC. In conclusion, these results reveal that CD73 may function as a promotor in cancer progression and a regulator in immune patterns via CD73-related pathways. Blockade of CD73 might be a promising therapeutic strategy for PC.

Current Role of Surgery in Pancreatic Cancer With Synchronous Liver Metastasis.

Pancreatic cancer with synchronous liver metastasis has an extremely poor prognosis, and surgery is not recommended for such patients by the current guidelines. However, an increasing body of studies have shown that concurrent resection of pancreatic cancer and liver metastasis is not only technically feasible but also beneficial to the survival in the selected patients. In this review, we aim to summarize the short- and long-term outcomes following synchronous liver metastasectomy for pancreatic cancer patients, and discuss the potential criteria in selecting appropriate surgical candidates, which might be helpful in clinical decision-making.

Clinical Analysis of Acinar Cell Carcinoma of the Pancreas: A Single-Center Experience of 45 Consecutive Cases.

BACKGROUNDS: Acinar cell carcinoma of the pancreas is a rare malignancy, and its features remain unclear. We aimed to analyze the clinical characteristics, treatment and prognosis of acinar cell carcinoma with our institutional case series. METHODS: Patients diagnosed with acinar cell carcinoma in our hospital between 2005 and 2019 were reviewed. Investigations on clinicopathological features, treatment details and long-term survival were performed. RESULTS: A total of 45 pathologically confirmed acinar cell carcinomas were identified. The median age at diagnosis was 58 years with a male-to-female ratio of 3.1:1. There were 24 (53.3%) localized, 5 (11.1%) locally advanced and 16 (35.6%) metastatic cases, with a pancreatic head-to-body/tail ratio of 1:1.4 for all the primary lesions. In the localized group, there were 10 pancreatoduodenectomy, 12 distal pancreatectomy, 1 total pancreatectomy, and 1 distal pancreatectomy combined with proximal gastrectomy. Among the locally advanced and metastatic cases, 13 patients received chemotherapy, 1 received concurrent radiochemotherapy, 1 underwent synchronous resection of primary tumor and liver metastasis, 1 underwent palliative operation, 1 underwent exploratory laparotomy, and 4 required no treatment. The median overall survival of this series was 18.9 months with a 5-year survival rate of 19.6%. Moreover, the resected acinar cell carcinoma patients were associated with prolonged survival compared with the unresected cases (36.6 vs. 8.5 months, P < 0.001). CONCLUSIONS: Surgical resection could improve the long-term survival of acinar cell carcinoma patients, which might also improve the prognosis of selected metastatic cases. Large-scale studies are needed to further clarify the biological behavior and clinical features, and to seek the optimal treatments.

Preoperative radiotherapy improves overall survival of pT4 pancreatic ductal adenocarcinoma patients after surgical resection.

OBJECTIVE: The aim of delivering radiotherapy for pancreatic ductal adenocarcinoma patients was to sterilize vessel margin, increase R0 resection rate and delay local progression. Whether preoperative radiotherapy could prolong overall survival of surgical candidates remained unknown. METHODS: Pancreatic ductal adenocarcinoma patients receiving radical resection from surveillance, epidemiology and end result database were enrolled. Propensity score matching was conducted to balance difference in baseline characteristics, and survival analyses were performed to compare overall survival between preoperative radiotherapy and upfront resection groups. Cox proportional hazard regression model and subgroup analyses were utilized to identify prognostic factors. RESULTS: A total of 11 665 and 597 pancreatic ductal adenocarcinoma patients receiving upfront resection and preoperative radiotherapy followed by resection from 2004 to 2016 were identified, respectively, while baseline characteristics were distinct between groups. After propensity score matching, preoperative radiotherapy was not associated with better overall survival (upfront resection vs preoperative radiotherapy, 26 vs 27 months). Subgroup analyses showed that preoperative radiotherapy was a protective factor in pT4 (hazard ratio = 0.64, 95% confidence interval: 0.47-0.88) but a negative predictor in pT1 (hazard ratio = 1.79, 95% confidence interval: 1.08-2.97) patient populations. Survival analyses showed that preoperative radiotherapy improved overall survival of patients with pT4 stage (upfront resection vs preoperative radiotherapy, 19 vs 25 months) and involvement of celiac axis, superior mesenteric artery and aorta (upfront resection vs preoperative radiotherapy, 20 vs 27 months), while preoperative radiotherapy was associated with worse overall survival in patients with pT1 tumor (upfront resection vs preoperative radiotherapy, 39 vs 24 months). CONCLUSION: Preoperative radiotherapy could improve survival of resected pancreatic ductal adenocarcinoma patients with pT4 stage or with celiac axis, superior mesenteric artery and aorta invasion.

Exosomal miRNA-106b from cancer-associated fibroblast promotes gemcitabine resistance in pancreatic cancer.

Gemcitabine (GEM)-based chemotherapy is commonly used to treat pancreatic cancer. However, acquired resistance to GEM remains a challenge in pancreatic cancer patients. Here we tested whether cancer-associated fibroblasts (CAFs) play vital roles in regulating drug resistance by transferring exosomal miRNA to cancer cells. CAFs were isolated from primary fibroblast of pancreatic cancer patients, and exosomes were collected and identified through transmission electron microscopy and western blotting analysis. The functions of CAFs-derived exosomal miRNA in regulating drug resistance were further investigated. We found that CAFs were innately resistant to GEM. The conditioned medium (CM) and the exosomes derived from CAFs contributed to GEM resistance, and GEM treatment further enhanced the effect of CAFs or CAFs-exosomes on pancreatic cancer cells proliferation. MiR-106b level was upregulated in CAFs and CAFs-exosomes following GEM treatment. MiR-106b was directly transferred from CAFs to pancreatic cancer cells through exosomes. Pretreatment of CAFs with miR-106b inhibitor suppressed miR-106b expression in CAFs-exosomes and resulted in a decreased resistance of cancer cells to GEM. MiR-106b promoted GEM resistance of cancer cells by directly targeting TP53INP1. Summarily, our data demonstrated that CAFs-derived exosomal miR-106b plays a vital role in causing GEM resistance of pancreatic cancer, thus offering a new target for sensitizing pancreatic cancer cells to GEM.

Risk factors affecting prognosis in metachronous liver metastases from WHO classification G1 and G2 gastroenteropancreatic neuroendocrine tumors after initial R0 surgical resection.

BACKGROUND: Here we describe the treatments and prognosis for metachronous metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs) after initial R0 surgical resection at a large center in China. METHODS: The clinicopathological data and survival outcomes for 108 patients (median age, 54.0 years) with metachronous hepatic metastatic GEP-NETs disease who were initially treated using R0 surgical resection between August 2003 and July 2014 were analyzed using one-way comparisons, survival analysis, and a predictive nomogram. RESULTS: Fifty-five (50.9%) patients had pancreatic NETs and 92 (85.2%) had G2 primary tumors. For treatment of the hepatic metastases, 48 (44.4%) patients received liver-directed local treatment (metastasectomy, radiofrequency ablation, transcatheter arterial chemoembolization, etc.), 15 (13.9%) received systemic treatment (interferon, somatostatin analogs, etc.), and 45 (41.7%) received both treatments. Multivariable analyses revealed that OS was associated with hepatic tumor number (P < 0.001), treatment modality (P = 0.045), and elevated Ki-67 index between the metastatic and primary lesions (P = 0.027). The predictive nomogram C-index was 0.63. CONCLUSIONS: A higher Ki-67 index in metastases compared to primary tumor was an independent factor for poor prognosis. Local treatment was associated with prolonged survival of hepatic metastatic GEP-NET patients. Optimal treatment strategies based on clinicopathological characteristics should be developed.

Optimized modification of the eighth edition of AJCC TNM staging system for resected pancreatic ductal adenocarcinoma.

Aim: To reassess the prognostic performance of the American Joint Committee on Cancer (AJCC) 8th edition for pancreatic ductal adenocarcinoma (PDAC) and optimize the categorization of PDAC staging. Patients & methods: A total of 11,858 patients with resected PDAC from the Surveillance, Epidemiology and End Results database were retrospectively enrolled by sequential analyses. Results: There was no statistical significance between stage IIA and IIB tumors with hazard ratios of 2.065 and 2.184 (p = 0.620) for stages IIA and IIB, respectively. With the proposed modification, there was a significant difference between the hazard ratios of stages IIIA and IIIB which were 2.481 and 2.715, respectively (p = 0.009). The C-index of modified system was 0.609, slightly higher than AJCC 8th staging system 0.604. Conclusion: We proposed a modified eighth edition of the AJCC staging system by combining stage IIA with IIB and further subclassifying stage III patients in order to lead to better discriminative power.

Difference analysis in prevalence of incidental pancreatic cystic lesions between computed tomography and magnetic resonance imaging.

BACKGROUND: The purpose was to investigate the difference of detection rate of incidental pancreatic cystic lesions (PCLs) with computed tomography (CT) and magnetic resonance imaging (MRI) and to compare the difference between CT and MRI and to explore the effect of this difference on surgical resection. METHODS: We reviewed the diagnostic reports for incidental PCLs between 2013 and 2016. Images of PCLs would be re-evaluated. Clinical and imaging data were recorded. The chi-square and independent t-test were conducted for categorical and continuous variables. RESULTS: The prevalence of PCLs was 1.91% (1038/54210) and 3.36% (1282/38099) on CT and MRI respectively, and increased with increasing age (P < 0.001). No significant differences were found in the annual prevalence of PCLs on CT (P = 0.796) and MRI (P = 0.213) from 2013 to 2016 while the number of examinations was increasing every year. The annual detection rate of MRI for small PCLs (< 20 mm) was significantly higher than CT (P < 0.001), but was not significantly different for large PCLs (≥20 mm). The rate of surgical resection of PCLs (≥20 mm) in MRI group was higher than CT (55.2% vs. 37.0%, P < 0.001). CONCLUSIONS: The detection rate of PCLs on CT and MRI tended to be stable despite increasing scan volumes. Female had a slightly more frequency of PCLs than male. MRI detected more small PCLs(< 20 mm) and had higher impact on surgical resection of large PCL(≥20 mm) compared with CT.