The Surgical and Therapeutic Activities of Non-Functional Pancreatic Neuroendocrine Tumors at a High-Volume Institution.

BACKGROUND: This study aimed to summarize the surgical and therapeutic activities of non-functional pancreatic neuroendocrine tumors (NF-PanNETs) and perform survival analyses of a 15-year single-institutional cohort of NF-PanNETs. METHODS: In total, 1001 patients with neuroendocrine neoplasms treated at Fudan University Shanghai Cancer Center were screened for inclusion, and 509 patients with NF-PanNETs from 2006 to 2020 were included. For time trend analyses, the 15-year study period was randomly divided into three periods. Survival analyses used the Kaplan-Meier method and Cox regression models. RESULTS: The total number of resected NF-PanNETs increased over the 15-year study period, from 5 resections in 2006 to 94 resections in 2020. A significant decrease in the tumor size was observed, from a mean of 4.0 cm to 3.3 cm, and to 3.0 cm in the most recent period (p = 0.006). Minimally invasive techniques gradually increased from 3.5% to 12.9%, and finally to 46.4% in the most recent period (p < 0.001). In non-metastatic and resected tumors, the tumor size (p < 0.001), positive lymph node (p < 0.001), adjuvant treatment (p = 0.048), and tumor grade (p < 0.001) were independent prognostic factors for recurrence-free survival (RFS). The microvascular invasion (p = 0.024) and tumor grade (p = 0.013) were independent prognostic factors for overall survival (OS). A malignant transformation from NET into neuroendocrine carcinoma was observed. CONCLUSIONS: An increasing number of NF-PanNETs resection and minimally invasive surgery was shown. In non-metastatic and resected tumors NF-PanNETs, tumor size, positive lymph node, adjuvant treatment, and tumor grade were independent predictors of RFS. Microvascular invasion and tumor grade were independent prognostic factors for OS.

A real-life treatment cohort of pancreatic neuroendocrine tumors: High-grade increase in metastases confers poor survival.

Background: Tumor grade determined by the Ki67 index is the best prognostic factor for pancreatic neuroendocrine tumors (PanNETs). However, we often observe that the grade of metastases differs from that of their primary tumors. This study aimed to investigate the frequency of grade changes between primary tumors and metastases, explore its association with clinical characteristics, and correlate the findings with the prognosis. Methods: Six hundred forty-eight patients with pancreatic neuroendocrine neoplasms treated at Fudan University Shanghai Cancer Center were screened for inclusion, and 103 patients with PanNETs who had paired primary tumors and metastases with an available Ki67 index were included. Re-evaluation of Ki67 was performed on 98 available samples from 69 patients. Results: Fifty cases (48.5%) had a Ki67 index variation, and 18 cases (17.5%) displayed a grade increase. Metachronous metastases showed significantly higher Ki67 index variation than synchronous metastases (P=0.028). Kaplan-Meier analyses showed that high-grade metastases compared to low-grade primary tumors were significantly associated with decreased progression-free survival (PFS, P=0.012) and overall survival (OS, P=0.027). Multivariable Cox regression analyses demonstrated that a low-grade increase to high-grade was an unfavorable and independent prognostic factor for PFS and OS (P=0.010, and P=0.041, respectively). Conclusions: A high-grade increase in metastases was an unfavorable predictor of PanNETs, which emphasized the importance of accurate pathological grading and could provide a reference for clinical decision-making.

Neoadjuvant chemotherapy endows CD9 with prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.

BACKGROUND: The selective pressure imposed by chemotherapy creates a barrier to tumor eradication and an opportunity for metastasis and recurrence. As a newly discovered stemness marker of pancreatic ductal adenocarcinoma (PDAC), the impact of CD9 on tumor progression and patient's prognosis remain controversial. METHODS: A total of 179 and 211 PDAC patients who underwent surgical resection with or without neoadjuvant chemotherapy, respectively, were recruited for immunohistochemical analyses of CD9 expression in both tumor and stromal areas prior to statistical analyses to determine the prognostic impact and predictive accuracy of CD9. RESULTS: The relationship between CD9 and prognostic indicators was not significant in the non-neoadjuvant group. Nevertheless, CD9 expression in both tumor (T-CD9) and stromal areas (S-CD9) was significantly correlated with the clinicopathological features in the neoadjuvant group. High levels of T-CD9 were significantly associated with worse OS (p = 0.005) and RFS (p = 0.007), while positive S-CD9 showed the opposite results (OS: p = 0.024; RFS: p = 0.008). Cox regression analyses identified CD9 in both areas as an independent prognostic factor. The T&S-CD9 risk-level system was used to stratify patients with different survival levels. The combination of T&S-CD9 risk level and TNM stage were accurate predictors of OS (C-index: 0.676; AIC: 512.51) and RFS (C-index: 0.680; AIC: 519.53). The calibration curve of the nomogram composed of the combined parameters showed excellent predictive consistency for 1-year RFS. These results were verified using a validation cohort. CONCLUSION: Neoadjuvant chemotherapy endows CD9 with a significant prognostic value that differs between tumor and stromal areas in patients with pancreatic cancer.

Role of Somatostatin Receptor 2 in Nonfunctional Pancreatic Neuroendocrine Tumors: Clinicopathological Analysis of 223 Cases and Whole Exome Sequencing of a Multifocal Case.

OBJECTIVES: Somatostatin receptors are commonly expressed in most pancreatic neuroendocrine tumors (pNETs), a rare type of pancreatic tumors with high heterogeneity. However, the role of somatostatin receptor 2 (SSTR2) has seldom been investigated separately in pNET. This retrospective study aims to evaluate the role of SSTR2 in the clinicopathological features and genomic background of nonfunctional and well-differentiated pNET. METHODS: A total of 223 cases of nonfunctional well-differentiated pNET were included, and the correlation between SSTR2 status and clinicopathological outcome was evaluated. In addition, we performed whole exome sequencing in SSTR2-positive and SSTR2-negative pNETs and identified that the 2 lesions harbored different mutational landscapes. RESULTS: Negative SSTR2 immunochemistry staining was significantly related to an earlier onset of disease, larger tumor size, advanced stage of American Joint Committee on Cancer, and tumor metastasis in lymph nodes and liver. Under pathological assessment, positive peripheral aggression, vascular invasion, and perineural invasion were markedly increased in SSTR2-negative cases. Moreover, SSTR2-negative patients exhibited significantly worse progression-free survival than SSTR2-positive patients (hazard ratio, 0.23; 95% confidence interval, 0.10-0.53; P = 0.001). CONCLUSIONS: Somatostatin receptor 2-negative nonfunctional pNET might represent a subtype of pNET with poor outcomes and evolve from a different genomic background.

Neutrophil Extracellular Traps and Macrophage Extracellular Traps Predict Postoperative Recurrence in Resectable Nonfunctional Pancreatic Neuroendocrine Tumors.

Background: Extracellular traps (ETs) and tumor-infiltrating immune cells can contribute to disease progression. The clinical significance of tumor-infiltrating neutrophils and macrophages and related extracellular traps in pancreatic neuroendocrine tumors (pNETs) has not been fully elucidated. This study aimed to explore the prognostic value of tumor infiltration and ET formation by neutrophils and macrophages in pNETs. Methods: A total of 135 patients with radical resection of nonfunctional pNETs were analyzed retrospectively. Immunohistochemistry and immunofluorescence were utilized to stain tumor tissue sections. The recurrence-free survival (RFS) of subgroups determined by Kaplan-Meier analysis was compared with the log-rank test. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. A nomogram was established to predict 3-year RFS. Results: Patients with high tumor-infiltrating neutrophils or macrophages or positive expression of neutrophils ETs or macrophage ETs displayed worse RFS (all p<0.05). Moreover, univariate and multivariate Cox regression analyses showed that neutrophil and macrophage infiltration and ETs were independent prognostic factors for RFS (all p<0.05). A combined parameter including WHO grade, TNM stage, tumor-infiltrating neutrophils and macrophages, and neutrophil and macrophage ETs had the highest C-index (0.866) and lowest Akaike information criteria (326.557). The calibration plot of nomogram composed of the combined parameter exhibited excellent prognostic values for 3-year RFS. Conclusions: Infiltration and ETs by neutrophils and macrophages can be used as biological indicators of patient prognosis, suggesting the treatment potential for targeting those in nonfunctional pNETs.

A novel risk factor panel predicts early recurrence in resected pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are indolent pancreatic tumors derived from neuroendocrine cells in pancreatic islets. To date, reliable predictors for identifying patients at high risk for recurrence after curative cancer resection are lacking. We aimed to determine independent predictors for high-risk PanNETs and patient outcomes after surgery. METHODS: We analyzed relevant clinicopathological parameters in 319 consecutive patients of derivation cohort 1 and 106 patients of validation cohort 2 who underwent pancreatectomy and were diagnosed with PanNETs. Association of tumor characteristics with recurrence-free survival (RFS) and overall survival (OS) was evaluated using Cox regression. RESULTS: PanNET grade 3 (G3), pancreatic duct dilatation, and perineural invasion were independent prognostic factors for RFS and were significantly associated with early recurrence (within 1.5 years) of PanNETs after curative resection (P = 0.019, P < 0.001, and P < 0.001, respectively). Using these factors, we established a novel risk factor panel (R-panel), which predicted early recurrence (P < 0.001, HR = 15.02, 95% CI 5.76-39.19). Predictive accuracy of this R-panel was favorable, with a C-index of 0.853, higher than AJCC TNM staging (0.713). We further built an integrated staging system combining R-panel scoring and TNM staging, which improved predictive probability of TNM staging. Finally, we showed that adjuvant therapy with long-acting somatostatin analogs (SSAs) significantly reduced postoperative recurrence (P < 0.001) and prolonged long-term survival (P = 0.021) in patients with the above risk factors. CONCLUSION: We identified a novel risk factor panel, which includes PanNET G3, pancreatic duct dilatation, and perineural invasion; this panel predicted early recurrence of PanNETs after curative resection. Patients with these risk factors can benefit from adjuvant therapy with SSAs.

Human splenic TER cells: A relevant prognostic factor acting via the artemin-GFRα3-ERK pathway in pancreatic ductal adenocarcinoma.

Splenectomy is routinely performed during distal or total pancreatectomy (DP or TP) for pancreatic ductal adenocarcinoma (PDAC), but information about its oncological value is limited. TER cells, nonimmune cells discovered in the spleens of tumour-bearing mice, are elicited by tumours and promote tumour progression, while their role in the clinical outcomes of patients with PDAC remains unclear. In our study, postoperative specimens from 622 patients who underwent DP or TP with splenectomy were analysed by flow cytometry or immunofluorescence, and the relationship between splenic TER cell count and clinical parameters was calculated. We also purified human TER cells for functional experiments and mechanistic studies. We found that TER cell numbers were increased only in the spleens of patients with PDAC but not in PDAC tissue and adjacent pancreatic tissue. High splenic TER cell counts independently predicted poor prognosis (P < .001) and indicated large tumour size, lymph node metastasis, advanced 8th AJCC/mAJCC stage and high CA19-9 classification (all P < .050) in patients with PDAC. Mechanistic analysis showed that TER cells express artemin, which facilitates the proliferation and invasion of PDAC cells by activating GFRα3-ERK signalling. Our study reveals that TER cell count is an indicator of poor prognosis of PDAC, while splenectomy during pancreatic surgery might provide oncological benefits in addition to ensuring the radical resection of PDAC.

Advances on diagnostic biomarkers of pancreatic ductal adenocarcinoma: A systems biology perspective.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is usually diagnosed at an advanced stage when curative surgery is no longer an option. Robust diagnostic biomarkers with high sensitivity and specificity for early detection are urgently needed. Systems biology provides a powerful tool for understanding diseases and solving challenging biological problems, allowing biomarkers to be identified and quantified with increasing accuracy, sensitivity, and comprehensiveness. Here, we present a comprehensive overview of efforts to identify biomarkers of PDAC using genomics, transcriptomics, proteomics, metabonomics, and bioinformatics. Systems biology perspective provides a crucial "network" to integrate multi-omics approaches to biomarker identification, shedding additional light on early PDAC detection.

Cancer-associated fibroblasts in therapeutic resistance of pancreatic cancer: Present situation, predicaments, and perspectives.

Pancreatic cancer is highly lethal, and the most effective treatment is curative resection followed by chemotherapy. Unfortunately, chemoresistance is an extremely common occurrence, and novel treatment modalities, such as immunotherapy and molecular targeted therapy, have shown limited success in clinical practice. Pancreatic cancer is characterized by an abundant stromal compartment. Cancer-associated fibroblasts (CAFs) and the extracellular matrix they deposit account for a large portion of the pancreatic tumor stroma. CAFs interact directly and indirectly with pancreatic cancer cells and can compromise the effects of, and even promote tumorigenic responses to, various treatment approaches. To eliminate these adverse effects, CAFs depletion strategies were developed. Instead of the anticipated antitumor effects of CAFs depletion, more aggressive tumor phenotypes were occasionally observed. The failure of universal stromal depletion led to the investigation of CAFs heterogeneity that forms the foundation for stromal remodeling and normalization. This review analyzes the role of CAFs in therapeutic resistance of pancreatic cancer and discusses potential CAFs-targeting strategies basing on the diverse biological functions of CAFs, thus to improve the outcome of pancreatic cancer treatment.

Infiltrating pattern and prognostic value of tertiary lymphoid structures in resected non-functional pancreatic neuroendocrine tumors.

BACKGROUND: Tertiary lymphoid structures (TLS) are associated with favorable survival and play a critical role in most solid tumors. However, investigations of TLS are lacking in patients with grade 1 or grade 2 (G1/G2) non-functional pancreatic neuroendocrine tumors (NF-PanNETs). This study aimed to investigate the presence, cellular composition, association with tumor-infiltrating immune cells, and prognostic value of TLS in G1/G2 NF-PanNETs. METHODS: Tumor tissues from a 182-patient Fudan cohort and a 125-patient external validation set were assessed by H&E staining, immunohistochemistry, and/or multispectral fluorescent immunohistochemistry. RESULTS: TLS were identified in more than one-third of patients with G1/G2 NF-PanNETs and were located peritumorally, either just outside the tumor tissue or in the stromal area. TLS were mainly composed of B-cell follicles with germinal centers and T-cell zones with dendritic cells. Kaplan-Meier analyses showed that the presence of TLS correlated with both longer recurrence-free survival (RFS, p<0.001) and overall survival (OS, p=0.001), but the number of TLS had no prognostic significance. Multivariate Cox-regression analyses demonstrated that the presence of TLS, WHO classification, and 8th edition American Joint Committee on Cancer (AJCC8th) tumor-node-metastasis (TNM) stage were independent prognostic factors for RFS (p=0.004, p=0.001, and p<0.001, respectively) and OS (p=0.009, p=0.008, and p=0.019, respectively). These results were confirmed using an external validation set. Finally, a nomogram incorporating the presence of TLS was constructed to predict the probability of 5-year RFS of resected G1/G2 NF-PanNETs, which improved on the current WHO classification and AJCC8th TNM stage. CONCLUSIONS: The presence of TLS is an independent and favorable predictor of resected G1/G2 NF-PanNETs, which may play a role in cancer immunobiology.

TET1 downregulates epithelial-mesenchymal transition and chemoresistance in PDAC by demethylating CHL1 to inhibit the Hedgehog signaling pathway.

Chemoresistance is a major obstacle to prolonging pancreatic ductal adenocarcinoma (PDAC) patient survival. TET1 is identified as the most important epigenetic modification enzyme that facilitates chemoresistance in cancers. However, the chemoresistance mechanism of TET1 in PDAC is unknown. This study aimed to determine the role of TET1 in the chemoresistance of PDAC. TET1-associated chemoresistance in PDAC was investigated in vitro and in vivo. The clinical significance of TET1 was analyzed in 228 PDAC patients by tissue microarray profiling. We identified that TET1 downregulation is caused by its promoter hypermethylation and correlates with poor survival in PDAC patients. In vitro and in vivo functional studies performed by silencing or overexpressing TET1 suggested that TET1 is able to suppress epithelial-mesenchymal transition (EMT) and sensitize PDAC cells to 5FU and gemcitabine. Then RNA-seq, whole genome bisulfite sequencing (WGBS) and ChIP-seq were used to explore the TET1-associated pathway, and showed that TET1 promotes the transcription of CHL1 by binding and demethylating the CHL1 promoter, which consequently inhibits the Hedgehog pathway. Additionally, inhibiting Hedgehog signaling by CHL1 overexpression or the Hedgehog pathway inhibitor, GDC-0449, reversed the chemoresistance induced by TET1 silencing. Regarding clinical significance, we found that high TET1 and high CHL1 expression predicted a better prognosis in resectable PDAC patients. In summary, we demonstrated that TET1 reverses chemoresistance in PDAC by downregulating the CHL1-associated Hedgehog signaling pathway. PDAC patients with a high expression levels of TET1 and CHL1 have a better prognosis.

Tumor-Infiltrating Neutrophils Predict Poor Survival of Non-Functional Pancreatic Neuroendocrine Tumor.

OBJECTIVE: This study retrospectively characterized the immune infiltrating profile in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs). METHODS: Tumor tissues from the 109-patient Fudan cohort and a 73-patient external validation set were evaluated by immunohistochemistry for 9 immune cell types: tumor-infiltrating neutrophils (TINs), tumor-associated macrophages (TAMs), CD11c+ dendritic cells, anti-NCR1+ natural killer (NK) cells, CD4+ and CD8+ T cells, CD45RO+ memory T cells, FOXP3+ regulatory T cells (Tregs), and CD20+ B cells. RESULTS: TINs were primarily distributed in the intratumoral area, dendritic cells and NK cells were scattered evenly in intratumoral and stromal areas, and Tregs were rarely detected. The remaining 5 cell types were primarily present in peritumoral stroma. Total TINs (P < .001) and TAMs (P = .002) increased as NF-PanNET grade rose. Kaplan-Meier analyses showed that high intratumoral TINs, total TAMs, and stromal CD4+ T-cell infiltration correlated with shorter recurrence-free survival (RFS, P = .010, P = .027, and P = .035, respectively) and overall survival (OS, P = .017, P = .029, and P = .045, respectively). Additionally, high intratumoral CD8+ T cell infiltration correlated with prolonged RFS (P = .039). Multivariate Cox regression demonstrated that intratumoral TINs, World Health Organization (WHO) classification, and eighth edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8th TNM) were independent factors for RFS (P = .043, P = .023, and P = .029, respectively), whereas intratumoral TINs and WHO classification were independent factors for OS (P = .010 and P = .007, respectively). Furthermore, the combination of TINs, WHO classification, and AJCC8th TNM remarkably improved prognostic accuracy for RFS. These results have been verified in the external validation set. CONCLUSION: Intratumoral TINs are an independent and unfavorable predictor of postoperative NF-PanNETs. A combination of TINs, WHO classification, and AJCC8th TNM could improve prognostic accuracy for RFS.

Haemoglobin, albumin, lymphocyte and platelet predicts postoperative survival in pancreatic cancer.

BACKGROUND: Systemic inflammation and nutrition status play an important role in cancer metastasis. The combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP), consisting of haemoglobin, albumin, lymphocytes, and platelets, is considered as a novel marker to reflect both systemic inflammation and nutrition status. However, no studies have investigated the relationship between HALP and survival of patients with pancreatic cancer following radical resection. AIM: To evaluate the prognostic value of preoperative HALP in pancreatic cancer patients. METHODS: The preoperative serum levels of hemoglobin, albumin, lymphocyte counts, and platelet counts were routinely detected in 582 pancreatic adenocarcinoma patients who underwent radical resection. The relationship between postoperative survival and the preoperative level of HALP was investigated. RESULTS: Low levels of HALP were significantly associated with lymph node metastasis (P = 0.002), poor tumor differentiation (P = 0.032), high TNM stage (P = 0.008), female patients (P = 0.005) and tumor location in the head of the pancreas (P < 0.001). Low levels of HALP were associated with early recurrence [7.3 mo vs 16.3 mo, P < 0.001 for recurrence-free survival (RFS)] and short survival [11.5 mo vs 23.6 mo, P < 0.001 for overall survival (OS)] in patients with resected pancreatic adenocarcinoma. A low level of HALP was an independent risk factor for early recurrence and short survival irrespective of sex and tumor location. CONCLUSION: Low levels of HALP may be a significant risk factor for RFS and OS in patients with resected pancreatic cancer.

Tumor-infiltrating platelets predict postoperative recurrence and survival in resectable pancreatic neuroendocrine tumor.

BACKGROUND: Platelets have been reported to participate in tumor cell growth, extravasation, epithelial-mesenchymal transition, metastasis, and drug resistance. However, the importance of platelets in pancreatic neuroendocrine tumor (pNET) lacks adequate literature support. The predictive value of tumor-infiltrating platelets (TIPs) in pNET remains unclear. AIM: To investigate the relationship between TIPs and the prognosis of patients with pNET following radical resection. METHODS: In total, 113 patients who had undergone radical surgical resection with a pathologic diagnosis of pNET were enrolled in this study. Immunohistochemical analysis of cluster of differentiation 42b (CD42b) expression in the tumor specimens was performed to determine the presence of TIPs. Univariate and multivariate analyses were used to analyze the prognostic value of TIPs. RESULTS: TIPs were observed in intratumoral areas in 54 patients. Neither basic characteristics nor preoperative platelet-associated indicators showed a significant relationship with the presence of TIPs (all P > 0.05). Patients with positive intratumoral CD42b expression had worse overall survival (P = 0.005) and recurrence-free survival (P < 0.001) than those with negative intratumoral CD42b expression. Multivariate analysis demonstrated that TIPs were independent prognostic factors for overall survival (P = 0.049) and recurrence-free survival (P = 0.003). Nevertheless, platelet count, mean platelet volume, and platelet-to-lymphocyte ratio were not associated with postoperative survival or recurrence in pNET patients (all P > 0.05). CONCLUSION: TIPs are a useful prognostic biomarker for patients with resectable pNET, and their detection represents a promising tool for pNET treatment strategy decisions.

The Loss of SMAD4/DPC4 Expression Associated with a Strongly Activated Hedgehog Signaling Pathway Predicts Poor Prognosis in Resected Pancreatic Cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) progression is mediated by mutations in driver genes and a complex stroma that is mainly dependent on the Sonic hedgehog (Shh) signaling pathway. However, the association between driver genes and Shh-pathway proteins and their potential prognostic significance remain unclear. Methods: We analyzed protein expressions of the KRAS, TP53, SMAD4, and CDKN2A/P16 driver genes and the Shh-pathway molecules, including Shh, glioma-associated oncogene (Gli) 1, Gli2, and smoothened (SMO) by immunohistochemistry using tissue microarrays in 237 patients with resectable PDAC and statistically determined their prognostic significance. Results: SMAD4 lost mutation was associated with shorter survival outcomes [overall survival (OS): Hazard ratio (HR) 1.887, p < 0.001]; recurrence-free survival (RFS): HR 1.886, p < 0.001) and abnormal p53 immunolabeling was associated with poor OS (HR 1.436, p = 0.011) in patients with PDAC. The mutational status of p16 had no effect on patient survival. High levels of SMO and Gli1 expression were associated with poor survival outcomes in both univariate and multivariate analyses. Pearson's χ2 test showed a medium correlation between the SMAD4 lost mutation and Shh (R = 0.343) and Gli1 (R = 0.505) expression levels (p < 0.001). Patients with the SMAD4 lost mutation and high levels of Shh and Gli1 expression showed the poorest survival outcomes (RFS: HR 2.976; OS: HR 3.598; p < 0.001 for both) compared with other patients in the study. Conclusion: Loss of SMAD4 associated with a strongly activated Shh pathway resulted in poor survival outcomes in patients with resected PDAC.

The tumor immune microenvironment in gastroenteropancreatic neuroendocrine neoplasms.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of rare tumors that are increasing in prevalence. The complex tumor immune microenvironment (TIME) plays an important role in tumor development and the response to immunotherapy but is poorly understood. In this review, the components of the TIME are described in detail, including discussion about infiltrating immune cells, the immune checkpoint system, the cytokine and chemokine milieu, and immunomodulatory factors. Moreover, a comparison between TIMEs among different types of GEP-NENs and the interplay among the TIME, tumor cells, and the stromal microenvironment is described. Novel treatment options for GEP-NENs and potential biomarkers for the immune response are also characterized. We provide a comprehensive generalized review of the TIME that can inform GEP-NEN treatment strategies.

Arpin downregulation is associated with poor prognosis in pancreatic ductal adenocarcinoma.

INTRODUCTION: Arpin (Arp2/3 complex inhibitor), a novel protein found in 2013, plays a pivotal role in cell motility and migration. However, the prognostic value of Arpin in pancreatic ductal adenocarcinoma (PDAC) remains unknown. MATERIALS AND METHODS: We analyzed the gene expression of ARPIN using the GEO dataset (GSE71989) and validated the results by immunohistochemistry (IHC) and Western blot in our clinical database. Tissue microarray specimens from 214 patients who underwent curative pancreatectomy for PDAC were used. The tumors that expressed high and low levels of Arpin were compared with patient outcome using Kaplan-Meier curves and the multivariate Cox proportional hazard regression model. IHC was then used in 43 paired primary tumor tissues and metastasis tissues to detect the expression of Arpin. RESULTS: Arpin had low expression in the tumor tissue compared with the paracancerous tissue in PDAC. Patients with low intratumoral Arpin expression had worse overall survival (OS) and recurrence-free survival (RFS) than patients with high expression in the training set (p < 0.001, p < 0.001) and validation set (p < 0.001, p < 0.001). The multivariate analysis revealed that the 8th edition TNM stage and Arpin expression were independent prognostic factors associated with OS and RFS in the training and validation sets, respectively. Arpin had lower expression in the metastasis tissues than in the primary tumors of patients with PDAC (p = 0.048). CONCLUSION: The Arpin level is an independent prognostic factor that can be a potential predictor to aid in the management of PDAC.