The GFPT2-O-GlcNAcylation-YBX1 axis promotes IL-18 secretion to regulate the tumor immune microenvironment in pancreatic cancer.

The immunosuppressive microenvironment caused by several intrinsic and extrinsic mechanism has brought great challenges to the immunotherapy of pancreatic cancer. We identified GFPT2, the key enzyme in hexosamine biosynthesis pathway (HBP), as an immune-related prognostic gene in pancreatic cancer using transcriptome sequencing and further confirmed that GFPT2 promoted macrophage M2 polarization and malignant phenotype of pancreatic cancer. HBP is a glucose metabolism pathway leading to the generation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which is further utilized for protein O-GlcNAcylation. We confirmed GFPT2-mediated O-GlcNAcylation played an important role in regulating immune microenvironment. Through cellular proteomics, we identified IL-18 as a key downstream of GFPT2 in regulating the immune microenvironment. Through CO-IP and protein mass spectrum, we confirmed that YBX1 was O-GlcNAcylated and nuclear translocated by GFPT2-mediated O-GlcNAcylation. Then, YBX1 functioned as a transcription factor to promote IL-18 transcription. Our study elucidated the relationship between the metabolic pathway of HBP in cancer cells and the immune microenvironment, which might provide some insights into the combination therapy of HBP vulnerability and immunotherapy in pancreatic cancer.

Suppression of pancreatic cancer proliferation through TXNIP-mediated inhibition of the MAPK signaling pathway.

Thioredoxin-interacting protein (TXNIP) is a crucial thioredoxin-binding protein that is recognized as a tumor suppressor in diverse malignancies, such as breast cancer, lung cancer, hepatocellular carcinoma, and thyroid cancer. However, the specific role and molecular mechanisms of TXNIP in the pathogenesis and progression of pancreatic cancer cells have not been determined. In this study, we investigate the relationship between TXNIP expression and overall survival prognosis in pancreatic cancer patients. Mechanistic studies are conducted to reveal the role of TXNIP in pancreatic cancer cell proliferation, migration, and regulation during malignancy. Our findings indicate that patients with high TXNIP expression have a more favorable prognosis. In vitro experiments with pancreatic cell lines show that overexpression of TXNIP suppresses the proliferation and migration of pancreatic cancer cells. Furthermore, we find that TXNIP inhibits the activation of the MAPK signaling pathway, thereby decreasing the malignant potential of pancreatic cancer. In conclusion, our study reveals TXNIP as a promising new predictive marker and therapeutic target for pancreatic cancer.

Knockdown of TACC3 inhibits tumor cell proliferation and increases chemosensitivity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant digestive tract tumor with limited clinical treatments. Transforming acidic coiled-coil-containing protein 3 (TACC3) is a component of the centrosome axis and a member of the TACC family, which affect mitosis and regulate chromosome stability and are involved in tumor development and progression. However, the role of TACC3 in PDAC remains elusive. In this study, by exploiting the TCGA database, we found that high TACC3 expression in PDAC is associated with poor prognosis. shRNA-mediated TACC3 knockdown caused S phase arrest of the cell cycle and inhibited proliferation in PDAC cell lines. Through RNA sequencing and protein co-immunoprecipitation combined with mass spectrometry, KIF11 was identified as a protein that interacts with TACC3. TACC3 stabilizes and regulates KIF11 protein expression levels in PDAC cells through physical interaction. Knockdown of TACC3 or KIF11 resulted in abnormal spindle formation during cell division both in vitro and in vivo. Pharmacological inhibition of TACC3 or KIF11 can suppress tumor cell proliferation and promote apoptosis. Our studies further demonstrated that high expression of TACC3 and KIF11 mediated the resistance of PDAC to gemcitabine, and deficiency of TACC3 or KIF11 increased the sensitivity of PDAC cells to chemotherapy. In conclusion, our study reveals the fundamental role of TACC3 expression in PDAC cell proliferation and chemoresistance, suggesting that TACC3 can be used as a molecular marker to evaluate the prognosis of PDAC.

Deubiquitinating PABPC1 by USP10 upregulates CLK2 translation to promote tumor progression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant with limited treatment options. Deubiquitinases (DUBs), which cleave ubiquitin on substrates, can regulate tumor progression and are appealing therapeutic targets, but there are few related studies in PDAC. In our study, we screened the expression levels and prognostic value of USP family members based on published databases and selected USP10 as the potential interventional target in PDAC. IHC staining of the PDAC microarray revealed that USP10 expression was an adverse clinical feature of PDAC. USP10 promoted tumor growth both in vivo and in vitro in PDAC. Co-IP experiments revealed that USP10 directly interacts with PABPC1. Deubiquitination assays revealed that USP10 decreased the K27/29-linked ubiquitination level of the RRM2 domain of PABPC1. Deubiquitinated PABPC1 was able to couple more CLK2 mRNA and eIF4G1, which increased the translation efficiency. Replacing PABPC1 with a mutant that could not be ubiquitinated impaired USP10 knock-down-mediated tumor suppression in PDAC. Targeting USP10 significantly delayed the growth of cell-derived xenograft and patient-derived xenograft tumors. Collectively, our study first identified USP10 as the DUB of PABPC1 and provided a rationale for potential therapeutic options for PDAC with high USP10 expression.

Inhibition of epithelial-to-mesenchymal transition augments antitumor efficacy of nanotherapeutics in pancreatic ductal adenocarcinoma.

Intrinsic drug resistance mechanisms of tumor cells often reduce intracellular drug concentration to suboptimal levels. Epithelial-to-mesenchymal transition (EMT) is a pivotal process in tumor progression and metastasis that confers an aggressive phenotype as well as resistance to chemotherapeutics. Therefore, it is imperative to develop novel strategies and identify new targets to improve the overall efficacy of cancer treatment. We developed SN38 (active metabolite of irinotecan)-assembled glycol chitosan nanoparticles (cSN38) for the treatment of pancreatic ductal adenocarcinoma (PDAC). Furthermore, cSN38 and the TGF-ß1 inhibitor LY364947 formed composite nanoparticles upon self-assembly (cSN38 + LY), which obviated the poor aqueous solubility of LY364947 and enhanced drug sensitivity. The therapeutic efficacy of cSN38 + LY nanotherapeutics was studied in vitro and in vivo using suitable models. The cSN38 nanoparticles exhibited an antitumor effect that was significantly attenuated by TGF-ß-induced EMT. The cellular uptake of SN38 was impeded during EMT, which affected the therapeutic efficacy. The combination of LY364947 and cSN38 markedly enhanced the cellular uptake of SN38, increased cytotoxic effects, and inhibited EMT in PDAC cells in vitro. Furthermore, cSN38 + LY significantly inhibited PDAC xenograft growth in vivo. The cSN38 + LY nanoparticles increased the therapeutic efficacy of cSN38 via repressing the EMT of PDAC cells. Our findings provide a rationale for designing nanoscale therapeutics to combat PDAC.

Novel strategy for oncogenic alteration-induced lipid metabolism reprogramming in pancreatic cancer.

The pathogenesis of pancreatic cancer involves substantial metabolic reprogramming, resulting in abnormal proliferation of tumor cells. This tumorigenic reprogramming is often driven by genetic mutations, such as activating mutations of the KRAS oncogene and inactivating or deletions of the tumor suppressor genes SMAD4, CDKN2A, and TP53, which play a critical role in the initiation and development of pancreatic cancer. As a normal cell gradually develops into a cancer cell, a series of signature characteristics are acquired: activation of signaling pathways that sustain proliferation; an ability to resist growth inhibitory signals and evade apoptosis; and an ability to generate new blood vessels and invade and metastasize. In addition to these features, recent research has revealed that metabolic reprogramming and immune escape are two other novel characteristics of tumor cells. The effect of the interactions between tumor and immune cells on metabolic reprogramming is a key factor determining the antitumor immunotherapy response. Lipid metabolism reprogramming, a feature of many malignancies, not only plays a role in maintaining tumor cell proliferation but also alters the tumor microenvironment by inducing the release of metabolites that in turn affect the metabolism of normal immune cells, ultimately leading to the attenuation of the antitumor immune response and resistance to immunotherapy. Pancreatic cancer has been found to have substantial lipid metabolism reprogramming, but the mechanisms remain elusive. Therefore, this review focuses on the mechanisms regulating lipid metabolism reprogramming in pancreatic cancer cells to provide new therapeutic targets and aid the development of new therapeutic strategies for pancreatic cancer.

Tissue-resident CXCR4+ macrophage as a poor prognosis signature promotes pancreatic ductal adenocarcinoma progression.

Macrophage is an essential part of the tumor immune microenvironment of pancreatic ductal adenocarcinoma. In our study, we explored the CXCR4+ macrophages subset on its prognosis value, immune profile and distinct function in pancreatic cancer progression. Specimens from 102 postoperative pancreatic patients were analyzed by flow cytometry or immune-fluorescence, and the prognostic value of CXCR4+ macrophages infiltration was further determined by Cox regression. In silico analysis on TCGA, ICGC database and single-cell sequencing of pancreatic ductal adenocarcinoma further validated our findings. We found that high CXCR4+ macrophages infiltration was associated with poor overall survival (P < .01) and disease-free survival (P < .05) as an independent factor. CXCR4+ macrophages exhibited an M2 protumor phenotype with high expression of CD206. The function of CXCR4+ macrophages was further analyzed in the murine orthotopic PDAC model with its tumor promotion effect and inhibition of CD8+ T cells. Mechanistic and RNA-seq analysis showed that CXCR4+ macrophages participated in extracellular matrix remodeling procedures and especially secreted SPARC through CXCR4/PI3K/Akt pathway promoting tumor proliferation and migration. Our study reveals that CXCR4+ macrophages infiltration is an indicator of poor prognosis of PDAC and targeting these cells was potentially crucial in immunotherapy of PDAC.

Focus on mast cells in the tumor microenvironment: Current knowledge and future directions.

Mast cells (MCs) are crucial cells participating in both innate and adaptive immune processes that play important roles in protecting human health and in the pathophysiology of various diseases, such as allergies, cardiovascular diseases, and autoimmune diseases. In the context of tumors, MCs are a non-negligible population of immune cells in the tumor microenvironment (TME). In most tumor types, MCs accumulate in both the tumor tissue and the surrounding tissue. MCs interact with multiple components of the TME, affecting TME remodeling and the tumor cell fate. However, controversy persists regarding whether MCs contribute to tumor progression or trigger an anti-tumor immune response. This review focuses on the context of the TME to explore the specific properties and functions of MCs and discusses the crosstalk that occurs between MCs and other components of the TME, which affect tumor angiogenesis and lymphangiogenesis, invasion and metastasis, and tumor immunity through different mechanisms. We also anticipate the potential role of MCs in cancer immunotherapy, which might expand upon the success achieved with existing cancer therapies.

Special issue "The advance of solid tumor research in China": Prediction of Sunitinib efficacy using computed tomography in patients with pancreatic neuroendocrine tumors.

Clinically effective methods to predict the efficacy of sunitinib, for patients with metastatic or locally advanced pancreatic neuroendocrine tumors (panNET) are scarce, making precision treatment difficult. This study aimed to develop and validate a computed tomography (CT)-based method to predict the efficacy of sunitinib in patients with panNET. Pretreatment CT images of 171 lesions from 38 patients with panNET were included. CT value ratio (CT value of tumor/CT value of abdominal aorta from the same patient) and radiomics features were extracted for model development. Receiver operating curve (ROC) with area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the proposed model. Tumor shrinkage of >10% at first follow-up after sunitinib treatment was significantly associated with longer progression-free survival (PFS; P < .001) and was used as the major treatment outcome. The CT value ratio could predict tumor shrinkage with AUC of 0.759 (95% confidence interval [CI], 0.685-0.833). We then developed a radiomics signature, which showed significantly higher AUC in training (0.915; 95% CI, 0.866-0.964) and validation (0.770; 95% CI, 0.584-0.956) sets than CT value ratio. DCA also confirmed the clinical utility of the model. Subgroup analysis showed that this radiomics signature had a high accuracy in predicting tumor shrinkage both for primary and metastatic tumors, and for treatment-naive and pretreated tumors. Survival analysis showed that radiomics signature correlated with PFS (P = .020). The proposed radiomics-based model accurately predicted tumor shrinkage and PFS in patients with panNET receiving sunitinib and may help select patients suitable for sunitinib treatment.

Neoadjuvant therapy alters the immune microenvironment in pancreatic cancer.

Pancreatic cancer has an exclusive inhibitory tumor microenvironment characterized by a dense mechanical barrier, profound infiltration of immunosuppressive cells, and a lack of penetration of effector T cells, which constitute an important cause for recurrence and metastasis, resistance to chemotherapy, and insensitivity to immunotherapy. Neoadjuvant therapy has been widely used in clinical practice due to its many benefits, including the ability to improve the R0 resection rate, eliminate tumor cell micrometastases, and identify highly malignant tumors that may not benefit from surgery. In this review, we summarize multiple aspects of the effect of neoadjuvant therapy on the immune microenvironment of pancreatic cancer, discuss possible mechanisms by which these changes occur, and generalize the theoretical basis of neoadjuvant chemoradiotherapy combined with immunotherapy, providing support for the development of more effective combination therapeutic strategies to induce potent immune responses to tumors.

TGF-ß1-induced RAP2 regulates invasion in pancreatic cancer.

Pancreatic cancer is highly lethal due to its aggressive invasive properties and capacity for metastatic dissemination. Additional therapeutic targets and effective treatment options for patients with tumours of high invasive capacity are required. Ras-related protein-2a (RAP2) is a member of the GTP-binding proteins. RAP2 has been reported to be widely upregulated in many types of cancers via regulating cytoskeleton reorganization, cell proliferation, migration, and adhesion, as well as inflammation. As a member of the RAS oncogene family, which has been demonstrated to drive pancreatic cancer oncogenesis and many other malignancies, the physiological roles of RAP2 in pancreatic cancer have seldom been discussed. In the present study, we explored the correlation between RAP2 expression and the prediction of overall survival of pancreatic cancer patients. Mechanistic studies were carried out to shed light on the role of RAP2 in pancreatic cancer invasion and how RAP2 is regulated in the invasive process. Our results demonstrated that patients with higher RAP2 expression showed unfavourable prognoses. studies demonstrated that silencing of inhibited the invasion of pancreatic cancer cells. Moreover, our results demonstrated that transforming growth factor-ß1 (TGF-ß1), an inducer of the metastatic potential of pancreatic cancer cells, regulates the expression of RAP2 via the transcription factor c-Myc. In conclusion, the present study uncovered RAP2 as a novel predictive marker and therapeutic target for pancreatic cancer.

Hypoxia-reprogrammed regulatory group 2 innate lymphoid cells promote immunosuppression in pancreatic cancer.

BACKGROUND: Previously, we uncovered a patient subgroup with highly malignant pancreatic cancer with serum markers CEA+/CA125+/CA19-9 ≥ 1000 U/mL (triple-positive, TP). However, the underlying immunosuppressive mechanism in the tumor immune microenvironment (TIME) of this subgroup is still unknown. METHODS: Human tissues were analyzed by flow cytometry, mass cytometry, and immunofluorescence staining. Mouse pancreatic ILC2s were expanded in vivo and used for RNA sequencing, chromatin immunoprecipitation (ChIP), and chemotaxis assays. FINDINGS: Through microarray data, we identified the accumulation of the hypoxia-induced factor-1α (HIF-1α) pathway in these TP patients. Via flow and mass cytometry, we discovered that a special subset of ILC2s were highly infiltrated in TP patients. Under the hypoxia microenvironment, ILC2s were found undergo a transition to a IL10+ regulatory phenotype, we named ILCregs which was correlated with pancreatic ductal adenocarcinoma (PDAC) progression. Further, neoadjuvant chemotherapy could ameliorate hypoxic tumor microenvironments so that significantly reverse the regulatory phenotype of ILCregs. Moreover, most tumor ILC2 were CD103-, which indicated its circulatory origin. The expression of Ccr2 was significantly upregulated on mouse ILCregs, and these cells selectively migrated to CCL2. INTERPRETATION: Our results indicate that the hypoxia microenvironment creates an immunosuppressive TIME by inducing ILCregs from a population of circulating group 2 ILCs in TP PDAC patients. FUNDING: This study was jointly supported by the National Natural Science Foundation of China (U21A20374, 82173091, and 81701630).

Innate Lymphoid Cells: Emerging Players in Pancreatic Disease.

Common pancreatic diseases have caused significant economic and social burdens worldwide. The interstitial microenvironment is involved in and plays a crucial part in the occurrence and progression of pancreatic diseases. Innate lymphoid cells (ILCs), an innate population of immune cells which have only gradually entered our visual field in the last 10 years, play an important role in maintaining tissue homeostasis, regulating metabolism, and participating in regeneration and repair. Recent evidence indicates that ILCs in the pancreas, as well as in other tissues, are also key players in pancreatic disease and health. Herein, we examined the possible functions of different ILC subsets in common pancreatic diseases, including diabetes mellitus, pancreatitis and pancreatic cancer, and discussed the potential practical implications of the relevant findings for future further treatment of these pancreatic diseases.

SIGLEC15 amplifies immunosuppressive properties of tumor-associated macrophages in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) usually presents infrequent infiltration of T lymphocytes. The known immune-checkpoint inhibitors to date focus on activating T cells and manifest limited effectiveness in PDAC. SIGLEC15 was identified as a novel tumor-associated macrophage (TAM)-related immune-checkpoint in other cancer types, while its immunosuppressive role and clinical significance remained unclear in PDAC. In our study, SIGLEC15 presented immunosuppressive relevance in PDAC via bioinformatic analysis and expressed on TAM and PDAC cells. SIGLEC15+ TAM, rather than SIGLEC15+ PDAC cells or SIGLEC15- TAM, correlated with poor prognosis and immunosuppressive microenvironment in the PDAC microarray cohort. Compared with SIGLEC15- TAM, SIGLEC15+ TAM presented an M2-like phenotype that could be modulated by SIGLEC15 in a tumor cell-dependent manner. In mechanism, SIGLEC15 interacted with PDAC-expressed sialic acid, preferentially α-2, 3 sialic acids, to stimulate SYK phosphorylation in TAM, which further promoted its immunoregulatory cytokines and chemokines production. In vivo, SIGLEC15+ TAM also presented an M2-like phenotype, accelerated tumor growth, and facilitated immunosuppressive microenvironment, which was greatly abolished by SYK inhibitor. Our study highlighted a novel M2-promoting function of SIGLEC15 and strongly suggested SIGLEC15 as a potential immunotherapeutic target for PDAC.

Body Composition and Response and Outcome of Neoadjuvant Treatment for Pancreatic Cancer.

To assess the correlation of body composition with the response and outcome of neoadjuvant treatment (NAT) in patients with pancreatic ductal adenocarcinoma (PDAC). One hundred and nineteen PDAC patients underwent curative resection after NAT. Computed tomography scans of the third lumbar vertebra were used to assess the body composition of these patients before and after NAT. Three distinct wasting phenotypes were identified during NAT, with 51 patients (42.9%) developing muscle and fat wasting (MFW), 17 patients (14.3%) developing fat-only wasting (FW), and 51 patients (42.9%) having no wasting (NW). The response rate was higher in the NW phenotype than in the MFW and FW phenotypes (P = 0.007). In univariate and multivariate analyses, histological grade, sarcopenia before NAT, and MFW during NAT were associated with decreased overall survival (OS). Sarcopenia before NAT and MFW during NAT were associated with decreased disease-free survival (DFS). Body composition was associated with the response and outcome of patients undergoing NAT for PDAC. The response rate was higher in patients having NW during NAT. Sarcopenia before NAT and MFW during NAT were associated with decreased OS and DFS.

Predictive Values of Preoperative Markers for Resectable Pancreatic Body and Tail Cancer Determined by MDCT to Detect Occult Metastases.

BACKGROUND: To evaluate the clinical value of preoperative markers in predicting occult metastases in resectable pancreatic body and tail cancer judged by a recent multidetector computed tomography (MDCT) scan of the abdomen. METHODS: The data from a retrospective collected database from 2010 to 2019 with 699 patients who had MDCT scan predicted resectable mass in pancreatic body and tail and were pathological confirmed as adenocarcinoma after surgery. Receiver operating characteristic (ROC) curve was plotted for serum CA19-9, CA125, CEA and tumor size measured by MDCT. The optimal cut-off point-related sensitivity and specificity were calculated, respectively. RESULTS: Occult metastases were found in 73 (73/699, 10.4%) pancreatic body and tail cancer patients underwent exploration. The area under curve (AUC) for CA19-9, CA125, CEA and tumor size were 0.624, 0.733, 0.561 and 0.697, respectively. The optimal cut-off for CA19-9, CA125 and tumor size is 226 U/ml, 22.1 U/ml and 3.3 cm, respectively. The sensitivity and specificity of CA19-9 for predicting occult metastases were 67.1% and 60.4%, 72.6% and 64.7% for CA125, 80.8% and 51.4% for tumor size. CONCLUSION: CA125 is superior to CA19-9 and tumor size for predicting occulting metastases in MDCT scan suggested resectable pancreatic body and tail cancer. The high level of CA125 (≥ 22.1 U/ml) is regarded as high risk for occulting metastases, and laparoscopy should be applied for these patients.

Mutation and Expression of Gene YY1 in Pancreatic Neuroendocrine Tumors and Its Clinical Significance.

OBJECTIVE: The clinical significance of the YY1 gene mutation and expression in pancreatic neuroendocrine tumors (PNETs) remains unknown. Therefore, this study aimed to comprehensively analyze the somatic mutation of YY1 in the different subtypes of PNETs. METHODS: A total of 143 PNETs were assessed by Sanger sequencing to identify the somatic mutation of YY1 gene in various subtypes of PNETs. YY1 protein expression was examined in 103 PNETs by immunohistochemical staining and western blot. Gene mutation and its protein expression were correlated with clinicopathologic features. RESULTS: A recurrent mutation (chr14:100743807C>G) in the YY1 gene was identified in 15 of 83 insulinomas (18%) and in only 1 of 60 noninsulinoma PNETs (1.7%) (P = .0045). The YY1 mutation was not found in MEN1-associated insulinomas. The YY1 mutation in insulinomas was correlated with older age and lower serum glucose levels (age, 57 vs 42.5 years, P = .006; blood glucose, 25.2 vs 33.6 mg/dL, P = .008). YY1 protein expression was found in 100 of 103 PNETs, although expression was weaker in metastases than in localized tumors (P = .036). The stronger expression of YY1 protein was associated with favorable disease-free survival of patients with PNETs (log-rank, P = .011; n = 70). Multivariable statistical analysis showed that YY1 protein expression could be an independent predictor of prognosis. CONCLUSION: The hotspot YY1 mutation mostly occurred in insulinomas and rarely in noninsulinoma PNETs. The stronger YY1 protein expression was correlated with the better prognosis of PNETs patients.

High GFPT1 expression predicts unfavorable outcomes in patients with resectable pancreatic ductal adenocarcinoma.

BACKGROUND: Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the first rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which plays a pivotal role in the progression of pancreatic ductal adenocarcinoma (PDAC). Therefore, we investigated the prognostic significance of GFPT1 expression in patients with resectable PDAC. METHODS: We analyzed public datasets to compare GFPT1 expression in tumor tissues and normal/adjacent pancreatic tissues. We measured the relative GFPT1 expression of 134 resected PDAC specimens in our institution, using real-time polymerase chain reaction (PCR). Survival was compared between high and low GFPT1 expression groups using Kaplan-Meier curves and log-rank tests. Multivariate analyses were estimated using Cox regression and logistic regression models. RESULTS: GFPT1 is generally upregulated in PDAC tissues, according to the analysis of public datasets. The data from our institution shows that high GFPT1 expression was correlated with a high rate of lymph node (LN) metastasis (p = 0.038) and was an independent risk factor for LN metastasis (odds ratio (OR) = 3.14, 95% confidence interval (CI) = 1.42 to 6.90, P = 0.005). High GFPT1 expression was significantly associated with poor overall survival (OS; P = 0.019) in patients with resected PDAC. The multivariable-adjusted hazard ratio (HR) for mortality when comparing patients with high and low GFPT1 expression was 2.54 (95% CI = 1.35 to 4.79, P = 0.004). CONCLUSIONS: GFPT1 is generally upregulated in PDAC tissue and is associated with a high risk of LN metastasis and an unfavorable outcome in patients with resectable PDAC, suggesting its crucial role in PDAC progression.

Fibrinogen/Albumin Ratio as a Promising Marker for Predicting Survival in Pancreatic Neuroendocrine Neoplasms.

BACKGROUND: The fibrinogen/albumin ratio (FAR) has been widely reported to be a possible biomarker for predicting prognosis in several types of tumors, but the prognostic value of the FAR in pancreatic neuroendocrine neoplasms (Pan-NENs) has not been systematically studied. PATIENTS AND METHODS: In total, 324 patients with Pan-NENs were recruited. The patients were divided into 2 subgroups according to the FAR cutoff value, and clinicopathological characteristics of the 2 subgroups were compared. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The prognostic value of the FAR was analyzed in univariate and multivariate analyses. RESULTS: The optimal cutoff value for the FAR was calculated to be 0.08 for OS. The patients with a FAR ≥0.08 had higher proportions of nonfunctioning tumors, Pan-NECs, grade 3 tumors, and stage IV tumors than those with a FAR <0.08. In the univariate analysis, a FAR ≥ 0.08 was associated with poor OS (hazard ratio (HR) = 2.37, P < 0.001) and PFS (HR = 2.37, P < 0.001). In the multivariate analysis, a FAR ≥0.08 was an independent risk factor for poor OS (HR = 4.70, P < 0.001) and PFS (HR = 1.80, P = 0.006). CONCLUSION: The pretreatment FAR, which includes fibrinogen and albumin, was a feasible and predictive biomarker for prognosis in patients with Pan-NENs. An elevated FAR, based on a cutoff value of 0.08, was an independent risk factor for poor OS and PFS.