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.

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.

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.

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.

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.

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.

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.

A Ki-67 Index to Predict Treatment Response to the Capecitabine/Temozolomide Regimen in Neuroendocrine Neoplasms: A Retrospective Multicenter Study.

OBJECTIVE: The efficacy of the capecitabine/temozolomide (CAPTEM) regimen has been demonstrated in metastatic neuroendocrine neoplasms (NENs), but because of varying response rates among the patients, biomarkers to predict its response are greatly needed. Here, we investigated the clinical utility of a Ki-67 index to predict the CAPTEM regimen objective responses and select patients who could benefit from this regimen. METHODS: Metastatic NENs patients treated with the CAPTEM regimen from 4 high-volume medical centers were selected and grouped in a training and validation cohort. The classification and regression tree (CART) was generated to identify the optimal threshold of Ki-67 for stratifying the patients into different Ki-67 range groups based on their response to the CAPTEM regimen. RESULTS AND CONCLUSIONS: The overall response rate (ORR) and disease control rate of the entire cohort (N = 151) were 26.5 and 76.2%, respectively, with a median progression-free survival (PFS) of 12.0 months. CART analysis showed that patients in the Ki-67 range group 10-40% demonstrated a significantly higher ORR than those in Ki-67 >40 and <10% groups (p < 0.001 in the training cohort and p = 0.036 in the validation cohort). Response to the CAPTEM regimen was not influenced by the expression of O6-methylguanine-DNA methyltransferase or primary tumor location. Multivariate analysis identified the Ki-67 index as the only independent prognostic factor for overall survival (p = 0.031) and PFS (p = 0.006). The proposed Ki-67 index was externally validated and could be used to clinically identify suitable metastatic NENs patients who could achieve an optimal cytoreduction using the CAPTEM regimen.

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.

Development and Validation of a Prognostic Nomogram to Guide Decision-Making for High-Grade Digestive Neuroendocrine Neoplasms.

BACKGROUND: The objective of this study was to develop and validate a nomogram to predict 1-year overall survival (OS) and 2-year OS in patients with high-grade digestive neuroendocrine neoplasms (NENs) as well as to guide selection of subgroups that could benefit from systemic chemotherapy. SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective analysis of 223 patients with NENs of the gut and hepato-biliary-pancreatic system from four centers included in the development cohort. The nomogram was externally validated in a cohort of 90 patients from another one. RESULTS: The final model included lactate dehydrogenase, performance status, stage, Ki67, and site of primary tumor, all of which had a significant effect on OS. The uncorrected C-index was 0.761 for OS, and the bias-corrected C-index was 0.744. Predictions correlated well with observed 1-year and 2-year outcomes (judged by eye). The area under the time-dependent receiver operating characteristic curve at 12 months and 24 months was 0.876 and 0.838, respectively. The nomogram performed well in terms of both discrimination and calibration when applied to the validation cohort, and OS was significantly different between the two groups classified by nomogram score (log-rank p < .001). CONCLUSION: The validated nomogram provided useful prediction of OS, which can be offered for clinicians to improve their abilities to assess patient prognosis, to create clinical risk groups for informing treatment or for patient stratification by disease severity in clinical trials. IMPLICATIONS FOR PRACTICE: The high-grade neuroendocrine neoplasms of the digestive system are rare malignancies with great heterogeneity. An overall survival nomogram was developed and externally validated in this study. Two subgroups were classified by the nomogram score, and platinum-based chemotherapy may not bring clinical benefit for the low-risk patients.

Prognostic Value of the C-Reactive Protein/Lymphocyte Ratio in Pancreatic Cancer.

BACKGROUND: Many inflammatory markers can be used for the prognostication of pancreatic cancer, but which combination of inflammatory factors may be the best remains unclear. This study focused on the potential feasibility of the newly discovered C-reactive protein (CRP)/lymphocyte ratio (CLR) as a prognostic biomarker for patients with pancreatic cancer. METHODS: The study enrolled 997 patients with pancreatic cancer. Six combinations of inflammatory markers, namely, the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR), the CRP/albumin ratio (CAR), the neutrophil/albumin ratio (NAR), the platelet/albumin ratio (PAR), and CLR, were examined to determine which combination offers the highest accuracy for predicting poor survival by receiver operating characteristic curve analysis. The prognostic value of the CLR was analyzed by uni- and multivariate analyses. RESULTS: The newly developed CLR was more accurate than the NLR, PLR, CAR, NAR, and PAR in predicting survival. The optimal cutoff value for the CLR was calculated to be 1.8 for survival. A CLR higher than 1.8 was associated with poor survival in both the univariate (hazard ratio [HR] 2.00; P < 0.001) and multivariate (HR 1.73; P < 0.001) analyses. In addition, a CLR higher than 1.8 was an independent risk factor for patients with stage 2 (HR 1.85; P = 0.001), stage 3 (HR 1.83; P = 0.001), or stage 4 (HR 1.70; P < 0.001) disease. CONCLUSIONS: Pretreatment CLR can be considered a feasible biomarker for the prognostic prediction of pancreatic cancer. An elevated CLR was an independent risk factor for poor survival, with a cutoff value of 1.8.

Prior history of acute pancreatitis predicts poor survival in patients with resectable pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVES: Mounting evidence has suggested that acute pancreatitis (AP) is a risk factor for pancreatic ductal adenocarcinoma (PDAC), but its role in survival in PDAC patients was rarely investigated. The objective was to investigate the association of a history of AP with survival among PDAC patients who underwent surgical resection. METHODS: A retrospective cohort study comprising 632 patients who were diagnosed with resectable PDAC was conducted. Survival was evaluated by history of AP prior to a diagnosis of PDAC using Kaplan-Meier methods and log-rank tests. Multivariate analyses for mortality were estimated using the Cox proportional hazards model. Propensity score matching methods were used to balance the difference of clinical characteristics between patients with and without AP history. RESULTS: The log-rank tests showed that patients with a history of AP had a worse overall survival than those without a history of AP (p = 0.006). The multivariable-adjusted hazard ratio (HR) for mortality comparing participants with AP to those without AP was 1.808 (95% CI: 1.241-2.632, p = 0.002). Patients with a recent history of AP (<2 years), rather than patients with a remote history of AP (≥2 years), were found to have significantly worse survival (p = 0.014) than those without a history of AP. After adjusted for PSM, history of AP remained an independent survival predictor of PDAC following surgical resection. CONCLUSIONS: Our findings indicate that a history of AP, especially a recent history of AP, is associated with poor survival among patients with resectable pancreatic ductal adenocarcinoma.

Resected Pancreatic Cancer With N2 Node Involvement Is Refractory to Gemcitabine-Based Adjuvant Chemotherapy.

Lymphatic metastasis is a major determinant of the outcome of resected pancreatic cancer. Gemcitabine-based adjuvant chemotherapy can improve the outcome of resected pancreatic cancer. However, the efficacy of gemcitabine against pancreatic cancer stratified by nodal involvement is unclear. In this study, patients who had undergone curative resection of pancreatic adenocarcinoma (612 cases) were included. The efficacy of adjuvant gemcitabine-based regimen, stratified by nodal status (negative, positive) or N substage (N0, no nodal involvement; N1, 1-3-node involvement; N2, ≥4-node involvement), was examined. Both the node-negative (hazard ratio [HR] = 0.62, 95% confidence interval [CI], 0.44-0.87, P = .006) and node-positive subgroups (HR = 0.45, 95% CI, 0.33-0.62, P < .001) benefited from gemcitabine-based adjuvant chemotherapy. Patients with N0 (ie, the node-negative subgroup) or N1 (HR = 0.36, 95% CI, 0.25-0.52, P < .001) disease benefited from gemcitabine-based chemotherapy. However, patients with N2 tumors (HR = 0.95, 95% CI, 0.50-1.78, P = .867) had poor response to gemcitabine-based treatment. Therefore, we postulate that resected pancreatic cancer with N2 node involvement is refractory to gemcitabine-based adjuvant chemotherapy. A more intensive adjuvant regimen may be required for N2 subgroup patients.

HNF-1a promotes pancreatic cancer growth and apoptosis resistance via its target gene PKLR.

Pancreatic ductal adenocarcinoma is one of the deadliest malignant tumors, and many genes play important roles in its development. The hepatocyte nuclear factor-1a (HNF-1a) gene encodes HNF-1a, which is a transcriptional activator. HNF-1a regulates the tissue-specific expression of multiple genes, especially in pancreatic islet cells and in the liver. However, the role of the HNF-1a gene in the development of pancreatic cancer is still unclear. Here, we used immunohistochemical staining and real-time PCR to analyze HNF-1a expression in pancreatic cancer tissue. Stable cell lines with HNF-1a knockdown or overexpression were established to analyze the role of HNF-1a in pancreatic cancer cell proliferation and apoptosis by colony formation assay and flow cytometry. We also analyzed the L-type pyruvate kinase (PKLR) promoter sequence to identify the regulatory effect of HNF-1a on PKLR transcription and confirmed the HNF-1a binding site in the PKLR promoter via a chromatin immunoprecipitation assay. HNF-1a was found to be overexpressed in pancreatic cancer and promoted proliferation while inhibiting apoptosis in pancreatic cancer cells. PKLR was identified as the downstream target gene of HNF-1a and binding of HNF-1a at two sites in PKLR (-1931/-1926 and -966/-961) regulated PKLR transcription. In conclusion, HNF-1a is overexpressed in pancreatic cancer, and the transcription factor HNF-1a can promote pancreatic cancer growth and apoptosis resistance via its target gene PKLR.

The role of necroptosis in cancer biology and therapy.

Apoptosis resistance is to a large extent a major obstacle leading to chemotherapy failure during cancer treatment. Bypassing the apoptotic pathway to induce cancer cell death is considered to be a promising approach to overcoming this problem. Necroptosis is a regulated necrotic cell death modality in a caspase-independent fashion and is mainly mediated by Receptor-Interacting Protein 1 (RIP1), RIP3, and Mixed Lineage Kinase Domain-Like (MLKL). Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis resistance and may trigger and amplify antitumor immunity in cancer therapy.The role of necroptosis in cancer is complicated. The expression of key regulators of the necroptotic pathway is generally downregulated in cancer cells, suggesting that cancer cells may also evade necroptosis to survive; however, in certain types of cancer, the expression level of key mediators is elevated. Necroptosis can elicit strong adaptive immune responses that may defend against tumor progression; however, the recruited inflammatory response may also promote tumorigenesis and cancer metastasis, and necroptosis may generate an immunosuppressive tumor microenvironment. Necroptosis also reportedly promotes oncogenesis and cancer metastasis despite evidence demonstrating its antimetastatic role in cancer. In addition, necroptotic microenvironments can direct lineage commitment to determine cancer subtype development in liver cancer. A plethora of compounds and drugs targeting necroptosis exhibit potential antitumor efficacy, but their clinical feasibility must be validated.Better knowledge of the necroptotic pathway mechanism and its physiological and pathological functions is urgently required to solve the remaining mysteries surrounding the role of necroptosis in cancer. In this review, we briefly introduce the molecular mechanism and characteristics of necroptosis, the interplay between necroptosis and other cell death mechanisms, crosstalk of necroptosis and metabolic signaling and detection methods. We also summarize the intricate role of necroptosis in tumor progression, cancer metastasis, prognosis of cancer patients, cancer immunity regulation, cancer subtype determination and cancer therapeutics.

Surgical Resection for Metastatic Tumors in the Pancreas: A Single-Center Experience and Systematic Review.

BACKGROUND: Metastatic lesion to the pancreas accounts for approximately 2% of pancreatic neoplasms. There is no prospective, randomized or case-controlled study evaluating the role of pancreatic metastasectomy. METHODS: The PubMed, EMBASE, and Cochrane Library electronic databases were searched for studies published between January 1, 2001 and December 31, 2017. Studies with five or more patients who received pancreatic metastasectomy and data from our institution (29 patients) were included. The Kaplan-Meier method was used for survival analysis. RESULTS: A total of 414 patients from 20 institutions who underwent pancreatic resections were included. Of the reported 31 kinds of primary neoplasms, renal-cell carcinoma (RCC) comprised the most (54.3%). At the time of diagnosis, although 40.3% patients were asymptomatic, abdominal pain (34.8%) and jaundice (20.6%) were relatively common. As for surgical type, pancreatoduodenectomy, total pancreatectomy, distal pancreatectomy, and enucleation took up 37.9%, 11.4%, 43.5%, and 7.2% respectively. The mortality and morbidity rates were 1.4% and 48.3% respectively. Patients with symptoms at the time of diagnosis had significantly shorter survival compared with asymptomatic patients (p = 0.017). Those with RCC as primary tumor had significantly longer survival compared with non-RCC patients (p < 0.001). Positive margin also predicts worse prognosis (p = 0.035). CONCLUSIONS: Pancreatic metastasectomy is safe and associated with acceptable short- and intermediate-term results. In the conditions of RCC as the primary tumor, being asymptomatic, or negative resection margin, a better prognosis after resection can be achieved.

AJCC 7th edition staging classification is more applicable than AJCC 8th edition staging classification for invasive IPMN.

BACKGROUND: Both the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging systems have been introduced for pancreatic adenocarcinoma. However, the applicability of these classifications for invasive intraductal papillary mucinous neoplasms (IPMN) has not been systematically examined. METHODS: Patients with invasive IPMN were retrieved from a cohort of 18 geographical sites (1973-2014 varying) in the Surveillance, Epidemiology, and End Results (SEER) cancer registry. The 7th and 8th editions of the AJCC staging were compared. Survival rates and multivariate analyses were computed. RESULTS: In total, 1216 patients with resected invasive IPMN were included. A major difference between the 7th and 8th systems is the definition of stage IIA (7th, beyond the pancreas without involvement of major arteries; 8th, maximum tumor diameter > 4 cm). The hazard ratio (HR) of stage IIA disease (versus stage IA, HR = 2.33, P < 0.001) was higher than that of stage IB disease (HR = 1.48, P = 0.087) by the 7th edition classification, whereas the HR of stage IIA disease (HR = 1.26, P = 0.232) was even lower than that of stage IB disease (HR = 1.48, P = 0.040) by the 8th edition classification. In addition, for the 8th edition staging system, tumor size was not a predictor of survival in patients with resectable tumor > 2 cm (size > 4 cm versus > 2 ≤ 4 cm, HR = 0.91, P = 0.420). CONCLUSIONS: The AJCC 7th edition staging classification is more applicable than the 8th edition classification for invasive IPMN.

Anergic natural killer cells educated by tumor cells are associated with a poor prognosis in patients with advanced pancreatic ductal adenocarcinoma.

INTRODUCTION: Natural killer cells (NK) are often believed to play a positive role in the antitumor immune response. However, this is not the case for patients with advanced pancreatic cancer. This study was performed to determine the unique subtype of "educated" NK cells and their prognostic value in patients with advanced pancreatic cancer. METHODS: We divided 378 eligible patients into a derivation cohort (September 2010 to December 2014, n = 239) and a validation cohort (January 2015 to April 2016, n = 139). Flow cytometry was performed to analyze NK cells. Enzyme-linked immunosorbent assay was used to detect interleukin-2 (IL-2), interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) production. The Kaplan-Meier method and the Cox proportional hazards model were used. RESULTS: Survival analysis showed that a high density of NK cells accompanied by a high neutrophil-to-lymphocyte ratio was associated with reduced overall survival in both the derivation and validation cohorts. Multivariable analysis also showed that high NK infiltration (HR 1.45, 95% CI 1.17 to 1.79, p = 0.001) was an independent prognostic factor. In these patients, high NK infiltration was associated with reduced levels of IL-2, IFN-γ and TNF-α, although only IFN-γ reached statistical significance, which accounted for this unique phenomenon. DISCUSSION: Natural killer cells in patients with advanced pancreatic cancer are a unique subtype with anergic features. A high density of NKs predicts poor survival in these patients, possibly because an active inflammatory response and reduced secretion of IL-2, IFN-γ and TNF-α inhibit NK activation.