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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. 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. 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

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.

Purpose To evaluate the perioperative complications of patients with cervical cancer who are treated with robot-assisted radical hysterectomy (RRH) and to further evaluate the safety of patients undergoing NACT. Methods A total of 805 consecutive cervical cancer patients undergoing RRH were involved in this report. Their clinical characteristics were retrieved from hospital medical records. Perioperative complications were subdivided into intraoperative and postoperative complications, which were graded according to the Clavien-Dindo classification (CDC), and the complications of grade III and above were defined as severe complications. Furthermore, the two-level logistic regression model was used to estimate the risk factors of perioperative and severe complications and to further confirm the relationship between NACT and perioperative and severe complications. Results The perioperative complication rate and severe complications were 45.09% and 7.83%, respectively. Poorly differentiated tumor and NACT were identified as independent risk factors for perioperative complications by multifactor analysis. Furthermore, we concentrated on the relations between NACT and complications. The risk of perioperative complications of the group with NACT (OR = 11.08, 95% CI: 5.70-21.54) was significantly higher than the group without NACT, especially in postoperative complications (OR=17.65, 95% CI: 8.63-36.08), even after adjusting confounding factors. However, there was no statistically significant difference in terms of severe complications (OR=1.68, 95% CI: 0.64-4.41) and intraoperative complications (OR=0.51, 95% CI: 0.18-1.41). Moreover, as the times of NACT increase, the impact on perioperative complications is more pronounced. A similar trend was observed in postoperative complications, while this statistical difference was still not observed in intraoperative and severe complications. Conclusion This result demonstrates the feasibility and safety of RRH of cervical carcinoma after NACT in generally, since it only causes mild complications, not severe complications.

ObjectiveThis study retrospectively characterized the immune infiltrating profile in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs).MethodsTumor 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.ResultsTINs 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.ConclusionIntratumoral 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.

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.

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.

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.

Purpose: The systemic inflammation response index (SIRI), based on peripheral neutrophil, monocyte, and lymphocyte counts, was recently emerged and used as a novel tool in predicting prognosis in different types of cancer. Our aim was to investigate the clinical significance of preoperative SIRI in patients with resectable pancreatic ductal adenocarcinoma (PDAC). Materials and methods: The SIRI was developed in a training cohort of 371 PDAC patients undergoing radical surgery between 2010 and 2013 and validated in a validation cohort of 310 patients from 2014 to 2015. Baseline clinicopathologic characteristics, preoperative laboratory parameters and follow-up information were collected. The optimal cutoff value of SIRI was determined by receiver operating characteristic curve. Univariate and multivariate analysis were performed to analyze the prognostic value of SIRI. Results: The optimal cutoff value of SIRI stratified patients into low SIRI group (≤0.69) and high SIRI group (>0.69). Survival analysis showed that the median overall survival (OS) and recurrence-free survival (RFS) were significantly better in patients with low SIRI. The SIRI was an independent predictor of OS and RFS in multivariate analysis. In addition, SIRI remained its prognostic significance both in patients with early-stage diseases and in patients with normal carbohydrate antigen 19-9 levels. High SIRI indicated poor treatment response for patients who received postoperative adjuvant chemotherapy. Conclusion: Preoperative SIRI was an independent prognostic indicator of poor outcomes in PDAC patients after radical resection. It might assist clinicians to identify high-risk patients and choose the optimal individualized treatment strategy.

Simple Summary The immunosuppressive microenvironment is closely related to the poor prognosis of patients with PDAC. Tfh cells play an anti-tumor function in various malignant solid tumors; however, the role of Tfh cells in PDAC has not been determined. In this study, we aimed to explore the function of Tfh cells in PDAC, and revealed a novel immunosuppressive mechanism mediated by Tfh cells. Tfh cells promoted the formation of an immunoactive tumor microenvironment by secreting CXCL13 and IL-21, and the high infiltration of Tfh cells correlated with better patient prognosis. However, the anti-tumor function of Tfh cells was inhibited by the PD-L1/PD-1 signaling pathway. Neoadjuvant chemotherapy could further reverse the function of Tfh cells. Our results provided new strategies to remodel the immunoactive tumor microenvironment of PDAC. Abstract Immunosuppression is an important factor for the poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Follicular helper T cells (Tfh cells) play an anti-tumor role in various malignant solid tumors and predict better patient prognosis. In the present study, we aimed to determine the immunosuppressive mechanism associated with Tfh cells and explore a new strategy to improve the tumor microenvironment of PDAC. Flow cytometry was used to detect the infiltration and proportion of Tfh cells in tumor tissues and peripheral blood from patients with PDAC. The spatial correlations of Tfh cells with related immune cells were evaluated using immunofluorescence. The function of Tfh cells was examined using in vitro and in vivo model systems. The high infiltration of Tfh cells predicted better prognosis in patients with PDAC. Tfh cells recruited CD8+ T cells and B cells by secreting C-X-C motif chemokine ligand 13 (CXCL13), and promoted the maturation of B cells into antibody-producing plasma cells by secreting interleukin 21 (IL-21), thereby promoting the formation of an immunoactive tumor microenvironment. The function of Tfh cells was inhibited by the programmed cell death 1 ligand 1 (PD-L1)/programmed cell death 1 (PD-1) signaling pathway in PDAC, which could be reversed using neoadjuvant chemotherapy. Treatment with recombinant CXCL13, IL-21 and Tfh cells alleviated tumor growth and enhanced the infiltration of CD8+ T cells and B cells, as well as B cell maturation in a PDAC mouse model. Our results revealed the important role of Tfh cells in mediating anti-tumor cellular immunity and humoral immunity in PDAC via secreting CXCL13 and IL-21 and determined a novel mechanism of immunosuppression in PDAC.

The accurate measurement of atmospheric refractive index can greatly improve the radar detection accuracy, communication equipment communication distance, and effectively predict the generation of atmospheric waveguide.The common atmospheric refractive index instruments include the five-nine sonde and the high precision microwave refractive index instrument.According to the principle that the oscillation frequency of the gas will change when the gas in the environment is changed, this paper designs the hardware module composition and software circuit of the light-duty capacitive atmospheric parameter tester, and the light-duty capacitive refractive index tester with LC oscillator as the main element.Finally, experiments show that the fitting degree and accuracy of the capacitive instrument data curve are second.

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.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with poor prognosis. Many preoperative biomarkers can predict postoperative survival of PDAC patients. In this study, we created a novel ratio index based on preoperative liver function test, γ‐glutamyltransferase‐to‐albumin ratio (GAR), and evaluated its prognostic value in predicting clinical outcomes of PDAC patients following radical surgery. We retrospectively enrolled 833 PDAC patients who had underwent radical surgery at our institution between January 2010 and January 2017. Patients were divided into two groups according to the cut‐off value of GAR. Univariate and multivariate survival analysis between the groups were evaluated. TNM stage, GAR, preoperative serum carbohydrate antigen 19‐9 (CA19‐9) and tumor differentiation were combined to generate a more accurate prognostic model. The optimal cut‐off value of GAR was 0.65. Significant correlations were found between GAR and tumor location, tumor size, vascular invasion, obstructive jaundice, biliary drainage and parameters of liver function test. Univariate and multivariate analysis showed that high level of GAR independently predicted poorer postoperative overall survival (OS, P < 0.001) and recurrence‐free survival (RFS, P < 0.001). Subgroup analysis demonstrated that GAR was predictive of survival in patients without biliary obstruction or severely impaired liver function. In addition, integration of GAR, preoperative serum CA19‐9, and tumor differentiation into TNM staging system could better stratify the prognosis for PDAC patients compared with TNM stage alone. Our study demonstrates that preoperative GAR is an independent prognostic factor for prediction of surgical outcomes in PDAC patients. Combination of TNM stage, GAR, preoperative serum CA19‐9, and tumor differentiation can enhance the prognostic accuracy.

Purpose To evaluate the perioperative complications of patients with cervical cancer who are treated with robot-assisted radical hysterectomy (RRH) and to further evaluate the safety of patients undergoing NACT. Methods A total of 805 consecutive cervical cancer patients undergoing RRH were involved in this report. Their clinical characteristics were retrieved from hospital medical records. Perioperative complications were subdivided into intraoperative and postoperative complications, which were graded according to the Clavien–Dindo classification (CDC), and the complications of grade III and above were defined as severe complications. Furthermore, the two-level logistic regression model was used to estimate the risk factors of perioperative and severe complications and to further confirm the relationship between NACT and perioperative and severe complications. Results The perioperative complication rate and severe complications were 45.09% and 7.83%, respectively. Poorly differentiated tumor and NACT were identified as independent risk factors for perioperative complications by multifactor analysis. Furthermore, we concentrated on the relations between NACT and complications. The risk of perioperative complications of the group with NACT (OR = 11.08, 95% CI: 5.70–21.54) was significantly higher than the group without NACT, especially in postoperative complications (OR=17.65, 95% CI: 8.63–36.08), even after adjusting confounding factors. However, there was no statistically significant difference in terms of severe complications (OR=1.68, 95% CI: 0.64–4.41) and intraoperative complications (OR=0.51, 95% CI: 0.18–1.41). Moreover, as the times of NACT increase, the impact on perioperative complications is more pronounced. A similar trend was observed in postoperative complications, while this statistical difference was still not observed in intraoperative and severe complications. Conclusion This result demonstrates the feasibility and safety of RRH of cervical carcinoma after NACT in generally, since it only causes mild complications, not severe complications.

Collagen is the major component of the tumor microenvironment and participates in cancer fibrosis. Collagen biosynthesis can be regulated by cancer cells through mutated genes, transcription factors, signaling pathways and receptors; furthermore, collagen can influence tumor cell behavior through integrins, discoidin domain receptors, tyrosine kinase receptors, and some signaling pathways. Exosomes and microRNAs are closely associated with collagen in cancer. Hypoxia, which is common in collagen-rich conditions, intensifies cancer progression, and other substances in the extracellular matrix, such as fibronectin, hyaluronic acid, laminin, and matrix metalloproteinases, interact with collagen to influence cancer cell activity. Macrophages, lymphocytes, and fibroblasts play a role with collagen in cancer immunity and progression. Microscopic changes in collagen content within cancer cells and matrix cells and in other molecules ultimately contribute to the mutual feedback loop that influences prognosis, recurrence, and resistance in cancer. Nanoparticles, nanoplatforms, and nanoenzymes exhibit the expected gratifying properties. The pathophysiological functions of collagen in diverse cancers illustrate the dual roles of collagen and provide promising therapeutic options that can be readily translated from bench to bedside. The emerging understanding of the structural properties and functions of collagen in cancer will guide the development of new strategies for anticancer therapy.