BackgroundThe systemic inflammatory response plays an important role in cancer development and progression. An original inflammation-based staging system for predicting survival in patients undergoing transarterial chemoembolization (TACE) combined with recombinant human type-5 adenovirus H101 is not available. This study aimed to validate the prognostic value of inflammation scores for patients with hepatocellular carcinoma (HCC) who were treated with TACE combined with H101.MethodsThe data from 216 patients with HCC who underwent TACE combined with H101 from January 2007 to July 2015 were retrospectively collected, and the association of the inflammation scores with overall survival (OS) was analyzed. Univariate and multivariate analyses were performed to identify variables associated with OS. The prognostic value of the inflammation scores, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), neutrophil/ platelet-to-lymphocyte ratio (NLR-PLR), modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI), prognostic index (PI), tumor-node-metastasis (TNM), Barcelona Clinic Liver Cancer (BCLC) and Cancer of the Liver Italian Program (CLIP) staging systems were analyzed and compared using the areas under the receiver operating characteristic curves (AUROCs).ResultsThe estimated 1-, 2-, and 3-year OS rates were 61.3%, 44.2%, and 40.5% for the entire study cohort, respectively; the median OS was 17 months. According to the multivariate Cox proportional hazards model, the pretreatment NLR, tumor diameter and pretreatment alpha-fetoprotein (AFP) levels were independent predictors of OS. The CLIP score had superior discriminative abilities compared with other staging systems, and the NLR-PLR score consistently displayed a higher AUROC value than the other inflammation-based prognostic scores. The combination of the NLR-PLR and CLIP scores exhibited a superior prognostic ability for OS compared to the NLR-PLR or CLIP scores alone.ConclusionsThe NLR-PLR score is a more powerful predictive system than the other inflammation-based scores for patients with HCC who were treated with TACE and H101. The predictive ability may be improved by utilizing a combination of the NLR-PLR and CLIP scores.

Background Irreversible electroporation is shown to induce immune changes in pancreatic cancer while the histology evidences are still lacking. The aim of this study is to show the immune changes in histology and explore whether irreversible electroporation (IRE) can induce immunogenic cell death (ICD) of tumor cells and activate specific immune responses. Methods Subcutaneous and orthotopic pancreatic cancer models were established and used to evaluate the effect of immune modulation of IRE. The infiltration of T cells was assessed in several tissue samples before and after IRE. Abscopal effect was then assessed by comparing the tumor growth of subcutaneous tumors after in situ ablation with IRE or exposure to tumor culture supernatant (TSN) of IRE‐treated Pan02. The expression of damage‐associated molecular patterns (DAMPs) of tumor cells after IRE was detected in vitro. Results IRE could significantly suppress the tumor growth and increase the infiltration of CD8 + T cells. After ablation with IRE or stimulation with TSN of Pan02 treated by IRE, the growth of untreated tumor was suppressed and the effector CD8 + T cells and memory T cells increased significantly in mice. Additionally, the inhibition effect of tumor growth increased along with the increasing strength levels of electroporation. IRE induced ICD of tumor cells by increasing the synthesis and secretion of DAMPs. Conclusions IRE induced local immunomodulation by increasing specific T cells infiltration. Through enhancing specific immune memory, IRE not only led a complete tumor regression in suit, but also induced abscopal effect, suppressing the growth of the latent lesions.

Background: The objective of this study was to estimate probabilities of overall survival (OS) and cancer-specific survival (CSS) in patients with pancreatic head adenocarcinoma after surgery. In addition, we attempted to build nomograms to predict prognosis of these patients.Methods: Patients diagnosed with surgically resected pancreatic head adenocarcinoma between 2004 and 2014 were selected for the study from the Surveillance, Epidemiology, and End Results (SEER) database. Nomograms were established for estimating 1-, 2- and 3-year OS and CSS based on Cox regression model and Fine and Grey's model. The performance of the nomogram was measured by concordance index (C-index) and the area under receiver operating characteristic (ROC) curve (AUC).Results: A total of 2374 patients were retrospectively collected from the SEER database. The discrimination of nomogram for OS prediction was superior to that of the Tumor-Node-Metastasis (TNM) 7th or 8th edition stage systems (C-index = 0.640, 95% CI, 0.618 - 0.662 vs 0.573, 95% CI, 0.554 - 0.593, P < 0.001; 0.640, 95% CI, 0.618 - 0.662 vs 0.596, 95% CI, 0.586 - 0.607, P < 0.001, respectively). The comparisons of values of AUC showed that the established nomograms displayed better discrimination power than TNM 7th or 8th stage systems for predicting both OS and CSS.Conclusions: The nomograms which could predict 1-, 2- and 3-year OS and CSS were established in this study. Our nomograms showed a relatively good performance and could be served as an effective tool for prognostic evaluation of patients with pancreatic head adenocarcinoma after surgery.

Purpose. Irreversible electroporation (IRE) has been demonstrated to be a safe and effective method for locally advanced pancreatic cancer (LAPC). The aim of this study was to evaluate the immunomodulatory effect after IRE and to evaluate the prognostic value of variations of the immune parameters in LAPC patients after IRE. Methods. Peripheral blood samples of 34 patients were obtained preoperatively and on the third day (D3) and seventh day (D7) after IRE, respectively. The phenotypes of lymphocytes were analyzed by flow cytometry, and dynamic changes of serum levels of cytokines, complement, and immunoglobulin were assayed by enzyme-linked immunosorbent assay. Receiver operating characteristic (ROC) curve and concordance index (C-index) were used to compare the survival predictive ability. Results. There was a transitory decrease followed by a steady increase for CD4+ T cell, CD8+ T cell, NK cell, IL-2, C3, C4, and IgG while a reverse trend was detected for Treg cell, IL-6, and IL10 after IRE. The alteration of CD8+ T cell between D3 and D7 was identified as a prognostic factor for both overall survival (OS) and progression-free survival (PFS). The values of ROC curve (AUC) and C-indexes of the alteration of CD8+ T cell for OS and PFS were 0.816 and 0.773 and 0.816 and 0.639, respectively, which were larger than those of other immune or inflammation-based indexes. Conclusions. This study presented the first evidence of IRE-based immunomodulatory in patients with LAPC. The alteration of CD8+ T cell between D3 and D7 showed relatively good performance and could be used as an effective tool for prognostic evaluation for LAPC patients after IRE.

Irreversible electroporation (IRE) is an effective method for treating pancreatic ductal adenocarcinoma (PDAC). It remains unclear whether IRE can induce a specific immune response by stimulating macrophages. Here, the associated markers of macrophages were analyzed after exposure to tumor culture supernatant (TSN) of tumor cells treated with electroporation. Subcutaneous and orthotopic PDAC models were also used to evaluate the effect of macrophage polarization induced by IRE. Aside from its direct killing effect, IRE could induce the immunogenic cell death of tumor cells by increasing the synthesis and secretion of damage associated molecular patterns. Moreover, IRE could increase the release of HMGB1, which activates the MAPK-p38 pathway and leads to the increased expression of M1 markers in macrophages, through binding to the receptor of the advanced glycation end-product (RAGE) receptor. M1 polarization was inhibited by the inhibitors of HMGB1 release, the RAGE receptor, and the MAPK-p38 signaling pathway, but it was activated by rHMGB1 or the stimulator of MAPK-p38. In addition, the promotion of M1 macrophage polarization was enhanced by the positive-feedback release or expression of HMGB1 and RAGE through the MAPK-ERK pathway in macrophages. The promotion of M1 macrophage polarization induced by IRE provided a specific rationale for the combination of IRE and immune therapy in treating PDAC.

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Background Cancer‐associated fibroblasts (CAFs) are among the most prominent cells during the desmoplastic reaction in pancreatic ductal adenocarcinoma (PDAC). However, CAFs are heterogeneous and the precise origins are not fully elucidated. This study aimed to explore whether monocytes can transdifferentiate into fibroblasts in PDAC and evaluate the clinical significance of this event. Methods CD14 + monocytes were freshly isolated from human peripheral blood. Immunofluorescence, reverse transcription‐quantitative PCR, western blot, flow cytometry and enzyme‐linked immunosorbent assay were used to detect the expression of αSMA, fibronectin, and other relevant molecules. In addition, latex beads with a mean particle size of 2.0 µm were used to assess the phagocytic capacity. Moreover, RNA sequencing (RNA‐seq) was performed to identify the differences induced by H 2 O 2 and the underlying mechanisms. Results Immunofluorescence identified αSMA and fibroblast‐specific protein 1 expression by tumor‐associated macrophages in PDAC. The in vitro experiment revealed that oxidative stress (H 2 O 2 or radiation) induced monocyte‐to‐myofibroblast transdifferentiation (MMT), as identified by upregulated αSMA expression at both the RNA and protein levels. In addition, compared with freshly isolated monocytes, human monocyte‐derived macrophages increased fibronectin expression. RNA‐seq analysis identified p53 activation and other signatures accompanying this transdifferentiation; however, the p53 stabilizer nutlin‐3 induced αSMA expression through reactive oxygen species generation but not through the p53 transcription/mitochondria‐dependent pathway, whereas the p38 inhibitor SB203580 could partially inhibit αSMA expression. Finally, MMT produced a unique subset of CAFs with reduced phagocytic capacity that could promote the proliferation of pancreatic cancer cells. Conclusions Oxidative stress in the tumor microenvironment could induce MMT in PDAC, thus inducing reactive stroma, modulating immunosuppression, and promoting tumor progression. Reducing oxidative stress may be a promising future therapeutic regimen.

Background: There are few diagnostic tools that can be used to determine which patient with intrahepatic cholangiocarcinoma (ICC) can benefit from surgery actually, highlighting that the need for new preoperative stratification strategies. The aim of this study was to investigate the predictive values of preoperative biomarkers in survival analyses for patients with ICC after surgical resection.Methods: A total of 285 patients with ICC were retrospectively reviewed. Receiver operating charateristics (ROC) curves were used to evaluate the predictive effects of preoperative carbohydrate antigen 19-9 (CA19-9) with different cutoff values and carcinoembryonic antigen (CEA) in patients with ICC.Results: Preoperative CA19-9 with a cutoff value of 200 U/ml performed better in predicting overall survival (OS) and progression free survival (PFS) in ICC patients. Patients with preoperative CA19-9 value > 200 U/ml generally had a poor surgical response. However, surgical resection could also benefit patients whose CA19-9 levels decreased postoperatively or preoperative CEA levels were negative.Conclusions: With the cutoff value of 200U/ml, CA19-9 was a better preoperative biomarker for predicting survival for ICC patients after surgical resection. Combination of preoperative CA19-9 and CEA showed the strongest predictive power in survival analyses in these patients and should be recognized in daily clinical care.