Taurine attenuates activation of hepatic stellate cells by inhibiting autophagy and inducing ferroptosis.

BACKGROUND: Liver fibrosis is a compensatory response during the tissue repair process in chronic liver injury, and finally leads to liver cirrhosis or even hepatocellular carcinoma. The pathogenesis of hepatic fibrosis is associated with the progressive accumulation of activated hepatic stellate cells (HSCs), which can transdifferentiate into myofibroblasts to produce an excess of the extracellular matrix (ECM). Myofibroblasts are the main source of the excessive ECM responsible for hepatic fibrosis. Therefore, activated hepatic stellate cells (aHSCs), the principal ECM producing cells in the injured liver, are a promising therapeutic target for the treatment of hepatic fibrosis. AIM: To explore the effect of taurine on aHSC proliferation and the mechanisms involved. METHODS: Human HSCs (LX-2) were randomly divided into five groups: Normal control group, platelet-derived growth factor-BB (PDGF-BB) (20 ng/mL) treated group, and low, medium, and high dosage of taurine (10 mmol/L, 50 mmol/L, and 100 mmol/L, respectively) with PDGF-BB (20 ng/mL) treated group. Cell Counting Kit-8 method was performed to evaluate the effect of taurine on the viability of aHSCs. Enzyme-linked immunosorbent assay was used to estimate the effect of taurine on the levels of reactive oxygen species (ROS), malondialdehyde, glutathione, and iron concentration. Transmission electron microscopy was applied to observe the effect of taurine on the autophagosomes and ferroptosis features in aHSCs. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to detect the effect of taurine on the expression of α-SMA, Collagen I, Fibronectin 1, LC3B, ATG5, Beclin 1, PTGS2, SLC7A11, and p62. RESULTS: Taurine promoted the death of aHSCs and reduced the deposition of the ECM. Treatment with taurine could alleviate autophagy in HSCs to inhibit their activation, by decreasing autophagosome formation, downregulating LC3B and Beclin 1 protein expression, and upregulating p62 protein expression. Meanwhile, treatment with taurine triggered ferroptosis and ferritinophagy to eliminate aHSCs characterized by iron overload, lipid ROS accumulation, glutathione depletion, and lipid peroxidation. Furthermore, bioinformatics analysis demonstrated that taurine had a direct targeting effect on nuclear receptor coactivator 4, exhibiting the best average binding affinity of -20.99 kcal/mol. CONCLUSION: Taurine exerts therapeutic effects on liver fibrosis via mechanisms that involve inhibition of autophagy and trigger of ferroptosis and ferritinophagy in HSCs to eliminate aHSCs.

Transarterial chemoembolization plus lenvatinib with or without a PD-1 inhibitor for advanced and metastatic intrahepatic cholangiocarcinoma: a retrospective real-world study.

OBJECTIVES: Most patients with intrahepatic cholangiocarcinoma (ICC) present with locally advanced or metastatic disease. We report the combined potency of transarterial chemoembolization (TACE), lenvatinib and programmed cell death-1 (PD-1) inhibitors in patients with advanced and metastatic ICC. METHODS: This retrospective study enrolled 32 patients with advanced or metastatic ICC between January 2017 and August 2021. Eligible patients had received gemcitabine-based TACE combined with lenvatinib with or without PD-1 inhibitor in any line of treatment. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Risk factors associated with OS were assessed using univariate and multivariate Cox regression analyses. RESULTS: Eighteen patients received a combination of TACE and lenvatinib (TL group) and 14 patients received TACE and lenvatinib plus aPD-1 inhibitor (TLP group). The median follow-up time was 19.8 months (range 1.8-37.8). The median OS was 25.3 months (95% CI 18.5-32.1) and the median PFS was 7.3 months (95% CI 4.9-9.7). Partial response was achieved in 10 patients (31.3%), and stable disease in 13 (40.6 %) with disease control rate of 71.9%. The median OS was comparable in the TL and TLP groups (22.4 vs 27.3 months, respectively; hazard ratio: 1.245, 95% CI 0.4245-3.653; p = 0.687). The regression analysis revealed that, regardless of treatment group, a favorable independent prognostic factor for OS was HBV/HCV infection (HR: 0.063, 95% CI 0.009-0.463; p = 0.007). There were no treatment-related deaths and 81.3% of study participants experienced adverse events (AEs), the majority of which were of moderate severity (71.8% Grade 1-2). CONCLUSIONS: Gemcitabine-based TACE plus lenvatinib with or without aPD-1 inhibitor was well tolerated and provided promising therapeutic outcomes for patients with advanced and metastatic ICC. ADVANCES IN KNOWLEDGE: Monotherapy with TACE, or Lenvatinib, or PD-1 inhibitors has shown limited efficacy over standard first-line chemotherapy in advanced and metastatic ICC. This work suggested the combined potency of these treatments and well-tolerance.

Relationship of depression and sleep quality, diseases and general characteristics.

BACKGROUND: Depression is the most common type of depressive disorder. The most common sleep disorder associated with depression is insomnia. Insomnia and depression are closely related. AIM: To investigate the relationship of designed questionnaire items and depression, and analyze the related factors with depression. METHODS: Questionnaire included Patient Health Questionnaire-9 (PHQ-9) and Pittsburgh sleep quality index (PSQI), 12 kinds of diseases, 8 general characteristics, and 20 insomnia characteristics, totally 56 items were filled out by 411 patients enrolled. RESULTS: All the 9 items of PHQ-9, 6 components of PSQI (except sleep duration), education, living situation, exercise, years of insomnia, western medicine treatment, Chinese medicine treatment, psychotherapy, kinds of insomnia, treatment expected to treat insomnia, psychological counseling, habit of 1 h before bed, habit of lunch break, diagnosed depression, coronary heart disease, mental illness showed significant difference between without and with depression group. By univariate analysis and multivariate analysis. The odds ratio of education, exercise, kinds of insomnia, habit of 1 h before bed, diagnosed depression, coronary heart disease (P = 0.01) showed significant difference. Their odds ratios were 0.71 (0.55, 0.93), 2.09 (1.32, 3.31), 0.76 (0.63, 0.91), 0.89 (0.81, 0.98), 0.32 (0.17, 0.60), 0.43 (0.23, 0.79). CONCLUSION: We demonstrated that education, exercise, kinds of insomnia, habit of 1 h before bed, diagnosed depression and coronary heart disease affect the depression.

Predictive role of the monocyte-to-lymphocyte ratio in advanced hepatocellular carcinoma patients receiving anti-PD-1 therapy.

Background: The immune checkpoint inhibitor (ICIs) therapy has been proven effective in a range of solid tumors including hepatocellular carcinoma (HCC), non-small cell lung carcinoma and metastatic melanoma. However, only a subset of approximately 20% of patients shows an objective response to anti-PD-1 therapy in HCC. Furthermore, the response to anti-PD-1 therapy is not correlated with programmed cell death 1 ligand expression in tumor tissue. Therefore, it is urgent to identify a biomarker to predict the response of anti-PD-1 therapy. Methods: This retrospective study was conducted at the Fudan University Shanghai Cancer Center from December 2019 to June 2021. The monocyte-to-lymphocyte ratio (MLR) was analyzed using a receiver operating characteristic (ROC) curve. A Cox regression model and the log-rank test were used to analyze the relationship between the MLR value and the time to progression (TTP). Results: A total of 34 advanced HCC patients were enrolled in this study. The cut-off point for the MLR at baseline was 0.35. Univariate and multivariate Cox regression models showed that the MLR at baseline was significantly correlated with the TTP (P<0.05). Consistent results were found for disease progression. The log-rank test showed that patients in the low MLR group had a longer TTP (P=0.0027). At the time of disease progression, the median TTP in the low and high MLR groups were 33 and 18 weeks, respectively (P=0.0047). Conclusions: The MLR can predict the response to anti-PD-1 therapy, and a high MLR is correlated with a short TTP in anti-PD-1-treated HCC patients.

Combined ablation-chemotherapy versus chemotherapy alone for pancreatic cancer with liver metastasis: a propensity score matching study.

Objectives: To retrospectively assess the efficacy of combined ablation-chemotherapy in comparison to that of chemotherapy alone in patients with liver metastasized pancreatic ductal adenocarcinoma (lmPDAC).Methods: In total 104 patients with hepatic oligo metastasized PDAC were identified; among them, 74 patients underwent combined thermal ablation-chemotherapy, and 30 patients underwent chemotherapy alone. Through propensity score matching, 1:1 matching of the combined ablation-chemotherapy group and chemotherapy group was achieved. The primary endpoint of this study was overall survival (OS). Clinical and tumor-related factors affecting OS were also analyzed through univariate and multivariate analyses using the Cox risk model.Results: For patients treated with combined ablation-chemotherapy, the median OS was 10.77 months, while it was 5.77 months for patients treated with chemotherapy alone (P = 0.011). The survival benefit for patients treated with combined ablation-chemotherapy was still preserved in the matched cohort, with a median OS of 8.17 months compared to 5.77 months in the chemotherapy group. Univariate and multivariate analyses in the matched population also showed treatment with combined ablation-chemotherapy was an independent prognostic factor (P < 0.05).Conclusions: For patients with liver metastases from pancreatic cancer, the combined use of thermal ablation and systemic chemotherapy offers a chance for a better survival outcome.

Overexpression of a Long Non-Coding RNA BC037916 is Associated with Pancreatic Tumorigenesis and Poor Prognosis.

BACKGROUND: Pancreatic cancer is one of the most lethal malignancies. Accumulating evidence supports for the critical contribution of long noncoding RNAs (lncRNAs) to the cancer development and progression. We tried to identify novel lncRNAs involved in the pancreatic carcinogenesis. MATERIALS AND METHODS: Two independent datasets (Gene Expression Omnibus datasets: GSE16515 and GSE32688) were obtained from the Gene Expression Omnibus (GEO). The level of BC037916 was detected in pancreatic cancer tissues and adjacent no-tumorous tissues (n=86) by qRT-PCR. Effects of BC037916 on proliferation, apoptosis, and invasion of pancreatic cancer cells were examined. RESULTS: We identified a novel lncRNA BC037916 involved in the pancreatic carcinogenesis by analyzing GEO datasets. Quantitative RT-PCR analysis showed that 86.0% (74/86) pancreatic cancer tissues had increased BC037916 expression as compared with normal counterparts. Further, positive correlation was observed between BC037916 expression and clinical stage, primary tumor, and regional lymph node invasion. Importantly, BC037916 was an independent prognostic factor of pancreatic cancer. Functionally, knockdown of BC037916 repressed cell proliferation, inhibited cell invasion, halted cell cycle progression, and promoted apoptosis in both PANC-1 and SW1990 cells. In contrast, overexpression of BC037916 in CAPAN-1 had opposite effects. Moreover, silencing of BC037916 significantly inhibited the tumor growth of xenografted SW1990 cells in vivo. Results of Western blot assays suggested that BC037916 knockdown also suppressed the activation of JAK2/STAT3 and TGF-ß signaling. Further experiments suggested that BC037916 positively regulated the expression of Twist through miR-3145-3p. CONCLUSION: BC037916 exhibited oncogenic potential in pancreatic cancer development.

ARHGAP4 mediates the Warburg effect in pancreatic cancer through the mTOR and HIF-1α signaling pathways.

OBJECTIVE: The phenomenon that cancer cells avidly exhibit glycolysis with lactate secretion and decrease in mitochondrial activity under aerobic conditions is known historically as the Warburg effect. Rho GTPase-activating protein 4 (ARHGAP4) is an important negative regulator of the Rho signaling pathway that was associated with the tumorigenesis. Our study aims to determine the function of ARHGAP4 in controlling the glycolytic process of pancreatic cancer in vitro and possible molecular mechanism involved. METHODS: ARHGAP4 and PKM2 expressions in pancreatic cancer tissues were measured by immunohistochemistry. Human pancreatic cancer cells transfected with ARHGAP4 expressing lentivirus or siRNA were treated with either mTOR inhibitor (Rapamycin) or HIF-1α inhibitor (YC-1), and the effects were analyzed on cell viability, glucose uptake, lactate release, and the levels of ARHGAP4, p-mTOR, mTOR, PKM2, and HIF-1α expression. RESULTS: Our findings showed that ARHGAP4 and PKM2 expressions were, respectively, down-regulated and up-regulated in pancreatic cancer tissues. Overexpression of ARHGAP4 significantly inhibited cell viability, glucose uptake, lactate release, PKM2 expression, and activation of mTOR and HIF-1α signaling pathways in pancreatic cancer cells while ARHGAP4 silencing and treatment of Rapamycin or YC-1 showed inverse effects. Additionally, ARHGAP4 downregulation induced cell morphology of pancreatic cancer was inhibited by Rapamycin or YC-1 treatment. CONCLUSION: These findings suggest that mTOR and HIF-1α signaling pathways can regulate the ARHGAP4-mediated glycolytic process of pancreatic cancer.

Site-specific metastases of intrahepatic cholangiocarcinoma and its impact on survival: a population-based study.

Aim: Limited data exist on impact of the metastatic sites on survival in patients with metastatic intrahepatic cholangiocarcinoma (ICC). Methods: Patients with metastatic ICC were identified in the SEER from 2010 to 2015. Results: A total of 981 patients were identified, of this population, liver (57.9%) is the most common site of ICC metastases, followed by lung, bone and brain. Respective median overall survival and cancer-specific survival were 6 and 9 months in entire population. Further analysis suggested that patients treated by surgery to primary and/or metastatic lesions had a better survival outcome than patients had no surgery (p ≤ 0.001). Conclusion: Liver is the most common site for ICC metastases, local treatment such as surgery to primary or metastatic lesions obviously benefit patients.

ARHGAP4 regulates the cell migration and invasion of pancreatic cancer by the HDAC2/ß-catenin signaling pathway.

ß-catenin is a subunit of the cadherin protein complex and acts as an intracellular signal transducer in the Wnt signaling pathway that mediates multiple cellular processes, such as cell migration and invasion. HDAC2 (histone deacetylase 2), a deacetylase that maintains histone H3 in a deacetylated state in the promoter region of Wnt-targeted genes where ß-catenin is bound, negatively regulating ß-catenin activation. However, the regulation of HDAC2/ß-catenin pathway remains unclear. Here, we report ARHGAP4 as a new regulator of the ß-catenin pathway that regulates cell invasion and migration of pancreatic cancer as well as the downstream effector MMP2 and MMP9 expression in vitro. Mechanistically, ARHGAP4 interacts with and ubiquitinates HDAC2, which in turn inhibits ß-catenin activation. Furthermore, treatment of CAY10683, an HDAC2 inhibitor, and XAV939, a Wnt/ß-catenin pathway inhibitor, attenuated the effects of ARHGAP4 silencing on pancreatic cancer cells. Overall, our findings establish ARHGAP4 as a novel regulator of HDAC2/ß-catenin pathway with a critical role in tumorigenesis.

High-intensity focused ultrasound enhances the effect of bufalin by inducing apoptosis in pancreatic cancer cells.

PURPOSE: High-intensity focused ultrasound (HIFU) has the potential to be an effective therapeutic strategy for pancreatic cancer (PC). However, owing to the high malignancy and poor prognosis of PC, the use of HIFU therapy alone is not sufficient to impair the progression of PC. Bufalin, a compound extracted from traditional medicine, is known to inhibit the growth and progression of PC cells. However, the effect of the combination therapy of HIFU plus bufalin (HIFU+bufalin) is still uncertain. MATERIALS AND METHODS: A colony formation assay and flow cytometry were performed to measure the growth and induction of apoptosis in PC cells. Western blotting was used to explore the potential mechanism of HIFU and bufalin therapy. The in vivo efficacy of HIFU+bufalin was tested in a MiaPaCa2 xenograft model. RESULTS: Bufalin inhibited the growth of PC cells more obviously compared to HIFU. Combining bufalin with HIFU further decreased the growth of MiaPaCa2 cells compared with single therapy in vitro. Flow cytometry results showed that the percentage of surviving MiaPaCa2 cells in the bufalin-treated group and the HIFU-treated group was approximately three-fold and two-fold higher than in the HIFU+bufalin-treated group. Contrasting results were found in Panc-1 cells. Biochemical analysis revealed that HIFU+bufalin treatment elevated PARP expression and increased caspase-8 activation in MiaPaCa2 and Panc-1 cells. HIFU+bufalin significantly reduced the growth of MiaPaCa2 tumors compared with HIFU or bufalin treatment alone. HIFU+bufalin treatment decreased Ki67 staining and increased activated caspase-3 and caspase 8 staining, when compared with HIFU or bufalin treatment alone in mouse tumors. CONCLUSION: HIFU enhanced the effect of bufailn by inducing apoptosis in PC cells. A combination of HIFU and bufalin may be employed as an alternative therapeutic strategy for PC.

HIFU is safe, effective, and feasible in pancreatic cancer patients: a monocentric retrospective study among 523 patients.

PURPOSE: This study aimed to evaluate the clinical value of high-intensity focused ultrasound (HIFU) combined with gemcitabine (GEM) in treating unresectable pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: A total of 523 unresectable PDAC patients were recruited from December 30, 2007 to January 30, 2015 at Fudan University Shanghai Cancer Center. Among them, 347 received HIFU combined with GEM (with regional intra-arterial chemotherapy [RIAC] or with systemic chemotherapy) and the remaining patients received GEM only. Postoperative complications were observed, and overall survival was recorded. RESULTS: The median overall survival of patients who received HIFU combined with GEM vs GEM alone was 7.4 vs 6.0 months (P=0.002); the 6-month, 10-month, 1-year, and 2-year survival rates for patients in these two groups were 66.3% vs 47.5% (P<0.0001), 31.12% vs 15.9% (P<0.0001), 21.32% vs 13.64% (P=0.033), and 2.89% vs 2.27% (P=0.78), respectively. In the combined therapy group, the most obvious survival benefits were obtained among patients who received HIFU plus RIAC and systemic chemotherapy (used in the intervals between RIAC treatments). There were no severe complications in patients undergoing HIFU treatment. CONCLUSION: We demonstrated the survival benefit of HIFU among PDAC patients treated with GEM. The benefit was most obvious in PDAC patients treated with HIFU plus RIAC and systemic chemotherapy.

Pleural effusion resulting from bronchial tuberculosis: A case report.

RATIONALE: The clinical manifestations in patients with bronchial tuberculosis (BTB) are nonspecific and may pose a great diagnostic challenge. PATIENT CONCERNS: Here we describe the case of a 57-year-old man presented with right chest pain, chest tightness, and discomfort for 2 days. DIAGNOSIS: Bronchoscopic biopsy was performed which revealed subepithelial and epithelioid cell granuloma of Langerhans cell structure. The definitive diagnosis was BTB with pleural effusion. INTERVENTIONS: Treatment with a quadruple combinational antituberculous therapy was initiated. OUTCOMES: Two months later, the patient's chest distress and discomfort significantly decreased. Repeat chest radiograph revealed that the pleural fluid had been absorbed. The patient recovered after 15 months of antituberculosis treatment. LESSONS: The patient exemplifies the difficulty of diagnosing BTB, particularly the low reliability of imaging modalities. The diagnosis of BTB currently relies on bronchoscopy as well as bacteriological or pathological evidence. This report will help to lower the incidences of misdiagnosis of this disease.

Role of monocyte-to-lymphocyte ratio in predicting sorafenib response in patients with advanced hepatocellular carcinoma.

PURPOSE: Sorafenib is the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC), and its clinical response rate is only about 10%. In clinical practice, some HCC patients obtain favorable overall survival (OS) to the treatment of sorafenib while some patients do not demonstrate a sensitive response to sorafenib. Therefore, it is valuable to determine the subgroups of patients who respond well as well as poorly to sorafenib. Thus, clinical variables of advanced HCC patients with sorafenib treatment were compiled to investigate whether monocyte-to-lymphocyte ratio (MLR) could be a biomarker for predicting sorafenib response. PATIENTS AND METHODS: In this study, a total of 142 patients with advanced HCC were enrolled from January 1, 2013 to December 31, 2016 at the Fudan University Shanghai Cancer Center. MLR was analyzed using a ROC curve. A Cox regression model and log-rank test were performed to analyze the relationship between clinical factors and OS, as well as progression free survival (PFS). RESULTS: The optimal cut-off point for MLR was 0.35, and MLR level had no significant correlation with age, gender, hepatitis B infection, grade, alpha-fetoprotein (AFP) level and state of portal vein tumor thrombus. Multivariate Cox regression model showed that grade (HR: 0.608, 95% CI: 0.409-0.904, P=0.014), AFP (HR: 0.445, 95% CI: 0.307-0.645, P=0.0001), MLR (HR: 0.445, 95% CI: 0.301-0.658, P=0.0001) and aspartate aminotransferase (AST) (HR: 1.005, 95% CI: 1.001-1.009, P=0.007) may serve as independent prognostic predictors for OS, and MLR maintained significant correlation with PFS in HCC patients (HR: 0.457, 95% CI: 0.308-0.678, P=0.0001). By log-rank test, there was longer PFS and OS in patients with low MLR than in those with high MLR (both P=0.0001). CONCLUSION: MLR can predict sorafenib response and a high MLR is correlated with poor prognosis in patients with advanced HCC.

Carbonic anhydrase 2 inhibits epithelial-mesenchymal transition and metastasis in hepatocellular carcinoma.

Carbonic anhydrase 2 (CA2) plays vital role in the regulation of ion transport and pH balance and is involved in many biological processes; however, its role in cancer remains obscure. In this study, we identified a novel function of CA2 in facilitating hepatocellular carcinoma (HCC) metastasis. CA2 expression was elevated in Na+-K+-ATPase α1 (ATP1A1)-downregulated HCC cells and was inversely correlated with that of ATP1A1 in HCC. ATP1A1 acted as an oncoprotein whereas CA2 overexpression inhibited cell migration and invasion by reversing epithelial-mesenchymal transition (EMT) in HCC. CA2 downregulation promoted HCC metastasis and invasion whereas ATP1A1 downregulation inhibited HCC metastasis. Because of the opposing effects of CA2 and ATP1A1 in HCC, we examined the role of their correlation in HCC metastasis. CA2 attenuated ATP1A1-triggered tumor growth in vivo and ATP1A1-induced metastasis in vitro. Taken together, the present results suggest that CA2 serves as a suppressor of HCC metastasis and EMT and is correlated with favorable overall survival (OS) in HCC patients.

Systemic inflammation response index (SIRI) predicts prognosis in hepatocellular carcinoma patients.

The systemic inflammation response index (SIRI) is a useful tool for predicting prognosis in some types of cancer. In this retrospective study, we evaluated the efficacy of SIRI in predicting overall survival in hepatocellular carcinoma (HCC) patients following local or systemic therapy. A cutoff value of 1.05 was identified for SIRI using ROC analysis in a training patient cohort. In the validation cohort, survival analysis revealed that median overall survival was longer in HCC patients with SIRI scores < 1.05 than in those with scores ≥ 1.05. Cox analysis of the validation cohort demonstrated that SIRI was associated with overall survival and was more predictive of overall survival that the AFP level or Child-Pugh score. However, SIRI and Barcelona Clinic Liver Cancer (BCLC) stage were equally effective for predicting survival. In addition, HCC patients with BCLC stage C had higher SIRI scores and poorer overall survival. SIRI also correlated with liver function parameters. Thus SIRI may be a convenient, low cost and reliable tumor marker for predicting prognosis in HCC patients.

Serum lactate dehydrogenase predicts prognosis and correlates with systemic inflammatory response in patients with advanced pancreatic cancer after gemcitabine-based chemotherapy.

Serum lactate dehydrogenase (LDH) concentrations correlate with tumor progression and poor outcome. We evaluated the predictive value of serum LDH level for overall survival (OS) of patients with advanced pancreatic cancer after gemcitabine-based chemotherapy. We retrospectively enrolled 364 patients with locally advanced or metastatic pancreatic adenocarcinoma who were then allocated to training (n = 139) and validation cohorts (n = 225). We evaluated the association between serum LDH levels and OS as well as with markers of systemic inflammation, including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and lymphocyte/monocyte ratio (LMR). Kaplan-Meier analyses revealed that low serum LDH levels in the training cohort significantly correlated with longer OS. Multivariate analysis identified the serum LDH levels as an independent prognostic predictor of OS (p = 0.005). Serum LDH levels correlated positively with NLR and PLR and correlated negatively with LMR. Similar results were obtained for the validation cohort, except that multivariate analysis identified the serum LDH level as a significant prognostic predictor and only a statistical trend for OS (p = 0.059). We conclude that serum LDH levels were associated with the systemic inflammatory response and served as a significant prognostic predictor of OS. Serum LDH levels predicted OS in patients with advanced pancreatic cancer after gemcitabine-based palliative chemotherapy.

Serum liver enzymes serve as prognostic factors in patients with intrahepatic cholangiocarcinoma.

OBJECTIVE: Liver functions, reflective of the overall status of the host, have been reported to be important factors affecting the prognosis in many types of cancers. In this study, we explored the influences of liver enzymes albumin (ALB), globulin (GELO), total protein (TP), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), gamma glutamyltranspeptidase (GGT), and lactate dehydrogenase (LDH) on the overall survival (OS) in a number of 173 patients with intrahepatic cholangiocarcinoma (ICC). PATIENTS AND METHODS: Between 2011 and 2015, we enrolled patients with pathologically proven locally advanced or metastatic ICC. The impact of ALB, GELO, TP, ALP, ALT, AST, TBIL, DBIL, GGT, and LDH on OS were analyzed using Kaplan-Meier analysis. Next, the associations between these liver enzymes and OS were evaluated by univariate and multivariate analyses. Finally, the role of these enzymes in OS was evaluated in the subgroups. RESULTS: Elevated liver enzymes were linked with OS. We revealed that independent prognostic factors of poor outcome were ALP, TBIL, DBIL, and GGT, whereas ALB is a protective factor in ICC patients. CONCLUSION: Our results demonstrate that these liver enzymes may serve as valuable predictive markers in ICC patients.

Prognostic nutritional index serves as a predictive marker of survival and associates with systemic inflammatory response in metastatic intrahepatic cholangiocarcinoma.

OBJECTIVE: The significance of the prognostic nutritional index (PNI) has been widely reported and confirmed in many types of cancers. However, few studies are available indicating its prognostic power in patients with intrahepatic cholangiocarcinoma (ICC). Thus, we investigated its relationship with overall survival (OS) to evaluate its role in predicting survival in patients with ICC. PATIENTS AND METHODS: Between October 2011 and October 2015, 173 consecutive patients with pathologically confirmed locally advanced or metastatic ICC were enrolled. First, the correlations between PNI and clinical factors were analyzed among these patients. Next, univariate and multivariate analyses were conducted to evaluate the association between PNI and OS among these patients with ICC. In addition, the relationships between PNI and three typical systemic inflammatory response (SIR) markers - the neutrophil/lymphocyte ratio (NLR), the platelet/lymphocyte ratio (PLR), and the lymphocyte/monocyte ratio (LMR) - were also assessed. RESULTS: A lower PNI was linked with a shorter OS in patients with ICC, as reflected obviously in the Kaplan-Meier analyses. The patients with ICC were divided into the locally advanced group and the metastatic group. Further analyses revealed that PNI is not associated with OS in the locally advanced group. However, in the subgroup of patients with metastatic ICC, a lower PNI significantly correlated with a worsened OS. The OS for patients with a low PNI is 5 months, whereas the OS is 10.17 months for patients with a high PNI. Multivariate analyses revealed that PNI is independently correlated with OS. We finally proved that PNI is negatively proportional to NLR and PLR and positively proportional to LMR. CONCLUSION: Our results demonstrate that decreased PNI signifies a poor OS and is associated with SIR in patients with metastatic ICC. Therefore, it may serve as a valuable predictive marker in patients with metastatic ICC.

Is chronic hepatitis B infection a protective factor for the progression of advanced pancreatic ductal adenocarcinoma? An analysis from a large multicenter cohort study.

PURPOSE: Whether the progression of advanced pancreatic ductal adenocarcinoma (PDAC) patients could be affected by HBV exposure remains to be determined. Therefore, we conducted this study to assess the effect of HBV infection on PDAC progression among a large cohort in China. METHODS: A multicenter cohort study was conducted to explore whether liver metastasis and overall survival in locally advanced and metastatic PDAC could be affected by HBV infection. In this study, we collected 1,526 advanced PDAC patients at three participating hospitals - Shanghai Cancer Center, Changhai Hospital and Ruijin Hospital from 2004 to 2013. The association between HBV status and advanced PDAC progression was then examined. RESULTS: In multivariable Logistic regression model, chronic hepatitis B(CHB) infection was inversely associated with synchronous liver metastasis compared to non HBV infection (OR 0.41, 95% CI 0.19-0.85) for stage IV patients. In a multivariable Cox model, CHB infection (HR=0.11, 95% CI 0.02-0.82) is considered as a protective factor of metachronous liver metastasis compared to Non HBV infection for stage III patients. For stage IV patients, CHB infection was inversely associated with overall survival compared to non HBV infection (HR 0.70, 95% CI 0.51-0.95). Inactive carrier(IC) and resolved HBV infection showed no significant association with survival compared to non HBV infection. CONCLUSION: This study indicated that CHB infection may serve as an independent factor which decrease synchronous or metachronous liver metastasis, and increase overall survival among advanced PDAC patients.

A retrospective analysis of survival factors of high intensity focused ultrasound (HIFU) treatment for unresectable pancreatic cancer.

OBJECTIVE: To retrospectively evaluate possible impact factors of HIFU treatment outcome for unresectable pancreatic cancer patients. PATIENTS AND METHODS: A total of 689 patients with unresectable pancreatic cancer were recruited in our center from December 30, 2007 to January 30, 2015. 436 patients with unresectable pancreatic cancers received HIFU treatment; the other 253 patients received non-HIFU treatment. Among these 436 patients, 345 patients received a one-time HIFU treatment, 91 patients received HIFU treatment from 2 to 5 times in the same pancreatic mass; 89 patients received HIFU treatment alone; 347 patients received HIFU-based combined therapies. Complications and overall survivals (OS) data in each group were collected. RESULTS: The median overall survivals (mOS) in HIFU group and non-HIFU group were 7.1 vs. 5 months (P=0.005): 9.3 vs. 7.3 months (P=0.202) for patients with stage II disease, 8.3 vs. 7.3 months (P=0.783) for patients with stage III disease, and 6.4 vs. 4.2 months (P<0.0001) for patients with stage IV disease, respectively. Furthermore, there was a significant difference between repeated HIFU and one-time HIFU (mOS: 8.6 vs. 6.8 months, P=0.011). Time of HIFU treatment (P=0.0027), chemotherapy (P<0.0001), radiotherapy (P=0.0006), regional intra-arterial chemotherapy (RIAC) (P<0.0001), and stage (P<0.0001) were independent prognostic factors for the patients who received HIFU treatment. Cox analysis on the relative risk of prognostic factors showed that repeated HIFU vs. one-time HIFU (HR=0.729: 95% CI=0.576-0.924), chemotherapy vs. non-chemotherapy (HR=0.664: 95% CI=0.576-0.766), radiotherapy vs. non-radiotherapy (HR=0.580: 95% CI=0.427-0.789), RIAC vs. non-RIAC (HR=0.737: 95% CI=0.648-0.837), and stage (HR=1.386, 95% CI=1.187-1.619) were associated with significantly inferior survival. Overall, adverse events occurred in 23.2% (101/436) in the HIFU group, which included increase of serum or urinary amylase levels, incomplete intestinal obstruction, mild fever, etc. There were no severe adverse events such as skin burns or GI perforation related to HIFU therapy in any of the patients treated. CONCLUSION: This retrospective analysis revealed that the use of a multimodal treatment approach (the combined therapy of HIFU, RIAC, and chemotherapy, with or without radiotherapy) could improve survival of patients with unresectable pancreatic cancer, and repeated HIFU presented a survival benefit and did not increase risk.