Feasibility and safety of trans-biliary cryoablation: Preclinical evaluation of a novel flexible cryoprobe.

Cryoablation, as a well-characterized technology, has multifarious clinical applications in solid malignancy. However, trans-biliary cryoablation for malignant biliary obstruction has not been reported yet. Thus, this study aimed to determine the efficacy and safety of trans-biliary cryoablation with a novel CO2 gas-based flexible cryoprobe in standardized preclinical settings. For fresh porcine liver ex vivo, the freezing efficacy of cryoablation was evaluated by using fresh porcine liver. The real-time CO2 flow rate, freezing temperature and freezing range were examined and the frozen appearance was visualized. In vivo study, acute and chronical effects were investigated by using the models of canine bile duct. Histopathology and laboratory examination were performed. The lowest temperature that the electrode could deliver to the tissue was -60.7 °C. At 60s after freezing, the tissue temperature dropped to -22.6 °C and -4.3 °C at 0.1 and 0.2 cm from the electrode center, respectively. The frozen size was greater in liver tissue ex vivo than that in bile duct tissue in vivo. No biliary hemorrhage, perforation, stricture, obstruction, and adjacent organ injury were observed. With histopathologic examination, acute intercellular vacuoles were observed in the lamina propria adjacent to the lumen. Chronic changes, including uneven coagulative necrosis, fibro-proliferation, inflammatory infiltration and connective tissue thickening were observed in the lamina propria of the all biliary samples. The results demonstrated CO2 gas-based trans-biliary cryoablation is safe and efficacious. These findings may provide a potential new modality for primary malignant biliary obstruction and malignant obstruction within a biliary stent and contribute to cryoablation of clinical practice.

Novel transcription regulatory sequences and factors of the immune evasion protein ICP47 (US12) of herpes simplex viruses.

BACKGROUND: Herpes simplex virus (HSV) can cause encephalitis. Its infected cell polypeptide 47 (ICP47), encoded by immediate-early gene US12, promotes immune escape. ICP47 was modified in the clinically approved oncolytic HSV (oHSV) T-Vec. However, transcription regulatory sequence (TRS) and transcription regulatory factor (TRF) of HSV US12 are seldom reported. METHODS: Previously, our laboratory isolated a new HSV strain named HSV-1-LXMW from a male patient with oral herpes in Beijing, China. Firstly, the genetic tree was used to analyze its genetic relationship. The US12 TRS and TRF in HSV-1-LXMW were found by using predictive software. Secondly, the further verification by the multi-sequence comparative analysis shown that the upstream DNA sequence of HSV US12 gene contained the conserved region. Finally, the results of literature search shown that the expression of transcription factors was related to the tissue affinity of HSV-1 and HSV-2, so as to increase the new understanding of the transcriptional regulation of HSV biology and oncolytic virus (OVs) therapy. RESULTS: Here we reported the transcriptional regulation region sequence of our new HSV-1-LXMW, and its close relationship with HSV-1-CR38 and HSV-1-17. Importantly we identified eight different kinds of novel TRSs and TRFs of HSV US12 for the first time, and found they are conserved among HSV-1 (c-Rel, Elk-1, Pax-4), HSV-2 (Oct-1, CF2-II, E74A, StuAp) or both HSVs (HNF-4). The TRFs c-Rel and Oct-1 are biologically functional respectively in immune escape and viral replication during HSV infection. CONCLUSIONS: Our findings have important implication to HSV biology, infection, immunity and oHSVs.

Target hepatic artery regional chemotherapy and bevacizumab perfusion in liver metastatic colorectal cancer after failure of first-line or second-line systemic chemotherapy.

Colorectal cancer liver metastasis (CRLM) is a refractory disease after failure of first-line or second-line chemotherapy. Bevacizumab is recommended as first-line therapy for advanced colorectal cancer, but is unproven in CRLM through the hepatic artery. We report favorable outcomes with targeted vessel regional chemotherapy (TVRC) for liver metastatic gastric cancer. TVRC with FOLFOX and bevacizumab perfusion through the hepatic artery was attempted for CRLM for efficacy and safety evaluation. In a single-institution retrospective observational study, 246 patients with CRLM after at least first-line or second-line failure of systemic chemotherapy received TVRC with FOLFOX (i.e. oxaliplatin, leucovorin, and 5-fluorouracil). Of 246 patients, 63 were enrolled into two groups: group 1 (n=30) received bevacizumab and TVRC following tumor progression during previous TVRC treatments; group 2 (n=33) received TVRC plus bevacizumab for CRLM on initiating TVRC. There were no significant differences in the median survival time (14.7 vs. 13.2 months, P=0.367), although the median time to progression was significant (3.3 vs. 5.5 months, P=0.026) between groups. No severe adverse events related to TVRC plus bevacizumab perfusion occurred. Target vessel regional chemotherapy with FOLFOX plus bevacizumab perfusion through the hepatic artery was effective and safe in CRLM. The optimal combination of TVRC and bevacizumab needs further confirmation in future phase II-III clinical trials.

Low-dose, short-interval target vessel regional chemotherapy through the hepatic artery combined with transarterial embolization in gastric cancer patients with liver metastases after failure of first-line or second-line chemotherapy: a preliminary analysis.

The objective of this study is to evaluate the efficacy and safety of combining low-dose, short-interval target vessel regional chemotherapy delivered through the hepatic artery (TVRC) with transarterial embolization (TAE) in advanced gastric cancer (AGC) patients with liver metastases after failure of first-line or second-line chemotherapy. All AGC patients with hepatic metastases had an indwelling arterial catheter placed in the hepatic artery and hepatic metastases were embolized with ultrafluid lipiodol, followed by two to three TVRC treatments in one cycle. After 3 weeks, the efficacy of TVRC treatment was evaluated using computed tomography (CT) or MRI scans before starting the next cycle. Follow-up assessments were performed every 2 months. The patients received a median of 7 (2-33) TVRC treatments together with TAE. All 22 AGC patients received a total of 191 TVRC treatments, which included 80.1% FOLFOX, 11.0% FOLFIRI, and 8.9% DC treatments. The median time-to-progression was 5.97 months; the median survival time was 11.6 months; and the 1-year and 2-year survival rates were 45.5 and 9.1%, respectively. The median overall survival from the diagnosis of liver metastasis (mOS) was 19.3 months. The most common side effects were grade I-II of abdominal pain, nausea, and vomiting. Combining TAE and TVRC administration through the hepatic artery for AGC patients with liver metastases resulted in decreased overall dose of chemotherapy, alleviation of side effects, and increased QOL of patient. This approach can be used as salvage therapy for AGC patients with predominant liver metastases after failure of intravenous chemotherapy.

A comparative study between Embosphere(®) and conventional transcatheter arterial chemoembolization for treatment of unresectable liver metastasis from GIST.

OBJECTIVE: Transcatheter arterial chemoembolization (TACE) is a standard treatment for hepatocellular carcinoma (HCC) and/or some unresectable liver metastasis tumors. Hypervascular liver metastatic lesions such as metastasis from gastrointestinal stromal tumor (GIST) are an indication for transcatheter arterial embolization (TAE). The purpose of this study was to evaluate the efficacy and safety of Embosphere(®)-TAE (Embo-TAE) in comparison with conventional TACE (cTACE) for the treatment of liver metastasis from GIST. METHODS: A total of 45 patients who underwent TACE between Aug 2008 and Feb 2013 were enrolled. Patients with GIST who underwent TAE with Embosphere(®) (n=19) were compared with controls who received cTACE (n=26). The primary end points were treatment response and treatment-related adverse events. The secondary end points were progression-free survival (PFS) and overall survival (OS). RESULTS: The treatment response of Embo-TAE group was significantly higher than that of the cTACE group (P<0.001). The PFS was significantly better in the Embosphere(®)-group than in the cTACE group (56.6 and 42.1 weeks, respectively; P=0.003). However, there was no statistically significant difference in liver toxicity between the two groups (P>0.05). The median OS in the Embo-TAE group was longer than that in the cTACE group (74.0 weeks, 95% CI: 68.2-79.8 vs. 61.7 weeks, 95% CI: 56.2-67.2 weeks) (unadjusted P=0.045). The use of Embo-TAE significantly reduced the risk of death in patients with GIST with liver metastases according to the Cox proportional hazards regression model [hazard ratio (HR): 0.149; 95% CI: 0.064-0.475]. CONCLUSIONS: TAE with Embosphere(®) showed better treatment response and delayed tumor progression compared with cTACE. There was no significant difference in treatment-related hepatic toxicities. Embo-TAE thus appears to be a feasible and promising approach in the treatment of liver metastasis from GIST.

[Extrahepatic collateral arteries are involved in the blood supply to hepatocellular carcinoma: angiographic demonstration and transcatheter arterial chemoembolization].

OBJECTIVE: To evaluate the incidence of extrahepatic collateral arteries involved in the blood supply to hepatocellular carcinoma (HCC) and to assess the technical success rates and complications of transcatheter arterial chemoembolization (TACE) through the collaterals. METHODS: 1356 TACE procedures were performed in 874 consecutive patients through extrahepatic collateral pathways to HCC between August 2006 and August 2010 in our department. The extrahepatic collateral pathways to HCC revealed on angiography were retrospectively evaluated. TACE through extrahepatic collaterals using iodized oil and gelatin sponge particles was performed when a catheter was advanced into the feeding branch to avoid nontarget embolization. RESULTS: Incidences of collateral source to HCC were 76.3% from the right inferior phrenic artery (RIPA), 2.4% from the left inferior phrenic artery (LIPA), 6.9% from the right and 0.4% from the left internal mammary arteries (RIMA, LIMA), 2.9% from the right intercostal artery (RICA), 2.0% from the omental artery, 0.8% from the right or middle colic artery, 2.3% from the cystic artery, 1.3% from the left and 1.1% from the right gastric arteries (LGA, RGA), 3.5% from the right renal capsular artery (RRCA), right middle adrenal artery (RMAA) and right inferior adrenal artery (IAA). Technical success rates of TACE were 95.9% in the RIPA, 93.8% in the LIPA, 100.0% in the RIMA and LIMA, 55.0% in the RICA, 77.8% in the omental artery, 63.6% in the colic artery, 67.7% in the cystic artery, 76.5% in the LGA, 73.3% in the RGA and 95.8% in the RRCA, RMAA, and RIAA. Complications included skin erythema and necrosis after TACE through the RIMA, skin erythema after TACE through the RICA, cholecystitis after TACE through the cystic artery (n = 1), and pleural effusion, basal atelectasis and hiccup after TACE through the IPA. CONCLUSION: TACE through extrahepatic collaterals is safe and feasible, and with a high success rate in the treatment of hepatocellular carcinoma.

[Action characteristics of the cell cycle nonspecific agents in cell lines in the state of continuous transartery chemotherapy infusion].

OBJECTIVE: To detect the acting pattern of different high concentrations of cell cycle nonspecific agents (CCNSA), epirubicin, oxaliplatin, cisplatin and fotemustine, acting with HepG-2 and 7702 cell lines respectively for different times; and to explore whether there are concentration and time dependent phenomena for each agent and relations between these two factors. METHODS: MTT assays were used to detect inhibition rates of different combinations of concentrations and times in all the agents. Five concentrations were chosen for each agent within the range of clinical practice in interventional therapy by the ratios of 20:10:5:2.5:1, the highest concentrations of epirubicin, oxaliplatin, cisplatin and fotemustine was 8 mg/L, 20 mg/L, 20 mg/L and 8 mg/L respectively, and each concentration acted with HepG-2 and 7702 cell lines at 5 different time points which lasted for 1 h, 2 h, 4 h, 6 h, and 8 h, respectively. RESULTS: Different combinations of concentrations and time points had different inhibition rates for HepG-2 and 7702 cell lines. For epirubicin and oxaliplatin, the inhibition rates of 5 concentrations had little difference, which mainly depended on time and increased with the increase of lasting time; cisplatin showed different characteristics: at low concentrations, the inhibition rate increased slowly with the increase of lasting time, but with the increase of concentration, the inhibition rate increased obviously with the increase of lasting time. The inhibition rate of fotemustine lacked obvious connection with the concentrations, but increased with the time at any cencentration. CONCLUSION: Different CCNSA have their own suitable concentration and time factors, both factors have obvious influence on the inhibition rate, and the time factor seems more important. Since transartery infusion can provide enough or even over-dose concentrations, the minimum effective concentration and enough time should be chosen, which could increase the killing of tumor cells, and at the same time decrease the total dose, thus realizing precise artery chemotherapy.

Identification and Validation of Hub Genes in the Stenosis of Arteriovenous Fistula.

Arteriovenous fistula (AVF) is the most widely used hemodialysis vascular access in China. However, stenosis of the AVF limits its use. The mechanism of AVF stenosis is currently unknown. Therefore, the purpose of our study was to explore the mechanisms of AVF stenosis. In this study, we identified the differentially expressed genes (DEGs) based on the Gene Expression Omnibus (GEO) dataset (GSE39488) between venous segments of AVF and normal veins. A protein-protein interaction (PPI) network was constructed to identify hub genes of AVF stenosis. Finally, six hub genes (FOS, NR4A2, EGR2, CXCR4, ATF3, and SERPINE1) were found. Combined with the results of the PPI network analysis and literature search, FOS and NR4A2 were selected as the target genes for further investigation. We validated the bioinformatic results via reverse transcription PCR (RT-PCR) and Western blot analyses on human and rat samples. The expression levels of the mRNA and protein of FOS and NR4A2 were upregulated in both human and rat samples. In summary, we found that FOS may play an important role in AVF stenosis, which could be a potential therapeutic target of AVF stenosis.

Role of ferroptosis-related molecular patterns in hepatocellular carcinoma microenvironment.

Heterogeneity and complexity of hepatocellular carcinoma (HCC) have been an impediment to effective diagnosis and treatment of HCC. Mounting evidence suggests that ferroptosis-related genes (FRGs) regulate the development of HCC by affecting the tumor microenvironment (TME). Herein, we explored the role of ferroptosis-related molecular patterns in the HCC microenvironment. The transcriptome and corresponding clinicopathological data of HCC patients were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, respectively. Molecular patterns of ferroptosis were explored using consensus clustering analysis and ferroptosis-related molecular patterns in the individual patients were analyzed using principal component analysis (PCA). The ability of ferroptosis-related patterns to predict the biological status and survival outcomes of HCC patients was investigated. Based on the expression of FRGs, three molecular patterns related to ferroptosis were identified. Single sample gene set enrichment analysis (ssGSEA) showed that the molecular patterns associated with the worst prognosis were significantly correlated with high infiltration of immunosuppressive cells in the TME. Besides, we identified three ferroptosis gene clusters underlying the different biological features of the three ferroptosis patterns. Patients in the high-risk group had a worse biological status and survival outcomes than those in the low-risk group. This study demonstrates that ferroptosis-related molecular patterns lead to high heterogeneity in HCC. These molecular patterns can be used to assess the survival of HCC patients and guide the design of immunotherapy strategies for HCC patients.

Hepatic Artery Injection of 131I-Metuximab Combined with Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: A Prospective Nonrandomized, Multicenter Clinical Trial.

This prospective nonrandomized, multicenter clinical trial was performed to investigate the efficacy and safety of 131I-labeled metuximab in adjuvant treatment of unresectable hepatocellular carcinoma. Methods: Patients were assigned to treatment with transcatheter arterial chemoembolization (TACE) combined with 131I-metuximab or TACE alone. The primary outcome was overall tumor recurrence. The secondary outcomes were safety and overall survival. Results: The median time to tumor recurrence was 6 mo in the TACE + 131I-metuximab group (n = 160) and 3 mo in the TACE group (n = 160) (hazard ratio, 0.55; 95% CI, 0.43-0.70; P < 0.001). The median overall survival was 28 mo in the TACE + 131I-metuximab group and 19 mo in the TACE group (hazard ratio, 0.62; 95% CI, 0.47-0.82; P = 0.001). Conclusion: TACE + 131I-metuximab showed a greater antirecurrence benefit, significantly improved the 5-y survival of patients with advanced hepatocellular carcinoma, and was well tolerated by patients.

[Design & fabrication of porous core implant with preset channel network for osteonecrosis of the femoral head].

Referring to the anatomical characterization of natural spongy bone and channel network in cortical bone, we designed a new pattern of biomimetic impalnt with preset channel for blood vessel inserting to treat early femoral head necrosis. The surgical ptrocedure was simulated by CAD model. Ceramic stereolithography was applied to fabricate the green part. Other process, such as dehydration, rinsing, drying and sintering, were taken successively. The final ceramic part kept identical with the engineered part either in the shape or in the internal structure. No deformation or crack happened. Pore size, interconnected pore size, porosity and interconnected porosity of ceramic part could satisfy cellular grouth. Spectrum analysis showed that no phase transition or chemical reaction happened during fabrication process. The biocompatibility of the final part kept the same with original during beta-TCP powder. The compressive strength was 23.54 MPa, close to natural spongy bone. It is an ideal implant to treat early femoral head necroseis because it makes preimplantation of cells and biological factors, blood velssel inserting, early establishment of blood supply possible. At the same time, it could provide enough mechanical support to prevent collapse of femoral head. It could provide a wide clinical foreground.

Characterization of diagnostic and prognostic significance of cell cycle-linked genes in hepatocellular carcinoma.

BACKGROUND: The high degree of heterogeneity of hepatocellular carcinoma (HCC) imposes a significant challenge to predict the prognosis. Currently, increasing evidence has indicated that cell cycle-linked genes are strongly linked to occurrence and progress of HCC. Herein, we purposed to create a prediction model on the basis of cell cycle-linked genes. METHODS: The transcriptome along with clinicopathological data abstracted from The Cancer Genome Atlas (TCGA) were used as a training cohort. Lasso regression analysis was employed to create a prediction model in TCGA cohort. The data of samples obtained from the International Cancer Genome Consortium (ICGC) data resource were applied in the verification of the model. A series of bioinformatics analyzed the relationship of the risk signature with overall survival (OS), biological function, and clinicopathological features. RESULTS: Six cell cycle-linked genes (PLK1, CDC20, HSP90AA1, CHEK1, HDAC1, and NDC80) were chosen to create the prognostic model, demonstrating a good prognostic capacity. Further analyses indicated that the model could independently assess the OS of HCC patients. A single-sample gene set enrichment analysis (ssGSEA) indicated that the risk signature was remarkably linked to immune status. Additionally, there was a remarkable association of the risk signature with TP53 mutation frequency, as well as immune checkpoint molecule expression levels. CONCLUSIONS: We created a prediction model using six cell cycle-linked genes to predict HCC prognosis. The six genes are expected to be novel markers for HCC diagnosis, as well as treatment.

Identification and validation of ADME genes as prognosis and therapy markers for hepatocellular carcinoma patients.

PURPOSE: ADME genes are genes involved in drug absorption, distribution, metabolism, and excretion (ADME). Previous studies report that expression levels of ADME-related genes correlate with prognosis of hepatocellular carcinoma (HCC) patients. However, the role of ADME gene expression on HCC prognosis has not been fully explored. The present study sought to construct a prediction model using ADME-related genes for prognosis of HCC. METHODS: Transcriptome and clinical data were retrieved from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC), which were used as training and validation cohorts, respectively. A prediction model was constructed using univariate Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) analysis. Patients were divided into high- and low-risk groups based on the median risk score. The predictive ability of the risk signature was estimated through bioinformatics analyses. RESULTS: Six ADME-related genes (CYP2C9, ABCB6, ABCC5, ADH4, DHRS13, and SLCO2A1) were used to construct the prediction model with a good predictive ability. Univariate and multivariate Cox regression analyses showed the risk signature was an independent predictor of overall survival (OS). A single-sample gene set enrichment analysis (ssGSEA) strategy showed a significant relationship between risk signature and immune status. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed differentially expressed genes (DEGs) in the high- and low-risk groups were enriched in biological process (BP) associated with metabolic and cell cycle pathways. CONCLUSION: A prediction model was constructed using six ADME-related genes for prediction of HCC prognosis. This signature can be used to improve HCC diagnosis, treatment, and prognosis in clinical use.

A hypoxia-linked gene signature for prognosis prediction and evaluating the immune microenvironment in patients with hepatocellular carcinoma.

BACKGROUND: Previous research indicates that hypoxia critically affects the initiation and progression of hepatocellular carcinoma (HCC). Nevertheless, the molecular mechanisms responsible for HCC development are poorly understood. Herein, we purposed to build a prognostic model using hypoxia-linked genes to predict patient prognosis and investigate the relationship of hypoxia with immune status in the tumor microenvironment (TME). METHODS: The training cohort included transcriptome along with clinical data abstracted from The Cancer Genome Atlas (TCGA). The validation cohort was abstracted from Gene Expression Omnibus (GEO). Univariate along with multivariate Cox regression were adopted to create the prediction model. We divided all patients into low- and high-risk groups using median risk scores. The estimation power of the prediction model was determined with bioinformatic tools. RESULTS: Six hypoxia-linked genes, HMOX1, TKTL1, TPI1, ENO2, LDHA, and SLC2A1, were employed to create an estimation model. Kaplan-Meier, ROC curve, and risk plot analyses demonstrated that the estimation potential of the risk model was satisfactory. Univariate along with multivariate regression data illustrated that the risk model could independently predict the overall survival (OS). A nomogram integrating the risk signature and clinicopathological characteristics showed a good potential to estimate HCC prognosis. Gene set enrichment analysis (GSEA) revealed that genes associated with cell proliferation and metabolism cascades were abundant in high-risk group. Furthermore, the signature showed a strong ability to distinguish the two groups in terms of immune status. CONCLUSIONS: A prediction model for predicting HCC prognosis using six hypoxia-linked genes was designed in this study, facilitating the diagnosis and treatment of HCC.

Identification and validation of ferroptosis-associated gene-based on immune score as prognosis markers for hepatocellular carcinoma patients.

BACKGROUND: Ferroptosis has been found to affect the prognosis and immunotherapy of hepatocellular carcinoma (HCC). However, the association between ferroptosis-related genes and infiltrating immune cells in tumor immune microenvironment (TIME) has not been fully elucidated. This study aimed at establishing a prediction model for the progression of HCC using ferroptosis-associated genes based on immune score. METHODS: Transcriptomic, mutation and clinicopathological information were downloaded from TCGA and International Cancer Genome Consortium (ICGC) for this study. Construction of the prediction model was done by Lasso regression analysis. Estimation of the clustering ability of the prediction model was done by t-distributed stochastic neighbor embedding (t-SNE) and principal component analysis (PCA) analyses. Assessment of the accuracy of the prediction model was done by receiver operating characteristic (ROC) and Kaplan-Meier curves. RESULTS: A prediction model was formulated utilizing three ferroptosis-related genes (G6PD, SAT1 and SLC1A5). The model independently predicted the overall survival (OS). Differentially expressed genes (DEGs) linked to based on Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analyses immune-associated pathways and functions. Single-sample gene set enrichment analysis (ssGSEA) strategy further confirmed the model was related to immune-associated functions as well as immune cell infiltration. CONCLUSIONS: The three ferroptosis-associated gene-based prediction model was good at predicting the OS outcomes of HCC, improve HCC prognostication and treatment in the clinic.

Combination Therapy of Chemoembolization and Hepatic Arterial Infusion Chemotherapy in Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis Compared with Chemoembolization Alone: A Propensity Score-Matched Analysis.

BACKGROUND: Survival of patients with portal vein tumor thrombosis (PVTT) is extremely poor; transarterial chemoembolization (TACE) is a treatment for patients with HCC and PVTT. Some studies showed that hepatic arterial infusion chemotherapy (HAIC) might improve the survival of HCC with PVTT. There were few researches of combining TACE with HAIC for patients with HCC and PVTT. AIM: This study was aimed at comparing overall survival (OS) and progression-free survival (PFS) following treatment with conventional transarterial chemoembolization plus hepatic arterial infusion chemotherapy (cTACE-HAIC) or conventional transarterial chemoembolization (cTACE) alone in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT). METHODS: From January 2011 to December 2016, 155 patients with HCC and PVTT who received cTACE-HAIC (cTACE-HAIC group) (n = 86) or cTACE alone (cTACE group) (n = 69) were retrospectively evaluated. Propensity score matching (PSM) reduced the confounding bias and yielded 60 matched patient pairs. The tumors' responses were evaluated using the modified response evaluation criteria in solid tumors (mRECIST). OS and PFS of groups were compared using the Kaplan-Meier method, log-rank test, and Cox proportional hazard regression models. RESULTS: The median follow-up duration was 93 months (range: 1-93 months). The cTACE-HAIC group's OS (9.0 months) and PFS (6.0 months) were significantly longer than the cTACE group's OS (5.0 months) and PFS (2.0 months) (p = 0.018 and p = 0.045, respectively) in the matched cohort. Multivariate analyses showed that cTACE-HAIC was independently associated with OS (hazard ratio (HR) 0.602, p = 0.010) and PFS (HR 0.66, p = 0.038). The matched groups did not differ regarding grade 3 or 4 adverse events. CONCLUSION: cTACE-HAIC was superior to cTACE alone regarding OS and PFS in patients with HCC and PVTT. Treatment-associated toxicities were generally well tolerated.

Genetic variations and haplotypes in TIM-3 gene and the risk of gastric cancer.

PURPOSE: T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) could weaken the Th1-mediated anti-tumor responses and accelerate the tumor cell proliferation by inhabiting the production of IL-2 or IFN-γ. This study was to assess the association between TIM-3 genetic variations and the development of gastric cancer. PATIENTS AND METHODS: Five polymorphisms located in the promoter or encoding region of TIM-3 gene were genotyped in 212 gastric cancer patients and 252 controls who matched with the patients on the frequency of age, gender, smoking, and drinking. Logistic regression was used to determine whether the inherited variations within TIM-3 gene were associated with gastric cancer risk. Linkage disequilibrium and Haplotype analyses were performed by using SHEsis program. RESULTS: By the individual genotype analysis, three polymorphisms (-574G/T, -882C/T, and -1516G/T) within TIM-3 gene were significantly associated with gastric cancer in the study population [ORs (95% CIs): 2.74 (1.21-6.20), 3.19 (1.29-7.91), and 2.03 (1.15-3.59); respectively]. Among the gastric cancer patients, the relationship between the -1516 polymorphic genotype and the distant metastasis of tumor was found (OR = 2.21, 95% CI = 1.05-4.63). Under the analysis of haplotypes, an even stronger association with haplotype TTGCT was observed in gastric cancer risk (OR = 5.57, 95% CI: 1.04-29.80, P = 0.024). CONCLUSION: These results indicated that the three genetic variations within the TIM-3 gene promoter may be associated with the increased susceptibility to gastric cancer, especially among the haplotypes with the risk.

Transarterial chemoembolization with hepatic arterial infusion chemotherapy plus S-1 for hepatocellular carcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) have shown promising local benefits for advanced hepatocellular carcinoma (HCC). S-1, a composite preparation of a 5-fluorouracil prodrug, has proven to be a convenient oral chemotherapeutic agent with definite efficacy against advanced HCC. AIM: To evaluate the efficacy and safety of TACE followed by HAIC with or without oral S-1 for treating advanced HCC. METHODS: In this single-center, open-label, prospective, randomized controlled trial, 117 participants with advanced HCC were randomized to receive TACE followed by oxaliplatin-based HAIC either with (TACE/HAIC + S-1, n = 56) or without (TACE/HAIC, n = 61) oral S-1 between December 2013 and September 2017. Two participants were excluded from final analysis for withdrawing consent. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate, disease control rate and safety. RESULTS: In total, 115 participants (100 males and 15 females; mean age, 57.7 years ± 11.9) were analyzed. The median PFS and OS were 5.0 mo (0.4-58.6 mo) (95% confidence interval (CI): 3.82 to 6.18) vs 4.4 mo (1.1-54.4 mo) (95%CI: 2.54 to 6.26; P = 0.585) and 8.4 mo (0.4-58.6 mo) (95%CI: 6.88 to 9.92) vs 8.3 mo (1.4-54.4 m) (95%CI: 5.71 to 10.96; P = 0.985) in the TACE/HAIC + S-1 and TACE/HAIC groups, respectively. The objective response rate and disease control rate were 30.9% vs 18.4% and 72.7% vs 56.7% in the TACE/HAIC + S-1 and TACE/HAIC groups, respectively. Grade 3/4 adverse events had a similar frequency in both treatment groups. CONCLUSION: No improvements in tumor response rates, PFS or OS were observed with the addition of S-1 to TACE/HAIC in advanced HCC. Both treatment regimens had a similar safety profile.

Transcatheter arterial chemoembolization experience for advanced hepatocellular carcinoma with right atrial tumor thrombus.

BACKGROUND: Hepatocellular carcinoma (HCC) with tumor thrombus extending to the inferior vena cava (IVC) and right atrium (RA) is rare, which is generally associated with serial syndromes and poor prognosis. The results of earlier observations revealed that the median survival was 1-5 months after diagnosis for untreated patients. The prognosis was poor with surgery, radiotherapy, transarterial chemoembolization (TACE), and chemotherapy. METHODS: A total of 1850 patients received TACE for advanced HCC at our institution from October 2011 to September 2016. Among them, 18 cases presented tumor thrombus extended from hepatic vein to IVC and RA. TACE was performed to deal with the tumor thrombus inside the RA, and angiography was performed for characterizing. The successful rate, survival, safety, and clinical adverse events were retrospectively studied. RESULTS: A total of 56 interventional procedures were conducted for the 18 cases of tumor thrombus extending to IVC and RA. TACE were successfully performed in all patients without significant complications. One case died of pneumonia, and no severe adverse effect was observed in the other 17 cases. The 1- and 3-year overall survival rates were 50% and 16.7%, respectively. The average survival from diagnosis of right atrial tumor thrombus (RATT) was 15.2 months. The blood supply was rich for all RATT. There were seven cases with single-feeding artery and 11 cases with two or three feeding arteries that originated from intra- or extra-hepatic arteries. The extrahepatic artery played a critical role in the blood supply of RATT, including right inferior phrenic artery (8/18), left inferior phrenic artery (1/18), and the left gastric artery (2/18). CONCLUSION: For HCC with tumor thrombus in the IVC and RA, TACE could safely improve the prognosis of these patients. Searching for multiple feeding arteries are essential for ensuring efficacy. In addition, careful examination and appropriate embolization technique are essential for safety and efficacy. Lipiodol was a safe and ideal agent for the embolization in RATT.

Hepatic Artery and Peripheral Vein Pharmacokinetics of Raltitrexed in Swine After the Administration of a Hepatic Arterial Infusion.

BACKGROUND: Hepatic Arterial Infusion (HAI) with raltitrexed has become an effective treatment for hepatocellular cancer and colorectal cancer liver metastases. However, traditional Body Surface Area (BSA)-based dosing is unsafe or ineffective, and a more accurate model-based approach is required. METHODS: In this study, domestic swine were given 1 mg or 4 mg raltitrexed administered by an HAI with infusion times of 30, 60 and 120 min. Hepatic Artery (HA) and Peripheral Vein (PV) samples were collected, and a twocompartment model with an elimination pathway was established to describe the in vivo behavior of raltitrexed. RESULTS: The clearance was 0.27 L/min, and the volumes of distribution were 0.35 and 6.65 L for the HA and PV compartments, respectively. The goodness-of-fit plots and visual predictive checks suggested that the proposed pharmacokinetic model agreed well with the observations. CONCLUSION: The pharmacokinetic model could be helpful in quantitatively describing the detailed processes of raltitrexed activity administered by HAI and determining an appropriate dosing regimen for preclinical and clinical studies.