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.

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.

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.

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.

Effect of primary tumor side on survival outcomes in metastatic colorectal cancer patients after hepatic arterial infusion chemotherapy.

AIM: To analyze the survival data between patients diagnosed with right-sided primary (RSP) tumors and patients diagnosed with left-sided primary (LSP) tumors after hepatic arterial infusion chemotherapy (HAIC) at our center. METHODS: A retrospective analysis of pretreated metastatic colorectal cancer patients who received HAIC from May 2006 to August 2015 was conducted. A Cox proportional hazard regression analysis was used to assess the long-term survival outcomes. The mean and median age of patients was 61 years (range 27-85 years). There were 115 males and 53 females in our study. RESULTS: One hundred sixty-eight patients were enrolled in this study. The overall response rate was 28.9% in LSP patients and 27.3% in RSP patients. The disease control rate was 76.3% in LSP patients and 69.7% in RSP patients. The median overall survival in response to HAIC was 16.3 mo in the LSP arm and 9.3 mo in the RSP arm (P = 0.164). The median progression-free survival was 5.7 mo in the LSP arm and 4.2 mo in the RSP arm (P = 0.851). CONCLUSION: There was no significant difference in survival between LSP patients and RSP patients after HAIC. Further prospective studies are needed to confirm these findings.

Transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed for hepatocellular carcinoma with major portal vein tumor thrombus.

AIM: To determine the efficacy and safety of transarterial embolization and low-dose continuous hepatic arterial infusion chemotherapy with oxaliplatin and raltitrexed in hepatocellular carcinoma (HCC) with major portal vein tumor thrombus (MPVTT). METHODS: Eighty-six patients with MPVTT accepted routine embolization. The catheter was kept in the hepatic artery and oxaliplatin (50 mg in 250 mL of glucose) was infused by pump for 4 h, followed by raltitrexed (2 mg in 100 mL of 0.9% saline) infusion by pump for the next 1 h. The efficacy and safety were evaluated after the transarterial chemoembolization (TACE). RESULTS: Full or partial embolization was achieved in 86 cases, where all the cases received low dose continuous hepatic arterial infusion chemotherapy. Complete responses (CRs), partial responses (PRs), stable disease (SD), and disease progression (PD) for intrahepatic disease were observed in 0, 45, 20, and 21 patients, respectively. The 1-, 2-and 3-year overall survival rates of the 86 patients were 40.7%, 22.1%, and 8.1% respectively, and the median survival time was 8.7 mo. Complication was limited. CONCLUSION: TACE with low dose continuous hepatic arterial infusion of oxaliplatin and raltitrexed could be an option in MPVTT patient; it was shown to be effective in patients with advanced HCC with MPVTT with less toxicity.

Role of inferior phrenic artery in the interventional treatment of lung metastases tumor: A report of 11 cases.

BACKGROUND: Lung metastases have been very common in advanced cancer, which were observed in 30%-40% of cancer cases. Transarterial chemoembolization (TACE) is one of the choice for treating lung cancer. In our center, 119 cases of lung metastases were treated with TACE, and we found that inferior phrenic artery (IPA) played an important role in this procedure. MATERIALS AND METHODS: From June 2011 to June 2015, 119 cases with malignant lung metastases received TACE procedure in our center. The TACE procedure was performed through bronchial artery (BA) and collateral arteries. In these 11 cases, we found that part of metastatic lesions was supplied by the IPA. Angiography and embolization technique, successful rate, safety and clinical adverse events, and survival were retrospectively studies. RESULTS: The lung metastases were mainly supplied by BA, thoracic artery, and intercostal artery. In 11 cases, the IPA was involved in the blood supply of lung metastases (9.2%). Right IPA (RIPA), left IPA (LIPA), and both LIPA and RIPA were involved in blood supply of 6, 3, and 2 cases of lung metastases, respectively, especially for the lesions located in the lower lobe of the lung. All lesions of the 11 cases were successfully embolized; no diaphragmatic dysfunction and spinal cord injury or other serious complications were observed. The average survival time was 14.7 months since the diagnosis of lung metastases. CONCLUSION: The IPA was an important feeding artery for lung metastases, especially for lesions in the lower lung lobe. It should be searched as much as possible for achieving complete embolization of metastases.

Cytotoxic activity of anticancer drugs on hepatocellular carcinoma cells in hypoxic-hyponutritional culture.

To investigate which anticancer drugs and combination of dual drugs could further promote the inhibition of cell growth in vitro against HCC cell line (HepG2) in the hypoxic and hyponutritional culture medium (HHCM) mimicked the different scenarios of transcatheter arterial chemoembolization (TACE). The cells of hepatocellular carcinoma (HCC) treated by TACE suffered various hypoxia and hyponutrition. The cells were treated for 2 hours, 4 hours, 6 hours, and 24 hours, respectively, using 10 drugs including epirubicin (EPI), cisplatin (DDP), mitomycin-C (MMC), oxaliplatin (OXA), hydroxycamptothecin (HCPT), 5-fluorouracil (5-FU), gemcitabine (GEM), docetaxel (DTX), thiotepa (TSPA), and pemetrexed disodium (PEM) in 4 concentrations of HHCM (5%, 10%, 25%, and 50%, respectively) mimicking the scenario of TACE and were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The cells treated with combinations of dual drugs for 24 hours were also tested. The sensitive drugs with inhibition rates more than 30% were EPI, MMC, HCPT, OXA, and PEM in 4 types of HHCMs. The sensitivity of the cells to treatment with drugs for 24 hours was significantly higher than the sensitivity of the cells to treatment with drugs for 2 hours in 5%, 10%, and 25% HHCM. The sensitivity of the combination of dual drugs was no more than the sensitivity of the single drug with higher sensitivity in 4 concentrations of HHCM. EPI, MMC, HCPT, OXA, and PEM exhibited cytotoxic activity against HepG2 cells in various hypoxia and hyponutrition states. Prolonging the time of exposure could increase the sensitivity of drug, and the combination of dual drugs cannot enhance the cytotoxic effect.

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.

[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.

[Digital subtraction angiography manifestation and interventional therapy of arteriovenous shunting in primary hepatocellular carcinoma of advanced stage].

OBJECTIVE: To explore the appearances of digital subtraction angiography (DSA) and therapeutic efficacy of interventional therapy of hepatic carcinoma accompanied with arteriovenous shunting (AVS). METHODS: To retrospectively analyze clinical material of 97 patients with hepatocellular carcinoma with hepatic artery-portal vein shunting(HA-PVS), of whom, 16 had upper gastrointestinal hemorrhage, 51 had middle to large amounts of ascites, and 53 had varices of esophagus and fundus gastricus. All the patients were treated with transcatheter arterial chemoembolization (TACE) or transcatheter arterial infusion chemotherapy (TAI). Shunts were embolized by lipidol in 40 patients, by lipidol and sponjgia gelatinosa particle in 34 patients, and by coil in 6 patients. The remaining 17 were treated only with TAI. RESULTS: Twelve (12.4%) cases had hepatic arteryjhepatic vein shunting (HA-HVS)ìwhile 32 (33%)cases had portal vein tumor thrombosis (PVTT). In 70(72.2%) patients, all shunts were completely closed successfully, in 15(15.5%) patients, the shunts were partly closed, and in 12(12.3%)patients, the shunts were not closed. In 12 patients, the shunts reopened in later therapy, their blood flow was smaller than before and they were closed after second embolization. In 17 patients, new shunts emerged. After TACE therapy ìthe tumors were smaller in 57(58.7%)ìbigger in 24 (24.7%)ìand 16(16.5%) were the same in size before and after TACE. Ascites disappeared in 29 patients, decreased in 18 patients and had no change in 4 patients. Five patients who had upper gastrointestinal hemorrhage prejoperation had new hemorrhage. Of the 47 patients who had diarrhea, 23 improved. In 67 alpha fetoprotein (AFP) positive patients, degree of AFP in 53 patients decreased. Eighty-one patients died and their middle survival period was 12.9 months. No serious damage to hepatic function due to the treatment was observed in most patients. CONCLUSION: Primary hepatic carcinoma with AVS increases difficulty of interventional therapyìbut as long as we take active and proper treating measureìwe could acquire satisfactory curative effect without serious syndrome. DSA can demonstrate the type, the site and the degree of AVS completely and directly, thus having important value in treating primary hepatic carcinoma and improving prognosis.

[Detection rate of human papillomavirus-16 in esophageal squamous cell carcinoma from different Chinese populations].

BACKGROUND & OBJECTIVE: Anyang in Henan Province of China is a hyperendemic area of esophageal cancer. The infection of human papillomavirus (HPV) is thought as an important pathogenesis of esophageal cancer in Anyang. This study was to detect infection rate and level of HPV-16 in esophageal squamous cell carcinoma (ESCC) patients from 3 different Chinese areas, and investigate its relationship with the pathogenesis of ESCC. METHODS: Infection status of HPV-16 in 119 ESCC specimens (43 collected from Anyang, 43 from Beijing, and the rest 33 from Mongolia nationality of Inner Mongolia) was detected by in situ hybridization (ISH) technique with digoxin-labeled HPV-16 E6 probe. RESULTS: HPV16 infection rates were 81.4%, 69.8%, and 63.6% in the specimens from Anyang, Beijing, and Inner Mongolia, respectively. Infection level of HPV-16 was significantly higher in Anyang group than in Beijing group (H=3.91, P<0.05) and Inner Mongolia group(H=4.22,P<0.05). There was no significant difference between the latter 2 groups. Furthermore, the proportion of strong expression of HPV16 (++ and +++) was significantly higher in Anyang group than in the other 2 groups(H=3.95, P<0.05). CONCLUSIONS: HPV-16 infection rate is high in the esophageal specimens from the 3 different areas. Infection status of HPV16 is serious in Anyang.

Studies on alginate-chitosan microcapsules and renal arterial embolization in rabbits.

Spherical and well-dispersed alginate-chitosan microcapsules, with a mean diameter of 77.28+/-0.93 microm (n=3), were prepared by the emulsification-gelation method. Adriamycin hydrochloride (ADM) was used as a model drug to investigate the drug loading capacity and release characteristics of the microcapsules. The drug/carrier ratio and chitosan concentration influenced the encapsulation efficiency of adriamycin. The adriamycin release from microcapsules was obviously different in 0.1 mol/l HCl from that in phosphate-buffered saline (PBS, pH 7.4). The drug was completely and rapidly released in 0.1 mol/l HCl, while it showed a sustained release after a burst release in PBS. The increase in chitosan concentration had no effect on adriamycin release in PBS. Using sulforhodamin B (SRB)-staining survival assay, the inhibition of adriamycin alginate-chitosan microcapsules (ADM-ACM) to different cancer cell lines (human BGC-823 cells, Bel-7402 cells and Hela cells) in vitro was determined. The inhibitory rate of ADM-ACM suspension to the three cell lines significantly outran that of ADM solution, no matter at high or low concentration. The effects of blank alginate-chitosan microcapsules (BACM) on renal arterial embolization were examined with transcatheter arterial embolization in rabbits. The angiogram and histopathological results indicated the blank microcapsules had excellent short- and long-term effects on renal arterial embolization.