Cryoablation with drug-loaded bead embolization in the treatment of unresectable hepatocellular carcinoma: safety and efficacy analysis.

This study aimed to explore the efficacy and safety of drug-eluting bead (DEB) embolization (DEB-TACE) when combined with cryoablation in the treatment of unresectable hepatocellular carcinoma (HCC). The study was a single-center randomized controlled trial comprised of 60 patients with HCC conducted between August 2015 and October 2017. The patients were randomly divided into two groups: DEB-TACE combined with cryoablation (DEB-TACE-Cryo group) or cryoablation alone (Cryo group). Inter-group differences in overall survival, progression-free survival, and adverse reactions were assessed. The operative success rates were 82.7% and 77.4% in the DEB-TACE-Cryo group and Cryo group, respectively, with no operative mortality. The overall survival and progression-free survival in the DEB-TACE-Cryo group were significantly higher than those in the Cryo group (16.8 months vs.13.4 months, P = 0.0493; 8.1 months vs. 6.0 months, P = 0.0089, respectively). The postoperative complications in the two groups were rated as grade 1 or grade 2, according to guidelines set by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE V4.0). We demonstrated that DEB-TACE combined with cryoablation was effective, well tolerated, and had a low complication rate. Therefore, this combination therapy may be a better choice for the treatment of unresectable hepatocellular carcinoma.

Digitoxin induces apoptosis in cancer cells by inhibiting nuclear factor of activated T-cells-driven c-MYC expression.

BACKGROUND: Cardiac glycosides such as digitoxin have been shown to directly cause apoptotic death of cancer cells both in vitro, and in vivo. However, the mechanism connecting cardiac glycoside action to apoptosis is not known. It has been reported that compounds resembling digitoxin are able to reduce c-MYC expression. Furthermore, it has been previously shown that the transcription of c-MYC depends on nuclear factor of activated T-cells (NFAT) binding sites in the c-MYC promoter. We have therefore hypothesized that NFAT might mediate digitoxin effects on c-MYC mRNA message. MATERIALS AND METHODS: We have chosen to study this process in HeLa cells where structurally intact c-MYC genes in 8q24 co-localize with human papilloma virus 18 at all integration sites. RESULTS: Here we show that within the 1(st) h following treatment with digitoxin, a significant reduction in c-MYC mRNA occurs. This is followed by a precipitous loss of c-MYC protein, activation of caspase 3, and subsequent apoptotic cell death. To test the NFAT-dependence mechanism, we analyzed the effects of digitoxin on NFAT isoform-dependent auto-activation of a NFAT-luciferase expression system. Drug dependent effects on expression varied according to each of the four canonical NFAT isoforms (1, 2, 3 or 4). The most digitoxin-sensitive NFAT isoform was NFAT1. Using c-MYC chromatin immune precipitation, we find that digitoxin inhibits interaction of NFAT1 with the proximal c-MYC promoter. CONCLUSIONS: These results suggest that the carcinotoxic activity of digitoxin includes suppression of NFAT-driven c-MYC expression.

Epidemiology of esophageal cancer in Yanting - regional report of a national screening programme in China.

BACKGROUND AND OBJECTIVES: Yanting in Sichuan Province is one of the highest risk areas of esophageal cancer (EC) in the world. We here summarize the epidemiology of EC in Yanting using data from the national screening programme during 2006-2011. METHODS: Random cluster sampling was used to select a proportion of natural villages from six towns in Yanting, and residents aged 40-69 years old were invited for screening. Participants were screened using endoscopy with iodine staining and then confirmed by histological examinations. RESULTS: The overall detection rates of low-grade hyperplasia (LH), moderate hyperplasia (MH), high-grade hyperplasia (HH), carcinoma in situ (CIS), intramucosal carcinoma (IC) and invasive carcinoma (INC) were 5.33%, 1.28%, 0.68% , 0.15% , 0.06% and 0.29%, respectively. The detection rates of LH, MH, HH and INC increased with age, reaching the peak among those aged 60-65 years, and the prevalences of LH and MH were higher among men than among women. In addition, the detection rates of hyperplasia were much higher in mountainous than in hilly areas. CONCLUSIONS: Among the high risk population, there are a great number of people with early-stage EC or precancerous conditions who do not have presenting symptoms. In particular, the elderly, men, or those living in mountainous areas are the most vulnerable population. It is therefore important to reinforce health education and screening services among such high risk populations.

[Results of a screening program on high incidence area of esophageal cancer in Yanting Sichuan from 2006 to 2011].

OBJECTIVE: To study the prevalence of esophageal cancer and various lesions of esophagus in high risk areas through a screening program for early diagnosis and treatment. METHODS: Random cluster sampling method was used to select some portions of a natural village as screening object in the high risk areas of esophageal cancer, from 2006 to 2011. Endoscope iodine staining and index biopsy screening methods were used on people with high risk and followed by pathological exams for confirmation. RESULTS: The detection rates regarding mild esophageal hyperplasia, moderate and severe esophageal hyperplasia were 5.33% (803/15 065), 1.28% (193/15 065), 0.68% (102/15 065) respectively while the detection rates on carcinoma in situ, intramucosal carcinoma and invasive cancer were 0.15% (22/15 065), 0.06% (9/15 065), 0.29% (43/15 065) respectively. The detection rate in male esophageal hyperplasia was higher than in female. People younger than 65 years old, the detection rates on mild, moderate or severe esophageal hyperplasia and invasive cancer showed an increase with age, with the 60-year-olds group reaching the highest. The detection rates on the above said diseases were 7.72% (198/2565), 2.07% (53/2565), 1.29% (33/2565), 0.51% (13/2565) respectively. The detection rates on mild, moderate or severe esophageal hyperplasia varied in different years and with statistically significant differences (P < 0.001) but did not show any obvious trend of changing. Geographical distribution of mild esophageal hyperplasia, moderate esophageal hyperplasia, severe esophageal hyperplasia also significantly varied in different villages (P < 0.001). The highest detection rate in the mountainous villages was seen the highest while the detection rate of village from hilly areas was the lowest. CONCLUSION: There were considerable numbers of patients with precancerous lesions in the general population from the high risk areas. The detection rate of esophageal cancer in the mountain residents was higher than the rate in the hilly areas. Men and the elderly were the key populations calling for esophageal cancer prevention programs to be carried out.

Effect of transarterial pulsed perfusion with heated saline on tumor vascular permeability in a rabbit VX2 liver tumor model.

PURPOSE: To evaluate the effect of transarterial pulsed perfusion with 60 °C saline on vascular permeability of tumor tissue, as well as its hepatic and renal toxicity, in a rabbit VX2 liver model. MATERIALS AND METHODS: VX2 carcinomas were grown in rabbit livers, forty male New Zealand white tumor-bearing rabbits were randomly divided into four groups, followed by transarterial perfusion with 37 °C saline 60 ml (n=10) (control 1 group), transarterial pulsed perfusion with 37 °C saline 60 ml (n=10) (control 2 group), transarterial continuous perfusion with 60 °C saline 60 ml (n=10) (TCP group), transarterial pulsed perfusion with 60 °C saline 60 ml (n=10) (TPP group), the duration of time for tumor tissues in the range 43-45 °C of the treated groups was measured with needle thermometer during perfusion. Vascular permeability was assessed using the extravasation of Evans blue (EB) dye in the tumor or normal liver tissues of the four groups separately, the tumor or normal liver tissues of the four groups were estimated by histopathologic examination, and hepatic and renal toxicity was evaluated by means of blood biochemical analysis. The vascular endothelial cells in the tumor were observed by transmission electron microscopy (TEM). RESULTS: The duration of time for tumor tissues in the range 43-45 °C of TPP group showed significantly longer than that of TCP group (12.3±3.3 min vs. 5.7±2.5 min) (P<0.01). After perfusion, the EB content of tumor tissue in TPP group showed significantly higher than that in TCP group (15.21±0.94 µg/100 mg vs. 10.71±0.84 µg/100 mg) (P<0.01), and also showed significantly higher than that in the two control group (3.42±0.87 µg/100 mg, 3.57±0.64 µg/100 mg) (P<0.01). Blood chemical analysis indicating there was an increase (P<0.05) in the serum ALT, AST levels in the two heated perfusion groups at 1, 2, 4, 8 h after infusion when compared to that in the two control group, but there was no significant difference in the serum ALT, AST levels among the four groups at 24 h after perfusion (P>0.05), and there was no significant difference in the serum BUN, Cr levels among the four groups at 1, 2, 4, 8, 24 h after perfusion. Observed by hematoxylin and eosin staining, there were no obvious signs of tissue destruction in liver tissue and tumor tissue. TEM indicating the endothelial cell gap was broadened and the endothelial cells' microvillus was decreased after heated perfusion. CONCLUSIONS: The vascular permeability of the rabbit VX2 tumor was significantly increased after transarterial pulsed perfusion with 60°C saline without significant increase in hepatic and renal toxicity.

Tumor necrosis factor-induced nonapoptotic cell death requires receptor-interacting protein-mediated cellular reactive oxygen species accumulation.

The mechanism of tumor necrosis factor (TNF)-induced nonapoptotic cell death is largely unknown, although the mechanism of TNF-induced apoptosis has been studied extensively. In wild-type mouse embryonic fibroblast cells under a caspase-inhibited condition, TNF effectively induced cell death that morphologically resembled necrosis. In this study, we utilized gene knockout mouse embryonic fibroblasts cells and found that tumor necrosis factor receptor (TNFR) I mediates TNF-induced necrotic cell death, and that RIP, FADD, and TRAF2 are critical components of the signaling cascade of this TNF-induced necrotic cell death. Inhibitors of NF-kappaB facilitated TNF-induced necrotic cell death, suggesting that NF-kappaB suppresses the necrotic cell death pathway. JNK, p38, and ERK activation seem not to be required for this type of cell death because mitogen-activated protein kinase inhibitors did not significantly affect TNF-induced necrotic cell death. In agreement with the previous reports that the reactive oxygen species (ROS) may play an important role in this type of cell death, the ROS scavenger butylated hydroxyanisole efficiently blocked TNF-induced necrotic cell death. Interestingly, during TNF-induced necrotic cell death, the cellular ROS level was significantly elevated in wild type, but not in RIP(-/-), TRAF2(-/-), and FADD(-/-) cells. These results suggest that RIP, TRAF2, and FADD are crucial in mediating ROS accumulation in TNF-induced necrotic cell death.

Protective effects of adenoviral cardiotrophin-1 gene transfer on rubrospinal neurons after spinal cord injury in adult rats.

Cardiotrophin-1 (CT-1), a muscle-derived cytokine, supports the survival of motoneurons in vivo and in vitro. The present study investigated whether adenoviral huCT-1 gene transfer protected injured neurons from cell death or atrophy and promoted regeneration of rubrospinal tract (RST) after spinal cord injury in adult rats. Administration of the adenoviral CT-1 vector (Adv-CT1) to C3-4 lateral funiculus hemisection cavity, that completely interrupted RST, led to sustained CT-1 expression. Providing Adv-CT1, which rescued 20% of neurons, could prevent the loss of injured rubrospinal neurons 8 weeks post-injury. Retrograde tracing with FluoroGold showed that 1.2% of RST neurons regenerated at least two segments caudal to the injury site. Anterograde tracing with biotinylated dextran amine revealed that the RST axons terminated in white matter and gray matter. Behavioral testing revealed a significant functional recovery in limb usage. This observation indicated that adenoviral CT-1 gene transfer into the injured cord promoted survival and regeneration of rubrospinal neurons in adult rats.