Better survival after stereotactic body radiation therapy following transarterial chemoembolization in nonresectable hepatocellular carcinoma: A propensity score matched analysis.

BACKGROUND: This study compared outcomes of nonresectable hepatocellular carcinoma (HCC) who had transarterial chemoembolization (TACE) vs. stereotactic body radiation therapy (SBRT) after TACE (TACE + SBRT). METHODS: This was a retrospective study of 2 centers in Hong Kong. There were 49 patients who had TACE + SBRT and 202 patients who had TACE alone. Propensity score matching was used to adjust for differences in patients' demographics and tumor characteristics between the 2 groups. The primary outcome was overall survival (OS) and secondary outcomes were progression-free survival (PFS) and treatment-related toxicity. RESULTS: After matching, 49 patients were in the TACE + SBRT group and 98 patients in the TACE group with similar baseline characteristics. The 1-&3-year OS were better in TACE + SBRT group (67.2 vs. 43.9% and 36.5 vs. 13.3%, p = 0.003). The 1-&3-year PFS was also better in TACE + SBRT group (32.5 vs. 21.4% and 15.1 vs. 5.1%, p = 0.012). Radiological disease control was better in the TACE + SBRT group (98 vs. 56.7%). Risk of severe toxicity was uncommon in both treatment arms. TACE + SBRT was an independent good prognostic factor for OS and PFS in multivariate analysis, whereas AFP>200 ng/ml, large tumor and multiple tumors predicted worse OS. CONCLUSION: TACE + SBRT is safe and results in better survivals in nonresectable HCC patients.

Induction of Oxidative Stress Through Inhibition of Thioredoxin Reductase 1 Is an Effective Therapeutic Approach for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide which lacks effective treatment. Cancer cells experience high levels of oxidative stress due to increased generation of reactive oxygen species (ROS). Increased antioxidant-producing capacity is therefore found in cancer cells to counteract oxidative stress. The thioredoxin system is a ubiquitous mammalian antioxidant system which scavenges ROS, and we demonstrate that it is vital for HCC growth as it maintains intracellular reduction-oxidation (redox) homeostasis. Transcriptome sequencing in human HCC samples revealed significant overexpression of thioredoxin reductase 1 (TXNRD1), the cytosolic subunit and key enzyme of the thioredoxin system, with significant correlations to poorer clinicopathological features and patient survival. Driven by the transcriptional activation of nuclear factor (erythroid-derived 2)-like 2, the master protector against oxidative stress, TXNRD1 counteracts intracellular ROS produced in human HCC. Inhibition of TXNRD1 through genetic inhibition hindered the proliferation of HCC cells and induced apoptosis in vitro. Administration of the pharmacological TXNRD1 inhibitor auranofin (AUR) effectively suppressed the growth of HCC tumors induced using the hydrodynamic tail vein injection and orthotopic implantation models in vivo. Furthermore, AUR sensitized HCC cells toward the conventional therapeutic sorafenib. Conclusion: Our study highlights the reliance of HCC cells on antioxidants for redox homeostasis and growth advantage; targeting TXNRD1 resulted in dramatic accumulation of ROS, which was found to be an effective approach for the suppression of HCC tumor growth.

Blocking CDK1/PDK1/ß-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma.

Rationale: Hepatocellular carcinoma (HCC) is an aggressive malignant solid tumor wherein CDK1/PDK1/ß-Catenin is activated, suggesting that inhibition of this pathway may have therapeutic potential. Methods: CDK1 overexpression and clinicopathological parameters were analyzed. HCC patient-derived xenograft (PDX) tumor models were treated with RO3306 (4 mg/kg) or sorafenib (30 mg/kg), alone or in combination. The relevant signaling of CDK1/PDK1/ß-Catenin was measured by western blot. Silencing of CDK1 with shRNA and corresponding inhibitors was performed for mechanism and functional studies. Results: We found that CDK1 was frequently augmented in up to 46% (18/39) of HCC tissues, which was significantly associated with poor overall survival (p=0.008). CDK1 inhibitor RO3306 in combination with sorafenib treatment significantly decreased tumor growth in PDX tumor models. Furthermore, the combinatorial treatment could overcome sorafenib resistance in the HCC case #10 PDX model. Western blot results demonstrated the combined administration resulted in synergistic down-regulation of CDK1, PDK1 and ß-Catenin as well as concurrent decreases of pluripotency proteins Oct4, Sox2 and Nanog. Decreased CDK1/PDK1/ß-Catenin was associated with suppression of epithelial mesenchymal transition (EMT). In addition, a low dose of RO3306 and sorafenib combination could inhibit 97H CSC growth via decreasing the S phase and promoting cells to enter into a Sub-G1 phase. Mechanistic and functional studies silencing CDK1 with shRNA and RO3306 combined with sorafenib abolished oncogenic function via downregulating CDK1, with downstream PDK1 and ß-Catenin inactivation. Conclusion: Anti-CDK1 treatment can boost sorafenib antitumor responses in PDX tumor models, providing a rational combined treatment to increase sorafenib efficacy in the clinic.

Serum and urinary biomarkers that predict hepatorenal syndrome in patients with advanced cirrhosis.

BACKGROUND: Prediction of hepatorenal syndrome (HRS) remains difficult in advanced cirrhotic patients. AIMS: To evaluate use of serum and urine biomarkers to predict HRS. METHODS: We prospectively recruited Child's B or C cirrhotic patients with normal serum creatinine, and followed them for 12 weeks for the development of HRS. Serum Cystatin C (CysC), serum and urine Neutrophil Gelatinase-Associated Lipocalin (NGAL), serum and urine IL-18, serum N-acetyl-ß-d glucosaminidase (NAG), urine kidney injury molecule-1 (KIM-1) and urine liver-type fatty acid binding protein (LFABP) were measured at recruitment (baseline), and their relationship with subsequent HRS investigated. RESULTS: 43 patients were included. 12 (27.9%) developed HRS at 7.3±5.1 weeks from baseline. Logistic regression analysis showed that baseline urinary NGAL and urinary KIM-1 were significantly associated with the development of HRS (RR 1.007, 95% CI 1.001-1.012, p=0.014; RR 1.973, 95% CI 1.002-3.886, p=0.049). The cut-off values for NGAL and KIM-1 to predict HRS were 18.72ng/mL and 1.499ng/mL respectively (AUCs 0.84, p=0.005; and 0.78, p=0.008). CONCLUSION: Urinary NGAL and KIM-1 could serve as biomarkers to predict HRS in advanced cirrhotic patients.

A detailed evaluation of cardiac function in cirrhotic patients and its alteration with or without liver transplantation.

BACKGROUND: Cirrhosis has been shown to be associated with left ventricular (LV) myocardial dysfunction, but studies of right ventricular (RV) function in cirrhotic patients compared with controls are scarce. Limited studies have prospectively evaluated the progression of myocardial function in patients with cirrhosis and assessed changes in cardiac function following liver transplantation (LTx). So the aim of the study was to evaluate biventricular myocardial function in cirrhotic patients and its alteration with or without liver transplantation. METHODS: A total of 103 patients with cirrhosis (age 55±7 years, male 75%) were recruited. Conventional and 2-dimensional speckle tracking echocardiography was performed to determine the presence of LV and RV (biventricular) dysfunction. For comparison, 48 matched control subjects were included. Follow-up echocardiography was performed in 41 patients following LTx and in 26 patients who did not undergo LTx. RESULTS: Patients with cirrhosis had biventricular dilatation, increased LV mass, impaired LV diastolic function, and biventricular systolic strain compared with controls. Following LTx, cirrhotic patients had reduced biventricular dilatation, a smaller LV mass, and improved biventricular systolic strain after a mean duration of 18.2±6.6 months. Patients who did not undergo LTx had a further increase in LV mass but no significant change in biventricular dimensions or systolic strain (mean duration of 20.4±8.3 months). CONCLUSIONS: The present study demonstrates that patients with cirrhosis had biventricular dilatation and impaired biventricular systolic strain compared with controls. Following LTx, biventricular dilatation reduced and biventricular systolic strain improved. In contrast, patients who did not undergo LTx experienced a further increase in LV mass.

Does hepatitis B seroconversion affect survival outcome in patients with hepatitis B related hepatocellular carcinoma?

BACKGROUND: Little is known about whether hepatitis B surface antigen (HBsAg) seroconversion (SC) contributes to any survival benefits for patients with hepatocellular carcinoma (HCC). METHODS: All patients with hepatitis B-related HCC and HBsAg seroclearance between 1989 and 2013 were identified. Case- and control-groups were matched according to their stage of disease and mode of treatment. Baseline demographics, liver function, and overall survivals (OS) were compared between these two groups. RESULTS: Thirty-nine HCC cases with HBsAg SC were identified, and 312 non-seroconversion (NSC) HCC cases were matched. Forty-eight percent of patients had curative resections, 14% were treated with ablation and 38% were for palliation. Age of patients in SC group was older than those in NSC group (P=0.026). Although there was significantly better liver function in SC vs. NSC groups in terms of bilirubin (P=0.027), albumin (P=0.003), AST (P=0.001) and ALT (P<0.001), there was no overall difference in Child-Pugh grade among the two groups. In regarding tumour pathology, SC commonly presented with solitary tumour nodule as compared to multiple nodules in NSC (P=0.027), and was also frequently associated with a normal background liver parenchyma (P<0.001). Although no survival benefit was confirmed in log-rank analysis between SC and NSC, the absolute 5-year survival of SC group was better in resection (72.2% vs. 55.3%), ablation (83.3% vs. 57.4%) and palliation (24.4% vs. 14.4%). CONCLUSIONS: HCC patients with HBsAg SC are associated with a better background liver parenchyma and function, and might contribute to an improved long-term survival.

The outcomes of elderly patients with hepatocellular carcinoma treated with transarterial chemoembolization.

BACKGROUND: The authors evaluated and compared the treatment outcomes of transarterial chemoembolization (TACE) between young (70 years) patients at their institute over an 18-year period. METHODS: Advanced hepatocellular carcinoma (HCC) patients who received TACE at the authors' center were analyzed retrospectively. The demographic data, TACE-related morbidities, and survival outcome were compared between these 2 age groups. RESULTS: Between 1989 and 2006, 843 patients who were 70 years old received TACE treatment for advanced HCC. There were significantly more comorbid illnesses associated with the elderly patients than the young patients (64 % vs 33%, P < .01). Moreover, elderly patients who received TACE treatment for HCC were at earlier stages of disease (P < .01). Both the overall median survival (14.0 months vs 8.1 months, P < .003) and disease-specific survival (15.2 months vs 8.7 months, P < .001) were significantly higher in elderly than young patients. The most commonly encountered TACE-related morbidity in both age groups was liver function derangement. Young patients had a significantly higher rate of developing liver derangement after TACE than elderly patients (21% vs 11%, P < .01). Conversely, the elderly patients had a significantly higher rate of developing peptic ulcer disease with TACE treatment than young patients (2.5% vs 0.5%, P = .01). Overall, there was no significant difference in TACE-related mortality between the young and elderly patients (3% vs 4%, P = .49). CONCLUSIONS: This study has confirmed the comparable efficacy and tolerability in using TACE for the treatment of advanced HCC in young and elderly patient populations.

Efficacy and tolerability of low-dose thalidomide as first-line systemic treatment of patients with advanced hepatocellular carcinoma.

OBJECTIVE: The systemic treatment of advanced hepatocellular carcinoma (HCC) has produced disappointing results thus far. HCC is a hypervascular tumor with over-expression of angiogenic factors such as vascular endothelial growth factor. Thalidomide is an anti-neoplastic agent with anti-angiogenic and other mechanisms of action. We aim to evaluate the efficacy and toxicity of low-dose (100 mg) thalidomide as the first-line treatment of advanced HCC. METHODS: Between August 2003 and March 2007, 45 patients who had received thalidomide 100 mg daily as first-line treatment of advanced HCC were reviewed retrospectively. Advanced HCC was defined as either metastatic or not amenable to surgical or locoregional therapies. Diagnosis of HCC was based on clinical, biochemical and radiological grounds. Survival was analyzed by the Kaplan-Meier method. RESULTS: Thirty-eight patients were evaluable for response and toxicity. Two (5%) patients had partial response and 8 (21%) had stable disease. The overall median survival of patients in this cohort was 3.2 months (95% CI: 2.8-3.7 months). The common toxicities were somnolence (13%), peripheral neuropathy (11%) and ankle edema (8%), with no grade 3 or 4 toxicities and treatment-related deaths. CONCLUSION: Our study shows that a single agent, low-dose thalidomide has a modest clinical activity with good tolerability in treating advanced HCC patients.

Breast sentinel lymph node biopsy using radioisotope injection: is one-day better than two-day protocol?

Sentinel lymph node (SLN) biopsy is an evolving treatment approach for patients with operable breast cancer. There have been a number of variations in the biopsy technique. One is the timing of radioisotope injection, which might have a significant influence on the radiation exposure of the personnel in the operating room. The present study aims to compare the one-day with the two-day protocol to see which one is associated with a lower radiation hazard while giving similar results. There were 60 patients recruited; half of them had the SLN biopsy 4 hours after the injection and the other half 24 hours later. Patient characteristics were comparable in both groups. The mean numbers of SLNs found per patient were 1.46 and 1.96 respectively. There was a statistically significant difference in the dosage of radioactivity present in the resected specimen between both groups of patients. However, there were still a number of confounding factors, so the proposed hypothesis of getting less radiation exposure to the medical personnel by using a two-day approach should be further investigated.