Liver disease severity predicts carcinogenesis of dysplastic liver nodules in cirrhosis.

While dysplastic liver nodules in cirrhosis are pre-malignant, little is known about the predictors of hepatocarcinogenesis of these lesions. This was a retrospective observational study of subjects with cirrhosis who had at least one hypervascular, non-malignant intrahepatic nodule on imaging while undergoing outpatient management by a tertiary hepatology referral centre between Jan 2009 and Jan 2019. Clinical and biochemical parameters were collected. The primary endpoint was transformation to hepatocellular carcinoma (HCC) as determined by Liver Imaging Reporting and Data System. During the study period, 163 non-malignant hypervascular nodules were identified in 77 patients; 147 had at least 6 months of follow up imaging and 16 received upfront radiofrequency ablation upon detection. During a median follow up of 38.5 months (IQR 16.5-74.5), 25 (17%) of the 147 hypervascular nodules being monitored transformed to HCC. On multivariate analysis, Child-Pugh grade was found to be the only independent predictor of nodule transformation into HCC (p = 0.02). Those with Child-Pugh B and C liver disease had a 10.1 (95% CI 1.22-83.8; p = 0.03) and 32.6-fold (95% CI 2.3-467; p = 0.01) increased risk respectively for HCC transformation compared to Child-Pugh A subjects. This large, single centre study demonstrates that around 20% of dysplastic nodules in cirrhotic patients undergo hepatocarcinogenesis during follow up, and that Child Pugh grade is the only independent predictor of transformation to HCC. Additional prospective studies are warranted to better understand the risk profile of these nodules, and how best they should be managed.

Curcumin and Photobiomodulation in Chronic Viral Hepatitis and Hepatocellular Carcinoma.

Immune modulation is a very modern medical field for targeting viral infections. In the race to develop the best immune modulator against viruses, curcumin, as a natural product, is inexpensive, without side effects, and can stimulate very well certain areas of the human immune system. As a bright yellow component of turmeric spice, curcumin has been the subject of thousands of scientific and clinical studies in recent decades to prove its powerful antioxidant properties and anticancer effects. Curcumin has been shown to influence inter- and intracellular signaling pathways, with direct effects on gene expression of the antioxidant proteins and those that regulate the immunity. Experimental studies have shown that curcumin modulates several enzyme systems, reduces nitrosative stress, increases the antioxidant capacity, and decreases the lipid peroxidation, protecting against fatty liver pathogenesis and fibrotic changes. Hepatitis B virus (HBV) affects millions of people worldwide, having sometimes a dramatic evolution to chronic aggressive infection, cirrhosis, and hepatocellular carcinoma. All up-to-date treatments are limited, there is still a gap in the scientific knowledge, and a sterilization cure may not yet be possible with the removal of both covalently closed circular DNA (cccDNA) and the embedded HBV DNA. With a maximum light absorption at 420 nm, the cytotoxicity of curcumin as photosensitizer could be expanded by the intravenous blue laser blood irradiation (IVBLBI) or photobiomodulation in patients with chronic hepatitis B infection, Hepatitis B e-antigen (HBeAg)-positive, noncirrhotic, but nonresponsive to classical therapy. Photobiomodulation increases DNA repair by the biosynthesis of complex molecules with antioxidant properties, the outset of repairing enzyme systems and new phospholipids for regenerating the cell membranes. UltraBioavailable Curcumin and blue laser photobiomodulation could suppress the virus and control better the disease by reducing inflammation/fibrosis and stopping the progression of chronic hepatitis, reversing fibrosis, and diminishing the progression of cirrhosis, and decreasing the incidence of hepatocellular carcinoma. Photodynamic therapy with blue light and curcumin opens new avenues for the effective prevention and cure of chronic liver infections and hepatocellular carcinoma. Blue laser light and UltraBioavailable Curcumin could be a new valuable alternative for medical applications in chronic B viral hepatitis and hepatocarcinoma, saving millions of lives.

MicroRNA-146a-5p Attenuates Fibrosis-related Molecules in Irradiated and TGF-beta1-Treated Human Hepatic Stellate Cells by Regulating PTPRA-SRC Signaling.

MicroRNAs (miRNAs) have been shown to play a pivotal role in the pathogenesis and maintenance of liver fibrosis by altering expression of their downstream target genes. However, their role in radiation-induced liver fibrosis has not been assessed in detail. Here, we investigated the role of miR-146a-5p and the target gene in regulation of fibrosis-related markers in the human hepatic stellate cell line LX2. LX2 cells were stimulated with 8 Gy of X rays and various concentrations of TGF-ß1 (0-5 ng/ml). Expression of α-SMA, collagen 1 and miR-146a-5p was evaluated. The MiR-146a-5p target gene predictions were performed using bioinformatics analysis and confirmed by dual-luciferase reporter experiment. The effect of miR-146a-5p and the involved target gene on the expression of these fibrogenic molecules was also assessed. Expression of α-SMA and collagen 1 were upregulated in response to radiation and/or TGF-ß1 treatment and miR-146a-5p levels were altered in LX2 cells. Restoration of miR-146a-5p expression suppressed expression of α-SMA and collagen 1 in irradiated and TGF-ß1-treated LX2 cells. Subsequent mechanism experiments revealed that miR-146a-5p overexpression inhibited PTPRA expression by binding to its 3'-untrans-lated region and reduced SRC activation. In addition, enhancement of PTPRA partially reversed the suppressive effect of miR-146a-5p on α-SMA and collagen 1 expression in LX2 cells. In conclusion, miR-146a-5p may negatively regulate the PTPRA-SRC signaling to inhibit expression of fibrosis-related markers in irradiated and TGF-ß1-stimulated LX2 cells.

Outcomes of Stereotactic Body Radiotherapy for Hepatocellular Carcinoma with Severe Cirrhosis and Ineligibility for Transplant.

BACKGROUND/AIM: Our study reviewed the results of patients with hepatocellular carcinoma and Child-Pugh score 8-11 cirrhosis treated with stereotactic body radiotherapy when liver transplant was not an option. PATIENTS AND METHODS: A retrospective review was performed on 15 patients with Child-Pugh class B and C cirrhosis treated with stereotactic body radiotherapy. The median total dose was 35 Gy in 4-5 fractions. None were listed for a liver transplant due to either being outside of the Milan criteria or to medical contraindications. RESULTS: The overall survival was 26.7% at 6 months, with a mean survival of 152 days. The mean survival with and without ascites was 3.3 months and 8.3 months, respectively. CONCLUSION: For hepatocellular carcinoma with cirrhosis of Child-Pugh score 8 or more, prognosis after liver stereotactic body radiotherapy was suboptimal. While irradiation achieved local tumor control, progressive cirrhosis was a common cause of death. Patients without ascites at the time of radiotherapy had the best prognosis.

Feasibility and efficacy of helical tomotherapy in cirrhotic patients with unresectable hepatocellular carcinoma.

BACKGROUND: This study is to evaluate the toxicity and outcomes of helical tomotherapy (HT) in patients treated for unresectable hepatocellular carcinoma (HCC). METHODS: From March 2008 to September 2010, 38 patients with unresectable HCC were treated with HT. The median patient age was 67 years (range, 45-85). The median follow-up period was 17.2 months (range, 7-46). All patients had liver cirrhosis. Median radiation dose was 54 Gy (range, 46-71.8) delivered in 1.8 to 2.4-Gy fractions. The planning target volumes were 241.2 ± 153.1 cm(3) (range, 45.8-722.4). Treatment responses were assessed in 3-6 months after HT. RESULTS: There was a complete response in 2 patients (5.2 %), partial response in 18 patients (47.4 %), stable disease in 13 patients (34.2 %), and progressive disease in 5 patients (13.2 %). The median overall survival was 12.6 months, and 1- and 2-year overall survival rates were 56.2 and 31.7 %, respectively. Eastern Cooperative Oncology Group (ECOG score, p = 0.008), Child-Pugh classification (p = 0.012), albumin (p = 0.046), and hemoglobin (p = 0.028) were significant parameters that predicted primary tumor response to radiotherapy in multivariate analysis. ECOG score (p = 0.012), Child-Pugh class (p = 0.026), and response to radiotherapy (p = 0.016) were independent prognostic factors for overall survival in multivariate analysis. Responders had better overall survival than non-responders (23.6 vs. 5.8 months, p < 0.001). The 1- and 2-year overall survival rates for responders were 68.3 and 57 %, respectively, while for non-responders, they were 0 %. The 1- and 2-year local control rates were 88.2 and 82.3 %, respectively. Five patients (13.2 %) had grade 3 or greater liver toxicity, and one patient (2.6 %) had a grade 3 gastric ulcer. No treatment-related liver failure or death was documented in this study. CONCLUSIONS: Radiotherapy using HT seems to be a safe and effective treatment option for unresectable HCC patients. This study indicates that HT is a feasible treatment even in patients without good performance status and hepatic function reservation.

Low-dose splenic irradiation in symptomatic congestive splenomegaly: report of five cases with literature data.

BACKGROUND: To show effectiveness of low-dose splenic irradiation in symptomatic congestive splenomegaly. METHODS: Five patients were referred to our department for symptomatic congestive splenomegaly within three years. Primary diseases were autoimmune hepatitis with liver cirrhosis (n=2), cystic fibrosis (n=1), granulomatous liver disease (n=1) and Werlhof disease with liver cirrhosis (n=1). Mean age was 54 years (range: 36-67). Patients received splenic irradiation with a total dose of 3 Gy (single dose: 0.5 Gy). One patient was re-irradiated after long-term failure with the same treatment schedule. RESULTS: In four patients long term relief of splenic pain could be observed during the follow-up time of median 20 (range: 2-36) months. Four patients showed haematological response after irradiation with an increase of erythrocytes, leucocytes and/or platelets. A slightly decrease in spleen size was found in two patients. CONCLUSIONS: Low-dose splenic irradiation in symptomatic congestive splenomegaly is feasible and perhaps as effective as in lympho-and myeloproliferative malignancies regarding pain relief and haematological response.

Radioembolization for hepatocellular carcinoma with portal vein thrombosis: impact of liver function on systemic treatment options at disease progression.

BACKGROUND & AIMS: Yttrium-90 ((90)Y) radioembolization is a microembolic procedure. Hence, it is commonly used in hepatocellular carcinoma (HCC) patients with portal venous thrombosis (PVT). We analyzed liver function, imaging findings, and treatment options (local/systemic) at disease progression following (90)Y treatment in HCC patients with PVT. METHODS: We treated 291 HCC patients with (90)Y radioembolization. From this cohort, we included patients with liver-only disease, PVT and Child-Pugh (CP) score ≤ 7; this identified 63 patients with HCC and PVT (CP-A:35, CP-B7:27). Liver function, CP status, and imaging findings at progression were determined in order to assess potential candidacy for systemic treatment/clinical trials. Survival, time-to-progression (TTP), and time-to-hepatic decompensation analyses were performed using Kaplan-Meier methodology. RESULTS: Of 35 CP-A and 28 CP-B7 patients, 29 and 15 progressed, respectively. Median survival and TTP were 13.8 and 5.6 months in CP-A and 6.5 and 4.9 months in CP-B7 patients, respectively. Of the 29 CP-A patients who progressed, 45% maintained their CP status at progression (55% decompensated to CP-B). Of the 15 CP-B7 patients who progressed, 20% improved to CP-A, 20% maintained their CP score and 60% decompensated. CONCLUSIONS: Knowledge of liver function and CP score of HCC with PVT progressing after (90)Y is critically relevant information, as these patients may be considered for systemic therapy/clinical trials. If a strict CP-A status is mandated, our study demonstrated that 64% of cases exhibited inadequate liver function and were ineligible for systemic therapy/clinical trials. An adjuvant approach using local therapy and systemic agents prior to progression should be investigated.

Prediction of liver function by using magnetic resonance-based portal venous perfusion imaging.

PURPOSE: To evaluate whether liver function can be assessed globally and spatially by using volumetric dynamic contrast-enhanced magnetic resonance imaging MRI (DCE-MRI) to potentially aid in adaptive treatment planning. METHODS AND MATERIALS: Seventeen patients with intrahepatic cancer undergoing focal radiation therapy (RT) were enrolled in institution review board-approved prospective studies to obtain DCE-MRI (to measure regional perfusion) and indocyanine green (ICG) clearance rates (to measure overall liver function) prior to, during, and at 1 and 2 months after treatment. The volumetric distribution of portal venous perfusion in the whole liver was estimated for each scan. We assessed the correlation between mean portal venous perfusion in the nontumor volume of the liver and overall liver function measured by ICG before, during, and after RT. The dose response for regional portal venous perfusion to RT was determined using a linear mixed effects model. RESULTS: There was a significant correlation between the ICG clearance rate and mean portal venous perfusion in the functioning liver parenchyma, suggesting that portal venous perfusion could be used as a surrogate for function. Reduction in regional venous perfusion 1 month after RT was predicted by the locally accumulated biologically corrected dose at the end of RT (P<.0007). Regional portal venous perfusion measured during RT was a significant predictor for regional venous perfusion assessed 1 month after RT (P<.00001). Global hypovenous perfusion pre-RT was observed in 4 patients (3 patients with hepatocellular carcinoma and cirrhosis), 3 of whom had recovered from hypoperfusion, except in the highest dose regions, post-RT. In addition, 3 patients who had normal perfusion pre-RT had marked hypervenous perfusion or reperfusion in low-dose regions post-RT. CONCLUSIONS: This study suggests that MR-based volumetric hepatic perfusion imaging may be a biomarker for spatial distribution of liver function, which could aid in individualizing therapy, particularly for patients at risk for liver injury after RT.

Low-level laser therapy ameliorates CCl4-induced liver cirrhosis in rats.

This study investigated the effects of low-level laser therapy (LLLT) in the liver function, structure and inflammation in a experimental model of carbon tetrachloride (CCl(4))-induced liver cirrhosis. Wistar rats were divided into Control, LLLT, CCl(4) and CCl(4) +LLLT groups. CCl(4) groups received CCl(4) (0.4 g kg(-1); i.p.), three times a week, for 12 weeks. A 830 nm LLLT was performed with a continuous wave, 35 mW, 2.5 J cm(-2) per point, applied to four points of the liver (right and left upper and lower extremities, in the four lobes of the liver) for 2 weeks. Liver structure and inflammation (cirrhotic areas, collagen deposition, inflammation, density of Kupffer and hepatic stellate cells) and function (aspartate aminotransferase, alkaline phosphatase, gamma glutamyltransferase, lactate dehydrogenase, total proteins and globulins) were evaluated. LLLT significantly reduced CCl(4)-increased aspartate aminotransferase (P < 0.001), alkaline phosphatase (P < 0.001), gamma-glutamyl transferase (P < 0.001) and lactate dehydrogenase (P < 0.01) activity, as well as total proteins (P < 0.05) and globulins (P < 0.01). LLLT also reduced the number of cirrhotic areas, the collagen accumulation and the hepatic inflammatory infiltrate. Of note, LLLT reduced CCl(4)-increased number of Kupffer cells (P < 0.05) and hepatic stellate cells (P < 0.05). We conclude that LLLT presents beneficial effects on liver function and structure in an experimental model of CCl(4)-induced cirrhosis.

The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma: a phase 2 prospective trial.

BACKGROUND: Proton beam therapy (PBT) may provide useful local-regional treatment for hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the safety and efficacy of PBT for HCC. METHODS: Patients with cirrhosis who had radiological features or biopsy-proven HCC were included in the study. Patients without cirrhosis and patients with extrahepatic metastasis were excluded. The mean age was 62.7 years. The mean tumor size was 5.5 cm. Eleven patients had multiple tumors, and 46% were within the Milan criteria. Patients received 63 Gy delivered over a 3-week period with PBT. RESULTS: Seventy-six patients were treated and followed prospectively for treatment outcomes at Loma Linda University Medical Center. Acute toxicity was minimal; all patients completed the full course of treatment. Radiation-induced liver disease was evaluated using liver enzyme, bilirubin, and albumin levels; no significant change supervened 6 months posttreatment. Median progression-free survival for the entire group was 36 months, with a 60% 3-year progression-free survival rate for patients within the Milan criteria. Eighteen patients subsequently underwent liver transplantation; 6 (33%) explants showed pathological complete response and 7 (39%) showed only microscopic residual. CONCLUSIONS: PBT was found to be a safe and effective local-regional therapy for inoperable HCC. A randomized controlled trial to compare its efficacy to a standard therapy has been initiated. Cancer 2011. © 2011 American Cancer Society.

Feasibility and efficacy of high-dose three-dimensional-conformal radiotherapy in cirrhotic patients with small-size hepatocellular carcinoma non-eligible for curative therapies--mature results of the French Phase II RTF-1 trial.

PURPOSE: Hepatocellular carcinoma (HCC) is a poor prognosis tumor, and only 20% of patients will benefit from curative therapies (surgery, liver transplantation, percutaneous ablation). Although conventional radiotherapy has been traditionally regarded as inefficient and toxic for cirrhotic patients, three-dimensional conformal radiotherapy (3DCRT) has provided promising preliminary data for the treatment of HCC. METHODS AND MATERIALS: Prospective phase II trial including Child-Pugh A/B cirrhotic patients with small-size HCC (1 nodule < or =5 cm, or 2 nodules < or =3 cm) nonsuitable for curative treatments, to assess tolerance and efficacy of high-dose (66 Gy, 2 Gy/fraction) 3DCRT. RESULTS: Twenty-seven patients were enrolled. Among the 25 assessable patients, tumor response was observed for 23 patients (92%), with complete response for 20 patients (80%), and partial response for 3 patients (12%). Stable disease was observed in 2 patients (8%). Grade 4 toxicities occurred in 2 of 11 (22%) Child-Pugh B patients only. Child-Pugh A patients tolerated treatment well, and 3/16 (19%) developed asymptomatic Grade 3 toxicities. CONCLUSION: High-dose 3DCRT is a noninvasive, well-tolerated modality that is highly suitable for the treatment of small HCCs in cirrhotic patients, with promising results. However, additional trials are needed to optimize this technique and formally compare it with the usual curative approaches.

Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes.

BACKGROUNDS & AIMS: Immunomodulatory cytokines, including interleukin-10 (IL-10), may mediate hepatic fibrosis. METHODS: We generated transgenic (TG) mice with hepatocyte expression of rat IL-10 (rIL-10) to assess its impact on lymphocyte subsets and activation of hepatic stellate cells following liver injury from carbon tetrachloride (CCl 4 ) or thioacetamide (TAA). RESULTS: Fibrosis was reduced in the TG animals in both models, which was not explained solely by differences in liver injury. By fluorescence-activated cell sorter (FACS), there were less CD4+ T cells in naive TG mice, and, following fibrosis induction, CD4+ T cells decreased only in wild-type (WT) mice, whereas increases in CD8+ T cells seen in WT animals were significantly attenuated in TG mice. Subtotal irradiation diminished fibrosis equally in both WT and TG groups, suggesting that rIL-10's antifibrotic effect was lymphocyte mediated. To assess the role of lymphocytes on stellate cell activation, either whole splenic lymphocytes, CD4+, or CD8+ T-cell subsets from WT animals with CCl 4 fibrosis were adoptively transferred to severe combined immunodeficiency (SCID) recipients, which led to stellate cell activation and fibrogenic stimulation as assessed by expression of transforming growth factor (TGF)-beta1 and collagen I messenger RNA (mRNA) and by immunoblot of alpha-smooth muscle actin. Moreover, serum aminotransferase levels and stellate cell activation mRNA were significantly higher among the CD8+ T-cell recipients. CONCLUSIONS: Transgenic expression of rIL-10 in liver leads to reduced fibrosis and alterations in liver lymphocyte subsets both in untreated liver and following fibrosis induction. In this model, fibrosis may be a CD8+ T-cell-mediated disease that is attenuated by rIL-10.