Definitive Stereotactic Body Radiation Therapy in Early-Stage Solitary Hepatocellular Carcinoma: An Australian Multi-Institutional Review of Outcomes.

AIMS: Standard curative options for early-stage, solitary hepatocellular carcinoma (HCC) are often unsuitable due to liver dysfunction, comorbidities and/or tumour location. Stereotactic body radiation therapy (SBRT) has shown high rates of local control in HCC; however, limited data exist in the treatment-naïve, curative-intent setting. We report the outcomes of patients with solitary early-stage HCC treated with SBRT as first-line curative-intent therapy. MATERIALS AND METHODS: A multi-institutional retrospective study of treatment-naïve patients with Barcelona Clinic Liver Cancer stage 0/A, solitary ≤5 cm HCC, Child-Pugh score (CPS) A liver function who underwent SBRT between 2010 and 2019 as definitive therapy. The primary end point was freedom from local progression. Secondary end points were progression-free survival, overall survival, rate of treatment-related clinical toxicities and change in CPS >1. RESULTS: In total, 68 patients were evaluated, with a median follow-up of 20 months (range 3-58). The median age was 68 years (range 50-86); 54 (79%) were men, 62 (91%) had cirrhosis and 50 (74%) were Eastern Cooperative Oncology Group 0. The median HCC diameter was 2.5 cm (range 1.3-5) and the median prescription biologically effective dose with a tumour a/b ratio of 10 Gy (BED10) was 93 Gy (interquartile range 72-100 Gy). Two-year freedom from local progression, progression-free survival and overall survival were 94.3% (95% confidence interval 86.6-100%), 59.5% (95% confidence interval 46.3-76.4%) and 88% (95% confidence interval 79.2-97.6%), respectively. Nine patients (13.2%) experienced grade ≥2 treatment-related clinical toxicities. A rise >1 in CPS was observed in six cirrhotic patients (9.6%). CONCLUSION: SBRT is an effective and well-tolerated option to consider in patients with solitary, early-stage HCC. Prospective, randomised comparative studies are warranted to further refine its role as a first-line curative-intent therapy.

Real-world outcomes of unrestricted direct-acting antiviral treatment for hepatitis C in Australia: The South Australian statewide experience.

In March 2016, the Australian government offered unrestricted access to direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) to the entire population. This included prescription by any medical practitioner in consultation with specialists until sufficient experience was attained. We sought to determine the outcomes and experience over the first twelve months for the entire state of South Australia. We performed a prospective, observational study following outcomes of all treatments associated with the state's four main tertiary centres. A total of 1909 subjects initiating DAA therapy were included, representing an estimated 90% of all treatments in the state. Overall, SVR12 was 80.4% in all subjects intended for treatment and 95.7% in those completing treatment and follow-up. 14.2% were lost to follow-up (LTFU) and did not complete SVR12 testing. LTFU was independently associated with community treatment via remote consultation (OR 1.50, 95% CI 1.04-2.18, P = .03), prison-based treatment (OR 2.02, 95% CI 1.08-3.79, P = .03) and younger age (OR 0.98, 95% CI 0.97-0.99, P = .05). Of the 1534 subjects completing treatment and follow-up, decreased likelihood of SVR12 was associated with genotype 2 (OR 0.23, 95% CI 0.07-0.74, P = .01) and genotype 3 (OR 0.23, 95% CI 0.12-0.43, P ≤ .01). A significant decrease in treatment initiation was observed over the twelve-month period in conjunction with a shift from hospital to community-based treatment. Our findings support the high responses observed in clinical trials; however, a significant gap exists in SVR12 in our real-world cohort due to LTFU. A declining treatment initiation rate and shift to community-based treatment highlight the need to explore additional strategies to identify, treat and follow-up remaining patients in order to achieve elimination targets.

Sofosbuvir and daclatasvir therapy in patients with hepatitis C-related advanced decompensated liver disease (MELD ≥ 15).

BACKGROUND: Antiviral therapy for hepatitis C has the potential to improve liver function in patients with decompensated cirrhosis. AIMS: To examine the virological response and effect of viral clearance in patients with decompensated hepatitis C cirrhosis all with MELD scores ≥15 following sofosbuvir/daclatasvir ± ribavirin. METHODS: We prospectively collected data on patients who commenced sofosbuvir/daclatasvir for 24-weeks under the Australian patient supply program (TOSCAR) and analysed outcomes including sustained viral response at 12 weeks (SVR12), death and transplant. RESULTS: 108 patients (M/F, 79/29; median age 56years; Child-Pugh 10; MELD 16; genotype 1/3, 55/47) received sofosbuvir/daclatasvir and two also received ribavirin. On intention-to-treat, the SVR12 rate was 70% (76/108). Seventy-eight patients completed 24-weeks therapy. SVR12 was achieved in 56 of these patients on per-protocol-analysis (76%). SVR12 was 80% in genotype 1 compared to 69% in genotype 3. Thirty patients failed to complete therapy. In patients achieving SVR12, median MELD and Child-Pugh fell from 16(IQR15-17) to 14(12-17) and 10(9-11) to 8(7-9), respectively (P<.001). In those who died, MELD increased from 16 to 23 at death (P=.036). Patients who required transplantation had a significantly higher baseline MELD (20) compared to those patients completing treatment (16) (P=.0010). The odds ratio for transplant in patients with baseline MELD ≥20 was 13.8(95%CI 2.78-69.04). CONCLUSIONS: SVR12 rates with sofosbuvir/daclatasvir in advanced liver disease are lower than in compensated disease. Although treatment improves MELD and Child-Pugh in most patients, a significant proportion will die or require transplantation. In those with MELD ≥20, it may be better to delay treatment until post-transplant.

Rising incidence of hepatitis B-related hepatocellular carcinoma in South Australia: 1996-2010.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is likely to be an important driver of increasing hepatocellular carcinoma (HCC) incidence in Australia. However, there is paucity of Australian data on HBV-related HCC incidence or outcomes. AIMS: To determine the incidence rates and survival trends of HBV-related HCC in South Australia (SA) over 15 years. METHODS: A population-based cohort study was performed in HBV patients notified to the SA Communicable Disease Control Branch between 1996 and 2010. The dataset was probabilistically linked with the SA Cancer Registry and death registry. Incidence rate trends and survival were determined for three 5-year time periods (1996-2000, 2001-2006 and 2006-2010). RESULTS: Forty-seven of 3881 notifications with HBV were linked to a HCC record (median (interquartile range) age at diagnosis: 58.9 (13.4) years, 83% males, 8.5% born in Australia, 62% diagnosed between 51-69 years). The overall crude HCC incidence was 111.3/100 000 person-years with an age-standardised HCC incidence of 189.1/100 000 person-years, the rate for men was higher than for women: 241.7 versus 88.6/100 000 person-years. The age-standardised HCC incidence increased over time with an annual percentage increase of 20.8% (95% CI: 10.06-32.54, P = 0.001). Median survival following HCC diagnosis was 12.5 months (95% CI: 3.6-21.4), with a trend towards longer survival during the 2006-2010 time period (21.8 months) compared to the previous two time periods (9.2 and 10.2 months, P = 0.056). CONCLUSION: Both crude and age-standardised incidences of HBV-related HCC increased between 1996 and 2010 in SA. There was a trend to longer survival in the latter time-period.

Prevalence of hepatic osteodystrophy and vitamin D deficiency in cirrhosis.

BACKGROUND: Hepatic osteodystrophy (HO) is a major complication of cirrhosis. However, the prevalence of HO in a general cirrhotic patient population is not well defined as previous studies were in single aetiology or pre-liver transplant patients. AIMS: The aims of this study were to investigate the prevalence of HO and vitamin D deficiency in patients with cirrhosis of mixed aetiology and disease severity and to determine the risk factors for HO. METHODS: This is a single-centre cross-sectional study of all patients newly diagnosed with cirrhosis between September 2009 and December 2012. All patients underwent bone mineral density assessment using dual energy X-ray absorptiometry within 3 months of diagnosis. Demographic and biochemical factors, severity of underlying liver disease, previous fragility fractures, smoking status and alcohol use were collected on diagnosis. Logistic regression analysis was used to assess risk factors for HO. RESULTS: Among the 406 patients (67% males), the median (range) age was 56 years (21-85) and most (84%) were Childs-Pugh A or B with a median (range) model for end-stage liver disease score of 11 (5-40). Alcohol (41%) was the most common underlying aetiology. The prevalence of HO and vitamin D deficiency (≤50 nmol/L) was 56% and 54%, respectively, and previous fragility fractures had occurred in 3%. Increasing age (odds ratio (95% confidence interval): 1.49 per 10 years (1.02-2.18), P = 0.04), excessive alcohol intake (2.34 (1.03-5.32), P = 0.04) and lower body mass index (0.92 per kg/m2 (0.87-0.98), P = 0.009) were independent risk factors for HO. CONCLUSION: There is a high prevalence of HO and vitamin D deficiency in patients with cirrhosis at presentation irrespective of disease severity or underlying aetiology.

Optimisation of hepatocellular carcinoma surveillance in patients with viral hepatitis: a quality improvement study.

BACKGROUND: Surveillance for hepatocellular carcinoma (HCC) with 6-monthly ultrasound is a standard of care for higher-risk patients with viral hepatitis. Adherence to screening guidelines is an important quality indicator in hepatology, but multiple studies have demonstrated poor HCC surveillance practices in real-world settings. AIMS: The aim of this project was to audit and then optimise HCC surveillance of viral hepatitis patients, who fulfilled criteria for screening, associated with a large tertiary hospital. METHODS: Clinical practice improvement principles were utilised. A baseline audit of 22 consecutive viral hepatitis patients was performed. Major barriers preventing adequate surveillance were identified and three interventions to improve adherence to guidelines were introduced. These included: improved doctor education, system redesign and improved patient education. The effects of interventions were measured by serial random audits of patients. A final audit occurred over 3 years after the initial baseline audit. RESULTS: At baseline, 46% and 0% of patients had appropriate surveillance performed during the prior 6 months (one surveillance cycle) and 2 years (four surveillance cycles) respectively. Three years after initiation of these strategies, a final audit revealed 92% (vs 46% at baseline) and 64% (vs 0% at baseline) of patients had appropriate HCC surveillance performed during the preceding 6 months and 2 years intervals respectively (P < 0.001 in each case). CONCLUSIONS: Simple and low-cost interventions can considerably improve the clinical effectiveness of HCC screening programmes in real world settings. Clinical practice improvement principles appear to be a valid methodology for achieving this positive change.

Liver resection and transplantation offer similar 5-year survival for Child-Pugh-Turcotte A HCC-patients with a single nodule up to 5 cm: a multicenter, exploratory analysis.

BACKGROUND AND AIM: The current guideline of the American Association for the Study of Liver Diseases recommends liver resection for Child-Pugh-Turcotte A patients with a single hepatocellular carcinoma, total serum bilirubin ≤ 1 mg/dL and absence of significant portal hypertension. This subset of patients would have a long-term survival comparable to transplantation. The main aim of this study is to evaluate the survival rates in patients with a single nodule ≤ 5 cm following resection. METHODS: Medical records of 105 Child-Pugh-Turcotte A patients who underwent liver resection between 1997 and 2009 were analyzed in 3 countries. RESULTS: One, 3-, and 5-year survival rate was 97%, 83%, and 66%, respectively, and no variable that can be assessed prior to liver resection predicted survival probabilities. CONCLUSIONS: Liver resection offers 5-year survival similar to transplantation for Child-Pugh-Turcotte A patients with hepatocellular carcinoma and a single nodule up to 5 cm, independently of any patient baseline characteristics.

Single centre experience with pegylated interferon and ribavirin for hepatitis C: looking back before moving forward.

BACKGROUND: Hepatitis C treatment is successful in 40-80% of patients in drug sponsored registration trials. However, few studies have examined treatment outcomes in non-trial, routine clinical practice settings. AIM: The aim of this study was to investigate the treatment outcomes and predictors of a sustained virological response in a routine clinical setting. METHODS: Data were collected retrospectively on patients treated for hepatitis C between January 2004 and March 2010 in a tertiary hospital setting. Demographics, treatment outcomes and potential predictors of outcome (viral genotype, viral load, virological response, platelet count, alanine transaminase level, glucose, ferritin, weight, fibrosis and cirrhosis, compliance, dose reductions, adverse events, psychiatric and alcohol history) were recorded. Univariate and multiple logistic regressions were performed. RESULTS: A total of 405 patients was treated during the study period. On an intention to treat basis, sustained virological response rates were 55%, 82% and 72% in genotypes 1, 2 and 3 respectively. Predictors of response were gender, age, genotype, weight, fibrosis, cirrhosis, platelet count and alanine transaminase on univariate analysis. Age, genotype, cirrhosis and platelet count were independently associated with sustained virological response on multiple logistic regression. CONCLUSION: In our cohort, treatment outcomes for genotype 1 and 2 were similar to results from clinical trials but results for genotype 3 were inferior. Clinicians should not assume that results from registration trials are transferable to their own clinical practice. This has particular relevance for the new era of triple therapy regimens containing direct antivirals.

Chronic kidney disease following liver transplantation: a South Australian experience.

The incidence of chronic kidney disease (CKD) and its impact on survival have not been widely studied in the Australian liver transplant (OLT) population. The aims of this study were to evaluate the prevalence of CKD stages at various time points, calculate the cumulative incidence of progression to severe CKD, and study the impact of CKD stages on patient survival and risk factors for severe CKD in a single-center post-OLT population. We studied retrospectively 130 patients who underwent OLT in South Australia with a minimum of 6 months of follow-up from 1992 to 2008. CKD was staged according to Kidney Diseases Outcome Quality Initiative Guidelines. Glomerular filtration rate (GFR) was calculated using the Modification of Diet in Renal Disease equation. Multiple pre- and post-OLT variables were examined for their association with severe CKD. Log-rank tests and Cox regression analysis were performed to evaluate the survival data. The cumulative incidences of severe CKD (stages 4 and 5) at 2, 5, and 15 years were 3.8%, 12.7%, and 14.8%, respectively. Severe CKD was associated with an increased mortality (hazard ratio 6.5; 95% confidence interval = 2.5-17.0; P < .001). Mild and moderate CKD stages were not associated with increased mortality. Risk factors for severe CKD were: female gender, hepatitis C infection, pre-OLT diabetes, acute renal failure post-OLT, and low 1-year GFR. Mild and moderate CKD are common post-OLT. The development of severe CKD, which can be predicted early in the post-OLT period, is strongly associated with an increased mortality rate.

Intra-articular fractures of the distal radius: a prospective randomised controlled trial comparing static bridging and dynamic non-bridging external fixation.

This prospective randomized trial compared a non-bridging external fixator with a bridging external fixator system for the treatment of severe comminuted intra-articular fractures of the distal radius. The results did not demonstrate a statistically significant difference in the radiological and clinical outcomes achieved with these two treatments.

Heterozygous recipient and donor HFE mutations associated with a hereditary haemochromatosis phenotype after liver transplantation.

We observed the development of phenotypic hereditary haemochromatosis in a non-hereditary haemochromatosis liver transplant recipient, following transplantation with a liver from a C282Y heterozygous donor. No cause for secondary iron overload was identified. Subsequent sequencing of the HFE gene of both donor and recipient revealed a strong candidate for a novel pathogenic HFE mutation. In the recipient, heterozygosity for a single base substitution in exon 1, g.18 G>C, resulting in the substitution of arginine by serine at codon 6 (R6S), was detected. This R6S variation is likely to represent a novel pathogenic missense mutation of the HFE gene. An interaction between R6S heterozygosity in the recipient and C282Y heterozygosity in the donor liver is the most likely explanation for the development of iron overload in this patient. The report suggests that an hepatic defect is required for expression of hereditary haemochromatosis and that the intestinal HFE genotype is not the exclusive determinant of iron status. It also raises the possibility that a hereditary haemochromatosis phenotype may result from transplantation of C282Y heterozygous donor livers into recipients with heterozygous pathogenic HFE mutations. This possibility may have significant implications for the common practice of transplanting C282Y heterozygous livers.

Changing incidence of primary total hip arthroplasty and total knee arthroplasty for primary osteoarthritis.

This study reports on the incidence of primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) for primary osteoarthritis in Australia. Age-specific and gender-specific numbers for Australia, 1994 through 1998, and South Australia, 1988 through 1998, were obtained. Incidences were calculated per 100,000 population. In Australia, primary THA increased from 50.9/10(5) (1994) to 60.9/10(5) (1998). TKA increased from 56.4/10(5) to 76.8/10(5). Stratified by age and gender, changes in incidence for South Australia with respect to time were tested using regression analysis. South Australia showed a significant increase in the overall incidence of THA (P=.012) and TKA (P<.001), although this was not uniform across all age groups. No significant gender differences were found. The incidence of THA is increasing, and the incidence of TKA is increasing at a greater rate.

Identification of dipeptidyl nitriles as potent and selective inhibitors of cathepsin B through structure-based drug design.

Cathepsin B is a member of the papain superfamily of cysteine proteases and has been implicated in the pathology of numerous diseases, including arthritis and cancer. As part of an effort to identify potent, reversible inhibitors of this protease, we examined a series of dipeptidyl nitriles, starting with the previously reported Cbz-Phe-NH-CH(2)CN (19, IC(50) = 62 microM). High-resolution X-ray crystallographic data and molecular modeling were used to optimize the P(1), P(2), and P(3) substituents of this template. Cathepsin B is unique in its class in that it contains a carboxylate recognition site in the S(2)' pocket of the active site. Inhibitor potency and selectivity were enhanced by tethering a carboxylate functionality from the carbon alpha to the nitrile to interact with this region of the enzyme. This resulted in the identification of compound 10, a 7 nM inhibitor of cathepsin B, with excellent selectivity over other cysteine cathepsins.

The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor alpha in the pathogenesis of non-alcoholic steatohepatitis.

BACKGROUND: Small intestinal bacterial overgrowth may contribute to the development of non-alcoholic steatohepatitis, perhaps by increasing intestinal permeability and promoting the absorption of endotoxin or other enteric bacterial products. AIMS: To investigate the prevalence of small intestinal bacterial overgrowth, increased intestinal permeability, elevated endotoxin, and tumour necrosis factor alpha (TNF-alpha) levels in patients with non-alcoholic steatohepatitis and in control subjects. PATIENTS AND METHODS: Twenty two patients with non-alcoholic steatohepatitis and 23 control subjects were studied. Small intestinal bacterial overgrowth was assessed by a combined (14)C-D-xylose and lactulose breath test. Intestinal permeability was assessed by a dual lactulose-rhamnose sugar test. Serum endotoxin levels were determined using the limulus amoebocyte lysate assay and TNF-alpha levels using an ELISA. RESULTS: Small intestinal bacterial overgrowth was present in 50% of patients with non-alcoholic steatosis and 22% of control subjects (p=0.048). Mean TNF-alpha levels in non-alcoholic steatohepatitis patients and control subjects were 14.2 and 7.5 pg/ml, respectively (p=0.001). Intestinal permeability and serum endotoxin levels were similar in the two groups. CONCLUSIONS: Patients with non-alcoholic steatohepatitis have a higher prevalence of small intestinal bacterial overgrowth, as assessed by the (14)C-D-xylose-lactulose breath test, and higher TNF-alpha levels in comparison with control subjects. This is not accompanied by increased intestinal permeability or elevated endotoxin levels.

Characterization of recombinant human cathepsin B expressed at high levels in baculovirus.

The lysosomal cysteine protease cathepsin B has been studied intensely for many years because of its unique characteristics and its potential involvement in disease states. A reproducible, high yield expression system for active recombinant protein is key to biochemical and biophysical studies as well as rational drug design. Although several microbial and mammalian expression systems for recombinant human cathepsin B have been described, these have been limited by low or variable yields. Further, in some of these systems hyper-glycosylation of the enzyme near the active site affects its activity. We describe a baculovirus expression system and purification scheme that solve all of these problems. Yields of active, protected enzyme were reproducibly in excess of 25 mg/L. Since this protein was not hyper-glycosylated, it had greater activity than cathepsin B produced in yeast systems as indicated by a threefold increase in Kcat. In addition, the biophysical properties of the baculovirus-expressed cathepsin B, as measured by dynamic light scattering, were more amenable to crystallographic study since the data indicated proteins of more uniform size. Therefore, this system for the production of recombinant human cathepsin B constitutes a major improvement in both quantity and quality over those previously reported. Further, we demonstrate that the manner of expression and purification of this enzyme has profound effects on its kinetic and physical parameters.