Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy.

Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.

Improving Concordance Between Clinicians With Australian Guidelines for Bowel Cancer Prevention Using a Digital Application: Randomized Controlled Crossover Study.

BACKGROUND: Australia's bowel cancer prevention guidelines, following a recent revision, are among the most complex in the world. Detailed decision tables outline screening or surveillance recommendations for 230 case scenarios alongside cessation recommendations for older patients. While these guidelines can help better allocate limited colonoscopy resources, their increasing complexity may limit their adoption and potential benefits. Therefore, tools to support clinicians in navigating these guidelines could be essential for national bowel cancer prevention efforts. Digital applications (DAs) represent a potentially inexpensive and scalable solution but are yet to be tested for this purpose. OBJECTIVE: This study aims to assess whether a DA could increase clinician adherence to Australia's new colorectal cancer screening and surveillance guidelines and determine whether improved usability correlates with greater conformance to guidelines. METHODS: As part of a randomized controlled crossover study, we created a clinical vignette quiz to evaluate the efficacy of a DA in comparison with the standard resource (SR) for making screening and surveillance decisions. Briefings were provided to study participants, which were tailored to their level of familiarity with the guidelines. We measured the adherence of clinicians according to their number of guideline-concordant responses to the scenarios in the quiz using either the DA or the SR. The maximum score was 18, with higher scores indicating improved adherence. We also tested the DA's usability using the System Usability Scale. RESULTS: Of 117 participants, 80 were included in the final analysis. Using the SR, the adherence of participants was rated a median (IQR) score of 10 (7.75-13) out of 18. The participants' adherence improved by 40% (relative risk 1.4, P<.001) when using the DA, reaching a median (IQR) score of 14 (12-17) out of 18. The DA was rated highly for usability with a median (IQR) score of 90 (72.5-95) and ranked in the 96th percentile of systems. There was a moderate correlation between the usability of the DA and better adherence (rs=0.4; P<.001). No differences between the adherence of specialists and nonspecialists were found, either with the SR (10 vs 9; P=.47) or with the DA (13 vs 15; P=.24). There was no significant association between participants who were less adherent with the DA (n=17) and their age (P=.06), experience with decision support tools (P=.51), or academic involvement with a university (P=.39). CONCLUSIONS: DAs can significantly improve the adoption of complex Australian bowel cancer prevention guidelines. As screening and surveillance guidelines become increasingly complex and personalized, these tools will be crucial to help clinicians accurately determine the most appropriate recommendations for their patients. Additional research to understand why some practitioners perform worse with DAs is required. Further improvements in application usability may optimize guideline concordance further.

Comparing the resource implications of old and new colorectal adenoma surveillance guidelines in Australia.

BACKGROUND: The latest update to the Australian adenoma surveillance guideline in 2018 introduced a novel risk stratification system with updated surveillance recommendations. The resource implications of adopting this new system are unclear. AIMS: To quanitfy the resource demands of adopting new over old adenoma surveillance guidelines. METHODS: We studied data from 2443 patients undergoing colonoscopies, in which a clinically significant lesion was identified in their latest, or previous procedure(s) across five Australian hospitals. We excluded procedures with inflammatory bowel disease, new or prior history of colorectal cancer or resection, inadequate bowel preparation and incomplete procedures. Old and new Australian surveillance intervals were calculated according to the number, size and histological characteristics of lesions identified. We used these data to compare the rate of procedures according to each guideline. RESULTS: Based on the procedures for 766 patients, the new surveillance guidelines significantly increased the number of procedures allocated an interval of 1 year (relative risk (RR): 1.57, P = 0.009) and 10 years (RR: 3.83, P < 0.00001) and reduced those allocated to half a year (RR: 0.08, P = 0.00219), 3 years (RR: 0.51, P < 0.00001) and 5 years (RR: 0.59, P < 0.00001). Overall, this reduced the relative number of surveillance procedures by 21% over 10 years (25.92 vs 32.78 procedures/100 patient-years), which increased to 22% after excluding patients 75 or older at the time of surveillance (19.9 vs 25.65 procedures/100 patient-years). CONCLUSION: The adoption of the latest Australian adenoma surveillance guidelines can reduce demand for surveillance colonoscopy by more than a fifth (21-22%) over 10 years.

Broadening and strengthening the health providers caring for patients with chronic hepatitis C may improve continuity of care.

BACKGROUND: Direct-acting antiviral (DAA) therapies for hepatitis C virus infection (HCV) lead to excellent rates of sustained virological response (SVR). However, loss to follow-up (LTFU) for SVR testing remains a challenge. We examine factors associated with LTFU in a real-world setting. METHODS: Adults who received DAA therapy for HCV in one of 26 centers across Australia during 2016-2021 were followed up for 2 years. Data sources included the patient medical records and the national Pharmaceutical and Medicare Benefits Schemes. Linkage to Medicare provided utilization data of other health-care providers and re-treatment with DAAs. LTFU was defined as no clinic attendance for SVR testing by at least 52 weeks after DAA treatment commencement. Multivariable logistic regression assessed factors associated with LTFU. RESULTS: In 3619 patients included in the study (mean age 52.0 years; SD = 10.5), 33.6% had cirrhosis (69.4% Child-Pugh class B/C), and 19.3% had HCV treatment prior to the DAA era. Five hundred and fifteen patients (14.2%) were LTFU. HCV treatment initiation in 2017 or later (adj-OR = 2.82, 95% confidence interval [CI] 2.25-3.54), younger age (adj-OR = 2.63, 95% CI 1.80-3.84), Indigenous identification (adj-OR = 1.99, 95% CI 1.23-3.21), current injection drug use or opioid replacement therapy (adj-OR = 1.66, 95% CI 1.25-2.20), depression treatment (adj-OR = 1.49, 95% CI 1.17-1.90), and male gender (adj-OR = 1.31, 95% CI 1.04-1.66) were associated with LTFU. CONCLUSIONS: These findings stress the importance of strengthening the network of providers caring for patients with HCV. In particular, services targeting vulnerable groups of patients such as First Nations Peoples, youth health, and those with addiction and mental health disorders should be equipped to treat HCV.

Dual effects of radiotherapy on tumor microenvironment and its contribution towards the development of resistance to immunotherapy in gastrointestinal and thoracic cancers.

Successful clinical methods for tumor elimination include a combination of surgical resection, radiotherapy, and chemotherapy. Radiotherapy is one of the crucial components of the cancer treatment regimens which allow to extend patient life expectancy. Current cutting-edge radiotherapy research is focused on the identification of methods that should increase cancer cell sensitivity to radiation and activate anti-cancer immunity mechanisms. Radiation treatment activates various cells of the tumor microenvironment (TME) and impacts tumor growth, angiogenesis, and anti-cancer immunity. Radiotherapy was shown to regulate signaling and anti-cancer functions of various TME immune and vasculature cell components, including tumor-associated macrophages, dendritic cells, endothelial cells, cancer-associated fibroblasts (CAFs), natural killers, and other T cell subsets. Dual effects of radiation, including metastasis-promoting effects and activation of oxidative stress, have been detected, suggesting that radiotherapy triggers heterogeneous targets. In this review, we critically discuss the activation of TME and angiogenesis during radiotherapy which is used to strengthen the effects of novel immunotherapy. Intracellular, genetic, and epigenetic mechanisms of signaling and clinical manipulations of immune responses and oxidative stress by radiotherapy are accented. Current findings indicate that radiotherapy should be considered as a supporting instrument for immunotherapy to limit the cancer-promoting effects of TME. To increase cancer-free survival rates, it is recommended to combine personalized radiation therapy methods with TME-targeting drugs, including immune checkpoint inhibitors.

The basis and implications of diverging approaches to colorectal adenoma surveillance in the West.

Algorithms for the surveillance of colorectal adenomas have recently undergone revision in Australia and abroad. Despite a shared evidence base, significant differences are observed and optimal intervals for surveillance remain controversial. We sought to explore their differences in relation to current evidence, practical aspects and how we may improve our own approach to adenoma surveillance in Australia.

MicroRNA-183 cluster: a promising biomarker and therapeutic target in gastrointestinal malignancies.

Small non-coding RNAs (microRNA, miR), powerful epigenetic regulators, were found involved in the regulation of most biological functions via post-translational inhibition of protein expression. Increased expression of pro-oncogenic miRs (known as miR cancer biomarkers) and inhibition of pro-apoptotic miR expression have been demonstrated in different tumors. The recently identified miR-183 was found implicated in gastrointestinal tumor metabolism regulation. Elevated miR-183 expression and cancer-promoting effects were reported in esophageal and colorectal cancers, which was partially contradicted by controversial data observed in gastric cancers. Anti-cancer effect of miR-183 in gastric cancer cells was associated with the Bim-1 and Ezrin genes regulation. Many studies indicated that miR-183 can inhibit tumor suppressor genes in most cell lines, promoting tumor cell proliferation and migration. Increased miR-183 level results in the downregulation of FOXO1, PDCD4, and other tumor suppressor genes in gastrointestinal tumor cells. MiR-183 also influences the signaling of PI3K/AKT/mTOR, Wnt/ß-catenin, and Bcl-2/p53 signaling pathways. Mir-183 inhibits apoptosis and autophagy, and promotes epithelial-to-mesenchymal transition, cancer cell proliferation, and migration. Accordingly, gastrointestinal cancer occurrence, development of chemoradiotherapy resistance, recurrence/metastasis, and prognosis were associated with miR-183 expression. The current study assessed reported miR-183 functions and signaling, providing new insights for the diagnosis and treatment of gastrointestinal malignancies.

Quality of colonoscopy performed by medical or surgical specialists and trainees in five Australian hospitals.

BACKGROUND: Ensuring colonoscopy procedure quality is vital to the success of screening and surveillance programmes for bowel cancer in Australia. However, the data on the performance of quality metrics, through adequate adenoma detection, bowel preparation, and procedure completion rates, in the Australian public sector is limited. Understanding these can inform quality improvement to further strengthen our capacity for prevention and early detection of colorectal cancer. AIM: To determine the quality of colonoscopy in Australian teaching hospitals and their association with proceduralist specialty, trainee involvement, and location. METHODS: We retrospectively evaluated 2443 consecutive colonoscopy procedure reports from 1 January to 1 April, 2018 from five public teaching tertiary hospitals in Australia (median 60 years old, 49% male). Data for bowel preparation quality, procedure completion rates, and detection rates of clinically significant adenomas, conventional adenomas, and serrated lesions was collected and compared to national criteria for quality in colonoscopy. Participating hospital, proceduralist specialty, and trainee involvement indicators were used for stratification. Data was analysed using Chi-squared tests of independence, Mann-Whitney U, One-way ANOVA, and multivariate binary logistic regression. RESULTS: Fifty-two point two percent (n = 1276) and 43.3% (n = 1057) were performed by medical and surgical proceduralists respectively, whilst 29.8% (n = 728) involved a trainee. Inadequate bowel preparation affected 7.3% of all procedures. The procedure completion rate was 95.1%, which increased to 97.5% after adjustment for bowel preparation quality. The pooled cancer, adenoma, and serrated lesion detection rates for all five hospitals were 3.5%, 40%, and 5.9% respectively. Assessed hospitals varied significantly by patient age (P < 0.001), work-force composition (P < 0.001), adequacy of bowel preparation (P < 0.001), and adenoma detection rate (P < 0.001). Two hospitals (40%) did not meet all national criteria for quality, due to a procedure completion rate of 94.5% or serrated lesion detection rate of 2.6%. Although lower than the other hospitals, the difference was not significant. Compared with surgical specialists, procedures performed by medical specialists involved older patients [65 years (inter-quartile range, IQR 58-73) vs 64 years (IQR 56-71); P = 0.04] and were associated with a higher adenoma detection rate [odds ratio (OR) 1.53; confidence interval: 1.21-1.94; P < 0.001]. Procedures involving trainee proceduralists were not associated with differences in the detection of cancer, adenoma, or serrated lesions, compared with specialists, or according to their medical or surgical background. On multivariate analysis, cancer detection was positively associated with patient age (OR 1.04; P < 0.001) and negatively associated with medical compared to surgical proceduralists (OR 0.54; P = 0.04). Conventional adenoma detection rates were independently associated with increasing patient age (OR 1.04; P < 0.001), positively associated with medical compared to surgical proceduralists (OR 1.41; P = 0.002) and negatively associated with male gender (OR 0.53; P < 0.001). CONCLUSION: Significant differences in the quality of colonoscopy in Australia exist, even when national benchmarks are achieved. The role of possible contributing factors, like procedural specialty and patient gender need further evaluation.

Pharmacogenetics of Drug Metabolism: The Role of Gene Polymorphism in the Regulation of Doxorubicin Safety and Efficacy.

Breast cancer (BC) is the prevailing malignancy and major cause of cancer-related death in females. Doxorubicin is a part of BC neoadjuvant and adjuvant chemotherapy regimens. The administration of anthracycline derivates, such as doxorubicin, may cause several side effects, including hematological disfunction, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, and cardiotoxicity. Cardiotoxicity is a major adverse reaction to anthracyclines, and it may vary depending on individual differences in doxorubicin pharmacokinetics. Determination of specific polymorphisms of genes that can alter doxorubicin metabolism was shown to reduce the risk of adverse reactions and improve the safety and efficacy of doxorubicin. Genes which encode cytochrome P450 enzymes (CYP3A4 and CYP2D6), p-glycoproteins (ATP-binding cassette (ABC) family members such as Multi-Drug Resistance 1 (MDR1) protein), and other detoxifying enzymes were shown to control the metabolism and pharmacokinetics of doxorubicin. The effectiveness of doxorubicin is defined by the polymorphism of cytochrome p450 and p-glycoprotein-encoding genes. This study critically discusses the latest data about the role of gene polymorphisms in the regulation of doxorubicin's anti-BC effects. The correlation of genetic differences with the efficacy and safety of doxorubicin may provide insights for the development of personalized medical treatment for BC patients.

Hepatitis C treatment outcomes for Australian First Nations Peoples: equivalent SVR rate but higher rates of loss to follow-up.

BACKGROUND: First Nations Peoples of Australia are disproportionally affected by hepatitis C (HCV) infection. Through a prospective study we evaluated the outcome of direct-acting antiviral (DAA) therapy among First Nations Peoples with HCV infection. METHODS: Adults who initiated DAA therapy at one of 26 hospitals across Australia, 2016-2019 were included in the study. Clinical data were obtained from medical records and the Pharmaceutical and Medicare Benefits Schemes. Outcomes included sustained virologic response (SVR) and loss to follow-up (LTFU). A multivariable analysis assessed factors associated with LTFU. RESULTS: Compared to non-Indigenous Australians (n = 3206), First Nations Peoples (n = 89) were younger (p < 0.001), morel likely to reside in most disadvantaged (p = 0.002) and in regional/remote areas (p < 0.001), and had similar liver disease severity. Medicines for mental health conditions were most commonly dispensed among First Nations Peoples (55.2% vs. 42.8%; p = 0.022). Of 2910 patients with follow-up data, both groups had high SVR rates (95.3% of First Nations Peoples vs. 93.2% of non-Indigenous patients; p = 0.51) and 'good' adherence (90.0% vs. 86.9%, respectively; p = 0.43). However, 28.1% of First Nations Peoples were LTFU vs. 11.2% of non-Indigenous patients (p < 0.001). Among First Nations Peoples, younger age (adj-OR = 0.93, 95% CI 0.87-0.99) and treatment initiation in 2018-2019 vs. 2016 (adj-OR = 5.14, 95% CI 1.23-21.36) predicted LTFU, while higher fibrosis score was associated with better engagement in HCV care (adj-OR = 0.71, 95% CI 0.50-0.99). CONCLUSIONS: Our data showed that First Nations Peoples have an equivalent HCV cure rate, but higher rates of LTFU. Better strategies to increase engagement of First Nations Peoples with HCV care are needed.

Mussel-inspired monomer - A new selective protease inhibitor against dentine collagen degradation.

OBJECTIVES: To evaluate the inhibitory effect of a novel mussel-inspired monomer (N-(3,4-dihydroxyphenethyl)methacrylamide (DMA) on the soluble and matrix-bound proteases. METHODS: The inhibitory effect of DMA (0, 1, 5, and 10 mM) and 1 mM chlorhexidine (CHX) dissolved in 50% ethanol/water on soluble recombinant human matrix metalloproteinases (rhMMP-2, -8, and -9), as well as cysteine cathepsins (B and K) were evaluated using both fluorometric assay kits and molecular docking. The effect of CHX and DMA on matrix-bound proteases was examined by in situ zymography, and the fluorescence intensity and relative area were calculated by Image J software. All data obtained were analyzed by one-way ANOVA followed by Tukey test (α = 0.05). RESULTS: The anti-proteolytic ability of DMA increased in a dose-dependent manner except that of rhMMP-9. Inhibitory effect of 1 mM DMA against rhMMP-2, - 8, - 9, as well as cathepsin B and K was all significantly lower than 1 mM CHX (p < 0.05). The molecular docking analysis was in good agreement with the experimental results, that the binding energy of DMA was lower than CHX for all proteases. In situ zymography revealed that all DMA- and CHX-treated groups significantly inactivated the matrix-bound proteases, with a dramatic reduction of the fluorescence intensity and relative area compared with the control group (p < 0.05). SIGNIFICANCE: Under the prerequisite condition that the overall inhibitory performance on matrix-bound proteases was comparable by DMA and CHX, the more selective property of DMA could avoid inducing potential negative effects by suppressing MMP-9 when applied in dental treatment compared with CHX.

Management, outcomes and survival of an Australian IgG4-SC cohort: The MOSAIC study.

BACKGROUND AND AIMS: IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. METHODS: We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. RESULTS: 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3 ± 14.5 years and a median IgG4 level of 3.6 g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9 years there was one hepatocellular carcinoma and no cholangiocarcinomas. CONCLUSIONS: Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.

eHealth Technologies for Screening, Diagnosis, and Management of Viral Hepatitis: A Systematic Review.

BACKGROUND & AIMS: Chronic viral hepatitis is a leading cause of worldwide liver-related morbidity and mortality, despite the availability of effective treatments that reduce or prevent complications in most patients. Electronic-health (eHealth) technologies have potential to intervene along the whole cascade of care. We aimed to summarize available literature on eHealth interventions with respect to conventional screening, diagnostic and treatment outcomes in chronic hepatitis B (HBV) and hepatitis C (HCV). METHODS: We systematically reviewed MEDLINE, EMBASE, Cochrane Library and international conference abstracts, including studies published from 2009 - 2020. Overall 80 studies were included, covering electronic medical record (EMR) interventions (n=39), telemedicine (n=20), mHealth (n=5), devices (n=4), clinical decision support (n=3), web-based (n=5), social media (n=1) and electronic communication (n=3). RESULTS: Compared to standard care, EMR alerts increase screening rates in eligible populations including birth cohort screening in HCV, universal HCV screening in Emergency Departments, ethnic groups with high HBV prevalence, and HBV screening prior to immunosuppression. Direct messaging alerts to providers and automated testing may have a greater effect. No significant difference was found in sustained virological response outcomes between telemedicine and face-to-face management for community, rural and prison cohorts in HCV in the direct acting antiviral era of treatment, with higher patient satisfaction in telemedicine groups. CONCLUSIONS: EMR alerts significantly increase screening rates in eligible cohorts in both chronic HBV and HCV. Telemedicine is equally efficacious to face-to-face care in HCV treatment. Other eHealth technologies show promise; however rigorous studies are lacking.

Shigella flexneri Targets Human Colonic Goblet Cells by O Antigen Binding to Sialyl-Tn and Tn Antigens via Glycan-Glycan Interactions.

Shigella flexneri targets colonic cells in humans to initiate invasive infection processes that lead to dysentery, and direct interactions between their lipopolysaccharide O antigens and blood group A related glycans are involved in the cell adherence interactions. Here, we show that treatment with Tn and sialyl-Tn glycans, monoclonal antibodies and lectins reactive to Tn/sialyl-Tn, and luteolin (a Tn antigen synthesis inhibitor) all significantly inhibited S. flexneri adherence and invasion of cells in vitro. Surface plasmon resonance analysis showed that lipopolysaccharide O antigen had a high affinity interaction with Tn/sialyl-Tn. Immunofluorescence probing of human colon tissue with antibodies detected expression of Tn/sialyl-Tn by MUC2 producing goblet cells (GCs), and S. flexneri incubated with human colon tissue colocalized with GCs. Our findings demonstrate that S. flexneri targets GCs in the human colonic crypts via glycan-glycan interactions, establishing new insight into the infection process in humans.

Cost effectiveness of treatment models of care for hepatitis C: the South Australian state-wide experience.

AIM: The objective was to study the long-term (lifetime) cost effectiveness of four different hepatitis C virus (HCV) treatment models of care (MOC) with directly acting antiviral drugs. METHODS: A cohort Markov model-based probabilistic cost-effectiveness analysis (CEA) was undertaken extrapolating to up to 30 years from cost and outcome data collected from a primary study involving a real-life Australian cohort. In this study, noncirrhotic patients treated for HCV from 1 March 2016 to 28 February 2017 at four major public hospitals and liaising sites in South Australia were studied retrospectively. The MOC were classified depending on the person providing patient workup, treatment and monitoring into MOC1 (specialist), MOC2 (mixed specialist and hepatitis nurse), MOC3 (hepatitis nurse) and MOC4 (general practitioner, GP). Incremental costs were estimated from the Medicare perspective. Incremental outcomes were estimated based on the quality-adjusted life years (QALY) gained by achieving a sustained virological response. A cost-effectiveness threshold of Australian dollar 50 000 per QALY gained, the implicit criterion used for assessing the cost-effectiveness of new pharmaceuticals and medical services in Australia was assumed. Net monetary benefit (NMB) estimates based on this threshold were calculated. RESULTS: A total of 1373 patients, 64% males, mean age 50 (SD ±11) years, were studied. In the CEA, MOC4 and MOC2 clearly dominated MOC1 over 30 years with lower costs and higher QALYs. Similarly, NMB was the highest in MOC4, followed by MOC2. CONCLUSION: Decentralized care using GP and mixed consultant nurse models were cost-effective ways of promoting HCV treatment uptake in the setting of unrestricted access to new antivirals.

Stereotactic body radiation therapy for early hepatocellular carcinoma: a retrospective analysis of the South Australian experience.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an emerging treatment option for liver tumours unsuitable for established curative treatment such as ablation or surgery. The aim of the study is to evaluate the efficacy and safety of SBRT in the treatment of small hepatocellular carcinoma (HCC) in South Australia. METHODS: From 2014 to 2018, 13 HCC patients were treated with SBRT. Eligibility criteria for SBRT included: unsuitable for standard curative therapies (resection or percutaneous ablation), lack of complete response to prior transarterial chemoembolization, Child-Pugh classification ≤B7, tumours ≤5 cm and minimum of up to 6 months follow-up post-SBRT. The prescribed radiation dose was determined by liver function with doses ranging from 40 to 45 Gy in three or five fractions. Records for all patients were reviewed, and treatment response was scored according to the modified response evaluation criteria in solid tumours. Toxicity was graded according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: The median follow-up time was 22.7 months, and the median tumour size was 40 mm. The 1 year local control was 92.3%, recurrence-free survival was 67.7% and overall survival was 86.4% at end of study. Three patients underwent liver transplant. No grade ≥3 non-haematological toxicities were observed. One patient experienced acute grade ≥3 haematological toxicity. CONCLUSION: SBRT is a safe, effective and non-invasive alternative treatment option for patients with small HCCs, unsuitable for standard, evidence-based therapies and lacking complete response to transarterial chemoembolization. Randomized controlled trials are required to further investigate the role of SBRT in HCC.

Saving costs through a coordinated care model for patients with hepatocellular cancer.

BACKGROUND: In keeping with recent trends, patients with hepatocellular cancer have had their care managed by a dedicated Nurse Coordinator at our tertiary Australian hospital since 2010. To date, there are few data to justify the cost-effectiveness of this approach. AIMS: To quantify the potential cost saved through the employment of a Nurse Coordinator in the management of patients with hepatocellular carcinoma at a single tertiary-level Australian hospital. METHODS: A retrospective audit of patients managed by the Nurse Coordinator between 2010 and 2015 was conducted. Consensus reports from previous meetings were reviewed, and nurse-initiated radiological procedures and encounters were identified. Clinical activities were prospectively evaluated over a 1-month period in July-August 2015. The equivalent annual number of outpatient medical encounters spared was calculated. Using the national average cost of each gastroenterology outpatient encounter, a total annual cost was determined and was compared against the cost of funding the position. RESULTS: The activity of the Nurse Coordinator resulted in an equivalent of at least 175 outpatient encounters being spared per year, with a minimum annual cost saving of $85 750. A total of 113 encounters resulted from the independent delivery and initiation of multidisciplinary team meeting plans; 10 were attributed to nurse-led patient education, and 52 were equated to weekly clinical activities. This represented a net annual saving of $17 050. CONCLUSION: The incorporation of the Nurse Coordinator in the care pathway of patients with hepatocellular cancer is associated with a reduction in medical outpatient load and, consequently, a significant annual cost saving.

Real-world efficacy and safety of ritonavir-boosted paritaprevir, ombitasvir, dasabuvir ± ribavirin for hepatitis C genotype 1 - final results of the REV1TAL study.

BACKGROUND: Limited data exist on the outcomes of ritonavir-boosted paritaprevir with ombitasvir and dasabuvir (PrOD) ± ribavirin in a real-world setting. The aim of this study was to compare the efficacy and safety of PrOD-based therapy in hepatitis C genotype 1 patients with and without cirrhosis, and to explore pre-treatment factors predictive of sustained viral response (SVR) and serious adverse events (SAEs) on treatment. METHODS: 451 patients with hepatitis C genotype 1 treated in 20 centres across Australia were included. Baseline demographic, clinical and laboratory information, on-treatment biochemical, virological and haematological indices and details on serious adverse events were collected locally. RESULTS: Cirrhosis was present in 340 patients (75.4%). Overall SVR was 95.1% with no differences in SVR between the cirrhosis and non-cirrhosis groups (94.7% versus 96.4%). SVR in subgenotypes 1a and 1b was 93.1% and 99.2%, respectively. On multivariate analysis, baseline bilirubin level and early treatment cessation predicted SVR. SAEs occurred in 10.9% of patients including hepatic decompensation (2.7%) and hepatocellular carcinoma (1.8%). On multivariate analysis of factors predictive of SAEs in the overall group, Child-Turcotte-Pugh (CTP) B was the only significant factor, while in those with cirrhosis, baseline albumin and creatinine levels were significant. CONCLUSIONS: In this large real-world cohort of HCV genotype 1 subjects, treatment with PrOD was highly effective and similar to clinical trials. Important determinants of reduced SVR include early cessation of therapy and baseline bilirubin concentration. SAEs were not infrequent with CTP B patients being at greatest risk.

Identification of carbon-encapsulated iron nanoparticles as active species in non-precious metal oxygen reduction catalysts.

The widespread use of fuel cells is currently limited by the lack of efficient and cost-effective catalysts for the oxygen reduction reaction. Iron-based non-precious metal catalysts exhibit promising activity and stability, as an alternative to state-of-the-art platinum catalysts. However, the identity of the active species in non-precious metal catalysts remains elusive, impeding the development of new catalysts. Here we demonstrate the reversible deactivation and reactivation of an iron-based non-precious metal oxygen reduction catalyst achieved using high-temperature gas-phase chlorine and hydrogen treatments. In addition, we observe a decrease in catalyst heterogeneity following treatment with chlorine and hydrogen, using Mössbauer and X-ray absorption spectroscopy. Our study reveals that protected sites adjacent to iron nanoparticles are responsible for the observed activity and stability of the catalyst. These findings may allow for the design and synthesis of enhanced non-precious metal oxygen reduction catalysts with a higher density of active sites.