Diana Hull

Virus-Directed Enzyme Prodrug Therapy: Intratumoral Administration of a Replication-Deficient Adenovirus Encoding Nitroreductase to Patients With Resectable Liver Cancer

PURPOSE Virus-directed enzyme prodrug therapy depends on selective delivery of virus encoding a prodrug-activating enzyme to tumor, followed by systemic treatment with prodrug to achieve high levels of the activated cytotoxic at the intended site of action. The use of the bacterial enzyme nitroreductase to activate CB1954 (5-(aziridin-1-yl)-2,4-dinitrobenzamide) to a short lived, highly toxic DNA cross-linking agent has been demonstrated in tumor xenografts. In this study, we report the first clinical trial investigating the feasibility, safety, and transgene expression of a replication-defective adenovirus encoding nitroreductase (CTL102) in patients with liver tumors. PATIENTS AND METHODS Patients with resectable primary or secondary (colorectal) liver cancer received a single dose of CTL102 delivered by direct intratumoral inoculation 3 to 8 days before surgical resection. RESULTS Eighteen patients were treated with escalating doses of CTL102 (range, 10(8)-5 x 10(11) virus particles). The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Dose-related increases in tumoral nitroreductase expression measured by immunohistochemical analysis have been observed. CONCLUSION Direct intratumoral inoculation of CTL102 to patients with primary and secondary liver cancer is feasible and well tolerated. The high level of nitroreductase expression observed at 1 to 5 x 10(11) virus particles mandates further studies in patients with inoperable tumors who will receive CTL102 and CB1954.

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.

Graphical abstract

The Detection of Hepatocellular Carcinoma Using a Prospectively Developed and Validated Model Based on Serological Biomarkers

Background: Hepatocellular carcinoma is a common complication of chronic liver disease (CLD), and is conventionally diagnosed by radiological means. We aimed to build a statistical model that could determine the risk of hepatocellular carcinoma in individual patients with CLD using objective measures, particularly serological tumor markers. Methods: A total of 670 patients with either CLD alone or hepatocellular carcinoma were recruited from a single UK center into a case–control study. Sera were collected prospectively and specifically for this study. A logistic regression analysis was used to determine independent factors associated with hepatocellular carcinoma and a model built and assessed in terms of sensitivity, specificity, and proportion of correct diagnoses. Results: The final model involving gender, age, AFP-L3, α fetoprotein (AFP), and des-carboxy-prothrombin (“GALAD”) was developed in a “discovery” data set and validated in independent data sets both from the same institution and from an external institution. When optimized for sensitivity and specificity, the model gave values of more than 0.88 irrespective of the disease stage. Conclusions: The presence of hepatocellular carcinoma can be detected in patients with CLD on the basis of a model involving objective clinical and serological factors. It is now necessary to test the models performance in a prospective manner and in a routine clinical practice setting, to determine if it may replace or, more likely, enhance current radiological approaches. Impact: Our data provide evidence that an entirely objective serum biomarker–based model may facilitate the detection and diagnosis of hepatocellular carcinoma and form the basis for a prospective study comparing this approach with the standard radiological approaches. Cancer Epidemiol Biomarkers Prev; 23(1); 144–53. ©2013 AACR.

Strategies for assessing and managing the adverse events of sorafenib and other targeted therapies in the treatment of renal cell and hepatocellular carcinoma: recommendations from a European nursing task group.

PURPOSE As a group of European nurses familiar with treating patients with renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) using targeted/chemo- therapies, we aimed to review strategies for managing adverse events (AEs) associated with one targeted therapy, sorafenib. METHOD Focusing on the AEs we considered the most difficult to manage (hand-foot skin reaction [HFSR], diarrhoea, fatigue and mucositis/stomatitis), we reviewed the literature to identify strategies relevant to sorafenib. Given the paucity of published work, this included strategies concerning targeted agents in general. This information was supplemented by considering the wider literature relating to management of these AEs in other tumour types and similar toxicities experienced during conventional anti-cancer therapy. Together with our own experience, this information was used to compile an AE management guide to assist nurses caring for patients receiving sorafenib. RESULTS Our collated experience suggests the most commonly reported AEs with sorafenib and other targeted agents are HFSR, diarrhoea, fatigue, rash and mucositis/stomatitis; these generally have an acute (appearing at ∼0-1 months) or delayed onset (appearing at ∼3 months). Most management strategies in the literature were experience-based rather than arising from controlled studies. However, strategies based on controlled studies are available for HFSR and mucositis/stomatitis. CONCLUSIONS Evidence, especially from controlled studies, is sparse concerning management of AEs associated with sorafenib and other targeted agents in RCC/HCC. However, recommendations can be made based on the literature and clinical experience that encompasses targeted and conventional therapies, particularly in the case of non-specific toxicities e.g. diarrhoea and fatigue.

Abdominal subcutaneous adipose tissue insulin resistance and lipolysis in patients with non-alcoholic steatohepatitis

Systemic insulin resistance (IR) is a primary feature in non‐alcoholic steatohepatitis (NASH), however, there remain limited data on tissue‐specific insulin sensitivity in vivo.

Sorafenib for advanced hepatocellular carcinoma (HCC): impact of rationing in the United Kingdom

Background:The prognosis for hepatocellular carcinoma (HCC) is dependent upon tumour stage, performance status (PS), severity of underlying liver disease, and the availability of appropriate therapies. The unavailability of sorafenib may have a significantly adverse effect on the prognosis of UK patients with advanced HCC. During the study period, access to sorafenib was at the discretion of local health funding bodies, a process that may delay or deny access to the drug and that remains in place for Wales, Scotland, and Northern Ireland. Here, we attempt to address the impact of this system on patients with advanced HCC in the United Kingdom.Methods:This is a retrospective study performed in the two largest specialist hepatobiliary oncology units in the United Kingdom. Funding applications were made to local funding bodies for patients with advanced HCC for whom sorafenib was considered appropriate (advanced HCC not suitable for loco-regional therapies, compensated chronic liver disease, PS 0–2).Results:A total of 133 applications were made, of which 57 (43%) were approved and 76 (57%) declined. Demographics and prognostic factors were balanced between the two groups. This cohort had a number of adverse prognostic features: patients were predominantly PS 1–2; the majority had multifocal disease with the largest lesion being >5 cm; and macroscopic vascular invasion, metastases, and AFP >1000 ng ml−1, were each present in one-third of cases. The median time from application to funding decision was 17 days (range 3–260 days). For the primary ‘intention-to-treat’ analysis, median overall survival was 4.1 months when funding was declined, and 9.5 months when funding was approved (hazard ratio (HR) 0.48; 95% CI 0.3186–0.7267; P=0.0005).Conclusion:These data support the use of sorafenib for patients with advanced HCC as an effective intervention. In the United Kingdom, this applies to a relatively small group of patients, estimated to total ∼800 per year who, unfortunately, do not survive long enough to themselves lobby for the availability of this drug. These data provide a comparison of sorafenib with supportive care and demonstrate the potential detrimental impact on patient outcomes of rationing health-care resources on the basis of cost.

Granulocyte colony-stimulating factor and autologous CD133-positive stem-cell therapy in liver cirrhosis (REALISTIC): an open-label, randomised, controlled phase 2 trial

Summary Background Results of small-scale studies have suggested that stem-cell therapy is safe and effective in patients with liver cirrhosis, but no adequately powered randomised controlled trials have been done. We assessed the safety and efficacy of granulocyte colony-stimulating factor (G-CSF) and haemopoietic stem-cell infusions in patients with liver cirrhosis. Methods This multicentre, open-label, randomised, controlled phase 2 trial was done in three UK hospitals and recruited patients with compensated liver cirrhosis and MELD scores of 11·0–15·5. Patients were randomly assigned (1:1:1) to receive standard care (control), treatment with subcutaneous G-CSF (lenograstim) 15 μg/kg for 5 days, or treatment with G-CSF for 5 days followed by leukapheresis and intravenous infusion of three doses of CD133-positive haemopoietic stem cells (0·2 × 106 cells per kg per infusion). Randomisation was done by Cancer Research UK Clinical Trials Unit staff with a minimisation algorithm that stratified by trial site and cause of liver disease. The coprimary outcomes were improvement in severity of liver disease (change in MELD) at 3 months and the trend of change in MELD score over time. Analyses were done in the modified intention-to-treat population, which included all patients who received at least one day of treatment. Safety was assessed on the basis of the treatment received. This trial was registered at Current Controlled Trials on Nov 18, 2009; ISRCTN, number 91288089; and the European Clinical Trials Database, number 2009-010335-41. Findings Between May 18, 2010, and Feb 26, 2015, 27 patients were randomly assigned to the standard care, 26 to the G-CSF group, and 28 to the G-CSF plus stem-cell infusion group. Median change in MELD from day 0 to 90 was −0·5 (IQR −1·5 to 1·1) in the standard care group, −0·5 (−1·7 to 0·5) in the G-CSF group, and −0·5 (−1·3 to 1·0) in the G-CSF plus stem-cell infusion group. We found no evidence of differences between the treatment groups and control group in the trends of MELD change over time (p=0·55 for the G-CSF group vs standard care and p=0·75 for the G-CSF plus stem-cell infusion group vs standard care). Serious adverse events were more frequent the in G-CSF and stem-cell infusion group (12 [43%] patients) than in the G-CSF (three [11%] patients) and standard care (three [12%] patients) groups. The most common serious adverse events were ascites (two patients in the G-CSF group and two patients in the G-CSF plus stem-cell infusion group, one of whom was admitted to hospital with ascites twice), sepsis (four patients in the G-CSF plus stem-cell infusion group), and encephalopathy (three patients in the G-CSF plus stem-cell infusion group, one of whom was admitted to hospital with encephalopathy twice). Three patients died, including one in the standard care group (variceal bleed) and two in the G-CSF and stem-cell infusion group (one myocardial infarction and one progressive liver disease). Interpretation G-CSF with or without haemopoietic stem-cell infusion did not improve liver dysfunction or fibrosis and might be associated with increased frequency of adverse events compared with standard care. Funding National Institute of Health Research, The Sir Jules Thorn Charitable Trust.

Effect of liraglutide on adipose insulin resistance and hepatic de-novo lipogenesis in non-alcoholic steatohepatitis: substudy of a phase 2, randomised placebo-controlled trial

Abstract Background Adipose tissue insulin resistance and lipotoxicity are key pathognomonic features in non-alcoholic steatohepatitis (NASH). Liraglutide is a once daily, glucagon-like peptide 1 (GLP-1) analogue that significantly improves glycaemic control, weight, and hepatic steatosis. The aim of this phase 2 study was to determine the effect of liraglutide on insulin sensitivity (hepatic, muscle, adipose), hepatic lipogenesis, and markers of adipose inflammation. Methods 14 patients with biopsy-proven NASH were randomly assigned to either 1·8 mg liraglutide or placebo (once a day subcutaneously) for 12 weeks as part of the metabolic substudy of the double-blind, randomised placebo-controlled LEAN trial. At baseline and 12 weeks, patients underwent paired two-step hyperinsulinaemic euglycaemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis. Serum adipocytokines were measured with Fluorokine MAP multiplex kits (R&D Systems, UK). In-vitro isotope experiments were performed with Huh-7 and primary human hepatocytes. The LEAN trial is registered with ClinicalTrials.gov, number NCT01237119. Findings Liraglutide significantly decreased weight, waist circumference, HbA 1c , fasting glucose, LDL, and liver enzymes compared with placebo. Liraglutide significantly increased the suppression of hepatic glucose production with low-dose insulin. Liraglutide significantly decreased circulating non-esterified fatty acid (NEFA) in the fasting, low-dose, and high-dose insulin states. Liraglutide significantly reduced the insulin concentration required to half-maximally suppress circulating NEFA and significantly decreased adipose tissue lipolysis, as shown by a reduction in interstitial fluid glycerol concentrations. Furthermore, liraglutide significantly improved serum markers of adipose inflammation—namely, leptin, adiponectin, and chemokine ligand 2. In addition, liraglutide significantly decreased de-novo lipogenesis in vivo, as measured by incorporation of deuterated 2H 2 0 into palmitate, compared with placebo. In support of our clinical observations, in-vitro experiments using both the Huh-7 cell line and primary cultures of human hepatocytes showed decreased de-novo lipogenesis, measured by incorporation of 14C-acetate into cellular lipid after treatment with GLP-1 (exendin-4). Interpretation Liraglutide significantly reduces metabolic dysfunction, hepatic lipogenesis, hepatic and adipose insulin resistance, and adipose inflammation in patients with NASH. GLP-1 analogue therapy might be a novel treatment for patients with this condition. Funding Wellcome Trust, National Institute of Health Research, Novo Nordisk.