Managing Select Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors.

The increased use of immune checkpoint inhibitors (ICIs) across cancer programs has created the need for standardized monitoring and management of immune-related adverse events (irAEs). Delayed recognition without appropriate treatment can have serious and life-threatening consequences. The management of irAEs presents a unique set of challenges that must be addressed at a multidisciplinary level.

Checkpoint inhibitor hepatotoxicity: pathogenesis and management.

Immunotherapy, including immune checkpoint inhibitor (ICI) therapy, has been a paradigm shift in cancer therapeutics, producing durable cancer responses across a range of primary malignancies. ICI drugs increase immune activity against tumor cells, but may also reduce immune tolerance to self-antigens, resulting in immune-mediated tissue damage. ICI-associated hepatotoxicity usually manifests as hepatocellular enzyme elevation and may occur in 2%-25% of ICI-treated patients.

Evaluation of liver enzyme elevations and hepatotoxicity in patients treated with checkpoint inhibitor immunotherapy.

Background And Aims: Immune checkpoint inhibitors (ICI) are increasingly used in cancer therapy. Elevated liver enzymes frequently occur in patients treated with ICI but evaluation is poorly described. We sought to better understand causes of liver enzyme elevation, investigation and management.

Risk of gallbladder cancer in patients with primary sclerosing cholangitis and radiographically detected gallbladder polyps.

Background & Aims: Primary sclerosing cholangitis (PSC) is associated with an increased risk of gallbladder cancer (GBC). Gallbladder polyps potentially harbour malignancy and thus international guidelines recommend prophylactic cholecystectomy for gallbladder polyps of any size in patients with PSC. To best inform patient care we sought to quantify the malignant risk of gallbladder polyps in patients with PSC.

Amino Acid Substitutions in Genotype 3a Hepatitis C Virus Polymerase Protein Affect Responses to Sofosbuvir.

Background & Aims: Sofosbuvir is a frequently used pan-genotype inhibitor of hepatitis C virus (HCV) polymerase. This drug eliminates most chronic HCV infections, and resistance-associated substitutions in the polymerase are rare. However, HCV genotype 3 responds slightly less well to sofosbuvir-based therapies than other genotypes.

Noninvasive Predictors of High-Risk Varices in Patients with Non-Cirrhotic Portal Hypertension.

Non-cirrhotic portal hypertension (NCPH) comprises a heterogeneous group of liver disorders causing portal hypertension without cirrhosis and carries a high risk of variceal bleeding. Recent guidelines, based largely on patients with viral cirrhosis, suggest low likelihood of high risk varices (HRV) in patients with a liver stiffness measurement (LSM) <20 kPa and platelet count >150 × 10/L. In NCPH, LSM is often higher than healthy controls but lower than matched cirrhotic patients.

SB 9200, a novel agonist of innate immunity, shows potent antiviral activity against resistant HCV variants.

SB 9200 is a novel, first-in-class oral modulator of innate immunity that is believed to act via the activation of the RIG-I and NOD2 pathways. SB 9200 has broad-spectrum antiviral activity against RNA viruses including hepatitis C virus (HCV), norovirus, respiratory syncytial virus, and influenza and has demonstrated activity against hepatitis B virus (HBV) in vitro and in vivo. In phase I clinical trials in chronically infected HCV patients, SB 9200 has been shown to reduce HCV RNA by up to 1.

Development and validation of a "capture-fusion" model to study drug sensitivity of patient-derived hepatitis C.

Unlabelled: Emerging therapies for chronic hepatitis C viral (HCV) infection involve inhibition of viral enzymes with drug combinations. Natural, or treatment-induced, enzyme polymorphisms reduce efficacy. We developed a phenotyping assay to aid drug selection based on viral transfer from monocytes to hepatocytes.

Endothelin-1 as a mediator and potential biomarker for interferon induced pulmonary toxicity.

Endothelin-1 is a potent vasoconstrictor and a therapeutic target in pulmonary arterial hypertension. Endothelial cells are the physiological source of endothelin-1 but in vitro data from our group shows that interferons (IFNα, IFNβ or IFNγ) induce endothelin-1 in pulmonary vascular smooth muscle cells. IFNs are integral to innate immunity and their antiviral and immunomodulatory capability has been harnessed therapeutically; for example, IFNα plays a critical role in the treatment of chronic hepatitis C infection.

Second generation direct antivirals and the way to interferon-free regimens in chronic HCV.

Treatment for those infected with chronic hepatitis C virus [HCV] has until recently been hampered by the lack of therapies other than pegylated interferon and ribavirin, which have limited efficacy and a difficult side effect profile. To address this, multiple new direct acting antiviral drugs which specifically target the non-structural proteins involved in HCV replication are in phase II/III development. This review will discuss the HCV replication cycle, mechanisms of action of the new direct acting antiviral drugs, results from published trials into their efficacy and the potential for interferon free treatment regimens in the future.

Efficacy and safety of telaprevir in patients with genotype 1 hepatitis C infection.

Chronic hepatitis C infection represents a significant and growing health problem worldwide. Patients with genotype 1 hepatitis C respond poorly to the current standard of care, pegylated interferon and ribavirin, which is frequently associated with unpleasant side effects. Consequently new agents with improved efficacy and tolerability are needed.

The emerging role of screen based simulators in the training and assessment of colonoscopists.

Incorporation of screen based simulators into medical training has recently gained momentum, as advances in technology have coincided with a government led drive to increase the use of medical simulation training to improve patient safety with progressive reductions in working hours available for junior doctors to train. High fidelity screen based simulators hold great appeal for endoscopy training. Potentially, their incorporation into endoscopy training curricula could enhance speed of acquisition of skills and improve patient comfort and safety during the initial phase of learning.

Effects of endothelin on submandibular salivary responses to parasympathetic stimulation in anaesthetized sheep.

Submandibular responses to stimulation of the parasympathetic chorda tympani nerve have been investigated in anaesthetized sheep before, during and after an intracarotid infusion of endothelin, which reduced the blood flow through the gland by 56+/-5%. Stimulation of the peripheral end of the chorda tympani nerve produced a frequency-dependent increase in the flow of submandibular saliva, and in sodium, potassium and protein output. The reduction in submandibular blood flow, which occurred in response to endothelin, was associated with a decrease in the flow of saliva at all frequencies tested amounting on average to 44+/-6% (P<0.