Dysregulation of Copper Metabolism in a Patient With Acute-on-Chronic Liver Failure Worked up for Fulminant Wilson Disease

Wilson disease (WD) is estimated present in 6%-12% of patients younger than 40 years hospitalized with acute liver failure (ALF). Fulminant WD carries a poor prognosis without treatment. A 36-year-old man with HIV, chronic hepatitis B virus, and alcohol use had ceruloplasmin 6.4 mg/dL and 24-hour urine copper 180 μg/L. WD workup was otherwise negative, including ophthalmic examination, hepatic copper quantification, ATP7B sequencing, and brain MRI. ALF commonly features copper dysregulation. Few studies on WD biomarkers have included fulminant WD. Our patient with WD biomarkers and other causes of liver failure highlights the need to study copper dysregulation in ALF

Immunotherapy for Hepatocellular Carcinoma in the Setting of Liver Transplantation: A Review

The emerging field of immuno-oncology has brought exciting developments in the treatment of hepatocellular carcinoma (HCC). It has also raised urgent questions about the role of immunotherapy in the setting of liver transplantation, both before and after transplant. A growing body of evidence points to the safety and efficacy of immunotherapeutic agents as potential adjuncts for successful down-staging of advanced HCCs to allow successful transplant in carefully selected patients. For patients with recurrent HCC post-transplant, immunotherapy has a limited, yet growing role. In this review, we describe optimal regimens in the setting of liver transplantation

Safety of computed tomography in patients with cardiac rhythm management devices: assessment of the U.S. Food and Drug Administration advisory in clinical practice.

OBJECTIVES: To assess the safety of computed tomography (CT) imaging in patients with cardiac rhythm management (CRM) devices, which was subject to an advisory from the U.S. Food and Drug Administration (FDA) in 2008. BACKGROUND: The FDA warned about potential interference of CT imaging with CRM devices and made recommendations for clinical practice despite only limited evidence. METHODS: All 516 CT scans that involved direct radiation exposure of CRM devices (332 defibrillators, 184 pacemakers) at 2 large-volume centers between July 2000 and May 2010 were included. The primary outcome was a composite endpoint of death, bradycardia or tachycardia requiring termination of the scan or an immediate intervention, unplanned hospital admission, reprogramming of the device, inappropriate defibrillator shocks, or device replacement/revision thought to be due to CT imaging. Significant changes in device parameters were sought as a secondary outcome (control group 4:1 ratio). RESULTS: The main finding was that none of the CTs were associated with the primary outcome. With serial device interrogations, there were no differences in changes in battery voltage or lead parameters between devices exposed to radiation and their controls. Potentially significant changes in device parameters were observed in a small group of devices (both the CT group and control group), but no definitive link to CT was confirmed, and there were no associated clinical consequences. CONCLUSIONS: The findings suggest that the presence of CRM devices should not delay or result in cancellation of clinically indicated CT imaging procedures, and provide evidence that would be helpful when the FDA advisory is re-evaluated

Biodegradable Polymeric Nanoparticles Show High Efficacy and Specificity at DNA Delivery to Human Glioblastoma <i>in Vitro</i> and <i>in Vivo</i>

Current glioblastoma therapies are insufficient to prevent tumor recurrence and eventual death. Here, we describe a method to treat malignant glioma by nonviral DNA delivery using biodegradable poly(β-amino ester)s (PBAEs), with a focus on the brain tumor initiating cells (BTICs), the tumor cell population believed to be responsible for the formation of new tumors and resistance to many conventional therapies. We show transfection efficacy of >60% and low biomaterial-mediated cytotoxicity in primary human BTICs <i>in vitro</i> even when the BTICs are grown as 3-D oncospheres. Intriguingly, we find that these polymeric nanoparticles show intrinsic specificity for nonviral transfection of primary human BTICs over primary healthy human neural progenitor cells and that this specificity is not due to differences in cellular growth rate or total cellular uptake of nanoparticles. Moreover, we demonstrate that biodegradable PBAE/DNA nanoparticles can be fabricated, lyophilized, and then stored for at least 2 years without losing efficacy, increasing the translational relevance of this technology. Using lyophilized nanoparticles, we show transgene expression by tumor cells after intratumoral injection into an orthotopic murine model of human glioblastoma. PBAE/DNA nanoparticles were more effective than naked DNA at exogenous gene expression <i>in vivo</i>, and tumor cells were transfected more effectively than noninvaded brain parenchyma <i>in vivo</i>. This work shows the potential of nonviral gene delivery tools to target human brain tumors