Clinical research resource support for off-site research coordinators in intensive and specialty care units.

Clinical Research Coordinators (CRCs) are vital collaborators in a clinical research project. They often are the primary liaisons between investigators and human participants in studies and are involved in every aspect of many protocols, including participant recruitment, care (both usual medical care and specific study-related monitoring and procedures), data collection, specimen processing, and follow-up. The Clinical Translational Science Award program, which was created by the National Institutes of Health in 2006, has significantly expanded the venues in which Clinical Research Resource (CRR) - based CRCs are embedded. CRCs functioning in these areas, outside of the research-focused in-patient environment of the CRR, are designated as "off-site" CRCs. Many of these locations, such as intensive care units and emergency departments, require that CRCs interact regularly with healthcare providers whose primary functions are focused on providing optimal patient care rather than research and often involving very complex patients. These off-site CRCs require additional training and support outside of the usual research-oriented environment of the CRR. They are required to function within the context of the patient-care team while fostering implementation of collaborative research. This is a description of such a program specifically geared to off-site CRCs with the goal of enhancing the quality of research and experiences of CRCs.

Antitumor activity of type I and type III interferons in BNL hepatoma model.

Hepatocellular carcinoma (HCC) occurs most commonly secondary to cirrhosis due to chronic hepatitis C or B virus (HCV/HBV) infections. Type I interferon (IFN-alpha) treatment of chronic HCV/HBV infections reduces the incidence of HCC in cirrhotic patients. However, IFN-alpha toxicity limits its tolerability and efficacy highlighting a need for better therapeutic treatments. A recently discovered type III IFN (IFN-lambda) has been shown to possess antiviral properties against HCV and HBV in vitro. In phase I clinical trials, IFN-lambda treatment did not cause significant adverse reactions. Using a gene therapy approach, we compared the antitumor properties of IFN-alpha and IFN-lambda in a transplantable hepatoma model of HCC. BALB/c mice were inoculated with syngeneic BNL hepatoma cells, or BNL cells expressing IFN-lambda (BNL.IFN-lambda cells) or IFN-alpha (BNL.IFN-alpha cells). Despite the lack of antiproliferative activity of IFNs on BNL cells, both BNL.IFN-lambda and BNL.IFN-alpha cells displayed retarded growth kinetics in vivo. Depletion of NK cells from splenocytes inhibited splenocyte-mediated cytotoxicity, demonstrating that NK cells play a role in IFN-induced antitumor responses. However, isolated NK cells did not respond directly to IFN-lambda. There was also a marked NK cell infiltration in IFN-lambda producing tumors. In addition, IFN-lambda and, to a lesser extent, IFN-alpha enhanced immunocytotoxicity of splenocytes primed with irradiated BNL cells. Splenocyte cytotoxicity against BNL cells was dependent on IL-12 and IFN-gamma, and mediated by dendritic cells. In contrast to NK cells, isolated from spleen CD11c+ and mPDCA+ dendritic cells responded directly to IFN-lambda. The antitumor activities of IFN-lambda against hepatoma, in combination with HCV and HBV antiviral activities warrant further investigation into the clinical use of IFN-lambda to prevent HCC in HCV/HBV-infected cirrhotic patients, as well as to treat liver cancer.

Impact of IMPACT: Longitudinal Analysis of an Integrated Participant Scheduling System in a Clinical Research Setting.

Rapidly increasing costs have been a major threat to our clinical research enterprise. Improvement in appointment scheduling is a crucial means to boost efficiency and save cost in clinical research and has been well studied in the outpatient setting. This study reviews nearly 5 years of usage data of an integrated scheduling system implemented at Columbia University/New York Presbyterian (CUIMC/NYP) called IMPACT and provides original insights into the challenges faced by a clinical research facility. Briefly, the IMPACT data shows that high rates of room and resource changes correlate with rescheduled appointments and that rescheduled visits are more likely to be attended than non-rescheduled visits. We highlight the differing roles of schedulers, coordinators, and investigators, and propose a highly accurate predictive model of participant no-shows in a research setting. This study sheds light on ways to reduce overall cost and improve the care we offer to clinical research participants.

A Phase I trial using local regional treatment, nonlethal irradiation, intratumoral and systemic polyinosinic-polycytidylic acid polylysine carboxymethylcellulose to treat liver cancer: in search of the abscopal effect.

PURPOSE: To determine the safety of an approach to immunologically enhance local treatment of hepatocellular cancer (HCC) by combining nonlethal radiation, local regional therapy with intratumoral injection, and systemic administration of a potent Toll-like receptor (TLR) immune adjuvant. METHODS: Patients with HCC not eligible for liver transplant or surgery were subject to: 1) 3 fractions of 2-Gy focal nonlethal radiation to increase tumor antigen expression, 2) intra-/peri-tumoral (IT) injection of the TLR3 agonist, polyinosinic-polycytidylic acid polylysine carboxymethylcellulose (poly-ICLC), to induce an immunologic "danger" response in the tumor microenvironment with local regional therapy, and 3) systemic boosting of immunity with intramuscular poly-ICLC. Primary end points were safety and tolerability; secondary end points were progression-free survival (PFS) and overall survival (OS) at 6 months, 1 year, and 2 years. RESULTS: Eighteen patients with HCC not eligible for surgery or liver transplant were treated. Aside from 1 embolization-related severe adverse event, all events were ≤grade II. PFS was 66% at 6 months, 39% at 12 months, and 28% at 24 months. Overall 1-year survival was 69%, and 2-year survival 38%. In patients <60 years old, 2-year survival was 62.5% vs. 11.1% in patients aged >60 years (P<0.05). Several patients had prolonged PFS and OS. CONCLUSION: Intra-tumoral injection of the TLR3 agonist poly-ICLC in patients with HCC is safe and tolerable when combined with local nonlethal radiation and local regional treatment. Further work is in progress to evaluate if this approach improves survival compared to local regional treatment alone and characterize changes in anticancer immunity.

Concerted action of IFN-α and IFN-λ induces local NK cell immunity and halts cancer growth.

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. No significant improvement has been reported with currently available systemic therapies. IFN-α has been tested in both clinic and animal models and only moderate benefits have been observed. In animal models, similar modest antitumor efficacy has also been reported for IFN-λ, a new type of IFN that acts through its own receptor complex. In the present study, the antitumor efficacy of the combination of IFN-α and IFN-λ was tested in the BNL mouse hepatoma model. This study was accomplished by using either engineered tumor cells (IFN-α/IFN-λ gene therapy) or by directly injecting tumor-bearing mice with IFN-α/IFN-λ. Both approaches demonstrated that IFN-α/IFN-λ combination therapy was more efficacious than IFN monotherapy based on either IFN-α or IFN-λ. In complement to tumor surgery, IFN-α/IFN-λ combination induced complete tumor remission. Highest antitumor efficacy has been obtained following local administration of IFN-α/IFN-λ combination at the tumor site that was associated with strong NK cells tumor infiltration. This supports the use of IFN-α/IFN-λ combination as a new cancer immunotherapy for stimulating antitumor response after cancer surgery.