How Has Intervention Fidelity Been Assessed in Smoking Cessation Interventions? A Systematic Review.

INTRODUCTION: Intervention fidelity concerns the degree to which interventions are implemented as intended. Fidelity frameworks propose fidelity is a multidimensional concept relevant at intervention designer, provider, and recipient levels; yet the extent to which it is assessed multidimensionally is unclear. Smoking cessation interventions are complex, including multiple components, often delivered over multiple sessions and/or at scale in clinical practice; this increases susceptibility variation in the fidelity with which they are delivered. This review examined the extent to which five dimensions from the Behaviour Change Consortium fidelity framework (design, training, delivery, receipt, and enactment) were assessed in fidelity assessments of smoking cessation interventions (randomised control trials (RCTs)). METHODS: Five electronic databases were searched using terms "smoking cessation," "interventions," "fidelity," and "randomised control trials." Eligible studies included RCTs of smoking cessation behavioural interventions, published post 2006 after publication of the framework, reporting assessment of fidelity. The data extraction form was structured around the framework, which specifies a number of items regarding assessment and reporting of each dimension. Data extraction included study characteristics, dimensions assessed, data collection, and analysis strategies. A score per dimension was calculated, indicating its presence. RESULTS: 55 studies were reviewed. There was a wide variability in data collection approaches used to assess fidelity. Fidelity of delivery was the most commonly assessed and linked to the intervention outcomes (73% of the studies). Fidelity of enactment scored the highest according to the framework (average of 92.7%), and fidelity of training scored the lowest (average of 37.1%). Only a quarter of studies linked fidelity data to outcomes (27%). CONCLUSION: There is wide variability in methodological and analytical approaches that precludes comparison and synthesis. In order to realise the potential of fidelity investigations to increase scientific confidence in the interpretation of observed trial outcomes, studies should include analyses of the association between fidelity data and outcomes. Findings have highlighted recommendations for improving fidelity evaluations and reporting practices.

CS-706, a novel cyclooxygenase-2 selective inhibitor, prolonged the survival of tumor-bearing mice when treated alone or in combination with anti-tumor chemotherapeutic agents.

The potent chemopreventive activity of cyclooxygenase-2 (COX-2) inhibitors has been demonstrated in a number of preclinical studies, but their potency in antitumor activity is still in dispute. In this report, we demonstrate the potent antitumor activity of a novel COX-2 inhibitor, CS-706 in mouse colorectal adenocarcinoma colon 26 tumor-bearing mice treated with or without antitumor chemotherapeutic agents. Daily oral administration of CS-706 at doses of 3-100 mg/kg from the day of tumor inoculation (Day 0) inhibited tumor growth dose-dependently, and the maximal inhibition was 67% at a dose of 100 mg/kg. In contrast, celecoxib, a well-known COX-2 inhibitor, did not inhibit tumor growth at doses up to 100 mg/kg. Furthermore, CS-706 at a dose of 1 mg/kg or above markedly prolonged the survival time of tumor-bearing mice. Administration of 30 mg/kg CS-706 from Day 7 combined with a single intravenous treatment of 10 mg/kg cisplatin on Day 7 completely regressed the tumors in all tumor-bearing mice examined, whereas only in 1 of 10 mice tumor was regressed with cisplatin treatment. Similar combination effects were observed with 10 mg/kg CS-706 and 60 mg/kg 5-fluorouracil (5-FU). Moreover, 10 mg/kg CS-706 significantly inhibited angiogenesis induced by implanted chambers with colon 26 cells in a dorsal air sac assay in mice. Collectively, these results suggest that CS-706 is a potent antitumor agent, especially in combination with conventional chemotherapeutic agents, and that the anti-angiogenic activity of CS-706 may contribute at least in part to its marked antitumor activity.

Accelerated antigen presentation and elicitation of humoral response in vivo by FcgammaRIIB- and FcgammaRI/III-mediated immune complex uptake.

It is well established that activating-type Fc receptors for IgG (FcgammaR), such as FcgammaRI and FcgammaRIII, are essential for inducing inflammatory responses, whereas a unique inhibitory FcgammaR, FcgammaRIIB, inhibits intracellular signaling upon ligation of IgG-immune complexes, and can suppress inflammation and autoimmunity. Although antigen presentation is a crucial step for evoking inflammatory responses, the contribution of FcgammaRIIB to antigen presentation is controversial as to whether it regulates antigen-presenting cells (APC), particularly dendritic cells (DC), positively or negatively. In the present report, we show that the antigen targeting to both activating-type FcgammaRs, FcgammaRI/III, and inhibitory FcgammaRIIB on bone marrow-derived DC and macrophages and primary epidermal Langerhans' cells augmented T cell proliferation in vitro and elicited humoral responses upon adoptive transfer of the antigen-pulsed DC. The DC lacking FcgammaRIIB showed a reduction in IC-uptake ability and a decreased T-cell stimulation, and induced less efficient IgG production than those of DC from wild-type mice. On the other hand, the DC lacking FcR common gamma subunit, which only expresses FcgammaRIIB, showed significant up-regulations of IC-uptake, T-cell proliferation, and IgG production compared to those of FcgammaR null DC, demonstrating a positive regulation of FcgammaRIIB for the efficient antigen presentation of IgG-complexed antigens. These results support the therapeutic benefits of antigen-targeting to FcgammaR on APC in the various inflammatory disorders.

Targeting apoptotic tumor cells to Fc gamma R provides efficient and versatile vaccination against tumors by dendritic cells.

Dendritic cells (DCs) loaded with tumor-associated Ags (TAAs) act as potent adjuvant that initiates antitumor immune responses in vivo. However, TAA-based DC vaccination requires prior identification of TAAs. Apoptotic tumor cells (ATCs) can be an excellent source for DC loading because their potential uncharacterized Ags would be efficiently presented to T cells without any prior characterization and isolation of these Ags. However, ATCs alone are considered to be inefficient for activating antitumor immunity, possibly because of their inability to induce DC maturation. In this study, the aim was to enhance antitumor immune response by taking advantage of ATCs that have been opsonized with IgG (ATC-immune complexes, ATC-ICs) so as to target them to FcR for IgG (FcgammaRs) on DCs. It was found that when compared with ATCs, ATC-ICs were efficiently internalized by DCs via FcgammaRs, and this process induced maturation of DCs, which was more efficient than that of ATCs. Importantly, ATC-IC loading was shown to be more efficient than ATCs alone in its capacity for inducing antitumor immunity in vivo, in terms of cytotoxic T cell induction and tumor rejection. These results show that using ATC-ICs may overcome the limitations and may enhance the immune response of current ATC-based DC vaccination therapy.