A quality improvement initiative to improve primary care referral rates for penicillin allergy delabeling.

BACKGROUND: Of the US population, 10% reports a penicillin allergy but more than 90% can ultimately tolerate penicillin. Confirmation of these allergies in the pediatric population may improve future health outcomes and decrease costs. Referring patients for confirmatory testing is the first step in clarifying penicillin allergies. OBJECTIVE: To increase the number of referrals of patients with listed penicillin allergies from the University of California, San Diego academic general pediatrics clinics to Rady Children's Hospital allergy clinics using an educational session and a best practice advisory (BPA) in the electronic medical record. METHODS: An educational session with attendings and 3 plan-do-study-act (PDSA) cycles were completed using a BPA alert that triggered for all patients with a documented penicillin-class drug allergy to draw attention and facilitate referral. The BPA was modified at each PDSA cycle based on physician input. RESULTS: At baseline, 1.9% of referrals to the allergy clinic were for penicillin-class drug allergies. After an attending physician educational session, the percentage increased to 13.7%. The BPA was implemented with further increase to 27.8% of all allergy referrals in the course of 3 PDSA cycles. Not all patients with penicillin-class drug allergies were referred, and the reasons were documented when the physicians dismissed the BPA. Physicians did not refer 35% of the time because of time constraints, as opposed to patient or parent disinterest, which was 8% of the time. CONCLUSION: Referrals to the allergist for confirmatory testing in patients with listed penicillin allergies increased by more than 10 fold. This study illustrates successful tools to support delabeling.

The transferrin receptor and the targeted delivery of therapeutic agents against cancer.

BACKGROUND: Traditional cancer therapy can be successful in destroying tumors, but can also cause dangerous side effects. Therefore, many targeted therapies are in development. The transferrin receptor (TfR) functions in cellular iron uptake through its interaction with transferrin. This receptor is an attractive molecule for the targeted therapy of cancer since it is upregulated on the surface of many cancer types and is efficiently internalized. This receptor can be targeted in two ways: 1) for the delivery of therapeutic molecules into malignant cells or 2) to block the natural function of the receptor leading directly to cancer cell death. SCOPE OF REVIEW: In the present article we discuss the strategies used to target the TfR for the delivery of therapeutic agents into cancer cells. We provide a summary of the vast types of anti-cancer drugs that have been delivered into cancer cells employing a variety of receptor binding molecules including Tf, anti-TfR antibodies, or TfR-binding peptides alone or in combination with carrier molecules including nanoparticles and viruses. MAJOR CONCLUSIONS: Targeting the TfR has been shown to be effective in delivering many different therapeutic agents and causing cytotoxic effects in cancer cells in vitro and in vivo. GENERAL SIGNIFICANCE: The extensive use of TfR for targeted therapy attests to the versatility of targeting this receptor for therapeutic purposes against malignant cells. More advances in this area are expected to further improve the therapeutic potential of targeting the TfR for cancer therapy leading to an increase in the number of clinical trials of molecules targeting this receptor. This article is part of a Special Issue entitled Transferrins: molecular mechanisms of iron transport and disorders.

Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers.

One-third of smokers primarily use menthol cigarettes and usage of these cigarettes leads to elevated serum nicotine levels and more difficulty quitting in standard treatment programmes. Previous brain imaging studies demonstrate that smoking (without regard to cigarette type) leads to up-regulation of ß(2)*-containing nicotinic acetylcholine receptors (nAChRs). We sought to determine if menthol cigarette usage results in greater nAChR up-regulation than non-menthol cigarette usage. Altogether, 114 participants (22 menthol cigarette smokers, 41 non-menthol cigarette smokers and 51 non-smokers) underwent positron emission tomography scanning using the α(4)ß(2)* nAChR radioligand 2-[(18)F]fluoro-A-85380 (2-FA). In comparing menthol to non-menthol cigarette smokers, an overall test of 2-FA total volume of distribution values revealed a significant between-group difference, resulting from menthol smokers having 9-28% higher α(4)ß(2)* nAChR densities than non-menthol smokers across regions. In comparing the entire group of smokers to non-smokers, an overall test revealed a significant between-group difference, resulting from smokers having higher α(4)ß(2)* nAChR levels in all regions studied (36-42%) other than thalamus (3%). Study results demonstrate that menthol smokers have greater up-regulation of nAChRs than non-menthol smokers. This difference is presumably related to higher nicotine exposure in menthol smokers, although other mechanisms for menthol influencing receptor density are possible. These results provide additional information about the severity of menthol cigarette use and may help explain why these smokers have more trouble quitting in standard treatment programmes.

A novel IgE antibody targeting the prostate-specific antigen as a potential prostate cancer therapy.

BACKGROUND: Prostate cancer (PCa) is the second leading cause of cancer deaths in men in the United States. The prostate-specific antigen (PSA), often found at high levels in the serum of PCa patients, has been used as a marker for PCa detection and as a target of immunotherapy. The murine IgG1 monoclonal antibody AR47.47, specific for human PSA, has been shown to enhance antigen presentation by human dendritic cells and induce both CD4 and CD8 T-cell activation when complexed with PSA. In this study, we explored the properties of a novel mouse/human chimeric anti-PSA IgE containing the variable regions of AR47.47 as a potential therapy for PCa. Our goal was to take advantage of the unique properties of IgE in order to trigger immune activation against PCa. METHODS: Binding characteristics of the antibody were determined by ELISA and flow cytometry. In vitro degranulation was determined by the release of ß-hexosaminidase from effector cells. In vivo degranulation was monitored in human FcεRIα transgenic mice using the passive cutaneous anaphylaxis assay. These mice were also used for a vaccination study to determine the in vivo anti-cancer effects of this antibody. Significant differences in survival were determined using the Log Rank test. In vitro T-cell activation was studied using human dendritic cells and autologous T cells. RESULTS: The anti-PSA IgE, expressed in murine myeloma cells, is properly assembled and secreted, and binds the antigen and FcεRI. In addition, this antibody is capable of triggering effector cell degranulation in vitro and in vivo when artificially cross-linked, but not in the presence of the natural soluble antigen, suggesting that such an interaction will not trigger systemic anaphylaxis. Importantly, the anti-PSA IgE combined with PSA also triggers immune activation in vitro and in vivo and significantly prolongs the survival of human FcεRIα transgenic mice challenged with PSA-expressing tumors in a prophylactic vaccination setting. CONCLUSIONS: The anti-PSA IgE exhibits the expected biological properties and is capable of triggering immune activation and anti-tumor protection. Further studies on this antibody as a potential PCa therapy are warranted.

A positive relationship between harm avoidance and brain nicotinic acetylcholine receptor availability.

Prior research indicates that disturbance of cholinergic neurotransmission reduces anxiety, leading to the hypothesis that people with heightened cholinergic function have a greater tendency toward anxiety-like and/or harm-avoidant behavior. We sought to determine if people with elevated levels of harm avoidance (HA), a dimension of temperament from the Temperament and Character Inventory (TCI), have high α4ß2* nicotinic acetylcholine receptor (nAChR) availability. Healthy adults (n=105; 47 non-smokers and 58 smokers) underwent bolus-plus-continuous infusion positron emission tomography (PET) scanning using the radiotracer 2-[18F]fluoro-3-(2(S)azetidinylmethoxy) pyridine (abbreviated as 2-FA). During the uptake period of 2-FA, participants completed the TCI. The central study analysis revealed a significant association between total HA and mean nAChR availability, with higher total HA scores being linked with greater nAChR availability. In examining HA subscales, both 'Fear of Uncertainty' and 'Fatigability' were significant, based on higher levels of these characteristics being associated with greater nAChR availabilities. This study adds to a growing body of knowledge concerning the biological basis of personality and may prove useful in understanding the pathophysiology of psychiatric disorders (such as anxiety disorders) that have similar characteristics to HA. Study findings may indicate that heightened cholinergic neurotransmission is associated with increased anxiety-like traits.

Treatment for tobacco dependence: effect on brain nicotinic acetylcholine receptor density.

Cigarette smoking leads to upregulation of brain nicotinic acetylcholine receptors (nAChRs), including the common α4ß2* nAChR subtype. Although a substantial percentage of smokers receive treatment for tobacco dependence with counseling and/or medication, the effect of a standard course of these treatments on nAChR upregulation has not yet been reported. In the present study, 48 otherwise healthy smokers underwent positron emission tomography (PET) scanning with the radiotracer 2-FA (for labeling α4ß2* nAChRs) before and after treatment with either cognitive-behavioral therapy, bupropion HCl, or pill placebo. Specific binding volume of distribution (VS/fP), a measure proportional to α4ß2* nAChR density, was determined for regions known to have nAChR upregulation with smoking (prefrontal cortex, brainstem, and cerebellum). In the overall study sample, significant decreases in VS/fP were found for the prefrontal cortex, brainstem, and cerebellum of -20 (±35), -25 (±36), and -25 (±31)%, respectively, which represented movement of VS/fP values toward values found in non-smokers (mean 58.2% normalization of receptor levels). Participants who quit smoking had significantly greater reductions in VS/fP across regions than non-quitters, and correlations were found between reductions in cigarettes per day and decreases in VS/fP for brainstem and cerebellum, but there was no between-group effect of treatment type. Thus, smoking reduction and cessation with commonly used treatments (and pill placebo) lead to decreased α4ß2* nAChR densities across brain regions. Study findings could prove useful in the treatment of smokers by providing encouragement with the knowledge that decreased smoking leads to normalization of specific brain receptors.