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AbstractBackgroundMedication discrepancies are common between transitions in healthcare and are associated with higher healthcare utilisation and hospital readmission following discharge. Medication reconciliation is a key intervention to reduce medication list discrepancy. The transition between discharge and first outpatient appointment is critical for patient recovery. The proportion of medication discrepancies during this interval is not well characterised.AimThe aim of this study was to evaluate the accuracy of patients’ medication list between discharge from hospital or emergency department to first outpatient follow‐up with their primary care physician.MethodsA cross‐sectional observational study was performed between November 2015 and May 2016. A 10‐question survey was designed to identify potential areas of inaccuracies in the medication lists.ResultsIn all, 106 patients completed the survey, of whom 67.9% (n = 72) had complete data. Eighty per cent of patients (n = 85) had a provider review their medication list prior to discharge. At the time of follow‐up, 22.6% (n = 28) were not taking the listed medications; of this cohort, 35% (n = 8) had a physician instruct them to stop taking medication. Six per cent of patients (n = 6) reported incorrect medication doses.ConclusionMedication discrepancies occur in the transition from hospital discharge to first follow‐up. This poses a threat to patient safety. A standardised process of medication review is critical to prevent such errors.

Different strains of mice exhibit different degrees of airway hyperresponsiveness after sensitization to and airway challenge with ovalbumin. Antibody responses in BALB/c mice far exceeded those in C57BL/6 mice; in contrast, although responsiveness to methacholine was much higher in the BALB/c mice, the number of eosinophils in the bronchoalveolar lavage fluid was higher in C57BL/6 animals. Sensitized and challenged BALB/c mice developed increases in lung resistance and decreases in dynamic compliance after methacholine or 5-hydroxytryptamine inhalation. C57BL/6 mice only exhibited significant levels of responsiveness when dynamic compliance was monitored in response to inhaled 5-hydroxytryptamine. Eosinophils accumulated in the peribronchial and peripheral lung tissue in BALB/c mice but were distributed diffusely in the peripheral lung tissue of C57BL/6 mice. Thus, in addition to differences in antibody responses and cholinergic agonist reactivity, differences in the responses of large and small airways may reflect the selective distribution of eosinophils in lung tissue.

Abstract Eosinophils and the release of cationic granule proteins have long been implicated in the development of the type 2–induced pathologies linked with respiratory inflammation. Paradoxically, the ablation of the two genes encoding the most abundant of these granule proteins, major basic protein-1 (MBP-1) and eosinophil peroxidase (EPX), results in a near collapse of eosinophilopoiesis. The specificity of this lineage ablation and the magnitude of the induced eosinopenia provide a unique opportunity to clarify the importance of eosinophils in acute and chronic inflammatory settings, as well as to identify potential mechanism(s) of action linked with pulmonary eosinophils in those settings. Specifically, we examined these issues by assessing the induced immune responses and pathologies occurring in MBP-1−/−/EPX−/− mice after 1) ovalbumin sensitization/provocation in an acute allergen-challenge protocol, and 2) crossing MBP-1−/−/EPX−/− mice with a double-transgenic model of chronic type 2 inflammation (i.e., I5/hE2). Acute allergen challenge and constitutive cytokine/chemokine expression each induced the accumulation of pulmonary eosinophils in wild-type controls that was abolished in the absence of MBP-1 and EPX (i.e., MBP-1−/−/EPX−/− mice). The expression of MBP-1 and EPX was also required for induced lung expression of IL-4/IL-13 in each setting and, in turn, the induced pulmonary remodeling events and lung dysfunction. In summary, MBP-1−/−/EPX−/− mice provide yet another definitive example of the immunoregulatory role of pulmonary eosinophils. These results highlight the utility of this unique strain of eosinophil-deficient mice as part of in vivo model studies investigating the roles of eosinophils in health and disease settings.

Abstract Rationale The release of eosinophil granule proteins in the lungs of patients with asthma has been dogmatically linked with lung remodeling and airway hyperresponsiveness. However, the demonstrated inability of established mouse models to display the eosinophil degranulation occurring in human subjects has prevented a definitive in vivo test of this hypothesis. Objectives To demonstrate in vivo causative links between induced pulmonary histopathologies/lung dysfunction and eosinophil degranulation. Methods A transgenic mouse model of chronic T-helper cell type 2–driven inflammation overexpressing IL-5 from T cells and human eotaxin 2 in the lung (I5/hE2) was used to test the hypothesis that chronic histopathologies and the development of airway hyperresponsiveness occur as a consequence of extensive eosinophil degranulation in the lung parenchyma. Measurement and Main Results Studies targeting specific inflammatory pathways in I5/hE2 mice surprisingly showed that eosinophil-dependent immunoregulative events and not the release of individual secondary granule proteins are the central contributors to T-helper cell type 2–induced pulmonary remodeling and lung dysfunction. Specifically, our studies highlighted a significant role for eosinophil-dependent IL-13 expression. In contrast, extensive degranulation leading to the release of major basic protein-1 or eosinophil peroxidase was not causatively linked to many of the induced pulmonary histopathologies. However, these studies did define a previously unappreciated link between the release of eosinophil peroxidase (but not major basic protein-1) and observed levels of induced airway mucin. Conclusions These data suggest that improvements observed in patients with asthma responding to therapeutic strategies ablating eosinophils may occur as a consequence of targeting immunoregulatory mechanisms and not by simply eliminating the destructive activities of these purportedly end-stage effector cells.

Abstract Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation. Clin Cancer Res; 21(12); 2722–9. ©2015 AACR. See related article by Paoletti et al., p. 2771

Abstract Background: CYP2D6 is the rate limiting enzyme responsible for the metabolic activation of tamoxifen (tam) to endoxifen. Compared to CYP2D6 poor metabolizers (PM), tam-treated CYP2D6 extensive metabolizers (EM) have higher endoxifen concentrations, more vasomotor symptoms (Goetz, MP J Clin Oncol 2005), and are more likely to discontinue tam (Rae, JM 2009. Pharmacogenomics J). Additionally, higher endoxifen concentrations are associated with a stepwise increase in tam side-effects (Lorizio, W Breast Cancer Res Treat 2012). The data regarding CYP2D6 genotype and recurrence is mixed. Venlafaxine is a weak CYP2D6 inhibitor not known to alter tam pharmacokinetics (PK) and commonly recommended for tam induced hot flashes. We conducted a multicenter pharmacological study to determine whether venlafaxine altered the PK of tam and to determine the distribution of CYP2D6 genotypes in this population Methods: Women taking tam for at least 4 weeks and for whom venlafaxine was recommended for the treatment of hot flashes were eligible. Blood samples were collected prior to and 8–16 weeks following initiation of venlafaxine for steady state tam and metabolites. Genotyping was performed for alleles associated with no (PM; *3, *4, *5,*6); reduced (intermediate, IM; *10, 17 and *41); and ultra-rapid (UM; *1×2) metabolism. Power calculations demonstrated that 17 patients with paired samples were required (two-sided alpha=0.05 t-test, 90% power) to detect a 25% change in endoxifen levels after at least 8 weeks of concurrent treatment. Results: 30 women (median age 48.5) initiated venlafaxine. CYP2D6 genotypes were within Hardy Weinberg Equilibrium (HWE). CYP2D6 UM allele frequency (6.7%) was higher while CYP2D6 *4 (13.3%) was lower than expected compared to an unselected population (0.5 and 21% respectively; Sachse Am. J. Hum. Genet. 1997), resulting in the absence of CYP2D6 PM/PM. Mean (min/max) baseline endoxifen concentrations (8.73; 1.5–20.5 ng/ml) were correlated with CYP2D6 phenotype as follows: intermediate (EM/PM, PM/IM): 6.8 (1.5–11.2); extensive (EM/EM, EM/IM): 9.4 (1.5–20.5) and ultra-rapid (UM/EM: 11.0; 7.8–14) (r2 = 0.35 p = 0.05). In patients with paired samples (n = 20), venlafaxine resulted in a 23% decrease in endoxifen (−2.06 ng/ml; 95% CI −0.69 to −3.04; p = 0.004), but not tam, NDMT, or 4HT concentrations. Following initiation of venlafaxine, CYP2D6 genotype was no longer associated with endoxifen concentrations (r2 = 0.28 p = 0.23). For women with reduced CYP2D6 metabolism [EM/PM (n = 9) or PM/IM (n = 1)], venlafaxine lowered endoxifen concentrations (−2.98 ng/ml) to a level (5.41 ng/ml) reported to be associated with a higher risk of recurrence in adjuvant tam treated patients (Madlensky, L Clin Pharmacol Ther 2011). Conclusions: In this study, women with tam-induced vasomotor symptoms requiring venlafaxine were comprised predominantly of CYP2D6 EM and UM metabolizers. Venlafaxine significantly decreased endoxifen concentrations. Although the optimal concentration of endoxifen is unknown, given prior data linking low endoxifen concentrations with recurrence, venlafaxine should be used with caution in tam treated patients. (Supported by R01CA133049) Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-08.

Abstract Background: Circulating Tumor cells (CTCs) are prognostic at baseline and first follow-up in patients with metastatic breast cancer (MBC). Using the most commonly used assay (CellSearch®), we have previously reported the ability to detect apoptotic vs. non-apoptotic CTCs in patients with MBC. However, there has been concern regarding the performance of the CellSearch® assay in patients with triple negative (TN) MBC. We hypothesized that CellSearch® is an effective assay in patients with TN MBC, and that CTC-apoptosis might further separate prognosis. Therefore, we studied CTCs in patients with TN MBC who participated in a prospective randomized phase II trial testing for activity of tigatuzumab (TIG) in combination with nanoparticle albumin-bound paclitaxel (nab-PAC) conducted by the Translational Breast Cancer Research Consortium (overall results reported by Forero A., et al, ASCO 2013). Methods: Whole blood (WB) was drawn into a CellSave tube at baseline, day 15, and day 29 and CTC counts were determined using the CXC CellSearch® kit. Apoptosis was characterized by staining with a monoclonal antibody that detects a neo-epitope on fragmented cytokeratin (M-30) and independently by visual inspection (nucleic condensation and/or fragmentation, as well as granular cytokeratin). Association between levels of CTCs and CTC-apoptosis with the overall response rate (ORR) and progression free survival (PFS) at baseline, day 15, and day 29 was assessed using logistic regression, Kaplan Meier curves, and Cox proportional hazards modeling. Results: Of the 60 patients entered into the trial, 52 were evaluable for CTCs. Of these, 19/52 (36.5%), 14/52 (26.9%), and 13/49 (26.5%) had elevated CTCs (≥5CTC/7.5 ml WB) at baseline, day 15, and day 29, respectively. Patients with elevated CTCs at each time point had worse PFS than patients with low or no CTCs. Hazard rates (HR) at baseline, day 15, and day 29 were 2.38 (95% CI: 1.27-4.45, p = 0.007), 2.87 (95% CI: 1.46-5.66, p = 0.002), and 3.40 (95% CI: 1.68-6.89, p = 0.001), respectively. The odds of overall response for those who had elevated CTCs compared to those who did not at baseline, day 15, and day 29, were 0.25 (95% CI: 0.073-0.81, p = 0.024), 0.18 (95% CI: 0.04-0.67, p = 0.014), and 0.06 (95% CI: 0.01-0.28, p = 0.001), respectively. There was no apparent prognostic effect comparing the degree of CTC-apoptosis vs. non-apoptosis. Conclusions: Similar to observations in other intrinsic subgroups, CTCs were detected in a large fraction of TN MBC patients at baseline using CellSearch® assay, and reductions in CTC levels reflected response. In these homogenously prospectively enrolled TN MBC patients, regardless of treatment, CTCs are prognostic at baseline, day 15, and day 29. It does not appear that analysis of CTC-apoptosis is prognostic. Supported by Susan G. Komen for the Cure, Veridex, LLC, Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale™ (DFH), Associazione Sandro Pitigliani and by a studentship from FIRC (CP), Triple Negative Breast Cancer Foundation, The AVON Foundation, and The Breast Cancer Research Foundation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-04-01.

Abstract Mouse models of allergen provocation and/or transgenic gene expression have provided significant insights regarding the cellular, molecular, and immune responses linked to the pathologies occurring as a result of allergic respiratory inflammation. Nonetheless, the inability to replicate the eosinophil activities occurring in patients with asthma has limited their usefulness to understand the larger role(s) of eosinophils in disease pathologies. These limitations have led us to develop an allergen-naive double transgenic mouse model that expresses IL-5 systemically from mature T cells and eotaxin-2 locally from lung epithelial cells. We show that these mice develop several pulmonary pathologies representative of severe asthma, including structural remodeling events such as epithelial desquamation and mucus hypersecretion leading to airway obstruction, subepithelial fibrosis, airway smooth muscle hyperplasia, and pathophysiological changes exemplified by exacerbated methacholine-induced airway hyperresponsiveness. More importantly, and similar to human patients, the pulmonary pathologies observed are accompanied by extensive eosinophil degranulation. Genetic ablation of all eosinophils from this double transgenic model abolished the induced pulmonary pathologies, demonstrating that these pathologies are a consequence of one or more eosinophil effector functions.

Abstract Leukotrienes (i.e., products of the 5-lipoxygenase pathway) are thought to be contributors to lung pathologies. Moreover, eosinophils have been linked with pulmonary leukotriene activities both as potential sources of these mediators and as responding effector cells. The objective of the present study was to define the role(s) of leukotrienes in the lung pathologies accompanying eosinophil-associated chronic respiratory inflammation. A transgenic mouse model of chronic T helper (Th) 2–driven inflammation expressing IL-5 from T cells and human eotaxin-2 locally in the lung (I5/hE2) was used to define potential in vivo relationships among eosinophils, leukotrienes, and chronic Th2-polarized pulmonary inflammation. Airway levels of cys-leukotrienes and leukotriene B4 (LTB4) are both significantly elevated in I5/hE2 mice. The eosinophil-mediated airway hyperresponsiveness (AHR) characteristic of these mice was abolished in the absence of leukotrienes (i.e., 5-lipoxygenase–deficient I5/hE2). More importantly, the loss of leukotrienes led to an unexpectedly significant decrease in collagen deposition (i.e., pulmonary fibrosis) that accompanied elevated levels of IL-4/-13 and TGF-β in the lungs of I5/hE2 mice. Further studies using mice deficient for the LTB4 receptor (BLT-1−/− /I5/hE2) and I5/hE2 animals administered a cys-leukotriene receptor antagonist (montelukast) demonstrated that the AHR and the enhanced pulmonary fibrosis characteristic of the I5/hE2 model were uniquely cys-leukotriene–mediated events. These data demonstrate that, similar to allergen challenge models of wild-type mice, cys-leukotrienes underlie AHR in this transgenic model of severe pulmonary Th2 inflammation. These data also suggest that an underappreciated link exists among eosinophils, cys-leukotriene–mediated events, and fibrotic remodeling associated with elevated levels of IL-4/-13 and TGF-β.

Abstract The effects of an anti-CD23 monoclonal antibody (B3B4) in CD23-deficient and CD23-overexpressing mice were compared in a murine model of allergic sensitization. After sensitization and challenge with OA, mice developed increased serum levels of OA-specific IgE and IgG1 with airway eosinophilia and AHR when compared with nonsensitized animals. Anti-CD23 treatment was studied under two protocols: 10-d OA aerosol exposure and intraperitoneal sensitization followed by aerosol challenge. In both protocols anti-CD23 significantly reduced IgE and IgG1 levels, abolished eosinophilia, and normalized AHR in BALB/c and wild-type CD23+ / + mice but not in CD23− / − mice. These changes were associated with increases in IFN- γ and decreases in IL-4 production, suggesting that CD23 binding may affect not only IgE production but also the Th1/Th2 imbalance during the development of allergic AHR. Absence of CD23 in gene-deficient mice significantly enhanced OA-specific IgE and IgG1 levels, airway eosinophilia, and AHR when compared with CD23+ / + wild-type littermates after sensitization and airway challenge. Sensitized and challenged CD23 transgenic mice also developed eosinophilic airway inflammation and methacholine hyperresponsiveness. However, the extent of AHR, BAL, and tissue eosinophilia in these animals showed a significant negative correlation with levels of CD23 expression on splenic T and B cells, demonstrating a limiting role of CD23 in the development of allergic AHR. Haczku A, Takeda K, Hamelmann E, Loader J, Joetham A, Redai I, Irvin CG, Lee JJ, Kikutani H, Conrad D, Gelfand EW. CD23 exhibits negative regulatory effects on allergic sensitization and airway hyperresponsiveness.