Mary Adams

Lenalidomide Enhances Natural Killer Cell and Monocyte-Mediated Antibody-Dependent Cellular Cytotoxicity of Rituximab-Treated CD20 + Tumor Cells

Purpose: Lenalidomide has significant activity in myelodysplastic syndromes, multiple myeloma, and non-Hodgkins lymphoma (NHL). In previous studies, natural killer (NK) cell expansion by lenalidomide was shown to enhance the cytotoxic effect of rituximab. This study assessed the ability of lenalidomide to enhance antibody-dependent cellular cytotoxicity (ADCC) in rituximab-treated NHL cell lines and primary tumor cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) in vitro. Experimental Design: An in vitro ADCC system was used to assess the ability of lenalidomide to enhance human NK cell and monocyte function in response to rituximab. Results: Lenalidomide directly enhanced IFN-γ production via Fc-γ receptor-mediated signaling in response to IgG. It was also a potent enhancer of NK cell-mediated and monocyte-mediated tumor cell ADCC for a variety of rituximab-treated NHL cell lines in vitro, an effect that was dependent on the presence of antibody and either interleukin-2 or interleukin-12. Lenalidomide also enhanced the ability of NK cells to kill primary tumor cells derived from three patients with B-CLL who have been treated previously with fludarabine plus cyclophosphamide. Enhanced NK cell ADCC was associated with enhanced granzyme B and Fas ligand expression and could be inhibited by a granzyme B inhibitor and partially inhibited by antibody to FasL. Enhanced NK cell Fc-γ receptor signaling is associated with enhanced phosphorylated extracellular signal-related kinase levels leading to enhanced effector function. Conclusions: These findings suggest that lenalidomide has the potential to enhance the rituximab-induced killing of NHL cell lines and primary B-cell chronic lymphocytic leukemia cells via a NK cell-mediated and monocyte-mediated ADCC mechanism in vitro, providing a strong rationale for the combination of lenalidomide with IgG1 antibodies to target tumor-specific antigens in patients with cancer.

Lenalidomide enhances antibody-dependent cellular cytotoxicity of solid tumor cells in vitro: influence of host immune and tumor markers

We evaluated the effect of combining lenalidomide with therapeutic antibodies on antibody-dependant cell-mediated cytotoxicity (ADCC) of solid tumor cells, and the requirement for expression of natural killer (NK) cell-activating receptors and their solid tumor surface ligands. Twenty-three human tumor cell lines (colon, breast, lung, head and neck, ovary, and bone sarcoma) were analyzed. NK effector cells were isolated from healthy donors, pre-treated with and without lenalidomide, and incubated with antibody-coated tumor cells to determine ADCC. In blocking experiments, NK cells were pre-incubated with anti-DNAM-1 or anti-NKG2D antibodies, and target colorectal cells were pre-incubated with anti-CD155 (PVR), anti-MIC-A/B, or anti-ULBP 3 antibodies. Differences between groups were assessed using unpaired and paired Student’s t test and one-way ANOVA. Lenalidomide enhanced NK cell-mediated ADCC of trastuzumab- and cetuximab-coated tumor cells. Activity against colorectal cancer cells was dependent on target antigen expression, but independent of KRAS status and FcγRIIIa genotype. The extent of ADCC and its enhancement by lenalidomide correlated with NK cell expression of NKG2D and DNAM-1, and tumor cell expression of PVR and MIC-A. Blocking of NKG2D and, to a lesser extent, DNAM-1 inhibited ADCC. Anti-MIC-A/B monoclonal antibody blocked natural cytotoxicity, but not ADCC. Lenalidomide enhances the ability of IgG1-isotype antibodies to mediate ADCC of solid tumor cells, the extent of which is largely dependent on NKG2D–NKG2D ligand interactions, but appears to be independent of MIC-A/B. This provides a rationale for exploratory clinical studies and an assessment of potential biomarkers predictive of clinical benefit.

Cellular and in Vivo Activity of JNJ-28871063, A Nonquinazoline Pan-ErbB Kinase Inhibitor That Crosses the Blood-Brain Barrier and Displays Efficacy against Intracranial Tumors

JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.

Lenalidomide enhances the anti-prostate cancer activity of docetaxel in vitro and in vivo.

In this study, we investigated the effects of combining lenalidomide and docetaxel on in vitro and in vivo models of prostate cancer as a potential strategy for treatment of castrate resistant prostate cancer (CRPC).

The anatomic variations of the circle of Willis in preterm-at-term and term-born infants: an MR angiography study at 3T.

BACKGROUND AND PURPOSE: It has been shown that the brain of a preterm infant develops differently from that of a term infant, but little is known about the neonatal cerebrovascular anatomy. Our aims were to establish reference data for the prevalence of the anatomic variations of the neonatal circle of Willis (CoW) and to explore the effect of prematurity, MR imaging abnormality, vascular-related abnormality, laterality, and sex on these findings. MATERIALS AND METHODS: We scanned 103 infants with an optimized MR angiography (MRA) protocol. Images were analyzed for different variations of the CoW, and results were compared for the following: 1) preterm-at-term and term-born infants, 2) infants with normal and abnormal MR imaging, 3) infants with and without a vascular-related abnormality, 4) boys and girls, and 5) left- and right-sided occurrence. RESULTS: The most common anatomic variation was absence/hypoplasia of the posterior communicating artery. Preterm infants at term had a higher prevalence of a complete CoW and a lower prevalence of anatomic variations compared with term-born infants; this finding was significant for the anterior cerebral artery (P = .02). There was increased prevalence of variations of the major cerebral arteries in those infants with vascular-related abnormalities, statistically significant for the posterior cerebral artery (P = .004). There was no statistically significant difference between boys and girls and left/right variations. CONCLUSIONS: Prematurity is associated with more complete CoWs and fewer anatomic variations. In vascular-related abnormalities, more variations involved major arterial segments, but fewer variations occurred in the communicating arteries. Overall reference values of the variations match those of the general adult population.

Barriers and opportunities for enhancing patient recruitment and retention in clinical research: findings from an interview study in an NHS academic health science centre

BackgroundIn the UK, the recruitment of patients into clinical research is a national health research and development policy priority. There has been limited investigation of how national level factors operate as barriers or facilitators to recruitment work, particularly from the perspective of staff undertaking patient recruitment work. The aim of this study is to identify and examine staff views of the key organisational barriers and facilitators to patient recruitment work in one clinical research group located in an NHS Academic Health Science Centre.MethodsA qualitative study utilizing in-depth, one-to-one semi-structured interviews with 11 purposively selected staff with particular responsibilities to recruit and retain patients as clinical research subjects. Thematic analysis classified interview data by recurring themes, concepts, and emergent categories for the purposes of establishing explanatory accounts.ResultsThe findings highlight four key factors that staff perceived to be most significant for the successful recruitment and retention of patients in research and identify how staff located these factors within patients, studies, the research centre, the trust, and beyond the trust. Firstly, competition for research participants at an organisational and national level was perceived to undermine recruitment success. Secondly, the tension between clinical and clinical research workloads was seen to interrupt patient recruitment into studies, despite national funding arrangements to manage excess treatment costs. Thirdly, staff perceived an imbalance between personal patient burden and benefit. Ethical committee regulation, designed to protect patients, was perceived by some staff to detract from clarification and systematisation of incentivisation strategies. Finally, the structure and relationships within clinical research teams, in particular the low tacit status of recruitment skills, was seen as influential.ConclusionsThe results of this case-study, conducted in an exemplary NHS academic research centre, highlight current systematic challenges to patient recruitment and retention in clinical studies more generally as seen from the perspective of staff at the sharp end’ of recruiting. Staff experience is that, beyond individual clinical research design and protocol factors, wider organisational and extra-organisational norms, structures, and processes operate as significant facilitators or hindrances in the recruitment of patients as research subjects.

Measuring relational aspects of hospital care in England with the ‘Patient Evaluation of Emotional Care during Hospitalisation’ (PEECH) survey questionnaire

Objectives To first, validate in English hospitals the internal structure of the ‘Patient Evaluation of Emotional Care during Hospitalisation’ (PEECH) survey tool which was developed in Australia and, second, to examine how it may deepen the understanding of patient experience through comparison with results from the Picker Patient Experience Questionnaire (PPE-15). Design A 48-item survey questionnaire comprising both PEECH and PPE-15 was fielded. We performed exploratory factor analysis and then confirmatory factor analysis using a number of established fit indices. The external validity of the PEECH factor scores was compared across four participating services and at the patient level, factor scores were correlated with the PPE-15. Setting Four hospital services (an Emergency Admissions Unit; a maternity service; a Medicine for the Elderly department and a Haemato-oncology service) that contrasted in terms of the reported patient experience performance. Participants Selection of these acute service settings was based on achieving variation of the following factors: teaching hospital/district general hospital, urban/rural locality and high-performing/low-performing organisations (using results of annual national staff and patient surveys). A total of 423 surveys were completed by patients (26% response rate). Results A different internal structure to the PEECH instrument emerged in English hospitals. However, both the existing and new factor models were similar in terms of fit. The correlations between the new PEECH factors and the PPE-15 were all in the expected direction, but two of the new factors (personal interactions and feeling valued) were more strongly associated with the PPE-15 than the remaining two factors (feeling informed and treated as an individual). Conclusions PEECH can help to build an understanding of complex interpersonal aspects of quality of care, alongside the more transactional and functional aspects typically captured by PPE-15. Further testing of the combined instrument should be undertaken in a wider range of healthcare settings.

‘Catching up’: The significance of occupational communities for the delivery of high quality home care by community nurses

This article examines the importance of some informal work practices among community nurses during a period of significant organizational change. Ethnographic fieldwork in two purposively selected adult community nursing services in England comprised 79 hours of observation of routine practice, 21 interviews with staff and 23 interviews with patients. We identified the informal work practice of ‘catching up’, informal work conversations between immediate colleagues, as an important but often invisible aspect of satisfying work relationships and of the relational care of patients. Drawing on anthropological literatures on ‘communities of practice’ the article examines two central issues concerning the practices of ‘catching up’: (1) how informal learning processes shape community nursing work; (2) how this informal learning is shaped both in relation to the ideals of community nursing work and the wider political and organizational contexts of community nursing practice. Our findings highlight the distinctive value of informal workplace ‘catch ups’ for nurses to manage the inherent challenges of good home care for patients and to develop a shared ethic of care and professional identity. Our findings also indicate the decline of ‘catching up’ between nurses along with diminishing time and opportunity for staff to care holistically for patients in present service climates.

Configuring the patient as clinical research subject in the UK national health service.

This paper examines a central image in UK academic clinical research – the patient as altruistic research subject – by means of an interpretive review of social science, bioethical and bioscience research and development policy literatures. The review examines this image as it is indicted in discussions about the nature of clinical science; is consolidated in the ethical regulation of this science; and is articulated in recent bioscience research and development government initiatives. Drawing on Stratherns notion of the virtual (public-sector) subject, the review identifies the anticipation of NHS patients as alternatively ‘available’ or ‘entitled’ to the expanding translational medicine industry.

Citizen Participation as Political Ritual: Towards a Sociological Theorizing of ‘Health Citizenship’

This article examines citizen participation in health research, where funders increasingly seek to promote and define ‘patient and public involvement’ (PPI). In England, the focus of our study, government policy articulates a specific set of meanings attached to PPI that fuse patients’ rights and responsibilities as citizens, as ‘consumers’ and as ‘lay experts’. However, little is known about the meanings those who take part in PPI activities attach to this participation. Drawing on ethnographic data of PPI in three clinical areas (stroke, cancer and pre-term birth) we investigate citizen participation in health research as political ritual. We identify tensions between policy-driven and ground-level performance of citizenship, and use ritual theory to show how such tensions are accommodated in participatory structures. We argue that the ritual performance of PPI neutralizes the transformational potential of citizen participation, and we draw wider sociological implications for citizen participation beyond the health arena.