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AIMS: To describe characteristics of applicant, tool, outcomes, regulatory responses and general learnings from European Medicines Agency (EMA) Qualification Procedures on patient-reported outcomes (PROs), observer-reported outcomes (ObsROs) and performance outcomes (PerfOs) finalized between January 2013 and December 2018. METHODS: Descriptive analysis, and qualitative review of the regulatory outcomes of the study procedures. RESULTS: Seventeen qualification programmes for PROs, 6 for ObsRO tools and 11 for PerfO tools were submitted by consortia, large and small/medium companies. Gastroenterology and neurology were the most frequent therapeutic areas. There was a high level of regulators' partial agreement (above 70%) with applicant's approaches with constructive input; EMA published Letters of Support for PRO (6), ObsRO (2) and PerfO (4) tools, and Qualification Opinions on PROs (2) and PerfOs (1). General issues related to Qualification Procedures on PROs raised by EU regulatorsincluded: population, appropriate studies to demonstrate ability to detect change, tool validation in interventional trials, anchoring, identification of the minimally important difference, item selection, weighting, and multiple domains. In addition, specific issues for ObsROs and PerfO tools validation are identified. CONCLUSIONS: Regulators discussed principles and challenges of validation tailored to specific setting in tool development, providing constructive feedback. Regulatory outputs supportive of further development were published in over one-third of programs. We encourage applicants intending to use or develop novel PRO, ObsRO and PerfO tools that will generate evidence for regulatory submissions on medicines to consider Qualification procedures for novel methods to seek feedback on the development and validation of these tools.
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Medición de Resultados Informados por el Paciente , Proyectos de Investigación , HumanosRESUMEN
The understanding of the benefit risk profile, and relative effectiveness of a new medicinal product, are initially established in a circumscribed patient population through clinical trials. There may be uncertainties associated with the new medicinal product that cannot be, or do not need to be resolved before launch. Postlicensing or postlaunch evidence generation (PLEG) is a term for evidence generated after the licensure or launch of a medicinal product to address these remaining uncertainties. PLEG is thus part of the continuum of evidence development for a medicinal product, complementing earlier evidence, facilitating further elucidation of a product's benefit/risk profile, value proposition, and/or exploring broader aspects of disease management and provision of healthcare. PLEG plays a role in regulatory decision making, not only in the European Union but also in other jurisdictions including the USA and Japan. PLEG is also relevant for downstream decision-making by health technology assessment bodies and payers. PLEG comprises studies of different designs, based on data collected in observational or experimental settings. Experience to date in the European Union has indicated a need for improvements in PLEG. Improvements in design and research efficiency of PLEG could be addressed through more systematic pursuance of Scientific Advice on PLEG with single or multiple decision makers. To date, limited information has been available on the rationale, process or timing for seeking PLEG advice from regulators or health technology assessment bodies. This article sets out to address these issues and to encourage further uptake of PLEG advice.
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Evaluación de la Tecnología Biomédica , Recolección de Datos , Unión Europea , Humanos , JapónRESUMEN
AIMS: The parallel regulatory-health technology assessment scientific advice (PSA) procedure allows manufacturers to receive simultaneous feedback from both EU regulators and health technology assessment (HTA) bodies on development plans for new medicines. The primary objective of the present study is to investigate whether PSA is integrated in the clinical development programmes for which advice was sought. METHODS: Contents of PSA provided by regulators and HTA bodies for each procedure between 2010 and 2015 were analysed. The development of all clinical studies for which PSA had been sought was tracked using three different databases. The rate of uptake of the advice provided by regulators and HTA bodies was assessed on two key variables: comparator/s and primary endpoint. RESULTS: In terms of uptake of comparator recommendations at the time of PSA in the actual development, our analysis showed that manufacturers implemented comparators to address both the needs of regulators and of at least one HTA body in 12 of 21 studies. For primary endpoints, in all included studies manufacturers addressed both the needs of the regulators and at least one HTA body. CONCLUSIONS: One of the key findings of this analysis is that manufacturers tend to implement changes to the development programme based on both regulatory and HTA advice with regards to the choice of primary endpoint and comparator. It also confirms the challenging choice of the study comparator, for which manufacturers seem to be more inclined to satisfy the regulatory advice. Continuous research efforts in this area are of paramount importance from a public health perspective.
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Desarrollo de Medicamentos/estadística & datos numéricos , Industria Farmacéutica/estadística & datos numéricos , Regulación Gubernamental , Evaluación de la Tecnología Biomédica/estadística & datos numéricos , HumanosRESUMEN
BACKGROUND: In 2010, the European Medicines Agency (EMA) initiated a pilot project on parallel scientific advice with Health Technology Assessment bodies (HTABs) that allows manufacturers to receive simultaneous feedback from both the European Union (EU) regulators and HTABs on their development plans for medicines. AIMS: The present retrospective qualitative analysis aimed to explore how the parallel scientific advice system is working and levels of commonality between the EU regulators and HTABs, and among HTABs, when applicants obtain parallel scientific advice from both a regulatory and an HTA perspective. METHODS: We analysed the minutes of discussion meetings held at the EMA between 2010, when parallel advice was launched, and 1 May 2015, when the cutoff date for data extraction was set. The analysis was based on predefined criteria and conducted at two different levels of comparison: the answers of the HTABs vs. those of the regulators, and between the answers of the participating HTA agencies. RESULTS: The analysis was based on 31 procedures of parallel scientific advice. The level of full agreements was highest for questions on patient population (77%), while disagreements reached a peak for questions on the study comparator (30%). With regard to comparisons among HTABs, there was a high level of agreement for all domains. CONCLUSIONS: There is evident commonality, in terms of evidence requirements between the EU regulators and participating HTABs, as well as among HTABs, on most aspects of clinical development. Indeed, regardless of the question content, the analysis showed that a high level of overall agreement was reached through the process of parallel scientific advice.
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Aprobación de Drogas/métodos , Unión Europea , Regulación Gubernamental , Evaluación de la Tecnología Biomédica , Humanos , Evaluación de Programas y Proyectos de SaludRESUMEN
Inherited Retinal Dystrophies (IRD) are diverse rare diseases that affect the retina and lead to visual impairment or blindness. Research in this field is ongoing, with over 60 EU orphan medicinal products designated in this therapeutic area by the Committee for Orphan Medicinal Products (COMP) at the European Medicines Agency (EMA). Up to now, COMP has used traditional disease terms, like retinitis pigmentosa, for orphan designation regardless of the product's mechanism of action. The COMP reviewed the designation approach for IRDs taking into account all previous Orphan Designations (OD) experience in IRDs, the most relevant up to date scientific literature and input from patients and clinical experts. Following the review, the COMP decided that there should be three options available for orphan designation concerning the condition: i) an amended set of OD groups for therapies that might be used in a broad spectrum of conditions, ii) a gene-specific designation for targeted therapies, and iii) an occasional term for products that do not fit in the above two categories. The change in the approach to orphan designation in IRDs caters for different scenarios to allow an optimum approach for future OD applications including the option of a gene-specific designation. By applying this new approach, the COMP increases the regulatory clarity, efficiency, and predictability for sponsors, aligns EU regulatory tools with the latest scientific and medical developments in the field of IRDs, and ensures that all potentially treatable patients will be included in the scope of an OD.
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Development of novel therapies for Duchenne muscular dystrophy (DMD) are driving the need for more efficient ways of detecting changes in disease- progression in DMD [1]. However, medicines' approval must be based on outcome measures that are acceptable from a regulatory perspective. In this article, European regulators provide an update on the recent regulatory consideration of a new endpoint (Stride Velocity 95th Centile (SV95C)) that could be used in therapeutic DMD trials. This new endpoint aims to quantify a patient's ambulation directly, reliably and continuously in a home environment with a wearable device.
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Distrofia Muscular de Duchenne/fisiopatología , Caminata , Dispositivos Electrónicos Vestibles/normas , Fenómenos Biomecánicos , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Determinación de Punto Final , Europa (Continente) , Marcha , Humanos , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/rehabilitación , Proyectos de InvestigaciónRESUMEN
Importance: To facilitate drug and device development for neonates, the International Neonatal Consortium brings together key stakeholders, including pharmaceutical companies, practitioners, regulators, funding agencies, scientists, and families, to address the need for objective, standardized clinical trial outcome measurements to fulfill regulatory requirements. Retinopathy of prematurity (ROP) is a disease that affects preterm neonates. The current International Classification of Retinopathy of Prematurity does not take into account all of the characteristics of ROP and does not adequately discriminate small changes in disease after treatment. These factors are critical for evaluating outcomes in clinical trials. Observations: There is need for an updated ROP acute disease activity and structure scale as well as end-stage structure and ophthalmologic outcome measures designed for use at different ages. The scale and measures, based on current diagnostic methods and treatments, could be used as a guideline for clinical intervention trials. The scale is intended to be validated against retrospective data and revised for use in future trials. An iterative revision process can be accomplished if new measures are added to clinical trials and evaluated at the end of each trial for prognostic value. The new measures would then be incorporated into a new version of the activity scale and the outcome measures revised. Conclusions and Relevance: An ROP activity scale and outcome measures to obtain the most robust and discriminatory data for clinical trials are needed. The scales should be dynamic and modified as knowledge and imaging modalities improve and then validated using data from well-documented clinical trials. This approach is relevant to improving clinical trial data quality.
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Ensayos Clínicos como Asunto , Evaluación de Resultado en la Atención de Salud/métodos , Retinopatía de la Prematuridad/diagnóstico , Humanos , Recién Nacido , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
A collaborative population-based project for bowel cancer prevention provided an ideal opportunity to involve nursing students in applying theory to practice. In this article, described is how the engagement of students and subsequent application of a population health template contributed to a community-based bowel cancer education and screening campaign. The campaign was a valuable teaching-learning experience for students and contributed to the goal of reducing and reporting on the number of bowel cancer deaths in the local area. Project evaluation data provide insight into student learning outcomes and reveal ways to strengthen the population health initiative for future years. Originally, a scholarly pursuit of discovery and application developed in response to growing rates of bowel cancer and advances in effective screening programs, the project has evolved into the domain of teaching and learning. This evolution has benefited students, project organizers and community members.
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Neoplasias del Colon/enfermería , Neoplasias del Colon/prevención & control , Conducta Cooperativa , Educación en Salud/métodos , Evaluación en Enfermería/métodos , Adulto , Canadá , Bachillerato en Enfermería/métodos , Femenino , Humanos , Masculino , Tamizaje Masivo/estadística & datos numéricos , Modelos Educacionales , Rol de la Enfermera , Investigación en Educación de Enfermería , Estudiantes de EnfermeríaRESUMEN
Purpose: To give a European regulatory overview of the requirements on and the use of biomarkers or surrogate endpoints in the development of drugs for ocular disease. Methods: Definitions, methods to validate new markers, and circumstances where surrogate endpoints can be appropriate are summarized. Results: The key endpoints that have been used in registration studies so far are based on visual acuity, signs, and symptoms, or on surrogate endpoints. In some ocular conditions, established outcome measures such as those based on visual acuity or visual field are not feasible (as with slowly progressing diseases), or lack relevance (e.g., when central visual acuity may be preserved even though the patient is legally blind owing to a severely restricted visual field, or vice versa). Conclusions: There are several ocular conditions for which there is an unmet medical need. In some of these conditions, surrogate endpoints as well as new clinical endpoints are needed to help speed up patient access to new medicines. Interaction with European regulators through the pathway specific for the development of biomarkers or novel methods is encouraged.
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Biomarcadores/análisis , Drogas en Investigación , Determinación de Punto Final/métodos , Oftalmopatías , Oftalmología/métodos , Europa (Continente) , Oftalmopatías/diagnóstico , Oftalmopatías/tratamiento farmacológico , Oftalmopatías/metabolismo , HumanosRESUMEN
INTRODUCTION: Studies in xenograft models and experimental models of metastasis have implicated several beta3 integrin-expressing cell populations, including endothelium, platelets and osteoclasts, in breast tumor progression. Since orthotopic human xenograft models of breast cancer are poorly metastatic to bone and experimental models bypass the formation of a primary tumor, however, the precise contribution of tumor-specific alphavbeta3 to the spontaneous metastasis of breast tumors from the mammary gland to bone remains unclear. METHODS: We used a syngeneic orthotopic model of spontaneous breast cancer metastasis to test whether exogenous expression of alphavbeta3 in a mammary carcinoma line (66cl4) that metastasizes to the lung, but not to bone, was sufficient to promote its spontaneous metastasis to bone from the mammary gland. The tumor burden in the spine and the lung following inoculation of alphavbeta3-expressing 66cl4 (66cl4beta3) tumor cells or control 66cl4pBabe into the mammary gland was analyzed by real-time quantitative PCR. The ability of these cells to grow and form osteolytic lesions in bone was determined by histology and tartrate-resistant acid phosphatase staining of bone sections following intratibial injection of tumor cells. The adhesive, migratory and invasive properties of 66cl4pBabe and 66cl4beta3 cells were evaluated in standard in vitro assays. RESULTS: The 66cl4beta3 tumors showed a 20-fold increase in metastatic burden in the spine compared with 66cl4pBabe. A similar trend in lung metastasis was observed. alphavbeta3 did not increase the proliferation of 66cl4 cells in vitro or in the mammary gland in vivo. Similarly, alphavbeta3 is not required for the proliferation of 66cl4 cells in bone as both 66cl4pBabe and 66cl4beta3 proliferated to the same extent when injected directly into the tibia. 66cl4beta3 tumor growth in the tibia, however, increased osteoclast recruitment and bone resorption compared with 66cl4 tumors. Moreover, alphavbeta3 increased 66cl4 tumor cell adhesion and alphavbeta3-dependent haptotactic migration towards bone matrix proteins, as well as their chemotactic response to bone-derived soluble factors in vitro. CONCLUSION: These results demonstrate for the first time that tumor-specific alphavbeta3 contributes to spontaneous metastasis of breast tumors to bone and suggest a critical role for this receptor in mediating chemotactic and haptotactic migration towards bone factors.
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Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Integrina alfaVbeta3/fisiología , Animales , Neoplasias Óseas/patología , Adhesión Celular , División Celular , Línea Celular , Células Epiteliales/citología , Células Epiteliales/patología , Femenino , Humanos , Glándulas Mamarias Animales/citología , Ratones , Metástasis de la Neoplasia , Neoplasias de la Columna Vertebral/patología , Neoplasias de la Columna Vertebral/secundarioRESUMEN
A clinically relevant model of spontaneous breast cancer metastasis to multiple sites, including bone, was characterized and used to identify genes involved in metastatic progression. The metastatic potential of several genetically related tumor lines was assayed using a novel real-time quantitative RT-PCR assay of tumor burden. Based on this assay, the tumor lines were categorized as nonmetastatic (67NR), weakly metastatic to lymph node (168FARN) or lung (66cl4), or highly metastatic to lymph node, lung, and bone (4T1.2 and 4T1.13). In vitro assays that mimic stages of metastasis showed that highly metastatic tumors lines were more adhesive, invasive, and migratory than the less metastatic lines. To identify metastasis-related genes in this model, each metastatic tumor was array profiled against the nonmetastatic 67NR using 15,000 mouse cDNA arrays. A significant proportion of genes relating to the extracellular matrix had elevated expression in highly metastatic tumors. The role of one of these genes, POEM, was further investigated in the model. In situ hybridization showed that POEM expression was specific to the tumor epithelium of highly metastatic tumors. Decreased POEM expression in 4T1.2 tumors significantly inhibited spontaneous metastasis to the lung, bone, and kidney. Taken together, our data support a role for the extracellular matrix in metastatic progression and describe, for the first time, a role for POEM in this process.
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Neoplasias Óseas/secundario , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Matriz Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Animales , Adhesión Celular , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Colágeno/química , ADN/metabolismo , ADN Complementario/metabolismo , Progresión de la Enfermedad , Combinación de Medicamentos , Genoma Humano , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Hibridación in Situ , Laminina/química , Metástasis Linfática , Ratones , Invasividad Neoplásica , Metástasis de la Neoplasia , Neovascularización Patológica , Hibridación de Ácido Nucleico , Proteoglicanos/química , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rodaminas/farmacología , Distribución TisularRESUMEN
Muscle invasive transitional cell carcinoma (TCC) of the bladder is associated with a high frequency of metastasis, resulting in poor prognosis for patients presenting with this disease. Models that capture and demonstrate step-wise enhancement of elements of the human metastatic cascade on a similar genetic background are useful research tools. We have utilized the transitional cell carcinoma cell line TSU-Pr1 to develop an in vivo experimental model of bladder TCC metastasis. TSU-Pr1 cells were inoculated into the left cardiac ventricle of SCID mice and the development of bone metastases was monitored using high resolution X-ray. Tumor tissue from a single bone lesion was excised and cultured in vitro to generate the TSU-Pr1-B1 subline. This cycle was repeated with the TSU-Pr1-B1 cells to generate the successive subline TSU-Pr1-B2. DNA profiling and karyotype analysis confirmed the genetic relationship of these three cell lines. In vitro, the growth rate of these cell lines was not significantly different. However, following intracardiac inoculation TSU-Pr1, TSU-Pr1-B1 and TSU-Pr1-B2 exhibited increasing metastatic potential with a concomitant decrease in time to the onset of radiologically detectable metastatic bone lesions. Significant elevations in the levels of mRNA expression of the matrix metalloproteases (MMPs) membrane type 1-MMP (MT1-MMP), MT2-MMP and MMP-9, and their inhibitor, tissue inhibitor of metalloprotease-2 (TIMP-2), across the progressively metastatic cell lines, were detected by quantitative PCR. Given the role of MT1-MMP and TIMP-2 in MMP-2 activation, and the upregulation of MMP-9, these data suggest an important role for matrix remodeling, particularly basement membrane, in this progression. The TSU-Pr1-B1/B2 model holds promise for further identification of important molecules.
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Neoplasias Óseas/secundario , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/fisiopatología , Perfilación de la Expresión Génica , Metaloendopeptidasas/biosíntesis , Metaloendopeptidasas/fisiología , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/fisiopatología , Inhibidor Tisular de Metaloproteinasa-2/biosíntesis , Inhibidor Tisular de Metaloproteinasa-2/fisiología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/fisiopatología , Animales , Membrana Basal/ultraestructura , Neoplasias Óseas/genética , Neoplasias Óseas/veterinaria , Carcinoma de Células Transicionales/veterinaria , Progresión de la Enfermedad , Cariotipificación , Masculino , Metaloproteinasa 14 de la Matriz , Metaloproteinasa 15 de la Matriz , Metaloproteinasas de la Matriz Asociadas a la Membrana , Ratones , Ratones SCID , Pronóstico , ARN Mensajero/biosíntesis , Regulación hacia Arriba , Neoplasias de la Vejiga Urinaria/veterinariaRESUMEN
This paper describes a new method of prioritising signals of potential adverse drug reactions (ADRs) detected from spontaneous reports that is called impact analysis. This is an interim step between signal detection and detailed signal evaluation. Using mathematical screening tools, large numbers of signals may now be detected from spontaneous ADR databases. Regulatory authorities need to rapidly prioritise them and focus on those that are most likely to require significant action. Using two scores ranging from one to 100, each with three input variables, signals may be categorised in terms of the strength of evidence (E) and the potential public health impact (P). In a two-by-two figure with empirically derived cut-off points of ten (the logarithmic mean) for each score, signals are placed in one of four categories (A-D) that are ranked according to their priority (A being the highest and D the lowest). A sensitivity analysis is then performed that tests the robustness of the categorisation in relation to each of the six input variables. A computer program has been written to facilitate the process and reduce error. Further work is required to test the feasibility and value of impact analysis in practice.
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Sistemas de Registro de Reacción Adversa a Medicamentos , Bases de Datos Factuales , Humanos , MatemáticaRESUMEN
BACKGROUND AND AIM: Statistical signal detection methods such as proportional reporting ratios (PRRs) detect many drug safety signals when applied to databases of spontaneous suspected adverse drug reactions (ADRs). Impact analysis is a tool that was developed as an aid to prioritisation of such signals. This paper describes a pilot project whereby impact analysis was simultaneously introduced into practice in a regulatory setting and tested in comparison with the existing approach. METHODS: Impact analysis was run on signals detected during a 26-week period from the UK Adverse Drug Reactions On-line Information Tracking (ADROIT) database of spontaneous ADRs that met minimum criteria (PRR>or=3.0, chi2>or=4.0 and >or=3 reported cases) and related to established drugs (i.e. those that have been available for at least 2 years and no longer carry the 'black triangle' symbol). The current method of signal prioritisation (i.e. the collective judgement at a weekly meeting) was initially performed without knowledge of the findings of impact analysis. Subsequently, the meeting was presented with the findings and, where appropriate, given the opportunity to reconsider the judgement made. The categories arising from the two methods were compared and the ultimate action recorded. Inter-observer variation between scientists performing impact analysis was also assessed. RESULTS: Eighty-six separate signals were analysed by impact analysis, of which 5% were categorised as high priority (A), 14% as requiring further information (B), 31% as low priority (C) and 50% as no action required (D). In general, the new method tended to give a higher level of priority to signals than the existing approach. Overall, there was 59% agreement between the impact analysis and the collective judgement at the meetings (kappa statistic=0.30). There was slightly greater agreement between impact analysis and the final action taken (kappa statistic=0.39), indicating that the findings of an impact analysis had an influence on the outcome. Assessment of inter-observer variation demonstrated that the method is repeatable (kappa statistic for overall category=0.77). Almost 70% of those who participated in the pilot study believed that impact analysis represented an improvement in how signals were prioritised. CONCLUSIONS: Impact analysis is a repeatable method of signal prioritisation that tended to give a higher level of priority to signals than the standard approach and which had an influence on the ultimate outcome.
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Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Bases de Datos Factuales , Humanos , Variaciones Dependientes del Observador , Proyectos PilotoRESUMEN
Risk management for European regulators means the detection and assessment of risks, the development and selection of measures to reduce risk, and monitoring of the effectiveness of risk control; all aspects of pharmacovigilance intended to minimise risk to European Union citizens associated with use of medicinal substances. This incorporates earlier and better planning of pharmacovigilance through formal product risk-management plans, better use of information tools to protect public health and routine audit of effectiveness of regulatory action.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Unión Europea/organización & administración , Salud Pública , Gestión de Riesgos , Humanos , Sistema de Registros , Gestión de Riesgos/legislación & jurisprudencia , Gestión de Riesgos/métodosRESUMEN
AIM: Parathyroid hormone-related protein (PTHrP) is one of the critical factors for the differentiation and growth of chondrocytes. We examined the correlation between the co-expression of PTHrP and PTH/PTHrP receptor and the grade of malignancy in cartilaginous tumours. METHODS: We analysed PTHrP and PTH/PTHrP receptor expression in chondrosarcoma by immunohistochemistry and compared specific staining with the expression in benign cartilaginous tumours. There were 38 cartilaginous bone tumours consisting of 26 chondrosarcoma, six enchondroma and six osteochondroma. Chondrosarcoma were composed of 20 conventional chondrosarcoma (10 grade 1, seven grade 2, and three grade 3), two dedifferentiated chondrosarcoma, two clear cell chondrosarcoma, and two myxoid chondrosarcoma. We performed the standard peroxidase-labelled streptavidin-biotin detection method for immunohistochemistry using an antibody raised against PTHrP (1-14) and PTH/PTHrP receptor. The magnitude of receptor positivity of PTHrP and PTH/ PTHrP in each tumour was assessed as a percentage of PTHrP and PTH/PTHrP-positive cells per thousand tumour cells in the most histologically aggressive area of the tumour. RESULTS: All chondrosarcoma, five of six enchondroma, and four of six osteochondroma showed PTHrP-positive cells, and all chondrosarcoma, five of six enchondroma and five of six osteochondroma showed PTHrP receptor-positive cells. The grade of malignancy correlated with the percentage of both PTHrP and PTH/PTHrP receptor-positive tumour cells (P < 0.0001, either). Each grade of chondrosarcoma showed statistically higher expression of both PTHrP and PTH/PTHrP receptor than benign cartilaginous tumour. CONCLUSION: This is the first report of the co-expression of PTHrP and PTH/PTHrP receptor in chondrosarcoma. PTHrP and PTH/PTHrP receptor positivity may be valuable for differentiating between benign and malignant cartilaginous tumours.
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Neoplasias Óseas/metabolismo , Condrosarcoma/metabolismo , Hormona Paratiroidea/metabolismo , Hormonas Peptídicas/metabolismo , Receptores de Hormona Paratiroidea/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/patología , Recuento de Células , Condrosarcoma/patología , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Proteína Relacionada con la Hormona Paratiroidea , Receptor de Hormona Paratiroídea Tipo 1Asunto(s)
Aprobación de Drogas/legislación & jurisprudencia , Agencias Gubernamentales/legislación & jurisprudencia , Ensayos Clínicos como Asunto/legislación & jurisprudencia , Toma de Decisiones , Europa (Continente) , Humanos , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudenciaRESUMEN
Parathyroid hormone-related protein (PTHrP) is required for mammary gland development and promotes the growth of breast cancer metastases within bone. However, there are conflicting reports of the prognostic significance of its expression in primary breast cancers. To study the role of PTHrP in early breast cancer, the effect of conditional deletion of PTHrP was examined in the context of neu-induced mammary tumorigenesis. Loss of PTHrP resulted in a higher tumor incidence. Transcriptional profiling of the tumors revealed that PTHrP influenced genes relevant to heterotypic cell signaling, including regulators of monocyte recruitment. Immunohistochemical analysis of human breast cancers revealed that PTHrP expression was associated with both HER-2/neu expression and macrophage infiltration in preinvasive ductal carcinoma in situ. The gene expression signature associated with loss of PTHrP expression in vivo correlated with poorer outcome in human breast cancer. Together, these data indicate that loss of PTHrP accelerates mammary tumorigenesis possibly by a non-cell-autonomous tumor suppressor pathway.
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Neoplasias de la Mama/metabolismo , Carcinoma Intraductal no Infiltrante/metabolismo , Neoplasias Mamarias Experimentales/metabolismo , Monocitos/inmunología , Proteína Relacionada con la Hormona Paratiroidea/biosíntesis , Animales , Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/inmunología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/inmunología , Carcinoma Intraductal no Infiltrante/patología , Femenino , Eliminación de Gen , Perfilación de la Expresión Génica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Masculino , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/patología , Virus del Tumor Mamario del Ratón/genética , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Monocitos/patología , Proteína Relacionada con la Hormona Paratiroidea/deficiencia , Proteína Relacionada con la Hormona Paratiroidea/genética , Receptor ErbB-2/biosíntesisRESUMEN
This study examined the impact of an infant-feeding classroom activity on the breast-feeding knowledge and intentions of adolescents living in Nova Scotia, Canada. One hundred twenty-one students attending two high schools were administered one pretest and two posttest questionnaires. Students were arbitrarily assigned to a control or intervention group. The intervention group partook in a 60-minute classroom activity on infant feeding. Findings indicated that students in the intervention group demonstrated significantly greater breast-feeding knowledge at Posttest 1 and at 10 weeks postintervention. Students in the intervention group reported a significantly greater intention toward breast-feeding their own future children; an increase was sustained at 10 weeks. These findings suggest that adolescents' knowledge of and intention toward breast-feeding may be positively influenced during their teen years. School nurses are well positioned to support and encourage the inclusion of breast-feeding content in school curricula to enhance adolescents' knowledge and intentions toward breast-feeding.