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Granular cell tumors involving the female reproductive tract are rare, with only a small number of cases described. Of the reported cases, none are documented within an ovarian mature cystic teratoma (MCT). This report documents a case of a granular cell tumor, incidentally discovered within an ovarian MCT in a 50-yr-old woman undergoing a supracervical hysterectomy and left salpingo-oophorectomy. Although malignant transformation and other secondary ovarian neoplasms in MCT have been well documented, synchronous nonovarian benign neoplasms are reported much less frequently. The histogenesis of secondary tumors arising in MCT is incompletely understood, and the current case provides additional insight, especially pertaining to schwannian and neuroectodermal tumors arising in this setting. The current case, to the best of our knowledge, represents the first report of a granular cell tumor involving a mature teratoma of any site, with the diagnosis being supported by morphologic and immunohistochemical staining characteristics.
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Tumor de Células Granulares/diagnóstico , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Ováricas/diagnóstico , Teratoma/diagnóstico , Femenino , Tumor de Células Granulares/patología , Tumor de Células Granulares/cirugía , Humanos , Histerectomía , Persona de Mediana Edad , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/cirugía , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Salpingooforectomía , Teratoma/patología , Teratoma/cirugíaRESUMEN
Mammary analog secretory carcinoma (MASC) is a recently recognized low-grade salivary carcinoma characterized by a specific ETV6 rearrangement. We describe 14 new MASCs and examine their immunophenotypic and genetic profiles in the context of look-alikes, namely, low-and high-grade salivary duct carcinoma and acinic cell carcinoma. ETV6 rearrangement, and robust expression of mammaglobin and S100, were demonstrated in 11/11, 14/14, and 12/14 MASCs, respectively. All low-grade salivary duct carcinomas coexpressed S100/mammaglobin (6/6); none harbored ETV6 rearrangements (0/5). Given that S100/mammaglobin coexpression and absence of zymogen granules are features of both MASC and low-grade salivary duct carcinoma, these two are best distinguished histologically. The former is predominantly an extraductal neoplasm with bubbly pink cytoplasm, whereas the latter is a distinct intraductal micropapillary and cribriform process. Querying ETV6 gene status may be necessary for difficult cases. No acinic cell carcinoma expressed mammaglobin (0/13) or harbored an ETV6 rearrangement (0/7); only 1/13 acinic cell carcinomas weakly expressed S100. DOG1 expression was limited or absent among all tumor types, except acinic cell carcinoma which expressed DOG1 diffusely in a canalicular pattern. Therefore, histology and immunohistochemistry (mammaglobin, S100, DOG1) suffices in distinguishing acinic cell carcinoma from both MASC and low-grade salivary duct carcinoma. HER2 (ERBB2) amplification was detected in only 1/10 acinic cell carcinomas, but none of the MASCs or low-grade salivary duct carcinomas tested. High-grade salivary duct carcinomas frequently expressed mammaglobin (11/18) and harbored HER2 amplifications (13/15); none harbored ETV6 rearrangements (0/12). High-grade salivary duct carcinomas can easily be distinguished from these other entities by histology and HER2 amplification.
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Carcinoma Secretor Análogo al Mamario/diagnóstico , Neoplasias de las Glándulas Salivales/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Anoctamina-1 , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Canales de Cloruro/análisis , Diagnóstico Diferencial , Femenino , Amplificación de Genes , Reordenamiento Génico , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Carcinoma Secretor Análogo al Mamario/química , Carcinoma Secretor Análogo al Mamario/genética , Carcinoma Secretor Análogo al Mamario/patología , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Proteínas Proto-Oncogénicas c-ets/genética , Receptor ErbB-2/genética , Proteínas Represoras/genética , Proteínas S100/análisis , Neoplasias de las Glándulas Salivales/química , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Secretoglobinas/análisis , Adulto Joven , Proteína ETS de Variante de Translocación 6RESUMEN
OBJECTIVE: Since a quantitative polymerase chain reaction (qPCR) assay targeting the E1 region of HPV genome is cost-effective/simple to perform, we evaluated the agreement between the Roche Diagnostics Linear Array (RDLA) genotyping test and qPCR-based E1 assay to detect HR-HPV genotypes that are included or not included in HPV vaccines and compared their accuracy to detect CIN 2+. METHODS: Study population included 257 African American (AA) and 266 Caucasian American (CA) diagnosed with intraepithelial neoplasia (CIN) grades ≤CIN 1 or ≥CIN 2 (CIN 2+) and tested for HPV by the RDLA and E1 assay. The concordance was determined using Gwet's AC1. The calculated positive predictive value (PPV) and negative predictive value (NPV) of the two assays were used to determine their suitability to detect CIN lesions. RESULTS: Overall, the E1 assay showed substantial agreement with the RDLA assay to detect any HR-HPV genotype and the agreement was higher in women diagnosed with CIN 2+ than ≤CIN 1. The concordance was largely higher in Cas than in Aas. The NPV and PPV values to detect CIN lesions were similar between the two assays. CONCLUSION: Utilization of the HPV E1 assay as a tool for CC screening could be a cost-effective approach that applies to both vaccinated and unvaccinated populations.
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The Nottingham histologic grade (NHG) is a prognostic marker for infiltrating ductal carcinoma. Its usefulness for invasive lobular carcinoma (ILC) has been less clear, given that 2 of the 3 parameters, tubule formation and mitotic activity, show little variation in ILC, placing much of the emphasis on nuclear grade. We have previously reported a trend for improved overall and relapse-free survival in patients with ILC of low nuclear grade, as classified by a 2-tiered nuclear grading system. Given the inherent potential for interobserver variability with any grading system, the goal of this study is to compare interobserver variability in the grading of ILC using a 2-tiered nuclear grade vs the NHG. Thirty-eight cases of ILC were graded independently by 5 pathologists using NHG criteria. Tumors were also categorized by a nuclear grading system as low grade (grade 1 nuclei) or high grade (grades 2-3 nuclei). Pairwise kappa values and interobserver agreement rates were calculated for both NHG and nuclear grade. Results were compared using the paired t test. Mean interobserver agreement rates and kappa values improved with use of the nuclear grading system as compared to NHG (83% vs 70%, 0.4738 vs 0.3228, respectively). The differences between the 2 were statistically significant. Because histologic grade has significant prognostic implications for patients with breast cancer, accurate reporting is paramount. For ILC, where use of the NHG places substantial weight on nuclear pleomorphism, a 2-tiered nuclear grading system may reduce interobserver variability yet still provide useful prognostic information.
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Neoplasias de la Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Núcleo Celular/patología , Variaciones Dependientes del Observador , Neoplasias de la Mama/patología , Carcinoma Lobular/patología , Femenino , Humanos , Invasividad Neoplásica/patología , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
The effect of using a 30% cutoff for the proportion of HER2+ cells on the interobserver variability in the interpretation of HER2 immunohistochemical results was evaluated. Immunostained sections from 96 cases of breast carcinoma were reviewed by 10 pathologists and scored as positive (3+) when uniform strong membranous staining was identified in at least 10% of tumor cells; the actual percentage of cells with such staining was also estimated. The agreement rates and the kappa values using a 30% cutoff were compared with those using a 10% cutoff. These proved to be higher in 62% and 66% of measurements, respectively, with average interobserver rates and kappa values of 72% and 0.54 using the 30% cutoff and 70% and 0.49 using the 10% cutoff (P=.001 for all comparisons). Using a 30% cutoff for the percentage of HER2+ cells by immunohistochemical analysis modestly decreased interobserver variability in the interpretation of HER2 immunohistochemical results.
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Neoplasias de la Mama/química , Inmunohistoquímica/normas , Variaciones Dependientes del Observador , Receptor ErbB-2/análisis , Neoplasias de la Mama/patología , Femenino , Humanos , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: The objective of this study was to evaluate whether mandatory fortification of grain products with folic acid in the United States is associated with changes in DNA methyltransferase-1 (Dnmt-1) expression in cells involved in cervical carcinogenesis. METHODS: Archived specimens of cervical intraepithelial neoplasia (CIN) diagnosed before (1990-1992) and after (2000-2002) mandatory folic acid fortification were used to examine the expression of Dnmt-1 in specific lesions involved in cervical carcinogenesis by immunohistochemistry. The total number of lesions examined was 101 in the prefortification period and 96 in the postfortification period. Immunohistochemical staining for Dnmt-1, its assessment, and data entry were blinded with regard to the fortification status. RESULTS: Age- and race-adjusted mean percentage of cells positive for Dnmt-1 or the Dnmt-1 score was significantly higher in all lesion types (i.e., normal cervical epithelium, reactive cervical epithelium, metaplastic cervical epithelium, CIN, or carcinoma in situ) detected in the postfortification period compared with the prefortification period (P < 0.05, all comparisons). The degree of Dnmt-1 was significantly higher (P < 0.0001) in CIN > or = 2 lesions compared with CIN < or = 1 lesions, regardless of the fortification group. CONCLUSION: These results suggest that mandatory fortification with folic acid in the United States seems to have resulted in a change in the degree of expression of Dnmt-1 in cells involved in cervical carcinogenesis. Because the approach we have taken to demonstrate these differences have limitations inherent to a study of this nature and this is the first study to report a folate fortification associated change in Dnmt-1, validating these results in other study populations and/or with other techniques of assessing Dnmt-1 will increase the scientific credibility of these findings.
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ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN , Ácido Fólico/efectos adversos , Alimentos Fortificados , Displasia del Cuello del Útero/enzimología , Neoplasias del Cuello Uterino/enzimología , Complejo Vitamínico B/efectos adversos , Adulto , Transformación Celular Neoplásica , ADN (Citosina-5-)-Metiltransferasa 1 , Metilación de ADN/efectos de los fármacos , Grano Comestible/química , Femenino , Ácido Fólico/administración & dosificación , Humanos , Inmunohistoquímica , Estados Unidos , Neoplasias del Cuello Uterino/inducido químicamente , Neoplasias del Cuello Uterino/patología , Complejo Vitamínico B/administración & dosificación , Displasia del Cuello del Útero/inducido químicamente , Displasia del Cuello del Útero/patologíaRESUMEN
Modern biomedical research requires access to high quality specimens of human tissue with or without extensive clinical annotation. Multiple types of organizations have developed to supply human tissues to support biomedical research. These organizations follow different models including the specific models of 1) prospective collection, 2) tissue banking, and 3) tissue collection associated with clinical trials as well as the model of 4) a tissue resource that incorporates features of the other models. These types of organizations devoted to supplying tissues for research have chosen different goals to meet the different tissue and informational needs of the investigators to whom they supply tissue. In order to provide high quality tissues to support research, all models should rely on a strong quality assurance program with extensive quality control of the tissues being provided to support research. In addition to facilities which collect, process, store and provide tissues, the need for a rigorous QA program applies to all resources and infrastructures used to support biomedical research. The UAB Tissue Collection and Banking Facility which provides human tissue to support biomedical research has been functioning and developing since 1979. To our knowledge, similar programs in providing tissues from animals are less developed, but could easily follow the models which UAB and other institutions providing human tissues have established, including the approaches of UAB and others to QA and QC. This manuscript reviews the current concepts of QA and QC in use in organizations supplying tissue to support biomedical research as well as new approaches in QA and QC that have been proposed.
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BACKGROUND: Even though novel therapies based on aberrant DNA methylation could be of particular importance for the treatment of cervical cancer (CC) because the oncoproteins E6/E7 of high-risk human papillomaviruses, the causative agents for developing CC, have the capacity to bind and upregulate DNA methyltransferases (DNMTs), to our knowledge, no previous studies have evaluated the expression of this enzyme in CC in relation to survival outcomes. The purpose of the study was to evaluate the expression of DNMT1 in CC and its association with survival outcomes. METHODS: The study population consisted of 76 women treated for primary CC and followed up by the University of Alabama at Birmingham (UAB) cancer registry. The expression of DNMT1 was examined using immunohistochemistry, and the degree of expression of DNMT1 was expressed as a percentage of cells positive for DNMT1 and its intensity. Cox proportional hazards model was used to assess the relationship between the degree of expression of DNMT1 and overall survival after adjusting for relevant covariates. RESULTS: The expression of DNMT1 was significantly higher in CC cells compared to that in the normal cervical epithelium. A higher percentage of cells positive for DNMT1 and a higher intensity score for DNMT1 were significantly associated with poor survival outcome (hazard ratio [HR] =4.3, P=0.03 and HR =4.9, P=0.02, respectively). CONCLUSION: Our findings suggested that the degree of expression of DNMT1 could be considered as a target in the epigenetic treatment of CC. Replication of our results in other study populations with CC could create the opportunity of using DNMT inhibitors to treat CC.
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Disparities in Cervical Cancer (CC) mortality outcomes between African American (AA) and White women have been studied for decades. However, conclusions about the effect of race on CC survival differ across studies. This study assessed differences in CC survival between AA and White women diagnosed between 1985 and 2010 and treated at two major hospitals in the southeastern US. The study sample included 925 AA and 1192 White women diagnosed with cervical adenocarcinoma, adenosquamous cell carcinoma, or squamous cell carcinoma. Propensity score adjustment and matching were employed to compare 5-year survival between the two racial groups. Crude comparisons suggested relevant racial differences in survival. However, the racial differences became of small magnitude after propensity-score adjustment and in matched analyses. Nonlinear models identified age at diagnosis, cancer stage, mode of treatment, and histological subtype as the most salient characteristics predicting 5-year survival of CC, yet these characteristics were also associated with race. Crude racial differences in survival might be partly explained by underlying differences in the characteristics of racial groups, such as age at diagnosis, histological subtype, cancer stage, and the mode of treatment. The study results highlight the need to improve access to early screening and treatment opportunities for AA women to improve posttreatment survival from CC.
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Negro o Afroamericano/estadística & datos numéricos , Neoplasias del Cuello Uterino/mortalidad , Población Blanca/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Persona de Mediana Edad , Sudeste de Estados Unidos/epidemiología , Sudeste de Estados Unidos/etnología , Análisis de Supervivencia , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/historia , Neoplasias del Cuello Uterino/terapia , Adulto JovenRESUMEN
The availability of high-quality human tissues is necessary to advance medical research. Although there are inherent and induced limitations on the use of human tissues in research, biorepositories play critical roles in minimizing the effects of such limitations. Specifically, the optimal utilization of tissues in research requires tissues to be diagnosed accurately, and the actual specimens provided to investigators must be carefully described (i.e., there must be quality control of each aliquot of the tissue provided for research, including a description of any damage to tissues). Tissues also should be collected, processed, stored, and distributed (i.e., handled) uniformly under a rigorous quality management system (QMS). Frequently, tissues are distributed to investigators by tissue banks which have collected, processed, and stored them by standard operating procedures (SOPs). Alternatively, tissues for research may be handled via SOPs that are modified to the specific requirements of investigators (i.e., using a prospective biorepository model). The primary goal of any type of biorepository should be to ensure its specimens are of high quality and are utilized appropriately in research; however, approaches may vary based on the tissues available and requested. For example, extraction of specific molecules (e.g., microRNA) to study molecular characteristics of a tissue may require less clinical annotation than tissues that are utilized to identify how the molecular expression might be used to clarify a clinical outcome of a disease or the response to a specific therapy. This review focuses on the limitations of the use of tissues in research and how the design and operations of a tissue biorepository can minimize some of these limitations.
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Bancos de Tejidos , Investigación Biomédica/métodos , Investigación Biomédica/organización & administración , Humanos , Control de Calidad , Manejo de Especímenes , Bancos de Tejidos/organización & administración , Fijación del Tejido/métodos , Conservación de Tejido/métodosRESUMEN
Although there is growing interest in the possibility that alterations in histone methylation may play a role in carcinogenesis, it has not been explored adequately in humans. Similarly, there are no reports of associations between this and a similar epigenetic event, DNA methylation. Using immunohistochemical staining, we compared the methylation of DNA and histones in histopathologically normal oral epithelium, dysplastic oral lesions, and squamous cell cancers (SCCs) from subjects with squamous cell cancer (n=48) with those of normal oral epithelium from subjects without oral cancer (n=93) who were matched on age and race. Monoclonal antibodies specific for 5 methyl cytosine (5-mc), lysine 4 of histone H_3 (H_3-Lys4), and lysine 9 of histone H_3 (H_3-Lys9) were used in this study. The percentages of cells positive and a weighted average of the immunostaining intensity scores were calculated for each of these tissues, and Spearman correlation analyses were employed to study associations between DNA and histone methylation. Correlations between DNA and histone methylation, H_3-Lys4 and H_3-Lys9 were positive and statistically significant in all tissue types; they were strongest in normal oral epithelium from non-cancer subjects (r=0.63, p < 0.001 and r=0.62, p < 0.001 respectively). Similarly, the positive correlations between H_3-Lys4 and H_3-Lys9 were statistically significant in all tissue types and strongest in normal oral epithelium from non-cancer subjects (r=0.77, p< 0.001). Patterns of DNA and histone methylation are similar in tissues across the spectrum of oral carcinogenesis, and there is a significant positive association between these two epigenetic mechanisms.
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Metilación de ADN , Epitelio/metabolismo , Histonas/metabolismo , Neoplasias de la Boca/metabolismo , Anciano , Anticuerpos Monoclonales/química , Carcinoma de Células Escamosas/genética , Estudios de Casos y Controles , ADN/química , ADN/genética , ADN/metabolismo , ADN de Neoplasias , Epigénesis Genética , Epitelio/patología , Silenciador del Gen , Humanos , Inmunohistoquímica , Masculino , Metilación , Persona de Mediana Edad , Neoplasias de la Boca/genética , Neoplasias/metabolismoRESUMEN
PURPOSE: This study was conducted to evaluate the clinical significance of the localization of epidermal growth factor receptor (EGF-r), transforming growth factor (TGF)-alpha, and erbB-2 in the development, progression and prognosis of squamous cell cancers (SCCs) of the lung. EXPERIMENTAL DESIGN: The localization of EGF-r, TGF-alpha, and erbB-2 was evaluated immunohistochemically in 60 archival specimens of SCC of the lung and in 60 lung specimens without cancer. To clarify the patterns of expression of EGF-r in these tumors, the patterns of expression of EGF-r in cells in culture were monitored after challenging normal human bronchial epithelial and SCC cell lines with either EGF or TGF-alpha at physiological concentrations. RESULTS AND CONCLUSIONS: The expression of EGF-r, erbB-2, and TGF-alpha were significantly higher in SCC and associated precancerous lesions than in the normal bronchial epithelium and hyperplastic lesions of noncancer specimens. A statistically significant stepwise increase in expression from uninvolved bronchial epithelium to precancerous lesions to SCC was observed with EGF-r and TGF-alpha. The localization of EGF-r in the cytoplasm (P = 0.04), but not in the membrane (P = 0.20), of SCCs was significantly associated with poor overall survival of subjects. To demonstrate the biological relevance of cytoplasmic expression of EGF-r, we noted that there was a prompt reduction in the membrane expression and a concomitant increase in cytoplasmic expression of EGF-r after adding either EGF or TGF-alpha to the cell culture medium. Overall, the study identified an involvement of EGF-r and TGF-alpha in the development of SCCs. The prognostic importance of EGF-r expression in the cytoplasm of lung cancer probably is an indication of the prognostic importance of trafficking of the EGF-r receptor between the Golgi apparatus and cell membranes and of internalization of EGF-r after an interaction with one of the EGF-r ligands at the cellular membrane surface.
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Carcinoma de Células Escamosas/metabolismo , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Lesiones Precancerosas/metabolismo , Receptor ErbB-2/metabolismo , Factor de Crecimiento Transformador alfa/metabolismo , Células Tumorales Cultivadas/metabolismo , Carcinoma de Células Escamosas/patología , Membrana Celular , Citoplasma/fisiología , Células Epiteliales/patología , Humanos , Hiperplasia/metabolismo , Hiperplasia/patología , Técnicas para Inmunoenzimas , Ligandos , Neoplasias Pulmonares/patología , Lesiones Precancerosas/patología , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas/patologíaRESUMEN
Biomedical investigators require high quality human tissue to support their research; thus, an important aspect of the provision of tissues by biorepositories is the assurance of high quality and consistency of processing specimens. This is best accomplished by a quality management system (QMS). This article describes the basis of a QMS program designed to aid biorepositories that want to improve their operations. In 1983, the UAB Tissue Collection and Biobanking Facility (TCBF) introduced a QMS program focused on providing solid tissues to support a wide range of research; this QMS included a quality control examination of the specific specimens provided for research. Similarly, the Division of Laboratory Sciences at the Centers for Disease Control and Prevention (CDC) introduced a QMS program for their laboratory analyses, focused primarily on bodily fluids. The authors of this article bring together the experience of the QMS programs at these two sites to facilitate the development or improvement of quality management systems of a wide range of biorepositories.
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Bancos de Muestras Biológicas/normas , Acreditación , Sesgo , Líquidos Corporales , Certificación , Auditoría Clínica , Humanos , Garantía de la Calidad de Atención de Salud , Control de Calidad , Bancos de TejidosRESUMEN
We previously reported that a higher degree of methylation of CpG sites in the promoter (positions 31, 37, 43, 52, and 58) and enhancer site 7862 of human papillomavirus (HPV) 16 was associated with a lower likelihood of being diagnosed with HPV 16-associated CIN 2+. The purpose of this study was to replicate our previous findings and, in addition, to evaluate the influence of plasma concentrations of folate and vitamin B12 on the degree of HPV 16 methylation (HPV 16m). The study included 315 HPV 16-positive women diagnosed with either CIN 2+ or ≤CIN 1. Pyrosequencing technology was used to quantify the degree of HPV 16m. We reproduced the previously reported inverse association between HPV 16m and risk of being diagnosed with CIN 2+. In addition, we observed that women with higher plasma folate and HPV 16m or those with higher plasma vitamin B12 and HPV 16m were 75% (P < 0.01) and 60% (P = 0.02) less likely to be diagnosed with CIN 2+, respectively. With a tertile increase in the plasma folate or vitamin B12, there was a 50% (P = 0.03) and 40% (P = 0.07) increase in the odds of having a higher degree of HPV 16m, respectively. This study provides initial evidence that methyl donor micronutrients, folate and vitamin B12, may play an important role in maintaining a desirably high degree of methylation at specific CpG sites in the HPV E6 promoter and enhancer that are associated with the likelihood of being diagnosed with CIN 2+.
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Metilación de ADN , ADN Viral/química , Ácido Fólico/sangre , Infecciones por Papillomavirus/virología , Displasia del Cuello del Útero/virología , Vitamina B 12/sangre , Adulto , Biopsia , Islas de CpG , Elementos de Facilitación Genéticos , Femenino , Genotipo , Papillomavirus Humano 16 , Humanos , Masculino , Micronutrientes/sangre , Persona de Mediana Edad , Proteínas Oncogénicas Virales/química , Infecciones por Papillomavirus/sangre , Regiones Promotoras Genéticas , Proteínas Represoras/química , Factores de Riesgo , Análisis de Secuencia de ADN , Adulto Joven , Displasia del Cuello del Útero/sangreAsunto(s)
Enfermedades de las Paratiroides/patología , Enfermedades de las Paratiroides/cirugía , Patología Quirúrgica , Adenoma/patología , Adenoma/cirugía , Carcinoma/patología , Carcinoma/cirugía , Humanos , Hiperparatiroidismo/patología , Hiperparatiroidismo/cirugía , Hiperplasia/patología , Periodo Intraoperatorio , Procedimientos Quirúrgicos Mínimamente Invasivos , Neoplasias de las Paratiroides/patología , Neoplasias de las Paratiroides/cirugía , Derivación y ConsultaRESUMEN
The availability of human tissues to support biomedical research is critical to advance translational research focused on identifying and characterizing approaches to individualized (personalized) medical care. Providing such tissues relies on three acceptable models - a tissue banking model, a prospective collection model and a combination of these two models. An unacceptable model is the "catch as catch can" model in which tissues are collected, processed and stored without goals or a plan or without standard operating procedures, i.e., portions of tissues are collected as available and processed and stored when time permits. In the tissue banking model, aliquots of tissues are collected according to SOPs. Usually specific sizes and types of tissues are collected and processed (e.g., 0.1 gm of breast cancer frozen in OCT). Using the banking model, tissues may be collected that may not be used and/or do not meet specific needs of investigators; however, at the time of an investigator request, tissues are readily available as is clinical information including clinical outcomes. In the model of prospective collection, tissues are collected based upon investigator requests including specific requirements of investigators. For example, the investigator may request that two 0.15 gm matching aliquots of breast cancer be minced while fresh, put in RPMI media with and without fetal calf serum, cooled to 4°C and shipped to the investigator on wet ice. Thus, the tissues collected prospectively meet investigator needs, all collected specimens are utilized and storage of specimens is minimized; however, investigators must wait until specimens are collected, and if needed, for clinical outcome. The operation of any tissue repository requires well trained and dedicated personnel. A quality assurance program is required which provides quality control information on the diagnosis of a specimen that is matched specifically to the specimen provided to an investigator instead of an overall diagnosis of the specimen via a surgical pathology report. This is necessary because a specific specimen may not match the diagnosis of the case due to many factors such as necrosis, unsuspected tumor invasion of apparently normal tissue, and areas of fibrosis which are mistaken grossly for tumor. Aliquots for quality control (QC) may or may not be collected at the time of collection and in some cases, QC may not occur until specimens are distributed to investigators. In establishing a tumor repository, multiple issues need to be considered. These include the available resources, long term support, space and equipment. The needs of the potential users need to be identified as to the types of tissues and services needed and the annotation expected. Other specific issues to be considered include collection of specimens potentially infected with blood borne pathogens (e.g., hepatitis B), charge back mechanisms, informatics needs and support, and investigator requirements (e.g., recognition of repository contributions in publications). In general, the repository should not perform the research of the investigators, but should provide the infrastructure necessary to support the research of the investigator. Thus, the goals of the repository must be established. Similarly, ethical and regulatory issues must be evaluated. In general, tissue repositories need ethical (e.g., IRB) and privacy (e.g., HIPAA) review. Also, safety issues need to be considered as well as how biohazards will be addressed by investigator-users. Considerations involving the transfer of specimens to other organization usually require a material transfer agreement (MTA). A MTA should address biohazards as well as indemnification. Thus, many issues must be considered and addressed in order to establish and operate successfully a biorepository.
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Investigación Biomédica , Informática , Bancos de Tejidos , Humanos , Control de Calidad , Manejo de Especímenes , Bancos de Tejidos/ética , Bancos de Tejidos/legislación & jurisprudenciaRESUMEN
Superior-quality human tissues are required to support many types of biomedical research. To be useful optimally in supporting research, not only must these tissues be accurately diagnosed, but also the specific aliquots of tissue supplied to investigators must be accurately described as part of the quality control analysis of the tissue. Tissues should be collected, processed, and stored uniformly. Some tissues are provided to investigators from tissue banks for which tissues have been collected and processed according to standard operating procedures (SOPs) of the tissue bank. Other tissues provided to support research are collected and processed according to SOPs modified to meet investigator needs and requirements, i.e., prospective collection/processing. These different models of tissue collection require different goals, designs, and SOPs. The objectives of tissue repositories also vary based on the types of tissues provided (e.g., fresh tissue aliquots, fixed paraffin-embedded tissue, paraffin tissue sections, etc.) and how the tissues are to be used in research. For example, the potential use of tissues affects the need for extensive annotation of the specimen including both clinical information (e.g., clinical outcomes) and demographics. Specifically, if the tissues are to be used for extraction of proteins or basic studies of disease processes, less clinical information, if any, may be needed than if the tissues are to be used for the correlation of an aspect of the disease process with clinical outcome or response to a specific therapy. In this review, we describe, based on our experience, the major issues that should be addressed in designing and establishing a tissue repository.
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Investigación Biomédica/organización & administración , Obtención de Tejidos y Órganos/organización & administración , Investigación Biomédica/ética , Humanos , Neoplasias/patología , Control de Calidad , Manejo de Especímenes/métodos , Factores de Tiempo , Bancos de Tejidos/ética , Bancos de Tejidos/organización & administración , Obtención de Tejidos y Órganos/éticaRESUMEN
OBJECTIVE: To evaluate whether mandatory fortification of grain products with folic acid in the US is associated with changes in histone methylation in cells involved in cervical carcinogenesis. METHODS: Cervical specimens obtained before (1990 to 1992) and after mandatory folic acid fortification (2000 to 2002) were used to examine the degree of histone methylation (H3 Lys-9) by immunohistochemistry. 91 women (51 before and 40 after fortification) were diagnosed with cervical intraepithelial neoplasia (CIN) grade 3 or carcinoma in situ (CIS) and sections utilized in the study also contained normal, reactive or metaplastic cervical epithelium, CIN 1 or CIN 2. 64 women (34 before and 30 after fortification) were free of CIN and these sections contained only normal or reactive cervical epithelium. Immunohistochemical staining for H3 Lys-9, its assessment in different cell or lesion types and data entry were blinded for fortification status. For each cell type or lesion category we used PROC MIXED in SAS with the specimen identifier as a random effect and the robust variance estimator to estimate age- and race-adjusted intensity score for H3 Lys-9 in the pre- and post-fortification periods. RESULTS: Degree of H3 Lys-9 methylation was significantly higher (P < 0.0001) in ≥CIN 2 lesions (CIN 2, CIN 3 and CIS) than in ≤CIN 1 lesions (CIN 1, normal, reactive and metaplastic), in both pre- and post-fortification CIN 3/CIS specimens. Age- and race-adjusted mean H3 Lys-9 score was significantly higher in all cell or lesion types in CIN 3/CIS specimens obtained in the post-fortification period compared to pre-fortification period (P < 0.05, all comparisons). In contrast, in specimens obtained from women free of CIN, Lys-9 methylation in normal/reactive cervical epithelium was significantly lower in post-fortification specimens than in pre-fortification specimens (P = 0.03). CONCLUSIONS: Higher levels of Lys-9 methylation in ≥CIN 2 compared to ≤CIN 1 lesions suggest that higher Lys-9 methylation is associated with progression of lower grade CIN to higher grade CIN. Higher Lys-9 methylation in cervical tissues of women diagnosed with CIN 3 in the post-fortification period than in pre-fortification period suggest that fortification may adversely affect histone methylation in already initiated cells. Lower Lys-9 methylation in normal/reactive cervical cells of women free of CIN in the post-fortification period than pre-fortification on the other hand suggests that fortification is likely to protect against initiation of carcinogenic process in the cervix. These results suggest that mandatory fortification with folic acid in the US seems to have different effects on cancer depending on the stage of carcinogenesis. Because this is the first study to report folic acid fortification-associated differences in histone methylation and because of the limitations inherent to the approach we have taken to demonstrate these differences, validation of the results in other study populations or with other techniques for assessing histone methylation is necessary.
RESUMEN
BACKGROUND: Local recurrence remains the major cause of death in patients with retroperitoneal sarcoma (RPS). There is no consensus regarding management of patients with recurrent RPS. STUDY DESIGN: We performed a retrospective review of patients with recurrent RPS managed at 2 tertiary care centers between 1983 and 2008. Presentation, treatments, and outcomes were analyzed. RESULTS: Seventy-eight patients were identified and analyzed. Sixteen patients (22%) presented with concurrent metastatic disease; survival in this subset of patients was poor (median 12 months). Forty-eight patients underwent resection of the first local recurrence of RPS. Palliation of tumor-related symptoms was achieved in 79% with operation. Survival was significantly better in patients having complete (p = 0.001) and incomplete resection (p = 0.02) compared with patients having biopsy only. Among patients with first local recurrence, high grade tumor (p = 0.0001) and no resection (p = 0.007) were significantly associated with reduced survival. On multivariate analysis, radiation therapy, multifocality, histologic subtype, and time to local recurrence did not significantly correlate with survival. Second and third local recurrences occurred at shorter intervals compared with first local recurrence and were less likely to be completely resectable. Patients undergoing resection of second and third local recurrences had survival similar to that in patients undergoing resection of first local recurrence. CONCLUSIONS: Tumor biology (high grade) is a significant prognostic factor for patients with recurrent RPS. Resection should be considered in patients with first and subsequent local recurrences (even if multifocal) of RPS because it is associated with improved survival. Operation should also be considered for palliation of symptoms in patients in whom resection is not possible.